Mast cell phenotypes in the allograft after lung transplantation.

PubMed

Banga, Amit; Han, Yingchun; Wang, Xiaofeng; Hsieh, Fred H

2016-07-01

The burden of mast cell (MC) infiltration and their phenotypes, MC-tryptase (MCT ) and MC-tryptase/chymase (MCTC ), after lung transplantation (LT) has not been evaluated in human studies. We reviewed 20 transbronchial lung biopsy (TBLB) specimen from patients with early normal allograft (<6 months post-LT, n=5), late normal allograft (>6 months, n=5), A2 or worse acute cellular rejection (ACR, n=5), and chronic lung allograft dysfunction (CLAD, n=5). Slides were immunostained for tryptase and chymase. Total MC, MCT , MCTC and MCTC to-MCT ratio were compared between the four groups using a generalized linear mixed model. Irrespective of clinicopathologic diagnosis, MC burden tends to increase with time (r(2) =.56, P=.009). MCTC phenotype was significantly increased in the CLAD group (8.2±4.9 cells per HPF) in comparison with the other three groups (early normal: 1.6±1.7, P=.0026; late normal: 2.5±2.3, P=.048; ACR: 2.7±3.5, P=.021). Further, the ratio of MCTC to MCT was significantly increased in CLAD group as compared to the other three groups (P<.001 for all comparisons). The burden of MC may increase in the allograft as function of time. Patients with CLAD have an increased relative and absolute burden of MCTC phenotype MC. Future studies are needed to confirm these findings and evaluate the potential pathologic role of MCTC in allograft dysfunction. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Macrophages: contributors to allograft dysfunction, repair, or innocent bystanders?

PubMed

Mannon, Roslyn B

2012-02-01

Macrophages are members of the innate immune response. However, their role in the adaptive immune response is not known. The purpose of this review is to highlight our current understanding of macrophage structure and function and how they may participate in allograft injury. Studies in acute kidney injury models identify macrophages as key mediators of inflammatory injury, while more recent studies indicate that they may play a reparative role, depending on phenotype - M1 or M2 type macrophages. Mregs, generated in vitro, appear to have immune suppressive abilities and a unique phenotype. In solid-organ transplant, the emphasis of studies has been on acute or chronic injury. These data are derived from animal models using depletion of macrophages or antagonizing their activation and inflammatory responses. The relative contribution of macrophage phenotype in transplantation has not been explored. These studies suggest that macrophages play an injurious role in acute cellular allograft rejection, as well as in chronic injury. Infiltration of an allograft with macrophages is also associated with worse graft function and poor prognosis. Further studies are needed to understand the mechanisms of macrophage-mediated injury, explore their potential reparative role, and determine if they or their functional products are biomarkers of poor graft outcomes.

The Lymphatic Phenotype of Lung Allografts in Patients With Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome.

PubMed

Traxler, Denise; Schweiger, Thomas; Schwarz, Stefan; Schuster, Magdalena Maria; Jaksch, Peter; Lang, Gyoergy; Birner, Peter; Klepetko, Walter; Ankersmit, Hendrik Jan; Hoetzenecker, Konrad

2017-02-01

Chronic lung allograft dysfunction (CLAD), presenting as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) is the major limiting factor of long-term survival in lung transplantation. Its pathogenesis is still obscure. In BOS, persistent alloimmune injury and chronic airway inflammation are suggested. One of the main tasks of the lymphatic vessel (LV) system is the promotion of immune cell trafficking. The formation of new LVs has been shown to trigger chronic allograft rejection in kidney transplants. We therefore sought to address the role of lymphangiogenesis in CLAD. Formalin-fixed paraffin-embedded tissue samples of 22 patients receiving a lung retransplantation due to BOS or RAS were collected. Lymphatic vessel density (LVD) was determined by immunohistochemical staining for podoplanin. Lung tissue obtained from 13 non-CLAD patients served as control. The impact of LVD on graft survival was assessed. Lymphatic vessel density in CLAD patients did not differ from those in control subjects (median number of LVs per bronchiole: 4.75 (BOS), 6.47 (RAS), 4.25 (control), P = 0.97). Moreover, the number of LVs was not associated with regions of cellular infiltrates (median number of LVs per bronchiole: with infiltrates, 5.00 (BOS), 9.00 (RAS), 4.00 (control), P = 0.62; without infiltrates, 4.5 (BOS), 0.00 (RAS), 4.56 (control), P = 0.74). Lymphatic vessel density did not impact the time to development of BOS or RAS in lung transplantation (low vs high LVD: 38.5 vs 86.0 months, P = 0.15 [BOS]; 60.5 vs 69.5 months, P = 0.80 [RAS]). Unlike chronic organ failure in kidney transplantation, lymphangiogenesis is not altered in CLAD patients. Our findings highlight unique immunological processes leading to BOS and RAS.

Gut microbiota and its implications in small bowel transplantation.

PubMed

Wang, Chenyang; Li, Qiurong; Li, Jieshou

2018-06-01

The gut microbiota is mainly composed of a diverse population of commensal bacterial species and plays a pivotal role in the maintenance of intestinal homeostasis, immune modulation and metabolism. The influence of the gut microbiota on solid organ transplantation has recently been recognized. In fact, several studies indicated that acute and chronic allograft rejection in small bowel transplantation (SBT) is closely associated with the alterations in microbial patterns in the gut. In this review, we focused on the recent findings regarding alterations in the microbiota following SBTand the potential roles of these alterations in the development of acute and chronic allograft rejection. We also reviewed important advances with respect to the interplays between the microbiota and host immune systems in SBT. Furthermore, we explored the potential of the gut microbiota as a microbial marker and/or therapeutic target for the predication and intervention of allograft rejection and chronic dysfunction. Given that current research on the gut microbiota has become increasingly sophisticated and comprehensive, large cohort studies employing metagenomic analysis and multivariate linkage should be designed for the characterization of host-microbe interaction and causality between microbiota alterations and clinical outcomes in SBT. The findings are expected to provide valuable insights into the role of gut microbiota in the development of allograft rejection and other transplant-related complications and introduce novel therapeutic targets and treatment approaches in clinical practice.

Long-term outcomes and management of lung transplant recipients.

PubMed

Costa, Joseph; Benvenuto, Luke J; Sonett, Joshua R

2017-06-01

Lung transplantation is an established treatment for patients with end-stage lung disease. Improvements in immunosuppression and therapeutic management of infections have resulted in improved long-term survival and a decline in allograft rejection. Allograft rejection continues to be a serious complication following lung transplantation, thereby leading to acute graft failure and, subsequently, chronic lung allograft dysfunction (CLAD). Bronchiolitis obliterans syndrome (BOS), the most common phenotype of CLAD, is the leading cause of late mortality and morbidity in lung recipients, with 50% having developed BOS within 5 years of lung transplantation. Infections in lung transplant recipients are also a significant complication and represent the most common cause of death within the first year. The success of lung transplantation depends on careful management of immunosuppressive regimens to reduce the rate of rejection, while monitoring recipients for infections and complications to help identify problems early. The long-term outcomes and management of lung transplant recipients are critically based on modulating natural immune response of the recipient to prevent acute and chronic rejection. Understanding the immune mechanisms and temporal correlation of acute and chronic rejection is thus critical in the long-term management of lung recipients. Copyright © 2017 Elsevier Ltd. All rights reserved.

CXCR3 ligands are associated with the continuum of diffuse alveolar damage to chronic lung allograft dysfunction.

PubMed

Shino, Michael Y; Weigt, S Samuel; Li, Ning; Palchevskiy, Vyacheslav; Derhovanessian, Ariss; Saggar, Rajan; Sayah, David M; Gregson, Aric L; Fishbein, Michael C; Ardehali, Abbas; Ross, David J; Lynch, Joseph P; Elashoff, Robert M; Belperio, John A

2013-11-01

After lung transplantation, insults to the allograft generally result in one of four histopathologic patterns of injury: (1) acute rejection, (2) lymphocytic bronchiolitis, (3) organizing pneumonia, and (4) diffuse alveolar damage (DAD). We hypothesized that DAD, the most severe form of acute lung injury, would lead to the highest risk of chronic lung allograft dysfunction (CLAD) and that a type I immune response would mediate this process. Determine whether DAD is associated with CLAD and explore the potential role of CXCR3/ligand biology. Transbronchial biopsies from all lung transplant recipients were reviewed. The association between the four injury patterns and subsequent outcomes were evaluated using proportional hazards models with time-dependent covariates. Bronchoalveolar lavage (BAL) concentrations of the CXCR3 ligands (CXCL9/MIG, CXCL10/IP10, and CXCL11/ITAC) were compared between allograft injury patterns and "healthy" biopsies using linear mixed-effects models. The effect of these chemokine alterations on CLAD risk was assessed using Cox models with serial BAL measurements as time-dependent covariates. There were 1,585 biopsies from 441 recipients with 62 episodes of DAD. An episode of DAD was associated with increased risk of CLAD (hazard ratio, 3.0; 95% confidence interval, 1.9-4.7) and death (hazard ratio, 2.3; 95% confidence interval, 1.7-3.0). There were marked elevations in BAL CXCR3 ligand concentrations during DAD. Furthermore, prolonged elevation of these chemokines in serial BAL fluid measurements predicted the development of CLAD. DAD is associated with marked increases in the risk of CLAD and death after lung transplantation. This association may be mediated in part by an aberrant type I immune response involving CXCR3/ligands.

Restrictive allograft syndrome (RAS): a novel form of chronic lung allograft dysfunction.

PubMed

Sato, Masaaki; Waddell, Thomas K; Wagnetz, Ute; Roberts, Heidi C; Hwang, David M; Haroon, Ayesha; Wagnetz, Dirk; Chaparro, Cecilia; Singer, Lianne G; Hutcheon, Michael A; Keshavjee, Shaf

2011-07-01

Bronchiolitis obliterans syndrome (BOS) with small-airway pathology and obstructive pulmonary physiology may not be the only form of chronic lung allograft dysfunction (CLAD) after lung transplantation. Characteristics of a form of CLAD consisting of restrictive functional changes involving peripheral lung pathology were investigated. Patients who received bilateral lung transplantation from 1996 to 2009 were retrospectively analyzed. Baseline pulmonary function was taken as the time of peak forced expiratory volume in 1 second (FEV(1)). CLAD was defined as irreversible decline in FEV(1) < 80% baseline. The most accurate threshold to predict irreversible decline in total lung capacity and thus restrictive functional change was at 90% baseline. Restrictive allograft syndrome (RAS) was defined as CLAD meeting this threshold. BOS was defined as CLAD without RAS. To estimate the effect on survival, Cox proportional hazards models and Kaplan-Meier analyses were used. Among 468 patients, CLAD developed in 156; of those, 47 (30%) showed the RAS phenotype. Compared with the 109 BOS patients, RAS patients showed significant computed tomography findings of interstitial lung disease (p < 0.0001). Prevalence of RAS was approximately 25% to 35% of all CLAD over time. Patient survival of RAS was significantly worse than BOS after CLAD onset (median survival, 541 vs 1,421 days; p = 0.0003). The RAS phenotype was the most significant risk factor of death among other variables after CLAD onset (hazard ratio, 1.60; confidential interval, 1.23-2.07). RAS is a novel form of CLAD that exhibits characteristics of peripheral lung fibrosis and significantly affects survival of lung transplant patients. Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Evaluating Renal Transplant Status Using Viscoelastic Response (VisR) Ultrasound.

PubMed

Hossain, Md Murad; Selzo, Mallory R; Hinson, Robert M; Baggesen, Leslie M; Detwiler, Randal K; Chong, Wui K; Burke, Lauren M; Caughey, Melissa C; Fisher, Melrose W; Whitehead, Sonya B; Gallippi, Caterina M

2018-05-10

Chronic kidney disease is most desirably and cost-effectively treated by renal transplantation, but graft survival is a major challenge. Although irreversible graft damage can be averted by timely treatment, intervention is delayed when early graft dysfunction goes undetected by standard clinical metrics. A more sensitive and specific parameter for delineating graft health could be the viscoelastic properties of the renal parenchyma, which are interrogated non-invasively by Viscoelastic Response (VisR) ultrasound, a new acoustic radiation force (ARF)-based imaging method. Assessing the performance of VisR imaging in delineating histologically confirmed renal transplant pathologies in vivo is the purpose of the study described here. VisR imaging was performed in patients with (n = 19) and without (n = 25) clinical indication for renal allograft biopsy. The median values of VisR outcome metrics (τ, relative elasticity [RE] and relative viscosity [RV]) were calculated in five regions of interest that were manually delineated in the parenchyma (outer, center and inner) and in the pelvis (outer and inner). The ratios of a given VisR metric for all possible region-of-interest combinations were calculated, and the corresponding ratios were statistically compared between biopsied patients subdivided by diagnostic categories versus non-biopsied, control allografts using the two-sample Wilcoxon test (p <0.05). Although τ ratios non-specifically differentiated allografts with vascular disease, tubular/interstitial scarring, chronic allograft nephropathy and glomerulonephritis from non-biopsied control allografts, RE distinguished only allografts with vascular disease and tubular/interstitial scarring, and RV distinguished only vascular disease. These results suggest that allografts with scarring and vascular disease can be identified using non-invasive VisR RE and RV metrics. Copyright © 2018 World Federation for Ultrasound in Medicine and Biology. Published by Elsevier Inc. All rights reserved.

Macrophages: Contributors to Allograft Dysfunction, Repair or Innocent Bystanders?

PubMed Central

Mannon, Roslyn B.

2012-01-01

Purpose of this review Macrophages are members of the innate immune response. However, their role in the adaptive immune response is not known. The purpose of this review is to highlight our current understanding of macrophage structure and function and how they may participate in allograft injury. Recent Findings Studies in acute kidney injury models identify macrophages as key mediators of inflammatory injury while more recent studies indicate that they may play a reparative role, depending on phenotype—M1 or M2 type macrophages. Mregs, generated in vitro, appear to have immune suppressive abilities and a unique phenotype. In solid organ transplant, the emphasis of studies has been on acute or chronic injury. These data are derived from animal models using depletion of macrophages or antagonizing their activation and inflammatory responses. The relative contribution of macrophage phenotype in transplantation has not been explored. Summary These studies suggest that macrophages play an injurious role in acute cellular allograft rejection, as well as in chronic injury. Infiltration of an allograft with macrophages is also associated with worse graft function and poor prognosis. Further studies are needed to understand the mechanisms of macrophage mediated injury, explore their potential reparative role and determine if they or their functional products are biomarkers of poor graft outcomes. PMID:22157320

Metabolic syndrome, insulin resistance, and chronic allograft dysfunction.

PubMed

Porrini, Esteban; Delgado, Patricia; Torres, Armando

2010-12-01

Metabolic syndrome (MS) is a cluster of cardiovascular (CV) risk factors (hypertension, dyslipidemia, obesity, and glucose homeostasis alterations), and insulin resistance (IR) is suggested to be a common pathogenic background. In the general population, MS and IR have been proven to be risk factors for diabetes, CV disease, and chronic kidney disease. In the renal transplant setting, few studies have analyzed the relevance of MS and IR. According to the few data available, the prevalence of MS in renal transplant patients has been described as 22.6% at 12 months, 37.7% at 36 months, and 64% at 6 years after transplantation. Importantly, MS has been shown to be an independent risk factor for chronic allograft dysfunction (CAD), graft failure, new-onset diabetes, and CV disease. Also, persistent hyperinsulinemia during the first posttransplant year has been related to an increase in glomerular filtration rate, probably reflecting glomerular hyperfiltration as observed in prediabetes and early type 2 diabetes. Importantly, prediabetes (impaired fasting glucose and impaired glucose tolerance), a state hallmarked by IR, proved to be highly frequent among stable renal transplant recipients (30%), which is nearly three times its incidence in the general population. Posttransplant IR has been associated with subclinical atheromatosis as assessed by carotid intima-media thickness, and with chronic subclinical inflammation. In conclusion, MS and IR are important modifiable risk factors in renal transplant recipients, and prompt interventions to avoid its deleterious effects at the metabolic, CV, and graft function levels are needed.

Overview of Clinical Lung Transplantation

PubMed Central

Yeung, Jonathan C.; Keshavjee, Shaf

2014-01-01

Since the first successful lung transplant 30 years ago, lung transplantation has rapidly become an established standard of care to treat end-stage lung disease in selected patients. Advances in lung preservation, surgical technique, and immunosuppression regimens have resulted in the routine performance of lung transplantation around the world for an increasing number of patients, with wider indications. Despite this, donor shortages and chronic lung allograft dysfunction continue to prevent lung transplantation from reaching its full potential. With research into the underlying mechanisms of acute and chronic lung graft dysfunction and advances in personalized diagnostic and therapeutic approaches to both the donor lung and the lung transplant recipient, there is increasing confidence that we will improve short- and long-term outcomes in the near future. PMID:24384816

Restrictive allograft syndrome and idiopathic pleuroparenchymal fibroelastosis: do they really have the same histology?

PubMed

Montero, Maria A; Osadolor, Tina; Khiroya, Reena; Salcedo, Maria Teresa; Robertus, Jan L; Rice, Alexandra; Nicholson, Andrew G; Roman, Antonio; Monforte, Victor

2017-06-01

Restrictive allograft syndrome (RAS) and idiopathic pleuroparenchymal fibroelastosis (IPPFE) are two different diseases reported to share the same histology. RAS relates to chronic allograft dysfunction in lung transplantation, with IPPFE being a rare condition in native lungs. Our aim is to compare their histologies alongside biopsies of usual interstitial pneumonia (UIP), to determine if there are differences that might help to elucidate the pathogenesis. We selected four postmortem allograft lungs from patients who developed a clear clinical RAS pattern, five biopsies diagnosed as IPPFE, five UIP biopsies and five sections of normal lung. Histopathological features were described without knowledge of clinical and radiological features. Both RAS allografts and IPPFE biopsies showed intra-alveolar fibrosis and elastosis (IAFE), but RAS allografts also showed concomitant obliterative bronchiolitis, vascular lymphoplasmacytic inflammation within fibrointimal thickening, less fibroblastic foci (FF) at the advancing edge of the fibrosis (one against 14.4 FF in 2 mm 2 ) and a slight reduction of the capillary network compared to UIP (P = 0.07) and controls (P = 0.06). The main differences seen in UIP were the lack of IAFE and the presence of honeycomb change. RAS and PPFE histopathology both show IAFE, but display various differences, particularly in their vascular morphology that may allow further understanding of pathogenesis. © 2017 John Wiley & Sons Ltd.

Lung transplantation in adults and children: putting lung function into perspective.

PubMed

Thompson, Bruce Robert; Westall, Glen Philip; Paraskeva, Miranda; Snell, Gregory Ian

2014-11-01

The number of lung transplants performed globally continues to increase year after year. Despite this growing experience, long-term outcomes following lung transplantation continue to fall far short of that described in other solid-organ transplant settings. Chronic lung allograft dysfunction (CLAD) remains common and is the end result of exposure to a multitude of potentially injurious insults that include alloreactivity and infection among others. Central to any description of the clinical performance of the transplanted lung is an assessment of its physiology by pulmonary function testing. Spirometry and the evaluation of forced expiratory volume in 1 s and forced vital capacity, remain core indices that are measured as part of routine clinical follow-up. Spirometry, while reproducible in detecting lung allograft dysfunction, lacks specificity in differentiating the different complications of lung transplantation such as rejection, infection and bronchiolitis obliterans. However, interpretation of spirometry is central to defining the different 'chronic rejection' phenotypes. It is becoming apparent that the maximal lung function achieved following transplantation, as measured by spirometry, is influenced by a number of donor and recipient factors as well as the type of surgery performed (single vs double vs lobar lung transplant). In this review, we discuss the wide range of variables that need to be considered when interpreting lung function testing in lung transplant recipients. Finally, we review a number of novel measurements of pulmonary function that may in the future serve as better biomarkers to detect and diagnose the cause of the failing lung allograft. © 2014 Asian Pacific Society of Respirology.

HLA Matching at the Eplet Level Protects Against Chronic Lung Allograft Dysfunction.

PubMed

Walton, D C; Hiho, S J; Cantwell, L S; Diviney, M B; Wright, S T; Snell, G I; Paraskeva, M A; Westall, G P

2016-09-01

Donor selection in lung transplantation (LTx) is historically based upon clinical urgency, ABO compatibility, and donor size. HLA matching is not routinely considered; however, the presence or later development of anti-HLA antibodies is associated with poorer outcomes, particularly chronic lung allograft dysfunction (CLAD). Using eplet mismatches, we aimed to determine whether donor/recipient HLA incompatibility was a significant predictor of CLAD. One hundred seventy-five LTx undertaken at the Alfred Hospital between 2008 and 2012 met criteria. Post-LTx monitoring was continued for at least 12 months, or until patient death. HLA typing was performed by sequence-based typing and Luminex sequence-specific oligonucleotide. Using HLAMatchmaker, eplet mismatches between each donor/recipient pairing were analyzed and correlated against incidences of CLAD. HLA-DRB1/3/4/5+DQA/B eplet mismatch was a significant predictor of CLAD (hazard ratio [HR] 3.77, 95% confidence interval [CI]: 1.71-8.29 p < 0.001). When bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) were analyzed independently, HLA-DRB1/3/4/5 + DQA/B eplet mismatch was shown to significantly predict RAS (HR 8.3, 95% CI: 2.46-27.97 p < 0.001) but not BOS (HR 1.92, 95% CI: 0.64-5.72, p = 0.237). HLA-A/B eplet mismatch was shown not to be a significant predictor when analyzed independently but did provide additional stratification of results. This study illustrates the importance of epitope immunogenicity in defining donor-recipient immune compatibility in LTx. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Altered Exosomal RNA Profiles in Bronchoalveolar Lavage from Lung Transplants with Acute Rejection.

PubMed

Gregson, Aric L; Hoji, Aki; Injean, Patil; Poynter, Steven T; Briones, Claudia; Palchevskiy, Vyacheslav; Weigt, S Sam; Shino, Michael Y; Derhovanessian, Ariss; Sayah, David; Saggar, Rajan; Ross, David; Ardehali, Abbas; Lynch, Joseph P; Belperio, John A

2015-12-15

The mechanism by which acute allograft rejection leads to chronic rejection remains poorly understood despite its common occurrence. Exosomes, membrane vesicles released from cells within the lung allograft, contain a diverse array of biomolecules that closely reflect the biologic state of the cell and tissue from which they are released. Exosome transcriptomes may provide a better understanding of the rejection process. Furthermore, biomarkers originating from this transcriptome could provide timely and sensitive detection of acute cellular rejection (AR), reducing the incidence of severe AR and chronic lung allograft dysfunction and improving outcomes. To provide an in-depth analysis of the bronchoalveolar lavage fluid exosomal shuttle RNA population after lung transplantation and evaluate for differential expression between acute AR and quiescence. Serial bronchoalveolar lavage specimens were ultracentrifuged to obtain the exosomal pellet for RNA extraction, on which RNA-Seq was performed. AR demonstrates an intense inflammatory environment, skewed toward both innate and adaptive immune responses. Novel, potential upstream regulators identified offer potential therapeutic targets. Our findings validate bronchoalveolar lavage fluid exosomal shuttle RNA as a source for understanding the pathophysiology of AR and for biomarker discovery in lung transplantation.

Altered Exosomal RNA Profiles in Bronchoalveolar Lavage from Lung Transplants with Acute Rejection

PubMed Central

Hoji, Aki; Injean, Patil; Poynter, Steven T.; Briones, Claudia; Palchevskiy, Vyacheslav; Sam Weigt, S.; Shino, Michael Y.; Derhovanessian, Ariss; Saggar, Rajan; Ross, David; Ardehali, Abbas; Lynch, Joseph P.; Belperio, John A.

2015-01-01

Rationale: The mechanism by which acute allograft rejection leads to chronic rejection remains poorly understood despite its common occurrence. Exosomes, membrane vesicles released from cells within the lung allograft, contain a diverse array of biomolecules that closely reflect the biologic state of the cell and tissue from which they are released. Exosome transcriptomes may provide a better understanding of the rejection process. Furthermore, biomarkers originating from this transcriptome could provide timely and sensitive detection of acute cellular rejection (AR), reducing the incidence of severe AR and chronic lung allograft dysfunction and improving outcomes. Objectives: To provide an in-depth analysis of the bronchoalveolar lavage fluid exosomal shuttle RNA population after lung transplantation and evaluate for differential expression between acute AR and quiescence. Methods: Serial bronchoalveolar lavage specimens were ultracentrifuged to obtain the exosomal pellet for RNA extraction, on which RNA-Seq was performed. Measurements and Main Results: AR demonstrates an intense inflammatory environment, skewed toward both innate and adaptive immune responses. Novel, potential upstream regulators identified offer potential therapeutic targets. Conclusions: Our findings validate bronchoalveolar lavage fluid exosomal shuttle RNA as a source for understanding the pathophysiology of AR and for biomarker discovery in lung transplantation. PMID:26308930

The Emerging Importance of Non-HLA Autoantibodies in Kidney Transplant Complications.

PubMed

Cardinal, Héloise; Dieudé, Mélanie; Hébert, Marie-Josée

2017-02-01

Antibodies that are specific to organ donor HLA have been involved in the majority of cases of antibody-mediated rejection in solid organ transplant recipients. However, recent data show that production of non-HLA autoantibodies can occur before transplant in the form of natural autoantibodies. In contrast to HLAs, which are constitutively expressed on the cell surface of the allograft endothelium, autoantigens are usually cryptic. Tissue damage associated with ischemia-reperfusion, vascular injury, and/or rejection creates permissive conditions for the expression of cryptic autoantigens, allowing these autoantibodies to bind antigenic targets and further enhance vascular inflammation and renal dysfunction. Antiperlecan/LG3 antibodies and antiangiotensin II type 1 receptor antibodies have been found before transplant in patients with de novo transplants and portend negative long-term outcome in patients with renal transplants. Here, we review mounting evidence suggesting an important role for autoantibodies to cryptic antigens as novel accelerators of kidney dysfunction and acute or chronic allograft rejection. Copyright © 2017 by the American Society of Nephrology.

Impact of gastroesophageal reflux and delayed gastric emptying on pediatric lung transplant outcomes.

PubMed

Jamie Dy, Fei; Freiberger, Dawn; Liu, Enju; Boyer, Debra; Visner, Gary; Rosen, Rachel

2017-08-01

Gastroesophageal reflux disease is thought to predispose to adverse lung allograft outcomes. However, little is known about the burden of gastroesophageal reflux (GER) and gastroparesis in pediatric patients. In this study we describe the burden of reflux and gastroparesis in children undergoing lung transplant, and evaluates their impact on allograft survival and rejection incidence. This study is a retrospective analysis of pediatric lung transplant recipients who had combined pH and multichannel intraluminal impedance testing (pH-MII) and gastric-emptying scans (GES). Hazard ratios with 95% confidence intervals (CIs) estimated from Cox proportional hazard models were used to examine the associations between reflux parameters and adverse allograft outcomes. Covariates considered in the multivariate analysis included abnormal pH-MII testing, abnormal GES and Nissen fundoplication status. Kaplan-Meier curves were created, with log-rank testing employed to assess differences between groups. Thirty lung transplant recipients, aged 1 to 21 years, were identified. Eight of 30 patients (27%) had abnormal reflux by impedance, and 12 (40%) had abnormal pH-metry. Of 19 patients tested, 5 (26.3%) had evidence of gastric dysmotility; however, the severity of GER did not trend with delays in gastric emptying. Neither reflux burden by pH-MII testing nor fundoplication status impacted survival or rejection. However, delayed gastric emptying appeared significantly linked to the development of chronic lung allograft dysfunction, independent of GER. In children, reflux burden and fundoplication status do not impact lung transplant outcomes, but gastric dysmotility may be linked to allograft dysfunction in children. Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Clinical outcomes of lung transplant recipients with telomerase mutations.

PubMed

Tokman, Sofya; Singer, Jonathan P; Devine, Megan S; Westall, Glen P; Aubert, John-David; Tamm, Michael; Snell, Gregory I; Lee, Joyce S; Goldberg, Hilary J; Kukreja, Jasleen; Golden, Jeffrey A; Leard, Lorriana E; Garcia, Christine K; Hays, Steven R

2015-10-01

Successful lung transplantation for patients with pulmonary fibrosis from telomerase mutations may be limited by systemic complications of telomerase dysfunction, including myelosuppression, cirrhosis, and malignancy. We describe clinical outcomes in 14 lung transplant recipients with telomerase mutations. Subjects underwent lung transplantation between February 2005 and April 2014 at 5 transplant centers. Data were abstracted from medical records, focusing on outcomes reflecting post-transplant treatment effects likely to be complicated by telomerase mutations. The median age of subjects was 60.5 years (interquartile range = 52.0-62.0), 64.3% were male, and the mean post-transplant observation time was 3.2 years (SD ± 2.9). A mutation in telomerase reverse transcriptase was present in 11 subjects, a telomerase RNA component mutation was present in 2 subjects, and an uncharacterized mutation was present in 1 subject. After lung transplantation, 10 subjects were leukopenic and 5 did not tolerate lymphocyte anti-proliferative agents. Six subjects developed recurrent lower respiratory tract infections, 7 developed acute cellular rejection (A1), and 4 developed chronic lung allograft dysfunction. Eight subjects developed at least 1 episode of acute renal failure and 10 developed chronic renal insufficiency. In addition, 3 subjects developed cancer. No subjects had cirrhosis. At data censorship, 13 subjects were alive. The clinical course for lung transplant recipients with telomerase mutations is complicated by renal disease, leukopenia with intolerance of lymphocyte anti-proliferative agents, and recurrent lower respiratory tract infections. In contrast, cirrhosis was absent, acute cellular rejection was mild, and development of chronic lung allograft dysfunction was comparable to other lung transplant recipients. Although it poses challenges, lung transplantation may be feasible for patients with pulmonary fibrosis from telomerase mutations. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Reversible renal allograft dysfunction and proteinuria from nutcracker-like syndrome: a case report.

PubMed

Krishnan, S G S; Pritsiolas, J; Susin, M; Linden, E; Beil-Levi, E; Gitman, M; Mossey, R; Bhaskaran, M

2007-06-01

A 27-year-old Hispanic man with hypertension and renal failure was on hemodialysis for 4 years prior to receiving a living donor renal transplant from his 19-year-old sister. His serum creatinine decreased to 1.7 mg/dL at 3 weeks posttransplant with a urine protein creatinine ratio (UP) of 0.1 (g/g). Over the next 2 months, he experienced repeated episodes of allograft dysfunction with elevation of creatinine and proteinuria levels, associated with a lymphocele. Doppler studies of the allograft revealed renal vein compression. His symptoms responded to aspiration of the fluid collection, resolving completely with surgical drainage. We believe that the episodes of allograft dysfunction and proteinuria were related to recurrent lymphocele, causing a nutcracker-like syndrome.

Low-dose computed tomography volumetry for subtyping chronic lung allograft dysfunction.

PubMed

Saito, Tomohito; Horie, Miho; Sato, Masaaki; Nakajima, Daisuke; Shoushtarizadeh, Hassan; Binnie, Matthew; Azad, Sassan; Hwang, David M; Machuca, Tiago N; Waddell, Thomas K; Singer, Lianne G; Cypel, Marcelo; Liu, Mingyao; Paul, Narinder S; Keshavjee, Shaf

2016-01-01

The long-term success of lung transplantation is challenged by the development of chronic lung allograft dysfunction (CLAD) and its distinct subtypes of bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). However, the current diagnostic criteria for CLAD subtypes rely on total lung capacity (TLC), which is not always measured during routine post-transplant assessment. Our aim was to investigate the utility of low-dose 3-dimensional computed tomography (CT) lung volumetry for differentiating RAS from BOS. This study was a retrospective evaluation of 63 patients who had developed CLAD after bilateral lung or heart‒lung transplantation between 2006 and 2011, including 44 BOS and 19 RAS cases. Median post-transplant follow-up was 65 months in BOS and 27 months in RAS. The median interval between baseline and the disease-onset time-point for CT volumetry was 11 months in both BOS and RAS. Chronologic changes and diagnostic accuracy of CT lung volume (measured as percent of baseline) were investigated. RAS showed a significant decrease in CT lung volume at disease onset compared with baseline (mean 3,916 ml vs 3,055 ml when excluding opacities, p < 0.0001), whereas BOS showed no significant post-transplant change (mean 4,318 ml vs 4,396 ml, p = 0.214). The area under the receiver operating characteristic curve of CT lung volume for differentiating RAS from BOS was 0.959 (95% confidence interval 0.912 to 1.01, p < 0.0001) and the calculated accuracy was 0.938 at a threshold of 85%. In bilateral lung or heart‒lung transplant patients with CLAD, low-dose CT volumetry is a useful tool to differentiate patients who develop RAS from those who develop BOS. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Bronchiolitis Obliterans Syndrome: The Achilles’ Heel of Lung Transplantation

PubMed Central

Weigt, S. Samuel; DerHovanessian, Ariss; Wallace, W. Dean; Lynch, Joseph P.; Belperio, John A.

2016-01-01

Lung transplantation is a therapeutic option for patients with end-stage pulmonary disorders. Unfortunately, chronic lung allograft dysfunction (CLAD), most commonly manifest as bronchiolitis obliterans syndrome (BOS), continues to be highly prevalent and is the major limitation to long-term survival. The pathogenesis of BOS is complex and involves alloimmune and nonalloimmune pathways. Clinically, BOS manifests as airway obstruction and dyspnea that are classically progressive and ultimately fatal; however, the course is highly variable, and distinguishable phenotypes may exist. There are few controlled studies assessing treatment efficacy, but only a minority of patients respond to current treatment modalities. Ultimately, preventive strategies may prove more effective at prolonging survival after lung transplantation, but their remains considerable debate and little data regarding the best strategies to prevent BOS. A better understanding of the risk factors and their relationship to the pathological mechanisms of chronic lung allograft rejection should lead to better pharmacological targets to prevent or treat this syndrome. PMID:23821508

Ultrasonography parameters and histopathology findings in transplanted kidney.

PubMed

Rigler, A A; Vizjak, A; Ferluga, D; Kandus, A; Buturović-Ponikvar, J

2013-05-01

Until now studies have shown conflicting results about morphologic and hemodynamic parameters in predicting histopathology results in renal graft malfunction. We sought to analyze whether parenchymal thickness relative to graft length and resistive index (RI) measured by ultrasonography can predict histopathology findings on renal biopsy. We retrospectively analyzed 72 deceased donor renal allograft biopsies and respective allograft ultrasounds, performed on 68 patients (57% men) with mean age of 50 years (range, 21-73), with kidney graft dysfunction in 2010 and 2011. Parenchymal thickness relative to graft length and RI were compared with different histopathology diagnoses: Acute rejection, chronic rejection, chronic kidney changes, acute tubular necrosis (ATN), and other diagnoses. The mean value of the RI and of the parenchymal thickness/graft length ratio (parenchyma size index [PSI]) was 0.81 ± 0.10 (SD) and 1.48 ± 0.27 (SD), respectively. Enlarged PSI was significantly higher in ATN (mean 1.72 ± 0.26) compared with no ATN (mean 1.39 ± 0.23; P < .001), and lower when chronic changes were present (mean 1.40 ± 0.25 for chronic changes vs mean 1.62 ± 0.28 for no chronic changes; P = .004). In the group without ATN, PSI was enlarged in acute graft rejection compared with no graft rejection (mean 1.50 ± 0.24 vs 1.24 ± 0.13, respectively; P < .001), whereas in the whole group, including ATN, PSI showed no differentiating power for acute rejection (P = .526). RI was significantly higher in ATN than without it (mean 0.91 ± 0.10 vs 0.79 ± 0.08, respectively; P < .001), whereas the RI was not increased (but was actually lower) in acute graft rejection compared with no graft rejection, neither in the whole group (mean 0.81 ± 0.09 vs 0.82 ± 0.12, respectively; P = .611). Enlarged parenchymal thickness/graft length ratio on ultrasonography was observed in ATN and acute allograft rejection. The RI was increased in ATN, but not in acute allograft rejection. Decreased parenchymal thickness/graft length ratio was observed in chronic kidney changes. Copyright © 2013 Elsevier Inc. All rights reserved.

Cold ischemia contributes to the development of chronic rejection and mitochondrial injury after cardiac transplantation.

PubMed

Schneeberger, Stefan; Amberger, Albert; Mandl, Julia; Hautz, Theresa; Renz, Oliver; Obrist, Peter; Meusburger, Hugo; Brandacher, Gerald; Mark, Walter; Strobl, Daniela; Troppmair, Jakob; Pratschke, Johann; Margreiter, Raimund; Kuznetsov, Andrey V

2010-12-01

Chronic rejection (CR) remains an unsolved hurdle for long-term heart transplant survival. The effect of cold ischemia (CI) on progression of CR and the mechanisms resulting in functional deficit were investigated by studying gene expression, mitochondrial function, and enzymatic activity. Allogeneic (Lew→F344) and syngeneic (Lew→Lew) heart transplantations were performed with or without 10 h of CI. After evaluation of myocardial contraction, hearts were excised at 2, 10, 40, and 60 days for investigation of vasculopathy, gene expression, enzymatic activities, and mitochondrial respiration. Gene expression studies identified a gene cluster coding for subunits of the mitochondrial electron transport chain regulated in response to CI and CR. Myocardial performance, mitochondrial function, and mitochondrial marker enzyme activities declined in all allografts with time after transplantation. These declines were more rapid and severe in CI allografts (CR-CI) and correlated well with progression of vasculopathy and fibrosis. Mitochondria related gene expression and mitochondrial function are substantially compromised with the progression of CR and show that CI impacts on progression, gene profile, and mitochondrial function of CR. Monitoring mitochondrial function and enzyme activity might allow for earlier detection of CR and cardiac allograft dysfunction. © 2010 The Authors. Journal compilation © 2010 European Society for Organ Transplantation.

Prolonged Allograft Survival in a Patient With Chronic Immunosuppression: A Case Report and Systematic Review.

PubMed

Vyas, Krishna S; Burns, Chase; Ryan, Dylan T; Wong, Lesley

2017-06-01

A 41-year-old man with past medical history of kidney-liver transplantation requiring chronic immunosuppression presented 2 years posttransplant with a necrotizing soft tissue infection of his right thigh. Serial debridement to remove necrotic tissue was performed, and a Matrix HD Allograft Fenestrated (RTI Surgical, Alachua, FL) was applied. At 5-months post grafting, the patient demonstrated fully vascularized and intact skin. Under normal circumstances, a cadaveric allograft sloughs over several weeks and is not usually considered a permanent solution for wound closure. A systematic review of transplant patients on chronic immunosuppression with skin allografts demonstrates the potential for the indefinite survival of an allograft. Necrotizing soft tissue infections can definitively be treated using serial debridement and allograft transplantation in the chronically immunosuppressed.

Metabolomic Profiling in Individuals with a Failing Kidney Allograft.

PubMed

Bassi, Roberto; Niewczas, Monika A; Biancone, Luigi; Bussolino, Stefania; Merugumala, Sai; Tezza, Sara; D'Addio, Francesca; Ben Nasr, Moufida; Valderrama-Vasquez, Alessandro; Usuelli, Vera; De Zan, Valentina; El Essawy, Basset; Venturini, Massimo; Secchi, Antonio; De Cobelli, Francesco; Lin, Alexander; Chandraker, Anil; Fiorina, Paolo

2017-01-01

Alteration of certain metabolites may play a role in the pathophysiology of renal allograft disease. To explore metabolomic abnormalities in individuals with a failing kidney allograft, we analyzed by liquid chromatography-mass spectrometry (LC-MS/MS; for ex vivo profiling of serum and urine) and two dimensional correlated spectroscopy (2D COSY; for in vivo study of the kidney graft) 40 subjects with varying degrees of chronic allograft dysfunction stratified by tertiles of glomerular filtration rate (GFR; T1, T2, T3). Ten healthy non-allograft individuals were chosen as controls. LC-MS/MS analysis revealed a dose-response association between GFR and serum concentration of tryptophan, glutamine, dimethylarginine isomers (asymmetric [A]DMA and symmetric [S]DMA) and short-chain acylcarnitines (C4 and C12), (test for trend: T1-T3 = p<0.05; p = 0.01; p<0.001; p = 0.01; p = 0.01; p<0.05, respectively). The same association was found between GFR and urinary levels of histidine, DOPA, dopamine, carnosine, SDMA and ADMA (test for trend: T1-T3 = p<0.05; p<0.01; p = 0.001; p<0.05; p = 0.001; p<0.001; p<0.01, respectively). In vivo 2D COSY of the kidney allograft revealed significant reduction in the parenchymal content of choline, creatine, taurine and threonine (all: p<0.05) in individuals with lower GFR levels. We report an association between renal function and altered metabolomic profile in renal transplant individuals with different degrees of kidney graft function.

Excretion of anti-angiogenic proteins in patients with chronic allograft dysfunction.

PubMed

Moskowitz-Kassai, Eliza; Mackelaite, Lina; Chen, Jun; Patel, Kaushal; Dadhania, Darshana M; Gross, Steven S; Chander, Praveen; Delaney, Vera; Deng, Luqin; Chen, Ligong; Cui, Xiangqin; Suthanthiran, Manikkam; Goligorsky, Michael S

2012-02-01

We have recently documented the appearance of an anti-angiogenic peptide, endorepellin, in the urine of patients with chronic allograft dysfunction (CAD). Here, we analyzed using enzyme-linked immunosorbent assay the excretion of anti-angiogenic peptides endostatin, pigment epithelium-derived factor (PEDF) and Kruppel-like factor-2 (KLF-2), in healthy individuals, patients with stable graft function and patients with various degrees of CAD. In healthy subjects and patients with CAD-0, endostatin, PEDF and KLF-2 excretions were at the level of detection. In contrast, there were significant differences between the patients with CAD-3 and CAD-0, CAD-1 and healthy controls for endostatin and CAD-0 versus CAD-3 for PEDF, but no differences in KLF-2 excretion. Receiver operating characteristic (ROC) curve analyses demonstrated a highly discriminative profile for all three biomarkers: the combination of these parameters offered 83% sensitivity and 90% specificity in distinguishing CAD-0 from CAD-1-3. The quality of these potential biomarkers of CAD was, however, highest in discriminating CAD status in biopsy-proven cases and dropped when CAD-0 was diagnosed based on clinical criteria. In conclusion, these findings indicate the diagnostic potential of urinary detection of endostatin, PEDF and to lesser degree KLF-2 and suggest a mechanistic role played by anti-angiogenic substances in the developing vasculopathy and vascular rarefaction in patients with CAD.

Antibody-mediated rejection of the lung: A consensus report of the International Society for Heart and Lung Transplantation.

PubMed

Levine, Deborah J; Glanville, Allan R; Aboyoun, Christina; Belperio, John; Benden, Christian; Berry, Gerald J; Hachem, Ramsey; Hayes, Don; Neil, Desley; Reinsmoen, Nancy L; Snyder, Laurie D; Sweet, Stuart; Tyan, Dolly; Verleden, Geert; Westall, Glen; Yusen, Roger D; Zamora, Martin; Zeevi, Adriana

2016-04-01

Antibody-mediated rejection (AMR) is a recognized cause of allograft dysfunction in lung transplant recipients. Unlike AMR in other solid-organ transplant recipients, there are no standardized diagnostic criteria or an agreed-upon definition. Hence, a working group was created by the International Society for Heart and Lung Transplantation with the aim of determining criteria for pulmonary AMR and establishing a definition. Diagnostic criteria and a working consensus definition were established. Key diagnostic criteria include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. Exclusion of other causes of allograft dysfunction increases confidence in the diagnosis but is not essential. Pulmonary AMR may be clinical (allograft dysfunction which can be asymptomatic) or sub-clinical (normal allograft function). This consensus definition will have clinical, therapeutic and research implications. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Blood Vessels in Allotransplantation.

PubMed

Abrahimi, P; Liu, R; Pober, J S

2015-07-01

Human vascularized allografts are perfused through blood vessels composed of cells (endothelium, pericytes, and smooth muscle cells) that remain largely of graft origin and are thus subject to host alloimmune responses. Graft vessels must be healthy to maintain homeostatic functions including control of perfusion, maintenance of permselectivity, prevention of thrombosis, and participation in immune surveillance. Vascular cell injury can cause dysfunction that interferes with these processes. Graft vascular cells can be activated by mediators of innate and adaptive immunity to participate in graft inflammation contributing to both ischemia/reperfusion injury and allograft rejection. Different forms of rejection may affect graft vessels in different ways, ranging from thrombosis and neutrophilic inflammation in hyperacute rejection, to endothelialitis/intimal arteritis and fibrinoid necrosis in acute cell-mediated or antibody-mediated rejection, respectively, and to diffuse luminal stenosis in chronic rejection. While some current therapies targeting the host immune system do affect graft vascular cells, direct targeting of the graft vasculature may create new opportunities for preventing allograft injury and loss. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Metabolomic Profiling in Individuals with a Failing Kidney Allograft

PubMed Central

Biancone, Luigi; Bussolino, Stefania; Merugumala, Sai; Tezza, Sara; D’Addio, Francesca; Ben Nasr, Moufida; Valderrama-Vasquez, Alessandro; Usuelli, Vera; De Zan, Valentina; El Essawy, Basset; Venturini, Massimo; Secchi, Antonio; De Cobelli, Francesco; Lin, Alexander; Chandraker, Anil; Fiorina, Paolo

2017-01-01

Background Alteration of certain metabolites may play a role in the pathophysiology of renal allograft disease. Methods To explore metabolomic abnormalities in individuals with a failing kidney allograft, we analyzed by liquid chromatography-mass spectrometry (LC-MS/MS; for ex vivo profiling of serum and urine) and two dimensional correlated spectroscopy (2D COSY; for in vivo study of the kidney graft) 40 subjects with varying degrees of chronic allograft dysfunction stratified by tertiles of glomerular filtration rate (GFR; T1, T2, T3). Ten healthy non-allograft individuals were chosen as controls. Results LC-MS/MS analysis revealed a dose-response association between GFR and serum concentration of tryptophan, glutamine, dimethylarginine isomers (asymmetric [A]DMA and symmetric [S]DMA) and short-chain acylcarnitines (C4 and C12), (test for trend: T1-T3 = p<0.05; p = 0.01; p<0.001; p = 0.01; p = 0.01; p<0.05, respectively). The same association was found between GFR and urinary levels of histidine, DOPA, dopamine, carnosine, SDMA and ADMA (test for trend: T1-T3 = p<0.05; p<0.01; p = 0.001; p<0.05; p = 0.001; p<0.001; p<0.01, respectively). In vivo 2D COSY of the kidney allograft revealed significant reduction in the parenchymal content of choline, creatine, taurine and threonine (all: p<0.05) in individuals with lower GFR levels. Conclusions We report an association between renal function and altered metabolomic profile in renal transplant individuals with different degrees of kidney graft function. PMID:28052095

Lung volumes predict survival in patients with chronic lung allograft dysfunction.

PubMed

Kneidinger, Nikolaus; Milger, Katrin; Janitza, Silke; Ceelen, Felix; Leuschner, Gabriela; Dinkel, Julien; Königshoff, Melanie; Weig, Thomas; Schramm, René; Winter, Hauke; Behr, Jürgen; Neurohr, Claus

2017-04-01

Identification of disease phenotypes might improve the understanding of patients with chronic lung allograft dysfunction (CLAD). The aim of the study was to assess the impact of pulmonary restriction and air trapping by lung volume measurements at the onset of CLAD.A total of 396 bilateral lung transplant recipients were analysed. At onset, CLAD was further categorised based on plethysmography. A restrictive CLAD (R-CLAD) was defined as a loss of total lung capacity from baseline. CLAD with air trapping (AT-CLAD) was defined as an increased ratio of residual volume to total lung capacity. Outcome was survival after CLAD onset. Patients with insufficient clinical information were excluded (n=95).Of 301 lung transplant recipients, 94 (31.2%) developed CLAD. Patients with R-CLAD (n=20) and AT-CLAD (n=21), respectively, had a significantly worse survival (p<0.001) than patients with non-R/AT-CLAD. Both R-CLAD and AT-CLAD were associated with increased mortality when controlling for multiple confounding variables (hazard ratio (HR) 3.57, 95% CI 1.39-9.18; p=0.008; and HR 2.65, 95% CI 1.05-6.68; p=0.039). Furthermore, measurement of lung volumes was useful to identify patients with combined phenotypes.Measurement of lung volumes in the long-term follow-up of lung transplant recipients allows the identification of patients who are at risk for worse outcome and warrant special consideration. Copyright ©ERS 2017.

Phenotyping Chronic Lung Allograft Dysfunction Using Body Plethysmography and Computed Tomography.

PubMed

Suhling, H; Dettmer, S; Greer, M; Fuehner, T; Avsar, M; Haverich, A; Welte, T; Gottlieb, J

2016-11-01

Restrictive subtype of chronic lung allograft dysfunction (CLAD) was recently described after lung transplantation. This study compares different definitions of a restrictive phenotype in CLAD patients and impact on survival. Eighty-nine CLAD patients out of 1191 screened patients (September 1987 to July 2012) were included as complete longitudinal lung volume measurements and chest computed tomography (CT) after CLAD onset was available. CT findings and lung volumes were quantified and survival was calculated for distinctive groups and predictive factors for worse survival were investigated. Graft survival in patients with total lung capacity (TLC) between 90% and 81% of baseline (BL) (n = 13, 15%) in CLAD course was similar to those with TLC >90% BL (n = 64, 56%; log-rank test p = 0.9). Twelve patients (13%) developed a TLC ≤80% BL and 10 (11%) had significant parenchymal changes on CT, of whom 6 (46%) also had TLC ≤80% BL. CT changes correlated with TLC ≤80% BL (Φ-coefficient = 0.48, p = 0.001). Patients with either TLC ≤80% or significant CT changes (n = 16, 18%) had a significantly reduced survival (log-rank p < 0.001). Forced vital capacity loss at CLAD onset was associated with poorer survival but did not correlate with the TLC or CT changes. A restrictive subtype of CLAD may be defined by either TLC ≤80% BL or severe parenchymal changes on chest CT. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Diagnostic value of plasma and bronchoalveolar lavage samples in acute lung allograft rejection: differential cytology.

PubMed

Speck, Nicole E; Schuurmans, Macé M; Murer, Christian; Benden, Christian; Huber, Lars C

2016-06-21

Diagnosis of acute lung allograft rejection is currently based on transbronchial lung biopsies. Additional methods to detect acute allograft dysfunction derived from plasma and bronchoalveolar lavage samples might facilitate diagnosis and ultimately improve allograft survival. This review article gives an overview of the cell profiles of bronchoalveolar lavage and plasma samples during acute lung allograft rejection. The value of these cells and changes within the pattern of differential cytology to support the diagnosis of acute lung allograft rejection is discussed. Current findings on the topic are highlighted and trends for future research are identified.

Clinical Courses of Graft Failure Caused by Chronic Allograft Dysfunction in Kidney Transplantation.

PubMed

Fujiwara, T; Teruta, S; Tsudaka, S; Ota, K; Matsuda, H

Chronic allograft dysfunction (CAD) is a main cause of graft failure in kidney transplantation. We retrospectively analyzed 279 kidney transplant recipients who survived with a functioning graft for at least 2 years. CAD was defined as chronic graft deterioration, excluding other specific causes. We defined the pattern of decline in estimated glomerular filtration rate (eGFR), as follows: (1) "plateau" was defined as decline in eGFR ≤2 mL/min/1.73 m 2 /year; "long plateaus" were those lasting more than 5 years; (2) "rapid decline" was a decrease in eGFR ≥20 mL/min/1.73 m 2 /year. Patients diagnosed with CAD were categorized according to the occurrence of rapid decline and/or long plateau as follows: group 1, neither rapid decline nor long plateau; group 2, rapid decline only; group 3, long plateau only; and group 4, both rapid decline and long plateau. From a total of 81 graft losses, 51 (63%) failed because of CAD, with a median of 9.4 years. Sixteen patients belonged to group 1, 14 to group 2, 12 to group 3, and nine to group 4. Mean graft survival times in the four groups were 7.7 ± 1.1, 6.1 ± 3.1, 16.2 ± 2.5, and 10.8 ± 3.6 years, respectively (P < .001). There were significant differences among groups in donor age, year of transplantation, mean eGFR at baseline, and acute rejection rate after transplantation. The results indicate that this cohort of kidney transplant recipients who had CAD comprised subgroups with different clinical courses. Copyright © 2016 Elsevier Inc. All rights reserved.

Recurrent AA Amyloidosis Combined With Chronic Active Antibody-mediated Rejection After Kidney Transplantation.

PubMed

Yeo, Min-Kyung; Ham, Young Rok; Choi, Song-Yi; Lee, Yong-Moon; Park, Moon Hyang; Suh, Kwang-Sun

2017-07-01

Kidney transplantation for amyloidosis remains a contentious issue. Recurrence of amyloidosis is one of the risks of transplantation. Chronic active antibody-mediated rejection is an important cause of chronic allograft dysfunction. A 47-year-old woman underwent kidney transplantation due to renal AA amyloidosis with unknown etiology. Six years posttransplantation, a kidney biopsy showed AA amyloidosis with chronic active antibody-mediated rejection. Donor-specific antibody class II was positive. The patient underwent intravenous plasmapheresis and treatment with rituximab and colchicine. The relationship between recurrence of amyloidosis and rejection was not obvious. Clinical characteristics of kidney transplantation for AA amyloidosis were subjected to literature review and 315 cases were identified. The incidence of amyloidosis recurrence and acute and chronic rejection rates were 15%, 15%, and 8%, respectively. Five-year patient and graft survival rates were 77% and 82%, respectively. Clinical courses of kidney transplantation in AA amyloidosis were, thus, identified.

Detection of cytomegalovirus (CMV) antigens in kidney biopsies and transplant nephrectomies as a marker for renal graft dysfunction.

PubMed

Gerstenkorn, C; Robertson, H; Mohamed, M A; O'Donnell, M; Ali, S; Talbot, D

2000-11-01

Chronic rejection accounts for the greatest loss of renal allografts. HLA mismatching has been minimised by organ allocation and new immunosuppressive drugs have been employed, but the average cadaveric graft survival still does not exceed 12 years. Though the aetiology is multifactorial, one contributory factor for this condition is cytomegalovirus (CMV). Detection of CMV in kidney biopsies and sera can diagnose and monitor this inflammatory event and define its role in chronic nephropathy. Twenty five biopsies taken at the time of transplantation, 10 biopsies for graft dysfunction and tissue blocks from 20 explanted kidney grafts were collected and investigated for CMV antigens by immunohistochemistry. Tissue samples were snap frozen and cryostat sections were incubated with monoclonal antibodies for CMV antigens followed by immunoperoxidase staining. In 12 out of 20 transplant nephrectomies CMV antigens were found. Only two of these patients had clinical CMV disease. Time 0 biopsies from CMV seronegative donors (n = 11) and CMV seropositive donors (n = 14) were negative for CMV antigens. The prevalence of CMV antigens in grafts lost due to chronic rejection was 60%. These antigens were not found within the time 0 biopsies, but were detected in 30% of biopsies taken at the time of clinical graft dysfunction. CMV appears to contribute to chronic rejection even without clinical disease.

Inhibition of WISE preserves renal allograft function.

PubMed

Qian, Xueming; Yuan, Xiaodong; Vonderfecht, Steven; Ge, Xupeng; Lee, Jae; Jurisch, Anke; Zhang, Li; You, Andrew; Fitzpatrick, Vincent D; Williams, Alexia; Valente, Eliane G; Pretorius, Jim; Stevens, Jennitte L; Tipton, Barbara; Winters, Aaron G; Graham, Kevin; Harriss, Lindsey; Baker, Daniel M; Damore, Michael; Salimi-Moosavi, Hossein; Gao, Yongming; Elkhal, Abdallah; Paszty, Chris; Simonet, W Scott; Richards, William G; Tullius, Stefan G

2013-01-01

Wnt-modulator in surface ectoderm (WISE) is a secreted modulator of Wnt signaling expressed in the adult kidney. Activation of Wnt signaling has been observed in renal transplants developing interstitial fibrosis and tubular atrophy; however, whether WISE contributes to chronic changes is not well understood. Here, we found moderate to high expression of WISE mRNA in a rat model of renal transplantation and in kidneys from normal rats. Treatment with a neutralizing antibody against WISE improved proteinuria and graft function, which correlated with higher levels of β-catenin protein in kidney allografts. In addition, treatment with the anti-WISE antibody reduced infiltration of CD68(+) macrophages and CD8(+) T cells, attenuated glomerular and interstitial injury, and decreased biomarkers of renal injury. This treatment reduced expression of genes involved in immune responses and in fibrogenic pathways. In summary, WISE contributes to renal dysfunction by promoting tubular atrophy and interstitial fibrosis.

Splicing alterations in human renal allografts: detection of a new splice variant of protein kinase Par1/Emk1 whose expression is associated with an increase of inflammation in protocol biopsies of transplanted patients.

PubMed

Hueso, Miguel; Beltran, Violeta; Moreso, Francesc; Ciriero, Eva; Fulladosa, Xavier; Grinyó, Josep Maria; Serón, Daniel; Navarro, Estanis

2004-05-24

Protein kinase Emk1/Par1 (GenBank accession no. X97630) has been identified as a regulator of the immune system homeostasis. Since immunological factors are critical for the development of chronic allograft nephropathy (CAN), we reasoned that expression of Par1/Emk1 could be altered in kidney allografts undergoing CAN. In this paper, we have analysed the association among renal allograft lesions and expression of Par1/Emk1, studied by RT-PCR on total RNA from 51 protocol biopsies of transplanted kidneys, five normal kidneys, and five dysfunctional allografts. The most significant result obtained has been the detection of alterations in the normal pattern of alternative splicing of the Par1/Emk1 transcript, alterations that included loss of expression of constitutively expressed isoforms, and the inclusion of a cryptic exon to generate a new Emk1 isoform (Emk1C). Expression of Emk1C was associated with an increase in the extension of the interstitial infiltrate (0.88+/-0.33 in Emk1C([+]) vs. 0.41+/-0.50 in Emk1C([-]); P<0.011), and with a trend to display higher interstitial scarring (0.66+/-0.70 vs. 0.29+/-0.52; P=0.09) in protocol biopsies when evaluated according to the Banff schema. Moreover, a higher mean arterial pressure (MAP) was also observed (110+/-11 vs. 99+/-11 mm Hg; P=0.012). From these results we propose that Par1/Emk1 could have a role in the development of CAN in kidney allografts.

Histopathological Findings Associated With Gastroesophageal Reflux Disease and Aspiration After Lung Transplantation: Initial Brazilian Single-Center Experience.

PubMed

Carraro, R M; Nascimento, E C T; Szachnowicz, S; Camargo, P C L B; Campos, S V; Afonso, J E; Samano, M N; Pêgo-Fernandes, P M; Dolhnikoff, M; Teixeiraa, R H O B; Costa, A N

2017-05-01

Gastro-esophageal reflux disease (GERD) and broncho-aspiration (BA) are known to increase the risk for chronic lung allograft dysfunction (CLAD). However, specific lung injury mechanisms are not clearly known. The objective of the study was to describe histopathological findings in surveillance lung transbronchial biopsies that can be correlated with episodes of BA in the lung allograft. This retrospective analysis of surveillance transbronchial biopsies was performed in lung transplant recipients, with available data of broncho-alveolar fluid (cultures and cytology), lung function parameters, and esophageal functional tests. Were analyzed 11 patients, divided into 3 groups: (1) GERD group: 4 patients with GERD and CLAD diagnosis; (2) control group: 2 patients without GERD or CLAD; and (3) BA group: 5 patients with foreign material in lung biopsies. A histopathological pattern of neutrophilic bronchitis (NB) was present in 4 of 4 cases in the GERD group and in 1 of 5 cases in the BA group in 2 or more biopsy samples; culture samples were all negative; the 5 NB-positive patients developed CLAD and died (3/5) or needed re-transplantation (2/5). The other 3 patients in the BA group had GERD without NB or CLAD. Both patients in the control group had transient NB in biopsies with positive cultures but remained free of CLAD. Surveillance transbronchial biopsies may provide useful information other than the evaluation of acute cellular rejection and can help to identify high-risk patients for allograft dysfunction related to gastro-esophageal reflux. Copyright © 2017 Elsevier Inc. All rights reserved.

Chronic aspiration of gastric fluid induces the development of obliterative bronchiolitis in rat lung transplants.

PubMed

Li, B; Hartwig, M G; Appel, J Z; Bush, E L; Balsara, K R; Holzknecht, Z E; Collins, B H; Howell, D N; Parker, W; Lin, S S; Davis, R D

2008-08-01

Long-term survival of a pulmonary allograft is currently hampered by obliterative bronchiolitis (OB), a form of chronic rejection that is unique to lung transplantation. While tracheobronchial aspiration from gastroesophageal reflux disease (GERD) has clinically been associated with OB, no experimental model exists to investigate this problem. Using a WKY-to-F344 rat orthotopic left lung transplant model, the effects of chronic aspiration on pulmonary allograft were evaluated. Recipients received cyclosporine with or without 8 weekly aspirations of gastric fluid into the allograft. Six (66.7%) of 9 allografts with aspiration demonstrated bronchioles with surrounding monocytic infiltrates, fibrosis and loss of normal lumen anatomy, consistent with the development of OB. In contrast, none of the allografts without aspiration (n = 10) demonstrated these findings (p = 0.002). Of the grafts examined grossly, 83% of the allografts with chronic aspiration but only 20% without aspiration appeared consolidated (p = 0.013). Aspiration was associated with increased levels of IL-1 alpha, IL-1 beta, IL-6, IL-10, TNF-alpha and TGF-beta in BAL and of IL-1 alpha, IL-4 and GM-CSF in serum. This study provides experimental evidence linking chronic aspiration to the development of OB and suggests that strategies aimed at preventing aspiration-related injuries might improve outcomes in clinical lung transplantation.

Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes

PubMed Central

Naesens, Maarten; Khatri, Purvesh; Li, Li; Sigdel, Tara K.; Vitalone, Matthew J.; Chen, Rong; Butte, Atul J.; Salvatierra, Oscar; Sarwal, Minnie M.

2015-01-01

The degree of progressive chronic histological damage is associated with long-term renal allograft survival. In order to identify promising molecular targets for timely intervention, we examined renal allograft protocol and indication biopsies from 120 low-risk pediatric and adolescent recipients by whole-genome microarray expression profiling. In data-driven analysis, we found a highly regulated pattern of adaptive and innate immune gene expression that correlated with established or ongoing histological chronic injury, and also with development of future chronic histological damage, even in histologically pristine kidneys. Hence, histologically unrecognized immunological injury at a molecular level sets the stage for the development of chronic tissue injury, while the same molecular response is accentuated during established and worsening chronic allograft damage. Irrespective of the hypothesized immune or nonimmune trigger for chronic allograft injury, a highly orchestrated regulation of innate and adaptive immune responses was found in the graft at the molecular level. This occurred months before histologic lesions appear, and quantitatively below the diagnostic threshold of classic T-cell or antibody-mediated rejection. Thus, measurement of specific immune gene expression in protocol biopsies may be warranted to predict the development of subsequent chronic injury in histologically quiescent grafts and as a means to titrate immunosuppressive therapy. PMID:21881554

Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes.

PubMed

Naesens, Maarten; Khatri, Purvesh; Li, Li; Sigdel, Tara K; Vitalone, Matthew J; Chen, Rong; Butte, Atul J; Salvatierra, Oscar; Sarwal, Minnie M

2011-12-01

The degree of progressive chronic histological damage is associated with long-term renal allograft survival. In order to identify promising molecular targets for timely intervention, we examined renal allograft protocol and indication biopsies from 120 low-risk pediatric and adolescent recipients by whole-genome microarray expression profiling. In data-driven analysis, we found a highly regulated pattern of adaptive and innate immune gene expression that correlated with established or ongoing histological chronic injury, and also with development of future chronic histological damage, even in histologically pristine kidneys. Hence, histologically unrecognized immunological injury at a molecular level sets the stage for the development of chronic tissue injury, while the same molecular response is accentuated during established and worsening chronic allograft damage. Irrespective of the hypothesized immune or nonimmune trigger for chronic allograft injury, a highly orchestrated regulation of innate and adaptive immune responses was found in the graft at the molecular level. This occurred months before histologic lesions appear, and quantitatively below the diagnostic threshold of classic T-cell or antibody-mediated rejection. Thus, measurement of specific immune gene expression in protocol biopsies may be warranted to predict the development of subsequent chronic injury in histologically quiescent grafts and as a means to titrate immunosuppressive therapy.

Impact of forced vital capacity loss on survival after the onset of chronic lung allograft dysfunction.

PubMed

Todd, Jamie L; Jain, Rahil; Pavlisko, Elizabeth N; Finlen Copeland, C Ashley; Reynolds, John M; Snyder, Laurie D; Palmer, Scott M

2014-01-15

Emerging evidence suggests a restrictive phenotype of chronic lung allograft dysfunction (CLAD) exists; however, the optimal approach to its diagnosis and clinical significance is uncertain. To evaluate the hypothesis that spirometric indices more suggestive of a restrictive ventilatory defect, such as loss of FVC, identify patients with distinct clinical, radiographic, and pathologic features, including worse survival. Retrospective, single-center analysis of 566 consecutive first bilateral lung recipients transplanted over a 12-year period. A total of 216 patients developed CLAD during follow-up. CLAD was categorized at its onset into discrete physiologic groups based on spirometric criteria. Imaging and histologic studies were reviewed when available. Survival after CLAD diagnosis was assessed using Kaplan-Meier and Cox proportional hazards models. Among patients with CLAD, 30% demonstrated an FVC decrement at its onset. These patients were more likely to be female, have radiographic alveolar or interstitial changes, and histologic findings of interstitial fibrosis. Patients with FVC decline at CLAD onset had significantly worse survival after CLAD when compared with those with preserved FVC (P < 0.0001; 3-yr survival estimates 9% vs. 48%, respectively). The deleterious impact of CLAD accompanied by FVC loss on post-CLAD survival persisted in a multivariable model including baseline demographic and clinical factors (P < 0.0001; adjusted hazard ratio, 2.73; 95% confidence interval, 1.86-4.04). At CLAD onset, a subset of patients demonstrating physiology more suggestive of restriction experience worse clinical outcomes. Further study of the biologic mechanisms underlying CLAD phenotypes is critical to improving long-term survival after lung transplantation.

Has the survival of the graft improved after renal transplantation in the era of modern immunosuppression?

PubMed

Moreso, Francesc; Hernández, Domingo

2013-01-18

The introduction of new immunosuppressant drugs in recent years has allowed for a reduction in acute rejection rates along with highly significant improvements in short-term kidney transplantation results. Nonetheless, this improvement has not translated into such significant changes in long-term results. In this manner, late graft failure continues to be a frequent cause of readmission onto dialysis programmes and re-entry onto the waiting list. Multiple entities of immunological and non-immunological origin act together and lead to chronic allograft dysfunction. The characteristics of the transplanted organ are a greater determinant of graft survival, and although various algorithms have been designed as a way of understanding the risk of the transplant organ and assigning the most adequate recipient accordingly. They are applied in the clinical setting only under exceptional circumstances. Characterising, for each patient, the immune factors (clinical and subclinical rejection, reactivation of dormant viral infections, adherence to treatment) and non-immune factors (hypertension, diabetes, anaemia, dyslipidaemia) that contribute to chronic allograft dysfunction could allow us to intervene more effectively as a way of delaying the progress of such processes. Therefore, identifying the causes of graft failure and its risk factors, applying predictive models, and intervening in causal factors could constitute strategies for improving kidney transplantation results in terms of survival. This review analyses some of the evidences conditioning graft failure as well as related therapeutic and prognostic aspects: 1) magnitude of the problem and causes of graft failure; 2) identification of graft failure risk factors; 3) therapeutic strategies for reducing graft failure, and; 4) graft failure prediction.

Suicidal hanging donors for lung transplantation

PubMed Central

Ananiadou, Olga; Schmack, Bastian; Zych, Bartlomiej; Sabashnikov, Anton; Garcia-Saez, Diana; Mohite, Prashant; Weymann, Alexander; Mansur, Ashham; Zeriouh, Mohamed; Marczin, Nandor; De Robertis, Fabio; Simon, Andre Rüdiger; Popov, Aron-Frederik

2018-01-01

Abstract In the context of limited donor pool in cardiothoracic transplantation, utilization of organs from high risk donors, such as suicidal hanging donors, while ensuring safety, is under consideration. We sought to evaluate the outcomes of lung transplantations (LTx) that use organs from this group. Between January 2011 and December 2015, 265 LTx were performed at our center. Twenty-two recipients received lungs from donors after suicidal hanging (group 1). The remaining 243 transplantations were used as a control (group 2). Analysis of recipient and donor characteristics as well as outcomes was performed. No statistically significant difference was found in the donor characteristics between analyzed groups, except for higher incidence of cardiac arrest, younger age and smoking history of hanging donors (P < .001, P = .022 and P = .0042, respectively). Recipient preoperative and perioperative characteristics were comparable. Postoperatively in group 1 there was a higher incidence of extracorporeal life support (27.3 vs 9.1%, P = .019). There were no significant differences in chronic lung allograft dysfunction-free survival between group 1 and 2: 92.3 vs 94% at 1 year and 65.9 vs 75.5% at 3 years (P = .99). The estimated cumulative survival rate was also similar between groups: 68.2 vs 83.2% at 1 year and 68.2% versus 72% at 3 years (P = .3758). Hanging as a donor cause of death is not associated with poor mid-term survival or chronic lung allograft dysfunction following transplantation. These results encourage assessment of lungs from hanging donors, and their consideration for transplantation. PMID:29620623

Monocyte-secreted inflammatory cytokines are associated with transplant glomerulopathy in renal allograft recipients.

PubMed

De Serres, Sacha A; Vadivel, Nidyanandh; Mfarrej, Bechara G; Grafals, Monica; DeJoseph, Maura; Dyer, Christine; Magee, Ciara N; Chandraker, Anil; Gallon, Lorenzo G; Najafian, Nader

2011-03-15

Although there is ample evidence about the role of adaptive immunity in the development of chronic allograft dysfunction, little is known about the contribution of innate immunity to this process. Herein, we studied the relationship between inflammation, chronic biopsy scores, and anti-human leukocyte antigen (HLA) circulating alloantibodies in a cohort of 57 patients recruited at our center. Available biopsies (n=27) were graded for chronic lesion scores according to Banff criteria. The production of cytokines by peripheral blood mononuclear cells after 48 hr of culture under resting conditions was quantified by Luminex. Tumor necrosis factor (TNF)-α secretion assay and depletion studies were used to identify the source of these cytokines. There was a high correlation between the levels of interleukin (IL)-1β, IL-6, and TNF-α (r>0.8, P<0.001 for all correlations). The levels of these cytokines were associated with transplant glomerulopathy (IL-1β, P=0.019; IL-6, P=0.015; and TNF-α, P=0.006) but not with other chronic lesions or anti-HLA circulating alloantibodies. TNF-α was predominantly secreted by monocytes (percent of TNF-α secreting cells: 20.4±4.8 vs. 1.2±0.5 vs. 1.4±0.6 vs. 1.7±0.5 for CD14, CD4, CD8, and CD19 cells, respectively; all P<0.01 vs. CD14). The levels of all three proinflammatory cytokines were significantly reduced after monocyte depletion. Intriguingly, cytokine levels increased after ex vivo depletion of regulatory T cells (all P<0.001). Taken together, these data suggest that in vivo-activated monocytes in peripheral blood spontaneously secrete proinflammatory cytokines in renal allograft recipients with transplant glomerulopathy and seem to be under the regulation of functional regulatory T cells in this setting.

Role of humoral immune reactions as target for antirejection therapy in recipients of a spousal-donor kidney graft.

PubMed

Böhmig, G A; Regele, H; Säemann, M D; Exner, M; Druml, W; Kovarik, J; Hörl, W H; Zlabinger, G J; Watschinger, B

2000-04-01

Excellent graft outcome has been reported for spousal-donor kidney transplantation. In husband-to-wife transplantation, however, a tendency toward inferior graft survival has been described for recipients who were previously pregnant. In our series of spousal-kidney transplantations (nine transplantations; three female recipients), actual graft survival is 100% (median observation time, 339 days). Five patients experienced early allograft rejection. In four transplant recipients, rejection was easily reversible by conventional antirejection therapy. In a multiparous recipient, however, mild interstitial allograft rejection associated with early graft dysfunction was resistant to anticellular treatment (antilymphocyte antibody, tacrolimus rescue therapy). The particular finding of polymorphonuclear neutrophils in peritubular capillaries and the finding of diffuse capillary deposits of the complement split product, C4d, in a posttransplantation biopsy specimen suggested a role of antibody-mediated graft injury. Retrospective flow cytometry cross-matching showed the presence of preformed immunoglobulin G (IgG) antibodies to HLA class I antigens that were not detectable by pretransplantation lymphocytotoxic cross-match testing or screening for panel reactive antibodies. After transplantation, however, complement-fixing antibodies, also presumably triggered by reexposure to spousal-donor HLA antigens, could be detected in the patient's serum. These findings suggested antibody-mediated allograft rejection and led to the initiation of immunoadsorption therapy (14 sessions) with staphylococcal protein A. Selective removal of recipient IgG resulted in complete reversal of graft dysfunction. Our findings suggest that in husband-to-wife transplantation, donor-specific antibodies, presumably triggered by previous pregnancies, might occasionally induce sustained allograft dysfunction. Thus, in this particular setting, a detailed immunologic and histopathologic work-up regarding antibody-mediated allograft dysfunction is warranted because immunoadsorption may be a highly effective treatment modality.

Primary graft dysfunction of the liver: definitions, diagnostic criteria and risk factors.

PubMed

Neves, Douglas Bastos; Rusi, Marcela Balbo; Diaz, Luiz Gustavo Guedes; Salvalaggio, Paolo

2016-01-01

Primary graft dysfunction is a multifactorial syndrome with great impact on liver transplantation outcomes. This review article was based on studies published between January 1980 and June 2015 and retrieved from PubMed database using the following search terms: "primary graft dysfunction", "early allograft dysfunction", "primary non-function" and "liver transplantation". Graft dysfunction describes different grades of graft ischemia-reperfusion injury and can manifest as early allograft dysfunction or primary graft non-function, its most severe form. Donor-, surgery- and recipient-related factors have been associated with this syndrome. Primary graft dysfunction definition, diagnostic criteria and risk factors differ between studies. RESUMO A disfunção primária do enxerto hepático é uma síndrome multifatorial com grande impacto no resultado do transplante de fígado. Foi realizada uma ampla revisão da literatura, consultando a base de dados PubMed, em busca de estudos publicados entre janeiro de 1980 e junho de 2015. Os termos descritivos utilizados foram: "primary graft dysfunction", "early allograft dysfunction", "primary non-function" e "liver transplantation". A disfunção traduz graus diferentes da lesão de isquemia e reperfusão do órgão, e pode se manifestar como disfunção precoce ou, na forma mais grave, pelo não funcionamento primário do enxerto. Fatores relacionados ao doador, ao transplante e ao receptor contribuem para essa síndrome. Existem definições diferentes na literatura quanto ao diagnóstico e aos fatores de risco associados à disfunção primária.

Hypertension accelerates the pace of chronic graft dysfunction in the rat.

PubMed

Szabo, A; Patschan, O; Kuttler, B; Müller, V; Philipp, T; Rettig, R; Heemann, U

1998-01-01

In this study we compared the effects of hypertension on chronic rejection in a rat model of renal transplantation utilizing genetically normotensive (BBOK) and spontaneously hypertensive rats (SHR). SHR received either a BBOK (BBOK-->SHR) or an SHR (SHR-->SHR) kidney; normotensive isografts served as controls. Before transplantation, SHR recipients were treated with hydralazine (50 mg/kg per day). To prevent acute rejection, an anti-CD4 antibody (3 mg/kg per day for 3 weeks) in combination with cyclosporin A (3 mg/kg per day for 1 week) was given to all groups. Six weeks after transplantation, blood pressure was measured, and the kidneys removed for histological and immunohistological analysis. SHR-->SHR developed a significantly higher blood pressure than BBOK-->SHR. Blood pressure in BBOK-->BBOK was significantly lower than in the other two groups. The degree of glomerulosclerosis was similarly increased in allografted (BBOK-->SHR) and SHR-->SHR kidneys as compared with the BBOK-->BBOK kidneys (P < 0.05). Infiltration of ED-1+ monocyte/macrophages and OX19 pan-T-cells was most pronounced in allografts (BBOK-->SHR) and was also increased in SHR-->SHR as compared with BBOK-->BBOK. Our results indicate that hypertension accelerates the morphological and immunohistological changes characteristic of grafts undergoing chronic rejection. However, our findings support the hypothesis that alloantigen-dependent factors are of greater important.

Fox smell abrogates the effect of herbal odor to prolong mouse cardiac allograft survival.

PubMed

Jin, Xiangyuan; Uchiyama, Masateru; Zhang, Qi; Niimi, Masanori

2014-05-09

Herbal medicines have unique odors, and the act of smelling may have modulatory effects on the immune system. We investigated the effect of olfactory exposure to Tokishakuyaku-san (TJ-23), a Japanese herbal medicine, on alloimmune responses in a murine model of cardiac allograft transplantation. Naïve or olfactory-dysfunctional CBA mice underwent transplantation of a C57BL/6 heart and were exposed to the odor of TJ-23 until rejection. Some naïve CBA recipients of an allograft were given olfactory exposure to Sairei-to (TJ-114), trimethylthiazoline (TMT), individual components of TJ-23, or a TJ-23 preparation lacking one component. Adoptive transfer studies were performed to determine whether regulatory cells were generated. Untreated CBA mice rejected their C57BL/6 allografts acutely, as did olfactory-dysfunctional CBA mice exposed to the odor of TJ-23. CBA recipients of a C57BL/6 heart given olfactory exposure to TJ-23 had significantly prolonged allograft survival, whereas those exposed to the odor of TJ-114, TMT, one component of TJ-23, or TJ-23 lacking a component did not. Secondary allograft recipients that were given, at 30 days after transplantation, either whole splenocytes, CD4+ cells, or CD4+CD25+ cells from primary recipients exposed to the odor of TJ-23 had indefinitely prolonged allograft survival. Prolonged survival of cardiac allografts and generation of regulatory cells was associated with exposure to the odor of TJ-23 in our model. The olfactory area of the brain may have a role in the modulation of immune responses.

The Presence of HLA-E-Restricted, CMV-Specific CD8+ T Cells in the Blood of Lung Transplant Recipients Correlates with Chronic Allograft Rejection.

PubMed

Sullivan, Lucy C; Westall, Glen P; Widjaja, Jacqueline M L; Mifsud, Nicole A; Nguyen, Thi H O; Meehan, Aislin C; Kotsimbos, Tom C; Brooks, Andrew G

2015-01-01

The human cytomegalovirus (CMV) immune evasion protein, UL40, shares an identical peptide sequence with that found in the leader sequence of many human leukocyte antigen (HLA)-C alleles and when complexed with HLA-E, can modulate NK cell functions via interactions with the CD94-NKG2 receptors. However the UL40-derived sequence can also be immunogenic, eliciting robust CD8+ T cell responses. In the setting of solid organ transplantation these T cells may not only be involved in antiviral immunity but also can potentially contribute to allograft rejection when the UL40 epitope is also present in allograft-encoded HLA. Here we assessed 15 bilateral lung transplant recipients for the presence of HLA-E-restricted UL40 specific T cells by tetramer staining of peripheral blood mononuclear cells (PBMC). UL40-specific T cells were observed in 7 patients post-transplant however the magnitude of the response varied significantly between patients. Moreover, unlike healthy CMV seropositive individuals, longitudinal analyses revealed that proportions of such T cells fluctuated markedly. Nine patients experienced low-grade acute cellular rejection, of which 6 also demonstrated UL40-specific T cells. Furthermore, the presence of UL40-specific CD8+ T cells in the blood was significantly associated with allograft dysfunction, which manifested as Bronchiolitis Obliterans Syndrome (BOS). Therefore, this study suggests that minor histocompatibility antigens presented by HLA-E can represent an additional risk factor following lung transplantation.

Annual literature review of donor-specific HLA antibodies after organ transplantation.

PubMed

Kaneku, Hugo

2011-01-01

The literature review of post-transplant DSA published in 2011 shows: Observations after kidney and lung transplant in non-sensitized transplant recipients show that monitoring post-transplant HLA antibodies offers limited benefit in predicting acute rejection episodes. It remains to be seen if a different monitoring schedule and/ or studying other organs may show otherwise. Nevertheless, others have shown that monitoring post-transplant antibodies does identify patients at higher risk for chronic rejection. Studies in kidney, heart, and liver patients transplanted in the presence of preformed DSA show that detecting these antibodies early after transplant identifies a group of patients with greater risk for allograft dysfunction. New and larger studies using bortezomib and eculizumab to treat acute antibody-mediated rejection confirm earlier observations that these two therapies are effective in treating and preventing rejections. In general, identification of HLAantibodies and DSA after transplant is associated with higher rates of rejection and poor allograft survival in all organs examined. IgM antibodies appear to play an important role after lung transplants.

Serum creatinine detection by a conducting-polymer-based electrochemical sensor to identify allograft dysfunction.

PubMed

Wei, Fang; Cheng, Scott; Korin, Yael; Reed, Elaine F; Gjertson, David; Ho, Chih-ming; Gritsch, H Albin; Veale, Jeffrey

2012-09-18

Kidney transplant recipients who have abnormally high creatinine levels in their blood often have allograft dysfunction secondary to rejection. Creatinine has become the preferred marker for renal dysfunction and is readily available in hospital clinical settings. We developed a rapid and accurate polymer-based electrochemical point-of-care (POC) assay for creatinine detection from whole blood to identify allograft dysfunction. The creatinine concentrations of 19 blood samples from transplant recipients were measured directly from clinical serum samples by the conducting polymer-based electrochemical (EC) sensor arrays. These measurements were compared to the traditional clinical laboratory assay. The time required for detection was <5 min from sample loading. Sensitivity of the detection was found to be 0.46 mg/dL of creatinine with only 40 μL sample in the creatinine concentration range of 0 mg/dL to 11.33 mg/dL. Signal levels that were detected electrochemically correlated closely with the creatinine blood concentration detected by the UCLA Ronald Reagan Medical Center traditional clinical laboratory assay (correlation coefficient = 0.94). This work is encouraging for the development of a rapid and accurate POC device for measuring creatinine levels in whole blood.

Peroxisome Proliferator-Activated Receptor γ Deficiency in T Cells Accelerates Chronic Rejection by Influencing the Differentiation of CD4+ T Cells and Alternatively Activated Macrophages

PubMed Central

Ye, Ping; Cheng, Chao; Wu, Jie; Wang, Sihua; Sun, Yuan; Liu, Zheng; Xie, Aini; Xia, Jiahong

2014-01-01

Background In a previous study, activation of the peroxisome proliferator–activated receptor γ (PPARγ) inhibited chronic cardiac rejection. However, because of the complexity of chronic rejection and the fact that PPARγ is widely expressed in immune cells, the mechanism of the PPARγ - induced protective effect was unclear. Materials and Methods A chronic rejection model was established using B6.C-H-2bm12KhEg (H-2bm12) mice as donors, and MHC II-mismatched T-cell-specific PPARγ knockout mice or wild type (WT) littermates as recipients. The allograft lesion was assessed by histology and immunohistochemistry. T cells infiltrates in the allograft were isolated, and cytokines and subpopulations were detected using cytokine arrays and flow cytometry. Transcription levels in the allograft were measured by RT-PCR. In vitro, the T cell subset differentiation was investigated after culture in various polarizing conditions. PPARγ-deficient regularory T cells (Treg) were cocultured with monocytes to test their ability to induce alternatively activated macrophages (AAM). Results T cell-specific PPARγ knockout recipients displayed reduced cardiac allograft survival and an increased degree of pathology compared with WT littermates. T cell-specific PPARγ knockout resulted in more CD4+ T cells infiltrating into the allograft and altered the Th1/Th2 and Th17/Treg ratios. The polarization of AAM was also reduced by PPARγ deficiency in T cells through the action of Th2 and Treg. PPARγ-deficient T cells eliminated the pioglitazone-induced polarization of AAM and reduced allograft survival. Conclusions PPARγ-deficient T cells influenced the T cell subset and AAM polarization in chronic allograft rejection. The mechanism of PPARγ activation in transplantation tolerance could yield a novel treatment without side effects. PMID:25383620

Fibrosing cholestatic hepatitis after successful interferon and ribavirin therapy for recurrent hepatitis C post living related liver transplantation: a case report.

PubMed

Yamamoto, Takatsugu; Tanaka, Shogo; Uenishi, Takahiro; Kanazawa, Akishige; Kubo, Shoji; Hirohashi, Kazuhiro

2014-12-01

A 33-year-old Japanese man who had suffered from liver cirrhosis due to hepatitis C virus (HCV) underwent living related liver transplantation (LRLT). The allograft was given by his brother, who was healthy with no history of hepatitis or hepatic virus infection. After LRLT, the patient's hepatitis C recurred. Liver biopsy revealed chronic viral hepatitis and no allograft rejection such as shown by portal lymphocytic infiltration or mild bridging fibrosis. Interferon and ribavirin were administered, and sustained viral response (SVR) was obtained. Although serum hepatitis B virus (HBV)-DNA/HCV-RNA polymerase chain reaction found no presence of hepatic virus, the serum examination demonstrated liver dysfunction seven months after SVR. Liver biopsies histopathologically showed portal fibrosis invading to the sinusoids, cholestasis, mild hyperplasia of the cholangioles, and no features of allograft rejection. Fibrosing cholestatic hepatitis (FCH) was diagnosed. The FCH was resistant to treatment and advanced, and the patient died 17 months post-LRLT. Several serum examinations failed to demonstrate the existence of HBV/HCV during the patient's course. FCH is a type of viral hepatitis that is characterized by recurrent viral hepatitis after allograft transplantation. Because SVR obtained by anti-viral therapy commonly resolves FCH, we believe that this patient represented a rare case of FCH. The present case suggests that not only direct viral cytotoxicity, but other factors as well, promote the development of fibrosis and cholestasis. FCH sometimes progresses irreversibly despite the absence of serum viral load. The present case informed us that immediate anti-viral therapy should be initiated when recurrent allograft viral hepatitis is diagnosed.

Long-term outcomes and management of the heart transplant recipient.

PubMed

McCartney, Sharon L; Patel, Chetan; Del Rio, J Mauricio

2017-06-01

Cardiac transplantation remains the gold standard in the treatment of advanced heart failure. With advances in immunosuppression, long-term outcomes continue to improve despite older and higher risk recipients. The median survival of the adult after heart transplantation is currently 10.7 years. While early graft failure and multiorgan system dysfunction are the most important causes of early mortality, malignancy, rejection, infection, and cardiac allograft vasculopathy contribute to late mortality. Chronic renal dysfunction is common after heart transplantation and occurs in up to 68% of patients by year 10, with 6.2% of patients requiring dialysis and 3.7% undergoing renal transplant. Functional outcomes after heart transplantation remain an area for improvement, with only 26% of patients working at 1-year post-transplantation, and are likely related to the high incidence of depression after cardiac transplantation. Areas of future research include understanding and managing primary graft dysfunction and reducing immunosuppression-related complications. Copyright © 2017 Elsevier Ltd. All rights reserved.

Banff schema for grading pancreas allograft rejection: working proposal by a multi-disciplinary international consensus panel.

PubMed

Drachenberg, C B; Odorico, J; Demetris, A J; Arend, L; Bajema, I M; Bruijn, J A; Cantarovich, D; Cathro, H P; Chapman, J; Dimosthenous, K; Fyfe-Kirschner, B; Gaber, L; Gaber, O; Goldberg, J; Honsová, E; Iskandar, S S; Klassen, D K; Nankivell, B; Papadimitriou, J C; Racusen, L C; Randhawa, P; Reinholt, F P; Renaudin, K; Revelo, P P; Ruiz, P; Torrealba, J R; Vazquez-Martul, E; Voska, L; Stratta, R; Bartlett, S T; Sutherland, D E R

2008-06-01

Accurate diagnosis and grading of rejection and other pathological processes are of paramount importance to guide therapeutic interventions in patients with pancreas allograft dysfunction. A multi-disciplinary panel of pathologists, surgeons and nephrologists was convened for the purpose of developing a consensus document delineating the histopathological features for diagnosis and grading of rejection in pancreas transplant biopsies. Based on the available published data and the collective experience, criteria for the diagnosis of acute cell-mediated allograft rejection (ACMR) were established. Three severity grades (I/mild, II/moderate and III/severe) were defined based on lesions known to be more or less responsive to treatment and associated with better- or worse-graft outcomes, respectively. The features of chronic rejection/graft sclerosis were reassessed, and three histological stages were established. Tentative criteria for the diagnosis of antibody-mediated rejection were also characterized, in anticipation of future studies that ought to provide more information on this process. Criteria for needle core biopsy adequacy and guidelines for pathology reporting were also defined. The availability of a simple, reproducible, clinically relevant and internationally accepted schema for grading rejection should improve the level of diagnostic accuracy and facilitate communication between all parties involved in the care of pancreas transplant recipients.

De Novo DQ Donor-Specific Antibodies Are Associated with Chronic Lung Allograft Dysfunction after Lung Transplantation.

PubMed

Tikkanen, Jussi M; Singer, Lianne G; Kim, S Joseph; Li, Yanhong; Binnie, Matthew; Chaparro, Cecilia; Chow, Chung-Wai; Martinu, Tereza; Azad, Sassan; Keshavjee, Shaf; Tinckam, Kathryn

2016-09-01

Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear. To describe the incidence, characteristics, and impact of dnDSA after lung transplantation. We investigated a single-center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis. The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA. dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients.

Suicidal hanging donors for lung transplantation: Is this chapter still closed? Midterm experience from a single center in United Kingdom.

PubMed

Ananiadou, Olga; Schmack, Bastian; Zych, Bartlomiej; Sabashnikov, Anton; Garcia-Saez, Diana; Mohite, Prashant; Weymann, Alexander; Mansur, Ashham; Zeriouh, Mohamed; Marczin, Nandor; De Robertis, Fabio; Simon, Andre Rüdiger; Popov, Aron-Frederik

2018-04-01

In the context of limited donor pool in cardiothoracic transplantation, utilization of organs from high risk donors, such as suicidal hanging donors, while ensuring safety, is under consideration. We sought to evaluate the outcomes of lung transplantations (LTx) that use organs from this group.Between January 2011 and December 2015, 265 LTx were performed at our center. Twenty-two recipients received lungs from donors after suicidal hanging (group 1). The remaining 243 transplantations were used as a control (group 2). Analysis of recipient and donor characteristics as well as outcomes was performed.No statistically significant difference was found in the donor characteristics between analyzed groups, except for higher incidence of cardiac arrest, younger age and smoking history of hanging donors (P < .001, P = .022 and P = .0042, respectively). Recipient preoperative and perioperative characteristics were comparable. Postoperatively in group 1 there was a higher incidence of extracorporeal life support (27.3 vs 9.1%, P = .019). There were no significant differences in chronic lung allograft dysfunction-free survival between group 1 and 2: 92.3 vs 94% at 1 year and 65.9 vs 75.5% at 3 years (P = .99). The estimated cumulative survival rate was also similar between groups: 68.2 vs 83.2% at 1 year and 68.2% versus 72% at 3 years (P = .3758).Hanging as a donor cause of death is not associated with poor mid-term survival or chronic lung allograft dysfunction following transplantation. These results encourage assessment of lungs from hanging donors, and their consideration for transplantation.

Early Focal Segmental Glomerulosclerosis as a Cause of Renal Allograft Primary Nonfunction

PubMed Central

Griffin, Emma J.; Thomson, Peter C.; Kipgen, David; Clancy, Marc; Daly, Conal

2013-01-01

Background. Primary focal segmental glomerulosclerosis (FSGS) is one of the commonest causes of glomerular disease and if left untreated will often progress to established renal failure. In many cases the best treatment option is renal transplantation; however primary FSGS may rapidly recur in renal allografts and may contribute to delayed graft function. We present a case of primary nonfunction in a renal allograft due to biopsy-proven FSGS. Case Report. A 32-year-old man presented with serum albumin of 22 g/L, proteinuria quantified at 12 g/L, and marked peripheral oedema. Renal biopsy demonstrated tip-variant FSGS. Despite treatment, the patient developed progressive renal dysfunction and was commenced on haemodialysis. Cadaveric renal transplantation was undertaken; however this was complicated by primary nonfunction. Renal biopsies failed to demonstrate evidence of acute rejection but did demonstrate clear evidence of FSGS. The patient was treated to no avail. Discussion. Primary renal allograft nonfunction following transplantation is often due to acute kidney injury or acute rejection. Recurrent FSGS is recognised as a phenomenon that drives allograft dysfunction but is not traditionally associated with primary nonfunction. This case highlights FSGS as a potentially aggressive process that, once active in the allograft, may prove refractory to targeted treatment. Preemptive therapies in patients deemed to be at high risk of recurrent disease may be appropriate and should be considered. PMID:23781382

ARFI-based tissue elasticity quantification and kidney graft dysfunction: first clinical experiences.

PubMed

Stock, K F; Klein, B S; Cong, M T Vo; Regenbogen, C; Kemmner, S; Büttner, M; Wagenpfeil, S; Matevossian, E; Renders, L; Heemann, U; Küchle, C

2011-01-01

Beyond the medical history, the clinical exam and lab findings, non-invasive ultrasound parameters such as kidney size and Doppler values (e.g. the resistive index) are important tools assisting clinical decision making in the monitoring of renal allografts. The gold standard for the diagnosis of renal allograft dysfunction remains the renal biopsy; while an invasive procedure, the justifiable necessity for this derives from its definitive nature a requirement beyond the synopses of all non-invasive tools. "Acoustic Radiation Force Impulse Imaging"(ARFI)-quantification is a novel ultrasound-based technology measuring tissue elasticity properties. So far experience related to this new method has not been reported in renal transplant follow-up. The purpose of this study was to evaluate changes in ARFI-measurements between clinically stable renal allografts and biopsy-proven transplant dysfunction. We employed "Virtual Touch™ tissue quantification" (Siemens Acuson, S2000) for the quantitative measurement of tissue stiffness in the cortex of transplant kidneys. We performed initial baseline and later disease-evaluative ultrasound examinations in 8 renal transplant patients in a prospective study design. Patients were first examined during stable allograft function with a routine post-transplant renal ultrasound protocol. A second follow-up examination was carried out on subsequent presentation with transplant dysfunction prior to allograft biopsy and histological evaluation. All patiens were examined using ARFI-quantification (15 measurements/kidney). Resistive indices (RI) were calculated using pulsed-wave Doppler ultrasound, and transplant kidney size was measured on B-mode ultrasound images. All biopsies were evaluated histologically by a reference nephropathologist unaware of the results of the ultrasound studies. Histopathological diagnoses were based on biopsy results, taking clinical and laboratory findings into account. Finally we calculated the relative changes in ARFI-quantification, resistive indices and the absolute change of kidney size on a percentage basis at these defined assessment times and compared the results with the final pathologic diagnosis. Histological results enumerated five cases of acute T-cell-mediated rejection, one case of calcineurin inhibitor toxicity and two cases of acute tubular necrosis. Calcineurin inhibitor toxicity and acute tubular necrosis were subsumed as "other pathologies". Mean ARFI-values showed an average increase of more than 15% percent in transplants with histologically proven acute rejection whereas no increase was seen in transplants with other pathologies. Mean RI-values showed no increase either in the diagnostic group of acute rejection, nor in the group with other pathologies. Kidney size showed a mean absolute increase of 0.5 centimetres in allografts with acute rejection, whereas a mean decrease of 0.17 centimetres was seen in the group with other pathologies. As shown before in other studies, RI values and kidney size are of doubtful utility in the evaluation of kidney allograft dysfunction. ARFI-based elasticity measurement shows promise as a complementary non-invasive parameter in follow-on diagnosis of renal allograft rejection.

Early allograft dysfunction in liver transplantation with donation after cardiac death donors results in inferior survival.

PubMed

Lee, David D; Singh, Amandeep; Burns, Justin M; Perry, Dana K; Nguyen, Justin H; Taner, C Burcin

2014-12-01

Donation after cardiac death (DCD) liver allografts have been associated with increased morbidity from primary nonfunction, biliary complications, early allograft failure, cost, and mortality. Early allograft dysfunction (EAD) after liver transplantation has been found to be associated with inferior patient and graft survival. In a cohort of 205 consecutive liver-only transplant patients with allografts from DCD donors at a single center, the incidence of EAD was found to be 39.5%. The patient survival rates for those with no EAD and those with EAD at 1, 3, and 5 years were 97% and 89%, 79% and 79%, and 61% and 54%, respectively (P = 0.009). Allograft survival rates for recipients with no EAD and those with EAD at 1, 3, and 5 years were 90% and 75%, 72% and 64%, and 53% and 43%, respectively (P = 0.003). A multivariate analysis demonstrated a significant association between the development of EAD and the cold ischemia time [odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.01-1.56, P = 0.037] and hepatocellular cancer as a secondary diagnosis in recipients (OR = 2.26, 95% CI = 1.11-4.58, P = 0.025). There was no correlation between EAD and the development of ischemic cholangiopathy. In conclusion, EAD results in inferior patient and graft survival in recipients of DCD liver allografts. Understanding the events that cause EAD and developing preventive or early therapeutic approaches should be the focus of future investigations. © 2014 American Association for the Study of Liver Diseases.

Donor information based prediction of early allograft dysfunction and outcome in liver transplantation.

PubMed

Hoyer, Dieter P; Paul, Andreas; Gallinat, Anja; Molmenti, Ernesto P; Reinhardt, Renate; Minor, Thomas; Saner, Fuat H; Canbay, Ali; Treckmann, Jürgen W; Sotiropoulos, Georgios C; Mathé, Zoltan

2015-01-01

Poor initial graft function was recently newly defined as early allograft dysfunction (EAD) [Olthoff KM, Kulik L, Samstein B, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl 2010; 16: 943]. Aim of this analysis was to evaluate predictive donor information for development of EAD. Six hundred and seventy-eight consecutive adult patients (mean age 51.6 years; 60.3% men) who received a primary liver transplantation (LT) (09/2003-12/2011) were included. Standard donor data were correlated with EAD and outcome by univariable/multivariable logistic regression and Cox proportional hazards to identify prognostic donor factors after adjustment for recipient confounders. Estimates of relevant factors were utilized for construction of a new continuous risk index to develop EAD. 38.7% patients developed EAD. 30-day survival of grafts with and without EAD was 59.8% and 89.7% (P < 0.0001). 30-day survival of patients with and without EAD was 68.5% and 93.1% (P < 0.0001) respectively. Donor body mass index (P = 0.0112), gGT (P = 0.0471), macrosteatosis (P = 0.0006) and cold ischaemia time (CIT) (P = 0.0031) were predictors of EAD. Internal cross validation showed a high predictive value (c-index = 0.622). Early allograft dysfunction correlates with early results of LT and can be predicted by donor data only. The newly introduced risk index potentially optimizes individual decisions to accept/decline high risk organs. Outcome of these organs might be improved by shortening CIT. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Protective effects of FTY720 on chronic allograft nephropathy by reducing late lymphocytic infiltration.

PubMed

Wang, Minghui; Liu, Shanying; Ouyang, Nengtai; Song, Erwei; Lutz, Jens; Heemann, Uwe

2004-09-01

Lymphocytic infiltration is obvious throughout early and late stages of chronic allograft nephropathy. Early infiltrating lymphocytes are involved in initial insults to kidney allografts, but the contribution of late infiltration to long-term allograft attrition is still controversial. Early application of FTY720 reduced the number of graft infiltrating lymphocytes, and inhibited acute rejection. The present study investigated the potential of FTY720 to reduce the number of infiltrating lymphocytes even at a late stage, and, thus, slow the pace of chronic allograft nephropathy. Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients with an initial 10-day course of cyclosporine A (1.5 mg/kg/day). FTY720, at a dose of 0.5 mg/kg/day, or vehicle was administered to recipients either from weeks 12 to 24 or from 20 to 24 after transplantation. Animals were harvested 24 weeks after transplantation for histologic, immunohistologic, and molecular analysis. FTY720, either initiated at 12 or 20 weeks after transplantation, reduced urinary protein excretion, and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, and intimal proliferation of graft arteries at 24 weeks after transplantation. Furthermore FTY720 markedly suppressed lymphocyte infiltration and decreased mRNA levels of interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and platelet-derived growth factor-B (PDGF-B) but enhanced the number of apoptotic cells in grafts. FTY720 ameliorated chronic allograft nephropathy even at advanced stages. Furthermore, our data suggest that this effect was achieved by a reduction of graft infiltrating lymphocytes.

Portal-endocrine and gastric-exocrine drainage technique of pancreas transplantation provides an easy access for evaluation of pancreatic allograft dysfunction: six-year experience at a single center.

PubMed

Zibari, Gazi B; Fallahzadeh, Mohammad Kazem; Hamidian Jahromi, Alireza; Zakhary, Joseph; Dies, David; Wellman, Greg; Singh, Neeraj; Shokouh-Amiri, Hosein

2014-01-01

The aim of this study is to report our six-year experience with portal-endocrine and gastric-exocrine drainage technique of pancreatic transplantation, which was first developed and implemented at our center in 2007. In this study, the outcomes of all patients at our center who had pancreas transplantation with portal-endocrine and gastric-exocrine drainage technique were evaluated. From October 2007 to November 2013, 38 patients had pancreas transplantation with this technique - 31 simultaneous kidney pancreas and seven pancreas alone. Median duration of follow-up was 3.8 years. One-, three-, and five-year patient and graft survival rates were 94%, 87%, 70% and 83%, 65%, 49%, respectively. For pancreas allograft dysfunction evaluation, 51 upper endoscopies were performed in 14 patients; donor duodenal biopsies were successfully obtained in 45 (88%). We detected nine episodes of acute rejection (eight patients) and seven episodes of cytomegalovirus (CMV) duodenitis (six patients). No patient developed any complication due to upper endoscopy. Portal-endocrine and gastric-exocrine drainage technique of pancreas transplantation provides lifelong easy access to the transplanted duodenum for evaluation of pancreatic allograft dysfunction.

Capillary Thrombosis in the Skin: A Pathologic Hallmark of Severe/Chronic Rejection of Human Vascularized Composite Tissue Allografts?

PubMed

Kanitakis, Jean; Petruzzo, Palmina; Gazarian, Aram; Karayannopoulou, Georgia; Buron, Fannie; Dubois, Valérie; Thaunat, Olivier; Badet, Lionel; Morelon, Emmanuel

2016-04-01

Vascularized composite tissue allografts (VCA) can undergo rejection, manifesting pathologically with skin changes that form the basis of the Banff 2007 classification of VCA rejection. We have followed 10 human VCA recipients (7 with hand allografts, 3 with face allografts) for pathological signs of rejection. All of them developed episodes of acute rejection. Two patients with hand allografts presented in some of their skin biopsies an as yet unreported pathological finding in human VCA, consisting of capillary thromboses (CT) in the upper dermis. Capillary thrombosis was associated with other typical changes of grade II to III VCA rejection, namely, perivascular T cell infiltrates, but not with vascular C4d deposits (in formalin-fixed tissue). Clinically, the lesions presented as red or violaceous (lichenoid) cutaneous maculopapules. The first patient had several episodes of acute rejection during the 7-year follow-up. The second patient developed donor-specific antibodies; some months after CT were first observed, he developed chronic rejection leading to partial amputation of the allograft. Pathological examination of the skin showed graft vasculopathy and occasional C4d deposits in cutaneous capillaries. Capillary thrombosis seems to be a novel pathologic finding associated with human VCA rejection. Although its mechanism (immunologic vs nonimmunologic) remains unclear, this finding could carry an unfavorable prognostic significance, prompting close monitoring of the patients for severe/chronic rejection.

The prognostic importance of CXCR3 chemokine during organizing pneumonia on the risk of chronic lung allograft dysfunction after lung transplantation

PubMed Central

Weigt, S. Samuel; Li, Ning; Palchevskiy, Vyacheslav; Derhovanessian, Ariss; Saggar, Rajan; Sayah, David M.; Huynh, Richard H.; Gregson, Aric L.; Fishbein, Michael C.; Ardehali, Abbas; Ross, David J.; Lynch, Joseph P.; Elashoff, Robert M.; Belperio, John A.

2017-01-01

Rationale Since the pathogenesis of chronic lung allograft dysfunction (CLAD) remains poorly defined with no known effective therapies, the identification and study of key events which increase CLAD risk is a critical step towards improving outcomes. We hypothesized that bronchoalveolar lavage fluid (BALF) CXCR3 ligand concentrations would be augmented during organizing pneumonia (OP) and that episodes of OP with marked chemokine elevations would be associated with significantly higher CLAD risk. Methods All transbronchial biopsies (TBBX) from patients who received lung transplantation between 2000 to 2010 were reviewed. BALF concentrations of the CXCR3 ligands (CXCL9, CXCL10 and CXCL11) were compared between episodes of OP and “healthy” biopsies using linear mixed-effects models. The association between CXCR3 ligand concentrations during OP and CLAD risk was evaluated using proportional hazards models with time-dependent covariates. Results There were 1894 bronchoscopies with TBBX evaluated from 441 lung transplant recipients with 169 (9%) episodes of OP and 907 (49%) non-OP histopathologic injuries. 62 (37%) episodes of OP were observed during routine surveillance bronchoscopy. Eight hundred thirty-eight (44%) TBBXs had no histopathology and were classified as “healthy” biopsies. There were marked elevations in BALF CXCR3 ligand concentrations during OP compared with “healthy” biopsies. In multivariable models adjusted for other injury patterns, OP did not significantly increase the risk of CLAD when BAL CXCR3 chemokine concentrations were not taken into account. However, OP with elevated CXCR3 ligands markedly increased CLAD risk in a dose-response manner. An episode of OP with CXCR3 concentrations greater than the 25th, 50th and 75th percentiles had HRs for CLAD of 1.5 (95% CI 1.0–2.3), 1.9 (95% CI 1.2–2.8) and 2.2 (95% CI 1.4–3.4), respectively. Conclusions This study identifies OP, a relatively uncommon histopathologic finding after lung transplantation, as a major risk factor for CLAD development when considered in the context of increased allograft expression of interferon-γ inducible ELR- CXC chemokines. We further demonstrate for the first time, the prognostic importance of BALF CXCR3 ligand concentrations during OP on subsequent CLAD risk. PMID:28686641

Long-term tolerance to kidney allografts in a preclinical canine model.

PubMed

Kuhr, Christian S; Yunusov, Murad; Sale, George; Loretz, Carol; Storb, Rainer

2007-08-27

Durable immune tolerance supporting vascularized allotransplantation offers the possibility of extending graft survival and avoiding harmful complications of chronic immunosuppression. Immune tolerance to renal allografts was induced in a preclinical canine model through engraftment of donor hematopoietic cells using a combination of low-dose total body irradiation and a short course of immunosuppression. Subsequently, donor renal allografts were transplanted accompanied by bilateral native nephrectomies. With 5-year follow up, we found normal renal function in all recipients and no histological evidence of acute or chronic rejection. This tolerance does not extend universally to donor skin grafts, however, with two of four animals rejecting delayed donor skin grafts. Hematopoietic chimerism produces durable and robust immune tolerance to kidney allografts, although incomplete tolerance to donor skin grafting.

Recurrence of clinically significant hepatitis A following liver transplantation for fulminant hepatitis A.

PubMed

Eisenbach, Christoph; Longerich, Thomas; Fickenscher, Helmut; Schalasta, Gunnar; Stremmel, Wolfgang; Encke, Jens

2006-01-01

We report hepatitis A virus (HAV) infection of a liver allograft following transplantation for fulminant liver failure due to HAV infection. This rare condition has been described in only three patients to date. After liver transplantation allograft function was good, but starting 80 days after transplantation, episodes of acute graft dysfunction were observed. To elucidate the reason for acute hepatic dysfunction a large number of differential diagnoses were tested. HAV RNA was undetectable for more than 80 days after transplantation. Detection of genomic HAV RNA by RT-PCR in serum and stool at the time of graft dysfunction led to the diagnosis of recurrent HAV infection. We suggest that the risk of HAV reinfection after liver transplantation may be far higher than expected as results may be misinterpreted as rejection episodes.

Urinary C‑X‑C motif chemokine 13 is a noninvasive biomarker of antibody‑mediated renal allograft rejection.

PubMed

Chen, Dajin; Zhang, Jian; Peng, Wenhan; Weng, Chunhua; Chen, Jianghua

2018-06-22

Noninvasive monitoring methods of immune status are preferred by transplant recipients. The present study investigated whether urinary C‑X‑C motif chemokine 13 (CXCL13) had the potential to reflect ongoing immune processes within renal allografts. Using an ELISA assay, the level of urinary CXCL13 was quantified in a total of 146 renal allograft recipients and 40 healthy controls at scheduled intervals and at the time of the indicated or protocol biopsy. The results of the present study revealed that urinary CXCL13/creatinine (Cr) was lower in normal transplants compared with in those with acute tubular necrosis (ATN; P=0.001), chronic allograft nephropathy (CAN; P=0.01), and acute rejection (AR; P<0.0001), which was associated with a good diagnostic performance for AR [area under the curve (AUC)=0.818, P<0.0001). In addition, urinary CXCL13/Cr levels in patients with AR were also higher than that of patients with graft dysfunction but no rejection, including ATN and CAN (P=0.034). Notably, urinary CXCL13 distinguished between acute antibody‑mediated rejection (ABMR) and acute cellular rejection, with an AUC of 0.856. Furthermore, patients with steroid‑resistant AR exhibited significantly increased urinary CXCL13/Cr levels than patients with reversible AR (P=0.001). Additionally, elevated levels of urinary CXCL13/Cr within the first month of transplant were predictive of graft function at 3 and 6 months (P=0.044 and P=0.04, respectively). Collectively, the findings of the present study indicated that the noninvasive investigation of urinary CXCL13/Cr may be valuable for the detection of AR, particularly ABMR. In addition, high urinary CXCL13/Cr levels predicted a poor response to steroid treatment and compromised graft function.

Development of injury in a rat model of chronic renal allograft rejection: effect of dietary protein restriction.

PubMed

Bombas, A; Stein-Oakley, A N; Baxter, K; Thomson, N M; Jablonski, P

1999-01-01

Non-allogeneic factors such as increased nephron "workload" may contribute to chronic renal allograft rejection. Reducing dietary protein from 20% to 8% was tested in a model of chronic rejection: Dark Agouti kidney to Albino Surgery recipient, "tolerised" by previous donor blood transfusions. Survival, weight gain, serum creatinine concentration and creatinine clearance were similar for both groups at all times. Urinary protein was significantly (P < 0.05) lower in the low-protein (LP) group 1 month after transplantation. After 3 and 6 months, both groups demonstrated mild chronic rejection. After 6 months, tubular atrophy was significantly (P < 0.05) less in the LP group and interstitial fibrosis was marginally reduced. Glomerular hypertrophy, glomerular sclerosis, tubular dilatation, leucocyte infiltration, adhesion molecule expression and TGF-beta1 mRNA expression were similarly increased in both groups. Thus, reducing dietary protein to 8% lowered urinary protein, but did not significantly affect the development of chronic rejection in renal allografts beyond affording a degree of protection from tubulointerstitial damage.

Glomerular enlargement assessed by paired donor and early protocol renal allograft biopsies.

PubMed

Alperovich, Gabriela; Maldonado, Rafael; Moreso, Francesc; Fulladosa, Xavier; Grinyó, Josep M; Serón, Daniel

2004-04-01

The aim of the study was to evaluate the evolution of glomerular volume 4 months after transplantation. Mean glomerular volume (Vg) was estimated according to the Weibel and Gomez method in a donor and a protocol biopsy done at 139 +/- 58 d in 41 stable grafts. Biopsies were also evaluated according to the Banff schema. Vg increased after transplantation from 4.1 +/- 1.4 to 5.1 +/- 2.4 x 10(6) micro3 (p=0.02). In patients with chronic allograft nephropathy in the protocol biopsy (n=14), the Vg enlargement was -0.3 +/-x 10(6) micro3 while in patients without chronic allograft nephropathy (n=27), glomerular enlargement was 1.6 +/- 2.1 x 10(6) micro3 (p=0.01). There was a negative association between glomerular volume in the donor biopsy and glomerular enlargement after transplantation (R=- 0.34, p=0.03). Multivariate regression analysis confirmed that Vg in the donor biopsy and chronic allograft nephropathy in the protocol biopsy were independent predictors of glomerular enlargement after transplantation (R=0.48, p=0.01). Moreover, Vg in the protocol biopsy correlated with creatinine clearance at the time of biopsy (R=0.38, p=0.01). Glomeruli enlarge after transplantation and glomerular volume after 4 months correlates with creatinine clearance, suggesting that glomerular enlargement is a necessary condition for renal adaptation to the recipient. Glomerular enlargement is impaired in patients with chronic allograft nephropathy.

Validation and Refinement of Chronic Lung Allograft Dysfunction Phenotypes in Bilateral and Single Lung Recipients

PubMed Central

Todd, Jamie L.; Zhang, Alice; Li, Ning; Mayalall, Aradhna; Finlen Copeland, C. Ashley; Shino, Michael; Pavlisko, Elizabeth N.; Wallace, W. Dean; Gregson, Aric; Ross, David J.; Saggar, Rajan; Lynch, Joseph P.; Belperio, John; Snyder, Laurie D.; Palmer, Scott M.

2016-01-01

Rationale: The clinical course of chronic lung allograft dysfunction (CLAD) is heterogeneous. Forced vital capacity (FVC) loss at onset, which may suggest a restrictive phenotype, was associated with worse survival for bilateral lung transplant recipients in one previously published single-center study. Objectives: We sought to replicate the significance of FVC loss in an independent, retrospectively identified cohort of bilateral lung transplant recipients and to investigate extended application of this approach to single lung recipients. Methods: FVC loss and other potential predictors of survival after the onset of CLAD were assessed using Kaplan-Meier and Cox proportional hazards models. Measurements and Main Results: FVC loss at the onset of CLAD was associated with higher mortality in an independent cohort of bilateral lung transplant recipients (hazard ratio [HR], 2.75; 95% confidence interval [CI], 2.02–3.73; P < 0.0001) and in a multicenter cohort of single lung recipients (HR, 1.80; 95% CI, 1.09–2.98; P = 0.02). Including all subjects, the deleterious impact of FVC loss on survival persisted after adjustment for other relevant clinical variables (HR, 2.36; 95% CI, 1.77–3.15; P < 0.0001). In patients who develop CLAD without FVC loss, chest computed tomography features suggestive of pleural or parenchymal fibrosis also predicted worse survival in both bilateral (HR, 2.01; 95% CI, 1.16–5.20; P = 0.02) and single recipients (HR, 2.47; 95% CI, 1.24–10.57; P = 0.02). Conclusions: We independently validated the prognostic significance of FVC loss for bilateral lung recipients and demonstrated that this approach to CLAD classification also confers prognostic information for single lung transplant recipients. Improved understanding of these discrete phenotypes is critical to the development of effective therapies. PMID:27144793

Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival.

PubMed

Gallagher, Harry M; Sarwar, Ghulam; Tse, Tracy; Sladden, Timothy M; Hii, Esmond; Yerkovich, Stephanie T; Hopkins, Peter M; Chambers, Daniel C

2015-11-01

Erratic tacrolimus blood levels are associated with liver and kidney graft failure. We hypothesized that erratic tacrolimus exposure would similarly compromise lung transplant outcomes. This study assessed the effect of tacrolimus mean and standard deviation (SD) levels on the risk of chronic lung allograft dysfunction (CLAD) and death after lung transplantation. We retrospectively reviewed 110 lung transplant recipients who received tacrolimus-based immunosuppression. Cox proportional hazard modeling was used to investigate the effect of tacrolimus mean and SD levels on survival and CLAD. At census, 48 patients (44%) had developed CLAD and 37 (34%) had died. Tacrolimus SD was highest for the first 6 post-transplant months (median, 4.01; interquartile range [IQR], 3.04-4.98 months) before stabilizing at 2.84 μg/liter (IQR, 2.16-4.13 μg/liter) between 6 and 12 months. The SD then remained the same (median, 2.85; IQR, 2.00-3.77 μg/liter) between 12 and 24 months. A high mean tacrolimus level 6 to 12 months post-transplant independently reduced the risk of CLAD (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.63-0.86; p < 0.001) but not death (HR, 0.96; 95% CI, 0.83-1.12; p = 0.65). In contrast, a high tacrolimus SD between 6 and 12 months independently increased the risk of CLAD (HR, 1.46; 95% CI, 1.23-1.73; p < 0.001) and death (HR, 1.27; 95% CI, 1.08-1.51; p = 0.005). Erratic tacrolimus levels are a risk factor for poor lung transplant outcomes. Identifying and modifying factors that contribute to this variability may significantly improve outcomes. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Functional Outcomes and Return to Sports After Acute Repair, Chronic Repair, and Allograft Reconstruction for Proximal Hamstring Ruptures.

PubMed

Rust, David A; Giveans, M Russell; Stone, Rebecca M; Samuelson, Kathryn M; Larson, Christopher M

2014-06-01

There are limited data regarding outcomes and return to sports after surgery for acute versus chronic proximal hamstring ruptures. Surgery for chronic proximal hamstring ruptures leads to improved outcomes and return to sports but at a lower level than with acute repair. Proximal hamstring reconstruction with an Achilles allograft for chronic ruptures is successful when direct repair is not possible. Cohort study; Level of evidence, 3. Between 2002 and 2012, a total of 72 patients with a traumatic proximal hamstring rupture (51 acute, 21 chronic) underwent either direct tendon repair with suture anchors (n = 58) or Achilles allograft tendon reconstruction (n = 14). Results from the Single Assessment Numeric Evaluation (SANE) for activities of daily living (ADL) and sports-related activities, Short Form-12 (SF-12), visual analog scale (VAS), and a patient satisfaction questionnaire were obtained. The mean time to surgery in the chronic group was 441.4 days versus 17.8 days in the acute group. At a mean follow-up of 45 months, patients with chronic tears had inferior sports activity scores (70.2% vs 80.3%, respectively; P = .026) and a trend for decreased ADL scores (86.5% vs 93.3%, respectively; P = .085) compared with those with acute tears. Patients with chronic tears, however, reported significant improvements postoperatively for both sports activity scores (30.3% to 70.2%; P < .01) and ADL scores (56.1% to 86.5%; P < .01). Greater than 5 to 6 cm of retraction in the chronic group was predictive of the need for allograft reconstruction (P = .015) and resulted in ADL and sports activity scores equal to those of chronic repair (P = .507 and P = .904, respectively). There were no significant differences between groups in SF-12, VAS, or patient satisfaction outcomes (mean, 85.2% satisfaction overall). Acute repair was superior to chronic surgery with regard to return to sports. Acute and chronic proximal hamstring repair and allograft reconstruction had favorable results for ADL. For low-demand patients or those with medical comorbidities, delayed repair or reconstruction might be considered with an expected 87% return to normal ADL. For patients who desire to return to sports, acute repair is recommended. © 2014 The Author(s).

Serial protocol biopsies to quantify the progression of chronic transplant nephropathy in stable renal allografts.

PubMed

Moreso, F; Lopez, M; Vallejos, A; Giordani, C; Riera, L; Fulladosa, X; Hueso, M; Alsina, J; Grinyó, J M; Serón, D

2001-05-01

To evaluate the utility of intimal thickness and interstitial width as a primary efficacy variable in the design of clinical trials aimed to modify the natural history of chronic allograft nephropathy. A donor and a 4-month protocol biopsy were evaluated in 40 stable grafts according to the Banff schema. In 27 patients, a second protocol biopsy was done at 1 yr. Arterial intimal volume fraction (Vvintima/artery) and cortical interstitial volume fraction (Vvinterstitium/cortex) were estimated with a point counting technique. Chronic Banff scores increased during follow-up, while acute scores reached its peak at 4 months. Vvintima/artery and Vvinterstitium/cortex significantly increased at 4 months, but not at 1 yr. Vvintima/artery at 4 months correlated with donor Vvintima/artery (r = 0.57, p < 0.001), histocompatibility (r = 0.38, p = 0.01) and serum cholesterol (r = 0.31, p = 0.047). Vvinterstitium/cortex at 4 months correlated with recipient body surface area (r = 0.44, p = 0.004) and delayed graft function (p = 0.016). Power calculations showed that Vvintima/artery and Vvinterstitium/cortex allow an important reduction in minimum sample size of a hypothetical trial aimed to prevent chronic allograft nephropathy. Intimal thickening and interstitial widening progresses rapidly during the first 4 months after transplantation and slowly thereafter. These parameters can be considered as a primary efficacy variable in trials aimed to prevent chronic allograft nephropathy.

13-cis Retinoic Acid Inhibits Development and Progression of Chronic Allograft Nephropathy

PubMed Central

Adams, Judith; Kiss, Eva; Arroyo, Ana B.V.; Bonrouhi, Mahnaz; Sun, Qiang; Li, Zhen; Gretz, Norbert; Schnitger, Anna; Zouboulis, Christos C.; Wiesel, Manfred; Wagner, Jürgen; Nelson, Peter J.; Gröne, Hermann-Josef

2005-01-01

Chronic allograft nephropathy is characterized by chronic inflammation and fibrosis. Because retinoids exhibit anti-proliferative, anti-inflammatory, and anti-fibrotic functions, the effects of low and high doses of 13-cis-retinoic acid (13cRA) were studied in a chronic Fisher344→Lewis transplantation model. In 13cRA animals, independent of dose (2 or 20 mg/kg body weight/day) and start (0 or 14 days after transplantation) of 13cRA administration, serum creatinine was significantly lower and chronic rejection damage was dramatically reduced, including subendothelial fibrosis of preglomerular vessels and chronic tubulointerstitial damage. The number of infiltrating mononuclear cells and their proliferative activity were significantly diminished. The mRNA expression of chemokines (MCP-1/CCL2, MIP-1α/CCL3, IP-10/CXCL10, RANTES/CCL5) and proteins associated with fibrosis (plasminogen activator inhibitor-1, transforming growth factor-β1, and collagens I and III) were strikingly lower in treated allografts. In vitro, activated peritoneal macrophages of 13cRA-treated rats showed a pronounced decrease in protein secretion of inflammatory cytokines (eg, tumor necrosis factor-α, interleukin-6). The suppression of the proinflammatory chemokine RANTES/CCL5 × 13cRA in fibroblasts could be mapped to a promoter module comprising IRF-1 and nuclear factor-κB binding elements, but direct binding of retinoid receptors to promoter elements could be excluded. In summary, 13cRA acted as a potent immunosuppressive and anti-fibrotic agent able to prevent and inhibit progression of chronic allograft nephropathy. PMID:15972972

Urine biomarkers informative of human kidney allograft rejection and tolerance.

PubMed

Nissaisorakarn, Voravech; Lee, John Richard; Lubetzky, Michelle; Suthanthiran, Manikkam

2018-05-01

We developed urinary cell messenger RNA (mRNA) profiling to monitor in vivo status of human kidney allografts based on our conceptualization that the kidney allograft may function as an in vivo flow cell sorter allowing access of graft infiltrating cells to the glomerular ultrafiltrate and that interrogation of urinary cells is informative of allograft status. For the profiling urinary cells, we developed a two-step preamplification enhanced real-time quantitative PCR (RT-QPCR) assays with a customized amplicon; preamplification compensating for the low RNA yield from urine and the customized amplicon facilitating absolute quantification of mRNA and overcoming the inherent limitations of relative quantification widely used in RT-QPCR assays. Herein, we review our discovery and validation of urinary cell mRNAs as noninvasive biomarkers prognostic and diagnostic of acute cellular rejection (ACR) in kidney allografts. We summarize our results reflecting the utility of urinary cell mRNA profiling for predicting reversal of ACR with anti-rejection therapy; differential diagnosis of kidney allograft dysfunction; and noninvasive diagnosis and prognosis of BK virus nephropathy. Messenger RNA profiles associated with human kidney allograft tolerance are also summarized in this review. Altogether, data supporting the idea that urinary cell mRNA profiles are informative of kidney allograft status and tolerance are reviewed in this report. Copyright © 2018. Published by Elsevier Inc.

Early application of Met-RANTES ameliorates chronic allograft nephropathy.

PubMed

Song, Erwei; Zou, Hequn; Yao, Yousheng; Proudfoot, Amanda; Antus, Balazs; Liu, Shanying; Jens, Lutz; Heemann, Uwe

2002-02-01

Initial insults to kidney allografts, characterized by infiltration of mononuclear inflammatory cells, contribute to chronic allograft nephropathy. Chemokines such as RANTES (regulated upon activation, normal T cell expressed) are thought to be responsible for the recruitment and activation of infiltrating cells. The present study investigated whether early application of Met-RANTES, a chemokine receptor antagonist that blocks the effects of RANTES, can protect renal allografts from long-term deterioration. Fisher (F344) rat kidneys were orthotopically transplanted into Lewis recipients and treated with cyclosporine A (1.5 mg/kg/day) for the first 10 days following transplantation, together with either Met-RANTES at 40 microg/day, 200 microg/day or vehicle for the first 7 days. Animals were harvested at 2 and 28 weeks after transplantation for histologic, immunohistologic and molecular analysis. Met-RANTES treatment reduced the infiltration of lymphocytes and macrophages in allografts at 2 weeks after transplantation, accompanied by decreased mRNA expression of interleukin (IL)-2, IL-1beta, tumor necrosis factor-alpha (TNF-alpha) and RANTES. At post-transplantation week 28, Met-RANTES treatment at high and low doses reduced urinary protein excretion and significantly ameliorated glomerulosclerosis, interstitial fibrosis, tubular atrophy, intimal proliferation of graft arteries and mononuclear cell infiltration. However, creatinine clearance was not influenced by Met-RANTES. Furthermore, Met-RANTES suppressed the mRNA expression of transforming growth factor-beta (TGF-beta) and platelet-derived growth factor-B (PDGF-B). Blockade of chemokine receptors by Met-RANTES diminishes early infiltration and activation of mononuclear cells in the grafts, and thus reduces the pace of chronic allograft nephropathy.

Treatment of Autonomous Hyperparathyroidism in Post Renal Transplant Recipients

ClinicalTrials.gov

2017-02-07

Chronic Allograft Nephropathy; Chronic Kidney Disease; Chronic Renal Failure; Disordered Mineral Metabolism; End Stage Renal Disease; Hyperparathyroidism; Hypophosphatemia; Kidney Disease; Kidney Transplantation; Post Renal Transplantation

CMV allograft pancreatitis: diagnosis, treatment, and histological features.

PubMed

Klassen, D K; Drachenberg, C B; Papadimitriou, J C; Cangro, C B; Fink, J C; Bartlett, S T; Weir, M R

2000-05-15

Cytomegalovirus (CMV) infection is a common problem in solid organ transplant recipients. CMV infection of pancreas allografts is not, however, well described. We report the clinical presentation, histologic findings, treatment, and outcome in four patients with CMV allograft pancreatitis. These patients presented 18 weeks to 44 months after transplantation with elevated serum amylase and lipase and were suspected to have acute rejection. Percutaneous pancreas allograft biopsy specimens showed evidence of tissue invasive CMV infection. One patient had simultaneous CMV infection and acute rejection. Prolonged treatment with ganciclovir resulted in clinical and histologic resolution of the CMV disease. Rejection was successfully treated. Primary CMV infection in seronegative recipients seemed to be a risk factor. Three patients maintain normal allograft function; one patient lost function due to chronic rejection. The histology of tissue-invasive CMV pancreas allograft infection and its differentiation from acute rejection is described. Prompt diagnosis and prolonged therapy with antiviral agents can result in maintenance of allograft function.

The Identification of Novel Potential Injury Mechanisms and Candidate Biomarkers in Renal Allograft Rejection by Quantitative Proteomics*

PubMed Central

Sigdel, Tara K.; Salomonis, Nathan; Nicora, Carrie D.; Ryu, Soyoung; He, Jintang; Dinh, Van; Orton, Daniel J.; Moore, Ronald J.; Hsieh, Szu-Chuan; Dai, Hong; Thien-Vu, Minh; Xiao, Wenzhong; Smith, Richard D.; Qian, Wei-Jun; Camp, David G.; Sarwal, Minnie M.

2014-01-01

Early transplant dysfunction and failure because of immunological and nonimmunological factors still presents a significant clinical problem for transplant recipients. A critical unmet need is the noninvasive detection and prediction of immune injury such that acute injury can be reversed by proactive immunosuppression titration. In this study, we used iTRAQ -based proteomic discovery and targeted ELISA validation to discover and validate candidate urine protein biomarkers from 262 renal allograft recipients with biopsy-confirmed allograft injury. Urine samples were randomly split into a training set of 108 patients and an independent validation set of 154 patients, which comprised the clinical biopsy-confirmed phenotypes of acute rejection (AR) (n = 74), stable graft (STA) (n = 74), chronic allograft injury (CAI) (n = 58), BK virus nephritis (BKVN) (n = 38), nephrotic syndrome (NS) (n = 8), and healthy, normal control (HC) (n = 10). A total of 389 proteins were measured that displayed differential abundances across urine specimens of the injury types (p < 0.05) with a significant finding that SUMO2 (small ubiquitin-related modifier 2) was identified as a “hub” protein for graft injury irrespective of causation. Sixty-nine urine proteins had differences in abundance (p < 0.01) in AR compared with stable graft, of which 12 proteins were up-regulated in AR with a mean fold increase of 2.8. Nine urine proteins were highly specific for AR because of their significant differences (p < 0.01; fold increase >1.5) from all other transplant categories (HLA class II protein HLA-DRB1, KRT14, HIST1H4B, FGG, ACTB, FGB, FGA, KRT7, DPP4). Increased levels of three of these proteins, fibrinogen beta (FGB; p = 0.04), fibrinogen gamma (FGG; p = 0.03), and HLA DRB1 (p = 0.003) were validated by ELISA in AR using an independent sample set. The fibrinogen proteins further segregated AR from BK virus nephritis (FGB p = 0.03, FGG p = 0.02), a finding that supports the utility of monitoring these urinary proteins for the specific and sensitive noninvasive diagnosis of acute renal allograft rejection. PMID:24335474

Contrasting roles of donor and recipient TGFB1 and IFNG gene polymorphic variants in chronic kidney transplant rejection.

PubMed

Coelho, Verônica Porto Carreiro de Vasconcellos; Ioschpe, Rafael; Caldas, Cristina; Spadafora-Ferreira, Monica; Fonseca, João Americo; Cardoso, Maria Regina Alves; Palacios, Selma Aliotti; Kalil, Jorge; Goldberg, Anna Carla

2011-03-01

To assess the long-term impact (minimum of 3 years follow-up) of polymorphisms in cytokine genes in donor:recipient pairs on the results of the transplant. We compared genetic cytokine polymorphisms and the primary factors of risk for the development of chronic rejection in paired groups of renal transplant patients with and without chronic allograft nephropathy [CAN]. Multivariate analysis indicated that the presence of the high-production TT genotype (codon 10) of the transforming growth factor beta-1 (TGFB1) was protective in receptors (p=0.017), contrasting with the increased risk when present in donor samples (p=0.049). On the other hand, in the case of the gamma interferon studied, the greater frequency of the high production allele was protective in the analysis of the donor group (p=0.013), increasing the risk of chronic nephropathy of the allograft when present in the recipients (p=0.036). Our results highlight the importance of TGFB1 genotyping in donors, and indicate that polymorphisms in the gene of this cytokine in donor cells might contribute to the development of chronic allograft nephropathy.

Induction of transplantation tolerance to fully mismatched cardiac allografts by T cell mediated delivery of alloantigen

PubMed Central

Tian, Chaorui; Yuan, Xueli; Jindra, Peter T.; Bagley, Jessamyn; Sayegh, Mohamed H.; Iacomini, John

2010-01-01

Induction of transplantation tolerance has the potential to allow for allograft acceptance without the need for life-long immunosuppression. Here we describe a novel approach that uses delivery of alloantigen by mature T cells to induce tolerance to fully allogeneic cardiac grafts. Adoptive transfer of mature alloantigen-expressing T cells into myeloablatively conditioned mice results in long-term acceptance of fully allogeneic heart transplants without evidence of chronic rejection. Since myeloablative conditioning is clinically undesirable we further demonstrated that adoptive transfer of mature alloantigen-expressing T cells alone into mice receiving non-myeloablative conditioning resulted in long-term acceptance of fully allogeneic heart allografts with minimal evidence of chronic rejection. Mechanistically, tolerance induction involved both deletion of donor-reactive host T cells and the development of regulatory T cells. Thus, delivery of alloantigen by mature T cells induces tolerance to fully allogeneic organ allografts in non-myeloablatively conditioned recipients, representing a novel approach for tolerance induction in transplantation. PMID:20452826

Application of Rotating Wall Vessel (RWV) Cell Culture for Pancreas Islet Cell Transplantation

NASA Technical Reports Server (NTRS)

Rutzky, Lynne P.

1998-01-01

Type I insulin-dependent diabetes mellitus (IDDM) remains a major cause of morbidity and mortality in both pediatric and adult populations, despite significant advances in medical management. While insulin therapy treats symptoms of acute diabetes, it fails to prevent chronic complications such as microvascular disease, blindness, neuropathy, and chronic renal failure. Strict control of blood glucose concentrations delays but does not prevent the onset and progression of secondary complications. Although, whole pancreas transplantation restores physiological blood glucose levels, a continuous process of allograft rejection causes vascular and exocrine-related complications. Recent advances in methods for isolation and purification of pancreatic islets make transplantation of islet allografts an attractive alternative to whole pancreas transplantation. However, immunosuppressive drugs are necessary to prevent rejection of islet allografts and many of these drugs are known to be toxic to the islets. Since auto-transplants of isolated islets following total pancreatectomy survive and function in vivo, it is apparent that a major obstacle to successful clinical islet transplantation is the immunogenicity of the islet allografts.

Absence of MyD88 Signaling Induces Donor-Specific Kidney Allograft Tolerance

PubMed Central

Noordmans, Gerda A.; O’Brien, Maya R.; Ma, Jin; Zhao, Cathy Y.; Zhang, Geoff Y.; Kwan, Tony K.T.; Alexander, Stephen I.; Chadban, Steven J.

2012-01-01

Toll-like receptors (TLRs) play a fundamental role in innate immunity and provide a link between innate and adaptive responses to an allograft; however, whether the development of acute and chronic allograft rejection requires TLR signaling is unknown. Here, we studied TLR signaling in a fully MHC-mismatched, life-sustaining murine model of kidney allograft rejection. Mice deficient in the TLR adaptor protein MyD88 developed donor antigen-specific tolerance, which protected them from both acute and chronic allograft rejection and increased their survival after transplantation compared with wild-type controls. Administration of an anti-CD25 antibody to MyD88-deficient recipients depleted CD4+CD25+FoxP3+ cells and broke tolerance. In addition, defective development of Th17 immune responses to alloantigen both in vitro and in vivo occurred, resulting in an increased ratio of Tregs to Th17 effectors. Thus, MyD88 deficiency was associated with an altered balance of Tregs over Th17 cells, promoting tolerance instead of rejection. This study provides evidence that targeting innate immunity may be a clinically relevant strategy to facilitate transplantation tolerance. PMID:22878960

Clinical utility of histological features of polyomavirus allograft nephropathy.

PubMed

Gaber, Lillian W; Egidi, M Francesca; Stratta, Robert J; Lo, Agnes; Moore, Linda W; Gaber, A Osama

2006-07-27

The purpose of this study was to determine if histological features of polyomavirus allograft nephropathy (PVAN) are associated with the clinical presentation and outcomes of PVAN. We examined the histological features of initial and follow-up biopsies of 20 kidney and kidney-pancreas transplant recipients with PVAN during a time prior to routine surveillance. The subjects' demographics, clinical characteristics, and outcomes were compared based upon classification of histological features of PVAN on initial biopsy. Diabetes mellitus (45%) and a history of tacrolimus-induced nephrotoxicity (35%) appeared to be prevalent in subjects with PVAN. Although histological severity of PVAN did not predict or correlate with the clinical course of PVAN, subjects with pattern C on initial PVAN biopsy presented later posttransplant, had higher serum creatinine level at presentation, and had significant allograft deterioration at follow-up than subjects with either pattern A or B on initial biopsy. Resolution of PVAN was noted in 60% of follow-up biopsies and occurred more frequently in subjects with pattern B on initial biopsy. Most subjects developed chronic allograft nephropathy after PVAN and viral clearance did not abrogate the progression to chronic allograft nephropathy. These data indicate that histologic patterns of PVAN may have clinical correlation to disease presentation and prognosis.

Donor Predictors of Allograft Utilization and Recipient Outcomes after Heart Transplantation

PubMed Central

Khush, Kiran K.; Menza, Rebecca; Nguyen, John; Zaroff, Jonathan G.; Goldstein, Benjamin A.

2013-01-01

Background Despite a national organ donor shortage and a growing population of patients with end-stage heart disease, the acceptance rate of donor hearts for transplantation is low. We sought to identify donor predictors of allograft non-utilization, and to determine whether these predictors are in fact associated with adverse recipient post-transplant outcomes. Methods and Results We studied a cohort of 1,872 potential organ donors managed by the California Transplant Donor Network from 2001–2008. Forty five percent of available allografts were accepted for heart transplantation. Donor predictors of allograft non-utilization included age>50 years, female sex, death due to cerebrovascular accident, hypertension, diabetes, a positive troponin assay, left ventricular dysfunction and regional wall motion abnormalities, and left ventricular hypertrophy. For hearts that were transplanted, only donor cause of death was associated with prolonged recipient hospitalization post-transplant, and only donor diabetes was predictive of increased recipient mortality. Conclusions While there are many donor predictors of allograft discard in the current era, these characteristics appear to have little effect on recipient outcomes when the hearts are transplanted. Our results suggest that more liberal use of cardiac allografts with relative contraindications may be warranted. PMID:23392789

Restrictive allograft syndrome after lung transplantation: new radiological insights.

PubMed

Dubbeldam, Adriana; Barthels, Caroline; Coolen, Johan; Verschakelen, Johny A; Verleden, Stijn E; Vos, Robin; Verleden, Geert M; De Wever, Walter

2017-07-01

To describe the CT changes in patients with restrictive allograft syndrome (RAS) after lung transplantation, before and after clinical diagnosis. This retrospective study included 22 patients with clinical diagnosis of RAS. Diagnosis was based on a combination of forced expiratory volume (FEV1) decline (≥20 %) and total lung capacity (TLC) decline (≥10 %). All available CT scans after transplantation were analyzed for the appearance and evolution of lung abnormalities. In 14 patients, non-regressing nodules and reticulations predominantly affecting the upper lobes developed an average of 13.9 months prior to the diagnosis of RAS. Median graft survival after onset of non-regressing abnormalities was 33.5 months, with most patients in follow-up (9/14). In eight patients, a sudden appearance of diffuse consolidations mainly affecting both upper and lower lobes was seen an average of 2.8 months prior to the diagnosis of RAS. Median graft survival was 6.4 months after first onset of non-regressing abnormalities, with graft loss in most patients (6/8). RAS has been previously described as a homogenous group. However, our study shows two different groups of RAS-patients: one with slow progression and one with fast progression. The two groups show different onset and progression patterns of CT abnormalities. • RAS is the newest discovered form of chronic lung allograft dysfunction (CLAD). • RAS is not a homogenous group, as survival varies greatly between patients. • In this study, we see two different CT onset and progression patterns. • These two different CT patterns also correlate with a different survival rate.

Augmenting kidney mass at transplantation abrogates chronic renal allograft injury in rats.

PubMed

Mackenzie, H S; Azuma, H; Troy, J L; Rennke, H G; Tilney, N L; Brenner, B M

1996-03-01

Conventional renal transplantation, which substitutes a single allograft for two native kidneys, imposes an imbalance between nephron supply and the metabolic and excretory demands of the recipient. This discrepancy, which stimulates hyperfunction and hypertrophy of viable allograft nephrons, may be intensified by nephron loss through ischemia-reperfusion injury or acute rejection episodes occurring soon after transplantation. In other settings where less than 50% of the total renal mass remains, progressive glomerular injury develops through mechanisms associated with compensatory nephron hyperfiltration and hypertrophy. To determine whether responses to nephron loss contribute to chronic injury in renal allografts, nephron supply was restored to near-normal levels by transplanting Lewis recipients with two Fisher 344 kidneys (group 2A) compared with the standard single allograft F344 --> LEW rat model of late renal allograft failure (group 1A). At 20 weeks, indices of injury were observed in 1A but not 2A rats. These indices included proteinuria (1A: 45 +/- 13; 2A: 4.0 +/- 0.29 mg/day) and glomerulosclerosis (1A: 23 +/- 4.9%, 2A: 0.7 +/- 0.3%) (p < .05). Double-allograft recipients maintained near normal renal structure and function, whereas 1A rats showed evidence of compensatory hyperfiltration (single-nephron glomerular filtration rate of 63 +/- 10 versus 44 +/- 2.0 nl/min in 2A rats) and hypertrophy (mean glomerular volume of 2.64 +/- 0.15 versus 1.52 +/- 0.05 microns3 x 10(6) in 2A rats) (p < .05). Thus, we conclude that a major component of late allograft injury is attributable to processes associated with inadequate transplanted renal mass, a finding that has major implications for kidney transplantation biology and policy.

Management of children undergoing cardiac transplantation with high Panel Reactive Antibodies.

PubMed

Asante-Korang, Alfred; Jacobs, Jeffrey P; Ringewald, Jeremy; Carapellucci, Jennifer; Rosenberg, Kristin; McKenna, Daniel; McCormack, Jorge; Wilmot, Ivan; Gjeldum, Abigail; Lopez-Cepero, Mayra; Sleasman, John

2011-12-01

Highly sensitised children in need of cardiac transplantation have overall poor outcomes because of increased risk for dysfunction of the cardiac allograft, acute cellular and antibody-mediated rejection, and vasculopathy of the cardiac allograft. Cardiopulmonary bypass and the frequent use of blood products in the operating room and cardiac intensive care unit, as well as the frequent use of homografts, have predisposed potential recipients of transplants to allosensitisation. The expansion in the use of ventricular assist devices and extracorporeal membrane oxygenation has also contributed to increasing rates of allosensitisation in candidates for cardiac transplantation. Antibodies to Human Leukocyte Antigen can be detected before transplantation using several different techniques, the most common being the "complement-dependent lymphocytotoxicity assays". "Solid-phase assays", particularly the "Luminex® single antigen bead method", offer improved specificity and more detailed information regarding specificities of antibodies, leading to improved matching of donors with recipients. Allosensitisation prolongs the time on the waiting list for potential recipients of transplantation and increases the risk of complications and death after transplantation. Aggressive reduction of antibodies to Human Leukocyte Antigen in these high-risk patients is therefore of vital importance for long-term survival of the patient and cardiac allograft. Strategies to decrease Panel Reactive Antibody or percent reactive antibody before transplantation include plasmapheresis, intravenous administration of immunoglobulin, and specific treatment to reduce B-cells, particularly Rituximab. These strategies have resulted in varying degrees of success. Antibody-mediated rejection and cardiac allograft vasculopathy are two of the most important complications of transplantation in patients with high Panel Reactive Antibody. The treatment of antibody-mediated rejection in recipients of cardiac transplants is largely empirical and includes the use of high-dose corticosteroids, plasmapheresis, intravenous administration of immunoglobulins, anti-thymocyte globulin, and Rituximab. Cardiac allograft vasculopathy is believed to be secondary to chronic complement-mediated endothelial injury and chronic vascular rejection. The use of proliferation signal inhibitors, such as sirolimus and everolimus, has been shown to delay the progression of cardiac allograft vasculopathy. In some non-sensitised recipients of cardiac transplants, the de novo formation of antibodies to Human Leukocyte Antigen after transplantation may increase the likelihood of adverse clinical outcomes. The use of serial testing for donor-specific antibodies after cardiac transplantation may be advisable in patients with frequent episodes of rejection and patients with history of sensitisation. Allosensitisation before transplantation can negatively influence outcomes after transplantation. A high incidence of antibody-mediated rejection and graft vasculopathy can result in graft failure and decreased survival. Current strategies to decrease allosensitisation have helped to expand the pool of donors, improve times on the waiting list, and decrease mortality. Centres of transplantation offering desensitisation are currently using plasmapheresis to remove circulating antibodies; intravenous immunoglobulin to inactivate antibodies; cyclophosphamide to suppress B-cell proliferation; and Rituximab to deplete B-lymphocytes. Similar approaches are also used to treat antibody-mediated rejection after transplantation with promising results.

Predictive factors of short term outcome after liver transplantation: A review

PubMed Central

Bolondi, Giuliano; Mocchegiani, Federico; Montalti, Roberto; Nicolini, Daniele; Vivarelli, Marco; De Pietri, Lesley

2016-01-01

Liver transplantation represents a fundamental therapeutic solution to end-stage liver disease. The need for liver allografts has extended the set of criteria for organ acceptability, increasing the risk of adverse outcomes. Little is known about the early postoperative parameters that can be used as valid predictive indices for early graft function, retransplantation or surgical reintervention, secondary complications, long intensive care unit stay or death. In this review, we present state-of-the-art knowledge regarding the early post-transplantation tests and scores that can be applied during the first postoperative week to predict liver allograft function and patient outcome, thereby guiding the therapeutic and surgical decisions of the medical staff. Post-transplant clinical and biochemical assessment of patients through laboratory tests (platelet count, transaminase and bilirubin levels, INR, factor V, lactates, and Insulin Growth Factor 1) and scores (model for end-stage liver disease, acute physiology and chronic health evaluation, sequential organ failure assessment and model of early allograft function) have been reported to have good performance, but they only allow late evaluation of patient status and graft function, requiring days to be quantified. The indocyanine green plasma disappearance rate has long been used as a liver function assessment technique and has produced interesting, although not univocal, results when performed between the 1th and the 5th day after transplantation. The liver maximal function capacity test is a promising method of metabolic liver activity assessment, but its use is limited by economic cost and extrahepatic factors. To date, a consensual definition of early allograft dysfunction and the integration and validation of the above-mentioned techniques, through the development of numerically consistent multicentric prospective randomised trials, are necessary. The medical and surgical management of transplanted patients could be greatly improved by using clinically reliable tools to predict early graft function. PMID:27468188

Predictive factors of short term outcome after liver transplantation: A review.

PubMed

Bolondi, Giuliano; Mocchegiani, Federico; Montalti, Roberto; Nicolini, Daniele; Vivarelli, Marco; De Pietri, Lesley

2016-07-14

Liver transplantation represents a fundamental therapeutic solution to end-stage liver disease. The need for liver allografts has extended the set of criteria for organ acceptability, increasing the risk of adverse outcomes. Little is known about the early postoperative parameters that can be used as valid predictive indices for early graft function, retransplantation or surgical reintervention, secondary complications, long intensive care unit stay or death. In this review, we present state-of-the-art knowledge regarding the early post-transplantation tests and scores that can be applied during the first postoperative week to predict liver allograft function and patient outcome, thereby guiding the therapeutic and surgical decisions of the medical staff. Post-transplant clinical and biochemical assessment of patients through laboratory tests (platelet count, transaminase and bilirubin levels, INR, factor V, lactates, and Insulin Growth Factor 1) and scores (model for end-stage liver disease, acute physiology and chronic health evaluation, sequential organ failure assessment and model of early allograft function) have been reported to have good performance, but they only allow late evaluation of patient status and graft function, requiring days to be quantified. The indocyanine green plasma disappearance rate has long been used as a liver function assessment technique and has produced interesting, although not univocal, results when performed between the 1(th) and the 5(th) day after transplantation. The liver maximal function capacity test is a promising method of metabolic liver activity assessment, but its use is limited by economic cost and extrahepatic factors. To date, a consensual definition of early allograft dysfunction and the integration and validation of the above-mentioned techniques, through the development of numerically consistent multicentric prospective randomised trials, are necessary. The medical and surgical management of transplanted patients could be greatly improved by using clinically reliable tools to predict early graft function.

Borderline Changes on Dysfunctional Renal Allograft Biopsies: Clinical Relevance in a Living Related Renal Transplant Setting.

PubMed

Mubarak, Muhammed; Shakeel, Shaheera; Abbas, Khawar; Aziz, Tahir; Zafar, Mirza Naqi; Naqvi, Syed Anwer; Rizvi, Syed Adibul Hasan

2017-02-01

Our aim was to determine the clinical significance of borderline lymphocytic infiltrates on indicated renal allograft biopsies in a living related renal transplant setting. The study was conducted at the histopathology department of Sindh Institute of Urology and Transplantation. A retrospective review of 421 renal transplant patients was conducted from October 2007 to September 2008 to identify patients in whom a histologic diagnosis of borderline changes was made on dysfunctional renal allograft biopsies. Demographic, clinical, and laboratory data; biopsy findings; treatments given; and responses to treatment were collected and analyzed. Standard biopsy indications determined the need for graft biopsies. Biopsies were reported according to Banff criteria. Mean age was 26.92 ± 9.14 years (range, 10-45) for recipients and 38.46 ± 9.16 years (range, 19-50) for donors. Males were predominant among recipients (84.6% vs 15.4%), and females were predominant among donors (57.7% vs 42.3%). The best serum creatinine levels were 1.79 ± 1.15 mg/dL (range, 0.83-6.12). These were achieved after a median of 3 days (interquartile range, 2-7.25). Dysfunctional biopsies exhibiting borderline infiltrates were performed at a median duration of 5.5 days (interquartile range, 3-14.25). Mean serum creatinine at the time of biopsy was 2.34 ± 1.43 mg/dL (range, 1.25-8.25). The biopsies showed borderline cellular infiltrates (interstitial inflammation 1 [i1] and tubulitis 1 and [t1] lesions). All recipients except one received antirejection treatment (antithymocyte globulin, n = 5; escalation of mycophenolate mofetil dosage, n = 1; pulse steroids, n = 19); all recipients responded with a decline in serum creatinine toward baseline, with a mean serum creatinine of 1.31 ± 0.42 mg/dL (range, 0.40-2.71). This response was achieved at a median duration of 9.73 ± 5.32 days (range, 1-23) after starting treatment. The borderline cellular infiltrates on dysfunctional renal allograft biopsies signify evolving phases of acute cellular rejection. These infiltrates responded favorably to antirejection treatment in our setting.

Role of Magnetic Resonance Elastography as a Noninvasive Measurement Tool of Fibrosis in a Renal Allograft: A Case Report.

PubMed

Kim, J K; Yuen, D A; Leung, G; Jothy, S; Zaltzman, J; Ramesh Prasad, G V; Prabhudesai, V; Mnatzakanian, G; Kirpalani, A

2017-09-01

A major reason for poor long-term kidney transplant outcomes is the development of chronic allograft injury, characterized by interstitial fibrosis and tubular atrophy. Currently, an invasive biopsy that samples only <1% of the kidney is the gold standard for detecting kidney allograft fibrosis. We report the use of magnetic resonance elastography (MRE) to quantify tissue stiffness as a noninvasive and whole-kidney measurement tool of allograft fibrosis in a kidney transplant patient at 2 time points. The MRE whole-kidney stiffness values reflected the changes in fibrosis of the kidney allograft as assessed by histologic examination. To our knowledge, this technique is the first observation of change over time in MRE-derived whole-kidney stiffness in an allograft that is consistent with changes in histology-derived fibrosis scores in a single patient. Copyright © 2017 Elsevier Inc. All rights reserved.

Allorecognition pathways in transplant rejection and tolerance.

PubMed

Ali, Jason M; Bolton, Eleanor M; Bradley, J Andrew; Pettigrew, Gavin J

2013-10-27

With the advent of cellular therapies, it has become clear that the success of future therapies in prolonging allograft survival will require an intimate understanding of the allorecognition pathways and effector mechanisms that are responsible for chronic rejection and late graft loss.Here, we consider current understanding of T-cell allorecognition pathways and discuss the most likely mechanisms by which these pathways collaborate with other effector mechanisms to cause allograft rejection. We also consider how this knowledge may inform development of future strategies to prevent allograft rejection.Although both direct and indirect pathway CD4 T cells appear active immediately after transplantation, it has emerged that indirect pathway CD4 T cells are likely to be the dominant alloreactive T-cell population late after transplantation. Their ability to provide help for generating long-lived alloantibody is likely one of the main mechanisms responsible for the progression of allograft vasculopathy and chronic rejection.Recent work has suggested that regulatory T cells may be an effective cellular therapy in transplantation. Given the above, adoptive therapy with CD4 regulatory T cells with indirect allospecificity is a rational first choice in attempting to attenuate the development and progression of chronic rejection; those with additional properties that enable inhibition of germinal center alloantibody responses hold particular appeal.

Treatment of Articular Cartilage Defects in the Goat with Frozen Versus Fresh Osteochondral Allografts: Effects on Cartilage Stiffness, Zonal Composition, and Structure at Six Months

PubMed Central

Pallante, Andrea L.; Görtz, Simon; Chen, Albert C.; Healey, Robert M.; Chase, Derek C.; Ball, Scott T.; Amiel, David; Sah, Robert L.; Bugbee, William D.

2012-01-01

Background: Understanding the effectiveness of frozen as compared with fresh osteochondral allografts at six months after surgery and the resultant consequences of traditional freezing may facilitate in vivo maintenance of cartilage integrity. Our hypothesis was that the state of the allograft at implantation affects its performance after six months in vivo. Methods: The effect of frozen as compared with fresh storage on in vivo allograft performance was determined for osteochondral allografts that were transplanted into seven recipient goats and analyzed at six months. Allograft performance was assessed by examining osteochondral structure (cartilage thickness, fill, surface location, surface degeneration, and bone-cartilage interface location), zonal cartilage composition (cellularity, matrix content), and cartilage biomechanical function (stiffness). Relationships between cartilage stiffness or cartilage composition and surface degeneration were assessed with use of linear regression. Results: Fresh allografts maintained cartilage load-bearing function, while also maintaining zonal organization of cartilage cellularity and matrix content, compared with frozen allografts. Overall, allograft performance was similar between fresh allografts and nonoperative controls. However, cartilage stiffness was approximately 80% lower (95% confidence interval [CI], 73% to 87%) in the frozen allografts than in the nonoperative controls or fresh allografts. Concomitantly, in frozen allografts, matrix content and cellularity were approximately 55% (95% CI, 22% to 92%) and approximately 96% (95% CI, 94% to 99%) lower, respectively, than those in the nonoperative controls and fresh allografts. Cartilage stiffness correlated positively with cartilage cellularity and matrix content, and negatively with surface degeneration. Conclusions: Maintenance of cartilage load-bearing function in allografts is associated with zonal maintenance of cartilage cellularity and matrix content. In this animal model, frozen allografts displayed signs of failure at six months, with cartilage softening, loss of cells and matrix, and/or graft subsidence, supporting the importance of maintaining cell viability during allograft storage and suggesting that outcomes at six months may be indicative of long-term (dys)function. Clinical Relevance: Fresh versus frozen allografts represent the “best versus worst” conditions with respect to chondrocyte viability, but “difficult versus simple” with respect to acquisition and distribution. The outcomes described from these two conditions expand the current understanding of in vivo cartilage remodeling and describe structural properties (initial graft subsidence), which may have implications for impending graft failure. PMID:23138239

Periodontal Regeneration Of 1-, 2-, and 3-Walled Intrabony Defects Using Accell Connexus (registered trademark) Versus Demineralized Freeze-Dried Bone Allograft: A Randomized Parallel Arm Clinical Control Trial

DTIC Science & Technology

2015-06-01

localized or generalized), duration ( chronic or aggressive) and severity (mild, moderate or severe) of periodontal disease which will assist in rendering...intrabony defects can be seen in chronic forms of periodontal disease. 9 Figure 4a shows a normal bony pattern in which the bone level follows the... PERIODONTAL REGENERATION OF 1-, 2-, AND 3-WALLED INTRABONY DEFECTS USING ACCELL CONNEXUS® VERSUS DEMINERALIZED FREEZE- DRIED BONE ALLOGRAFT: A

[Parenchymal complications of the transplanted kidney: the role of color-Doppler imaging].

PubMed

Granata, Antonio; Clementi, Silvia; Clementi, Anna; Di Pietro, Fabio; Scarfia, Viviana R; Insalaco, Monica; Aucella, Filippo; Prencipe, Michele; Fiorini, Fulvio; Sicurezza, Elvia

2012-01-01

Kidney transplantation is the treatment of choice for end-stage renal disease, given the better quality of life of transplanted patients when compared to patients on maintenance dialysis. In spite of surgical improvements and new immunosuppressive regimens, part of the transplanted grafts still develop chronic dysfunction. Ultrasonography, both in B-mode and with Doppler ultrasound, is an important diagnostic tool in case of clinical conditions which might impair kidney function. Even though ultrasonography is considered fundamental in the diagnosis of vascular and surgical complications of the transplanted kidney, its role is not fully understood in case of parenchymal complications of the graft. The specificity of Doppler ultrasound is low both in case of acute complications such as acute tubular necrosis, drug toxicity and acute rejection, and in case of chronic conditions such as chronic allograft nephropathy. Single determinations of resistance indices present low diagnostic accuracy, which is higher in case of successive measurements performed during the follow-up of the graft. Modern techniques including tissue pulsatility index, maximal fractional area and contrast-enhanced ultrasound increase the diagnostic power of ultrasonography in case of parenchymal complications of the transplanted kidney.

Comparison of a novel bone-tendon allograft with a human dermis-derived patch for repair of chronic large rotator cuff tears using a canine model.

PubMed

Smith, Matthew J; Cook, James L; Kuroki, Keiichi; Jayabalan, Prakash S; Cook, Cristi R; Pfeiffer, Ferris M; Waters, Nicole P

2012-02-01

This study tested a bone-tendon allograft versus human dermis patch for reconstructing chronic rotator cuff repair by use of a canine model. Mature research dogs (N = 15) were used. Radiopaque wire was placed in the infraspinatus tendon (IST) before its transection. Three weeks later, radiographs showed IST retraction. Each dog then underwent 1 IST treatment: debridement (D), direct repair of IST to bone with a suture bridge and human dermis patch augmentation (GJ), or bone-tendon allograft (BT) reconstruction. Outcome measures included lameness grading, radiographs, and ultrasonographic assessment. Dogs were killed 6 months after surgery and both shoulders assessed biomechanically and histologically. BT dogs were significantly (P = .01) less lame than the other groups. BT dogs had superior bone-tendon, tendon, and tendon-muscle integrity compared with D and GJ dogs. Biomechanical testing showed that the D group had significantly (P = .05) more elongation than the other groups whereas BT had stiffness and elongation characteristics that most closely matched normal controls. Radiographically, D and GJ dogs showed significantly more retraction than BT dogs (P = .003 and P = .045, respectively) Histologically, GJ dogs had lymphoplasmacytic infiltrates, tendon degeneration and hypocellularity, and poor tendon-bone integration. BT dogs showed complete incorporation of allograft bone into host bone, normal bone-tendon junctions, and well-integrated allograft tendon. The bone-tendon allograft technique re-establishes a functional IST bone-tendon-muscle unit and maintains integrity of repair in this model. Clinical trials using this bone-tendon allograft technique are warranted. Copyright © 2012 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Acute allograft failure in thoracic organ transplantation.

PubMed

Jahania, M S; Mullett, T W; Sanchez, J A; Narayan, P; Lasley, R D; Mentzer, R M

2000-01-01

Thoracic organ transplantation is an effective form of treatment for end-stage heart and lung disease. Despite major advances in the field, transplant patients remain at risk for acute allograft dysfunction, a major cause of early and late mortality. The most common causes of allograft failure include primary graft failure secondary to inadequate heart and lung preservation during cold storage, cellular rejection, and various donor-recipient-related factors. During cold storage and early reperfusion, heart and lung allografts are vulnerable to intracellular calcium overload, acidosis, cell swelling, injury mediated by reactive oxygen species, and the inflammatory response. Brain death itself is associated with a reduction in myocardial contractility, and recipient-related factors such as preexisting pulmonary hypertension can lead to acute right heart failure and the pulmonary reimplantation response. The development of new methods to prevent or treat these various causes of acute graft failure could lead to a marked improvement in short- and long-term survival of patients undergoing thoracic organ transplantation.

Ferret lung transplant: an orthotopic model of obliterative bronchiolitis.

PubMed

Sui, H; Olivier, A K; Klesney-Tait, J A; Brooks, L; Tyler, S R; Sun, X; Skopec, A; Kline, J; Sanchez, P G; Meyerholz, D K; Zavazava, N; Iannettoni, M; Engelhardt, J F; Parekh, K R

2013-02-01

Obliterative bronchiolitis (OB) is the primary cause of late morbidity and mortality following lung transplantation. Current animal models do not reliably develop OB pathology. Given the similarities between ferret and human lung biology, we hypothesized an orthotopic ferret lung allograft would develop OB. Orthotopic left lower lobe transplants were successfully performed in 22 outbred domestic ferrets in the absence of immunosuppression (IS; n = 5) and presence of varying IS protocols (n = 17). CT scans were performed to evaluate the allografts. At intervals between 3-6 months the allografts were examined histologically for evidence of acute/chronic rejection. IS protects allografts from acute rejection and early graft loss. Reduction of IS dosage by 50% allowed development of controlled rejection. Allografts developed infiltrates on CT and classic histologic acute rejection and lymphocytic bronchiolitis. Cycling of IS, to induce repeated episodes of controlled rejection, promoted classic histologic hallmarks of OB including fibrosis-associated occlusion of the bronchiolar airways in all allografts of long-term survivors. In conclusion, we have developed an orthotopic lung transplant model in the ferret with documented long-term functional allograft survival. Allografts develop acute rejection and lymphocytic bronchiolitis, similar to humans. Long-term survivors develop histologic changes in the allografts that are hallmarks of OB. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

Human Cytomegalovirus-Encoded Receptor US28 Is Expressed in Renal Allografts and Facilitates Viral Spreading In Vitro.

PubMed

Lollinga, Wouter T; de Wit, Raymond H; Rahbar, Afsar; Vasse, Gwenda F; Davoudi, Belghis; Diepstra, Arjan; Riezebos-Brilman, Annelies; Harmsen, Martin C; Hillebrands, Jan-Luuk; Söderberg-Naucler, Cecilia; van Son, Willem J; Smit, Martine J; Sanders, Jan-Stephan; van den Born, Jacob

2017-03-01

Renal transplantation is the preferred treatment for patients with end-stage renal disease. Human cytomegalovirus (HCMV) activation is associated with decreased renal graft function and survival. Human cytomegalovirus encodes several immune modulatory proteins, including the G protein-coupled receptor US28, which scavenges human chemokines and modulates intracellular signaling. Our aim was to identify the expression and localization of US28 in renal allograft biopsies by immunohistochemistry and determine its role in viral spreading in vitro. Immunohistochemistry revealed US28 in 31 of 34 renal transplant biopsies from HCMV-seropositive donors. Expression was independent of HCMV viremia or IgG serostatus. US28 was predominantly expressed in the cytoplasm of vascular smooth muscle cells (VSMCs) and tubular epithelial cells, with a median positivity of 20% and 40%, respectively. Also, US28-positive cells were present within arterial neointima. In contrast to US28, HCMV-encoded immediate early antigen was detected in less than 5% of VSMCs, tubular epithelial cells, interstitial endothelium, interstitial inflammatory infiltrates, and glomerular cells.Primary VSMCs were infected with green fluorescent protein-tagged wild type or US28-deficient HCMV. The viral spreading of US28-deficient HCMV, via culture medium or cell-to-cell transmission, was significantly impeded as shown by green fluorescent protein (ie, infected) cell quantification and quantitative real-time polymerase chain reaction. Additionally, the number and size of foci was smaller. In summary, HCMV-encoded US28 was detected in renal allografts from HCMV-positive donors independent of viremia and serostatus. Also, US28 facilitates HCMV spreading in VSMCs in vitro. Because the vasculature is affected in chronic renal transplant dysfunction, US28 may provide a potential target for therapeutic intervention.

Non-HLA antibodies post-transplantation: clinical relevance and treatment in solid organ transplantation.

PubMed

Dragun, Duska; Hegner, Bjorn

2009-01-01

Antibodies and B cells are increasingly recognized as major modulators of allograft function and survival. Improved immunohistochemical and serologic diagnostic procedures have been developed to monitor antibody responses against HLA antigens during the last decade. Acute and chronic allograft rejection can occur in HLA-identical sibling transplants implicating the importance of immune response against non-HLA targets. Non-HLA anti-bodies may occur as alloantiboides, yet they seem to be predominantly autoantibodies. Antigenic targets of non-HLA antibodies described thus far include various minor histocompatibility antigens, vascular receptors, adhesion molecules, and intermediate filaments. Non-HLA antibodies may function as complement- and non-complement-fixing antibodies and they may induce a wide variety of allograft injuries, reflecting the complexity of their acute and chronic actions. Refined approaches considering the subtle mechanistic differences in the individual antibody responses directed against non-HLA antigens may help to define patients at particular risk for irreversible acute or chronic allograft injuries and improve over-all outcomes. We attempted to summarize the current state of research, development in diagnostic and therapeutic strategies, and to address some emerging problems in the area of humoral response against non-HLA antigens beyond ABO blood group and MHC class I chain-related gene A and B (MICA and MICB) antigens in solid organ transplantation. Copyright (c) 2009 S. Karger AG, Basel.

Gastroesophageal reflux and lung disease.

PubMed

Meyer, Keith C

2015-08-01

Gastroesophageal reflux (GER) can cause respiratory symptoms and may trigger, drive and/or worsen airway disorders, interstitial lung diseases and lung allograft dysfunction. Whether lifestyle changes and acid suppression alone can counter and prevent the adverse effects of GER on the respiratory tract remains unclear. Recent data suggest that antireflux surgery may be more effective in preventing lung disease progression in patients with idiopathic pulmonary fibrosis or lung transplant recipients who have evidence of allograft dysfunction associated with the presence of excessive GER. Additional research and clinical trials are needed to determine the role of GER in various lung disorders and identify which interventions are most efficacious in preventing the respiratory consequences of gastroesophageal reflux disease. In addition, measuring biomarkers that indicate that gastric refluxate has been aspirated into the lower respiratory tract (e.g., pepsin and bile acid concentrations in bronchoalveolar lavage fluid) may prove helpful in both diagnosis and therapeutic decision making.

Effect of Cordyceps sinensis on renal function of patients with chronic allograft nephropathy.

PubMed

Zhang, Zhihong; Wang, Xiangwei; Zhang, Yuanning; Ye, Gang

2011-01-01

To investigate the effect of Cordyceps sinensis (Bailing capsule, fermented agent of C. sinensis) on renal function of patients with chronic allograft nephropathy (CAN). A total of 231 CAN patients who underwent transplantation between 2005 and 2008 and experienced chronic graft dysfunction were randomly divided into 2 groups. Patients in group A (n = 122) were treated with immunosuppressive agents and C. sinensis (2.0 g/day, 3 times a day), while patients in group B (n = 109) were treated with traditional immunosuppressive drugs. Serum creatinine (SCr), blood urea nitrogen (BUN), creatinine clearance rate (C(Cr)) and urinary protein in 24 h (24-hour Upro) of all patients were measured before and after treatment. Urinary concentrations of transforming growth factor (TGF)-β(1), retinol-binding protein (RBP) and β(2)-microglobulin (β(2)-MG) were detected at the same time. After 6-month treatment with C. sinensis, SCr and C(Cr) in group A were significantly improved (p < 0.05), while there was no significant improvement observed for group B. There was no significant change in BUN in groups A and B (p > 0.05). 24-hour Upro, RBP and β(2)-MG were lower in group A after treatment with C. sinensis (p < 0.05 or p < 0.01), and urinary TGF-β(1) in group A was significantly lower than the values before C. sinensis treatment (p < 0.05), but showed no change in patients of group B. In group A, renal function had improved in 72 cases, stabilized in 38 cases, and worsened in 12 cases. In group B, renal function had improved in 14 cases, stabilized in 50 cases, and worsened in 45 cases (p < 0.05). C. sinensis therapy is advantageous in improving renal function of CAN patients by retarding CAN progression. Copyright © 2011 S. Karger AG, Basel.

Lipidomics comparing DCD and DBD liver allografts uncovers lysophospholipids elevated in recipients undergoing early allograft dysfunction.

PubMed

Xu, Jin; Casas-Ferreira, Ana M; Ma, Yun; Sen, Arundhuti; Kim, Min; Proitsi, Petroula; Shkodra, Maltina; Tena, Maria; Srinivasan, Parthi; Heaton, Nigel; Jassem, Wayel; Legido-Quigley, Cristina

2015-12-04

Finding specific biomarkers of liver damage in clinical evaluations could increase the pool of available organs for transplantation. Lipids are key regulators in cell necrosis and hence this study hypothesised that lipid levels could be altered in organs suffering severe ischemia. Matched pre- and post-transplant biopsies from donation after circulatory death (DCD, n = 36, mean warm ischemia time = 2 min) and donation after brain death (DBD, n = 76, warm ischemia time = none) were collected. Lipidomic discovery and multivariate analysis (MVA) were applied. Afterwards, univariate analysis and clinical associations were conducted for selected lipids differentiating between these two groups. MVA grouped DCD vs. DBD (p = 6.20 × 10(-12)) and 12 phospholipids were selected for intact lipid measurements. Two lysophosphatidylcholines, LysoPC (16:0) and LysoPC (18:0), showed higher levels in DCD at pre-transplantation (q < 0.01). Lysophosphatidylcholines were associated with aspartate aminotransferase (AST) 14-day post-transplantation (q < 0.05) and were more abundant in recipients undergoing early allograft dysfunction (EAD) (p < 0.05). A receiver-operating characteristics (ROC) curve combining both lipid levels predicted EAD with 82% accuracy. These findings suggest that LysoPC (16:0) and LysoPC (18:0) might have a role in signalling liver tissue damage due to warm ischemia before transplantation.

Post-operative imaging in liver transplantation: State-of-the-art and future perspectives

PubMed Central

Girometti, Rossano; Como, Giuseppe; Bazzocchi, Massimo; Zuiani, Chiara

2014-01-01

Orthotopic liver transplantation (OLT) represents a major treatment for end-stage chronic liver disease, as well as selected cases of hepatocellular carcinoma and acute liver failure. The ever-increasing development of imaging modalities significantly contributed, over the last decades, to the management of recipients both in the pre-operative and post-operative period, thus impacting on graft and patients survival. When properly used, imaging modalities such as ultrasound, multidetector computed tomography, magnetic resonance imaging (MRI) and procedures of direct cholangiography are capable to provide rapid and reliable recognition and treatment of vascular and biliary complications occurring after OLT. Less defined is the role for imaging in assessing primary graft dysfunction (including rejection) or chronic allograft disease after OLT, e.g., hepatitis C virus (HCV) recurrence. This paper: (1) describes specific characteristic of the above imaging modalities and the rationale for their use in clinical practice; (2) illustrates main imaging findings related to post-OLT complications in adult patients; and (3) reviews future perspectives emerging in the surveillance of recipients with HCV recurrence, with special emphasis on MRI. PMID:24876739

Pediatric lung transplantation

PubMed Central

2017-01-01

Pediatric lung transplantation has been undertaken since the 1980s, and it is today considered an accepted therapy option in carefully selected children with end-stage pulmonary diseases, providing carefully selected children a net survival benefit and improved health-related quality of life. Nowadays, >100 pediatric lung transplants are done worldwide every year. Here, specific pediatric aspects of lung transplantation are reviewed such as the surgical challenge, effects of immunosuppression on the developing pediatric immune system, and typical infections of childhood, as it is vital to comprehend that children undergoing lung transplants present a real challenge as children are not ‘just small adults’. Further, an update on the management of the pediatric lung transplant patient is provided in this review, and future challenges outlined. Indications for lung transplantation in children are different compared to adults, the most common being cystic fibrosis (CF). However, the primary diagnoses leading to pediatric lung transplantation vary considerably by age group. Furthermore, there are regional differences regarding the primary indication for lung transplantation in children. Overall, early referral, careful patient selection and appropriate timing of listing are crucial to achieve real survival benefit. Although allograft function is to be preserved, immunosuppressant-related side effects are common in children post-transplantation. Strategies need to be put into practice to reduce drug-related side effects through careful therapeutic drug monitoring and lowering of target levels of immunosuppression, to avoid acute-reversible and chronic-irreversible renal damage. Instead of a “one fits all approach”, tailored immunosuppression and a personalized therapy is to be advocated, particularly in children. Further, infectious complications are a common in children of all ages, accounting for almost 50% of death in the first year post-transplantation. However, chronic lung allograft dysfunction (CLAD) remains the major obstacle for improved long-term survival. PMID:28932575

Expression of bone morphogenetic proteins 4, 6 and 7 is downregulated in kidney allografts with interstitial fibrosis and tubular atrophy.

PubMed

Furic-Cunko, Vesna; Kes, Petar; Coric, Marijana; Hudolin, Tvrtko; Kastelan, Zeljko; Basic-Jukic, Nikolina

2015-07-01

Bone morphogenetic proteins (BMPs) are pleiotropic growth factors. This paper investigates the connection between the expression pattern of BMPs in kidney allograft tissue versus the cause of allograft dysfunction. The expression pattern of BMP2, BMP4, BMP6 and BMP7 in 50 kidney allografts obtained by transplant nephrectomy is investigated. Immunohistochemical staining is semiquantitatively evaluated for intensity to identify the expression pattern of BMPs in normal and allograft kidney tissues. The expression of BMP4 is unique between different tubular cell types in grafts without signs of fibrosis. This effect is not found in specimens with high grades of interstitial fibrosis and tubular atrophy (IFTA). In samples with IFTA grades II and III, the BMP7 expression is reduced in a significant fraction of specimens relative to those without signs of IFTA. The expression pattern of BMP6 indicates that its activation may be triggered by the act of transplantation and subsequent reperfusion injury. The expression of BMP2 is strong in all types of tubular epithelial cells and does not differ between the compared allografts and control kidney specimens. The intensity and expression pattern of BMP4, BMP6 and BMP7 in transplanted kidney tissue are found to be dependent upon the length of the transplanted period, the clinical indication for transplant nephrectomy and signs of IFTA in kidney tissue.

BK Virus-Associated Nephropathy: Current Situation in a Resource-Limited Country.

PubMed

Yooprasert, P; Rotjanapan, P

Data on BK virus-associated nephropathy (BKVAN) and treatment strategy in a resource-limited country are scarce. This study aimed to evaluate epidemiology of BKVAN and its situation in Thailand. A retrospective analysis was conducted among adult kidney transplant recipients at Ramathibodi Hospital from October 2011 to September 2016. Patients' demographic data, information on kidney transplantation, immunosuppressive therapy, cytomegalovirus and BK virus infections, and allograft outcomes were retrieved and analyzed. This study included 623 kidney transplant recipients. Only 327 patients (52.49%) received BK virus infection screening, and 176 of 327 patients had allograft dysfunction as a trigger for screening. BKVAN was identified in 39 of 327 patients (11.93%). Deceased donor transplantation and cytomegalovirus infection were associated with a higher risk of BKVAN (odds ratio = 2.2, P = .024, 95% confidence intervals [1.1, 4.43], and odds ratio = 2.6, P = .006, 95% confidence intervals [1.29, 5.26], respectively). BKVAN patients were at significantly higher risk for allograft rejection (P < .001) and allograft failure (P = .036). At the end of the study, 4 graft losses were documented (12.12%). BKVAN was associated with high rate of allograft rejection and failure. However, surveillance of its complications has been underperformed at our facility. Implementing a formal practice guideline may improve allograft outcome in resource-limited countries. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Nitration and inactivation of manganese superoxide dismutase in chronic rejection of human renal allografts.

PubMed Central

MacMillan-Crow, L A; Crow, J P; Kerby, J D; Beckman, J S; Thompson, J A

1996-01-01

Inflammatory processes in chronic rejection remain a serious clinical problem in organ transplantation. Activated cellular infiltrate produces high levels of both superoxide and nitric oxide. These reactive oxygen species interact to form peroxynitrite, a potent oxidant that can modify proteins to form 3-nitrotyrosine. We identified enhanced immunostaining for nitrotyrosine localized to tubular epithelium of chronically rejected human renal allografts. Western blot analysis of rejected tissue demonstrated that tyrosine nitration was restricted to a few specific polypeptides. Immunoprecipitation and amino acid sequencing techniques identified manganese superoxide dismutase, the major antioxidant enzyme in mitochondria, as one of the targets of tyrosine nitration. Total manganese superoxide dismutase protein was increased in rejected kidney, particularly in the tubular epithelium; however, enzymatic activity was significantly decreased. Exposure of recombinant human manganese superoxide dismutase to peroxynitrite resulted in a dose-dependent (IC50 = 10 microM) decrease in enzymatic activity and concomitant increase in tyrosine nitration. Collectively, these observations suggest a role for peroxynitrite during development and progression of chronic rejection in human renal allografts. In addition, inactivation of manganese superoxide dismutase by peroxynitrite may represent a general mechanism that progressively increases the production of peroxynitrite, leading to irreversible oxidative injury to mitochondria. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:8876227

Infections and reduced functioning kidney mass induce chronic rejection in rat kidney allografts.

PubMed

Heemann, U W; Azuma, H; Tullius, S G; Schmid, C; Philipp, T; Tilney, N L

1996-07-01

The etiology of chronic rejection of kidney allografts is unknown, although hyperfiltration, acute rejection, viral infection and initial graft ischemia have been implicated. To test whether endothelial activation may be the link between these factors and chronic rejection, the endotoxin (lipopolysaccharide-LPS), a potent activator of endothelial cells, was evaluated in an established chronic rejection model. Bilaterally nephrectomized Lewis recipients of orthotopically transplanted Fisher 344 kidneys were treated briefly with low dose cyclosporine (1.5 mg/kg/day x 10). Recipients were given a non-lethal dose of LPS (2 mg) i.p. at 8 weeks and compared to allografted controls treated with vehicle. Urine protein was measured every 4 weeks. Rats in the treated group were sacrificed at 12 and 16 weeks, control animals at 12, 16 and 24 weeks (20/group) and examined histologically. In the chronically rejecting control allografts, progressive interstitial and glomerular sclerosis and vascular intimal proliferation had become apparent by 12 weeks. Infiltration of glomeruli, particularly by macrophages (M phi), and the coincident presence of cytokines were prominent, peaking at 16 weeks. LPS treatment accelerated and intensified these changes; proteinuria was more pronounced (16 weeks: 79 mg/24 h vs. 49 mg/24 h, p < 0.05). Numbers of infiltrating M phi peaked at 12 weeks in LPS treated hosts (69 c/FV vs. 27 c/FV in untreated controls, p < 0.01), accompanied by an increased upregulation of MHC class II and cytokine expression, particularly TNF alpha and PDGF around arteries and areas of infiltration. BY 16 weeks, 35 +/- 3% of glomeruli in LPS treated recipients had become sclerotic vs. 15 +/- 6% (p < 0.05) in controls, again associated with increased expression of cytokines (PDGF, TNF alpha, TGF beta), adhesion molecules (ICAM-1) and extracellular matrix proteins. Overall, the extent of chronic rejection of grafts in LPS treated rats at 16 weeks was similar to that developing in non-treated rats at 24 weeks. Activation of graft endothelium and/or host leucocytes increased the pace of graft infiltration and the expression of cytokines and other molecules. These events accelerate the process of chronic rejection.

Improvement in late renal allograft survival between 1990 and 2002 in Spain: results from a multicentre case-control study.

PubMed

Moreso, Francesc; Alonso, Angel; Gentil, Miguel A; González-Molina, Miguel; Capdevila, Lluis; Marcén, Roberto; Pascual, Julio; Serón, Daniel

2010-09-01

Epidemiological studies have failed to show an improvement in graft survival beyond 1 year after kidney transplantation possibly because of an increased number of expanded donors and older recipients. Thus, we performed a case-control study matching patients transplanted in different eras by donor and recipient characteristics. We considered renal transplant recipients included in the database of the Spanish Chronic Allograft Dysfunction Study Group in 1990, 1994, 1998 and 2002 (n = 4842). We matched patients from these cohorts considering the following variables: donor and recipient age, cause of donor death, hepatitis C virus, panel reactive antibodies and re-transplantation. We identified a total of 896 patients distributed in four cohorts of 224 matched patients. Between 1990 and 2002, the use of cyclosporin decreased (96%, 94%, 80% and 23% respectively, P = 0.001), while the use of tacrolimus increased (0%, 1%, 15% and 63% respectively, P = 0.001) and the prevalence of acute rejection decreased (46%, 37.9%, 20.6% and 15.8% respectively, P < 0.001). One-year serum creatinine was 1.63 +/- 0.66, 1.64 +/- 0.70, 1.44 +/- 0.52 and 1.38 +/- 0.75 respectively, P = 0.001. Graft survival beyond the first year between 1990 and 2002 significantly improved while patient survival did not. Transplant outcome has improved between 1990 and 2002 when donors and recipients of similar characteristics are compared.

Comprehensive outcomes after lung retransplantation: a single center review.

PubMed

Halloran, Kieran; Aversa, Meghan; Tinckam, Kathryn; Martinu, Tereza; Binnie, Matthew; Chaparro, Cecilia; Chow, Chung-Wai; Waddell, Tom; McRae, Karen; Pierre, Andrew; de Perrot, Marc; Yasufuku, Kazuhiro; Cypel, Marcelo; Keshavjee, Shaf; Singer, Lianne G

2018-05-13

Lung retransplantation is an important therapy for a growing population of lung transplant recipients with graft failure, but detailed outcome data are lacking. We conducted a retrospective cohort study of adult lung retransplant in the Toronto Lung Transplant Program from 2001 to 2013 (n=38). We analyzed the post-operative course, graft function, renal function, microbiology, donor specific antibodies (DSA), quality of life and survival compared to a control cohort of primary transplant recipients matched for age and era. Indication for retransplant was chronic lung allograft dysfunction in most retransplant recipients (35/38, 82%). The post-operative course was more complex after retransplant than primary (ventilation time, 8 vs. 2 days, p<0.01; ICU stay 14 vs. 4 days, 0<0.01) and peak lung function was lower (FEV1 2.2L vs. 3L, p<0.01). Quality of life scores were comparable, as were renal function, microbiology and donor specific antibody formation. Median survival was 1988 days after primary and 1475 days after retransplant (p=0.39). Lung retransplantation is associated with a more complex post-operative course and lower peak lung function, but the long term medical profile is similar to primary transplant. Lung retransplantation can be beneficial for carefully selected candidates with allograft failure. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Role of inducible nitric oxide synthase in transplant arteriosclerosis.

PubMed

Lee, P C; Shears, L L; Billiar, T R

1999-12-01

1. Transplant arteriosclerosis is a major obstacle to long-term allograft survival. Nitric oxide (NO) has been implicated as a mediator in the development of this disease. 2. We and others have shown that inducible nitric oxide synthase (iNOS) is up-regulated in allografts with transplant arteriosclerosis. Despite the acute cytotoxic effects produced by high levels of NO, a chronic increase in NO availability is protective against neointimal hyperplasia, mainly by suppressing the inflammatory cell recruitment and neointimal smooth muscle cell accumulation. 3. Currently, we have the technology to directly transfer the iNOS gene to allografts. We have demonstrated that this exciting strategy is feasible and therapeutic and may improve the long-term survival and function of allografts. Future challenges include optimizing the methods and the vectors of gene delivery.

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop.

PubMed

Lama, Vibha N; Belperio, John A; Christie, Jason D; El-Chemaly, Souheil; Fishbein, Michael C; Gelman, Andrew E; Hancock, Wayne W; Keshavjee, Shaf; Kreisel, Daniel; Laubach, Victor E; Looney, Mark R; McDyer, John F; Mohanakumar, Thalachallour; Shilling, Rebecca A; Panoskaltsis-Mortari, Angela; Wilkes, David S; Eu, Jerry P; Nicolls, Mark R

2017-05-04

Lung transplantation, a cure for a number of end-stage lung diseases, continues to have the worst long-term outcomes when compared with other solid organ transplants. Preclinical modeling of the most common and serious lung transplantation complications are essential to better understand and mitigate the pathophysiological processes that lead to these complications. Various animal and in vitro models of lung transplant complications now exist and each of these models has unique strengths. However, significant issues, such as the required technical expertise as well as the robustness and clinical usefulness of these models, remain to be overcome or clarified. The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in March 2016 to review the state of preclinical science addressing the three most important complications of lung transplantation: primary graft dysfunction (PGD), acute rejection (AR), and chronic lung allograft dysfunction (CLAD). In addition, the participants of the workshop were tasked to make consensus recommendations on the best use of these complimentary models to close our knowledge gaps in PGD, AR, and CLAD. Their reviews and recommendations are summarized in this report. Furthermore, the participants outlined opportunities to collaborate and directions to accelerate research using these preclinical models.

Comparison of peritoneal dialysis and hemodialysis after kidney transplant failure.

PubMed

Kang, G W; Jang, M H; Hwang, E A; Park, S B; Han, S Y

2013-10-01

Patients with a failed kidney transplant represent a unique chronic kidney disease population that is increasing in number and is at high risk of morbidity and mortality. Among transplant-naïve patients, those treated with peritoneal dialysis (PD) show an early survival advantage compared with those treated with hemodialysis (HD). But any advantage of PD after allograft failure is unknown. The aim of this study was to investigate the clinical outcomes of patients with failed allografts according to the type of dialysis modality. We reviewed medical records of patients who initiated dialysis after kidney transplant failure from November 1982 to May 2011. Demographics features, clinical data, and survival outcomes were compared between PD and HD patients who had experienced allograft failure. The 182 patients with failed allografts showed the most common cause to be chronic rejection. The median duration of function before allograft failure was 74.0 months. After allograft failure, 145 (79.7%) patients returned to HD and 37 (20.3%) to PD. Twenty-three patients (12.6%) died over the median 69.1 months duration of follow-up. During the observation period, 16 HD (11%) and 7 PD (8.9%) patients died. The survival rates of PD patients at 1 year were 91.2% and 84.4%, respectively, at 1 and 3 years, and those of HD patients 94.8% and 88.9%. There was no significant difference in the survivals of the 2 groups. The study suggests that the outcome of patients starting PD after kidney transplant failure was similar to those starting HD. Therefore, PD can be regarded to be a good treatment option for patients returning to dialysis after kidney transplant failure. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Nocturnal polyuria and saluresis in renal allograft recipients.

PubMed Central

Chan, M K; Varghese, Z; Fernando, O N; Moorhead, J F

1980-01-01

The evolution of nocturnal polyuria and saluresis in renal allograft recipients was studied by comparing the day to night (D:N) ratios of urine volume and sodium excretion in 15 patients who had undergone transplantation less than one year previously (recent-transplant group) with those in 11 patients who had undergone transplantation at least one year previously. Eleven patients with chronic renal failure and 12 normal subjects served as controls. Patients in the recent-transplant group had significantly lower D:N ratios of urine volume and sodium excretion than the patients who had undergone transplantation at least a year before, while the ratios in this last group did not differ significantly from those in the normal subjects. Nocturnal polyuria and saluresis gradually subsided in five patients studied for three months. Chronic renal failure and uraemic autonomic neuropathy were unlikely causes of the nocturia. The patients in the recent-transplant group had significantly lower D:N ratios of urine volume than the controls with chronic renal failure, and the mean Valsalva ratio in eight of them was not significantly different from that in the normal subjects. An undue sensitivity of renal allografts to postural influences was proposed. PMID:6986946

The Impact of Timing and Graft Dysfunction on Survival and Cardiac Allograft Vasculopathy in Antibody Mediated Rejection

PubMed Central

Clerkin, Kevin J.; Restaino, Susan W.; Zorn, Emmanuel; Vasilescu, Elena R.; Marboe, Charles C.; Mancini, Donna M.

2017-01-01

Background Antibody mediated rejection (AMR) has been associated with increased mortality and cardiac allograft vasculopathy (CAV). Early studies suggested that late AMR was rarely associated with graft dysfunction while recent reports have demonstrated an association with increased mortality. We sought to investigate the timing of AMR and its association with graft dysfunction, mortality, and CAV. Methods This retrospective cohort study identified all adult heart transplant recipients at Columbia University Medical Center from 2004–2013 (689 patients). There were 68 primary cases of AMR, which were stratified by early (<1 year post-OHT) or late (>1-year post-OHT) AMR. Kaplan-Meier survival analysis and modeling was performed with multivariable logistic regression and Cox proportional hazards regression. Results From January 1, 2004 through October 1, 2015 43 patients had early AMR (median 23 days post-OHT) and 25 had late AMR (median 1084 days post-OHT). Graft dysfunction was less common with early compared with late AMR (25.6% vs. 56%, p=0.01). Patients with late AMR had decreased post-AMR survival compared with early AMR (1-year 80% vs. 93%, 5-year 51% vs. 73%, p<0.05). When stratified by graft dysfunction, only those with late AMR and graft dysfunction had worse survival (30-day 79%, 1-year 64%, and 5-year 36%, p<0.006). The association remained irrespective of age, sex, DSA, LVAD use, reason for OHT, and recovery of graft function. Similarly, those with late AMR and graft dysfunction had accelerated development of de-novo CAV (50% at 1 year, HR 5.42, p=0.009), while all other groups were all similar to the general transplant population. Conclusion Late AMR is frequently associated with graft dysfunction. When graft dysfunction is present in late AMR there is an early and sustained increased risk of mortality and rapid development of de-novo CAV despite aggressive treatment. PMID:27423693

Surgical Anatomy and Microvascular Surgical Technique Relevant to Experimental Renal Transplant in Rat Employing Aortic and Inferior Venacaval Conduits.

PubMed

Shrestha, Badri Man; Haylor, John

2017-11-15

Rat models of renal transplant are used to investigate immunologic processes and responses to therapeutic agents before their translation into routine clinical practice. In this study, we have described details of rat surgical anatomy and our experiences with the microvascular surgical technique relevant to renal transplant by employing donor inferior vena cava and aortic conduits. For this study, 175 rats (151 Lewis and 24 Fisher) were used to establish the Fisher-Lewis rat model of chronic allograft injury at our institution. Anatomic and technical details were recorded during the period of training and establishment of the model. A final group of 12 transplanted rats were studied for an average duration of 51 weeks for the Lewis-to-Lewis isografts (5 rats) and 42 weeks for the Fisher-to-Lewis allografts (7 rats). Functional measurements and histology confirmed the diagnosis of chronic allograft injury. Mastering the anatomic details and microvascular surgical techniques can lead to the successful establishment of an experimental renal transplant model.

Local immunomodulation with Fas ligand-engineered biomaterials achieves allogeneic islet graft acceptance.

PubMed

Headen, Devon M; Woodward, Kyle B; Coronel, María M; Shrestha, Pradeep; Weaver, Jessica D; Zhao, Hong; Tan, Min; Hunckler, Michael D; Bowen, William S; Johnson, Christopher T; Shea, Lonnie; Yolcu, Esma S; García, Andrés J; Shirwan, Haval

2018-06-04

Islet transplantation is a promising therapy for type 1 diabetes. However, chronic immunosuppression to control rejection of allogeneic islets induces morbidities and impairs islet function. T effector cells are responsible for islet allograft rejection and express Fas death receptors following activation, becoming sensitive to Fas-mediated apoptosis. Here, we report that localized immunomodulation using microgels presenting an apoptotic form of the Fas ligand with streptavidin (SA-FasL) results in prolonged survival of allogeneic islet grafts in diabetic mice. A short course of rapamycin treatment boosted the immunomodulatory efficacy of SA-FasL microgels, resulting in acceptance and function of allografts over 200 days. Survivors generated normal systemic responses to donor antigens, implying immune privilege of the graft, and had increased CD4 + CD25 + FoxP3 + T regulatory cells in the graft and draining lymph nodes. Deletion of T regulatory cells resulted in acute rejection of established islet allografts. This localized immunomodulatory biomaterial-enabled approach may provide an alternative to chronic immunosuppression for clinical islet transplantation.

Early treatment with xenon protects against the cold ischemia associated with chronic allograft nephropathy in rats.

PubMed

Zhao, Hailin; Luo, Xianghong; Zhou, Zhaowei; Liu, Juying; Tralau-Stewart, Catherine; George, Andrew J T; Ma, Daqing

2014-01-01

Chronic allograft nephropathy (CAN) is a common finding in kidney grafts with functional impairment. Prolonged hypothermic storage-induced ischemia-reperfusion injury is associated with the early onset of CAN. As the noble gas xenon is clinically used as an anesthetic and has renoprotective properties in a rodent model of ischemia-reperfusion injury, we studied whether early treatment with xenon could attenuate CAN associated with prolonged hypothermic storage. Exposure to xenon enhanced the expression of insulin growth factor-1 (IGF-1) and its receptor in human proximal tubular (HK-2) cells, which, in turn, increased cell proliferation. Xenon treatment before or after hypothermia-hypoxia decreased cell apoptosis and cell inflammation after reoxygenation. The xenon-induced HK-2 cell proliferation was abolished by blocking the IGF-1 receptor, mTOR, and HIF-1α individually. In the Fischer-to-Lewis rat allogeneic renal transplantation model, xenon exposure of donors before graft retrieval or recipients after engraftment enhanced tubular cell proliferation and decreased tubular cell death and cell inflammation associated with ischemia-reperfusion injury. Compared with control allografts, xenon treatment significantly suppressed T-cell infiltration and fibrosis, prevented the development of CAN, and improved renal function. Thus, xenon treatment promoted recovery from ischemia-reperfusion injury and reduced susceptibility to the subsequent development of CAN in allografts.

Assessment of pathological changes associated with chronic allograft rejection and tolerance in two experimental models of rat lung transplantation.

PubMed

Matsumura, Y; Marchevsky, A; Zuo, X J; Kass, R M; Matloff, J M; Jordan, S C

1995-06-15

Lung transplantation is now routinely performed for a wide range of end-stage cardiopulmonary disorders. Despite overcoming the problems associated with early acute rejection, chronic rejection (CR) in the form of obliterative bronchiolitis has emerged as the primary cause of late graft loss. The mechanisms involved in the development of CR of lung allografts are poorly understood, and no effective therapy is currently available. To better understand the pathological events associated with CR and tolerance, we examined two models of lung allograft rejection established in our laboratory. First, we exchanged left lung allografts between moderately histoincompatible inbred rat strains (WKY-->F344: n = 42 and F344-->WKY: n = 40). The WKY-->F344 model was previously shown to develop spontaneous tolerance, while the converse model (F344-->WKY) showed persistent acute rejection. The purpose of this investigation was to assess histopathological changes associated with long-term grafts left in place up to 140 days after transplant. To confirm that tolerance had developed, skin-grafting experiments were performed. Five skin grafts from each strain were placed on lung allograft recipients on day 35 after transplant and skin allograft survival was assessed and compared with controls. Acute rejection (AR) was graded histologically (stage O-IV) and the pathologic intensity of inflammation and CR were graded (0-4: 0 = 0%, 1 = 1-25%, 2 = 26-50%, 3 = 51-75%, and 4 = 76-100%) on percentage of involvement with the following categories being examined: (a) lymphocytic infiltration (perivascular, peribronchial, and peribronchiolar) and (b) vasculitis, edema, hemorrhage, and necrosis. Finally, chronic rejection was diagnosed by the presence of intimal hyperplasia, interstitial fibrosis, peribronchiolar fibrosis, bronchiolitis obliterans, and bronchiectasis. The WKY-->F344 animals showed progressive AR (stage III, day 21). Thereafter, the AR subsided spontaneously and was stage 0 on day 140. There were no signs of CR in these animals. In the F344-->WKY model, the AR progressed up to stage III-IV (day 21) and maintained for several weeks at stage III. Thereafter, pictures of the lungs showed CR on days 49, 70, and 98. There were significant differences between the two models during the chronic phase, such as interstitial fibrosis (0 +/- 0 vs. 1.8 +/- 1.3, P < 0.005), peribronchiolar fibrosis (0 +/- 0 vs. 3.6 +/- 0.55, P < 0.01), vasculitis (0.2 +/- 0.45 vs. 2.0 +/- 0, P < 0.008), and intimal hyperplasia (0.2 +/- 0.45 vs. 2.6 +/- 0.9, P < 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)

Defining kidney allograft benefit from successful pancreas transplant: separating fact from fiction.

PubMed

Wiseman, Alexander C; Stites, Erik; Kennealey, Peter

2018-06-06

To define the natural history of kidney allograft loss related to recurrent diabetes following transplant, and to understand the potential benefit of pancreas transplantation upon kidney allograft survival. A postulated benefit of simultaneous pancreas kidney transplant is that, unlike kidney transplant alone, euglycemia from the added pancreas allograft may confer a nephroprotective benefit and prevent recurrent diabetic nephropathy in the renal allograft. Recent large database analyses and long-term histological assessments have been published that assist in quantifying the problem of recurrent diabetic nephropathy and answering the question of the potential benefits of euglycemia. Further data may be extrapolated from larger single-center series that follow the prognosis of early posttransplant diabetes mellitus as another barometer of risk from diabetic nephropathy and graft loss. Recurrent diabetic nephropathy following kidney transplant is a relatively rare, late occurrence and its clinical significance is significantly diminished by the competing risks of death and chronic alloimmune injury. Although there are hints of a protective effect upon kidney graft survival with pancreas transplant, these improvements are small and may take decades to appreciate. Clinical decision-making regarding pancreas transplant solely based upon nephroprotective effects of the kidney allograft should be avoided.

Serum Uromodulin: A Biomarker of Long-Term Kidney Allograft Failure.

PubMed

Bostom, Andrew; Steubl, Dominik; Garimella, Pranav S; Franceschini, Nora; Roberts, Mary B; Pasch, Andreas; Ix, Joachim H; Tuttle, Katherine R; Ivanova, Anastasia; Shireman, Theresa; Kim, S Joseph; Gohh, Reginald; Weiner, Daniel E; Levey, Andrew S; Hsu, Chi-Yuan; Kusek, John W; Eaton, Charles B

2018-01-01

Uromodulin is a kidney-derived glycoprotein and putative tubular function index. Lower serum uromodulin was recently associated with increased risk for kidney allograft failure in a preliminary, longitudinal single-center -European study involving 91 kidney transplant recipients (KTRs). The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial is a completed, large, multiethnic controlled clinical trial cohort, which studied chronic, stable KTRs. We conducted a case cohort analysis using a randomly selected subset of patients (random subcohort, n = 433), and all individuals who developed kidney allograft failure (cases, n = 226) during follow-up. Serum uromodulin was determined in this total of n = 613 FAVORIT trial participants at randomization. Death-censored kidney allograft failure was the study outcome. The 226 kidney allograft failures occurred during a median surveillance of 3.2 years. Unadjusted, weighted Cox proportional hazards modeling revealed that lower serum uromodulin, tertile 1 vs. tertile 3, was associated with a threefold greater risk for kidney allograft failure (hazards ratio [HR], 95% CI 3.20 [2.05-5.01]). This association was attenuated but persisted at twofold greater risk for allograft failure, after adjustment for age, sex, smoking, allograft type and vintage, prevalent diabetes mellitus and cardiovascular disease (CVD), total/high-density lipoprotein cholesterol ratio, systolic blood pressure, estimated glomerular filtration rate, and natural log urinary albumin/creatinine: HR 2.00, 95% CI (1.06-3.77). Lower serum uromodulin, a possible indicator of less well-preserved renal tubular function, remained associated with greater risk for kidney allograft failure, after adjustment for major, established clinical kidney allograft failure and CVD risk factors, in a large, multiethnic cohort of long-term, stable KTRs. © 2018 S. Karger AG, Basel.

Role of airway epithelial injury in murine orthotopic tracheal allograft rejection.

PubMed

Kuo, Elbert; Bharat, Ankit; Shih, Jennifer; Street, Tyler; Norris, Jenyi; Liu, Wei; Parks, William; Walter, Michael; Patterson, G Alexander; Mohanakumar, T

2006-10-01

Murine tracheal transplantation is a model used to study bronchiolitis obliterans syndrome, a major cause of morbidity and mortality after lung transplantation. Unlike murine heterotopic tracheal transplants, orthotopic transplantation does not cause luminal obliteration despite major histocompatibility antigen mismatch. Repopulation of the tracheal allografts with recipient-derived epithelium confers protection against luminal obliteration. The purpose of this study was to determine whether (1) orthotopic tracheal transplantation showed signs of allograft rejection, and (2) airway epithelial cell injury promoted orthotopic tracheal allograft rejection. Forty isogeneic (C57BL/6 to C57BL/6) and 40 allogeneic (BALB/c to C57BL/6) orthotopic tracheal transplants were performed. Damage to airway epithelial cells was induced by Sendai viral (SdV) infection and tracheal transplantation into non-reepithelializing matrix metalloproteinase-7 knockout (MMP7-KO) recipient mice. Percent fibrosis and lamina propria to cartilage ratio were calculated with computer assistance on harvested allografts. Allografts showed significantly more intramural fibrosis compared with isografts at 30, 60, and 180 days after transplant without luminal occlusion. Tracheal allografts infected with SdV showed an increase in fibrosis and lamina propria to cartilage ratio compared with noninfected controls. Allografts retrieved from MMP7-KO recipients also showed a significant increase in fibrosis and lamina propria to cartilage ratio. Although orthotopic tracheal transplantation does not cause luminal obliteration, it results in increased fibrosis in allografts. Damage to the respiratory epithelium by viral infection or defective reepithelialization after transplant as seen in MMP7-KO recipient mice leads to changes consistent with chronic allograft rejection, suggesting a role for epithelial injury in bronchiolitis obliterans syndrome development.

Local Origin of Mesenchymal Cells in a Murine Orthotopic Lung Transplantation Model of Bronchiolitis Obliterans

PubMed Central

Mimura, Takeshi; Walker, Natalie; Aoki, Yoshiro; Manning, Casey M.; Murdock, Benjamin J.; Myers, Jeffery L.; Lagstein, Amir; Osterholzer, John J.; Lama, Vibha N.

2016-01-01

Bronchiolitis obliterans is the leading cause of chronic graft failure and long-term mortality in lung transplant recipients. Here, we used a novel murine model to characterize allograft fibrogenesis within a whole-lung microenvironment. Unilateral left lung transplantation was performed in mice across varying degrees of major histocompatibility complex mismatch combinations. B6D2F1/J (a cross between C57BL/6J and DBA/2J) (Haplotype H2b/d) lungs transplanted into DBA/2J (H2d) recipients were identified to show histopathology for bronchiolitis obliterans in all allogeneic grafts. Time course analysis showed an evolution from immune cell infiltration of the bronchioles and vessels at day 14, consistent with acute rejection and lymphocytic bronchitis, to subepithelial and intraluminal fibrotic lesions of bronchiolitis obliterans by day 28. Allografts at day 28 showed a significantly higher hydroxyproline content than the isografts (33.21 ± 1.89 versus 22.36 ± 2.33 μg/mL). At day 40 the hydroxyproline content had increased further (48.91 ± 7.09 μg/mL). Flow cytometric analysis was used to investigate the origin of mesenchymal cells in fibrotic allografts. Collagen I–positive cells (89.43% ± 6.53%) in day 28 allografts were H2Db positive, showing their donor origin. This novel murine model shows consistent and reproducible allograft fibrogenesis in the context of single-lung transplantation and represents a major step forward in investigating mechanisms of chronic graft failure. PMID:25848843

Respiratory viral infection in obliterative airway disease after orthotopic tracheal transplantation.

PubMed

Kuo, Elbert; Bharat, Ankit; Goers, Trudie; Chapman, Will; Yan, Le; Street, Tyler; Lu, Wei; Walter, Michael; Patterson, Alexander; Mohanakumar, Thalachallour

2006-09-01

The long-term survival after human lung transplantation is limited by bronchiolitis obliterans syndrome (BOS). Clinically, community-acquired respiratory viral infections have been correlated with an increased incidence of BOS. The goal of this study was to investigate the role of respiratory viral infections in chronic lung allograft rejection using the murine orthotopic tracheal transplantation model. Eighty orthotopic tracheal transplants were performed using BALB/c and C57BL/6 mice. Recipient mice were infected intranasally with Sendai virus (SdV), a murine parainfluenza type I virus. Experiments altering the infectious dose, infection time, harvest time, allogeneic response, and viral response were performed. Tracheal allograft rejection was monitored using percent fibrosis and lamina propria to cartilage ratio measurements. Interferon-gamma ELISPOT analysis against irradiated donor (BALB/c) splenocytes was used as immunologic indicator of alloreactivity after transplantation. Sendai virus infection revealed a dose-dependent transient suppression of alloreactivity with a decrease in tracheal allograft fibrosis and frequency of alloreactive T cells at 30 days. This immunosuppression was reversed by day 60, leading to increased tracheal allograft fibrosis with a concomitant increase in the frequency of interferon-gamma producing alloreactive T cells. Pretransplant sensitization with donor antigens prevented the initial suppression of alloreactivity due to SdV infection. Furthermore, pretransplant immunization against SdV infection resulted in rapid clearing of the infection and reduced the immunopathology of rejection. Respiratory viral infections can cause enhanced tracheal allograft rejection despite the initial phase of transient immunosuppression. Early treatment or vaccination against the respiratory infections may represent a viable intervention to reduce the risk of chronic rejection.

CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection.

PubMed

Afford, S C; Randhawa, S; Eliopoulos, A G; Hubscher, S G; Young, L S; Adams, D H

1999-01-18

We propose that a novel mechanism of hepatocyte apoptosis, involving a cooperative interaction between CD40 and Fas, is involved in the hepatocyte loss of chronic liver allograft rejection. We detected increased hepatocyte expression of Fas, Fas ligand (FasL), and CD40 associated with dropout of centrilobular (acinar zone 3) hepatocytes in chronic allograft rejection. Expression of CD40 ligand (CD40L) was also increased but was largely restricted to CD68(+) macrophages. A functional role for CD40 and Fas in hepatocyte apoptosis was demonstrated in vitro using primary human hepatocytes and the HepG2 cell line in both of which apoptosis was induced, not only by cross-linking Fas directly but also via CD40 activation. Our data suggest that CD40 activation induces apoptosis via Fas because (a) ligation of CD40 upregulated hepatocyte FasL expression, and (b) apoptosis induced via activation of CD40 was prevented by a neutralizing monoclonal antibody to FasL. Thus, CD40 engagement triggers apoptosis of human hepatocytes and might amplify Fas-dependent hepatocyte apoptosis in chronic rejection and other inflammatory liver diseases in which Fas-mediated apoptosis is involved.

Gynaecomastia with hypergonadotrophic hypogonadism and Leydig cell insufficiency in recipients of high-dose chemotherapy or chemo-radiotherapy.

PubMed

Harris, E; Mahendra, P; McGarrigle, H H; Linch, D C; Chatterjee, R

2001-12-01

Late side-effects of stem cell transplantation include hypogonadism with infertility and sexual dysfunction, but gynaecomastia is less well recognised. We report five cases of gynaecomastia with features of hypergonadotrophic hypogonadism (primary testicular failure), who received either a TBI/cyclophosphamide conditioned allograft (n = 3) or a BEAM autograft (n = 2). Patients receiving an allograft had gynaecomastia, Leydig cell insufficiency (LCI) diminished libido and erectile dysfunction. Surgery was required in one case, while in two cases the gynaecomastia resolved spontaneously after 6 months. Two patients also had gynaecomastia and sexual dysfunction, severe hypogonadism, very low testosterone levels and marked hyperprolactinaemia following autoBMT. Both responded well to testosterone replacement therapy (TRT). As a group, all patients had primary testicular failure and all except one, had LCI (compensated or frank). However, there was no correlation between the severity of gynaecomastia and the degree of endocrine dysfunction. This preliminary study is the first to suggest that gynaecomastia, due to primary hypogonadism and LCI, may be a significant complication of myeloablative conditioning therapy. Therefore gynaecomastia in BMT recipients must always be treated as a pathological entity as it may be the external manifestation of a complex endocrine pathology. It is a potentially treatable condition. Although spontaneously reversible, some patients may require TRT or even surgery. We recommend comprehensive endocrine testing in conjunction with a reproductive endocrinologist and prompt intervention to alleviate embarrassment and anxiety in afflicted BMT recipients.

Early Allograft Dysfunction After Liver Transplantation Is Associated With Short- and Long-Term Kidney Function Impairment.

PubMed

Wadei, H M; Lee, D D; Croome, K P; Mai, M L; Golan, E; Brotman, R; Keaveny, A P; Taner, C B

2016-03-01

Early allograft dysfunction (EAD) after liver transplantation (LT) is related to ischemia-reperfusion injury and may lead to a systemic inflammatory response and extrahepatic organ dysfunction. We evaluated the effect of EAD on new-onset acute kidney injury (AKI) requiring renal replacement therapy within the first month and end-stage renal disease (ESRD) within the first year post-LT in 1325 primary LT recipients. EAD developed in 358 (27%) of recipients. Seventy-one (5.6%) recipients developed AKI and 38 (2.9%) developed ESRD. Compared with those without EAD, recipients with EAD had a higher risk of AKI and ESRD (4% vs. 9% and 2% vs. 6%, respectively, p < 0.001 for both). Multivariate logistic regression analysis showed an independent relationship between EAD and AKI as well as ESRD (odds ratio 3.5, 95% confidence interval 1.9-6.4, and odds ratio 3.1, 95% confidence interval 11.9-91.2, respectively). Patients who experienced both EAD and AKI had inferior 1-, 3-, 5-, and 10-year patient and graft survival compared with those with either EAD or AKI alone, while those who had neither AKI nor EAD had the best outcomes (p < 0.001). Post-LT EAD is a risk factor for both AKI and ESRD and should be considered a target for future intervention to reduce post-LT short- and long-term renal dysfunction. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Could Sentinel Skin Transplants Have Some Utility in Solid Organ Transplantation?

PubMed

Ali, J M; Catarino, P; Dunning, J; Giele, H; Vrakas, G; Parmar, J

2016-10-01

Accurate diagnosis of allograft rejection can be hazardous and challenging. A strategy that has emerged from experience with vascularized composite allografts (VCAs) is the use of sentinel skin transplants (SSTs)-portions of donor skin transplanted synchronously to an allograft. Work in nonhuman animal models and experience with VCAs suggest concordance between rejection occurring in the primary allograft and the SST, and that appearance of rejection in the SST may precede rejection in the primary allograft, permitting early therapeutic intervention that may improve outcomes with lower rates of chronic rejection. The encouraging findings reported in VCA transplantation raise the possibility that SST may also be useful in solid organ transplantation. Some evidence is provided by experience with abdominal wall transplantation in some intestinal and multivisceral transplant recipients. Results from those reports raise the possibility that rejection may manifest in the skin component before emergence in the intestinal allograft, providing a "lead time" during which treatment of rejection of the abdominal wall could prevent the emergence of intestinal rejection. It is plausible that these findings may be extrapolated to other solid organ allografts, especially those for which obtaining an accurate diagnosis of acute rejection can be hazardous and challenging, such as the lung or pancreas. However, more data are required to support widespread adoption of this technique. Copyright © 2016 Elsevier Inc. All rights reserved.

Clinical Outcomes of Lung Transplantation in Patients with Telomerase Mutations

PubMed Central

Tokman, Sofya; Singer, Jonathan P.; Devine, Megan S.; Westall, Glen P.; Aubert, John-David; Tamm, Michael; Snell, Gregory I.; Lee, Joyce S.; Goldberg, Hilary J.; Kukreja, Jasleen; Golden, Jeffrey A.; Leard, Lorriana E.; Garcia, Christine K.; Hays, Steven R.

2017-01-01

Background Successful lung transplantation (LT) for patients with pulmonary fibrosis from telomerase mutations is limited by systemic complications of telomerase dysfunction including myelosuppression, cirrhosis, and malignancy. We describe clinical outcomes among 14 LT recipients with telomerase mutations. Methods Subjects underwent LT between February 2005 and April 2014 at 5 LT centers. We abstracted data from medical records, focusing on outcomes reflecting post-LT treatment effects likely to be complicated by telomerase mutations. Results The median age of subjects was 60.5 years (IQR 52.0–62.0), 64.3% were male, and the mean post-LT observation time was 3.2 years (SD ±2.9). Eleven subjects had a mutation in telomerase reverse transcriptase, 2 in telomerase RNA component, and 1 had an uncharacterized mutation. Ten subjects were leukopenic post-LT; leukopenia prompted cessation of mycophenolate mofetil in 5 and treatment with filgrastim in 4. Six subjects had recurrent lower respiratory tract infections (LRTI), 7 had acute cellular rejection (ACR) (A1), and 4 developed chronic lung allograft dysfunction (CLAD). Ten LT recipients developed chronic renal insufficiency and 8 experienced acute, reversible renal failure. Three developed cancer, none had cirrhosis. Thirteen subjects were alive at data censorship. Conclusions The clinical course for LT recipients with telomerase mutations is complicated by renal disease, leukopenia prompting a change in the immunosuppressive regimen, and recurrent LTRI. In contrast, cirrhosis was absent, ACR was mild, and development of CLAD was comparable to other LT populations. While posing challenges, lung transplantation may be feasible for patients with pulmonary fibrosis due to telomerase mutations. PMID:26169663

Do Alloreactivity and Prolonged Cold Ischemia Cause Different Elementary Lesions in Chronic Allograft Nephropathy?

PubMed Central

Herrero-Fresneda, Immaculada; Torras, Joan; Cruzado, Josep M.; Condom, Enric; Vidal, August; Riera, Marta; Lloberas, Nuria; Alsina, Jeroni; Grinyo, Josep M.

2003-01-01

This study assesses the individual contributions of the nonalloreactive factor, cold ischemia (CI), and alloreactivity to late functional and structural renal graft changes, and examines the effect of the association of both factors on the progression of chronic allograft nephropathy. Lewis rats acted as receptors of kidneys from either Lewis or Fischer rats. For CI, kidneys were preserved for 5 hours. The rats were divided into four groups: Syn, syngeneic graft; SynI, syngeneic graft and CI; Allo, allogeneic graft; AlloI, allogeneic graft and CI. Renal function was assessed every 4 weeks for 24 weeks. Grafts were evaluated for acute inflammatory response at 1 week and for chronic histological damage at 24 weeks. Only when CI and allogenicity were combined did immediate posttransplant mortality occur, while survivors showed accelerated renal insufficiency that induced further mortality at 12 weeks after transplant. Solely ischemic rats developed renal insufficiency. Renal structural damage in ischemic rats was clearly tubulointerstitial, while significant vasculopathy and glomerulosclerosis appeared only in the allogeneic groups. There was increased infiltration of macrophages and expression of mRNA-transforming growth factor-β1 in the ischemic groups, irrespective of the allogeneic background. The joint association of CI plus allogenicity significantly increased cellular infiltration at both early and late stages, aggravating tubulointerstitial and vascular damage considerably. In summary, CI is mainly responsible for tubulointerstitial damage, whereas allogenicity leads to vascular lesion. The association of both factors accelerates and aggravates the progression of experimental chronic allograft nephropathy. PMID:12507896

Role of T-cell-specific nuclear factor κB in islet allograft rejection.

PubMed

Porras, Delia Lozano; Wang, Ying; Zhou, Ping; Molinero, Luciana L; Alegre, Maria-Luisa

2012-05-27

Pancreatic islet transplantation has the potential to cure type 1 diabetes, a chronic lifelong disease, but its clinical applicability is limited by allograft rejection. Nuclear factor κB (NF-κB) is a transcription factor important for survival and differentiation of T cells. In this study, we tested whether NF-κB in T cells is required for the rejection of islet allografts. Mice expressing a superrepressor form of NF-κB selectively in T cells (IκBαΔN-Tg mice) with or without the antiapoptotic factor Bcl-xL, or mice with impaired T-cell receptor (TCR)- and B cell receptor-driven NF-κB activity (CARMA1-KO mice) were rendered diabetic and transplanted with islet allografts. Secondary skin transplantation in long-term acceptors of islet allografts was used to test for the development of donor-specific tolerance. Immune infiltration of the transplanted islets was examined by immunofluorescence. TCR-transgenic CD4 T cells were used to follow T-cell priming and differentiation. Islet allograft survival was prolonged in IκBαΔN-Tg mice, although the animals did not develop donor-specific tolerance. Reduced NF-κB activity did not prevent T-cell priming or differentiation but reduced survival of activated T cells, as transgenic expression of Bcl-xL restored islet allograft rejection in IκBαΔN-Tg mice. Abolishing TCR- and B cell receptor-driven activation of NF-κB selectively by CARMA1 deficiency prevented T-cell priming and islet allograft rejection. Our data suggest that T cell-NF-κB plays an important role in the rejection of islet allografts. Targeting NF-κB selectively in lymphocytes seems a promising approach to facilitate acceptance of transplanted islets.

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

PubMed Central

Lama, Vibha N.; Belperio, John A.; Christie, Jason D.; El-Chemaly, Souheil; Fishbein, Michael C.; Gelman, Andrew E.; Hancock, Wayne W.; Keshavjee, Shaf; Kreisel, Daniel; Looney, Mark R.; McDyer, John F.; Shilling, Rebecca A.; Panoskaltsis-Mortari, Angela; Wilkes, David S.; Eu, Jerry P.; Nicolls, Mark R.

2017-01-01

Lung transplantation, a cure for a number of end-stage lung diseases, continues to have the worst long-term outcomes when compared with other solid organ transplants. Preclinical modeling of the most common and serious lung transplantation complications are essential to better understand and mitigate the pathophysiological processes that lead to these complications. Various animal and in vitro models of lung transplant complications now exist and each of these models has unique strengths. However, significant issues, such as the required technical expertise as well as the robustness and clinical usefulness of these models, remain to be overcome or clarified. The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop in March 2016 to review the state of preclinical science addressing the three most important complications of lung transplantation: primary graft dysfunction (PGD), acute rejection (AR), and chronic lung allograft dysfunction (CLAD). In addition, the participants of the workshop were tasked to make consensus recommendations on the best use of these complimentary models to close our knowledge gaps in PGD, AR, and CLAD. Their reviews and recommendations are summarized in this report. Furthermore, the participants outlined opportunities to collaborate and directions to accelerate research using these preclinical models. PMID:28469087

The effect of timing and graft dysfunction on survival and cardiac allograft vasculopathy in antibody-mediated rejection.

PubMed

Clerkin, Kevin J; Restaino, Susan W; Zorn, Emmanuel; Vasilescu, Elena R; Marboe, Charles C; Mancini, Donna M

2016-09-01

Antibody-mediated rejection (AMR) has been associated with increased death and cardiac allograft vasculopathy (CAV). Early studies suggested that late AMR was rarely associated with graft dysfunction, whereas recent reports have demonstrated an association with increased mortality. We investigated the timing of AMR and its association with graft dysfunction, death, and CAV. This retrospective cohort study identified all adult orthotopic heart transplant (OHT) recipients (N = 689) at Columbia University Medical Center from 2004 to 2013. There were 68 primary cases of AMR, which were stratified by early (< 1 year post-OHT) or late (> 1 year post-OHT) AMR. Kaplan-Meier survival analysis and modeling was performed with multivariable logistic regression and Cox proportional hazards regression. From January 1, 2004, through October 1, 2015, early AMR (median 23 days post-OHT) occurred in 43 patients and late AMR (median 1,084 days post-OHT) occurred in 25. Graft dysfunction was less common with early compared with late AMR (25.6% vs 56%, p = 0.01). Patients with late AMR had decreased post-AMR survival compared with early AMR (1 year: 80% vs 93%, 5 years: 51% vs 73%, p < 0.05). When stratified by graft dysfunction, only those with late AMR and graft dysfunction had worse survival (30 days: 79%, 1 year: 64%, 5 years: 36%; p < 0.006). The association remained irrespective of age, sex, donor-specific antibodies, left ventricular assist device use, reason for OHT, and recovery of graft function. Similarly, those with late AMR and graft dysfunction had accelerated development of de novo CAV (50% at 1 year; hazard ratio, 5.42; p = 0.009), whereas all other groups were all similar to the general transplant population. Late AMR is frequently associated with graft dysfunction. When graft dysfunction is present in late AMR, there is an early and sustained increased risk of death and rapid development of de novo CAV despite aggressive treatment. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Rapid adaptation drives invasion of airway donor microbiota by Pseudomonas after lung transplantation.

PubMed

Beaume, M; Köhler, T; Greub, G; Manuel, O; Aubert, J-D; Baerlocher, L; Farinelli, L; Buckling, A; van Delden, C

2017-01-17

In cystic fibrosis (CF) patients, chronic airway infection by Pseudomonas leads to progressive lung destruction ultimately requiring lung transplantation (LT). Following LT, CF-adapted Pseudomonas strains, potentially originating from the sinuses, may seed the allograft leading to infections and reduced allograft survival. We investigated whether CF-adapted Pseudomonas populations invade the donor microbiota and adapt to the non-CF allograft. We collected sequential Pseudomonas isolates and airway samples from a CF-lung transplant recipient during two years, and followed the dynamics of the microbiota and Pseudomonas populations. We show that Pseudomonas invaded the host microbiota within three days post-LT, in association with a reduction in richness and diversity. A dominant mucoid and hypermutator mutL lineage was replaced after 11 days by non-mucoid strains. Despite antibiotic therapy, Pseudomonas dominated the allograft microbiota until day 95. We observed positive selection of pre-LT variants and the appearance of novel mutations. Phenotypic adaptation resulted in increased biofilm formation and swimming motility capacities. Pseudomonas was replaced after 95 days by a microbiota dominated by Actinobacillus. In conclusion, mucoid Pseudomonas adapted to the CF-lung remained able to invade the allograft. Selection of both pre-existing non-mucoid subpopulations and of novel phenotypic traits suggests rapid adaptation of Pseudomonas to the non-CF allograft.

Transplantation after ex vivo lung perfusion: A midterm follow-up.

PubMed

Wallinder, Andreas; Riise, Gerdt C; Ricksten, Sven-Erik; Silverborn, Martin; Dellgren, Göran

2016-11-01

A large proportion of donor lungs are discarded due to known or presumed organ dysfunction. Ex vivo lung perfusion (EVLP) has proven its value as a tool for discrimination between reversible and irreversible donor lung pathology. However, the long-term outcome after transplantation of lungs after EVLP is essentially unknown. We report short-term and midterm outcomes of recipients who received transplants of EVLP-evaluated lungs. Single-center results of recipients of lungs with prior EVLP were compared with consecutive recipients of non-EVLP lungs (controls) during the same period. Short-term follow-up included time to extubation, time in the intensive care unit, and the presence of primary graft dysfunction at 72 hours postoperatively. Mortality and incidence of chronic lung allograft dysfunction were monitored for up to 4 years after discharge. During a 4-year period, 32 pairs of initially rejected donor lungs underwent EVLP. After EVLP, 22 double lungs and 5 single lungs were subsequently transplanted. During this period, 145 patients received transplants of conventional donor lungs that did not have EVLP and constituted the control group. Median time to extubation was 7 hours in the EVLP group and 6 hours in the non-EVLP control group (p = 0.45). Median intensive care unit stay was 4 days vs. 3 days, respectively (p = 0.15). Primary graft dysfunction grade > 1 was present in 14% in the EVLP group and in 12% in the non-EVLP group at 72 hours after transplant. Survival at 1 year was 92% in the EVLP group and 79% in the non-EVLP group. Cumulative survival and freedom from retransplantation or chronic rejection were also comparable between the 2 groups (p = 0.43) when monitored up to 4 years. Selected donor lungs rejected for transplantation can be used after EVLP. This technique is effective for selection of transplantable donor lungs. Patients who received lungs evaluated under EVLP have short-term and midterm outcomes comparable to recipients of non-EVLP donor lungs. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Impact of post-kidney transplant parathyroidectomy on allograft function

PubMed Central

Parikh, Samir; Nagaraja, Haikady; Agarwal, Anil; Samavedi, Srinivas; Von Visger, Jon; Nori, Uday; Andreoni, Kenneth; Pesavento, Todd; Singh, Neeraj

2013-01-01

Background The impact of parathyroidectomy on allograft function in kidney transplant patients is unclear. Methods We conducted a retrospective, observational study of all kidney transplant recipients from 1988 to 2008 who underwent parathyroidectomy for uncontrolled hyperparathyroidism (n = 32). Post-parathyroidectomy, changes in estimated glomerular filtration rate (eGFR) and graft loss were recorded. Cross-sectional associations at baseline between eGFR and serum calcium, phosphate, and parathyroid hormone (PTH), and associations between their changes within subjects during the first two months post-parathyroidectomy were assessed. Results Post-parathyroidectomy, the mean eGFR declined from 51.19 mL/min/1.73 m2 at parathyroidectomy to 44.78 mL/min/1.73 m2 at two months (p < 0.0001). Subsequently, graft function improved, and by 12 months, mean eGFR recovered to 49.76 mL/min/1.73 m2 (p = 0.035). Decrease in serum PTH was accompanied by a decrease in eGFR (p = 0.0127) in the first two months post-parathyroidectomy. Patients whose eGFR declined by ≥ 20% (group 1) in the first two months post-parathyroidectomy were distinguished from the patients whose eGFR declined by <20% (group 2). The two groups were similar except that group 1 had a higher baseline mean serum PTH compared with group 2, although not significant (1046.7 ± 1034.2 vs. 476.6 ± 444.9, p = 0.14). In group 1, eGFR declined at an average rate of 32% (p < 0.0001) during the first month post-parathyroidectomy compared with 7% (p = 0.1399) in group 2, and the difference between these two groups was significant (p = 0.0003). The graft function recovered in both groups by one yr. During median follow-up of 66.00 ± 49.45 months, 6 (18%) patients lost their graft with a mean time to graft loss from parathyroidectomy of 37.2 ± 21.6 months. The causes of graft loss were rejection (n = 2), pyelonephritis (n = 1) and chronic allograft nephropathy (n = 3). No graft loss occurred during the first-year post-surgery. Conclusion Parathyroidectomy may lead to transient kidney allograft dysfunction with eventual recovery of graft function by 12 months post-parathyroidectomy. Higher level of serum PTH pre-parathyoidectomy is associated with a more profound decrease in eGFR post-parathyroidectomy. PMID:23448282

A score model for the continuous grading of early allograft dysfunction severity.

PubMed

Pareja, Eugenia; Cortes, Miriam; Hervás, David; Mir, José; Valdivieso, Andrés; Castell, José V; Lahoz, Agustín

2015-01-01

Early allograft dysfunction (EAD) dramatically influences graft and patient outcomes. A lack of consensus on an EAD definition hinders comparisons of liver transplant outcomes and management of recipients among and within centers. We sought to develop a model for the quantitative assessment of early allograft function [Model for Early Allograft Function Scoring (MEAF)] after transplantation. A retrospective study including 1026 consecutive liver transplants was performed for MEAF score development. Multivariate data analysis was used to select a small number of postoperative variables that adequately describe EAD. Then, the distribution of these variables was mathematically modeled to assign a score for each actual variable value. A model, based on easily obtainable clinical parameters (ie, alanine aminotransferase, international normalized ratio, and bilirubin) and scoring liver function from 0 to 10, was built. The MEAF score showed a significant association with patient and graft survival at 3-, 6- and 12-month follow-ups. Hepatic steatosis and age for donors; cold/warm ischemia times and postreperfusion syndrome for surgery; and intensive care unit and hospital stays, Model for End-Stage Liver Disease and Child-Pugh scores, body mass index, and fresh frozen plasma transfusions for recipients were factors associated significantly with EAD. The model was satisfactorily validated by its application to an independent set of 200 patients who underwent liver transplantation at a different center. In conclusion, a model for the quantitative assessment of EAD severity has been developed and validated for the first time. The MEAF provides a more accurate graft function assessment than current categorical classifications and may help clinicians to make early enough decisions on retransplantation benefits. Furthermore, the MEAF score is a predictor of recipient and graft survival. The standardization of the criteria used to define EAD may allow reliable comparisons of recipients' treatments and transplant outcomes among and within centers. © 2014 American Association for the Study of Liver Diseases.

Predicting Post-Transplant Recurrence of IgA Nephropathy: The Importance of Crescents.

PubMed

Avasare, Rupali S; Rosenstiel, Paul E; Zaky, Ziad S; Tsapepas, Demetra S; Appel, Gerald B; Markowitz, Glen S; Bomback, Andrew S; Canetta, Pietro A

2017-01-01

Most studies that have assessed the predictors of recurrent IgA nephropathy (IgAN) in the renal allograft have focused on post-transplant features. Identifying high-risk pre-transplant features of IgAN is useful for counseling patients and may help in tailoring post-transplant immunosuppression. We investigated the pre-transplant clinical and biopsy features of 62 patients with IgAN who received transplants at Columbia University Medical Center from 2001 to 2012 and compared the characteristics and outcomes of patients with IgAN recurrence to those without recurrence. The primary outcome was time to recurrent IgAN. Secondary outcomes were a composite of doubling of creatinine or allograft failure, and recurrent IgAN as a cause of allograft dysfunction. Of the 62 patients, 14 had recurrent IgAN in the allograft. Mean time to recurrence was 2.75 years. Those with recurrent disease were younger at the time of native kidney biopsy (29 vs. 41 years, p < 0.0009). Black race and Hispanic ethnicity composed a higher proportion of the recurrent disease group. On multivariable analysis, significant predictors of recurrent IgAN included age at diagnosis (hazards ratio (HR) 0.911, 95% CI 0.85-0.98), burden of crescents on native biopsy (HR 1.21 per 10% increase in crescents, 95% CI 1.00-1.47) and allograft rejection (HR 3.59, 95% CI 1.10-11.7). Features of native IgAN can help predict the risk of recurrent disease in the renal allograft. In particular, immunologically active disease represented by earlier age of onset and greater burden of crescents on native biopsy is more likely to recur after transplant. © 2017 S. Karger AG, Basel.

Predicting Post-transplant Recurrence of IgA Nephropathy: The Importance of Crescents

PubMed Central

Avasare, Rupali S.; Rosenstiel, Paul E.; Zaky, Ziad S.; Tsapepas, Demetra; Appel, Gerald B.; Markowitz, Glen S.; Bomback, Andrew S.; Canetta, Pietro A.

2017-01-01

Background Most studies assessing the predictors of recurrent IgA nephropathy in the renal allograft have focused on post-transplant features. Identifying high risk pre-transplant features of IgA nephropathy is useful for counseling patients and may help tailor immunosuppression post-transplant. Methods We investigated the pre-transplant clinical and biopsy features of 62 patients with IgAN who received transplants at Columbia University Medical Center from 2001 to 2012 and compared the characteristics and outcomes of patients with IgAN recurrence to those without recurrence. The primary outcome was time to recurrent IgAN. Secondary outcomes were a composite of doubling of creatinine or allograft failure, and recurrent IgAN as a cause of allograft dysfunction. Results Of the 62 patients, 14 had recurrent IgAN in the allograft. Mean time to recurrence was 2.75 years. Those with recurrent disease were younger at time of native kidney biopsy (29 years vs. 41 years, P < 0.0009). Black race and Hispanic ethnicity composed a higher proportion of the recurrent disease group. On multivariable analysis, significant predictors of recurrent IgAN included age at diagnosis (HR 0.911, 95% CI 0.85 to 0.98), burden of crescents on native biopsy (HR 1.21 per 10% increase in crescents, 95% CI 1.00 to 1.47), and allograft rejection (HR 3.59, 95% CI 1.10 to 11.7) Conclusions Features of native IgAN can help predict the risk of recurrent disease in the renal allograft. In particular, immunologically active disease represented by earlier age of onset and greater burden of crescents on native biopsy is more likely to recur post-transplant. PMID:28056461

Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection

PubMed Central

Cui, Ye; Liu, Kaifeng; Monzon-Medina, Maria E.; Padera, Robert F.; Wang, Hao; George, Gautam; Toprak, Demet; Abdelnour, Elie; D’Agostino, Emmanuel; Goldberg, Hilary J.; Perrella, Mark A.; Forteza, Rosanna Malbran; Rosas, Ivan O.; Visner, Gary; El-Chemaly, Souheil

2015-01-01

Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes. PMID:26485284

Tacrolimus/Everolimus vs. Tacrolimus/MMF in Pediatric Heart Transplant Recipients Using the MATE Score

ClinicalTrials.gov

2018-03-05

Pediatric Heart Transplantation; Immunosuppression; Chronic Kidney Diseases; Cardiac Allograft Vasculopathy; Heart Transplant Failure and Rejection; Post-transplant Lymphoproliferative Disorder; Heart Transplant Infection

A Small Molecule β2 Integrin Agonist Improves Chronic Kidney Allograft Survival by Reducing Leukocyte Recruitment and Accompanying Vasculopathy

PubMed Central

Khan, Samia Q.; Guo, Lingling; Cimbaluk, David J.; Elshabrawy, Hatem; Faridi, Mohd Hafeez; Jolly, Meenakshi; George, James F.; Agarwal, Anupam; Gupta, Vineet

2014-01-01

Kidney allograft rejection is associated with infiltration of inflammatory CD11b+ leukocytes. A CD11b agonist leukadherin-1 (LA1) increases leukocyte adhesion, preventing their transmigration and tissue recruitment in vivo. Here, we test the extent to which LA1-mediated activation of CD11b/CD18 enhances kidney allograft survival in a mouse model of fully MHC-mismatched orthotopic kidney transplantation, where C57BL/6J (H-2b) recipients received kidney allografts from Balb/c mice (H-2d). Isograft control recipients received a kidney from a littermate. Control isograft and allograft recipients were treated daily with cyclosporine (CsA) for 2 weeks, while the test group received CsA therapy and daily LA1 injections during week 1 and alternate days during weeks 2–8. LA1 treatment reduced interstitial leukocyte infiltration in the allograft, reduced neointimal hyperplasia and glomerular damage, and prolonged graft survival from 48.5% (CsA only) to 100% (CsA and LA1) on day 60. Serum creatinine levels showed significantly improved kidney function in LA1-treated mice compared to CsA-treated allograft controls [0.52 ± 0.18 mg/dL vs 0.24 ± 0.07 mg/dL (n = 5), respectively]. Furthermore, combination therapy reduced macrophage infiltration and increased the frequency of FoxP3 + Tregs in the allograft. These findings indicate a crucial role for CD11b/CD18 in the control of leukocyte migration to the transplanted kidney and identify integrin agonist LA1 as a novel potential therapeutic agent for kidney transplantation. PMID:25593918

Lacertus Fibrosus Versus Achilles Allograft Reconstruction for Distal Biceps Tears: A Biomechanical Study.

PubMed

Murthi, Anand M; Ramirez, Miguel A; Parks, Brent G; Carpenter, Shannon R

2017-12-01

The bicipital aponeurosis, or lacertus fibrosus, can potentially be used as a reconstruction graft in chronic distal biceps tendon tears. To evaluate construct stiffness, load to failure, and failure mechanism with lacertus fibrosus versus Achilles allograft for distal biceps tendon reconstruction. Controlled laboratory study. Ten fresh-frozen matched cadaveric pairs of elbows were used. Three centimeters of the distal biceps tendon was resected. Specimens were randomized to the lacertus fibrosus or Achilles tendon group. In one group, the lacertus fibrosus was released from its distal attachment and then tubularized and repaired intraosseously to the radius. In the other group, an Achilles tendon graft was sutured to the biceps muscle and repaired to the ulna. The prepared radii were rigidly mounted at a 45° angle on a load frame. The proximal biceps muscle was secured in a custom-fabricated cryogenic grip. Displacement was measured using a differential variable reluctance transducer mounted at the radius-soft tissue junction and in the muscle- or muscle allograft-tissue junction proximal to the repair. Specimens were loaded at 20 mm/min until failure, defined as a 3-mm displacement at the radius-soft tissue junction. No significant difference was found in mean load to failure between the lacertus fibrosus and Achilles tendon group (mean ± SD, 20.2 ± 5.5 N vs 16.89 ± 4.54 N; P = .18). Stiffness also did not differ significantly between the lacertus fibrosus and Achilles tendon group (12.3 ± 7.1 kPa vs 10.5 ± 5.7 kPa; P = .34). The primary mode of failure in the lacertus fibrosus group was suture pullout from the tissue at the musculotendinous junction (7 of 10). In the Achilles group, failures were observed at the muscle-allograft interface (3) and the allograft-bone (radial tuberosity) interface (3), and 3 suture failures were observed. The button fixation did not fail in any specimens. The mean stiffness and load-to-failure values were not significantly different between a lacertus fibrosus construct and Achilles tendon allograft. Use of the lacertus fibrosus may be a potential alternative to Achilles tendon allograft reconstruction of chronic distal biceps tears when primary repair is not possible.

Recent Advances in Allograft Vasculopathy

PubMed Central

Merola, Jonathan; Jane-Wit, Daniel D.; Pober, Jordan S.

2017-01-01

Purpose of review Despite considerable advances in controlling acute rejection, the longevity of cardiac and renal allografts remains significantly limited by chronic rejection in the form of allograft vasculopathy (AV). This review discusses recently reported mechanistic insights of AV pathogenesis as well recent clinical evaluations of new therapeutic approaches. Recent findings Although adaptive immunity is the major driver of AV, natural killer cells mediate vasculopathic changes in a transplanted mouse heart following treatment with donor-specific antibody (DSA). However, NK cells may also dampen chronic inflammatory responses by killing donor-derived tissue-resident CD4 T cells that provide help to host B cells, the source of DSA. DSA may directly contribute to vascular inflammation by inducing intracellular signaling cascades that upregulate leukocyte adhesion molecules, facilitating recruitment of neutrophils and monocytes. DSA-mediated complement activation additionally enhances endothelial alloimmunogenicity through activation of non-canonical NF-κB signaling. New clinical studies evaluating mTOR and proteasome inhibitors to target these pathways have been reported. Summary AV is a pathology resultant from several innate and adaptive alloimmune responses. Mechanistic insights from preclinical studies have identified agents that are currently being investigated in clinical trials. PMID:27898462

Risk factors associated with the deterioration of renal function after kidney transplantation.

PubMed

Serón, Daniel; Fulladosa, Xavier; Moreso, Francesc

2005-12-01

Renal function early after transplantation is associated with a large number of risk factors, including donor age and acute rejection. During the 1990s, donor age increased and the incidence of acute rejection decreased. Renal function between the third and sixth month improved slightly, while renal function deterioration between the third or sixth month and the 12th month improved significantly. This modification coincides with the introduction of mycophenolate mofetil and tacrolimus. The tendency for sustained renal improvement early after transplantation became more evident after the introduction of anti-calcineurin-free regimens. Studies of protocol biopsies have shown that there is an increase of glomerular volume after transplantation and that a larger glomerular volume at 4 months is associated with a better glomerular filtration rate. This adaptation mechanism is impaired in patients with chronic allograft nephropathy or in patients with high cyclosporin levels. Taken together, these data suggest that the steady improvement of renal allograft function may be partly explained by a better glomerular adaptation after transplantation because of the avoidance of the vasoconstrictive effect of anti-calcineurinic agents, and a significant decrease in the prevalence of chronic allograft nephropathy early after transplantation.

The Interplay between inflammation and fibrosis in kidney transplantation.

PubMed

Torres, Irina B; Moreso, Francesc; Sarró, Eduard; Meseguer, Anna; Serón, Daniel

2014-01-01

Serial surveillance renal allograft biopsies have shown that early subclinical inflammation constitutes a risk factor for the development of interstitial fibrosis. More recently, it has been observed that persistent inflammation is also associated with fibrosis progression and chronic humoral rejection, two histological conditions associated with poor allograft survival. Treatment of subclinical inflammation with steroid boluses prevents progression of fibrosis and preserves renal function in patients treated with a cyclosporine-based regimen. Subclinical inflammation has been reduced after the introduction of tacrolimus based regimens, and it has been shown that immunosuppressive schedules that are effective in preventing acute rejection and subclinical inflammation may prevent the progression of fibrosis and chronic humoral rejection. On the other hand, minimization protocols are associated with progression of fibrosis, and noncompliance with the immunosuppressive regime constitutes a major risk factor for chronic humoral rejection. Thus, adequate immunosuppressive treatment, avoiding minimization strategies and reinforcing educational actions to prevent noncompliance, is at present an effective approach to combat the progression of fibrosis.

The Interplay between Inflammation and Fibrosis in Kidney Transplantation

PubMed Central

Torres, Irina B.; Moreso, Francesc; Sarró, Eduard; Serón, Daniel

2014-01-01

Serial surveillance renal allograft biopsies have shown that early subclinical inflammation constitutes a risk factor for the development of interstitial fibrosis. More recently, it has been observed that persistent inflammation is also associated with fibrosis progression and chronic humoral rejection, two histological conditions associated with poor allograft survival. Treatment of subclinical inflammation with steroid boluses prevents progression of fibrosis and preserves renal function in patients treated with a cyclosporine-based regimen. Subclinical inflammation has been reduced after the introduction of tacrolimus based regimens, and it has been shown that immunosuppressive schedules that are effective in preventing acute rejection and subclinical inflammation may prevent the progression of fibrosis and chronic humoral rejection. On the other hand, minimization protocols are associated with progression of fibrosis, and noncompliance with the immunosuppressive regime constitutes a major risk factor for chronic humoral rejection. Thus, adequate immunosuppressive treatment, avoiding minimization strategies and reinforcing educational actions to prevent noncompliance, is at present an effective approach to combat the progression of fibrosis. PMID:24991565

Outcomes After Dermal Allograft Reconstruction of Chronic or Subacute Pectoralis Major Tendon Ruptures.

PubMed

Neumann, Julie A; Klein, Christopher M; van Eck, Carola F; Rahmi, Hithem; Itamura, John M

2018-01-01

Avoiding delay in the surgical management of pectoralis major (PM) ruptures optimizes outcomes. However, this is not always possible, and when a tear becomes chronic or when a subacute tear has poor tissue quality, a graft can facilitate reconstruction. The primary aim was to evaluate the clinical outcomes of PM reconstruction with dermal allograft augmentation for chronic tears or for subacute tears with poor tissue quality. A second aim was to determine patient and surgical factors affecting outcome. Case series; Level of evidence, 4. Nineteen consecutive patients (19 PM ruptures) with a mean ± SD age of 39.1 ± 8.4 years were retrospectively reviewed at 26.4 ± 16.0 months following PM tendon reconstruction with dermal allograft. Surgery was performed at 19.2 ± 41.2 months after injury (median, 7.6 months; range, 1.1-185.4 months). Several outcome scores were recorded pre- and postoperatively, including Disabilities of the Arm, Shoulder, and Hand (DASH), as well as visual analog scale (VAS) (range, 0-10; 0 = no pain) and Single Assessment Numeric Evaluation (SANE). Range of motion, Constant score, American Shoulder and Elbow Surgeons (ASES) score, Simple Shoulder Test score, and complications/reoperations were recorded postoperatively. Scores improved significantly for the DASH (preoperative, 34.9; postoperative, 8.0; P < .001) and VAS (preoperative, 5.0; postoperative, 1.5; P = .011). There was a trend toward improved SANE scores (preoperative, 15.0; postoperative, 80.0; P = .097), but the difference was not statistically significant, likely because of the small number of patients having preoperative SANE scores for review. Increased age was associated with higher VAS scores ( r = 0.628, P = .016) and less forward flexion ( r = -0.502, P = .048) and external rotation ( r = -0.654, P = .006). Patients with workers' compensation had lower scores for 3 measures: SANE (75.8 vs 88.4, P = .040), Constant (86.7 vs 93.4, P = .019), and ASES (81.9 vs 97.4, P = .016). Operating on the dominant extremity resulted in lower Constant scores (87.8 vs 95.4, P = .012). A 2-head tendon tear (107.5° vs 123.3°, P = .033) and the use of >1 graft (105.0° vs 121.3°, P = .040) resulted in decreased abduction. This was the first large series to observe patients with chronic or subacute PM tendon tears treated with dermal allograft reconstruction. PM tendon reconstruction with dermal allografts resulted in good objective and subjective patient-reported outcomes.

Percutaneous lateral ligament reconstruction with allograft for chronic lateral ankle instability.

PubMed

Youn, Hyunkook; Kim, Yong Sang; Lee, Jongseok; Choi, Woo Jin; Lee, Jin Woo

2012-02-01

The majority of lateral ankle instability can be treated successfully with conservative method. However, if such treatments fail, surgical treatment should be considered. A wide variety of procedures have been introduced to treat chronic lateral ankle instability. The percutaneous method avoids dissection which is associated with open surgery and can lead to excessive morbidity. The purpose of this study was to evaluate the clinical and radiological outcomes of percutaneous lateral ligament reconstruction with an allograft in the treatment of chronic lateral ankle instability. Between October 2006 and April 2009, percutaneous lateral ligament reconstruction using an allograft was performed on 15 ankles in 13 patients for chronic lateral ankle instability. The patients included in this study satisfied at least one of the following criteria: a previously failed reconstruction of the ligament, severe ankle instability (more than 15 degrees of talar tilt, more than 10 mm of anterior drawer), general laxity of ligaments, body mass index (BMI) higher than 25. The mean followup period was 18.1 (range, 12 to 40) months. The grafted tendon was secured by double tenodeses at both the talus and calcaneus or triple tenodeses which included a fibular tenodesis. The clinical outcomes were evaluated with Visual Analogue Scale (VAS) for pain, Karlsson-Peterson ankle score, and patients' subjective satisfaction. The radiological results were evaluated using the varus tilting angle and the anterior displacement distance. The VAS improved from preoperative 3.7 ±2.2 to 1.6 ±1.3 at the last followup (p = 0.002). The Karlsson-Peterson ankle score increased from 54.2 ±8.8 to 80.9 ±7.2 (p = 0.001). Patients were satisfied in 13 cases (86.7%) with excellent or good results. Radiologically, the mean varus tilting angle was 15.5 ±4.4 degrees preoperatively and 7.3 ±3.6 at the last followup (p = 0.001). The anterior drawer distance was 10.1 ±3.3 mm preoperatively and 7.2 ±2.7 mm at last followup (p = 0.001). We believe percutaneous lateral ligament reconstruction with allograft to be a useful method as a salvage procedure for the treatment of severe and complicated types of chronic lateral ankle instability. Furthermore, the minimal invasiveness of this technique provides a good cosmetic outcome and we found it to be a technically easy and fast procedure.

Urine Fibrosis Markers and Risk of Allograft Failure in Kidney Transplant Recipients: A Case-Cohort Ancillary Study of the FAVORIT Trial.

PubMed

Ix, Joachim H; Katz, Ronit; Bansal, Nisha; Foster, Meredith; Weiner, Daniel E; Tracy, Russell; Jotwani, Vasantha; Hughes-Austin, Jan; McKay, Dianne; Gabbai, Francis; Hsu, Chi-Yuan; Bostom, Andrew; Levey, Andrew S; Shlipak, Michael G

2017-03-01

Kidney tubulointerstitial fibrosis marks risk for allograft failure in kidney transplant recipients, but is poorly captured by estimated glomerular filtration rate (eGFR) or urine albumin-creatinine ratio (ACR). Whether urinary markers of tubulointerstitial fibrosis can noninvasively identify risk for allograft failure above and beyond eGFR and ACR is unknown. Case-cohort study. The FAVORIT (Folic Acid for Vascular Outcome Reduction in Transplantation) Trial was a randomized double-blind trial testing vitamin therapy to lower homocysteine levels in stable kidney transplant recipients. We selected a subset of participants at random (n=491) and all individuals with allograft failure during follow-up (cases; n=257). Using spot urine specimens from the baseline visit, we measured 4 urinary proteins known to correlate with tubulointerstitial fibrosis on biopsy (urine α 1 -microglobulin [A1M], monocyte chemoattractant protein 1 [MCP-1], and procollagen type III and type I amino-terminal amino pro-peptide). Death-censored allograft failure. In models adjusted for demographics, chronic kidney disease risk factors, eGFR, and ACR, higher concentrations of urine A1M (HR per doubling, 1.73; 95% CI, 1.43-2.08) and MCP-1 (HR per doubling, 1.60; 95% CI, 1.32-1.93) were strongly associated with allograft failure. When additionally adjusted for concentrations of other urine fibrosis and several urine injury markers, urine A1M (HR per doubling, 1.76; 95% CI, 1.27-2.44]) and MCP-1 levels (HR per doubling, 1.49; 95% CI, 1.17-1.89) remained associated with allograft failure. Urine procollagen type III and type I levels were not associated with allograft failure. We lack kidney biopsy data, BK titers, and HLA antibody status. Urine measurement of tubulointerstitial fibrosis may provide a noninvasive method to identify kidney transplant recipients at higher risk for future allograft failure, above and beyond eGFR and urine ACR. Published by Elsevier Inc.

Chronic mucosal inflammation/inflammatory bowel disease-like inflammation after intestinal transplantation: where are we now?

PubMed

Matsumoto, Cal S; Zasloff, Michael A; Fishbein, Thomas M

2014-06-01

The purpose of this review is to highlight the similarities between inflammatory bowel disease and the state of the intestine allograft after transplantation. The mutant nucleotide-binding oligomerization protein 2 (NOD2) gene, which encodes for an intracellular protein that serves as an innate immune system microbial sensor in macrophages, dendritic cells, and certain intestinal epithelial cells, has been recognized as a risk factor in Crohn's disease. Similarly, recent studies have also highlighted the contribution the NOD2 mutation may have on intestinal failure itself. More specifically, in intestinal transplant recipients with the NOD2 mutation, the discovery of the reduced ability to prevent bacterial clearance, increased enterocyte stress response, and failure of key downstream expression of important cytokines and growth factors have been implicated as major factors in intestinal transplant outcomes, namely graft loss and septic death. Treatment strategies with anti tumor necrosis factor (TNF) α, similar to inflammatory bowel disease, have been employed in intestinal transplantation with promising results. In intestinal transplantation, there is evidence that the classical alloimmunity pathways that lead toward graft dysfunction and eventual graft loss may, in fact, be working in concert with a disordered innate immune system to produce a state of chronic inflammation not unlike that seen in inflammatory bowel disease.

Circumocular exanthema associated with chronic rejection after kidney transplantation.

PubMed

Morishita, Yoshiyuki; Umino, Tetsuo; Kobayashi, Takahisa; Miyata, Yukio; Kusano, Eiji

2010-12-01

A 43-year-old man had severe circumocular exanthema associated with chronic rejection 10 years after receiving a kidney transplant to treat end-stage renal failure. After the renal allograft was extracted, the exanthema diminished rapidly without any treatment. Donor-reactive immune cells seem to have cross-reacted with unknown pathogens on the skin and contributed to inflammation.

"Resuscitation" of marginal liver allografts for transplantation with machine perfusion technology.

PubMed

Graham, Jay A; Guarrera, James V

2014-08-01

As the rate of medically suitable donors remains relatively static worldwide, clinicians have looked to novel methods to meet the ever-growing demand of the liver transplant waiting lists worldwide. Accordingly, the transplant community has explored many strategies to offset this deficit. Advances in technology that target the ex vivo "preservation" period may help increase the donor pool by augmenting the utilization and improving the outcomes of marginal livers. Novel ex vivo techniques such as hypothermic, normothermic, and subnormothermic machine perfusion may be useful to "resuscitate" marginal organs by reducing ischemia/reperfusion injury. Moreover, other preservation techniques such as oxygen persufflation are explored as they may also have a role in improving function of "marginal" liver allografts. Currently, marginal livers are frequently discarded or can relegate the patient to early allograft dysfunction and primary non-function. Bench to bedside advances are rapidly emerging and hold promise for expanding liver transplantation access and improving outcomes. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Repair of Chronic Tibialis Anterior Tendon Rupture With a Major Defect Using Gracilis Allograft.

PubMed

Burton, Alex; Aydogan, Umur

2016-08-01

Tibialis anterior tendon (TAT) rupture is an uncommon injury, however, it can cause substantial deficit. Diagnosis is often delayed due to lack of initial symptoms; yet loss of function over time typically causes the patient to present for treatment. This delay usually ends up with major defects creating a great technical challenge for the operating surgeon. We present a novel technique and operative algorithm for the management of chronic TAT ruptures with a major gap after a delayed diagnosis not otherwise correctable with currently described techniques in the literature. This technique has been performed in 4 cases without any complications with fairly successful functional outcomes. For the reconstruction of chronic TAT rupture with an average delay of nine weeks after initial injury and gap of greater than 10 cm, a thorough operative algorithm was implemented in 4 patients using a double bundle gracilis allograft. Patients were then kept nonweightbearing for 6 weeks followed by weightbearing as tolerated. They began physical therapy with a focus on ankle exercises and gradual return to normal activity at 8 weeks, with resistance training exercises allowed at 12 weeks. At a mean follow-up time of 24.5 months, all patients reported significant pain relief with normal gait pattern. There were no reported intra- or postoperative complications. The average Foot and Ankle Ability Measure score increased to 90 from 27.5 in the postoperative period. All patients were able to return their previous activity levels. Gracilis allograft reconstruction as used in this study is a viable and reproducible alternative to primary repair with postoperative results being favorable without using complex tendon transfer techniques or autograft use necessitating the functional sacrifice of transferred or excised tendon. To the best of our knowledge, this is the first study demonstrating a successful technique and operative algorithm of gracilis allograft reconstruction of the TAT with a substantial deficit of greater than 10 cm with favorable results. Level IV: Operative algorithm with case series. © 2016 The Author(s).

Resistive index and chronic allograft nephropathy evaluated in protocol biopsies as predictors of graft outcome.

PubMed

Vallejos, Augusto; Alperovich, Gabriela; Moreso, Francesc; Cañas, Concepcion; de Lama, M Eugenia; Gomà, Montserrat; Fulladosa, Xavier; Carrera, Marta; Hueso, Miguel; Grinyó, Josep M; Serón, Daniel

2005-11-01

The presence of chronic allograft nephropathy (CAN) in protocol biopsies is negatively associated with graft survival. Although recent studies have indicated that the resistive index (RI) is a predictor of graft failure, it does not correlate with CAN in stable grafts. We therefore studied the relationship between RI and CAN and examined the predictive value of both parameters on graft outcome. Included were patients transplanted between 1997 and 2002 and who had protocol biopsies and RI determinations. Renal lesions were blindly evaluated according to Banff 97 criteria. Mean glomerular volume, cortical interstitial volume fraction and intimal arterial volume fraction were estimated using a point counting technique. RI was determined before biopsy in at least two different renal locations. The outcome variable was defined as graft failure or a 30% serum creatinine increase between protocol biopsy and last follow-up. Eighty-seven patients were included. RI correlated with recipient age (R = 0.52, P < 0.0001), diastolic blood pressure (R = -0.36, P = 0.0006), pulse pressure index (R = 0.27, P = 0.009) and g-score for histological glomerulitis (rho = 0.30, P = 0.0054), but there were no correlations between RI and chronic Banff scores or any morphometric parameter. The presence of CAN (relative risk, 3.5; 95% confidence interval 1.2-10.2; P = 0.02) but not RI was associated with the outcome variable. RI was associated with surrogate measures of vascular compliance such as recipient age and pulse pressure index but not with chronic allograft damage, even when it was evaluated by histomorphometry. Our results indicate that histology may be superior to RI in predicting graft function deterioration, at least in patients with stable renal function.

The role of TGF-β in the association between primary graft dysfunction and bronchiolitis obliterans syndrome

PubMed Central

DerHovanessian, Ariss; Weigt, S. Samuel; Palchevskiy, Vyacheslav; Shino, Michael Y.; Sayah, David M.; Gregson, Aric L.; Noble, Paul W.; Palmer, Scott M.; Fishbein, Michael C.; Kubak, Bernard M.; Ardehali, Abbas; Ross, David J.; Saggar, Rajan; Lynch, Joseph P.; Elashoff, Robert M.; Belperio, John A.

2016-01-01

Primary graft dysfunction (PGD) is a possible risk factor for bronchiolitis obliterans syndrome (BOS) following lung transplantation; however, the mechanism for any such association is poorly understood. Based on TGF-β's association with acute and chronic inflammatory disorders, we hypothesized that it may play a role in the continuum between PGD and BOS. Thus, the association between PGD and BOS was assessed in a single-center cohort of lung transplant recipients. Bronchoalveolar lavage fluid concentrations of TGF-β and procollagen collected within 24 hours of transplantation were compared across the spectrum of PGD, and incorporated into Cox models of BOS. Immunohistochemistry localized expression of TGF-β and its receptor in early lung biopsies post-transplant. We found an association between PGD and BOS in both bilateral and single lung recipients with a hazard ratio of 3.07 (95% CI 1.76-5.38) for the most severe form of PGD. TGF-β and procollagen concentrations were elevated during PGD (p<0.01), and associated with increased rates of BOS. Expression of TGF-β and its receptor localized to allograft infiltrating mononuclear and stromal cells, and the airway epithelium. These findings validate the association between PGD and the subsequent development of BOS, and suggest that this association may be mediated by receptor/TGF-β biology. PMID:26461171

Endoscopic versus transcranial procurement of allograft tympano-ossicular systems: a prospective double-blind randomized controlled audit.

PubMed

Caremans, Jeroen; Hamans, Evert; Muylle, Ludo; Van de Heyning, Paul; Van Rompaey, Vincent

2016-06-01

Allograft tympano-ossicular systems (ATOS) have proven their use over many decades in tympanoplasty and reconstruction after resection of cholesteatoma. The transcranial bone plug technique has been used in the past 50 years to procure en bloc ATOS (tympanic membrane with malleus, incus and stapes attached). Recently, our group reported the feasibility of the endoscopic procurement technique. The aim of this study was to assess whether clinical outcome is equivalent in ATOS acquired by using the endoscopic procurement technique compared to ATOS acquired by using the transcranial technique. A double-blind randomized controlled audit was performed in a tertiary referral center in patients that underwent allograft tympanoplasty because of chronic otitis media with and without cholesteatoma. Allograft epithelialisation was evaluated at the short-term postoperative visit by microscopic examination. Failures were reported if reperforation was observed. Fifty patients underwent allograft tympanoplasty: 34 received endoscopically procured ATOS and 16 received transcranially procured ATOS. One failed case was observed, in the endoscopic procurement group. We did not observe a statistically significant difference between the two groups in failure rate. This study demonstrates equivalence of the clinical outcome of allograft tympanoplasty using either endoscopic or transcranial procured ATOS and therefore indicates that the endoscopic technique can be considered the new standard procurement technique. Especially because the endoscopic procurement technique has several advantages compared to the former transcranial procurement technique: it avoids risk of prion transmission and it is faster while lacking any noticeable incision.

New approaches to the prevention of organ allograft rejection and tolerance induction.

PubMed

Bagley, Jessamyn; Tian, Chaorui; Iacomini, John

2007-07-15

The therapeutic use of organ allograft transplantation is dependent on the discovery and clinical application of immunologic strategies to blunt the immune response and prevent graft rejection. It was the discovery of powerful immunotherapeutics such as cyclosporine A and rapamycin that has allowed for the widespread use of organ transplantation to treat organ failure. However, despite the attainment of impressive survival rates 1 year after organ transplantation, a significant number of organ allografts are lost to immune-mediated chronic rejection. Furthermore, significant morbidity and mortality can be associated with the use of currently available immunosuppressive regimens. Thus, the development of novel approaches to prevent of organ allograft rejection remains extremely important. Here we discuss two promising and novel avenues of research. First, the discovery and characterization of naturally occurring immune inhibitory signals have led to recent research aimed at exploiting these pathways to induce peripheral tolerance to alloantigen. Furthermore, we discuss new approaches to the induction of donor-specific tolerance by induction of molecular chimerism and the transfer of alloantigen-expressing mature T cells.

Radiographic failure and rates of re-operation after acromioclavicular joint reconstruction: a comparison of surgical techniques.

PubMed

Spencer, H T; Hsu, L; Sodl, J; Arianjam, A; Yian, E H

2016-04-01

To compare radiographic failure and re-operation rates of anatomical coracoclavicular (CC) ligament reconstructional techniques with non-anatomical techniques after chronic high grade acromioclavicular (AC) joint injuries. We reviewed chronic AC joint reconstructions within a region-wide healthcare system to identify surgical technique, complications, radiographic failure and re-operations. Procedures fell into four categories: (1) modified Weaver-Dunn, (2) allograft fixed through coracoid and clavicular tunnels, (3) allograft loop coracoclavicular fixation, and (4) combined allograft loop and synthetic cortical button fixation. Among 167 patients (mean age 38.1 years, (standard deviation (sd) 14.7) treated at least a four week interval after injury, 154 had post-operative radiographs available for analysis. Radiographic failure occurred in 33/154 cases (21.4%), with the lowest rate in Technique 4 (2/42 4.8%, p = 0.001). Half the failures occurred by six weeks, and the Kaplan-Meier survivorship at 24 months was 94.4% (95% confidence interval (CI) 79.6 to 98.6) for Technique 4 and 69.9% (95% CI 59.4 to 78.3) for the other techniques when combined. In multivariable survival analysis, Technique 4 had better survival than other techniques (Hazard Ratio 0.162, 95% CI 0.039 to 0.068, p = 0.013). Among 155 patients with a minimum of six months post-operative insurance coverage, re-operation occurred in 9.7% (15 patients). However, in multivariable logistic regression, Technique 4 did not reach a statistically significant lower risk for re-operation (odds ratio 0.254, 95% CI 0.05 to 1.3, p = 0.11). In this retrospective series, anatomical CC ligament reconstruction using combined synthetic cortical button and allograft loop fixation had the lowest rate of radiographic failure. Anatomical coracoclavicular ligament reconstruction using combined synthetic cortical button and allograft loop fixation had the lowest rate of radiographic failure. ©2016 The British Editorial Society of Bone & Joint Surgery.

Isolated heart and liver transplant recipients are at low risk for polyomavirus BKV nephropathy.

PubMed

Puliyanda, Dechu P; Amet, Nurmamet; Dhawan, Archana; Hilo, Lara; Radha, Raju K; Bunnapradist, Suphamai; Czer, Lawrence; Martin, Paul; Jordan, Stanley; Toyoda, Mieko

2006-01-01

BKV infection and nephropathy is a significant cause of allograft dysfunction in kidney transplantation. BKV viremia, rather than viruria, corresponds to BKV nephropathy. The prevalence of BKV viremia in non-renal solid organ transplants has not been systematically evaluated. We determined prevalence of BKV viremia in kidney, combined kidney-heart, kidney-liver, kidney-pancreas, kidney-heart-liver, and heart and liver transplant recipients using BKV-PCR. Seven out of 173 (4%) kidney transplant recipients had BKV viremia, with BKV>2 x 10(5) copies/mL in 6/7 and 1.9 x 10(3) in the remaining one patient. BKV viremia was not found in 24 heart transplant recipients, whereas 1/37 (2.7%) liver transplants showed low copy numbers (< or =10(3)). BKV-PCR< or =10(3) copies/mL were also found in one of each combined kidney-heart and kidney-liver transplant recipients. BKV nephropathy was proven by biopsy in 4/6 patients with high BKV viral loads. All six patients showed renal dysfunction, requiring reduction in immunosuppression and antiviral therapy. All four patients with low BKV viral loads (1.9 x 10(3) or < or =10(3)) showed stable renal function after reduction of immunosuppression or no treatment, respectively. Higher BKV levels in plasma are associated with renal dysfunction. Kidney transplant recipients are at high risk compared with recipients of isolated heart or liver allografts, for development of BKV nephropathy.

Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection

PubMed Central

Jiang, Xinguo; Khan, Mohammad A.; Tian, Wen; Beilke, Joshua; Natarajan, Ramesh; Kosek, Jon; Yoder, Mervin C.; Semenza, Gregg L.; Nicolls, Mark R.

2011-01-01

Chronic rejection, manifested as small airway fibrosis (obliterative bronchiolitis [OB]), is the main obstacle to long-term survival in lung transplantation. Recent studies demonstrate that the airways involved in a lung transplant are relatively hypoxic at baseline and that OB pathogenesis may be linked to ischemia induced by a transient loss of airway microvasculature. Here, we show that HIF-1α mediates airway microvascular repair in a model of orthotopic tracheal transplantation. Grafts with a conditional knockout of Hif1a demonstrated diminished recruitment of recipient-derived Tie2+ angiogenic cells to the allograft, impaired repair of damaged microvasculature, accelerated loss of microvascular perfusion, and hastened denudation of epithelial cells. In contrast, graft HIF-1α overexpression induced via an adenoviral vector prolonged airway microvascular perfusion, preserved epithelial integrity, extended the time window for the graft to be rescued from chronic rejection, and attenuated airway fibrotic remodeling. HIF-1α overexpression induced the expression of proangiogenic factors such as Sdf1, Plgf, and Vegf, and promoted the recruitment of vasoreparative Tie2+ cells. This study demonstrates that a therapy that enhances vascular integrity during acute rejection may promote graft health and prevent chronic rejection. PMID:21606594

Treatment of erectile dysfunction with sildenafil citrate in renal allograft recipients: a randomized, double-blind, placebo-controlled, crossover trial.

PubMed

Sharma, Raj K; Prasad, Narayan; Gupta, Amit; Kapoor, Rakesh

2006-07-01

Erectile dysfunction (ED) is observed frequently in patients with end-stage renal disease, hemodialysis patients, and renal allograft recipients. There are few studies of sildenafil use in renal allograft recipients. The study is designed as a randomized, double-blind, placebo-controlled, crossover trial. Efficacy was assessed by using the self-administered International Index of Erectile Function (IIEF), a 15-question validated measure of ED, and a global efficacy question (Did the treatment improve your erection?). Thirty-two eligible renal transplant recipients were included in this study. After treatment with sildenafil citrate, patients had significantly better scores in 13 of 15 questions, except for questions 11 (desire frequency; P = 0.39) and 12 (desire level; P = 0.61). Treatment efficacy assessed through questions 3 (penetration ability; P < 0.001) and 4 (maintenance frequency; P < 0.001) was significantly better after sildenafil therapy. There were no significant differences between baseline and post-placebo treatment scores, except for question 13 (relationship satisfaction). Patients treated with sildenafil had significantly better scores in 4 domains compared with baseline, but a difference was not observed in the sexual desire domain (P = 0.32). There were no significant differences in scores between placebo and baseline in any domain. On the global efficacy question, 81.3% of patients showed improvement compared with 18.7% with placebo. There were no differences in areas under the curve and maximum cyclosporine concentrations before and after sildenafil therapy. No patient discontinued the drug because of side effects except for 1 patient with visual hallucination. Treatment with sildenafil in renal transplant recipients is a valid option with an effective response.

Influence of preformed donor-specific antibodies and C4d on early liver allograft function.

PubMed

Perera, M T; Silva, M A; Murphy, N; Briggs, D; Mirza, D F; Neil, D A H

2013-12-01

INTRODUCTION. The impact of preformed donor-specific antibodies (DSA) is incompletely understood in liver transplantation. The incidence and impact of preformed DSA on early post liver transplant were assessed and these were correlated with compliment fragment C4d on allograft biopsy. METHODS. Pretransplant serum from 41 consecutive liver transplant recipients (brain dead donors; DBD = 27 and cardiac death donors; DCD = 14) were tested for class-specific anti-human leukocyte antigen (HLA) and compared against donor HLA types. Liver biopsies were taken during cold storage (t-1) and post-reperfusion (t0) stained with C4d and graded for preservation-reperfusion injury (PRI). RESULTS. Of the 41 recipients, 8 (20%) had anti-HLA class I/II antibodies pretransplant, 3 (7%) were confirmed preformed DSA; classes I and II (n=1) and class I only (n=2). No biopsies showed definite evidence of antibody-mediated rejection. Graft biopsies in overall showed only mild PRI with ischemic hepatocyte C4d pattern similar in both positive and negative DSA patients. One DSA-positive (33%) compared with four DSA-negative patients (10%) had significant early graft dysfunction; severe PRI causing graft loss from primary nonfunction was seen only in DSA-negative group. Allograft biopsy of preformed DSA-positive patient demonstrated only minimal PRI; however, no identifiable cause could be attributed to graft dysfunction other than preformed DSA. CONCLUSION. Preformed DSA are present in 5-10% liver transplant recipients. There is no association between anti-HLA DSA and PRI and C4d, but preformed DSA may cause early morbidity. Larger studies on the impact of DSA with optimization of C4d techniques are required.

Randomized trial of single-dose versus divided-dose rabbit anti-thymocyte globulin induction in renal transplantation: an interim report.

PubMed

Stevens, R Brian; Mercer, David F; Grant, Wendy J; Freifeld, Alison G; Lane, James T; Groggel, Gerald C; Rigley, Theodore H; Nielsen, Kathleen J; Henning, Megan E; Skorupa, Jill Y; Skorupa, Anna J; Christensen, Kecia A; Sandoz, John P; Kellogg, Anna M; Langnas, Alan N; Wrenshall, Lucile E

2008-05-27

The optimal dosing protocol for rabbit anti-thymocyte globulin (rATG) induction in renal transplantation has not been determined, but evidence exists that rATG infusion before renal allograft reperfusion improves early graft function. Infusing a large rATG dose over a short interval has not previously been evaluated for its effect on renal function and allograft nephropathy in a prospective, randomized comparison against conventional rATG induction. Between April 20, 2004 and December 26, 2007 we enrolled renal transplant patients into a prospective, randomized, nonblinded trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment=160) followed after 6 months by calcineurin-inhibitor withdrawal. Primary endpoints are renal function by calculated glomerular filtration rate (GFR) and chronic allograft nephropathy at protocol biopsy. We now present the early GFR data of all 160 patients and safety and efficacy data of the first 142 patients with 6 months follow up and before calcineurin inhibitor withdrawal (average follow up=23.3+/-11.6 months). There were no differences between groups in rATG-related adverse events, patient and graft survival, acute rejection, or chronic allograft nephropathy rate at 6 months. Calculated DeltaGFR (POD 1-4) was significantly better in the single-dose group (P=0.02), with a trend toward improved renal function from months 2 to 6 in recipients of deceased donor kidneys (P=0.08). This study demonstrates that administering 6 mg/kg of rATG over 24 hr is safe and is associated with improved early renal function compared with administering rATG in alternate-day doses.

Pre- and Posttransplant IgA Anti-Fab Antibodies to Predict Long-term Kidney Graft Survival.

PubMed

Amirzargar, M A; Amirzargar, A; Basiri, A; Hajilooi, M; Roshanaei, G; Rajabi, G; Solgi, G

2015-05-01

Immunologic factors are reliable markers for allograft monitoring, because of their seminal role in rejection process. One of these factors is the immunoglobulin (Ig)A anti-Fab of the IgG antibody. This study aimed to evaluate the predictive value of pre- and posttransplant levels of this marker for kidney allograft function and survival. Sera samples of 59 living unrelated donor kidney recipients were collected before and after transplantation (days 7, 14, and 30) and investigated for IgA anti-Fab of IgG antibody levels using enzyme-linked immunosorbent assay in relation with allograft outcome. Among 59 patients, 15 cases (25%) including 10 with acute rejection and 5 with chronic rejection episodes showed graft failure during a mean of 5 years of follow-up. High posttransplant levels of IgA anti-Fab antibodies were observed more frequently in patients with stable graft function (SGF) compared with patients with graft failure (P = 2 × 10(-6)). None of patients with acute or chronic rejection episodes had high levels of IgA anti-Fab antibodies at day 30 posttransplant compared with the SGF group (P = 10(-6) and P = .01, respectively). In addition, high levels of IgA anti-Fab antibody correlated with lesser concentration of serum creatinine at 1 month posttransplantation (P = .01). Five-year graft survival was associated with high levels of pre- and posttransplant IgA anti-Fab antibodies (P = .02 and P = .003, respectively). Our findings indicate the protective effect of higher levels of IgA anti-Fab antibodies regarding to kidney allograft outcomes and long-term graft survival. Copyright © 2015 Elsevier Inc. All rights reserved.

Gene Expression Profiling of Bronchoalveolar Lavage Cells During Aspergillus Colonization of the Lung Allograft.

PubMed

Weigt, S Samuel; Wang, Xiaoyan; Palchevskiy, Vyacheslav; Patel, Naman; Derhovanessian, Ariss; Shino, Michael Y; Sayah, David M; Lynch, Joseph P; Saggar, Rajan; Ross, David J; Kubak, Bernie M; Ardehali, Abbas; Palmer, Scott; Husain, Shahid; Belperio, John A

2018-06-01

Aspergillus colonization after lung transplant is associated with an increased risk of chronic lung allograft dysfunction (CLAD). We hypothesized that gene expression during Aspergillus colonization could provide clues to CLAD pathogenesis. We examined transcriptional profiles in 3- or 6-month surveillance bronchoalveolar lavage fluid cell pellets from recipients with Aspergillus fumigatus colonization (n = 12) and without colonization (n = 10). Among the Aspergillus colonized, we also explored profiles in those who developed CLAD (n = 6) or remained CLAD-free (n = 6). Transcription profiles were assayed with the HG-U133 Plus 2.0 microarray (Affymetrix). Differential gene expression was based on an absolute fold difference of 2.0 or greater and unadjusted P value less than 0.05. We used NIH Database for Annotation, Visualization and Integrated Discovery for functional analyses, with false discovery rates less than 5% considered significant. Aspergillus colonization was associated with differential expression of 489 probe sets, representing 404 unique genes. "Defense response" genes and genes in the "cytokine-cytokine receptor" Kyoto Encyclopedia of Genes and Genomes pathway were notably enriched in this list. Among Aspergillus colonized patients, CLAD development was associated with differential expression of 69 probe sets, representing 64 unique genes. This list was enriched for genes involved in "immune response" and "response to wounding", among others. Notably, both chitinase 3-like-1 and chitotriosidase were associated with progression to CLAD. Aspergillus colonization is associated with gene expression profiles related to defense responses including cytokine signaling. Epithelial wounding, as well as the innate immune response to chitin that is present in the fungal cell wall, may be key in the link between Aspergillus colonization and CLAD.

Management of BK virus nephropathy in kidney transplant recipients at the Royal Hospital - Clinical Audit - Oman.

PubMed

Al-Raisi, Fatma; Mohsin, Nabil; Kamble, Pramod

2015-04-01

Nephropathy from BK virus (BKV) infection is a growing challenge in kidney transplant recipients globally. It is the result of contemporary potent immunosuppressives aimed at reducing acute rejection and improving allograft survival. Untreated BK virus infections lead to kidney allograft dysfunction or loss. Decreased immunosuppression is the principle treatment but predisposes to acute and chronic rejection. Screening for early detection and prevention of symptomatic BK virus nephropathy may improve outcomes. Although no approved antiviral drug is available, leflunomide, cidofovir, quinolones, and intravenous immunoglobulin have been used. Since the introduction of the new immunosuppressive agents in the transplant regimen at the Royal Hospital, Few cases of BK virus have been detected, and the challenge was to decide upon the best treatment option. The audit was carried out at the Royal Hospital-Oman between January 2010 and December 2012. The nephrology consultant and the clinical pharmacist reviewed all the BK cases and the Royal Hospital. Extensive literature review carried out by the pharmacist to look into the prevalence, prognosis and treatment of BK nephropathy. A treatment protocol was prepared by the clinical pharmacist through guidance of the consultant and was peer reviewed by team of clinical pharmacists and nephrology doctors and approved by the consultant. The audit included 19 patients with positive BK virus ployoma nephropathy. The treatment options were applied stepwise in all the patients with BK virus nephropathy with success rate more than 70%. BK virus nephropathy is emerging at an alarming rate and requires increasing awareness. The uses of current treatment options are still questionable. Our audit confirms that reducing immunosuppression appears to be the criterian standard for the treatment of BK nephropathy.

Pancreas allograft biopsies in the management of pancreas transplant recipients: histopathologic review and clinical correlations.

PubMed

Gaber, Lillian W

2007-08-01

Pancreas transplantation has become a therapeutic option for patients with type 1 diabetes mellitus who are in end-stage renal failure. It also is indicated for a subset of nonuremic, insulin-dependent diabetics who experience extreme difficulties in maintaining proper glucose homeostasis by insulin therapy that compromises their productivity and safety. To provide a review of the literature and expert experiences for understanding the histologic findings in pancreas transplantation. The published literature between 1990 and 2005 was reviewed for this report. Additionally, personal files of the author were used, along with biopsy slides that were used for figures. Pancreas transplantation reestablishes the physiologic state of insulin secretion, and pancreas transplant recipients are able to maintain a state of long-term euglycemia and are less likely to be exposed to hyperglycemia and its systemic complications. Key to the success of transplantation is the scrupulous management and close monitoring of the pancreas transplant recipients. To that end, histologic evaluation of pancreas allografts assumed a pivotal role in management of pancreas allograft dysfunction episodes, and in some centers surveillance biopsies are used to monitor immunologically high-risk situations.

Chronic effects of air pollution on lung function after lung transplantation in the Systems prediction of Chronic Lung Allograft Dysfunction (SysCLAD) study.

PubMed

Benmerad, Meriem; Slama, Rémy; Botturi, Karine; Claustre, Johanna; Roux, Antoine; Sage, Edouard; Reynaud-Gaubert, Martine; Gomez, Carine; Kessler, Romain; Brugière, Olivier; Mornex, Jean-François; Mussot, Sacha; Dahan, Marcel; Boussaud, Véronique; Danner-Boucher, Isabelle; Dromer, Claire; Knoop, Christiane; Auffray, Annick; Lepeule, Johanna; Malherbe, Laure; Meleux, Frederik; Nicod, Laurent; Magnan, Antoine; Pison, Christophe; Siroux, Valérie

2017-01-01

An irreversible loss in lung function limits the long-term success in lung transplantation. We evaluated the role of chronic exposure to ambient air pollution on lung function levels in lung transplant recipients (LTRs).The lung function of 520 LTRs from the Cohort in Lung Transplantation (COLT) study was measured every 6 months. The levels of air pollutants (nitrogen dioxide (NO 2 ), particulate matter with an aerodynamic cut-off diameter of x µm (PM x ) and ozone (O 3 )) at the patients' home address were averaged in the 12 months before each spirometry test. The effects of air pollutants on forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) in % predicted were estimated using mixed linear regressions. We assessed the effect modification of macrolide antibiotics in this relationship.Increased 12-month levels of pollutants were associated with lower levels of FVC % pred (-2.56%, 95% CI -3.86--1.25 for 5 µg·m -3 of PM 10 ; -0.75%, 95% CI -1.38--0.12 for 2 µg·m -3 of PM 2.5 and -2.58%, 95% CI -4.63--0.53 for 10 µg·m -3 of NO 2 ). In patients not taking macrolides, the deleterious association between PM and FVC tended to be stronger and PM 10 was associated with lower FEV 1 Our study suggests a deleterious effect of chronic exposure to air pollutants on lung function levels in LTRs, which might be modified with macrolides. Copyright ©ERS 2017.

An update on renal involvement in hemophagocytic syndrome (macrophage activation syndrome).

PubMed

Esmaili, Haydarali; Mostafidi, Elmira; Mehramuz, Bahareh; Ardalan, Mohammadreza; Mohajel-Shoja, Mohammadali

2016-01-01

Hemophagocytic syndrome (HPS) is mainly characterized by massive infiltration of bone marrow by activated macrophages and often presents with pancytopenia. Thrombotic microangiopathy (TMA) is also present with thrombocytopenia and renal involvement. Both conditions could coexist with each other and complicate the condition. Directory of Open Access Journals (DOAJ), EMBASE, Google Scholar, PubMed, EBSCO, and Web of Science with keywords relevant to; Hemophagocytic syndrome, macrophage activation syndrome, interferon-gamma and thrombotic microangiopathy, have been searched. Viral infection, rheumatologic disease and malignancies are the main underlying causes for secondary HPS. calcineurin inhibitors and viral infections are also the main underlying causes of TMA in transplant recipients. In this review, we discussed a 39-year-old male who presented with pancytopenia and renal allograft dysfunction. With the diagnosis of HPS induced TMA his renal condition and pancytopenia improved after receiving intravenous immunoglobulin (IVIG) and plasmapheresis therapy. HPS is an increasingly recognized disorder in the realm of different medical specialties. Renal involvement complicates the clinical picture of the disease, and this condition even is more complex in renal transplant recipients. We should consider the possibility of HPS in any renal transplant recipient with pancytopenia and allograft dysfunction. The combination of HPS with TMA future increases the complexity of the situation.

An update on renal involvement in hemophagocytic syndrome (macrophage activation syndrome)

PubMed Central

Esmaili, Haydarali; Mostafidi, Elmira; Mehramuz, Bahareh; Ardalan, Mohammadreza; Mohajel-Shoja, Mohammadali

2016-01-01

Context: Hemophagocytic syndrome (HPS) is mainly characterized by massive infiltration of bone marrow by activated macrophages and often presents with pancytopenia. Thrombotic microangiopathy (TMA) is also present with thrombocytopenia and renal involvement. Both conditions could coexist with each other and complicate the condition. Evidence Acquisition: Directory of Open Access Journals (DOAJ), EMBASE, Google Scholar, PubMed, EBSCO, and Web of Science with keywords relevant to; Hemophagocytic syndrome, macrophage activation syndrome, interferon-gamma and thrombotic microangiopathy, have been searched. Results: Viral infection, rheumatologic disease and malignancies are the main underlying causes for secondary HPS. calcineurin inhibitors and viral infections are also the main underlying causes of TMA in transplant recipients. In this review, we discussed a 39-year-old male who presented with pancytopenia and renal allograft dysfunction. With the diagnosis of HPS induced TMA his renal condition and pancytopenia improved after receiving intravenous immunoglobulin (IVIG) and plasmapheresis therapy. Conclusions: HPS is an increasingly recognized disorder in the realm of different medical specialties. Renal involvement complicates the clinical picture of the disease, and this condition even is more complex in renal transplant recipients. We should consider the possibility of HPS in any renal transplant recipient with pancytopenia and allograft dysfunction. The combination of HPS with TMA future increases the complexity of the situation. PMID:27047804

Serum Iron Protects from Renal Postischemic Injury.

PubMed

Vaugier, Céline; Amano, Mariane T; Chemouny, Jonathan M; Dussiot, Michael; Berrou, Claire; Matignon, Marie; Ben Mkaddem, Sanae; Wang, Pamella H M; Fricot, Aurélie; Maciel, Thiago T; Grapton, Damien; Mathieu, Jacques R R; Beaumont, Carole; Peraldi, Marie-Noëlle; Peyssonnaux, Carole; Mesnard, Laurent; Daugas, Eric; Vrtovsnik, François; Monteiro, Renato C; Hermine, Olivier; Ginzburg, Yelena Z; Benhamou, Marc; Camara, Niels O S; Flamant, Martin; Moura, Ivan C

2017-12-01

Renal transplants remain a medical challenge, because the parameters governing allograft outcome are incompletely identified. Here, we investigated the role of serum iron in the sterile inflammation that follows kidney ischemia-reperfusion injury. In a retrospective cohort study of renal allograft recipients ( n =169), increased baseline levels of serum ferritin reliably predicted a positive outcome for allografts, particularly in elderly patients. In mice, systemic iron overload protected against renal ischemia-reperfusion injury-associated sterile inflammation. Furthermore, chronic iron injection in mice prevented macrophage recruitment after inflammatory stimuli. Macrophages cultured in high-iron conditions had reduced responses to Toll-like receptor-2, -3, and -4 agonists, which associated with decreased reactive oxygen species production, increased nuclear localization of the NRF2 transcription factor, increased expression of the NRF2-related antioxidant response genes, and limited NF- κ B and proinflammatory signaling. In macrophage-depleted animals, the infusion of macrophages cultured in high-iron conditions did not reconstitute AKI after ischemia-reperfusion, whereas macrophages cultured in physiologic iron conditions did. These findings identify serum iron as a critical protective factor in renal allograft outcome. Increasing serum iron levels in patients may thus improve prognosis of renal transplants. Copyright © 2017 by the American Society of Nephrology.

Metabolomics discloses donor liver biomarkers associated with early allograft dysfunction.

PubMed

Cortes, Miriam; Pareja, Eugenia; García-Cañaveras, Juan C; Donato, M Teresa; Montero, Sandra; Mir, Jose; Castell, José V; Lahoz, Agustín

2014-09-01

Early allograft dysfunction (EAD) dramatically influences graft and patient outcome after orthotopic liver transplantation and its incidence is strongly determined by donor liver quality. Nevertheless, objective biomarkers, which can assess graft quality and anticipate organ function, are still lacking. This study aims to investigate whether there is a preoperative donor liver metabolomic biosignature associated with EAD. A comprehensive metabolomic profiling of 124 donor liver biopsies collected before transplantation was performed by mass spectrometry coupled to liquid chromatography. Donor liver grafts were classified into two groups: showing EAD and immediate graft function (IGF). Multivariate data analysis was used to search for the relationship between the metabolomic profiles present in donor livers before transplantation and their function in recipients. A set of liver graft dysfunction-associated biomarkers was identified. Key changes include significantly increased levels of bile acids, lysophospholipids, phospholipids, sphingomyelins and histidine metabolism products, all suggestive of disrupted lipid homeostasis and altered histidine pathway. Based on these biomarkers, a predictive EAD model was built and further evaluated by assessing 24 independent donor livers, yielding 91% sensitivity and 82% specificity. The model was also successfully challenged by evaluating donor livers showing primary non-function (n=4). A metabolomic biosignature that accurately differentiates donor livers, which later showed EAD or IGF, has been deciphered. The remarkable metabolomic differences between donor livers before transplant can relate to their different quality. The proposed metabolomic approach may become a clinical tool for donor liver quality assessment and for anticipating graft function before transplant. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Cardio-renal syndromes: a systematic approach for consensus definition and classification.

PubMed

Ronco, Claudio; Ronco, Federico

2012-03-01

The "Cardio-Renal Syndrome" (CRS) is a disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The general definition has been expanded to five subtypes reflecting the primacy of organ dysfunction and the time-frame of the syndrome: CRS type I: acute worsening of heart function (AHF-ACS) leading to kidney injury and/or dysfunction. CRS type II: chronic abnormalities in heart function (CHF-CHD) leading to kidney injury or dysfunction. CRS type III: acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction. CRS type IV: chronic kidney disease (CKD) leading to heart injury, disease and/or dysfunction. CRS type V: systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. Different pathophysiological mechanisms are involved in the combined dysfunction of heart and kidney in these five types of the syndrome.

The Basics of Renal Allograft Pathology.

PubMed

Troxell, Megan L; Houghton, Donald C

2014-09-01

Renal allograft biopsy provides critical information in the management of renal transplant patients, and must be analyzed in close collaboration with the clinical team. The histologic correlates of acute T-cell mediated rejection are interstitial inflammation, tubulitis, and endothelialitis; polyomavirus nephropathy is a potential mimic. Evidence of antibody-mediated rejection includes C4d deposition; morphologic acute tissue injury; and donor specific antibodies. Acute tubular injury/necrosis is a reversible cause of impaired graft function, especially in the immediate post-transplant period. Drug toxicity, recurrent disease, chronic injury, and other entities affecting both native and transplant kidneys must also be evaluated. Copyright © 2014 Elsevier Inc. All rights reserved.

Staged Hand-Assisted Bilateral Native Nephrectomy for Management of Posttransplant Polyuria in an Adult with Dent's Disease

PubMed Central

Montero, Rosa M.; Olsburgh, Jonathon

2015-01-01

Polyuria after kidney transplantation causes graft dysfunction and increased thrombotic risk. We present a case of a polyuric adult with Dent's disease who underwent staged bilateral native nephrectomies, the first operation before transplant and the second four months after transplant. This led to improved allograft function maintained during four years of follow-up. The retroperitoneal laparoscopic approach was well tolerated and allowed continuation of peritoneal dialysis before transplantation. A staged approach helps regulate fluid balance perioperatively and may be tailored to individual need according to posttransplant urine output. This novel approach should be considered for polyuric patients with tubular dysfunction including Dent's disease. PMID:25649339

A Multicenter Study on Long-Term Outcomes After Lung Transplantation Comparing Donation After Circulatory Death and Donation After Brain Death.

PubMed

van Suylen, V; Luijk, B; Hoek, R A S; van de Graaf, E A; Verschuuren, E A; Van De Wauwer, C; Bekkers, J A; Meijer, R C A; van der Bij, W; Erasmus, M E

2017-10-01

The implementation of donation after circulatory death category 3 (DCD3) was one of the attempts to reduce the gap between supply and demand of donor lungs. In the Netherlands, the total number of potential lung donors was greatly increased by the availability of DCD3 lungs in addition to the initial standard use of donation after brain death (DBD) lungs. From the three lung transplant centers in the Netherlands, 130 DCD3 recipients were one-to-one nearest neighbor propensity score matched with 130 DBD recipients. The primary end points were primary graft dysfunction (PGD), posttransplant lung function, freedom from chronic lung allograft dysfunction (CLAD), and overall survival. PGD did not differ between the groups. Posttransplant lung function was comparable after bilateral lung transplantation, but seemed worse after DCD3 single lung transplantation. The incidence of CLAD (p = 0.17) nor the freedom from CLAD (p = 0.36) nor the overall survival (p = 0.40) were significantly different between both groups. The presented multicenter results are derived from a national context where one third of the lung transplantations are performed with DCD3 lungs. We conclude that the long-term outcome after lung transplantation with DCD3 donors is similar to that of DBD donors and that DCD3 donation can substantially enlarge the donor pool. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

BK nephropathy in the native kidneys of patients with organ transplants: Clinical spectrum of BK infection

PubMed Central

Vigil, Darlene; Konstantinov, Nikifor K; Barry, Marc; Harford, Antonia M; Servilla, Karen S; Kim, Young Ho; Sun, Yijuan; Ganta, Kavitha; Tzamaloukas, Antonios H

2016-01-01

Nephropathy secondary to BK virus, a member of the Papoviridae family of viruses, has been recognized for some time as an important cause of allograft dysfunction in renal transplant recipients. In recent times, BK nephropathy (BKN) of the native kidneys has being increasingly recognized as a cause of chronic kidney disease in patients with solid organ transplants, bone marrow transplants and in patients with other clinical entities associated with immunosuppression. In such patients renal dysfunction is often attributed to other factors including nephrotoxicity of medications used to prevent rejection of the transplanted organs. Renal biopsy is required for the diagnosis of BKN. Quantitation of the BK viral load in blood and urine are surrogate diagnostic methods. The treatment of BKN is based on reduction of the immunosuppressive medications. Several compounds have shown antiviral activity, but have not consistently shown to have beneficial effects in BKN. In addition to BKN, BK viral infection can cause severe urinary bladder cystitis, ureteritis and urinary tract obstruction as well as manifestations in other organ systems including the central nervous system, the respiratory system, the gastrointestinal system and the hematopoietic system. BK viral infection has also been implicated in tumorigenesis. The spectrum of clinical manifestations from BK infection and infection from other members of the Papoviridae family is widening. Prevention and treatment of BK infection and infections from other Papovaviruses are subjects of intense research. PMID:27683628

[A case report of simultaneous liver, pancreas-duodenum, and kidney transplantation in a patient with post-hepatitic cirrhosis combined with uremia and insulin-dependent diabetes related to chronic pancreatitis].

PubMed

Wang, He; Dou, Ke-feng; Yang, Xiao-jian; Qin, Wei-jun; Zhang, Geng; Yu, Lei; Kang, Fu-xia; Chen, Shao-yang; Xiong, Li-ze; Song, Zhen-shun; Liu, Zheng-cai

2006-09-12

To study the effect of triple organ transplantation (liver, kidney, and pancreas) in patient of end-stage liver disease with renal failure and diabetes, and to explore the optimal surgical procedure. Simultaneous piggyback orthotopic heterotopic liver, pancreas-duodenum, and kidney transplantation was performed on a 43-year-old male patient with exocrine pancreatic insufficiency and insulin-dependent diabetes related to chronic pancreatitis (CP) who developed hepatic and renal failure. The pancreatic exocrine secretions were drained enterically to the jejunum. Prednisone, tacrolimus, mycophenolate mofetil, and ATG were used as immunosuppression therapy. Good liver and pancreas allograft function recovery was achieved within 7 days after the operation. And the recovery of renal allograft function was delayed. The renal allograft was removed because of break-down of renal blood flow 16 days after the transplantation. A new renal transplantation was performed at the same position. The second kidney graft recovered its normal function 3 days later. Up to the writing of this paper no acute rejection of organs and such complications as pancreatitis, thrombosis, and localized infection occurred. The patient became insulin independent with normal liver and renal function. Simultaneous piggyback orthotopic heterotopic liver, pancreas-duodenum, and kidney transplantation can be a good method for the patients with exocrine pancreatic insufficiency and insulin-dependent diabetes combined with hepatic and renal failure.

Renal transplantation in systemic lupus erythematosus: outcome and prognostic factors in 50 cases from a single centre.

PubMed

Cairoli, Ernesto; Sanchez-Marcos, Carolina; Espinosa, Gerard; Glucksmann, Constanza; Ercilla, Guadalupe; Oppenheimer, Federico; Cervera, Ricard

2014-01-01

End-stage renal disease (ESRD) is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). To analyze the outcome and prognostic factors of renal transplantation in patients with ESRD due to SLE from January 1986 to December 2013 in a single center. Fifty renal transplantations were performed in 40 SLE patients (32 female (80%), mean age at transplantation 36±10.4 years). The most frequent lupus nephropathy was type IV (72.2%). Graft failure occurred in a total of 15 (30%) transplantations and the causes of graft failure were chronic allograft nephropathy (n=12), acute rejection (n=2), and chronic humoral rejection (1). The death-censored graft survival rates were 93.9% at 1 year, 81.5% at 5 years, and 67.6% at the end of study. The presence of deceased donor allograft (P=0.007) and positive anti-HCV antibodies (P=0.001) negatively influence the survival of the renal transplant. The patient survival rate was 91.4% at the end of the study. Recurrence of lupus nephritis in renal allograft was observed in one patient. Renal transplantation is a good alternative for renal replacement therapy in patients with SLE. In our cohort, the presence of anti-HCV antibodies and the type of donor source were related to the development of graft failure.

Renal Transplantation in Systemic Lupus Erythematosus: Outcome and Prognostic Factors in 50 Cases from a Single Centre

PubMed Central

Cairoli, Ernesto; Sanchez-Marcos, Carolina; Espinosa, Gerard; Glucksmann, Constanza; Ercilla, Guadalupe; Oppenheimer, Federico; Cervera, Ricard

2014-01-01

Background. End-stage renal disease (ESRD) is an important cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Objectives. To analyze the outcome and prognostic factors of renal transplantation in patients with ESRD due to SLE from January 1986 to December 2013 in a single center. Results. Fifty renal transplantations were performed in 40 SLE patients (32 female (80%), mean age at transplantation 36 ± 10.4 years). The most frequent lupus nephropathy was type IV (72.2%). Graft failure occurred in a total of 15 (30%) transplantations and the causes of graft failure were chronic allograft nephropathy (n = 12), acute rejection (n = 2), and chronic humoral rejection (1). The death-censored graft survival rates were 93.9% at 1 year, 81.5% at 5 years, and 67.6% at the end of study. The presence of deceased donor allograft (P = 0.007) and positive anti-HCV antibodies (P = 0.001) negatively influence the survival of the renal transplant. The patient survival rate was 91.4% at the end of the study. Recurrence of lupus nephritis in renal allograft was observed in one patient. Conclusion. Renal transplantation is a good alternative for renal replacement therapy in patients with SLE. In our cohort, the presence of anti-HCV antibodies and the type of donor source were related to the development of graft failure. PMID:25013800

Protective function of pirfenidone and everolimus on the development of chronic allograft rejection after experimental lung transplantation.

PubMed

von Suesskind-Schwendi, M; Heigel, E; Pfaehler, S; Haneya, A; Schmid, C; Hirt, S W; Lehle, K

2016-07-01

Long-term survival of lung allografts is limited by chronic rejection (CR). Oxidative stress (OxS) plays a central role in the development of CR. We investigated the influence of pirfenidone (alone or in combination with everolimus) on OxS and CR. A rat model of left lung allo-transplantation (F344-to-WKY) was used to evaluate the effects of pirfenidone alone [0,85% in chow from postoperative day (POD) -3 to 20/60] and in combination with everolimus [2,5 mg/kg bw daily from POD 7 to 20/60]. Allografts of non-treated animals, everolimus treated animals and right, non-transplanted lungs were used as references. Immunohistology of myeloperoxidase (MPO), haemoxygenase-1 (HO-1), iron and platelet-derived-growth-factor-receptor-alpha (PDGFR-a) were performed. On POD 20, all groups showed severe acute rejection (ISHLT A3-4/B1R-B2R). Groups treated with pirfenidone showed a lower interstitial inflammatory infiltration and a lower participation of highly fibrotic degenerated vessels (ISHLT-D2R). In the long term follow up (POD 60), pirfenidone alone significantly reduced chronic airway rejection (ISHLT-C; p≤0.05), interstitial fibrosis (IF; p≤0.05), content of collagen (p≤0.05), expression of PDGFR-a (p≤0.05) and the deposition of iron (p≤0.05). All groups treated with pirfenidone showed a high expression of the cytoprotective enzyme HO-1 (p≤0.05). The additional application of everolimus resulted in a significant decrease of chronic airway rejection (ISHLT-C; p≤0.05), vasculopathy (ISHLT; p≤0.05) and IF (p≤0.05). In conclusion, early application of pirfenidone inhibited the progression of CR by its anti-fibrotic and anti-oxidative properties. The additional application of an m-TOR-inhibitor increased the anti-fibrotic effects of pirfenidone which resulted in a reduction of CR after experimental LTx.

Use of [18F]FDG PET to Monitor The Development of Cardiac Allograft Rejection

PubMed Central

Daly, Kevin P.; Dearling, Jason L. J.; Seto, Tatsuichiro; Dunning, Patricia; Fahey, Frederic; Packard, Alan B.; Briscoe, David M.

2014-01-01

Background Positron Emission Tomography (PET) has the potential to be a specific, sensitive and quantitative diagnostic test for transplant rejection. To test this hypothesis, we evaluated 18F-labeled fluorodeoxyglucose ([18F]FDG) and 13N-labeled ammonia ([13N]NH3) small animal PET imaging in a well-established murine cardiac rejection model. Methods Heterotopic transplants were performed using minor MHC mismatched B6.C-H2bm12 donor hearts in C57BL/6(H-2b) recipients. C57BL/6 donor hearts into C57BL/6 recipients served as isograft controls. [18F]FDG PET imaging was performed weekly between post-transplant days 7 and 42 and the percent injected dose was computed for each graft. [13N]NH3 imaging was performed to evaluate myocardial perfusion. Results There was a significant increase in [18F]FDG uptake in allografts from day 14 to day 21 (1.6% to 5.2%; P<0.001) and uptake in allografts was significantly increased on post-transplant days 21 (5.2% vs. 0.9%; P=0.005) and 28 (4.8% vs. 0.9%; P=0.006) compared to isograft controls. Furthermore, [18F]FDG uptake correlated with an increase in rejection within allografts between days 14 and 28 post-transplant. Finally, the uptake of [13N]NH3 was significantly lower relative to the native heart in allografts with chronic vasculopathy compared to isograft controls on day 28 (P=0.01). Conclusions PET imaging with [18F]FDG can be used following transplantation to monitor the evolution of rejection. In addition, decreased uptake of [13N]NH3 in rejecting allografts may be reflective of decreased myocardial blood flow. These data suggest that combined [18F]FDG and [13N]NH3 PET imaging could be used as a non-invasive, quantitative technique for serial monitoring of allograft rejection and has potential application in human transplant recipients. PMID:25675207

[Estimation of soluble serum CD30 in the diagnosis of early renal allograft dysfunction].

PubMed

Trailin, A V

2009-10-01

We aimed to reveal factors influencing serum soluble CD30 level in the recipients of kidney allograft and to estimate its pathogenetic significance. We tested the sCD30 level in the serum before and the 4th day after operation by ELISA. It was established, thats CD30 levels before transplantation were virtually the same in patients who experienced rejection and in non-rejecting patients. However, there was a significant decrease in the level of sCD30 after transplantation in non-rejecting patients, contrary to rejecting patients. A significant decrease of sCD30 level was detected on the day 4th after the transplantation independently of dialysis requirement. The decrease of sCD30 on the day 4th after operation in the patients with delayed graft function and its stability in the patients with acute rejection may be used distinguish these complications.

Proton Pump Inhibitors Independently Protect Against Early Allograft Injury or Chronic Rejection After Lung Transplantation.

PubMed

Lo, Wai-Kit; Goldberg, Hilary J; Boukedes, Steve; Burakoff, Robert; Chan, Walter W

2018-02-01

Acid reflux has been associated with poor outcomes following lung transplantation. Unlike surgical fundoplication, the role of noninvasive, pharmacologic acid suppression remains uncertain. To assess the relationship between post-transplant acid suppression with proton pump inhibitors (PPI) or histamine-2 receptor antagonists (H2RA) and onset of early allograft injury or chronic rejection following lung transplantation. This was a retrospective cohort study of lung transplant recipients at a tertiary center in 2007-2014. Patients with pre-transplant antireflux surgery were excluded. Time-to-event analysis using the Cox proportional hazards model was applied to assess acid suppression therapy and onset of acute or chronic rejection, defined histologically and clinically. Subgroup analyses were performed to assess PPI versus H2RA use. A total of 188 subjects (60% men, mean age 54, follow-up 554 person-years) met inclusion criteria. During follow-up, 115 subjects (61.5%) developed rejection, with all-cause mortality of 27.6%. On univariate analyses, acid suppression and BMI, but not other patient demographics, were associated with rejection. The Kaplan-Meier curve demonstrated decreased rejection with use of acid suppression therapy (log-rank p = 0.03). On multivariate analyses, acid suppression (HR 0.39, p = 0.04) and lower BMI (HR 0.67, p = 0.04) were independently predicted against rejection. Subgroup analyses demonstrated that persistent PPI use was more protective than H2RA or no antireflux medications. Post-lung transplant exposure to persistent PPI therapy results in the greatest protection against rejection in lung transplant recipients, independent of other clinical predictors including BMI, suggesting that PPI may have antireflux or anti-inflammatory effects in enhancing allograft protection.

3-dimensional digital reconstruction of the murine coronary system for the evaluation of chronic allograft vasculopathy.

PubMed

Fónyad, László; Shinoda, Kazunobu; Farkash, Evan A; Groher, Martin; Sebastian, Divya P; Szász, A Marcell; Colvin, Robert B; Yagi, Yukako

2015-03-28

Chronic allograft vasculopathy (CAV) is a major mechanism of graft failure of transplanted organs in humans. Morphometric analysis of coronary arteries enables the quantitation of CAV in mouse models of heart transplantation. However, conventional histological procedures using single 2-dimensional sections limit the accuracy of CAV quantification. The aim of this study is to improve the accuracy of CAV quantification by reconstructing the murine coronary system in 3-dimensions (3D) and using virtual reconstruction and volumetric analysis to precisely assess neointimal thickness. Mouse tissue samples, native heart and transplanted hearts with chronic allograft vasculopathy, were collected and analyzed. Paraffin embedded samples were serially sectioned, stained and digitized using whole slide digital imaging techniques under normal and ultraviolet lighting. Sophisticated software tools were used to generate and manipulate 3D reconstructions of the major coronary arteries and branches. The 3D reconstruction provides not only accurate measurements but also exact volumetric data of vascular lesions. This virtual coronary arteriography demonstrates that the vasculopathy lesions in this model are localized to the proximal coronary segments. In addition, virtual rotation and volumetric analysis enabled more precise measurements of CAV than single, randomly oriented histologic sections, and offer an improved readout for this important experimental model. We believe 3D reconstruction of 2D histological slides will provide new insights into pathological mechanisms in which structural abnormalities play a role in the development of a disease. The techniques we describe are applicable to the analysis of arteries, veins, bronchioles and similar sized structures in a variety of tissue types and disease model systems. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3772457541477230 .

Management of chronic spinal cord dysfunction.

PubMed

Abrams, Gary M; Ganguly, Karunesh

2015-02-01

Both acute and chronic spinal cord disorders present multisystem management problems to the clinician. This article highlights key issues associated with chronic spinal cord dysfunction. Advances in symptomatic management for chronic spinal cord dysfunction include use of botulinum toxin to manage detrusor hyperreflexia, pregabalin for management of neuropathic pain, and intensive locomotor training for improved walking ability in incomplete spinal cord injuries. The care of spinal cord dysfunction has advanced significantly over the past 2 decades. Management and treatment of neurologic and non-neurologic complications of chronic myelopathies ensure that each patient will be able to maximize their functional independence and quality of life.

Hypothermic oxygenated machine perfusion (HOPE) for orthotopic liver transplantation of human liver allografts from extended criteria donors (ECD) in donation after brain death (DBD): a prospective multicentre randomised controlled trial (HOPE ECD-DBD).

PubMed

Czigany, Zoltan; Schöning, Wenzel; Ulmer, Tom Florian; Bednarsch, Jan; Amygdalos, Iakovos; Cramer, Thorsten; Rogiers, Xavier; Popescu, Irinel; Botea, Florin; Froněk, Jiří; Kroy, Daniela; Koch, Alexander; Tacke, Frank; Trautwein, Christian; Tolba, Rene H; Hein, Marc; Koek, Ger H; Dejong, Cornelis H C; Neumann, Ulf Peter; Lurje, Georg

2017-10-10

Orthotopic liver transplantation (OLT) has emerged as the mainstay of treatment for end-stage liver disease. In an attempt to improve the availability of donor allografts and reduce waiting list mortality, graft acceptance criteria were extended increasingly over the decades. The use of extended criteria donor (ECD) allografts is associated with a higher incidence of primary graft non-function and/or delayed graft function. As such, several strategies have been developed aiming at reconditioning poor quality ECD liver allografts. Hypothermic oxygenated machine perfusion (HOPE) has been successfully tested in preclinical experiments and in few clinical series of donation after cardiac death OLT. HOPE ECD-DBD is an investigator-initiated, open-label, phase-II, prospective multicentre randomised controlled trial on the effects of HOPE on ECD allografts in donation after brain death (DBD) OLT. Human whole organ liver grafts will be submitted to 1-2 hours of HOPE (n=23) via the portal vein before implantation and are going to be compared with a control group (n=23) of patients transplanted after conventional cold storage. Primary (peak and Δ peak alanine aminotransferase within 7 days) and secondary (aspartate aminotransferase, bilirubin and international normalised ratio, postoperative complications, early allograft dysfunction, duration of hospital and intensive care unit stay, 1-year patient and graft survival) endpoints will be analysed within a 12-month follow-up. Extent of ischaemia-reperfusion (I/R) injury will be assessed using liver tissue, perfusate, bile and serum samples taken during the perioperative phase of OLT. The study was approved by the institutional review board of the RWTH Aachen University, Aachen, Germany (EK 049/17). The current paper represent the pre-results phase. First results are expected in 2018. NCT03124641. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Associated Clinical and Laboratory Markers of Donor on Allograft Function After Heart Transplant.

PubMed

Braulio, Renato; Sanches, Marcelo Dias; Teixeira Junior, Antonio Lúcio; Costa, Paulo Henrique Nogueira; Moreira, Maria da Consolação Vieira; Rocha, Monaliza Angela; Andrade, Silvio Amadeu de; Gelape, Cláudio Léo

2016-04-01

Primary graft dysfunction is a major cause of mortality after heart transplantation. To evaluate correlations between donor-related clinical/biochemical markers and the occurrence of primary graft dysfunction/clinical outcomes of recipients within 30 days of transplant. The prospective study involved 43 donor/recipient pairs. Data collected from donors included demographic and echocardiographic information, noradrenaline administration rates and concentrations of soluble tumor necrosis factor receptors (sTNFR1 and sTNFR2), interleukins (IL-6 and IL-10), monocyte chemoattractant protein-1, C-reactive protein and cardiac troponin I. Data collected from recipients included operating, cardiopulmonary bypass, intensive care unit and hospitalization times, inotrope administration and left/right ventricular function through echocardiography. Recipients who developed moderate/severe left ventricular dysfunction had received organs from significantly older donors (P =0.020). Recipients from donors who required moderate/high doses of noradrenaline (>0.23 µg/kg/min) around harvesting time exhibited lower post-transplant ventricular ejection fractions (P =0.002) and required longer CPB times (P =0.039). Significantly higher concentrations of sTNFR1 (P =0.014) and sTNFR2 (P =0.030) in donors were associated with reduced intensive care unit times (≤5 days) in recipients, while higher donor IL-6 (P =0.029) and IL-10 (P =0.037) levels were correlated with reduced hospitalization times (≤25 days) in recipients. Recipients who required moderate/high levels of noradrenaline for weaning off cardiopulmonary bypass were associated with lower donor concentrations of sTNFR2 (P =0.028) and IL-6 (P =0.001). High levels of sTNFR1, sTNFR2, IL-6 and IL-10 in donors were associated with enhanced evolution in recipients. Allografts from older donors, or from those treated with noradrenaline doses >0.23 µg/kg/min, were more frequently affected by primary graft dysfunction within 30 days of surgery.

Humoral theory of transplantation: some hot topics.

PubMed

Cai, Junchao; Qing, Xin; Tan, Jianming; Terasaki, Paul I

2013-01-01

Antibody is a major cause of allograft injury. However, it has not been routinely tested post-transplant. A literature search was performed using PubMed on the topics of 'antibody monitoring', 'autoantibody and allograft dysfunction' and 'prevention and treatment of antibody-mediated rejection (AMR)'. Donor-specific antibody (DSA) monitoring not only helps to identify patients at risk of AMR, but also serves as a biomarker to personalize patient's maintenance immunosuppression. Development of autoantibody is a secondary response following primary tissue injury. Some autoantibodies are directly involved in allograft injury, while others only serve as biomarkers of tissue injury. It remains controversial whether DSA-positive patients without symptoms need to be treated. In addition, given the variation in study designs and patient's characteristics, there is discrepancy regarding which treatment regimens provide optimal clinical outcome in preventing/treating AMR. Efficacy of B-cell and/or antibody-targeted therapies in treating or preventing AMR would be better measured by the incorporation of antibody monitoring into current functional and pathological assays. Research in B-cell targeted therapies to prevent and treat AMR is rapidly growing, which includes monoclonal antibodies against B-cell markers CD20, CD40, CD19, BlyS, etc. It requires extensive clinical research to determine the best approach to inhibit or delete antibody and how to balance the drug efficacy with safety.

Are drowned donors marginal donors? A single pediatric center experience.

PubMed

Kumm, Kayla R; Galván, N Thao N; Koohmaraie, Sarah; Rana, Abbas; Kueht, Michael; Baugh, Katherine; Hao, Liu; Yoeli, Dor; Cotton, Ronald; O'Mahony, Christine A; Goss, John A

2017-09-01

Drowning, a common cause of death in the pediatric population, is a potentially large donor pool for OLT. Anecdotally, transplant centers have deemed these organs high risk over concerns for infection and graft dysfunction. We theorized drowned donor liver allografts do not portend worse outcomes and therefore should not be excluded from the donation pool. We reviewed our single-center experience of pediatric OLTs between 1988 and 2015 and identified 33 drowned donor recipients. These OLTs were matched 1:2 to head trauma donor OLTs from our center. A chart review assessed postoperative peak AST and ALT, incidence of HAT, graft and recipient survival. Recipient survival at one year between patients with drowned donor vs head trauma donor allografts was not statistically significant (94% vs 97%, P=.63). HAT incidence was 6.1% in the drowned donor group vs 7.6% in the control group (P=.78). Mean postoperative peak AST and ALT was 683 U/L and 450 U/L for drowned donors vs 1119 U/L and 828 U/L in the matched cohort. These results suggest drowned donor liver allografts do not portend worse outcomes in comparison with those procured from head trauma donors. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Successful Single-Lung Transplant for Severe Lung Graft-Versus-Host Disease Two Years After Sibling Allograft for Acute Lymphoblastic Leukemia: A Case Report.

PubMed

Irhimeh, M R; Musk, M; Cooney, J P

2016-11-01

Bone marrow transplantation (BMT) has been performed as a successful life-saving treatment for hematological and neoplastic diseases. Despite the predictable long-term survival rates in BMT, pulmonary complications reduce the survival rates significantly mainly because of chronic graft-versus-host disease (GVHD). This report briefly discusses a successful lung transplantation case for severe lung GVHD after allograft for acute lymphoblastic leukemia. This case report supports the scarce evidence in the literature for the importance of lung transplantation as a therapeutic option for patients who develop respiratory failure secondary to BMT. Copyright © 2016. Published by Elsevier Inc.

Allograft Bone: What Is the Role of Platelet-Derived Growth Factor in Hindfoot and Ankle Fusions.

PubMed

Scott, Ryan T; McAlister, Jeffrey E; Rigby, Ryan B

2018-01-01

Arthrodesis of the ankle or foot is a common procedure for chronic pain and disability. Nonunion remains a prevalent complication among arthrodesis procedures. Some patients present with an inherent risk of developing a nonunion. Allograft biologics have gained popularity in an effort to reduce complications such as nonunion. Various biologics bring unique properties while maintaining a singular purpose. Platelet-derived growth factor (PDGF) may be introduced into a fusion site to facilitate healthy bony consolidation. The purpose of this article is to review the benefits and modalities of PDGF and how it can improve patient outcomes in ankle and hindfoot fusions. Copyright © 2017 Elsevier Inc. All rights reserved.

The Chronic Illness Problem Inventory as a measure of dysfunction in chronic pain patients.

PubMed

Romano, J M; Turner, J A; Jensen, M P

1992-04-01

Assessment of physical and psychosocial dysfunction is recognized as essential in chronic pain patient evaluation. One instrument, the Sickness Impact Profile (SIP), has demonstrated good reliability and validity as a measure of dysfunction among chronic pain patients. An alternate measure, the Chronic Illness Problem Inventory (CIPI), is shorter and more easily scored than the SIP, but as yet has not been applied widely to chronic pain problems. In the present study, 95 chronic low back pain patients completed the SIP, the CIPI, activity diaries, the McGill Pain Questionnaire (MPQ), and the Center for Epidemiologic Studies-Depression scale (CES-D), before participating in a chronic pain treatment study. Overt pain behaviors were also coded from videotapes of a standardized assessment protocol. Seventy-five subjects completed the measures post-treatment. The results indicate that although the SIP and the CIPI are significantly correlated and appear to be measuring similar constructs, there is also substantial unshared variance between them, suggesting that they may tap somewhat different aspects of dysfunction in chronic pain. The CIPI shows promise as a useful alternative measure of dysfunction in chronic low back pain patients, but requires further validation for this purpose.

Donor-specific anti-HLA antibodies with antibody-mediated rejection and long-term outcomes following heart transplantation.

PubMed

Clerkin, Kevin J; Farr, Maryjane A; Restaino, Susan W; Zorn, Emmanuel; Latif, Farhana; Vasilescu, Elena R; Marboe, Charles C; Colombo, Paolo C; Mancini, Donna M

2017-05-01

Donor-specific anti-HLA antibodies (DSA) are common after heart transplantation and are associated with rejection, cardiac allograft vasculopathy, and mortality. A noninvasive diagnostic test for pathologic antibody-mediated rejection (pAMR) does not exist. From January 1, 2010, through August 31, 2013, 221 consecutive adult patients underwent heart transplantation and were followed through October 1, 2015. The primary objective was to determine whether the presence of DSA could detect AMR at the time of pathologic diagnosis. Secondary analyses included association of DSA (stratified by major histocompatibility complex class and de novo status) during AMR with new graft dysfunction, graft loss (mortality or retransplantation), and development of cardiac allograft vasculopathy. During the study period, 69 patients (31.2%) had DSA (24% had de novo DSA), and there were 74 episodes of pAMR in 38 patients. Sensitivity of DSA at any mean fluorescence intensity to detect concurrent pAMR was only 54.3%. The presence of any DSA during pAMR increased the odds of graft dysfunction (odds ratio = 5.37; 95% confidence interval [CI], 1.34-21.47; p = 0.018), adjusting for age, sex, and timing of AMR. Circulating class II DSA after transplantation increased risk of future pAMR (hazard ratio = 2.97; 95% CI, 1.31-6.73; p = 0.009). Patients who developed de novo class II DSA had 151% increased risk of graft loss (contingent on 30-day survival) compared with patients who did not have DSA (95% CI, 1.11-5.69; p = 0.027). DSA were inadequate to diagnose pAMR. Class II DSA provided prognostic information regarding future pAMR, graft dysfunction with pAMR, and graft loss. Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Tolerability of sirolimus: a decade of experience at a single cardiac transplant center.

PubMed

Thibodeau, Jennifer T; Mishkin, Joseph D; Patel, Parag C; Kaiser, Patricia A; Ayers, Colby R; Mammen, Pradeep P A; Markham, David W; Ring, William Steves; Peltz, Matthias; Drazner, Mark H

2013-01-01

Sirolimus is used in cardiac transplant recipients to prevent rejection, progression of cardiac allograft vasculopathy, and renal dysfunction. However, sirolimus has many potential side effects and its tolerability when used outside of clinical trials is not well established. We describe a decade of experience with sirolimus in cardiac transplant recipients at our institution. We retrospectively reviewed records of all adult cardiac transplant recipients living between September 1999 and February 2010 (n = 329) and identified 67 patients (20%) who received sirolimus. The indications for sirolimus were cardiac allograft vasculopathy (67%), renal dysfunction (25%), rejection (4%), and intolerability of tacrolimus (3%). One-third of patients discontinued sirolimus at a median (25th, 75th percentiles) of 0.9 (0.2, 1.6) yr of duration. Over 70% of subjects experienced an adverse event attributed to sirolimus. Adverse events were associated with higher average sirolimus levels (9.1 ng/mL vs. 7.1 ng/mL, p = 0.004). We conclude that sirolimus is frequently used in cardiac transplant recipients (20%) and commonly causes side effects, often necessitating discontinuation. Higher average sirolimus levels were associated with adverse events, suggesting that tolerability may improve if levels are maintained within the lower end of the current therapeutic range; however, the improvement in tolerability would need to be balanced with the potential for decreased efficacy. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cardio-renal syndromes: from foggy bottoms to sunny hills.

PubMed

Ronco, Claudio

2011-11-01

"Cardio-renal syndromes" (CRS) are disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The current definition has been expanded into five subtypes whose etymology reflects the primary and secondary pathology, the time-frame and simultaneous cardiac and renal co-dysfunction secondary to systemic disease: CRS type I: acute worsening of heart function (AHF-ACS) leading to kidney injury and/or dysfunction. CRS type II: chronic abnormalities in heart function (CHF-CHD) leading to kidney injury or dysfunction. CRS type III: acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction. CRS type IV: chronic kidney disease (CKD) leading to heart injury, disease and/or dysfunction. CRS type V: systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. These different subtypes may have a different pathophysiological mechanism and they may represent separate entities in terms of prevention and therapy.

Optimal surgical management of severe tricuspid regurgitation in cardiac transplant patients.

PubMed

Filsoufi, Farzan; Salzberg, Sacha P; Anderson, Curtis A; Couper, Gregory S; Cohn, Lawrence H; Adams, David H

2006-03-01

Severe tricuspid regurgitation (TR) with signs of right-sided heart failure is rare after orthotopic heart transplantation (OHT). In some instances, this condition will require surgical correction using reconstructive surgery or prosthetic valve replacement. Repair techniques of atrioventricular valves are now well described. However, the results of the different surgical procedures in this setting have not been widely reported and may depend on the type of valvular dysfunction and lesions present. Herein we report our experience in a group of patients requiring surgical correction of symptomatic severe TR after OHT. We reviewed our transplant experience during the period from July 1992 to July 1999 (n = 138 cardiac transplants). Eight patients (5.8%) developed symptomatic severe TR requiring surgical correction after a mean duration of 21 months after OHT. Patients were divided into 2 groups based on the mechanism of regurgitation using Carpentier's functional classification. In Group 1 (n = 4), the mechanism of tricuspid regurgitation was Carpentier's Type I, secondary to annular dilation. In Group 2 (n = 4) the mechanism of TR was leaflet prolapse (Type II), due to chordal rupture after biopsy injury. Initially, tricuspid valve integrity was surgically restored in all 8 patients with either valve repair (n = 6) or replacement (n = 2). In Group 1, 2 patients underwent valve repair using a ring annuloplasty and 2 patients underwent valve replacement with a bioprosthetic valve (n = 1) or pulmonary allograft (n = 1). In Group 2, all patients underwent valve repair using a variety of techniques in combination with tricuspid annuloplasty. During the follow-up period, 3 of the 6 (50%) primary repairs (1 patient in Group 1 and 2 in Group 2) failed and required replacement with a bioprosthesis at 8 days, 14 days and 4 years, respectively. The pulmonary allograft failed secondary to valvular stenosis and was replaced with a bioprosthesis after 10 months. Overall, no failures occurred in any of the 5 bioprosthetic valves placed at the primary operation (n = 1) or after failed tricuspid repair/pulmonary allograft (n = 4), after a mean follow-up of 55 months. TR requiring surgical correction after OHT is a rare condition and requires a tailored surgical strategy. This strategy should take into account the mechanism of valve dysfunction and specific valvular lesions. In patients with Type I dysfunction secondary to annular dilation, valve repair with a remodeling annuloplasty should be performed; however, in the presence of any residual TR on transesophageal echocardiography (TEE) at the completion of cardiopulmonary bypass (CPB), a valve replacement with a bioprosthesis is warranted during the same procedure. In patients with Type II dysfunction with leaflet prolapse and biopsy-induced chordal injury, a bioprosthetic valve replacement seems a reliable surgical option.

Characteristics of Donor-Specific Antibodies Associated With Antibody-Mediated Rejection in Lung Transplantation

PubMed Central

Roux, Antoine; Bendib Le Lan, Ines; Holifanjaniaina, Sonia; Thomas, Kimberly A.; Picard, Clément; Grenet, Dominique; De Miranda, Sandra; Douvry, Benoit; Beaumont-Azuar, Laurence; Sage, Edouard; Devaquet, Jérôme; Cuquemelle, Elise; Le Guen, Morgan; Suberbielle, Caroline; Gautreau, Chantal; Stern, Marc; Rossetti, Maura; Hamid, Abdul Monem; Parquin, Francois

2017-01-01

Although donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) are frequently found in recipients after lung transplantation (LT), the characteristics of DSA which influence antibody-mediated rejection (AMR) in LT are not fully defined. We retrospectively analyzed 206 consecutive LT patients of our center (2010–2013). DSAs were detected by using luminex single antigen beads assay and mean fluorescence intensity was assessed. Within the study population, 105 patients had positive DSA. Patients with and without AMR (AMRPos, n = 22, and AMRNeg, n = 83, respectively) were compared. AMRPos patients had significantly greater frequencies of anti-HLA DQ DSA (DQ DSA) than AMRNeg patients (95 vs 58%, respectively, p < 0.0001). Compared to AMRNeg patients, AMRPos patients had higher DQ DSA sum MFI [7,332 (2,067–10,213) vs 681 (0–1,887), p < 0.0001]. DQ DSA when associated with AMR, had more frequent graft loss and chronic lung allograft dysfunction (CLAD). These data suggest (i) that DSA characteristics clearly differ between AMRPos and AMRNeg patients and (ii) the deleterious impact of DQ DSA on clinical outcome. PMID:29075627

Practical Guidelines: Lung Transplantation in Patients with Cystic Fibrosis

PubMed Central

Hirche, T. O.; Knoop, C.; Hebestreit, H.; Shimmin, D.; Solé, A.; Elborn, J. S.; Ellemunter, H.; Aurora, P.; Hogardt, M.; Wagner, T. O. F.; ECORN-CF Study Group

2014-01-01

There are no European recommendations on issues specifically related to lung transplantation (LTX) in cystic fibrosis (CF). The main goal of this paper is to provide CF care team members with clinically relevant CF-specific information on all aspects of LTX, highlighting areas of consensus and controversy throughout Europe. Bilateral lung transplantation has been shown to be an important therapeutic option for end-stage CF pulmonary disease. Transplant function and patient survival after transplantation are better than in most other indications for this procedure. Attention though has to be paid to pretransplant morbidity, time for referral, evaluation, indication, and contraindication in children and in adults. This review makes extensive use of specific evidence in the field of lung transplantation in CF patients and addresses all issues of practical importance. The requirements of pre-, peri-, and postoperative management are discussed in detail including bridging to transplant and postoperative complications, immune suppression, chronic allograft dysfunction, infection, and malignancies being the most important. Among the contributors to this guiding information are 19 members of the ECORN-CF project and other experts. The document is endorsed by the European Cystic Fibrosis Society and sponsored by the Christiane Herzog Foundation. PMID:24800072

Revision allograft reconstruction of the lateral collateral ligament complex in elbows with previous failed reconstruction and persistent posterolateral rotatory instability.

PubMed

Baghdadi, Yaser M K; Morrey, Bernard F; O'Driscoll, Shawn W; Steinmann, Scott P; Sanchez-Sotelo, Joaquin

2014-07-01

Primary reconstruction of the lateral collateral ligament complex (LCLC) using graft tissue restores elbow stability in many, but not all, elbows with acute or chronic posterolateral rotatory instability (PLRI). Revision reconstruction using a tendon allograft is occasionally considered for persistent PLRI, but the outcome of revision ligament reconstruction in this setting is largely unknown. We determined whether revision allograft ligament reconstruction can (1) restore the stability and (2) result in improved elbow scores for patients with persistent PLRI of the elbow after a previous failed primary reconstructive attempt and in the context of the diverse pathology being addressed. Between 2001 and 2011, 160 surgical elbow procedures were performed at our institution for the LCLC reconstruction using allograft tissue. Only patients undergoing revision allograft reconstruction of the LCLC for persistent PLRI with a previous failed primary reconstructive attempt using graft tissue and at least I year of followup were included in the study. Eleven patients (11 elbows) fulfilled our inclusion criteria and formed our study cohort. The cohort consisted of six female patients and five male patients. The mean age at the time of revision surgery was 36 years (range, 14-59 years). The revision allograft reconstruction was carried out after a mean of 3 years (range, 2.5 months to 9 years) from a failed attempted reconstruction of the LCLC. Osseous deficiency to some extent was identified in the preoperative radiographs of eight elbows. Mean followup was 5 years (range, 1-12 years). Revision allograft reconstruction of the LCLC restored elbow stability in eight of the 11 elbows; two of the three elbows with persistent instability were operated on a third time (at 6 and 7 months after allograft revision reconstruction). For elbows with no persistent instability, the mean Mayo Elbow Performance Score at most recent followup was 83 points (range, 60-100 points), and six elbows were rated with a good or excellent result. All patients with persistent instability had some degree of preoperative bone loss. Revision allograft reconstruction of the LCLC is an option for treating recurrent PLRI, although this is a complex and resistant problem, and nearly ½ of the patients in this cohort either had persistent instability and/or had a fair or poor elbow score. Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

The biophysical characteristics of human composite flexor tendon allograft for upper extremity reconstruction.

PubMed

DeGeorge, Brent R; Rodeheaver, George T; Drake, David B

2014-01-01

Devastating volar hand injuries with significant damage to the skin and soft tissues, pulley structures and fibro-osseous sheath, flexor tendons, and volar plates pose a major problem to the reconstructive hand surgeon. Despite advances in tendon handling, operative technique, and postoperative hand rehabilitation, patients who have undergone flexor tendon reconstruction are often plagued by chronic pain, stiffness, and decreased range of motion with resultant decreased ability to work and poor quality of life. In this article, we expand the technique of human composite flexor tendon allografts (CFTAs), pioneered by Dr E.E. Peacock, Jr, which consist of both the intrasynovial and extrasynovial flexor digitorum superficialis and flexor digitorum profundus tendons and their respective fibro-osseous sheath consisting of the digital pulley structures, periosteum, and volar plates procured from cadaveric donors with the use of modern tissue processing techniques. Human cadaveric CFTAs were procured and divided into 2 groups-unprocessed CFTAs and processed CFTAs, which are cleansed and sterilized to a sterility assurance level of 10(-6). Physical length and width relationships as well as tensile strength and gliding resistance assessments were recorded pre-tissue and post-tissue processing. The histologic properties of the composite allografts were assessed before and after tissue processing. There was no significant difference with respect to physical properties of the composite allografts before or after tissue processing. The processed composite allografts demonstrated equivalent maximum load to failure and elastic modulus compared to unprocessed tendons. The gliding resistance of the composite tendon allografts was not significantly different between the 2 groups. The use of CFTAs addresses the issues of adhesion formation and lack of suitable donor material by providing a source of intrasynovial tendon in its unaltered fibro-osseous sheath without donor morbidity. This approach represents an important step toward designing an ideal material for complex flexor tendon reconstruction, which takes advantage of an intrasynovial flexor tendon in its native fibro-osseous sheath without the need for additional donor morbidity using a construct which can be engineered to have minimal tissue reactivity, negligible potential for disease transmission, and improved tendon healing properties versus standard tendon allograft.

Blood Gene Expression Predicts Bronchiolitis Obliterans Syndrome

PubMed Central

Danger, Richard; Royer, Pierre-Joseph; Reboulleau, Damien; Durand, Eugénie; Loy, Jennifer; Tissot, Adrien; Lacoste, Philippe; Roux, Antoine; Reynaud-Gaubert, Martine; Gomez, Carine; Kessler, Romain; Mussot, Sacha; Dromer, Claire; Brugière, Olivier; Mornex, Jean-François; Guillemain, Romain; Dahan, Marcel; Knoop, Christiane; Botturi, Karine; Foureau, Aurore; Pison, Christophe; Koutsokera, Angela; Nicod, Laurent P.; Brouard, Sophie; Magnan, Antoine; Jougon, J.

2018-01-01

Bronchiolitis obliterans syndrome (BOS), the main manifestation of chronic lung allograft dysfunction, leads to poor long-term survival after lung transplantation. Identifying predictors of BOS is essential to prevent the progression of dysfunction before irreversible damage occurs. By using a large set of 107 samples from lung recipients, we performed microarray gene expression profiling of whole blood to identify early biomarkers of BOS, including samples from 49 patients with stable function for at least 3 years, 32 samples collected at least 6 months before BOS diagnosis (prediction group), and 26 samples at or after BOS diagnosis (diagnosis group). An independent set from 25 lung recipients was used for validation by quantitative PCR (13 stables, 11 in the prediction group, and 8 in the diagnosis group). We identified 50 transcripts differentially expressed between stable and BOS recipients. Three genes, namely POU class 2 associating factor 1 (POU2AF1), T-cell leukemia/lymphoma protein 1A (TCL1A), and B cell lymphocyte kinase, were validated as predictive biomarkers of BOS more than 6 months before diagnosis, with areas under the curve of 0.83, 0.77, and 0.78 respectively. These genes allow stratification based on BOS risk (log-rank test p < 0.01) and are not associated with time posttransplantation. This is the first published large-scale gene expression analysis of blood after lung transplantation. The three-gene blood signature could provide clinicians with new tools to improve follow-up and adapt treatment of patients likely to develop BOS. PMID:29375549

Effect of Single vs Bilateral Lung Transplantation on Plasma Surfactant Protein D Levels in Idiopathic Pulmonary Fibrosis

PubMed Central

Beers, Michael F.; Ahya, Vivek N.; Kawut, Steven M.; Sims, Karen D.; Lederer, David J.; Palmer, Scott M.; Wille, Keith; Lama, Vibha N.; Shah, Pali D.; Orens, Jonathan B.; Bhorade, Sangeeta; Crespo, Maria; Weinacker, Ann; Demissie, Ejigayehu; Bellamy, Scarlett; Christie, Jason D.; Ware, Lorraine B.

2011-01-01

Background: Serum levels of surfactant protein D (SP-D) have been suggested as reflecting epithelial damage in acute lung injury, COPD, and idiopathic pulmonary fibrosis (IPF). However, little is known about SP-D levels in the setting of lung transplantation. Methods: We examined plasma SP-D levels in 104 subjects from a prospective, multicenter cohort study of lung allograft recipients. Plasma SP-D was measured by enzyme-linked immunosorbent assay prior to transplant and daily for 3 days after transplant. Results: Subjects undergoing transplant for IPF had higher baseline SP-D levels (median, 325 ng/mL) compared with subjects with cystic fibrosis, COPD, and pulmonary hypertension (median, 100, 80, and 82 ng/mL, respectively; P = .0001). Among subjects with IPF undergoing bilateral transplant, SP-D levels declined rapidly postoperatively. In contrast, SP-D levels in subjects undergoing single lung transplant for IPF remained significantly higher than those of bilateral allograft recipients. Among subjects undergoing single lung transplant for IPF, the development of primary graft dysfunction (PGD) was associated with a subsequent rise in SP-D levels, whereas SP-D levels in IPF subjects undergoing bilateral transplant declined, even in the presence of grade 3 PGD. Importantly, single lung allograft recipients without PGD had higher postoperative SP-D levels than bilateral allograft recipients with PGD. Conclusions: Subjects undergoing lung transplant for IPF have significantly higher baseline plasma SP-D levels compared with those with other diagnoses. Plasma SP-D is likely a biomarker of the air-blood barrier integrity in the native IPF lung, but may be less useful as a biomarker of PGD after transplant. PMID:21349925

Re-exposure to beta cell autoantigens in pancreatic allograft recipients with preexisting beta cell autoantibodies.

PubMed

Mujtaba, Muhammad Ahmad; Fridell, Jonathan; Book, Benita; Faiz, Sara; Sharfuddin, Asif; Wiebke, Eric; Rigby, Mark; Taber, Tim

2015-11-01

Re-exposure to beta cell autoantigens and its relevance in the presence of donor-specific antibodies (DSA) in pancreatic allograft recipients is not well known. Thirty-three patients requiring a pancreas transplant were enrolled in an IRB approved study. They underwent prospective monitoring for DSA and beta cell autoantibody (BCAA) levels to GAD65, insulinoma-associated antigen 2 (IA-2), insulin (micro-IAA [mIAA]), and islet-specific zinc transporter isoform-8 (ZnT8). Twenty-five (75.7%) had pre-transplant BCAA. Twenty had a single antibody (mIAA n = 15, GAD65 n = 5); five had two or more BCAA (GAD65 + mIAA n = 2, GAD65 + mIAA+IA-2 n = 2, GA65 + mIAA+IA-2 + ZnT8 = 1). No changes in GAD65 (p > 0.29), IA-2 (>0.16), and ZnT8 (p > 0.07) were observed between pre-transplant and post-transplant at 6 or 12 months. A decrease in mIAA from pre- to post-6 months (p < 0.0001), 12 months (p < 0.0001), and from post-6 to post-12 months (p = 0.0002) was seen. No new BCAA was observed at one yr. Seven (21.0%) developed de novo DSA. The incidence of DSA was 24% in patients with BCAA vs. 25% in patients without BCAA (p = 0.69). Pancreatic allograft function of patients with vs. without BCAA, and with and without BCAA + DSA was comparable until last follow-up (three yr). Re-exposure to beta cell autoantigens by pancreas transplant may not lead to increased levels or development of new BCAA or pancreatic allograft dysfunction. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Evaluation of the Potential Risk of Hepatitis B Virus Transmission in Skin Allografting.

PubMed

Wang, D; Xie, W; Chen, T; Dong, C; Zhao, C; Tan, H; Tian, H; Xie, Q

2015-01-01

Skin transplantation is associated with potential risk of infectious disease transmission; however, the exclusion of donors owing to hepatitis B virus (HBV) infection will worsen the shortage of allograft skin supply. We report a paired study to evaluate the potential risk of HBV transmission in skin allografting. The presence of HBV DNA in the serum and skin from 37 burn patients with chronic HBV infection (CHB) was monitored by a HBV polymerase chain reaction (PCR) and the positive rates were compared by Fisher's exact probability test. There was a high consistency in the HBV serology profile between HBV DNA PCR (83.78%) and the clinical HBV test. Only 2 patients who were positive for hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B core antibody had detectable HBV DNA in the skin tissue; however, no hepatitis B surface antigen was detected as examined by immunohistochemistry staining. There was a significant difference between the positive rates of HBV DNA in the serum and skin (χc(2) = 27.03; P < .001). The potential risk for HBV transmission by skin allografting is very low. Given that China has a large population of patients with HBV, the acceptance of skin from donors with CHB to the skin bank would increase the number of tissue donations to meet the urgent medical need for skin transplantation. Copyright © 2015 Elsevier Inc. All rights reserved.

Use of dehydrated human amniotic membrane allografts to promote healing in patients with refractory non healing wounds.

PubMed

Sheikh, Emran S; Sheikh, Ednan S; Fetterolf, Donald E

2014-12-01

Non healing wounds present a significant social and economic burden. Chronic non healing wounds are estimated to affect as many as 1-2% of individuals during their lifetime, and account for billions of dollars of expense annually on both a national and global basis. Our purpose is to describe the use of a novel dehydrated amniotic membrane allograft (EpiFix(®) ; MiMedx Group, Inc., Kennesaw, GA) for the treatment of chronic non healing wounds. We describe the results of EpiFix treatment in four patients who had not achieved wound closure with both conservative and advanced measures, and had been referred for a definitive plastic surgery procedure. Healing was observed in a variety of wounds with one to three applications of the dehydrated amniotic membrane material. The material was well tolerated by patients. Healed wounds did not recur in long-term follow-up. Further investigation of the use of dehydrated amniotic membrane in broader application to various types of dermal wounds should be considered. © 2013 The Authors. International Wound Journal © 2013 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Soluble CD30 levels as a diagnostic marker for bronchiolitis obliterans syndrome following human lung transplantation

PubMed Central

Golocheikine, Anjali .S.; Saini, Deepti; Ramachandran, Sabarinathan; Trulock, Elbert P.; Patterson, Alexander; Mohanakumar, T.

2007-01-01

The long term survival of human lung allograft is hampered by the occurrence of chronic rejection, Bronchiolitis Obliterans Syndrome (BOS). This end-stage disease is normally diagnosed clinically by using the pulmonary function tests. This results in delay of BOS diagnosis and consequently prevents early intervention. It is generally accepted that alloimmunity plays an important role in chronic rejection of the allograft. In this study we analyzed serial serum samples from BOS+ and BOS− patients for sCD30 levels to determine the role of sCD30 to predict the onset of BOS. In contrast to BOS negative patients and normal subjects, 6 out of 9 BOS+ patients (P<0.05) studied had an increase in the sCD30 levels. Significantly, the rise was noted 7.57 ±2.63 months before the clinical diagnosis was evident. Therefore, we propose that the rise in serum sCD30 levels can be used as a marker for the detection of patients who are at risk of development of BOS. PMID:18047935

Soluble CD30 levels as a diagnostic marker for bronchiolitis obliterans syndrome following human lung transplantation.

PubMed

Golocheikine, Anjali S; Saini, Deepti; Ramachandran, Sabarinathan; Trulock, Elbert P; Patterson, Alexander; Mohanakumar, T

2008-01-01

The long term survival of human lung allograft is hampered by the occurrence of chronic rejection, Bronchiolitis Obliterans Syndrome (BOS). This end-stage disease is normally diagnosed clinically by using the pulmonary function tests. This results in delay of BOS diagnosis and consequently prevents early intervention. It is generally accepted that alloimmunity plays an important role in chronic rejection of the allograft. In this study we analyzed serial serum samples from BOS+ and BOS- patients for sCD30 levels to determine the role of sCD30 to predict the onset of BOS. In contrast to BOS negative patients and normal subjects, 6 out of 9 BOS+ patients (p<0.05) studied had an increase in the sCD30 levels. Significantly, the rise was noted 7.57+/-2.63 months before the clinical diagnosis was evident. Therefore, we propose that the rise in serum sCD30 levels can be used as a marker for the detection of patients who are at risk of development of BOS.

Angiotensin converting enzyme genotype and chronic allograft nephropathy in protocol biopsies.

PubMed

Hueso, Miguel; Alía, Pedro; Moreso, Francesc; Beltrán-Sastre, Violeta; Riera, Luis; González, Carlota; Navarro, Miguel Angel; Grinyó, Josep Maria; Navarro, Estanis; Serón, Daniel

2004-08-01

Genotype DD of the angiotensin-converting enzyme (ACE) is not associated with an increased incidence of native renal diseases, although it could modulate progression to renal failure in patients who already display chronic lesions. Because its role in renal allograft degeneration is not well characterized, whether ACE genotype was associated with the prevalence of chronic allograft nephropathy (CAN) was studied, in a group of protocol biopsies from 180 patients, or with the incidence of CAN in 152 patients with at least two sequential biopsies. As a control group, ACE genotype was also studied in 41 donors and 72 healthy subjects. For analyzing the influence of ACE genotype in graft survival, patients were grouped into six categories (II-normal biopsy, ID-normal, DD-normal, II-CAN, ID-CAN and DD-CAN). Finally, relative renal ACE mRNA levels were measured in 67 cases by real-time PCR using the delta threshold cycle method. ACE-DD genotype was more frequent in patients who received a transplant than in control subjects (43.3% versus 30.1%, P = 0.026), but prevalence (DD = 42.7% versus non-DD = 42.2%) or incidence (DD = 24.6% versus non-DD = 29.9%) of CAN was not different regarding recipient ACE genotype. Furthermore, patients with the ACE-DD genotype and CAN had the poorest graft survival (II-normal = 100%, ID-normal = 91%, DD-normal = 84%, II-CAN = 100%, ID-CAN = 66%, and DD-CAN = 36%; P = 0.034) and higher ACE mRNA levels than non-DD and CAN (DD = -3.36 +/- 2.35 versus non-DD = -5.65 +/- 1.72-fold in ACE copies; P = 0.012). It is concluded that ACE-DD genotype is not associated with an increased prevalence or incidence of CAN but is actually associated with higher ACE mRNA levels and poorer graft survival in patients who already display CAN.

Impact of Leukocyte Function-Associated Antigen-1 Blockade on Endogenous Allospecific T Cells to Multiple Minor Histocompatibility Antigen Mismatched Cardiac Allograft.

PubMed

Kwun, Jean; Farris, Alton B; Song, Hyunjin; Mahle, William T; Burlingham, William J; Knechtle, Stuart J

2015-12-01

Blocking leukocyte function-associated antigen (LFA)-1 in organ transplant recipients prolongs allograft survival. However, the precise mechanisms underlying the therapeutic potential of LFA-1 blockade in preventing chronic rejection are not fully elucidated. Cardiac allograft vasculopathy (CAV) is the preeminent cause of late cardiac allograft failure characterized histologically by concentric intimal hyperplasia. Anti-LFA-1 monoclonal antibody was used in a multiple minor antigen-mismatched, BALB.B (H-2B) to C57BL/6 (H-2B), cardiac allograft model. Endogenous donor-specific CD8 T cells were tracked down using major histocompatibility complex multimers against the immunodominant H4, H7, H13, H28, and H60 minor Ags. The LFA-1 blockade prevented acute rejection and preserved palpable beating quality with reduced CD8 T-cell graft infiltration. Interestingly, less CD8 T cell infiltration was secondary to reduction of T-cell expansion rather than less trafficking. The LFA-1 blockade significantly suppressed the clonal expansion of minor histocompatibility antigen-specific CD8 T cells during the expansion and contraction phase. The CAV development was evaluated with morphometric analysis at postoperation day 100. The LFA-1 blockade profoundly attenuated neointimal hyperplasia (61.6 vs 23.8%; P < 0.05), CAV-affected vessel number (55.3 vs 15.9%; P < 0.05), and myocardial fibrosis (grade 3.29 vs 1.8; P < 0.05). Finally, short-term LFA-1 blockade promoted long-term donor-specific regulation, which resulted in attenuated transplant arteriosclerosis. Taken together, LFA-1 blockade inhibits initial endogenous alloreactive T-cell expansion and induces more regulation. Such a mechanism supports a pulse tolerance induction strategy with anti-LFA-1 rather than long-term treatment.

Clinical outcomes in overweight heart transplant recipients.

PubMed

Jalowiec, Anne; Grady, Kathleen L; White-Williams, Connie

2016-01-01

Few studies have examined the impact of patient weight on heart transplant (HT) outcomes. Nine outcomes were compared in 2 groups of HT recipients (N = 347) based on their mean body mass index (BMI) during the first 3 years post-HT. Group 1 consisted of 108 non-overweight patients (BMI <25; mean age 52; 29.6% females; 16.7% minorities). Group 2 consisted of 239 overweight patients (BMI ≥25; mean age 52; 15.9% females; 13.8% minorities). Outcomes were: survival, re-hospitalization, rejections, infections, cardiac allograft vasculopathy (CAV), stroke, renal dysfunction, diabetes, and lymphoma. Non-overweight patients had shorter survival, were re-hospitalized more days after the HT discharge, and had more lymphoma and severe renal dysfunction. Overweight patients had more CAV, steroid-induced diabetes, and acute rejections. Overweight HT patients had better survival, but more rejections, CAV, and diabetes. Non-overweight HT patients had worse survival, plus more re-hospitalization time, lymphoma, and renal dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

Pseudomonas aeruginosa Induced Airway Epithelial Injury Drives Fibroblast Activation: A Mechanism in Chronic Lung Allograft Dysfunction.

PubMed

Borthwick, L A; Suwara, M I; Carnell, S C; Green, N J; Mahida, R; Dixon, D; Gillespie, C S; Cartwright, T N; Horabin, J; Walker, A; Olin, E; Rangar, M; Gardner, A; Mann, J; Corris, P A; Mann, D A; Fisher, A J

2016-06-01

Bacterial infections after lung transplantation cause airway epithelial injury and are associated with an increased risk of developing bronchiolitis obliterans syndrome. The damaged epithelium is a source of alarmins that activate the innate immune system, yet their ability to activate fibroblasts in the development of bronchiolitis obliterans syndrome has not been evaluated. Two epithelial alarmins were measured longitudinally in bronchoalveolar lavages from lung transplant recipients who developed bronchiolitis obliterans syndrome and were compared to stable controls. In addition, conditioned media from human airway epithelial cells infected with Pseudomonas aeruginosa was applied to lung fibroblasts and inflammatory responses were determined. Interleukin-1 alpha (IL-1α) was increased in bronchoalveolar lavage of lung transplant recipients growing P. aeruginosa (11.5 [5.4-21.8] vs. 2.8 [0.9-9.4] pg/mL, p < 0.01) and was significantly elevated within 3 months of developing bronchiolitis obliterans syndrome (8.3 [1.4-25.1] vs. 3.6 [0.6-17.1] pg/mL, p < 0.01), whereas high mobility group protein B1 remained unchanged. IL-1α positively correlated with elevated bronchoalveolar lavage IL-8 levels (r(2)  = 0.6095, p < 0.0001) and neutrophil percentage (r(2)  = 0.25, p = 0.01). Conditioned media from P. aeruginosa infected epithelial cells induced a potent pro-inflammatory phenotype in fibroblasts via an IL-1α/IL-1R-dependent signaling pathway. In conclusion, we propose that IL-1α may be a novel therapeutic target to limit Pseudomonas associated allograft injury after lung transplantation. © Copyright 2015 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of the American Society of Transplantation and the American Society of Transplant Surgeons.

Primary Cardiac Allograft Dysfunction-Validation of a Clinical Definition.

PubMed

Dronavalli, Vamsidhar B; Rogers, Chris A; Banner, Nicholas R

2015-09-01

Heart transplantation is an established treatment for advanced heart failure. Primary allograft dysfunction (PGD) is reported in up to 40% of transplants and is associated with a poor outcome. As part of Heart Evaluation and Retrieval for Transplantation study, an investigation of the assessment of donor hearts for transplantation, we proposed a clinical definition for cardiac PGD comprising severely impaired systolic function affecting one or both ventricles accompanied by hypotension, low cardiac output, and high filling pressures occurring in the first 72 hours (in the absence of hyper acute rejection and technical surgical factors, such as cardiac tamponade). Here, we examine the prospective application of this definition to 290 heart transplants. We compared the clinical outcome of PGD and non-PGD cases. Ninety-four of 290 transplants developed PGD (32.4%). Inotrope use (score) was higher in the PGD group at 24, 48, and 72 hours after transplantation (P < 0.01). In the PGD group, there was a greater requirement for, intra-aortic balloon pump (50% vs 15%, P < 0.01), mechanical support (27% vs 0%, P < 0.01), and renal replacement therapy (61% vs 26%, P < 0.01). Intensive care stay was longer for recipients with PGD (median 14 vs 5 days, P < 0.01) and early mortality was higher (37% vs 4% at 30 days, 42% vs 8% at 1 year, P < 0.01). In conclusion, our definition of PGD could be applied in a national multicenter study, and the cases it defined had more frequent complications and higher mortality.

Evaluation of coronary microvascular function in patients with end-stage renal disease, and renal allograft recipients.

PubMed

Bozbas, Huseyin; Pirat, Bahar; Demirtas, Saadet; Simşek, Vahide; Yildirir, Aylin; Sade, Elif; Sayin, Burak; Sezer, Siren; Karakayali, Hamdi; Muderrisoglu, Haldun

2009-02-01

Approximately half of all deaths in patients with end-stage renal disease (ESRD) are due to cardiovascular diseases. Although renal transplant improves survival and quality of life in these patients, cardiovascular events significantly affect survival. We sought to evaluate coronary flow reserve (CFR), an indicator of coronary microvascular function, in patients with ESRD and in patients with a functioning kidney graft. Eighty-six patients (30 with ESRD, 30 with a functioning renal allograft, and 26 controls) free of coronary artery disease or diabetes mellitus were included. Transthoracic Doppler echocardiography was used to measure coronary peak flow velocities at baseline and after dipyridamole infusion. CFR was calculated as the ratio of hyperemic to baseline diastolic peak flow velocities and was compared among the groups. The mean age of the study population was 36.1+/-7.3 years. No between-group differences were found regarding age, sex, or prevalences of traditional coronary risk factors other than hypertension. Compared with the renal transplant and control groups, the ESRD group had significantly lower mean CFR values. On multivariate regression analysis, serum levels of creatinine, age, and diastolic dysfunction were independent predictors of CFR. CFR is impaired in patients with ESRD suggesting that coronary microvascular dysfunction, an early finding of atherosclerosis, is evident in these patients. Although associated with a decreased CFR compared with controls, renal transplant on the other hand seems to have a favorable effect on coronary microvascular function.

Working with Chronically Dysfunctional Families.

ERIC Educational Resources Information Center

Younger, Robert; And Others

This paper reviews family therapy with chronically dysfunctional families including the development of family therapy and current trends which appear to give little guidance toward working with severely dysfunctional families. A theoretical stance based upon the systems approach to family functioning and pathology is presented which suggests: (1)…

Major Histocompatibility Mismatch and Donor Choice for Second Allogeneic Bone Marrow Transplantation.

PubMed

Imus, Philip H; Blackford, Amanda L; Bettinotti, Maria; Iglehart, Brian; Dietrich, August; Tucker, Noah; Symons, Heather; Cooke, Kenneth R; Luznik, Leo; Fuchs, Ephraim J; Brodsky, Robert A; Matsui, William H; Huff, Carol Ann; Gladstone, Douglas; Ambinder, Richard F; Borrello, Ivan M; Swinnen, Lode J; Jones, Richard J; Bolaños-Meade, Javier

2017-11-01

Large alternative donor pools provide the potential for selecting a different donor for a second allogeneic (allo) bone or marrow transplant (BMT). As HLA disparity may contribute to the graft-versus-tumor effect, utilizing new mismatched haplotype donors may potentially improve the antitumor activity for relapsed hematologic malignancies despite a previous alloBMT. Data from patients who received a second alloBMT for relapsed hematologic malignancies at Johns Hopkins were analyzed. Outcomes were compared between patients who received a second allograft with the same MHC composition and those who received an allograft with a new mismatched haplotype. Loss of heterozygosity analysis was performed for patients with acute myeloid leukemia (AML) whose first allograft was haploidentical. Between 2005 and 2015, 40 patients received a second BMT for a relapsed hematologic malignancy. The median follow-up is 750 (range, 26 to 2950) days. The median overall survival (OS) in the cohort is 928 days (95% confidence interval [CI], 602 to not reached [NR]); median event-free survival (EFS) for the cohort is 500 days (95% CI, 355 to NR). The 4-year OS is 40% (95% CI, 25% to 64%), and the 4-year EFS is 36% (95% CI, 24% to 55%). The cumulative incidence of nonrelapsed mortality by 2 years was 27% (95% CI, 13% to 42%). The cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) at 100 days was 15% (95% CI, 4% to 26%); the cumulative incidence of extensive chronic GVHD at 2 years was 22% (95% CI, 9% to 36%). The median survival was 552 days (95% CI, 376 to 2950+) in the group who underwent transplantation with a second allograft that did not harbor a new mismatched haplotype, while it was not reached in the group whose allograft contained a new mismatched haplotype (hazard ratio [HR], .36; 95% CI, .14 to .9; P = .02). EFS was also longer in the group who received an allograft containing a new mismatched haplotype, (NR versus 401 days; HR, .50; 95% CI, .22 to 1.14; P = .09). Although the allograft for this patient's second BMT contained a new mismatched haplotype, AML nevertheless relapsed a second time. Second BMTs are feasible and provide a reasonable chance of long-term survival. An allograft with a new mismatched haplotype may improve outcomes after second BMTs for relapsed hematologic malignancies. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Right Ventricular Dysfunction in Chronic Lung Disease

PubMed Central

Kolb, Todd M.; Hassoun, Paul M.

2012-01-01

Right ventricular dysfunction arises in chronic lung disease when chronic hypoxemia and disruption of pulmonary vascular beds contribute to increase ventricular afterload, and is generally defined by hypertrophy with preserved myocardial contractility and cardiac output. Although the exact prevalence is unknown, right ventricular hypertrophy appears to be a common complication of chronic lung disease, and more frequently complicates advanced lung disease. Right ventricular failure is rare, except during acute exacerbations of chronic lung disease or when multiple co-morbidities are present. Treatment is targeted at correcting hypoxia and improving pulmonary gas exchange and mechanics. There are presently no convincing data to support the use of pulmonary hypertension-specific therapies in patients with right ventricular dysfunction secondary to chronic lung disease. PMID:22548815

Assessment of cryopreserved donor skin viability: the experience of the regional tissue bank of Siena.

PubMed

Pianigiani, E; Tognetti, L; Ierardi, F; Mariotti, G; Rubegni, P; Cevenini, G; Perotti, R; Fimiani, M

2016-06-01

Skin allografts from cadaver donors are an important resource for treating extensive burns, slow-healing wounds and chronic ulcers. A high level of cell viability of cryopreserved allografts is often required, especially in burn surgery, in Italy. Thus, we aimed to determine which conditions enable procurement of highly viable skin in our Regional Skin Bank of Siena. For this purpose, we assessed cell viability of cryopreserved skin allografts procured between 2011 and 2013 from 127 consecutive skin donors, before and after freezing (at day 15, 180, and 365). For each skin donor, we collected data concerning clinical history (age, sex, smoking, phototype, dyslipidemia, diabetes, cause of death), donation process (multi-tissue or multi-organ) and timing of skin procurement (assessment of intervals such as death-harvesting, harvesting-banking, death-banking). All these variables were analysed in the whole case study (127 donors) and in different groups (e.g. multi-organ donors, non refrigerated multi-tissue donors, refrigerated multi-tissue donors) for correlations with cell viability. Our results indicated that cryopreserved skin allografts with higher cell viability were obtained from female, non smoker, heartbeating donors died of cerebral haemorrhage, and were harvested within 2 h of aortic clamping and banked within 12 h of harvesting (13-14 h from clamping). Age, cause of death and dyslipidaemia or diabetes did not appear to influence cell viability. To maintain acceptable cell viability, our skin bank needs to reduce the time interval between harvesting and banking, especially for refrigerated donors.

Transient blockade of Delta-like Notch ligands prevents allograft rejection mediated by cellular and humoral mechanisms in a mouse model of heart transplantation

PubMed Central

Wood, Sherri; Feng, Jiane; Chung, Jooho; Radojcic, Vedran; Sandy, Ashley R.; Friedman, Ann; Shelton, Amy; Yan, Minhong; Siebel, Christian W.; Bishop, D. Keith; Maillard, Ivan

2015-01-01

Rejection remains a major clinical challenge limiting allograft survival after solid organ transplantation. Both cellular and humoral immunity contribute to this complication, with increased recognition of antibody-mediated damage during acute and chronic rejection. Using a mouse model of MHC-mismatched heart transplantation, we report markedly protective effects of Notch inhibition, dampening both T cell and antibody-driven rejection. T cell-specific pan-Notch blockade prolonged heart allograft survival and decreased IFNγ and IL-4 production by alloreactive T cells, especially when combined with depletion of recipient CD8+ T cells. These effects were associated with decreased infiltration by conventional T cells and an increased proportion of regulatory T cells in the graft. Transient administration of neutralizing antibodies specific for Delta-like1/4 (Dll1/4) Notch ligands in the peri-transplant period led to prolonged acceptance of allogeneic hearts, with superior outcome over Notch inhibition only in T cells. Systemic Dll1/4 inhibition decreased T cell cytokines and graft infiltration, but also germinal center B cell and plasmablast numbers as well as production of donor-specific alloantibodies and complement deposition in the transplanted hearts. Dll1 or Dll4 inhibition alone provided partial protection. Thus, pathogenic signals delivered by Dll1/4 Notch ligands early after transplantation promote organ rejection through several complementary mechanisms. Transient interruption of theses signals represents a new attractive therapeutic strategy to enhance long-term allograft survival. PMID:25687759

Translation, validation and cultural adaptation of "The Eustachian Tube Dysfunction Questionnaire-7" (ETDQ-7) to Brazilian Portuguese (BR).

PubMed

Gallardo, Fernanda Pires; Onishi, Ektor Tsuneo; Lira, Francisco Iure; Suzuki, Flávia Barros; Testa, José Ricardo Gurgel

2018-04-19

Chronic Eustachian tube dysfunction can cause several symptoms and middle ear conditions that can impact patient quality of life. It is estimated to be relatively frequent, affecting approximately 5% of adults. The diagnostic tools for this condition are still inadequate. In 2012, McCoul et al. published a questionnaire for the evaluation of Eustachian tube dysfunction named ETDQ-7. They established its replicability and validity. The cutoff point for the diagnosis of chronic Eustachian tube dysfunction was equal to or greater than 14.5, with 100% sensitivity and 100% specificity. To translate, adapt and validate the ETDQ-7 questionnaire to Brazilian Portuguese. We translated the questionnaire into Brazilian Portuguese and applied it to 50 patients, 20 of whom had chronic Eustachian tube dysfunction, and 30 controls. The results obtained with the North-American questionnaire were confirmed in its Brazilian version. The cut-off point for the diagnosis of chronic Eustachian tube dysfunction was ≥14, also exhibiting high sensitivity and specificity, very similar to that of ETDQ-7. It is recommended that ETDQ-7 be used to complement the clinical history of patients with chronic Eustachian tube dysfunction; it can also be used as an important tool for diagnosis, patient follow-up and treatment management. Copyright © 2018 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

The postoperative Model for End stage Liver Disease score as a predictor of short-term outcome after transplantation of extended criteria donor livers.

PubMed

Benko, Tamas; Gallinat, Anja; Minor, Thomas; Saner, Fuat H; Sotiropoulos, Georgios C; Paul, Andreas; Hoyer, Dieter P

2017-06-01

Recently, the postoperative Model for End stage Liver Disease score (POPMELD) was suggested as a definition of postoperative graft dysfunction and a predictor of outcome after liver transplantation (LT). The aim of the present study was to validate this concept in the context of extended criteria donor (ECD) organs. Single-center prospectively collected data (OPAL study/01/11-12/13) of 116 ECD LTs were utilized. For each recipient, the Model for End stage Liver Disease (MELD) score was calculated for 7 postoperative days (PODs). The ability of international normalized ratio, bilirubin, aspartate aminotransferase, Donor Risk Index, a recent definition of early allograft dysfunction, and the POPMELD was compared to predict 90-day graft loss. Predictive abilities were compared by receiver operating characteristic curves, sensitivity and specificity, and positive and negative predictive values. The median Donor Risk Index was 1.8. In all, 60.3% of recipients were men [median age of 54 (23-68) years]. The median POD1-7 peak-aspartate aminotransferase value was 1052 (194-17 577) U/l. The rate of early allograft dysfunction was 22.4%. The 90-day graft survival was 89.7%. Out of possible predictors of the 90-day graft loss MELD on POD5 was the best predictor of outcome (area under the curve=0.84). A MELD score of 16 or more on POD5 predicted the 90-day graft loss with a specificity of 80.8%, a sensitivity of 81.8%, and a positive and negative predictive value of 31 and 97.7%. A MELD score of 16 or more on POD5 is an excellent predictor of outcome in ECD donor LT. Routine evaluation of POPMELD scores might support clinical decision-making and should be reported routinely in clinical trials.

The Prevalence and Severity of Autonomic Dysfunction in Chronic Inflammatory Demyelinating Polyneuropathy

PubMed Central

Pasangulapati, Suresh Babu; Murthy, T. V.; Sivadasan, Ajith; Gideon, L. Rynjah; Prabhakar, A. T.; Sanjith, Aaron; Mathew, Vivek; Alexander, Mathew

2017-01-01

Introduction: In chronic inflammatory demyelinating polyneuropathy (CIDP), emphasis has been on motor disabilities, and autonomic dysfunction in these patients has not been addressed systematically. Materials and Methods: Autonomic function was prospectively analyzed in 38 patients with CIDP. Quantitative autonomic function testing was done using Finometer® PRO and severity of adrenergic and cardiovagal dysfunction graded according to composite autonomic severity score and sudomotor dysfunction assessed using sympathetic skin response. Results: Thirty-four (89%) patients had features of autonomic dysfunction. Thirty-three (86%) patients had cardiovagal dysfunction, 21 (55%) had adrenergic dysfunction, and 24 (63%) had sudomotor dysfunction. Autonomic dysfunction was mild to moderate in the majority (86%). Conclusions: Autonomic dysfunction in CIDP is underreported and potentially amenable to therapy. Our cohort had a high proportion of adrenergic dysfunction compared to previous studies. PMID:28904461

Pilot Analysis of Late Conversion to Belatacept in Kidney Transplant Recipients for Biopsy-Proven Chronic Tacrolimus Toxicity

PubMed Central

Rosales, Ivy

2018-01-01

Background Calcineurin inhibitors are associated with chronic nephrotoxicity, manifesting as interstitial fibrosis/tubular atrophy (IF/TA) and arteriolar hyalinosis. Conversion from tacrolimus to belatacept may be one strategy to preserve renal function. Methods We conducted a retrospective review of renal transplant patients followed at our institution who were converted to belatacept and found to have chronic tacrolimus toxicity on biopsy. The primary outcome was eGFR at conversion as compared to eGFR at 3, 6, 12, and 24 months after conversion. We also assessed incidence of infection and rates of allograft survival at 1 year. Results The average time between transplant and conversion was 11.9 years. There was no decrease in eGFR at any postconversion time point as compared with preconversion. The mean eGFR at time of preconversion was 32.9 mL/min, as compared with 35.6 mL/min at 3 months (p = 0.09), 34.1 mL/min at 6 months (p = 0.63), 34.9 mL/min at 12 months (p = 0.57), and 39.6 mL/min at 24 months after conversion (p = 0.92). Four of 7 patients had increases in their eGFR after conversion. All grafts were functioning at 1 year after conversion. Conclusion While this study was limited by a small number of patients, belatacept conversion stabilized eGFR at all time points in patients with late allograft function due to chronic tacrolimus toxicity, with a trend towards increased eGFR at 3 months. PMID:29854421

Filgrastim-Stimulated Bone Marrow Compared with Filgrastim-Mobilized Peripheral Blood in Myeloablative Sibling Allografting for Patients with Hematologic Malignancies: A Randomized Canadian Blood and Marrow Transplant Group Study.

PubMed

Couban, Stephen; Aljurf, Mahmoud; Lachance, Sylvie; Walker, Irwin; Toze, Cynthia; Rubinger, Morel; Lipton, Jeffrey H; Lee, Stephanie J; Szer, Jeff; Doocey, Richard; Lewis, Ian D; Huebsch, Lothar; Howson-Jan, Kang; Lalancette, Michel; Almohareb, Fahad; Chaudhri, Nadeem; Ivison, Sabine; Broady, Raewyn; Levings, Megan; Fairclough, Diane; Devins, Gerald; Szwajcer, David; Foley, Ronan; Smith, Clayton; Panzarella, Tony; Kerr, Holly; Kariminia, Amina; Schultz, Kirk R

2016-08-01

In adult hematopoietic cell transplantation (HCT), filgrastim-mobilized peripheral blood (G-PB) has largely replaced unstimulated marrow for allografting. Although the use of G-PB results in faster hematopoietic recovery, it is also associated with more chronic graft-versus-host disease (cGVHD). A potential alternative allograft is filgrastim-stimulated marrow (G-BM), which we hypothesized may be associated with prompt hematopoietic recovery but with less cGVHD. We conducted a phase 3, open-label, multicenter randomized trial of 230 adults with hematologic malignancies receiving allografts from siblings after myeloablative conditioning to compare G-PB with G-BM. The primary endpoint was time to treatment failure, defined as a composite of extensive cGVHD, relapse/disease progression, and death. With a median follow-up of 36 months (range, 9.6 to 48), comparing G-BM with G-PB, there was no difference between the 2 arms with respect to the primary outcome of this study (hazard ratio [HR], .91; 95% confidence interval [CI], .68 to 1.22; P = .52). However, the cumulative incidence of overall cGVHD was lower with G-BM (HR, .66; 95% CI, .46 to .95; P = .007) and there was no difference in the risk of relapse or progression (P = .35). The median times to neutrophil recovery (P = .0004) and platelet recovery (P = .012) were 3 days shorter for recipients allocated to G-PB compared with those allocated to G-BM, but there were no differences in secondary engraftment-related outcomes, such as time to first hospital discharge (P = .17). In addition, there were no graft failures in either arm. This trial demonstrates that, compared with G-PB, the use of G-BM allografts leads to a significantly lower rate of overall cGVHD without a loss of the graft-versus-tumor effect and comparable overall survival. Our findings suggest that further study of this type of allograft is warranted. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

The Spectrum of Renal Allograft Failure

PubMed Central

Chand, Sourabh; Atkinson, David; Collins, Clare; Briggs, David; Ball, Simon; Sharif, Adnan; Skordilis, Kassiani; Vydianath, Bindu; Neil, Desley; Borrows, Richard

2016-01-01

Background Causes of “true” late kidney allograft failure remain unclear as study selection bias and limited follow-up risk incomplete representation of the spectrum. Methods We evaluated all unselected graft failures from 2008–2014 (n = 171; 0–36 years post-transplantation) by contemporary classification of indication biopsies “proximate” to failure, DSA assessment, clinical and biochemical data. Results The spectrum of graft failure changed markedly depending on the timing of allograft failure. Failures within the first year were most commonly attributed to technical failure, acute rejection (with T-cell mediated rejection [TCMR] dominating antibody-mediated rejection [ABMR]). Failures beyond a year were increasingly dominated by ABMR and ‘interstitial fibrosis with tubular atrophy’ without rejection, infection or recurrent disease (“IFTA”). Cases of IFTA associated with inflammation in non-scarred areas (compared with no inflammation or inflammation solely within scarred regions) were more commonly associated with episodes of prior rejection, late rejection and nonadherence, pointing to an alloimmune aetiology. Nonadherence and late rejection were common in ABMR and TCMR, particularly Acute Active ABMR. Acute Active ABMR and nonadherence were associated with younger age, faster functional decline, and less hyalinosis on biopsy. Chronic and Chronic Active ABMR were more commonly associated with Class II DSA. C1q-binding DSA, detected in 33% of ABMR episodes, were associated with shorter time to graft failure. Most non-biopsied patients were DSA-negative (16/21; 76.1%). Finally, twelve losses to recurrent disease were seen (16%). Conclusion This data from an unselected population identifies IFTA alongside ABMR as a very important cause of true late graft failure, with nonadherence-associated TCMR as a phenomenon in some patients. It highlights clinical and immunological characteristics of ABMR subgroups, and should inform clinical practice and individualised patient care. PMID:27649571

Importance of liver biopsy findings in immunosuppression management: biopsy monitoring and working criteria for patients with operational tolerance.

PubMed

2012-10-01

Obstacles to morbidity-free long-term survival after liver transplantation (LT) include complications of immunosuppression (IS), recurrence of the original disease and malignancies, and unexplained chronic hepatitis and graft fibrosis. Many programs attempt to minimize chronic exposure to IS by reducing dosages and stopping steroids. A few programs have successfully weaned a highly select group of recipients from all IS without apparent adverse consequences, but long-term follow-up is limited. Patients subjected to adjustments in IS are usually followed by serial liver chemistry tests, which are relatively insensitive methods for detecting allograft damage. Protocol biopsy has largely been abandoned for hepatitis C virus-negative recipients, at least in part because of the inability to integrate routine histopathological findings into a rational clinical management algorithm. Recognizing a need to more precisely categorize and determine the clinical significance of findings in long-term biopsy samples, the Banff Working Group on Liver Allograft Pathology has reviewed the literature, pooled the experience of its members, and proposed working definitions for biopsy changes that (1) are conducive to lowering IS and are compatible with operational tolerance (OT) and (2) raise concern for closer follow-up and perhaps increased IS during or after IS weaning. The establishment of guidelines should help us to standardize analyses of the effects of various treatments and/or weaning protocols and more rigorously categorize patients who are assumed to show OT. Long-term follow-up using standardized criteria will help us to determine the consequences of lowering IS and to define and determine the incidence and robustness of OT in liver allografts. Copyright © 2012 American Association for the Study of Liver Diseases.

Tacrolimus concentration to dose ratio in solid organ transplant patients treated with fecal microbiota transplantation for recurrent Clostridium difficile infection.

PubMed

Woodworth, Michael H; Kraft, Colleen S; Meredith, Erika J; Mehta, Aneesh K; Wang, Tiffany; Mamo, Yafet T; Dhere, Tanvi; Sitchenko, Kaitlin L; Patzer, Rachel E; Friedman-Moraco, Rachel J

2018-04-01

Fecal microbiota transplantation (FMT) is increasingly being performed for Clostridium difficile infection in solid organ transplant (SOT) patients; however, little is known about the potential pharmacokinetic or pharmacomicrobial effects this may have on tacrolimus levels. We reviewed the medical records of 10 SOT patients from September 2012-December 2016 who were taking tacrolimus at time of FMT for recurrent C. difficile infection. We compared the differences in tacrolimus concentration/dose ratio (C/D ratio) 3 months prior to FMT vs 3 months after FMT. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/kg/d) was -17.65 (95% CI -1.25 to 0.58) (ng/mL)/(mg/kg/d), P-value .43 by Wilcoxon signed-rank test. The mean of the differences in C/D ratio calculated as (ng/mL)/(mg/d) was -0.33 (95% CI -1.25 to 0.58) (ng/mL)/(mg/d), P-value .28 by Wilcoxon signed-rank test. Of these patients, 2/10 underwent allograft biopsy for allograft dysfunction in the year after FMT, with no evidence of allograft rejection on pathology. These preliminary data suggest that FMT may not predictably alter tacrolimus levels and support its safety for SOT patients however further study in randomized trials is needed. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Ambulatory blood pressure monitoring in solid organ transplantation.

PubMed

Ramesh Prasad, G V

2012-01-01

Solid organ transplant recipients are at an increased risk for hypertension and cardiovascular disease. To assist in their management, 24-h ambulatory blood pressure monitoring (ABPM) has become increasingly used in both clinical research settings and practice. ABPM has been used to better define post-transplant hypertension incidence and prevalence in different solid organ transplantation populations. ABPM provides additional information on cardiovascular risk beyond that obtained by clinic-based readings, based on its ability to assess 24-h blood pressure (BP) load, detect nocturnal non-dipping, and predict target organ damage. It has provided some assurance about the safety of living kidney donation. Information from ABPM can be used to guide living kidney donor selection, and because ABPM-related data has been correlated with clinically important kidney and heart transplant recipient outcomes, it may be a valuable adjunct in their management. Despite these advantages, barriers to wider use of ABPM include expense, clinical inertia in hypertension management, lack of prospective clinical trial data, and clinical problems that compete with hypertension for attention such as acute or chronic allograft dysfunction. The increasing amount of research and clinical use for ABPM may allow for closer assessment and intervention to help address the increased cardiovascular risk faced by many solid organ transplant recipients. © 2011 John Wiley & Sons A/S.

[The role of percutaneous renal biopsy in kidney transplant].

PubMed

Manfro, R C; Lee, J Y; Lewgoy, J; Edelweiss, M I; Gonçalves, L F; Prompt, C A

1994-01-01

Percutaneous renal biopsy (PRB) is an useful tool for diagnostic and therapeutic orientation in renal transplantation. PURPOSE--To evaluate the current role of PRB in post-transplant acute renal dysfunction (ARD) of renal allografts. METHODS--Sixty-five renal transplant patients were submitted to 95 valid renal biopsies with no major complications. RESULTS--There was disagreement between the clinical and the pathological diagnosis in 28 occasions (29.5%). In 36 cases (37.9%) the results of the pathological examination led to a modification in patient's management. These modifications were most commonly the avoidance or witholding of a steroid pulse (8 cases); nephrectomy of the renal allograft (8 cases); witholding or decrease of cyclosporine dosage (6 cases); giving a steroid pulse (5 cases) and giving antibiotics to treat acute pyelonephritis in 4 cases. The use of kidneys from cadaveric donors was significantly associated with an increased number of biopsies (p < 0.05). CONCLUSION--These results demonstrate that even though several less invasive procedures are currently employed, renal biopsy is still an indispensable method to the management of ARD in renal transplant patients.

Immune dysfunction in cirrhosis.

PubMed

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-03-14

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality.

Immune dysfunction in cirrhosis

PubMed Central

Sipeki, Nora; Antal-Szalmas, Peter; Lakatos, Peter L; Papp, Maria

2014-01-01

Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality. PMID:24627592

Erectile dysfunction in patients with chronic viral hepatitis: a systematic review of the literature.

PubMed

Fusco, Ferdinando; D'Anzeo, Gianluca; Rossi, Andrea; Sciorio, Carmine; Buonomo, Antonio Riccardo; d'Emmanuele di Villa Bianca, Roberta; Borgia, Guglielmo; Mirone, Vincenzo; Gentile, Ivan

2013-12-01

This article reviews the literature on epidemiology and pathogenetic factors of erectile dysfunction in patients with chronic viral hepatic (CVH) diseases in men and the potential implications for diagnosis and treatment. A search to identify original articles, reviews and any other article suitable for the purposes of this review was conducted by combining the following terms: erectile dysfunction and/or sexual dysfunction, chronic viral hepatitis, hepatitis B virus infection and hepatitis C virus infection. The results of this review have led to the following main observations: i) there is scarce documentation on the association between CVH and sexual dysfunction; ii) hormonal impairment seems to be a major component in the development of erectile dysfunction in CVH; however, published evidence concerning the contribution of other pathogenetic factors is rare and inconclusive and iii) available treatment options for CVH potentially contribute to the development of sexual dysfunction in these patients. Due to the scarce body of evidence, more research is needed to better clarify the mechanisms underlying the association between CVH and sexual dysfunction, the impact of therapy and associated comorbidities on sexual dysfunction and the role of pharmacological treatments in the management of these patients.

Early outcomes of liver transplants in patients receiving organs from hypernatremic donors.

PubMed

Khosravi, Mohammad Bagher; Firoozifar, Mohammad; Ghaffaripour, Sina; Sahmeddini, Mohammad Ali; Eghbal, Mohammad Hossien

2013-12-01

Uncorrected hypernatremia in organ donors has been associated with poor graft or patient survival during liver transplants. However, recent studies have found no association between the donor serum sodium and transplant outcome. This study sought to show the negative effect donor hypernatremia has on initial liver allograft function. This is the first study to investigate international normalized ratio and renal factors of patients with normal and those with hypernatremic donor livers. This study was conducted at the Shiraz Transplant Research Center in Shiraz, Iran, between May 2009, and July 2011. Four hundred seven consecutive adult orthotopic liver transplants were performed at the University of Shiraz Medical Center. There were 93 donors in the group with hypernatremia with terminal serum sodium of 155 mEq/L or greater (group 1), and 314 with terminal serum sodium less than 155 mEq/L (group 2). Posttransplant data after 5 days showed that aspartate aminotransferase, alanine aminotransferase, international normalized ratio, and kidney function did not differ between the groups. Hypernatremia is the most important complication after brain death. Previous studies have suggested donor hypernatremia results in a greater incidence of early postoperative graft dysfunction in liver transplant and is considered one of the extended criteria donor. However, in recent years, this hypothesis has been questioned. Our study shows no difference between patients' initial results of liver and kidney functioning with normal and hypernatremic donor livers. This is the first study to investigate international normalized ratio as a fundamental factor in defining early allograft dysfunction and renal factors between patients with normal and hypernatremic donor's livers.

MELD score measured day 10 after orthotopic liver transplantation predicts death and re-transplantation within the first year.

PubMed

Rostved, Andreas A; Lundgren, Jens D; Hillingsø, Jens; Peters, Lars; Mocroft, Amanda; Rasmussen, Allan

2016-11-01

The impact of early allograft dysfunction on the outcome after liver transplantation is yet to be established. We explored the independent predictive value of the Model for End-Stage Liver Disease (MELD) score measured in the post-transplant period on the risk of mortality or re-transplantation. Retrospective cohort study on adults undergoing orthotopic deceased donor liver transplantation from 2004 to 2014. The MELD score was determined prior to transplantation and daily until 21 days after. The risk of mortality or re-transplantation within the first year was assessed according to quartiles of MELD using unadjusted and adjusted stepwise Cox regression analysis. We included 374 consecutive liver transplant recipients of whom 60 patients died or were re-transplanted. The pre-transplant MELD score was comparable between patients with good and poor outcome, but from day 1 the MELD score significantly diversified and was higher in the poor outcome group (MELD score quartile 4 versus quartile 1-3 at day 10: HR 5.1, 95% CI: 2.8-9.0). This association remained after adjustment for non-identical blood type, autoimmune liver disease and hepatocellular carcinoma (adjusted HR 5.3, 95% CI: 2.9-9.5 for MELD scores at day 10). The post-transplant MELD score was not associated with pre-transplant MELD score or the Eurotransplant donor risk index. Early determination of the MELD score as an indicator of early allograft dysfunction after liver transplantation was a strong independent predictor of mortality or re-transplantation and was not influenced by the quality of the donor, or preoperative recipient risk factors.

Classifying Patients with Chronic Pelvic Pain into Levels of Biopsychosocial Dysfunction Using Latent Class Modeling of Patient Reported Outcome Measures

PubMed Central

Fenton, Bradford W.; Grey, Scott F.; Tossone, Krystel; McCarroll, Michele; Von Gruenigen, Vivian E.

2015-01-01

Chronic pelvic pain affects multiple aspects of a patient's physical, social, and emotional functioning. Latent class analysis (LCA) of Patient Reported Outcome Measures Information System (PROMIS) domains has the potential to improve clinical insight into these patients' pain. Based on the 11 PROMIS domains applied to n=613 patients referred for evaluation in a chronic pelvic pain specialty center, exploratory factor analysis (EFA) was used to identify unidimensional superdomains. Latent profile analysis (LPA) was performed to identify the number of homogeneous classes present and to further define the pain classification system. The EFA combined the 11 PROMIS domains into four unidimensional superdomains of biopsychosocial dysfunction: Pain, Negative Affect, Fatigue, and Social Function. Based on multiple fit criteria, a latent class model revealed four distinct classes of CPP: No dysfunction (3.2%); Low Dysfunction (17.8%); Moderate Dysfunction (53.2%); and High Dysfunction (25.8%). This study is the first description of a novel approach to the complex disease process such as chronic pelvic pain and was validated by demographic, medical, and psychosocial variables. In addition to an essentially normal class, three classes of increasing biopsychosocial dysfunction were identified. The LCA approach has the potential for application to other complex multifactorial disease processes. PMID:26355825

Vestibular rehabilitation outcomes in the elderly with chronic vestibular dysfunction.

PubMed

Bayat, Arash; Pourbakht, Akram; Saki, Nader; Zainun, Zuraida; Nikakhlagh, Soheila; Mirmomeni, Golshan

2012-11-01

Chronic vestibular dysfunction is a frustrating problem in the elderly and can have a tremendous impact on their life, but only a few studies are available. Vestibular rehabilitation therapy (VRT) is an important therapeutic option for the neuro-otologist in treating patients with significant balance deficits. The purpose of this study was to assess the effect of vestibular rehabilitation on dizziness in elderly patients with chronic vestibular dysfunction. A total of 33 patients older than 60 years with chronic vestibular dysfunction were studied. Clinical and objective vestibular tests including videonystagmography (VNG) and dizziness handicap inventory (DHI) were carried out at their first visit, 2 weeks, and 8 weeks post-VRT. The VRT exercises were performed according to Cawthorne and Cooksey protocols. Oculomotor assessments were within normal limits in all patients. Nineteen patients (57.57%) showed abnormal canal paralysis on caloric testing which at follow-up sessions; CP values were decreased remarkably after VRT exercises. We found a significant improvement between pre-VRT and post-VRT total DHI scores (P < 0.001). This improvement was most prominent in functional subscore. Our study demonstrated that VRT is an effective therapeutic method for elderly patients with chronic vestibular dysfunction.

BK-virus nephropathy and simultaneous C4d positive staining in renal allografts.

PubMed

Honsová, E; Lodererová, A; Viklický, O; Boucek, P

2005-10-01

The role of antibodies in rejection of transplanted kidneys was the subject of debate at the last two Banff meetings and in medical journals. Diffuse C4d positive staining of peritubular capillaries (PTCs) was recognized as a marker of antibody-mediated rejection and this morphological feature was included in the updated Banff schema. At the same time polyomavirus infection of the renal allografts has been reported more frequently and is emerging as an important cause of renal allograft dysfunction and graft loss. At the present time, BK-virus nephropathy (BKN) represents the most common viral disease affecting renal allografts. BKN was identified in 6 patients in 12 biopsies and 2 graft nephrectomy specimens of 1115 biopsies between September 2000 and December 2003. Definite virus identification was done by immunohistochemistry. The reason for graft nephrectomies was graft failure due to BKN in a recipient after kidney-pancreas transplantation with good function of his pancreas graft and the necessity of continuing immunosuppression. Detection of C4d deposits was performed by immunofluorescence or by immunohistochemistry. In graftectomy samples C4d detection was performed by immunohistochemistry and retrospectively in all cases of BKN. Focal C4d positive PTCs and BKN were found simultaneously in 9 of 12 needle biopsies and in both graft nephrectomy samples. Detection of C4d by immunohistochemistry disclosed focal C4d positive staining in kidney tissue but diffuse in the sites where BK-virus inclusions in tubular epithelial cells were found. The complement system is part of the host defense response and is crucial to our natural ability to ward off infection. In cases of BKN, virus likely gains access to the bloodstream through injured tubular walls and via PTCs. Vascular endothelium in the PTCs represents a potential target antigen for alloresponse, and simultaneously possibly represents an imprint of complement activation or complement production in the places with BK-virus infection.

Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty

PubMed Central

Stout, Michael B.; Justice, Jamie N.; Nicklas, Barbara J.; Kirkland, James L.

2016-01-01

Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age. PMID:27927801

Chronic periodontitis is associated with erectile dysfunction. A case-control study in european population.

PubMed

Martín, Amada; Bravo, Manuel; Arrabal, Miguel; Magán-Fernández, Antonio; Mesa, Francisco

2018-07-01

To determine the association between chronic periodontitis and erectile dysfunction adjusting for biochemical markers and other comorbidities. A case-control study was conducted on 158 male patients; 80 cases with erectile dysfunction according to the International Index of Erectile Function and 78 controls. Sociodemographic data were gathered, and a periodontal examination was performed. Testosterone, lipid profile, C-reactive protein and glycaemic parameters were assessed. All variables were compared between groups, and multivariate logistic regression analyses were performed. 74% of the cases were diagnosed with chronic periodontitis. Number of sites with pocket probing depth 4-6 mm (p = 0.05) and number of sites with clinical attachment loss >3 mm (p < 0.01) were higher in the cases. Triglycerides (p < 0.01), C-reactive protein (p = 0.02) and glycosylated haemoglobin (p = 0.04) were also higher in the cases. Logistic regression showed that patients with chronic periodontitis were more likely to have erectile dysfunction (OR=2.17; 95% CI (1.06-4.43); p = 0.03) independently of other confounders. Patients with erectile dysfunction showed worse periodontal condition. Chronic periodontitis seems to play a key role as a risk factor in the pathogenesis of erectile dysfunction independently of other morbidities. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Predictors of renal recovery in patients with pre-orthotopic liver transplant (OLT) renal dysfunction.

PubMed

Iglesias, Jose; Frank, Elliot; Mehandru, Sushil; Davis, John M; Levine, Jerrold S

2013-07-13

Renal dysfunction occurs commonly in patients awaiting orthotopic liver transplantation (OLT) for end-stage liver disease. The use of simultaneous liver-kidney transplantation has increased in the MELD scoring era. As patients may recover renal function after OLT, identifying factors predictive of renal recovery is a critical issue, especially given the scarcity of available organs. Employing the UNOS database, we sought to identify donor- and patient-related predictors of renal recovery among 1720 patients with pre-OLT renal dysfunction and transplanted from 1989 to 2005. Recovery of renal function post-OLT was defined as a composite endpoint of serum creatinine (SCr) ≤1.5 mg/dL at discharge and survival ≥29 days. Pre-OLT renal dysfunction was defined as any of the following: SCr ≥2 mg/dL at any time while awaiting OLT or need for renal replacement therapy (RRT) at the time of registration and/or OLT. Independent predictors of recovery of renal function post-OLT were absence of hepatic allograft dysfunction, transplantation during MELD era, recipient female sex, decreased donor age, decreased recipient ALT at time of OLT, decreased recipient body mass index at registration, use of anti-thymocyte globulin as induction therapy, and longer wait time from registration. Contrary to popular belief, a requirement for RRT, even for prolonged periods in excess of 8 weeks, was not an independent predictor of failure to recover renal function post-OLT. These data indicate that the duration of renal dysfunction, even among those requiring RRT, is a poor way to discriminate reversible from irreversible renal dysfunction.

Physiological Aging: Links Among Adipose Tissue Dysfunction, Diabetes, and Frailty.

PubMed

Stout, Michael B; Justice, Jamie N; Nicklas, Barbara J; Kirkland, James L

2017-01-01

Advancing age is associated with progressive declines in physiological function that lead to overt chronic disease, frailty, and eventual mortality. Importantly, age-related physiological changes occur in cellularity, insulin-responsiveness, secretory profiles, and inflammatory status of adipose tissue, leading to adipose tissue dysfunction. Although the mechanisms underlying adipose tissue dysfunction are multifactorial, the consequences result in secretion of proinflammatory cytokines and chemokines, immune cell infiltration, an accumulation of senescent cells, and an increase in senescence-associated secretory phenotype (SASP). These processes synergistically promote chronic sterile inflammation, insulin resistance, and lipid redistribution away from subcutaneous adipose tissue. Without intervention, these effects contribute to age-related systemic metabolic dysfunction, physical limitations, and frailty. Thus adipose tissue dysfunction may be a fundamental contributor to the elevated risk of chronic disease, disability, and adverse health outcomes with advancing age. ©2017 Int. Union Physiol. Sci./Am. Physiol. Soc.

Structural allograft reconstruction of the foot and ankle after tumor resections.

PubMed

Ayerza, M A; Piuzzi, N S; Aponte-Tinao, L A; Farfalli, G L; Muscolo, D L

2016-08-01

Structural allografts have been used to correct deformities or to fill bone defects secondary to tumor excisions, trauma, osteochondral lesions, or intercalary arthrodesis. However, the quality of published evidence supporting the use of allograft transplantation in foot and ankle surgery has been reported as fair. The purpose of this study was to report the overall survival of structural allograft in the foot and ankle after tumor resection, and the survival according to the type of allograft and the complication rates in the medium to long term. From January 1989 to June 2011, 44 structural allograft reconstructions of the foot and ankle were performed in 42 patients (28 men and 14 women) due to musculoskeletal tumor resections. Mean age at presentation was 27 years. Mean follow-up was 53 months. Demographic data, diagnosis, site of the neoplasm, operations performed, operative complications, outcomes after surgery, date of last follow-up evaluation, and local recurrences were reviewed for all patients. Regarding the type of 44 allograft reconstructions, 16 were hemicylindrical allografts (HA), 12 intercalary allografts (IA), 10 osteoarticular allografts (OA), and 6 were total calcaneal allograft (CA). The overall allograft survival rate, as calculated with the Kaplan-Meier method, at 5 and 10 years was 79 % (95 % CI 64-93 %). When allocated by type of allograft reconstruction the specific allograft survival at 5 and 10 years was: 83 % for CA, 80 % for HA, 77 % for OA, and 75 % for IA. The complications rate for this series was 36 % including: articular failure, local recurrence, infection, fracture and nonunion. This study showed that structural allograft reconstruction in the foot and ankle after tumor resection may be durable with a 79 % survival rate at 5 and 10 years. The two types of allografts that showed better survival rate were hemicylindrical allografts (80 %) and calcaneus allografts (83 %). The highest complication rates occurred after calcaneus allografts and osteoarticular allografts. IV.

Mental health screening in women with severe pelvic organ prolapse, chronic fourth-degree obstetric tear and genital tract fistula in western Uganda.

PubMed

Krause, Hannah G; Hall, Barbara A; Ng, Shu-Kay; Natukunda, Harriet; Singasi, Isaac; Goh, Judith T W

2017-06-01

High levels of mental health dysfunction have been identified in women with genital tract fistula. The aim of this study was to use the General Health Questionnaire-28 (GHQ-28) to screen women in western Uganda with severe pelvic organ prolapse, chronic fourth-degree obstetric tear and genital tract fistula for risk of mental health dysfunction. Women undergoing surgery for severe pelvic organ prolapse, chronic fourth-degree obstetric tear, and genital tract fistula were interviewed using the GHQ-28 to screen for the risk of mental health dysfunction. A total of 125 women completed the GHQ-28, including 22 with pelvic organ prolapse, 47 with fourth-degree obstetric tear, 21 with genital tract fistula, and 35 controls. Nearly all women with these serious gynaecological conditions were positive for the risk of mental health dysfunction. In the domain assessing symptoms of severe depression, women with fourth-degree obstetric tear and genital tract fistula scored higher than women with pelvic organ prolapse. A significant risk of mental health dysfunction was identified in women with severe pelvic organ prolapse and chronic fourth-degree obstetric tear. These rates are similar to the high rates of mental health dysfunction in women with genital tract fistula. Identification and management of mental health dysfunction in women with these conditions should be a priority.

Management of acute and chronic ankle instability.

PubMed

Maffulli, Nicola; Ferran, Nicholas A

2008-10-01

Acute lateral ankle ligament injuries are common. If left untreated, they can result in chronic instability. Nonsurgical measures, including functional rehabilitation, are the management methods of choice for acute injuries, with surgical intervention reserved for high-demand athletes. Chronic lateral ankle instability is multifactorial. Failed nonsurgical management after appropriate rehabilitation is an indication for surgery. Of the many surgical options available, anatomic repair of the anterior talofibular and calcaneofibular ligaments is recommended when the quality of the ruptured ligaments permits. Anatomic reconstruction with autograft or allograft should be performed when the ruptured ligaments are attenuated. Ankle arthroscopy is an important adjunct to ligamentous repair and should be performed at the time of repair to identify and address intra-articular conditions associated with chronic ankle instability. Tenodesis procedures are not recommended because they may disturb ankle and hindfoot biomechanics.

Lung Transplant Outcomes in Systemic Sclerosis with Significant Esophageal Dysfunction. A Comprehensive Single-Center Experience

PubMed Central

Schwab, Kristin; Saggar, Rajeev; Duffy, Erin; Elashoff, David; Tseng, Chi-Hong; Weigt, Sam; Charan, Deepshikha; Abtin, Fereidoun; Johannes, Jimmy; Derhovanessian, Ariss; Conklin, Jeffrey; Ghassemi, Kevin; Khanna, Dinesh; Siddiqui, Osama; Ardehali, Abbas; Hunter, Curtis; Kwon, Murray; Biniwale, Reshma; Lo, Michelle; Volkmann, Elizabeth; Torres Barba, David; Belperio, John A.; Mahrer, Thomas; Furst, Daniel E.; Kafaja, Suzanne; Clements, Philip; Shino, Michael; Gregson, Aric; Kubak, Bernard; Lynch, Joseph P.; Ross, David

2016-01-01

Rationale: Consideration of lung transplantation in patients with systemic sclerosis (SSc) remains guarded, often due to the concern for esophageal dysfunction and the associated potential for allograft injury and suboptimal post–lung transplantation outcomes. Objectives: The purpose of this study was to systematically report our single-center experience regarding lung transplantation in the setting of SSc, with a particular focus on esophageal dysfunction. Methods: We retrospectively reviewed all lung transplants at our center from January 1, 2000 through August 31, 2012 (n = 562), comparing the SSc group (n = 35) to the following lung transplant diagnostic subsets: all non-SSc (n = 527), non-SSc diffuse fibrotic lung disease (n = 264), and a non-SSc matched group (n = 109). We evaluated post–lung transplant outcomes, including survival, primary graft dysfunction, acute rejection, bronchiolitis obliterans syndrome, and microbiology of respiratory isolates. In addition, we defined severe esophageal dysfunction using esophageal manometry and esophageal morphometry criteria on the basis of chest computed tomography images. For patients with SSc referred for lung transplant but subsequently denied (n = 36), we queried the reason(s) for denial with respect to the concern for esophageal dysfunction. Measurements and Main Results: The 1-, 3-, and 5-year post–lung transplant survival for SSc was 94, 77, and 70%, respectively, and similar to the other groups. The remaining post–lung transplant outcomes evaluated were also similar between SSc and the other groups. Approximately 60% of the SSc group had severe esophageal dysfunction. Pre–lung transplant chest computed tomography imaging demonstrated significantly abnormal esophageal morphometry for SSc when compared with the matched group. Importantly, esophageal dysfunction was the sole reason for lung transplant denial in a single case. Conclusions: Relative to other lung transplant indications, our SSc group experienced comparable survival, primary graft dysfunction, acute rejection, bronchiolitis obliterans syndrome, and microbiology of respiratory isolates, despite the high prevalence of severe esophageal dysfunction. Esophageal dysfunction rarely precluded active listing for lung transplantation. PMID:27078625

Innate Immunity and Resistance to Tolerogenesis in Allotransplantation

PubMed Central

Benichou, Gilles; Tonsho, Makoto; Tocco, Georges; Nadazdin, Ognjenka; Madsen, Joren C.

2012-01-01

The development of immunosuppressive drugs to control adaptive immune responses has led to the success of transplantation as a therapy for end-stage organ failure. However, these agents are largely ineffective in suppressing components of the innate immune system. This distinction has gained in clinical significance as mounting evidence now indicates that innate immune responses play important roles in the acute and chronic rejection of whole organ allografts. For instance, whereas clinical interest in natural killer (NK) cells was once largely confined to the field of bone marrow transplantation, recent findings suggest that these cells can also participate in the acute rejection of cardiac allografts and prevent tolerance induction. Stimulation of Toll-like receptors (TLRs), another important component of innate immunity, by endogenous ligands released in response to ischemia/reperfusion is now known to cause an inflammatory milieu favorable to graft rejection and abrogation of tolerance. Emerging data suggest that activation of complement is linked to acute rejection and interferes with tolerance. In summary, the conventional wisdom that the innate immune system is of little importance in whole organ transplantation is no longer tenable. The addition of strategies that target TLRs, NK cells, complement, and other components of the innate immune system will be necessary to eventually achieve long-term tolerance to human allograft recipients. PMID:22566954

Native kidney function following liver transplantation using calcineurin inhibitors: single-center analysis with 20 years of follow-up.

PubMed

LaMattina, John C; Mezrich, Joshua D; Fernandez, Luis A; D'Alessandro, Anthony M; Djamali, Arjang; Musat, Alexandru I; Pirsch, John D; Foley, David P

2013-01-01

The incidence of chronic kidney disease (CKD) in liver transplant recipients has been estimated to be from 18% to 28% at 10 yr after transplantation. As outcomes from liver transplantation continue to improve, long-term native kidney function in these recipients becomes more critical to patient survival. We analyzed 1151 adult, deceased-donor, single-organ primary liver transplantations performed at our center between 7/17/84 and 12/31/07. Analysis of renal function was performed on 972 patients with liver allograft survival >1 yr. Kaplan-Meier analysis revealed that 3%, 7%, and 18% of liver transplant recipients with allograft survival >1 yr developed end-stage renal disease (ESRD) at five, 10, and 20 yr, respectively. Significant independent risk factors for ESRD included dialysis during the transplant hospitalization, the stage of CKD at one yr, hypercholesterolemia, non-Caucasian race, and hepatitis C as the primary indication for liver transplantation. The initial immunosuppression of essentially all recipients was a calcineurin inhibitor-based regimen. Close, long-term follow-up of liver transplant recipients permits optimal management of liver allograft and native renal function and can lead to excellent long-term outcomes despite a calcineurin inhibitor-based immunosuppressive regimen. © 2013 John Wiley & Sons A/S.

The cellular lesion of humoral rejection: predominant recruitment of monocytes to peritubular and glomerular capillaries.

PubMed

Fahim, T; Böhmig, G A; Exner, M; Huttary, N; Kerschner, H; Kandutsch, S; Kerjaschki, D; Bramböck, A; Nagy-Bojarszky, K; Regele, H

2007-02-01

Accumulation of inflammatory cells within capillaries is a common morphologic feature of humoral renal allograft rejection and is most easily appreciated if it occurs in glomeruli. The aim of our study was to determine the amount and composition of immune cells within glomeruli and peritubular capillaries (PTC) in cellular and humoral allograft rejection. Immunofluorescent double-labeling for CD31 and CD3 or CD68 was used for phenotyping and enumerating immune cells within glomeruli and PTC. The major findings are: (1) accumulation of immune cells in PTC is far more common than it would be anticipated based on the assessment by conventional histology; (2) it is not the absolute number of immune cells accumulating within capillaries, but rather the composition of the intracapillary cell population that distinguishes humoral rejection from cellular rejection and (3) in C4d positive biopsies a predominantly monocytic cell population accumulates not only within glomeruli but also within PTC. The median value of monocyte/T-cell ratio within PTC was 2.3 in C4d positive biopsies but only 1 (p = 0.0008) in C4d negative biopsies. Given their prominent presence within capillaries and their extensive biological versatility monocytes might contribute to the capillary damage observed in acute and chronic allograft rejection.

Urinary Angiogenin Reflects the Magnitude of Kidney Injury at the Infrahistologic Level

PubMed Central

Tavernier, Quentin; Mami, Iadh; Rabant, Marion; Karras, Alexandre; Laurent-Puig, Pierre; Chevet, Eric; Thervet, Eric; Anglicheau, Dany

2017-01-01

The ribonuclease angiogenin is a component of the mammalian stress response that is secreted by renal epithelial cells on activation of the inositol–requiring enzyme 1α (IRE1α)–active spliced X–box binding protein 1 (sXBP1) axis and instrumental to the adaptation to AKI associated with endoplasmic reticulum stress. To determine whether the amount of angiogenin in urine of individuals with a kidney injury reflects the magnitude of the lesions and provides information on the risk of organ failure, we examined individuals referred for a kidney injury and determined the biochemical characteristics of urinary angiogenin and its diagnostic and prognostic values. Urinary angiogenin did not correlate with the urinary concentrations of high molecular weight proteins and correlated only weakly with low molecular weight proteins, suggestive of tubular production. In a cohort of 242 kidney transplant recipients with acute allograft dysfunction, higher urinary angiogenin concentrations at the time of the biopsy associated with worse renal function and higher proteinuria but did not correlate with histologic lesions as defined in the Banff classification. Kidney transplant recipients with urinary angiogenin amounts in the highest 50% had a risk of graft failure 3.59 times as high (95% confidence interval, 1.12 to 15.94) as that of patients with amounts in the lowest 50%. Finally, the amount of urinary angiogenin reflected the activity of the IRE1α-XBP1 axis in allografts. Our approach identified urinary angiogenin as a noninvasive indicator of the extent of tissue damage, independent of the histologic lesions, and a risk predictor of kidney allograft failure. PMID:27436854

Transplantectomy is associated with presensitization with donor-reactive T cells and graft failure after kidney retransplantation: a cohort study.

PubMed

Schachtner, Thomas; Otto, Natalie M; Stein, Maik; Reinke, Petra

2018-05-01

The number of kidney transplant recipients (KTRs) being waitlisted for a subsequent transplantation has disproportionately increased to almost 25%. Evidence for the optimal management of the failed allograft, however, remains inconsistent. We studied 111 KTRs who underwent their second kidney transplantation from 1998 to 2015. In 51/111 KTRs (46%) the failed allograft was removed and in 60/111 (54%) the failed allograft was retained. KTRs with primary non-function and allograft loss <12  months of the first failed allograft were excluded from analysis. Samples were collected before transplantation and at  1  month posttransplantation and donor-reactive T cells were measured using an interferon-γ enzyme-linked immunosorbent spot assay. KTRs with the previous allograft removed showed significantly higher rates of acute cellular rejection compared with KTRs with the previous allograft retained [27/51 KTRs (53%) versus 18/60 KTRs (30%); P = 0.019]. KTRs with the previous allograft removed showed significantly inferior death-censored allograft survival compared with KTRs with the previous allograft retained (P = 0.022). Here, KTRs with the previous allograft removed showed significantly higher donor-reactive T cells pretransplantation compared with KTRs with the previous allograft retained (P = 0.012). Interestingly, no differences were observed for the presence of panel reactive antibodies and for the development of de novo donor-specific antibodies. Our data suggest higher cellular presensitization among KTRs with the previous allograft removed, which is associated with higher rates of acute cellular rejection and inferior allograft survival. Immunological mechanisms that may account for these differences may include prolonged maintenance immunosuppression to save urine output in KTRs with the first kidney allograft retained and cellular presensitization after withdrawal of maintenance immunosuppression, which lead to allograft rejection and ultimately to allograft nephrectomy.

Mechanism of tacrolimus-induced chronic renal fibrosis following transplantation is regulated by ox-LDL and its receptor, LOX-1

PubMed Central

Deng, Shi; Jin, Tao; Zhang, Li; Bu, Hong; Zhang, Peng

2016-01-01

Chronic renal allograft dysfunction (CRAD) is the most common cause of graft failure following renal transplantation. However, the underlying mechanisms remain to be fully elucidated. Immunosuppressants and hyperlipidemia are associated with renal fibrosis following long-term use. The present study aimed to determine the effects of tacrolimus (FK506) and lipid metabolism disorder on CRAD. In vitro and in vivo models were used for this investigation. Cells of the mouse proximal renal tubular epithelial cell strain, NRK-52E, were cultured either with oxidized low-density lipoprotein (ox-LDL), FK506, ox-LDL combined with FK506, or vehicle, respectively. Changes in cell morphology and changes in the levels of lectin-like ox-LDL receptor-1 (LOX-1), reactive oxygen species (ROS), hydrogen peroxide and fibrosis-associated genes were evaluated at 24, 48 and 72 h. In separate experiment, total of 60 Sprague-Dawley rats were divided randomly into four groups, which included a high-fat group, FK506 group, high-fat combined with FK506 group, and control group. After 2, 4 and 8 weeks, the serum lipid levels, the levels of ox-LDL, ROS, and the expression levels of transforming growth factor (TGF)-β1 and connective tissue growth factor were determined. The in vitro and in vivo models revealed that lipid metabolism disorder and FK506 caused oxidative stress and a fibrogenic response. In addition, decreased levels of LOX-1 markedly reduced the levels of TGF-β1 in the in vitro model. Taken together, FK506 and dyslipidemia were found to be associated with CRAD following transplantation. PMID:27633115

Kidney-induced cardiac allograft tolerance in miniature swine is dependent on MHC-matching of donor cardiac and renal parenchyma.

PubMed

Madariaga, M L; Michel, S G; La Muraglia, G M; Sekijima, M; Villani, V; Leonard, D A; Powell, H J; Kurtz, J M; Farkash, E A; Colvin, R B; Allan, J S; Cetrulo, C L; Huang, C A; Sachs, D H; Yamada, K; Madsen, J C

2015-06-01

Kidney allografts possess the ability to enable a short course of immunosuppression to induce tolerance of themselves and of cardiac allografts across a full-MHC barrier in miniature swine. However, the renal element(s) responsible for kidney-induced cardiac allograft tolerance (KICAT) are unknown. Here we investigated whether MHC disparities between parenchyma versus hematopoietic-derived "passenger" cells of the heart and kidney allografts affected KICAT. Heart and kidney allografts were co-transplanted into MHC-mismatched recipients treated with high-dose tacrolimus for 12 days. Group 1 animals (n = 3) received kidney and heart allografts fully MHC-mismatched to each other and to the recipient. Group 2 animals (n = 3) received kidney and heart allografts MHC-matched to each other but MHC-mismatched to the recipient. Group 3 animals (n = 3) received chimeric kidney allografts whose parenchyma was MHC-mismatched to the donor heart. Group 4 animals (n = 3) received chimeric kidney allografts whose passenger leukocytes were MHC-mismatched to the donor heart. Five of six heart allografts in Groups 1 and 3 rejected <40 days. In contrast, heart allografts in Groups 2 and 4 survived >150 days without rejection (p < 0.05). These data demonstrate that KICAT requires MHC-matching between kidney allograft parenchyma and heart allografts, suggesting that cells intrinsic to the kidney enable cardiac allograft tolerance. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

MicroRNA-146b-5p Identified in Porcine Liver Donation Model is Associated with Early Allograft Dysfunction in Human Liver Transplantation

PubMed Central

Li, Cheukfai; Zhao, Qiang; Zhang, Wei; Chen, Maogen; Ju, Weiqiang; Wu, Linwei; Han, Ming; Ma, Yi; Zhu, Xiaofeng; Wang, Dongping; Guo, Zhiyong; He, Xiaoshun

2017-01-01

Background Poor transplant outcome was observed in donation after brain death followed by circulatory death (DBCD), since the donor organs suffered both cytokine storm of brain death and warm ischemia injury. MicroRNAs (miRNAs) have emerged as promising disease biomarkers, so we sought to establish a miRNA signature of porcine DBCD and verify the findings in human liver transplantation. Material/Methods MiRNA expression was determined with miRNA sequencing in 3 types of the porcine model of organ donation, including donation after brain death (DBD) group, donation after circulatory death (DCD) group, and DBCD group. Bioinformatics analysis was performed to reveal the potential regulatory behavior of target miRNA. Human liver graft biopsy samples after reperfusion detected by fluorescence in situ hybridization were used to verify the expression of target miRNA. Results We compared miRNA expression profiles of the 3 donation types. The porcine liver graft miR-146b was significantly increased and selected in the DBCD group versus in the DBD and DCD groups. The donor liver expression of human miR-146b-5p, which is homologous to porcine miR-146b, was further examined in 42 cases of human liver transplantations. High expression of miR-146b-5p successfully predicted the post-transplant early allograft dysfunction (EAD) with the area under the ROC curve (AUC) 0.759 (P=0.004). Conclusions Our results revealed the miRNA signature of DBCD liver grafts for the first time. The miR-146b-5p may have important clinical implications for monitoring liver graft function and predicating transplant outcomes. PMID:29227984

Ventricular assist device elicits serum natural IgG that correlates with the development of primary graft dysfunction following heart transplantation.

PubMed

See, Sarah B; Clerkin, Kevin J; Kennel, Peter J; Zhang, Feifan; Weber, Matthew P; Rogers, Kortney J; Chatterjee, Debanjana; Vasilescu, Elena R; Vlad, George; Naka, Yoshifumi; Restaino, Susan W; Farr, Maryjane A; Topkara, Veli K; Colombo, Paolo C; Mancini, Donna M; Schulze, P Christian; Levin, Bruce; Zorn, Emmanuel

2017-08-01

Pre-transplant sensitization is a limiting factor in solid-organ transplantation. In heart transplants, ventricular assist device (VAD) implantation has been associated with sensitization to human leukocyte antigens (HLA). The effect of VAD on non-HLA antibodies is unclear. We have previously shown that polyreactive natural antibodies (Nabs) contribute to pre-sensitization in kidney allograft recipients. Here we assessed generation of Nabs after VAD implantation in pre-transplant sera and examined their contribution to cardiac allograft outcome. IgM and IgG Nabs were tested in pre-transplant serum samples collected from 206 orthotopic heart transplant recipients, including 128 patients with VAD (VAD patients) and 78 patients without VAD (no-VAD patients). Nabs were assessed by testing serum reactivity to apoptotic cells by flow cytometry and to the generic oxidized epitope, malondialdehyde, by enzyme-linked immunosorbent assay. No difference was observed in serum levels of IgM Nabs between VAD and no-VAD patients. However, serum IgG Nabs levels were significantly increased in VAD compared with no-VAD patients. This increase was likely due to the presence of the VAD, as revealed by lower serum IgG Nabs levels before implantation. Elevated pre-transplant IgG Nabs level was associated with development of primary graft dysfunction (PGD). Our study demonstrates that VAD support elicits IgG Nabs reactive to apoptotic cells and oxidized epitopes. These findings further support broad and non-specific B-cell activation by VAD, resulting in IgG sensitization. Moreover, the association of serum IgG Nabs levels with development of PGD suggests a possible role for these antibodies in the inflammatory reaction accompanying this complication. Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Extended-criteria donors in liver transplantation Part II: reviewing the impact of extended-criteria donors on the complications and outcomes of liver transplantation.

PubMed

Nemes, Balázs; Gámán, György; Polak, Wojciech G; Gelley, Fanni; Hara, Takanobu; Ono, Shinichiro; Baimakhanov, Zhassulan; Piros, Laszlo; Eguchi, Susumu

2016-07-01

Extended-criteria donors (ECDs) have an impact on early allograft dysfunction (EAD), biliary complications, relapse of hepatitis C virus (HCV), and survivals. Early allograft dysfunction was frequently seen in grafts with moderate and severe steatosis. Donors after cardiac death (DCD) have been associated with higher rates of graft failure and biliary complications compared to donors after brain death. Extended warm ischemia, reperfusion injury and endothelial activation trigger a cascade, leading to microvascular thrombosis, resulting in biliary necrosis, cholangitis, and graft failure. The risk of HCV recurrence increased by donor age, and associated with using moderately and severely steatotic grafts. With the administration of protease inhibitors sustained virological response was achieved in majority of the patients. Donor risk index and EC donor scores (DS) are reported to be useful, to assess the outcome. The 1-year survival rates were 87% and 40% respectively, for donors with a DS of 0 and 3. Graft survival was excellent up to a DS of 2, however a DS >2 should be avoided in higher-risk recipients. The 1, 3 and 5-year survival of DCD recipients was comparable to optimal donors. However ECDs had minor survival means of 85%, 78.6%, and 72.3%. The graft survival of split liver transplantation (SLT) was comparable to that of whole liver orthotopic liver transplantation. SLT was not regarded as an ECD factor in the MELD era any more. Full-right-full-left split liver transplantation has a significant advantage to extend the high quality donor pool. Hypothermic oxygenated machine perfusion can be applied clinically in DCD liver grafts. Feasibility and safety were confirmed. Reperfusion injury was also rare in machine perfused DCD livers.

Histologic damage of lung allografts according to magnitude of acute rejection in the re-isotransplant model.

PubMed

Marui, Tsutomu; Iwata, Hisashi; Shirahashi, Koyo; Matsumoto, Shinsuke; Mizuno, Yoshimasa; Matsui, Masafumi; Takemura, Hirofumi

2008-06-01

Graft damage due to acute rejection has been reported as one of the risk factors in the chronic stage of cardiac and renal allografts. This study was designed to elucidate the histologic changes of grafts after ongoing acute allograft rejection was discontinued in models of lung re-isotransplantation. WKAH rat lungs were orthotopically transplanted into F344 recipients. Three days (3A group) and 5 days (5A group) after the first allotransplantation, the grafts were re-isotransplanted back into the WKAH rats (3RA and 5RA groups, respectively). Five days (5I group) after the first isotransplantation, the grafts were re-isotransplanted back into the WKAH rats (5RI group). The grafts were removed 30 and 60 days after re-isotransplantation and assessed histologically. Typical acute allograft rejection developed in the 3A and 5A groups, and the changes were reduced after re-isotransplantation, although they remained significantly greater in the 5RA group than in the 3RA and 5RI groups. For intimal hyperplasia, the graft score 60 days after re-isotransplantation in the 5RA group was significantly higher than in the 5RI and 3RA groups. The changes in airway inflammation were significantly greater in the 5RA group than in the 3RA and 5RI groups at 60 days. Peribronchiolar fibrosis was significantly more frequent in the 5RA and 3RA groups than in the 5RI group. Acute rejection and airway inflammation corresponded to the magnitude of rejection before retransplantation. Significant intimal hyperplasia developed in severe acute rejection, and peribronchiolar fibrosis occurred after the first acute rejection.

Recipient body surface area as a predictor of posttransplant renal allograft evolution.

PubMed

Moreso, F; Serón, D; Anunciada, A I; Hueso, M; Ramón, J M; Fulladosa, X; Gil-Vernet, S; Alsina, J; Grinyó, J M

1998-03-15

The aim of the present study was to analyze whether minor differences in recipient body surface area have any predictive value on renal allograft evolution. For this study, we considered 236 pairs of recipients who received a kidney from the same donor at our center between March 1985 and December 1995. Pairs in whom at least one patient presented any of the following events were excluded: graft loss during the first year of follow-up, diabetes mellitus, noncompliance with treatment, chronic pyelonephritis, and recurrent or de novo glomerulonephritis. Recipients of each pair were classified as large or small according to their body surface area (BSA). The percentage difference of BSA in each pair was calculated, and two cohorts of pairs were defined: BSA difference < or = 10% (n=76 pairs) and BSA difference >10% (n=70 pairs). The large recipients of the cohort with a BSA difference >10% showed a higher incidence of posttransplant delayed graft function (22/70 vs. 12/70, P=0.075), hypertension at 1 year of follow-up (51/70 vs. 35/70, P=0.006), and a higher serum creatinine level at 1-year follow-up (173 vs. 142 micromol/L, P=0.003), whereas in the cohort with a BSA difference < or = 10%, posttransplant evolution in large and small recipients was not different. Multivariate analysis showed that recipient BSA was an independent predictor of delayed graft function, posttransplant hypertension, and serum creatinine at 1-year follow-up. Relatively small differences in recipient BSA influence renal allograft evolution. Consequently, our data support that recipient size should be taken into consideration for renal allograft allocation.

Commercial kidney transplantation: trends, outcomes and challenges-a single-centre experience.

PubMed

Adamu, Bappa; Ahmed, Mustafa; Mushtaq, Raees F; Alshaebi, Fuad

2012-01-01

Many experts believe that commercial organ transplants continue unabated despite international efforts to curb them. The aim was to determine the trends, outcomes and challenges of commercial living unrelated renal transplants (LURT) as seen in our institution. A retrospective study of LURT patients on follow-up at our institution. The list of all LURT patients was obtained from our renal registry. Inclusion criteria for the study were 1) Presentation to our hospital within the first month post transplant; 2) Completion of one-year follow-up OR patient or allograft losses prior to completing one-year follow-up. SPSS 17.0 was used for data analysis. Forty-five patients satisfied the entry criteria; 33 males and 12 females with age range 13-68 years, and mean ± SD of 40 + 15 years. The majority (28) of the transplants were carried out in Pakistan, the remaining in Egypt, Philippines, and China. There has been a steady decline in the number of new patients with commercial transplants over a four-year period. Complications encountered included infections in 19 (42.2%) patients, biopsy-proven acute rejections in nine patients (20%), surgical complications in 10 patients (22.2%), post-transplant diabetes in seven (15.6%), delayed graft function in one (2.2%), and chronic allograft nephropathy in one (2.2%) patient. Patient survival at one year was 97.8% and allograft survival was 88.9%. Commercial kidney transplant is on the decline as seen in our center, likely as a result of international efforts to curb it, as well as due to a parallel increase in renal transplants in the country. One-year patient and allograft survivals are good but there is a relatively high rate of infections.

Maslow's Hierarchy of Needs and the individual with chronic vestibular dysfunction.

PubMed

Haybach, P J

1994-01-01

Individuals with chronic vestibular dysfunction may have unmet physiological or safety needs on a chronic basis. Their inability to fulfill the basic needs and progress to higher needs can lead to a patient population with many psychosocial problems. Very often such problems are ignored or unrecognized or are misdiagnosed, and treated inappropriately. This disruption in the individual's life can lead to an inability to progress as a human being. Nursing assessment and appropriate interventions should be developed to treat psychosocial problems in this patient population. The nursing profession should serve patients with vestibular dysfunction through direct care, teaching, counseling, support group facilitation, and research into appropriate interventions.

Predictors of renal recovery in patients with pre-orthotopic liver transplant (OLT) renal dysfunction

PubMed Central

2013-01-01

Background Renal dysfunction occurs commonly in patients awaiting orthotopic liver transplantation (OLT) for end-stage liver disease. The use of simultaneous liver-kidney transplantation has increased in the MELD scoring era. As patients may recover renal function after OLT, identifying factors predictive of renal recovery is a critical issue, especially given the scarcity of available organs. Methods Employing the UNOS database, we sought to identify donor- and patient-related predictors of renal recovery among 1720 patients with pre-OLT renal dysfunction and transplanted from 1989 to 2005. Recovery of renal function post-OLT was defined as a composite endpoint of serum creatinine (SCr) ≤1.5 mg/dL at discharge and survival ≥29 days. Pre-OLT renal dysfunction was defined as any of the following: SCr ≥2 mg/dL at any time while awaiting OLT or need for renal replacement therapy (RRT) at the time of registration and/or OLT. Results Independent predictors of recovery of renal function post-OLT were absence of hepatic allograft dysfunction, transplantation during MELD era, recipient female sex, decreased donor age, decreased recipient ALT at time of OLT, decreased recipient body mass index at registration, use of anti-thymocyte globulin as induction therapy, and longer wait time from registration. Contrary to popular belief, a requirement for RRT, even for prolonged periods in excess of 8 weeks, was not an independent predictor of failure to recover renal function post-OLT. Conclusion These data indicate that the duration of renal dysfunction, even among those requiring RRT, is a poor way to discriminate reversible from irreversible renal dysfunction. PMID:23849513

Allopurinol improves endothelial dysfunction in chronic heart failure.

PubMed

Farquharson, Colin A J; Butler, Robert; Hill, Alexander; Belch, Jill J F; Struthers, Allan D

2002-07-09

Increased oxidative stress in chronic heart failure is thought to contribute to endothelial dysfunction. Xanthine oxidase produces oxidative stress and therefore we examined whether allopurinol improved endothelial dysfunction in chronic heart failure. We performed a randomized, placebo-controlled, double-blind crossover study on 11 patients with New York Heart Association class II-III chronic heart failure, comparing 300 mg allopurinol daily (1 month) versus placebo. Endothelial function was assessed by standard forearm venous occlusion plethysmography with acetylcholine, nitroprusside, and verapamil. Plasma malondialdehyde levels were also compared to assess significant changes in oxidative stress. Allopurinol significantly increased the forearm blood flow response to acetylcholine (percentage change in forearm blood flow [mean+/-SEM]: 181+/-19% versus 120+/-22% allopurinol versus placebo; P=0.003). There were no significant differences in the forearm blood flow changes between the placebo and allopurinol treatment arms with regard to sodium nitroprusside or verapamil. Plasma malondialdehyde was significantly reduced with allopurinol treatment (346+/-128 nmol/L versus 461+/-101 nmol/L, allopurinol versus placebo; P=0.03), consistent with reduced oxidative stress with allopurinol therapy. We have shown that allopurinol improves endothelial dysfunction in chronic heart failure. This raises the distinct possibility that allopurinol might reduce cardiovascular events and even improve exercise capacity in chronic heart failure.

[Application of yellow turpentine baths in patients with chronic prostatitis complicated by sexual dysfunctions].

PubMed

2005-01-01

Patients with chronic prostatitis complicated by sexual dysfunction took turpentine baths with yellow solution in concentration rising from 5 to 55 ml solution per 200 l water, temperature 35-40 degrees C, duration 5-16 min, daily, 12-15 procedures. Yellow turpentine baths raise efficacy of treatment of patients with copulative dysfunction to 64% due to intensive arterial blood inflow to the sexual organs including the cavernous bodies of the penis.

Effects of bile acids on human airway epithelial cells: implications for aerodigestive diseases.

PubMed

Aldhahrani, Adil; Verdon, Bernard; Ward, Chris; Pearson, Jeffery

2017-01-01

Gastro-oesophageal reflux and aspiration have been associated with chronic and end-stage lung disease and with allograft injury following lung transplantation. This raises the possibility that bile acids may cause lung injury by damaging airway epithelium. The aim of this study was to investigate the effect of bile acid challenge using the immortalised human bronchial epithelial cell line (BEAS-2B). The immortalised human bronchial epithelial cell line (BEAS-2B) was cultured. A 48-h challenge evaluated the effect of individual primary and secondary bile acids. Post-challenge concentrations of interleukin (IL)-8, IL-6 and granulocyte-macrophage colony-stimulating factor were measured using commercial ELISA kits. The viability of the BEAS-2B cells was measured using CellTiter-Blue and MTT assays. Lithocholic acid, deoxycholic acid, chenodeoxycholic acid and cholic acid were successfully used to stimulate cultured BEAS-2B cells at different concentrations. A concentration of lithocholic acid above 10 μmol·L -1 causes cell death, whereas deoxycholic acid, chenodeoxycholic acid and cholic acid above 30 μmol·L -1 was required for cell death. Challenge with bile acids at physiological levels also led to a significant increase in the release of IL-8 and IL6 from BEAS-2B. Aspiration of bile acids could potentially cause cell damage, cell death and inflammation in vivo . This is relevant to an integrated gastrointestinal and lung physiological paradigm of chronic lung disease, where reflux and aspiration are described in both chronic lung diseases and allograft injury.

Histologic findings in protocol biopsies performed in stable renal allografts under different immunosuppressive schedules.

PubMed

Moreso, F; Alperovich, G; Fulladosa, X; Gil-Vernet, S; Ibernon, M; Carrera, M; Castelao, A M; Hueso, M; Grinyo, J M; Serón, D

2003-08-01

Protocol biopsies performed in stable renal allografts show different degrees of acute and chronic lesions. Histologic findings in protocol biopsies have been related to graft outcome. We evaluated histologic lesions observed in protocol biopsies performed in patients under different immunosuppression therapies. From June 1988 a protocol biopsy was performed at approximately 4 months in patients who fulfilled the following criteria: serum creatinine <300 micromol/L; stable renal function; and proteinuria <1 g/d. Histologic lesions were graded according to 1997 Banff criteria. For the present study we considered the following groups according to immunosuppressive schedule: (i) induction therapy with polyclonal or monoclonal antilymphocytic antibodies associated with cyclosporine and prednisone (n=201); (ii) cyclosporine, mycophenolate mofetil, and prednisone (n=127); and (iii) tacrolimus, mycophenolate mofetil, and prednisone (n=51). On protocol biopsy patients treated with tacrolimus displayed a lower acute score (0.61+/-1.01 vs 1.24+/-1.23 in group I, 1.28+/-1.41 in group II; P<.0001) and a higher proportion of normal biopsies (57.1% vs 41.9% in group I, 45.1% in group II; P=.016). A similar proportion of chronic lesions (chronic score of group I: 1.30+/-1.56; group II: 1.34+/-1.80; group III: 1.51+/-0.95; P=NS) was observed in the three groups. Protocol biopsies displayed fewer acute lesions in patients treated with tacrolimus. This result suggests that the efficacy of new immunosuppression schedules can be evaluated using the protocol biopsy as a surrogate marker of graft outcome.

Brain natriuretic peptide and right heart dysfunction after heart transplantation.

PubMed

Talha, Samy; Charloux, Anne; Piquard, François; Geny, Bernard

2017-06-01

Heart transplantation (HT) should normalize cardiac endocrine function, but brain natriuretic peptide (BNP) levels remain elevated after HT, even in the absence of left ventricular hemodynamic disturbance or allograft rejection. Right ventricle (RV) abnormalities are common in HT recipients (HTx), as a result of engraftment process, tricuspid insufficiency, and/or repeated inflammation due to iterative endomyocardial biopsies. RV function follow-up is vital for patient management as RV dysfunction is a recognized cause of in-hospital death and is responsible for a worse prognosis. Interestingly, few and controversial data are available concerning the relationship between plasma BNP levels and RV functional impairment in HTx. This suggests that infra-clinical modifications, such as subtle immune system disorders or hypoxic conditions, might influence BNP expression. Nevertheless, due to other altered circulating molecular forms of BNP, a lack of specificity of BNP assays is described in heart failure patients. This phenomenon could exist in HT population and could explain elevated BNP plasmatic levels despite a normal RV function. In clinical practice, intra-individual change in BNP over time, rather than absolute BNP values, might be more helpful in detecting right cardiac dysfunction in HTx. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Calcium channel blockers as the treatment of choice for hypertension in renal transplant recipients: fact or fiction.

PubMed

Baroletti, Steven A; Gabardi, Steven; Magee, Colm C; Milford, Edgar L

2003-06-01

Posttransplantation hypertension has been identified as an independent risk factor for chronic allograft dysfunction and loss. Based on available morbidity and mortality data, posttransplantation hypertension must be identified and managed appropriately. During the past decade, calcium channel blockers have been recommended by some as the antihypertensive agents of choice in this population, because it was theorized that their vasodilatory effects would counteract the vasoconstrictive effects of the calcineurin inhibitors. With increasing data becoming available, reexamining the use of traditional antihypertensive agents, including diuretics and beta-blockers, or the newer agents, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers, may be beneficial. Transplant clinicians must choose antihypertensive agents that will provide their patients with maximum benefit, from both a renal and a cardiovascular perspective. Beta-blockers, diuretics, and ACE inhibitors have all demonstrated significant benefit on morbidity and mortality in patients with cardiovascular disease. Calcium channel blockers have been shown to possess the ability to counteract cyclosporine-induced nephrotoxicity. When compared with beta-blockers, diuretics, and ACE inhibitors, however, the relative risk of cardiovascular events is increased with calcium channel blockers. With the long-term benefits of calcium channel blockers on the kidney unknown and a negative cardiovascular profile, these agents are best reserved as adjunctive therapy to beta-blockers, diuretics, and ACE inhibitors.

Oral kanglaite injection (KLTI) attenuates the lung cancer-promoting effect of high-fat diet (HFD)-induced obesity.

PubMed

Cao, Ning; Ma, Xiaofang; Guo, Zhenzhen; Zheng, Yaqiu; Geng, Shengnan; Meng, Mingjing; Du, Zhenhua; Lin, Haihong; Duan, Yongjian; Du, Gangjun

2016-09-20

Obesity is a risk factor for cancer and cancer-related mortality, however, its role in lung cancer progression remains controversial. This study aimed to assess whether high-fat diet (HFD)-induced obesity promotes lung cancer progression and whether the promotion can be decreased by Kanglaite injection (KLTI). In vivo, HFD-induced overweight or obesity increases the lung carcinoma incidence and multiplicity in a urethane-induced lung carcinogenic model and cancer-related mortality in a LLC allograft model by increasing oxidative stress and cellular signaling molecules including JAK, STAT3, Akt, mTOR, NF-κB and cyclin D1. These changes resulted in increases in vascular disruption and the lung water content, thereby promoting lung epithelial proliferation and the epithelial-mesenchymal transition (EMT) during carcinogenesis. Chronic KLTI treatment substantially prevented the weight gain resulting from HFD consumption, thereby reversing the metabolic dysfunction-related physiological changes and reducing susceptibility to lung carcinogenesis. In vitro, KLTI significantly suppressed the proliferation and induced apoptosis and differentiation in 3T3-L1 preadipocyte cells and attenuated endothelial cell permeability in HUVECs. Our study indicates that there is a potential relationship between obesity and lung cancer. This is the first study to show that obesity can directly accelerate carcinogen-induced lung cancer progression and that KLTI can decrease the lung cancer-promoting effect of HFD-induced obesity.

Cytomegalovirus neutralization by hyperimmune and standard intravenous immunoglobulin preparations.

PubMed

Planitzer, Christina B; Saemann, Marcus D; Gajek, Hartwig; Farcet, Maria R; Kreil, Thomas R

2011-08-15

Cytomegalovirus (CMV) remains one of the most important pathogens after transplantation, potentially leading to CMV disease, allograft dysfunction, acute, and chronic rejection and opportunistic infections. Immunoglobulin G (IgG) preparations with high antibody titers against CMV are a valuable adjunctive prevention and treatment option for clinicians and apart from standard intravenous immunoglobulin (IVIG), CMV hyperimmune preparations are available. The CMV antibody titer of these preparations is typically determined by Enzyme-linked immunosorbent assay (ELISA), also used for the selection of high titer plasma donors for the production of the CMV Hyperimmune product. However, CMV ELISA titers do not necessarily correlate with CMV antibody function which is determined by virus neutralization tests. CMV antibody titers were determined by both ELISA and virus neutralization assay and the IgG subclass distribution was compared between a CMV hyperimmune licensed in Europe and standard IVIG preparations. Although the expected high CMV IgG ELISA antibody titers were confirmed for three lots of a CMV hyperimmune preparation, the functionally more relevant CMV neutralizing antibody titers were significantly higher for 31 lots of standard IVIG preparations. Moreover, considerably lower IgG3 levels were found for the CMV hyperimmune preparation compared with standard IVIG preparations. The higher functional CMV neutralization titers of standard IVIG preparations and the better availability of these preparations, suggest that these products could be a valuable alternative to the CMV hyperimmune preparation.

Should fractures in massive intercalary bone allografts of the lower limb be treated with ORIF or with a new allograft?

PubMed

Aponte-Tinao, Luis A; Ayerza, Miguel A; Muscolo, D Luis; Farfalli, Germán L

2015-03-01

Massive bone allografts have been used for limb salvage of bone tumor resections as an alternative to endoprostheses, although they have different outcomes and risks. There is no general consensus about when to use these alternatives, but when it is possible to save the native joints after the resection of a long bone tumor, intercalary allografts offer some advantages despite complications, such as fracture. The management and outcomes of this complication deserve more study. The purposes of this study were to (1) analyze the fracture frequency in a group of patients treated with massive intercalary bone allografts of the femur and tibia; (2) compare the results of allografts treated with open reduction and internal fixation (ORIF) with those treated with resection and repeat allograft reconstruction; and (3) determine the likelihood that treatment of a fracture resulted in a healed intercalary reconstruction. We reviewed patients treated with intercalary bone allografts between 1991 and 2011. During this period, patients were generally treated with intercalary allografts when after tumor resection at least 1 cm of residual epiphysis remained to allow fixation of the osteotomy junction. To obtain a homogeneous group of patients, we excluded allograft-prosthesis composites and osteoarticular and hemicylindrical intercalary allografts from this study. We analyzed the fracture rate of 135 patients reconstructed with segmental intercalary bone allografts of the lower extremities (98 femurs and 37 tibias). In patients whose grafts fractured were treated either by internal fixation or a second allograft, ORIF generally was attempted but after early failures in femur fractures, these fractures were treated with a second allograft. Using a chart review, we ascertained the frequency of osseous union, complications, and reoperations after the treatment of fractured intercalary allografts. Followup was at a mean of 101 months (range, 24-260 months); of the original 135 patients, no patient was lost to followup. At latest followup, 19 patients (14%) had an allograft fracture (16 femurs [16%] and three tibias [8%]). Six patients were treated with internal fixation and addition of autologous graft (three femurs and three tibias) and 13 patients were treated with a second intercalary allograft (13 femurs). The three patients with femoral allograft fractures treated with internal fixation and autologous grafts failed and were treated with a second allograft, whereas those patients with tibia allograft fractures treated by the same procedure healed without secondary complications. When we analyzed the 16 patients with a second intercalary allograft (13 as primary treatment of the fracture and three as secondary treatment of the fracture), five failed (31%) and were treated with resection of the allograft and reconstructed with an endoprosthesis (four patients) or an osteoarticular allograft (one patient). Fractures of intercalary allografts of the tibia could successfully be treated with internal fixation and autologous iliac crest bone graft; however, this treatment failed when used for femur allograft fractures. Femoral fractures could be treated with resection and repeat allograft reconstruction, however, with a higher refracture frequency. The addition of a vascularized fibular graft in the second attempt should be considered. Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Allograft-prosthesis composites after bone tumor resection at the proximal tibia.

PubMed

Biau, David Jean; Dumaine, Valérie; Babinet, Antoine; Tomeno, Bernard; Anract, Philippe

2007-03-01

The survival of irradiated allograft-prosthesis composites at the proximal tibia is mostly unknown. However, allograft-prosthesis composites have proved beneficial at other reconstruction sites. We presumed allograft-prosthesis composites at the proximal tibia would improve survival and facilitate reattachment of the extensor mechanism compared with that of conventional (megaprostheses) reconstructions. We retrospectively reviewed 26 patients who underwent resection of proximal tibia tumors followed by reconstruction with allo-graft-prosthesis composites. Patients received Guepar massive custom-made fully constrained prostheses. Allografts were sterilized with gamma radiation, and the stems were cemented into the allograft and host bone. The minimum followup was 6 months (median, 128 months; range, 6-195 months). Fourteen patients had one or more components removed. The median allograft-prosthesis composite survival was 102 months (95% confidence interval, 64.2-infinity). Of the 26 allografts, seven fractured, six showed signs of partial resorption, and six had infections develop. Seven allografts showed signs of fusion with the host bone. Six extensor mechanism reconstructions failed. Allograft-prosthesis composites sterilized by gamma radiation yielded poor results for proximal tibial reconstruction as complications and failures were common. We do not recommend irradiated allograft-prosthesis composites for proximal tibia reconstruction.

Inability to determine tissue health is main indication of allograft use in intermediate extent burns.

PubMed

Fletcher, John L; Cancio, Leopoldo C; Sinha, Indranil; Leung, Kai P; Renz, Evan M; Chan, Rodney K

2015-12-01

Cutaneous allograft is commonly used in the early coverage of excised burns when autograft is unavailable. However, allograft is also applied in intermediate-extent burns (25-50%), during cases in which it is possible to autograft. In this population, there is a paucity of data on the indications for allograft use. This study explores the indications for allograft usage in moderate size burns. Under an IRB-approved protocol, patients admitted to our burn unit between March 2003 and December 2010 were identified through a review of the burn registry. Data on allograft use, total burn surface area, operation performed, operative intent, number of operations, intensive care unit length of stay, and overall length of stay were collected and analyzed. Data are presented as means±standard deviations, except where noted. In the study period, 146 patients received allograft during their acute hospitalization. Twenty-five percent of allograft recipients sustained intermediate-extent burns. Patients with intermediate-extent burns received allograft later in their hospitalization than those with large-extent (50-75% TBSA) burns (6.8 days vs. 3.4 days, p=0.01). Allografted patients with intermediate-extent burns underwent more operations (10.8 vs. 6.1, p=0.002) and had longer hospitalizations (78.3 days vs. 40.9 days, p<0.001) than non-allografted patients, when controlled for TBSA. Clinical rationale for placement of allograft in this population included autograft failure, uncertain depth of excision, lack of autograft donor site, and wound complexity. When uncertain depth of excision was the indication, allograft was universally applied onto the face. In half of allografted intermediate-extent burn patients the inability to identify a viable recipient bed was the ultimate reason for allograft use. Unlike large body surface area burns, allograft skin use in intermediate-extent injury occurs later in the hospitalization and is driven by the inability to determine wound bed suitability for autograft application. Allograft application can be utilized to test recipient site viability in cases of autograft failure or uncertain depth of excision. Published by Elsevier Ltd.

Non-celiac gluten sensitivity triggers gut dysbiosis, neuroinflammation, gut-brain axis dysfunction, and vulnerability for dementia.

PubMed

Daulatzai, Mak Adam

2015-01-01

The non-celiac gluten sensitivity (NCGS) is a chronic functional gastrointestinal disorder which is very common world wide. The human gut harbors microbiota which has a wide variety of microbial organisms; they are mainly symbiotic and important for well being. However, "dysbiosis" - i.e. an alteration in normal commensal gut microbiome with an increase in pathogenic microbes, impacts homeostasis/health. Dysbiosis in NCGS causes gut inflammation, diarrhea, constipation, visceral hypersensitivity, abdominal pain, dysfunctional metabolic state, and peripheral immune and neuro-immune communication. Thus, immune-mediated gut and extra-gut dysfunctions, due to gluten sensitivity with comorbid diarrhea, may last for decades. A significant proportion of NCGS patients may chronically consume alcohol, non-steroidal anti-inflammatory drugs, and fatty diet, as well as suffer from various comorbid disorders. The above pathophysiological substrate and dysbiosis are underpinned by dysfunctional bidirectional "Gut-Brain Axis" pathway. Pathogenic gut microbiota is known to upregulate gut- and systemic inflammation (due to lipopolysaccharide from pathogenic bacteria and synthesis of pro-inflammatory cytokines); they enhance energy harvest, cause obesity, insulin resistance, and dysfunctional vago-vagal gut-brain axis. Conceivably, the above cascade of pathology may promote various pathophysiological mechanisms, neuroinflammation, and cognitive dysfunction. Hence, dysbiosis, gut inflammation, and chronic dyshomeostasis are of great clinical relevance. It is argued here that we need to be aware of NCGS and its chronic pathophysiological impact. Therapeutic measures including probiotics, vagus nerve stimulation, antioxidants, alpha 7 nicotinic receptor agonists, and corticotropin-releasing factor receptor 1 antagonist may ameliorate neuroinflammation and oxidative stress in NCGS; they may therefore, prevent cognitive dysfunction and vulnerability to Alzheimer's disease.

Evaluation of chronic kidney disease in chronic heart failure: From biomarkers to arterial renal resistances

PubMed Central

Iacoviello, Massimo; Leone, Marta; Antoncecchi, Valeria; Ciccone, Marco Matteo

2015-01-01

Chronic kidney disease and its worsening are recurring conditions in chronic heart failure (CHF) which are independently associated with poor patient outcome. The heart and kidney share many pathophysiological mechanisms which can determine dysfunction in each organ. Cardiorenal syndrome is the condition in which these two organs negatively affect each other, therefore an accurate evaluation of renal function in the clinical setting of CHF is essential. This review aims to revise the parameters currently used to evaluate renal dysfunction in CHF with particular reference to the usefulness and the limitations of biomarkers in evaluating glomerular dysfunction and tubular damage. Moreover, it is reported the possible utility of renal arterial resistance index (a parameter associated with abnormalities in renal vascular bed) for a better assesment of kidney disfunction. PMID:25610846

Inflammatory macrophage-associated 3-gene signature predicts subclinical allograft injury and graft survival.

PubMed

Azad, Tej D; Donato, Michele; Heylen, Line; Liu, Andrew B; Shen-Orr, Shai S; Sweeney, Timothy E; Maltzman, Jonathan Scott; Naesens, Maarten; Khatri, Purvesh

2018-01-25

Late allograft failure is characterized by cumulative subclinical insults manifesting over many years. Although immunomodulatory therapies targeting host T cells have improved short-term survival rates, rates of chronic allograft loss remain high. We hypothesized that other immune cell types may drive subclinical injury, ultimately leading to graft failure. We collected whole-genome transcriptome profiles from 15 independent cohorts composed of 1,697 biopsy samples to assess the association of an inflammatory macrophage polarization-specific gene signature with subclinical injury. We applied penalized regression to a subset of the data sets and identified a 3-gene inflammatory macrophage-derived signature. We validated discriminatory power of the 3-gene signature in 3 independent renal transplant data sets with mean AUC of 0.91. In a longitudinal cohort, the 3-gene signature strongly correlated with extent of injury and accurately predicted progression of subclinical injury 18 months before clinical manifestation. The 3-gene signature also stratified patients at high risk of graft failure as soon as 15 days after biopsy. We found that the 3-gene signature also distinguished acute rejection (AR) accurately in 3 heart transplant data sets but not in lung transplant. Overall, we identified a parsimonious signature capable of diagnosing AR, recognizing subclinical injury, and risk-stratifying renal transplant patients. Our results strongly suggest that inflammatory macrophages may be a viable therapeutic target to improve long-term outcomes for organ transplantation patients.

Liver transplantation: Current status and challenges

PubMed Central

Jadlowiec, Caroline C; Taner, Timucin

2016-01-01

Great progress has been made in the field of liver transplantation over the past two decades. This progress, however, also brings up the next set of challenges: First, organ shortage remains a major limitation, and accounts for a large proportion of wait list mortality. While living donation has successfully increased the total number of liver transplants done in Asian countries, the total number of such transplants has been stagnant in the western hemisphere. As such, there has been a significant effort over the past decade to increase the existing deceased donor pool. This effort has resulted in a greater use of liver allografts following donation after cardiac death (DCD) along with marginal and extended criteria donors. Improved understanding of the pathophysiology of liver allografts procured after circulatory arrest has not only resulted in better selection and management of DCD donors, but has also helped in the development of mechanical perfusion strategies. Early outcomes demonstrating the clinical applicability of both hypothermic and normothermic perfusion and its potential to impact patient survival and allograft function have generated much interest. Second, long-term outcomes of liver transplant recipients have not improved significantly, as recipients continue to succumb to complications of long-term immunosuppression, such as infection, malignancy and renal failure. Furthermore, recent evidence suggests that chronic immune-mediated injury to the liver may also impact graft function. PMID:27182155

Metformin use in kidney transplant recipients in the United States: an observational study.

PubMed

Stephen, Jenise; Anderson-Haag, Teresa L; Gustafson, Sally; Snyder, Jon J; Kasiske, Bertram L; Israni, Ajay K

2014-01-01

Although metformin is contraindicated in patients with increased serum creatinine levels (≥1.5 mg/dl in men, ≥1.4 mg/dl in women) in the United States, its use has not been systematically examined in kidney transplant recipients. We aimed to determine the frequency of metformin use and its associations among kidney transplant recipients, and to assess allograft and patient survival associated with metformin use. In this retrospective cohort study, we linked Scientific Registry of Transplant Recipients data for all incident kidney transplants 2001-2012 and national pharmacy claims (n = 46,914). We compared recipients having one or more pharmacy claims for a metformin-containing product (n = 4,609) and recipients having one or more claims for a non-metformin glucose-lowering agent (n = 42,305). On average, metformin claims were filled later after transplant and were associated with higher estimated glomerular filtration rates before the first claim. Median serum creatinine (mg/dl) levels before the first claim were lower in recipients with metformin claims than in those with non-metformin claims (1.3 [interquartile range 1.0-1.7] vs. 1.6 [1.2-2.5], respectively; p < 0.0001). Metformin was associated with lower adjusted hazards for living donor (0.55, 95% confidence interval 0.38-0.80; p = 0.002) and deceased donor (0.55, 0.44-0.70; p < 0.0001) allograft survival at 3 years posttransplant, and with lower mortality. Despite metformin being contraindicated in renal dysfunction, many kidney transplant recipients receive it, and it is not associated with worse patient or allograft survival. © 2015 S. Karger AG, Basel.

Inhalative pre-treatment of donor lungs using the aerosolized prostacyclin analog iloprost ameliorates reperfusion injury.

PubMed

Wittwer, Thorsten; Franke, Ulrich F W; Ochs, Matthias; Sandhaus, Tim; Schuette, Alex; Richter, Stefan; Dreyer, Niels; Knudsen, Lars; Müller, Thomas; Schubert, Harald; Richter, Joachim; Wahlers, Thorsten

2005-10-01

Lung transplantation is effective for end-stage pulmonary disease, but its successful application is still limited by organ shortage and sub-optimal preservation techniques. Therefore, optimal allograft protection is essential to reduce organ dysfunction, especially in the early post-operative period. Intravenous prostanoids are routinely used to ameliorate reperfusion injury. However, the latest evidence suggests similar efficacy using inhaled prostacyclin. Thus, we evaluated the impact of donor pre-treatment using the prostacyclin analog, iloprost, on post-ischemic function of Perfadex-protected allografts. In Group 1, 5 pig lungs were preserved with Perfadex (PER group) solution and stored for 27 hours. In Group 2, 100 microg of iloprost was aerosolized over 30 minutes using a novel mobile ultrasonic nebulizer (Optineb) before identical organ harvest (PER-ILO group). After left lung transplantation and contralateral lung exclusion, hemodynamic variables, Po2/Fio2 and dynamic compliance were monitored for 6 hours and compared with sham-operated controls. Pulmonary edema was determined stereologically and by wet-to-dry (W/D) weight ratio. Statistical assessment included analysis of variance (ANOVA) with repeated measures. Dynamic compliance and pulmonary vascular resistance (PVR) were superior in iloprost-treated compared with untreated organs (p < 0.05), whereas oxygenation was comparable between groups. W/D ratio revealed a significantly smaller amount of lung water in PER-ILO organs (p = 0.048), whereas stereologic data showed a trend toward less intra-alveolar edema. Endobronchial application of iloprost in donor lungs before Perfadex preservation decreases post-ischemic edema and significantly improves lung compliance and vascular resistance. This innovative approach is easily applicable in the clinical setting and offers a new strategy for improvement of pulmonary allograft preservation.

Assessment of tissue allograft safety monitoring with administrative healthcare databases: a pilot project using Medicare data.

PubMed

Dhakal, Sanjaya; Burwen, Dale R; Polakowski, Laura L; Zinderman, Craig E; Wise, Robert P

2014-03-01

Assess whether Medicare data are useful for monitoring tissue allograft safety and utilization. We used health care claims (billing) data from 2007 for 35 million fee-for-service Medicare beneficiaries, a predominantly elderly population. Using search terms for transplant-related procedures, we generated lists of ICD-9-CM and CPT(®) codes and assessed the frequency of selected allograft procedures. Step 1 used inpatient data and ICD-9-CM procedure codes. Step 2 added non-institutional provider (e.g., physician) claims, outpatient institutional claims, and CPT codes. We assembled preliminary lists of diagnosis codes for infections after selected allograft procedures. Many ICD-9-CM codes were ambiguous as to whether the procedure involved an allograft. Among 1.3 million persons with a procedure ascertained using the list of ICD-9-CM codes, only 1,886 claims clearly involved an allograft. CPT codes enabled better ascertainment of some allograft procedures (over 17,000 persons had corneal transplants and over 2,700 had allograft skin transplants). For spinal fusion procedures, CPT codes improved specificity for allografts; of nearly 100,000 patients with ICD-9-CM codes for spinal fusions, more than 34,000 had CPT codes indicating allograft use. Monitoring infrequent events (infections) after infrequent exposures (tissue allografts) requires large study populations. A strength of the large Medicare databases is the substantial number of certain allograft procedures. Limitations include lack of clinical detail and donor information. Medicare data can potentially augment passive reporting systems and may be useful for monitoring tissue allograft safety and utilization where codes clearly identify allograft use and coding algorithms can effectively screen for infections.

Quality control processes in allografting: A twenty-year retrospective review of a hospital-based bone bank in Taiwan.

PubMed

Fu, Shau-Huai; Liu, Jyh-You; Huang, Chuan-Ching; Lin, Feng-Ling; Yang, Rong-Sen; Hou, Chun-Han

2017-01-01

Musculoskeletal allografts are now commonly used. To decrease the potential risks of transmission of pathogenic bacteria, fungi, or viruses to the transplant recipients, certain issues regarding the management of patients who receive contaminated allografts need to be addressed. We aimed to clarify the incidence and extent of disease transmission from allografts by analyzing the allografting procedures performed in the bone bank of our hospital over the past 20 years. We retrospectively reviewed the data from our allograft registry center on 3979 allografts that were implanted in 3193 recipients throughout a period of two decades, from July 1991 to June 2011. The source of the allografts, results of all screening tests, dates of harvesting and implantation, and recipients of all allografts were checked. With the help of the Center for Infection Control of our hospital, a strict prospective, hospital-wide, on-site surveillance was conducted, and every patient with healthcare-associated infection was identified. Fisher's exact test was used to compare the infection rate between recipients with sterile allografts and those with contaminated allografts. The overall discard and infection rates were, respectively, 23% and 1.3% in the first decade (1991-2001); and 18.4% and 1.25% in the second decade (2001-2011). The infection rate of contaminated allograft recipients was significantly higher than that of sterile allograft recipients (10% vs. 1.15%, P < 0.01) in the second decade. Both infection and discard rates of our bone bank are comparable with those of international bone banks. Strict allograft processing and adequate prophylactic use of antibiotics are critical to prevent infection and disease transmission in such cases.

Quality control processes in allografting: A twenty-year retrospective review of a hospital-based bone bank in Taiwan

PubMed Central

Fu, Shau-Huai; Liu, Jyh-You; Huang, Chuan-Ching; Lin, Feng-ling; Yang, Rong-Sen; Hou, Chun-han

2017-01-01

Musculoskeletal allografts are now commonly used. To decrease the potential risks of transmission of pathogenic bacteria, fungi, or viruses to the transplant recipients, certain issues regarding the management of patients who receive contaminated allografts need to be addressed. We aimed to clarify the incidence and extent of disease transmission from allografts by analyzing the allografting procedures performed in the bone bank of our hospital over the past 20 years. We retrospectively reviewed the data from our allograft registry center on 3979 allografts that were implanted in 3193 recipients throughout a period of two decades, from July 1991 to June 2011. The source of the allografts, results of all screening tests, dates of harvesting and implantation, and recipients of all allografts were checked. With the help of the Center for Infection Control of our hospital, a strict prospective, hospital-wide, on-site surveillance was conducted, and every patient with healthcare-associated infection was identified. Fisher’s exact test was used to compare the infection rate between recipients with sterile allografts and those with contaminated allografts. The overall discard and infection rates were, respectively, 23% and 1.3% in the first decade (1991–2001); and 18.4% and 1.25% in the second decade (2001–2011). The infection rate of contaminated allograft recipients was significantly higher than that of sterile allograft recipients (10% vs. 1.15%, P < 0.01) in the second decade. Both infection and discard rates of our bone bank are comparable with those of international bone banks. Strict allograft processing and adequate prophylactic use of antibiotics are critical to prevent infection and disease transmission in such cases. PMID:29049290

In Vivo Efficacy of Fresh vs. Frozen Osteochondral Allografts in the Goat at 6 Months is Associated with PRG4 Secretion

PubMed Central

Pallante-Kichura, Andrea L.; Chen, Albert C.; Temple-Wong, Michele M.; Bugbee, William D.; Sah, Robert L.

2014-01-01

The long-term efficacy of osteochondral allografts is due to the presence of viable chondrocytes within graft cartilage. Chondrocytes in osteochondral allografts, especially those at the articular surface that normally produce the lubricant proteoglycan-4 (PRG4), are susceptible to storage-associated death. The hypothesis of this study was that the loss of chondrocytes within osteochondral grafts leads to decreased PRG4 secretion, after graft storage and subsequent implant. The objectives were to determine the effect of osteochondral allograft treatment (FROZEN vs. FRESH) on secretion of functional PRG4 after (i) storage, and (ii) 6months in vivo in adult goats. FROZEN allograft storage reduced PRG4 secretion from cartilage by ~85% compared to FRESH allograft storage. After 6months in vivo, the PRG4-secreting function of osteochondral allografts was diminished with prior FROZEN storage by ~81% versus FRESH allografts and by ~84% versus non-operated control cartilage. Concomitantly, cellularity at the articular surface in FROZEN allografts was ~96% lower than FRESH allografts and non-operated cartilage. Thus, the PRG4-secreting function of allografts appears to be maintained in vivo based on its state after storage. PRG4 secretion may be not only a useful marker of allograft performance, but also a biological process protecting the articular surface of grafts following cartilage repair. PMID:23362152

Risk of Infection After Allograft Anterior Cruciate Ligament Reconstruction: Are Nonprocessed Allografts More Likely to Get Infected? A Cohort Study of Over 10,000 Allografts.

PubMed

Yu, Anthony; Prentice, Heather A; Burfeind, William E; Funahashi, Tadashi; Maletis, Gregory B

2018-03-01

Allograft tissue is frequently used in anterior cruciate ligament reconstruction (ACLR). It is often irradiated and/or chemically processed to decrease the risk of disease transmission, but some tissue is aseptically harvested without further processing. Irradiated and chemically processed allograft tissue appears to have a higher risk of revision, but whether this processing decreases the risk of infection is not clear. To determine the incidence of deep surgical site infection after ACLR with allograft in a large community-based sample and to evaluate the association of allograft processing and the risk of deep infection. Cohort study; Level of evidence, 3. The authors conducted a cohort study using the Kaiser Permanente Anterior Cruciate Ligament Reconstruction Registry. Primary isolated unilateral ACLR with allograft were identified from February 1, 2005 to September 30, 2015. Ninety-day postoperative deep infections were identified via an electronic screening algorithm and then validated through chart review. Logistic regression was used to evaluate the likelihood of 90-day postoperative deep infection per allograft processing method: processed (graft treated chemically and/or irradiated) or nonprocessed (graft not irradiated or chemically processed). Of 10,190 allograft cases, 8425 (82.7%) received a processed allograft, and 1765 (17.3%) received a nonprocessed allograft. There were 15 (0.15%) deep infections during the study period: 4 (26.7%) coagulase-negative Staphylococcus, 4 (26.7%) methicillin-sensitive Staphylococcus aureus, 1 (6.7%) Peptostreptococcus micros, and 6 (40.0%) with no growth. There was no difference in the likelihood for 90-day deep infection for processed versus nonprocessed allografts (odds ratio = 1.36, 95% CI = 0.31-6.04). The overall incidence of deep infection after ACLR with allograft tissue was very low (0.15%), suggesting that the methods currently employed by tissue banks to minimize the risk of infection are effective. In this cohort, no difference in the likelihood of infection between processed and nonprocessed allografts could be identified.

Orthotopic Transplantation of Achilles Tendon Allograft in Rats

PubMed Central

Aynardi, Michael; Zahoor, Talal; Mitchell, Reed; Loube, Jeffrey; Feltham, Tyler; Manandhar, Lumanti; Paudel, Sharada; Schon, Lew; Zhang, Zijun

2018-01-01

The biology and function of orthotopic transplantation of Achilles tendon allograft are unknown. Particularly, the revitalization of Achilles allograft is a clinical concern. Achilles allografts were harvested from donor rats and stored at −80 °C. Subcutaneous adipose tissue was harvested from the would-be allograft recipient rats for isolation of mesenchymal stem cells (MSCs). MSCs were cultured with growth differentiation factor-5 (GDF-5) and applied onto Achilles allografts on the day of transplantation. After the native Achilles tendon was resected from the left hind limb of the rats, Achilles allograft, with or without autologous MSCs, was implanted and sutured with calf muscles proximally and calcaneus distally. Animal gait was recorded presurgery and postsurgery weekly. The animals were sacrificed at week 4, and the transplanted Achilles allografts were collected for biomechanical testing and histology. The operated limbs had altered gait. By week 4, the paw print intensity, stance time, and duty cycle (percentage of the stance phase in a step cycle) of the reconstructed limbs were mostly recovered to the baselines recorded before surgery. Maximum load of failure was not different between Achilles allografts, with or without MSCs, and the native tendons. The Achilles allograft supplemented with MSCs had higher cellularity than the Achilles allograft without MSCs. Deposition of fine collagen (type III) fibers was active in Achilles allograft, with or without MSCs, but it was more evenly distributed in the allografts that were incubated with MSCs. In conclusion, orthotopically transplanted Achilles allograft healed with host tissues, regained strength, and largely restored Achilles function in 4 wk in rats. It is therefore a viable option for the reconstruction of a large Achilles tendon defect. Supplementation of MSCs improved repopulation of Achilles allograft, but large animal models, with long-term follow up and cell tracking, may be required to fully appreciate the functional benefits of MSCs. PMID:29637821

Chronic fatigue in Ehlers-Danlos syndrome-Hypermobile type.

PubMed

Hakim, Alan; De Wandele, Inge; O'Callaghan, Chris; Pocinki, Alan; Rowe, Peter

2017-03-01

Chronic fatigue is an important contributor to impaired health-related quality of life in Ehlers-Danlos syndrome. There is overlap in the symptoms and findings of EDS and chronic fatigue syndrome. A proportion of those with CFS likely have EDS that has not been identified. The evaluation of chronic fatigue in EDS needs to include a careful clinical examination and laboratory testing to exclude common causes of fatigue including anemia, hypothyroidisim, and chronic infection, as well as dysfunction of major physiological or organ systems. Other problems that commonly contribute to fatigue in EDS include sleep disorders, chronic pain, deconditioning, cardiovascular autonomic dysfunction, bowel and bladder dysfunction, psychological issues, and nutritional deficiencies. While there is no specific pharmacological treatment for fatigue, many medications are effective for specific symptoms (such as headache, menstrual dysfunction, or myalgia) and for co-morbid conditions that result in fatigue, including orthostatic intolerance and insomnia. Comprehensive treatment of fatigue needs to also evaluate for biomechanical problems that are common in EDS, and usually involves skilled physical therapy and attention to methods to prevent deconditioning. In addition to managing specific symptoms, treatment of fatigue in EDS also needs to focus on maintaining function and providing social, physical, and nutritional support, as well as providing on-going medical evaluation of new problems and review of new evidence about proposed treatments. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Orthotopic Transplantation of Achilles Tendon Allograft in Rats: With or without Incorporation of Autologous Mesenchymal Stem Cells.

PubMed

Aynardi, Michael; Zahoor, Talal; Mitchell, Reed; Loube, Jeffrey; Feltham, Tyler; Manandhar, Lumanti; Paudel, Sharada; Schon, Lew; Zhang, Zijun

2018-02-01

The biology and function of orthotopic transplantation of Achilles tendon allograft are unknown. Particularly, the revitalization of Achilles allograft is a clinical concern. Achilles allografts were harvested from donor rats and stored at -80 °C. Subcutaneous adipose tissue was harvested from the would-be allograft recipient rats for isolation of mesenchymal stem cells (MSCs). MSCs were cultured with growth differentiation factor-5 (GDF-5) and applied onto Achilles allografts on the day of transplantation. After the native Achilles tendon was resected from the left hind limb of the rats, Achilles allograft, with or without autologous MSCs, was implanted and sutured with calf muscles proximally and calcaneus distally. Animal gait was recorded presurgery and postsurgery weekly. The animals were sacrificed at week 4, and the transplanted Achilles allografts were collected for biomechanical testing and histology. The operated limbs had altered gait. By week 4, the paw print intensity, stance time, and duty cycle (percentage of the stance phase in a step cycle) of the reconstructed limbs were mostly recovered to the baselines recorded before surgery. Maximum load of failure was not different between Achilles allografts, with or without MSCs, and the native tendons. The Achilles allograft supplemented with MSCs had higher cellularity than the Achilles allograft without MSCs. Deposition of fine collagen (type III) fibers was active in Achilles allograft, with or without MSCs, but it was more evenly distributed in the allografts that were incubated with MSCs. In conclusion, orthotopically transplanted Achilles allograft healed with host tissues, regained strength, and largely restored Achilles function in 4 wk in rats. It is therefore a viable option for the reconstruction of a large Achilles tendon defect. Supplementation of MSCs improved repopulation of Achilles allograft, but large animal models, with long-term follow up and cell tracking, may be required to fully appreciate the functional benefits of MSCs.

tuberculous otitis media in a renal transplant recipient.

PubMed

Ergün, Ihsan; Keven, Kenan; Sengül, Sule; Kutlay, Sim; Sertcelik, Ayse; Ertürk, Sehsuvar; Erbay, Bülent

2004-06-01

Tuberculous otitis media is a rare cause of chronic suppurative infection of the middle ear and a very uncommon form of extrapulmonary tuberculosis. Although there have been several case reports in the nonimmunosuppressive population of tuberculous otitis media, it has never been reported in an immunosuppressed allograft recipient. We present a case of diagnosed tuberculous otitis media after recurrent chronic otitis media treated several times with empiric antibiotic treatment. After the patient developed postauricular fistula and underwent surgical removal of granulation tissue, the diagnosis was made on the basis of histopathology and growth in culture of Ziehl-Neelsen. Clinical response promptly followed institution of antituberculous treatment including isoniazid, rifampicin, ethambutol, and pyrazinamide.

A biomechanical cadaveric study comparing superior capsule reconstruction using fascia lata allograft with human dermal allograft for irreparable rotator cuff tear.

PubMed

Mihata, Teruhisa; Bui, Christopher N H; Akeda, Masaki; Cavagnaro, Matthew A; Kuenzler, Michael; Peterson, Alexander B; McGarry, Michelle H; Itami, Yasuo; Limpisvasti, Orr; Neo, Masashi; Lee, Thay Q

2017-12-01

Biomechanical and clinical success of the superior capsule reconstruction (SCR) using fascia lata (FL) grafts has been reported. In the United States, human dermal (HD) allograft has been used successfully for SCRs; however, the biomechanical characteristics have not been reported. Eight cadaveric shoulders were tested in 5 conditions: (1) intact; (2) irreparable supraspinatus tear; (3) SCR using FL allograft with anterior and posterior suturing; (4) SCR using HD allograft with anterior and posterior suturing; and (5) SCR using HD allograft with posterior suturing. Rotational range of motion, superior translation, glenohumeral joint force, and subacromial contact were measured at 0°, 30°, and 60° of glenohumeral abduction in the scapular plane. Graft dimensions before and after testing were also recorded. Biomechanical parameters were compared using a repeated-measures analysis of variance with Tukey post hoc test, and graft dimensions were compared using a Student t-test (P < .05). Irreparable supraspinatus tear significantly increased superior translation, superior glenohumeral joint force, and subacromial contact pressure, which were completely restored with the SCR FL allografts. Both SCR HD allograft repairs partially restored superior translation and completely restored subacromial contact and superior glenohumeral joint force. The HD allografts significantly elongated by 15% during testing, whereas the FL allograft lengths were unchanged. Single-layered HD SCR allografts partially restored superior glenohumeral stability, whereas FL allograft SCR completely restored the superior glenohumeral stability. This may be due to the greater flexibility of the HD allograft, and the SCR procedure used was developed on the basis of FL grafts. Published by Elsevier Inc.

Characterization of skin allograft use in thermal injury.

PubMed

Fletcher, John L; Caterson, E J; Hale, Robert G; Cancio, Leopoldo C; Renz, Evan M; Chan, Rodney K

2013-01-01

This study provides objective data on the practice of allograft usage in severely burned patients. Furthermore, gaps in our knowledge are identified, and areas for further research are delineated. Using an institutional review board-approved protocol, active duty military patients injured while deployed in support of overseas contingency operations and treated at our burn center between March 2003 and December 2010 were identified. Their electronic medical records were reviewed for allograft use, TBSA burned, injury severity score, anatomic distribution of burns, operative burden, length of stay, transfusions, and outcome. Among 844 patients, 112 (13.3%) received allograft and 732 (86.7%) did not. The amount of allograft used per patient varied and was not normally distributed (median, 23.5; interquartile range, 69.5). Patients received allograft skin an average of 12.75 times during their admission. Allografted patients sustained severe burns (μ, 53.8% TBSA); most were transfused (71.2%) and grafted frequently, averaging every 7.45 days. Most commonly, allograft was placed on the extremities (66.5%) followed by the trunk (44.2%); however, the vast majority of allografted patients also had concomitant burns of the head (91.1%) and hands (87.5%). All-cause mortality among the allografted patients was 19.1%. In conclusion, allograft is commonly used in the surgical treatment of severe burns. Although there are no anatomic limitations to allograft placement, there are distinct patterns of use. Given the role of allograft in the acute management of large burns, there is need for further investigation of its effect on mortality, morbidity, and antigenicity.

Experience with a bone bank operation and allograft bone infection in recipients at a medical centre in southern Taiwan.

PubMed

Liu, J W; Chao, L H; Su, L H; Wang, J W; Wang, C J

2002-04-01

To assess the contamination rate of allograft bones at retrieval and the infection rate of the implanted allograft bone, we audited a bone bank retrospectively and reviewed the medical charts of allograft bone recipients between June 1999 and June 2000 at a medical centre in southern Taiwan. The bone bank did its utmost to minimize allograft contamination with hospital-acquired pathogens by adopting purposefully designed criteria for selection of donors. This protocol included sterilization with soaking of the retrieved allograft in a solution of a first-generation cephalosporin before storage and prophylaxis in recipients with first-generation cephalosporin. The contamination rates at allograft retrieval from living and cadaveric donors were 2.7% and 12.4%, respectively (P<0.001). Culture of 262 specimens taken at allograft implant revealed 12 (4.6%) positive for culture. Of the 12 patients implanted with allograft bones positive for culture, nine (75.0%) had allograft bone infection, while three (25.0%) did not. Among the 250 recipients with sterile allograft bones, four (1.6%) were found to have allograft infection. None of the cases of infection required removal of the allograft bones, and all cases were successfully treated with tailored antimicrobial therapy based on susceptibility tests on isolated bacteria. The overall infection rate was 5.0%, which compared favourably with those in other series. A prospective cohort study is needed to determine which of the varied sterilization methodologies gives the best and/or most cost-effective outcome. Copyright 2002 The Hospital Infection Society.

Cryopreserved Cadaveric Arterial Allograft for Arterial Reconstruction in Patients with Prosthetic Infection.

PubMed

Lejay, Anne; Delay, Charline; Girsowicz, Elie; Chenesseau, Bettina; Bonnin, Emilie; Ghariani, Mohamed-Zied; Thaveau, Fabien; Georg, Yannick; Geny, Bernard; Chakfe, Nabil

2017-11-01

The aim of this study was to report outcomes of cryopreserved arterial allografts used as a vascular substitute in the setting of prosthetic material infection. A retrospective analysis of prospectively collected data was conducted including all consecutive interventions performed with cryopreserved arterial allografts used for vascular reconstruction in the setting of prosthetic material infection between January 2005 and December 2014. Five year outcomes included allograft related re-interventions, survival, primary patency, and limb salvage rates. Fifty-three procedures were performed using cryopreserved allografts for vascular prosthetic infection: 25 procedures (47%) were performed at aorto-iliac level (Group 1) and 28 procedures (53%) at peripheral level (Group 2). The mean follow-up was 52 months. Five year allograft related re-intervention was 55% in Group 1 (6 allograft ruptures and 5 allograft aneurysm degenerations) and 33% in Group 2 (2 allograft ruptures and 7 allograft aneurysm degenerations). Five year survival was 40% and 68%, primary patency was 89% and 59% and limb salvage was 100% and 89% for Group 1 and 2 respectively. Use of cryopreserved arterial allografts provides acceptable results but is tempered by suboptimal 5 year outcomes with high re-intervention rates. Copyright © 2017 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Current Expectations for Cardiac Transplantation in Patients With Congenital Heart Disease.

PubMed

Kirklin, James K; Carlo, Waldemar F; Pearce, F Bennett

2016-11-01

Congenital heart disease accounts for 40% of pediatric heart transplants and presents unique challenges to the transplant team. Suitability for transplantation is defined in part by degree of sensitization, pulmonary vascular resistance, and hepatic reserves. The incremental transplant risk for patients with congenital heart disease occurs within the first 3 months, after which survival is equivalent to transplantation for cardiomyopathy. Single ventricle with prior palliation, and especially the failing Fontan, carry the highest risk for transplantation and are least amenable to bridging with mechanical circulatory support. More effective bridging to transplant with mechanical circulatory support will require improvements in the adverse event profile of available pumps and the introduction of miniaturized continuous flow technology. The major barriers to routine long-term survival are chronic allograft failure and allograft vasculopathy. Despite these many challenges, continuing improvements in the care of pediatric heart transplant patients have pushed the median posttransplant survival past 15 years for children and to 20 years for infants. © The Author(s) 2016.

Expression of allograft inflammatory factor-1 in inflammatory skin disorders.

PubMed

Orsmark, Christina; Skoog, Tiina; Jeskanen, Leila; Kere, Juha; Saarialho-Kere, Ulpu

2007-01-01

Allograft inflammatory factor-1 (AIF-1) is an evolutionarily conserved, inflammatory protein produced by activated macrophages during chronic transplant rejection and in inflammatory brain lesions. Since T-cell-mediated inflammation is common to various dermatoses and nothing is known about AIF-1 in skin, we studied its protein expression at the tissue level and regulation in monocytic cell lines by various agents. Using immunohistochemistry, we found that AIF-1 is expressed at low levels in normal skin, but is highly upregulated in various inflammatory skin disorders, such as psoriasis, lichen planus, graft-versus-host disease and mycosis fungoides. The main cell types expressing AIF-1 in affected skin are macrophages and Langerhans' cells. We also show by real-time PCR that AIF-1 mRNA levels in monocytic THP-1 and U937 cell lines are significantly upregulated by retinoic acid as well as a number of cytokines. We conclude that AIF-1 may mediate survival and pro-inflammatory properties of macrophages in skin diseases.

Immunomodulatory Effect of Mesenchymal Stem Cells on B Cells

PubMed Central

Franquesa, Marcella; Hoogduijn, M. J.; Bestard, O.; Grinyó, J. M.

2012-01-01

The research on T cell immunosuppression therapies has attracted most of the attention in clinical transplantation. However, B cells and humoral immune responses are increasingly acknowledged as crucial mediators of chronic allograft rejection. Indeed, humoral immune responses can lead to renal allograft rejection even in patients whose cell-mediated immune responses are well controlled. On the other hand, newly studied B cell subsets with regulatory effects have been linked to tolerance achievement in transplantation. Better understanding of the regulatory and effector B cell responses may therefore lead to new therapeutic approaches. Mesenchymal stem cells (MSC) are arising as a potent therapeutic tool in transplantation due to their regenerative and immunomodulatory properties. The research on MSCs has mainly focused on their effects on T cells and although data regarding the modulatory effects of MSCs on alloantigen-specific humoral response in humans is scarce, it has been demonstrated that MSCs significantly affect B cell functioning. In the present review we will analyze and discuss the results in this field. PMID:22833744

Utility of HLA Antibody Testing in Kidney Transplantation

PubMed Central

Konvalinka, Ana

2015-01-01

HLA antigens are polymorphic proteins expressed on donor kidney allograft endothelium and are critical targets for recipient immune recognition. HLA antibodies are risk factors for acute and chronic rejection and allograft loss. Solid-phase immunoassays for HLA antibody detection represent a major advance in sensitivity and specificity over cell-based methods and are widely used in organ allocation and pretransplant risk assessment. Post-transplant, development of de novo donor–specific HLA antibodies and/or increase in donor-specific antibodies from pretransplant levels are associated with adverse outcomes. Although single antigen bead assays have allowed sensitive detection of recipient HLA antibodies and their specificities, a number of interpretive considerations must be appreciated to understand test results in clinical and research contexts. This review, which is especially relevant for clinicians caring for transplant patients, discusses the technical aspects of single antigen bead assays, emphasizes their quantitative limitations, and explores the utility of HLA antibody testing in identifying and managing important pre- and post-transplant clinical outcomes. PMID:25804279

Non-invasive quantification of collagen turnover in renal transplant recipients

PubMed Central

Brix, Susanne; Karsdal, Morten Asser; Seelen, Marc A.; van Goor, Harry; Bakker, Stephan J. L.; Olinga, Peter; Mutsaers, Henricus A. M.; Genovese, Federica

2017-01-01

Kidney allograft failure due to chronic injury/rejection remains the main cause of graft loss in renal transplant recipients (RTR). Here, we investigated whether specific biomarkers of extracellular matrix (ECM) turnover are associated with allograft function and chronic kidney disease (CKD) stage in RTR. Seventy-eight patients who attended the University Medical Center Groningen for a routine check-up after kidney transplantation were enrolled in the study. Plasma and/or 24h-urine samples were collected and specific matrix-metalloproteinase-generated neo-epitope fragments of collagens were measured by enzyme-linked immunosorbent assay. Our results demonstrated that urinary levels of C3M, a marker for collagen type III degradation, correlated with estimated glomerular filtration rate (eGFR; r = 0.58, p<0.0001), with lower levels detected in the urine of patients with advanced CKD. In addition, plasma levels of Pro-C6, a marker for collagen type VI formation, significantly increased with disease progression and correlated with eGFR (r = -0.72, p<0.0001). Conversely, plasma C3M and urinary Pro-C6 levels showed no correlation with renal function. We identified two neo-epitope biomarkers of tissue turnover associated with ECM remodeling and fibrosis that can stratify patients by CKD stage. This is as promising first step towards non-invasive monitoring of ECM turnover in the kidneys. PMID:28430784

Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV‐Naïve Recipients of Infected Donor Allograft Hearts

PubMed Central

Hwee, Y. K.; Kreklywich, C. N.; Andoh, T.; Denton, M.; Smith, P.; Hart, E.; Broekel, R.; Pallett, C.; Rogers, K.; Streblow, A. D.; Chuop, M.; Perry, A.; Slifka, M.; Messaoudi, I.; Orloff, S. L.

2015-01-01

Cytomegalovirus accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants; however, the mechanisms involved are unclear. We determined the efficacy of a CMV vaccine in preventing CMV‐accelerated rat cardiac allograft rejection in naïve recipients of CMV+ donor hearts. F344 donor rats were infected with RCMV 5 days prior to heterotopic cardiac transplantation into CMV‐naïve or H2O2‐inactivated RCMV‐vaccinated Lewis recipients. Recipients of RCMV‐infected donor hearts rejected at POD59, whereas vaccinated recipients exhibited a significantly prolonged time to rejection‐POD97, similar to recipients of uninfected donor hearts (POD108). Although all of the donor hearts were preinfected, the vaccinated recipients had lower graft and PBMC viral loads at POD 7 compared to unvaccinated controls. Adoptive T cell and passive antibody transfers from vaccinated Lewis rats into naïve recipients demonstrate that both T‐cell and B‐cell arms of the adaptive immune response provide protection against CMV‐accelerated rejection. Similar findings were obtained when testing three different adjuvants in passive transfer experiments. We have determined that the timing of the vaccine prior to transplantation and the specific adjuvant play critical roles in mediating anti‐viral responses and promoting graft survival. CMV vaccination prior to transplantation may effectively increase graft survival. PMID:25766876

Subclinical rejection associated with chronic allograft nephropathy in protocol biopsies as a risk factor for late graft loss.

PubMed

Moreso, F; Ibernon, M; Gomà, M; Carrera, M; Fulladosa, X; Hueso, M; Gil-Vernet, S; Cruzado, J M; Torras, J; Grinyó, J M; Serón, D

2006-04-01

Chronic allograft nephropathy (CAN) in protocol biopsies is associated with graft loss while the association between subclinical rejection (SCR) and outcome has yielded contradictory results. We analyze the predictive value of SCR and/or CAN in protocol biopsies on death-censored graft survival. Since 1988, a protocol biopsy was done during the first 6 months in stable grafts with serum creatinine <300 micromol/L and proteinuria <1 g/day. Biopsies were evaluated according to Banff criteria. Borderline changes and acute rejection were grouped as SCR. CAN was defined as presence of interstitial fibrosis and tubular atrophy. Mean follow-up was 91 +/- 46 months. Sufficient tissue was obtained in 435 transplants. Biopsies were classified as normal (n = 186), SCR (n = 74), CAN (n = 110) and SCR with CAN (n = 65). Presence of SCR with CAN was associated with old donors, percentage of panel reactive antibodies and presence of acute rejection before protocol biopsy. Cox regression analysis showed that SCR with CAN (relative risk [RR]: 1.86, 95% confidence interval [CI]: 1.11-3.12; p = 0.02) and hepatitis C virus (RR: 2.27, 95% CI: 1.38-3.75; p = 0.01) were independent predictors of graft survival. In protocol biopsies, the detrimental effect of interstitial fibrosis/tubular atrophy on long-term graft survival is modulated by SCR.

Association of high post-transplant soluble CD30 serum levels with chronic allograft nephropathy.

PubMed

Grenzi, Patricia C; Campos, Érika F; Tedesco-Silva, Hélio; Felipe, Claudia R; Franco, Marcello F; Soares, Maria Fernanda; Medina-Pestana, José Osmar; Gerbase-Delima, Maria

2013-12-01

The purpose of this study was to evaluate the association of post-transplant soluble CD30 (sCD30) levels, isolated or in combination with of anti-HLA class II antibodies and of serum creatinine levels, with kidney graft loss due to chronic allograft nephropathy (CAN), and type of lesions in graft biopsies for cause. The study comprised 511 first kidney graft recipients, transplanted at a single center, with a graft functioning for at least 2.8 years. A single blood sample was collected from each patient. sCD30 levels were determined by ELISA, and HLA antibodies by Luminex assay. The minimum follow-up after testing was 9.3 years. High sCD30 levels, set at sCD30 ≥ 34.15 ng/mL, the presence of HLA class II antibodies, and serum creatinine ≥ 1.9 mg/dL were independently associated with CAN-graft loss (P values <0.0001, 0.05, <0.0001, respectively), and the combined hazard ratio for CAN-graft loss was 20.2. Analyses of 166 biopsies for cause showed that high sCD30 levels and creatinine were independently associated with interstitial lesions. Post-transplant sCD30 serum levels, especially in conjunction with information regarding HLA class II antibodies and serum creatinine levels, provide valuable information regarding graft outcome and could be useful for the management of kidney transplant recipients. © 2013.

Acellular Nerve Allografts in Peripheral Nerve Regeneration: A Comparative Study

PubMed Central

Moore, Amy M.; MacEwan, Matthew; Santosa, Katherine B.; Chenard, Kristofer E.; Ray, Wilson Z.; Hunter, Daniel A.; Mackinnon, Susan E.; Johnson, Philip J.

2011-01-01

Background Processed nerve allografts offer a promising alternative to nerve autografts in the surgical management of peripheral nerve injuries where short deficits exist. Methods Three established models of acellular nerve allograft (cold-preserved, detergent-processed, and AxoGen® -processed nerve allografts) were compared to nerve isografts and silicone nerve guidance conduits in a 14 mm rat sciatic nerve defect. Results All acellular nerve grafts were superior to silicone nerve conduits in support of nerve regeneration. Detergent-processed allografts were similar to isografts at 6 weeks post-operatively, while AxoGen®-processed and cold-preserved allografts supported significantly fewer regenerating nerve fibers. Measurement of muscle force confirmed that detergent-processed allografts promoted isograft-equivalent levels of motor recovery 16 weeks post-operatively. All acellular allografts promoted greater amounts of motor recovery compared to silicone conduits. Conclusions These findings provide evidence that differential processing for removal of cellular constituents in preparing acellular nerve allografts affects recovery in vivo. PMID:21660979

Allografts for Ligament Reconstruction: Where Are We Now?

PubMed

Wydra, Frank B; York, Philip J; Johnson, Christopher R; Silvestri, Lorenzo

The use of musculoskeletal allografts by orthopedic surgeons continues to rise. The process of procuring and sterilizing allografts is evolving with much consideration to limiting the spread of infectious diseases and preserving tissue integrity. Research involving the application of allografts, particularly for ligament repair, is quite active, necessitating an update for the practicing orthopedist. Avoiding donor site morbidities is one of the most commonly cited advantages of allografts over autografts. There is controversy amongst studies for allografts in terms of their biological incorporation and clinical outcomes compared to autografts. This article focuses on reviewing the most current literature and usage of allograft tissue for ligamentous reconstruction amongst orthopedic surgeons today. It includes an in-depth analysis of the current processing, handling, and safety standards employed today, in addition to the advantages and disadvantages of allograft use.

Intraoperative culture positive allograft bone and subsequent postoperative infections: a retrospective review.

PubMed

Sims, Laura; Kulyk, Paul; Woo, Allan

2017-04-01

Obtaining intraoperative cultures of allograft bone just before use in orthopedic procedures is standard practice in many centres; however, the association between positive cultures and subsequent surgical infections is unknown. Our study had 3 goals: to determine the prevalence of positive intraoperative allograft culture and subsequent infection; to determine if, in cases of subsequent infection, organisms isolated at reoperation were the same as those cultured from the allograft at the time of the index procedure; and to assess the costs associated with performing intraoperative allograft cultures. In this retrospective case series, we obtained data on patients receiving allograft bone between 2009 and 2012. Patients receiving allograft with positive cultures were reviewed to identify cases of significant infection. Organisms isolated at reoperation were compared with the allograft culture taken at the time of implantation, and we performed a cost assessment. Of the 996 allograft bone grafts used, 43 (4.3%) had positive intraoperative cultures and significant postoperative infections developed in 2, requiring reoperation. Antibiotics based on culture results were prescribed in 24% of cases. Organisms cultured at the time of reoperation differed from those isolated initially. The cost of performing 996 allograft cultures was $169 320. This series suggests that rates of positive intraoperative bone allograft culture are low, and subsequent infection is rare. In cases of postoperative infection, primary allograft culture and secondary tissue cultures isolated different organisms. Costs associated with performing cultures are high. Eliminating initial culture testing could save $42 500 per year in our health region.

Can Skin Allograft Occasionally Act as a Permanent Coverage in Deep Burns? A Pilot Study 

PubMed Central

Rezaei, Ezzatollah; Beiraghi-Toosi, Arash; Ahmadabadi, Ali; Tavousi, Seyed Hassan; Alipour Tabrizi, Arash; Fotuhi, Kazem; Jabbari Nooghabi, Mehdi; Manafi, Amir; Ahmadi Moghadam, Shokoofeh

2017-01-01

BACKGROUND Skin allograft is the gold standard of wound coverage in patients with extensive burns; however, it is considered as a temporary wound coverage and rejection of the skin allograft is considered inevitable. In our study, skin allograft as a permanent coverage in deep burns is evaluated. METHODS Skin allograft survival was assessed in 38 patients from March 2009 to March 2014, retrospectively. Because of the lack of tissue specimen from the skin donors, patients with long skin allograft survival in whom the gender of donor and recipient of allograft was the same were excluded. Seven cases with skin allograft longevity and opposite gender in donor and recipient were finally enrolled. A polymerase chain reaction (PCR) test on the biopsy specimen from recipients and donors were undertaken. RESULTS PCR on the biopsy specimen from recipients confirmed those specimens belong to the donors. All patients received allograft from the opposite sex. Two (28.57%) patients received allograft from their first-degree blood relatives, and in one (14.29%) case, the allograft was harvested from an alive individual with no blood relation. The rest were harvested from multiorgan donors. In eight months of follow up, no clinical evidence of graft rejection was noted. CONCLUSION Long term persistence of skin allograft in patients is worthy of more attention. Further studies An increase in knowledge of factors influencing this longevity could realize the dream of burn surgeons to achieve a permanent coverage other than autograft for major burn patients. PMID:28289620

Can Skin Allograft Occasionally Act as a Permanent Coverage in Deep Burns? A Pilot Study.

PubMed

Rezaei, Ezzatollah; Beiraghi-Toosi, Arash; Ahmadabadi, Ali; Tavousi, Seyed Hassan; Alipour Tabrizi, Arash; Fotuhi, Kazem; Jabbari Nooghabi, Mehdi; Manafi, Amir; Ahmadi Moghadam, Shokoofeh

2017-01-01

Skin allograft is the gold standard of wound coverage in patients with extensive burns; however, it is considered as a temporary wound coverage and rejection of the skin allograft is considered inevitable. In our study, skin allograft as a permanent coverage in deep burns is evaluated. Skin allograft survival was assessed in 38 patients from March 2009 to March 2014, retrospectively. Because of the lack of tissue specimen from the skin donors, patients with long skin allograft survival in whom the gender of donor and recipient of allograft was the same were excluded. Seven cases with skin allograft longevity and opposite gender in donor and recipient were finally enrolled. A polymerase chain reaction (PCR) test on the biopsy specimen from recipients and donors were undertaken. PCR on the biopsy specimen from recipients confirmed those specimens belong to the donors. All patients received allograft from the opposite sex. Two (28.57%) patients received allograft from their first-degree blood relatives, and in one (14.29%) case, the allograft was harvested from an alive individual with no blood relation. The rest were harvested from multiorgan donors. In eight months of follow up, no clinical evidence of graft rejection was noted. Long term persistence of skin allograft in patients is worthy of more attention. Further studies An increase in knowledge of factors influencing this longevity could realize the dream of burn surgeons to achieve a permanent coverage other than autograft for major burn patients.

Chronic symptoms and pulmonary dysfunction in post-tuberculosis Brazilian patients.

PubMed

Nihues, Simone de Sousa Elias; Mancuzo, Eliane Viana; Sulmonetti, Nara; Sacchi, Flávia Patussi Correia; Viana, Vanessa de Souza; Netto, Eduardo Martins; Miranda, Silvana Spindola; Croda, Julio

2015-01-01

Questionnaire and spirometry were applied to post-tuberculosis indigenous and non-indigenous individuals from Dourados, Brazil, to investigate the prevalence of chronic respiratory symptoms and pulmonary dysfunction. This was a cross-sectional study in cured tuberculosis individuals as reported in the National System on Reportable Diseases (SINAN) from 2002 to 2012. One hundred and twenty individuals were included in the study and the prevalence of chronic respiratory symptoms was 45% (95% CI, 34-59%). Respiratory symptoms included cough (28%), sputum (23%), wheezing (22%) and dyspnea (8%). These symptoms were associated with alcoholism, AOR: 3.1 (1.2-8.4); less than 4 years of schooling, AOR: 5.0 (1.4-17.7); and previous pulmonary diseases, AOR: 5.4 (1.7-17.3). Forty-one percent (95% CI, 29-56) had pulmonary disorders, of which the most prevalent were obstructive disorders (49%), followed by obstructive disorder with reduced forced vital capacity disorders (46%) and restrictive disorders (5%). The lifestyle difference could not explain differences in chronic symptoms and/or the prevalence of pulmonary dysfunction. The high prevalence of chronic respiratory symptoms and pulmonary dysfunction in post-tuberculosis patients indicates a need for further interventions to reduce social vulnerability of patients successfully treated for tuberculosis. Copyright © 2015 Elsevier Editora Ltda. All rights reserved.

Decellularized Versus Fresh-Frozen Allografts in Anterior Cruciate Ligament Reconstruction: An In Vitro Study in a Rabbit Model.

PubMed

Dong, Shikui; Huangfu, Xiaoqiao; Xie, Guoming; Zhang, Yang; Shen, Peng; Li, Xiaoxi; Qi, Jin; Zhao, Jinzhong

2015-08-01

The common fresh-frozen allografts that are used for anterior cruciate ligament (ACL) reconstructions behave slower during the remodeling process and produce weaker tendon-bone integrations than do autografts. Decellularization of allogenic tendons results in a clean and porous collagen scaffold with low antigenicity and high compatibility, which may be more suitable for ACL reconstructions. Allograft decellularization will result in a tissue structure with suitable mechanical characteristics for ACL reconstruction, thereby promoting graft remodeling and enhancing tendon-bone healing. Controlled laboratory study. Decellularized allograft tissues were prepared with a pH-modified decellularization process and evaluated for their biocompatibility and biomechanical character in vitro. Eighty New Zealand White rabbits were divided into 2 groups, with 40 in each group, to receive ACL reconstruction with either fresh-frozen (common) allografts or decellularized allografts on both knees. At 2, 4, 8, and 12 weeks postoperatively, the rabbits were euthanized for biomechanical testing, micro-computed tomography analysis, and histologic analysis. The pH-modified decellularized allograft tissues kept excellent biocompatibility and biomechanical character during the in vitro study. Biomechanical testing indicated that the decellularized allograft had significantly higher ultimate load (P = .02) and stiffness (P = .01) levels than the common allograft at 12 weeks, and there was no significant difference between the 2 groups at any other time point. The micro-CT evaluation determined significantly higher bone mineral density (P < .01) in the decellularized allograft group than that in the common allograft group at 12 weeks, but no difference between the 2 groups was observed at any other time point. Regarding bone volume/total volume, there was no difference between the 2 groups at any time point. Fibroblast ingrowths, vascular formation, and connective tissue formation in the tendon-bone interface were better in the decellularized group within 8 weeks. New bone formation was more common in the decellularized allograft group. The collagen birefringence was restored more quickly in the decellularized allograft group than in the common allograft group at all time points. The use of pH-modified decellularized allografts compared with the common allografts resulted in better cellularity, vascularity, collagen matrix remolding, new bone formation around the graft, enhanced tendon-bone healing, and higher ultimate failure load and stiffness of the graft after ACL reconstruction in the rabbit model. The pH-modified decellularized allograft may be a better graft option than the common fresh-frozen allograft for knee ligament reconstructions. © 2015 The Author(s).

Fresh-frozen Complete Extensor Mechanism Allograft versus Autograft Reconstruction in Rabbits

PubMed Central

Chen, Guanyin; Zhang, Hongtao; Ma, Qiong; Zhao, Jian; Zhang, Yinglong; Fan, Qingyu; Ma, Baoan

2016-01-01

Different clinical results have been reported in the repair of extensor mechanism disruption using fresh-frozen complete extensor mechanism (CEM) allograft, creating a need for a better understanding of fresh-frozen CME allograft reconstruction. Here, we perform histological and biomechanical analyses of fresh-frozen CEM allograft or autograft reconstruction in an in vivo rabbit model. Our histological results show complete incorporation of the quadriceps tendon into the host tissues, patellar survival and total integration of the allograft tibia, with relatively fewer osteocytes, into the host tibia. Vascularity and cellularity are reduced and delayed in the allograft but exhibit similar distributions to those in the autograft. The infrapatellar fat pad provides the main blood supply, and the lowest cellularity is observed in the patellar tendon close to the tibia in both the allograft and autograft. The biomechanical properties of the junction of quadriceps tendon and host tissues and those of the allograft patellar tendon are completely and considerably restored, respectively. Therefore, fresh-frozen CEM allograft reconstruction is viable, but the distal patellar tendon and the tibial block may be the weak links of the reconstruction. These findings provide new insight into the use of allograft in repairing disruption of the extensor mechanism. PMID:26911538

Fresh-frozen Complete Extensor Mechanism Allograft versus Autograft Reconstruction in Rabbits.

PubMed

Chen, Guanyin; Zhang, Hongtao; Ma, Qiong; Zhao, Jian; Zhang, Yinglong; Fan, Qingyu; Ma, Baoan

2016-02-25

Different clinical results have been reported in the repair of extensor mechanism disruption using fresh-frozen complete extensor mechanism (CEM) allograft, creating a need for a better understanding of fresh-frozen CME allograft reconstruction. Here, we perform histological and biomechanical analyses of fresh-frozen CEM allograft or autograft reconstruction in an in vivo rabbit model. Our histological results show complete incorporation of the quadriceps tendon into the host tissues, patellar survival and total integration of the allograft tibia, with relatively fewer osteocytes, into the host tibia. Vascularity and cellularity are reduced and delayed in the allograft but exhibit similar distributions to those in the autograft. The infrapatellar fat pad provides the main blood supply, and the lowest cellularity is observed in the patellar tendon close to the tibia in both the allograft and autograft. The biomechanical properties of the junction of quadriceps tendon and host tissues and those of the allograft patellar tendon are completely and considerably restored, respectively. Therefore, fresh-frozen CEM allograft reconstruction is viable, but the distal patellar tendon and the tibial block may be the weak links of the reconstruction. These findings provide new insight into the use of allograft in repairing disruption of the extensor mechanism.

Fresh Osteochondral Allograft Versus Autograft: Twelve-Month Results in Isolated Canine Knee Defects.

PubMed

McCarty, Eric C; Fader, Ryan R; Mitchell, Justin J; Glenn, R Edward; Potter, Hollis G; Spindler, Kurt P

2016-09-01

Osteochondral autografts and allografts have been widely used in the treatment of isolated grade 4 articular cartilage lesions of the knee. However, there is a paucity of literature regarding the basic science investigating the direct comparison between fresh osteochondral allografts to autografts. At 12 months, fresh osteochondral allografts are equal to autografts with respect to function, bony incorporation into host bone, and chondrocyte viability. Controlled laboratory study. Eight adult mongrel dogs underwent bilateral hindlimb osteochondral graft implantation in the knee after creation of an acute Outerbridge grade 4 cartilage defect. One hindlimb of each dog knee received an autograft, and the contralateral knee received an allograft. All dogs were sacrificed at 12 months. Graft analysis included gross examination, radiographs, magnetic resonance imaging (MRI), biomechanical testing, and histology. MRI demonstrated excellent bony incorporation of both autografts and allografts, except for 1 allograft that revealed partial incorporation. Histologic examination of cartilage showed intact hyaline appearance for both autografts and allografts, with fibrocartilage at the host-graft interface of both. Biomechanical testing demonstrated no significant difference between allografts and autografts (P = .76). Furthermore, no significant difference was observed between allografts and the native cartilage with biomechanical testing (P = .84). After 12 months from time of implantation, fresh osteochondral allograft tissue and autograft tissue in this study were not statistically different with respect to biomechanical properties, gross morphology, bony incorporation, or overall histologic characteristics. When compared with the previously reported 6-month incorporation rates, there was improved allograft and autograft incorporation at 12 months. With no significant differences in gross examination, radiographs, MRI, biomechanical testing, or histology in the canine model, the use of allograft tissue to treat osteochondral defects may eliminate the morbidity associated with autograft harvest. © 2016 The Author(s).

ANTIBACTERIAL ACTIVITY OF BONE ALLOGRAFTS: COMPARISON OF A NEW VANCOMYCIN-TETHERED ALLOGRAFT WITH ALLOGRAFT LOADED WITH ADSORBED VANCOMYCIN

PubMed Central

Ketonis, Constantinos; Barr, Stephanie; Shapiro, Irving M.; Parvizi, Javad; Adams, Christopher S.; Hickok, Noreen J.

2010-01-01

Bacterial contamination of bone allograft is a significant complication of orthopaedic surgery. To address this issue, we have engineered a method for covalently modifying bone allograft tissue with the antibiotic vancomycin. The goal of this investigation was to compare the biocidal properties of this new allograft material with those of vancomycin physisorbed onto graft material. The duration of antibiotic release from the vancomycin-modified allograft matrix was determined and no elution was observed. In contrast, the adsorbed antibiotic showed a peak elution at 24 h that then decreased over several days. We next used an S. aureus disk diffusion assay to measure the activity of the eluted vancomycin. Again we found that no active antibiotic was eluted from the covalently–modified allograft. Similarly, when the vancomycin-modified allograft morsel was used in the assay, no measurable elution was observed; amounts of antibiotic released from the adsorbed samples inhibited S. aureus growth for 4-7 days. Probably the most telling property of the allograft was that after two weeks, the tethered-allograft was able to resist bacterial colonization. Unlike the elution system in which vancomycin was depleted over the course of days-weeks, the antibiotic on the allograft was stably bound even after 300 days, while its biocidal activity remained undiminished for 60 days. This finding was in stark contrast to the antibiotic impregnated allograft which was readily colonized by bacteria. Finally we chose to evaluate three indicators of cell function: expression of a key transcription factor, expression of selected transcripts, and assessment of cell morphology. Since the tethered antibiotic appeared to have little or no effect on any of these activities, it was concluded that the stable, tethered antibiotic prevented bacterial infection while not modifying bone cell function. PMID:21035576

Radioprotection provides functional mechanics but delays healing of irradiated tendon allografts after ACL reconstruction in sheep.

PubMed

Seto, Aaron U; Culp, Brian M; Gatt, Charles J; Dunn, Michael

2013-12-01

Successful protection of tissue properties against ionizing radiation effects could allow its use for terminal sterilization of musculoskeletal allografts. In this study we functionally evaluate Achilles tendon allografts processed with a previously developed radioprotective treatment based on (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) crosslinking and free radical scavenging using ascorbate and riboflavin, for ovine anterior cruciate ligament reconstruction. Arthroscopic anterior cruciate ligament (ACL) reconstruction was performed using double looped allografts, while comparing radioprotected irradiated and fresh frozen allografts after 12 and 24 weeks post-implantation, and to control irradiated grafts after 12 weeks. Radioprotection was successful at preserving early subfailure mechanical properties comparable to fresh frozen allografts. Twelve week graft stiffness and anterior-tibial (A-T) translation for radioprotected and fresh frozen allografts were comparable at 30 % of native stiffness, and 4.6 and 5 times native A-T translation, respectively. Fresh frozen allograft possessed the greatest 24 week peak load at 840 N and stiffness at 177 N/mm. Histological evidence suggested a delay in tendon to bone healing for radioprotected allografts, which was reflected in mechanical properties. There was no evidence that radioprotective treatment inhibited intra-articular graft healing. This specific radioprotective method cannot be recommended for ACL reconstruction allografts, and data suggest that future efforts to improve allograft sterilization procedures should focus on modifying or eliminating the pre-crosslinking procedure.

Ankle bipolar fresh osteochondral allograft survivorship and integration: transplanted tissue genetic typing and phenotypic characteristics.

PubMed

Neri, Simona; Vannini, Francesca; Desando, Giovanna; Grigolo, Brunella; Ruffilli, Alberto; Buda, Roberto; Facchini, Andrea; Giannini, Sandro

2013-10-16

Fresh osteochondral allografts represent a treatment option for early ankle posttraumatic arthritis. Transplanted cartilage survivorship, integration, and colonization by recipient cells have not been fully investigated. The aim of this study was to evaluate the ability of recipient cells to colonize the allograft cartilage and to assess allograft cell phenotype. Seventeen ankle allograft samples were studied. Retrieved allograft cartilage DNA from fifteen cases was compared with recipient and donor constitutional DNA by genotyping. In addition, gene expression was evaluated on six allograft cartilage samples by means of real-time reverse transcription-polymerase chain reaction. Histology and immunohistochemistry were performed to support molecular observations. Of fifteen genotyped allografts, ten completely matched to the host, three matched to the donor, and two showed a mixed profile. Gene expression analysis showed that grafted cartilage expressed cartilage-specific markers. The rare persistence of donor cells and the prevailing presence of host DNA in retrieved ankle allografts suggest the ingrowth of recipient cells into the allograft cartilage, presumably migrating from the subchondral bone, in accordance with morphological findings. The expression of chondrogenic markers in some of the samples argues for the acquisition of a chondrocyte-like phenotype by these cells. To our knowledge, this is the first report describing the colonization of ankle allograft cartilage by host cells showing the acquisition of a chondrocyte-like phenotype.

Neurologic manifestations of chronic methamphetamine abuse

PubMed Central

Rusyniak, Daniel E.

2011-01-01

Summary Chronic methamphetamine abuse has devastating effects on the central nervous system. The degree to which addicts will tolerate the dysfunction in the way they think, feel, move, and even look, is a powerful testimony to the addictive properties of this drug. While the mechanisms behind these disorders are complex, at their heart they involve the recurring increase in the concentrations of central monoamines with subsequent dysfunction in dopaminergic neurotransmission. The mainstay of treatment for the problems associated with chronic methamphetamine abuse is abstinence. However, by recognizing the manifestations of chronic abuse, clinicians will be better able to help their patients get treatment for their addiction and to deal with the neurologic complications related to chronic abuse. PMID:21803215

Cyclosporine A and azathioprine are equipotent in chronic kidney allograft rejection.

PubMed

Hamar, P; Liu, S; Viklický, O; Szabó, A; Múller, V; Heemann, U

2000-04-15

Chronic rejection is the major cause of graft loss after kidney transplantation. Various immunosuppressive protocols have been used to ameliorate this process. We investigated whether cyclosporin A- (CyA) or azathioprine- (Aza) based immunosuppression is better able to slow the progression of chronic rejection. Fisher kidneys were transplanted into bilaterally nephrectomized Lewis rats. Recipients received CyA (1.5 mg/kg/day, s.c.) for 10 days, and were treated from day 11 with either CyA (1.5 mg/kg)+pred (0.15 mg/kg) (C+P),Aza (2 mg/kg)+pred (A+P), vehicle+pred (P), or vehicle alone (controls) (n = 8/group). Proteinuria was regularly assessed and grafts were harvested for morphological, immunohistological, and molecular biological analysis at week 24. By week 12 proteinuria had increased to significant levels. At week 24, proteinuria was significantly lower and creatinine clearance was significantly higher in C+P and A+P, than in P or controls. Morphological analysis supported these functional results: at week 24, glomerulopathy, tubular atrophy and intimal proliferation (as assessed according to the BANFF score) were less pronounced in C+P and A+P, as compared with P or controls. These morphological parameters were accompanied by a reduced infiltration of ED-1+ macrophages and CD-5+ T lymphocytes. In P or controls the synthesis of IL-2Ralpha mRNA was markedly elevated at this time. In parallel to the reduced cellular infiltration, IL-2Ralpha mRNA expression was markedly inhibited, both, in C+P and A+P. There were no significant differences between C+P and A+P regarding the parameters studied. In conclusion, both C+P and A+P reduced the infiltration of activated T lymphocytes, and the pace of chronic kidney allograft rejection. The outcome of C+P and A+P based therapy did not differ significantly.

Somatic dysfunction and its association with chronic low back pain, back-specific functioning, and general health: results from the OSTEOPATHIC Trial.

PubMed

Licciardone, John C; Kearns, Cathleen M

2012-07-01

Somatic dysfunction is diagnosed by the presence of any of 4 TART criteria: tissue texture abnormality, asymmetry, restriction of motion, or tenderness. To measure the prevalence of somatic dysfunction in patients with chronic low back pain (LBP) and to study the associations of somatic dysfunction with LBP severity, back-specific functioning, and general health. Cross-sectional study nested within a randomized controlled trial. University-based study in Dallas-Fort Worth, Texas. A total of 455 adult research patients with non-specific chronic LBP. Somatic dysfunction in the lumbar, sacrum/pelvis, and pelvis/innominate regions, including key lesions representing severe somatic dysfunction. A 10-cm visual analog scale (VAS), the Roland-Morris Disability Questionnaire (RMDQ), and the Medical Outcomes Study Short Form-36 Health Survey (SF-36) were used to measure LBP severity, back-specific functioning, and general health, respectively. Severe somatic dysfunction was most prevalent in the lumbar (225 [49%]), sacrum/pelvis (129 [28%]), and pelvis/innominate (48 [11%]) regions. Only 30 patients (7%) had no somatic dysfunction in the lumbar, sacrum/pelvis, or pelvis/innominate regions. There were 4 statistically significant pairwise correlations for severe somatic dysfunction: thoracic (T) 10-12 with ribs; T10-12 with lumbar; lumbar with sacrum/pelvis; and sacrum/pelvis with pelvis/innominate. Having a key lesion in the lumbar region (ρ=0.80) or sacrum/pelvis region (ρ=0.71) was strongly correlated with the overall number of key lesions. There were no consistent demographic or clinical predictors of somatic dysfunction. The presence (vs absence) of severe somatic dysfunction in the lumbar region was associated with greater LBP severity (median VAS score, 4.7 vs 3.8, respectively; P=.003) and greater back-specific disability (median RMDQ score, 6 vs 4, respectively; P=.01). The presence (vs absence) of severe somatic dysfunction in the sacrum/pelvis region was associated with greater back-specific disability (median RMDQ score, 6 vs 5, respectively; P=.02) and poorer general health (median SF-36 score, 62 vs 72, respectively; P=.002). An increasing number of key lesions was associated with back-specific disability (P=.009) and poorer general health (P=.02). The present study demonstrates that somatic dysfunction, particularly in the lumbar and sacrum/pelvis regions, is common in patients with chronic LBP. Forthcoming extensions of the OSTEOPATHIC Trial will assess the efficacy of OMT according to baseline levels of somatic dysfunction.

PTH promotes allograft integration in a calvarial bone defect.

PubMed

Sheyn, Dmitriy; Cohn Yakubovich, Doron; Kallai, Ilan; Su, Susan; Da, Xiaoyu; Pelled, Gadi; Tawackoli, Wafa; Cook-Weins, Galen; Schwarz, Edward M; Gazit, Dan; Gazit, Zulma

2013-12-02

Allografts may be useful in craniofacial bone repair, although they often fail to integrate with the host bone. We hypothesized that intermittent administration of parathyroid hormone (PTH) would enhance mesenchymal stem cell recruitment and differentiation, resulting in allograft osseointegration in cranial membranous bones. Calvarial bone defects were created in transgenic mice, in which luciferase is expressed under the control of the osteocalcin promoter. The mice were given implants of allografts with or without daily PTH treatment. Bioluminescence imaging (BLI) was performed to monitor host osteprogenitor differentiation at the implantation site. Bone formation was evaluated with the aid of fluorescence imaging (FLI) and microcomputed tomography (μCT) as well as histological analyses. Reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate the expression of key osteogenic and angiogenic genes. Osteoprogenitor differentiation, as detected by BLI, in mice treated with an allograft implant and PTH was over 2-fold higher than those in mice treated with an allograft implant without PTH. FLI also demonstrated that the bone mineralization process in PTH-treated allografts was significantly higher than that in untreated allografts. The μCT scans revealed a significant increase in bone formation in allograft + PTH treated mice comparing to allograft + PBS treated mice. The osteogenic genes osteocalcin (Oc/Bglap) and integrin binding sialoprotein (Ibsp) were upregulated in the allograft + PTH treated animals. In summary, PTH treatment enhances osteoprogenitor differentiation and augments bone formation around structural allografts. The precise mechanism is not clear, but we show that infiltration pattern of mast cells, associated with the formation of fibrotic tissue, in the defect site is significantly affected by the PTH treatment.

Intraoperative culture positive allograft bone and subsequent postoperative infections: a retrospective review

PubMed Central

Sims, Laura; Kulyk, Paul; Woo, Allan

2017-01-01

Background Obtaining intraoperative cultures of allograft bone just before use in orthopedic procedures is standard practice in many centres; however, the association between positive cultures and subsequent surgical infections is unknown. Our study had 3 goals: to determine the prevalence of positive intraoperative allograft culture and subsequent infection; to determine if, in cases of subsequent infection, organisms isolated at reoperation were the same as those cultured from the allograft at the time of the index procedure; and to assess the costs associated with performing intraoperative allograft cultures. Methods In this retrospective case series, we obtained data on patients receiving allograft bone between 2009 and 2012. Patients receiving allograft with positive cultures were reviewed to identify cases of significant infection. Organisms isolated at reoperation were compared with the allograft culture taken at the time of implantation, and we performed a cost assessment. Results Of the 996 allograft bone grafts used, 43 (4.3%) had positive intraoperative cultures and significant postoperative infections developed in 2, requiring reoperation. Antibiotics based on culture results were prescribed in 24% of cases. Organisms cultured at the time of reoperation differed from those isolated initially. The cost of performing 996 allograft cultures was $169 320. Conclusion This series suggests that rates of positive intraoperative bone allograft culture are low, and subsequent infection is rare. In cases of postoperative infection, primary allograft culture and secondary tissue cultures isolated different organisms. Costs associated with performing cultures are high. Eliminating initial culture testing could save $42 500 per year in our health region. PMID:28234217

Chronic aerobic exercise training attenuates aortic stiffening and endothelial dysfunction through preserving aortic mitochondrial function in aged rats.

PubMed

Gu, Qi; Wang, Bing; Zhang, Xiao-Feng; Ma, Yan-Ping; Liu, Jian-Dong; Wang, Xiao-Ze

2014-08-01

Aging leads to large vessel arterial stiffening and endothelial dysfunction, which are important determinants of cardiovascular risk. The aim of present work was to assess the effects of chronic aerobic exercise training on aortic stiffening and endothelial dysfunction in aged rats and investigate the underlying mechanism about mitochondrial function. Chronic aerobic exercise training attenuated aortic stiffening with age marked by reduced collagen concentration, increased elastin concentration and reduced pulse wave velocity (PWV), and prevented aging-related endothelial dysfunction marked by improved endothelium-mediated vascular relaxation of aortas in response to acetylcholine. Chronic aerobic exercise training abated oxidative stress and nitrosative stress in aortas of aged rats. More importantly, we found that chronic aerobic exercise training in old rats preserved aortic mitochondrial function marked by reduced reactive oxygen species (ROS) formation and mitochondrial swelling, increased ATP formation and mitochondrial DNA content, and restored activities of complexes I and III and electron-coupling capacity between complexes I and III and between complexes II and III. In addition, it was found that chronic aerobic exercise training in old rats enhanced protein expression of uncoupling protein 2 (UCP-2), peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), manganese superoxide dismutase (Mn-SOD), aldehyde dehydrogenase 2 (ALDH-2), prohibitin (PHB) and AMP-activated kinase (AMPK) phosphorylation in aortas. In conclusion, chronic aerobic exercise training preserved mitochondrial function in aortas, which, at least in part, explained the aorta-protecting effects of exercise training in aging. Copyright © 2014 Elsevier Inc. All rights reserved.

Allografts with autogenous platelet-rich plasma for tibial defect reconstruction: a rabbit study.

PubMed

Nather, Aziz; Wong, Keng Lin; David, Vikram; Pereira, Barry P

2012-12-01

To evaluate the effect of autogenous platelet-rich plasma (PRP) for fresh-frozen allografts in tibial defect reconstruction in rabbits. 40 adult New Zealand white rabbits underwent tibial defect reconstruction with autografts (n=12), allografts without PRP (n=12), or allografts with PRP (n=12) and were observed for 12, 16, and 24 weeks (4 for each period). Tibias of the remaining 4 rabbits were used as donor allografts, and the remaining allografts were procured from recipient rabbits. A 1.5- cm cortical segment of the tibia was osteotomised, and then fixed with a 9-hole mini-compression plate and 2 cerclage wires. Allografts were stripped off the periosteum and soft tissues and medullary contents, and then stored in a freezer at -80 ºC. All allografts were deep frozen for at least 4 weeks before transplantation. 7 ml of whole blood was drawn to prepare 1 ml of PRP. The PRP was then mixed with 1.0 ml of human thrombin to form a platelet gel. The PRP gel was then packed into the medullary canal of the allograft and applied on the cortical surface before tibial defect reconstruction. Rabbits were sacrificed at 12, 16, and 24 weeks. The specimens were assessed for bone union at host-graft junctions and for bone resorption, new bone formation, callus encasement, and viable osteocyte counts. There were 4 specimens in each group at each observation period. Osteoid bridging the gap at host-graft junctions was noted in all specimens in the autograft and allograft-with-PRP groups at week 12 and in the allograft-without-PRP group at week 24. Bone union in allografts without PRP was delayed. All indices for biological incorporation (resorption index, new bone formation index, callus encasement index, and viable osteocyte count) were significantly greater in the autograft than allograft-without-PRP groups, except for the resorption index at week 24, whereas the differences were not significant between the autograft and allograft-with-PRP groups. The differences between the 2 allograft groups were usually not significant, except for the resorption index. PRP-augmented allografts behaved similarly to autografts for tibial defect reconstruction in rabbits. PRP increased bone union and bone resorption.

Divergent Annexin A1 expression in periphery and gut is associated with systemic immune activation and impaired gut immune response during SIV infection

PubMed Central

Sena, Angela A. S.; Glavan, Tiffany; Jiang, Guochun; Sankaran-Walters, Sumathi; Grishina, Irina; Dandekar, Satya; Goulart, Luiz R.

2016-01-01

HIV-1 disease progression is paradoxically characterized by systemic chronic immune activation and gut mucosal immune dysfunction, which is not fully defined. Annexin A1 (ANXA1), an inflammation modulator, is a potential link between systemic inflammation and gut immune dysfunction during the simian immunodeficiency virus (SIV) infection. Gene expression of ANXA1 and cytokines were assessed in therapy-naïve rhesus macaques during early and chronic stages of SIV infection and compared with SIV-negative controls. ANXA1 expression was suppressed in the gut but systemically increased during early infection. Conversely, ANXA1 expression increased in both compartments during chronic infection. ANXA1 expression in peripheral blood was positively correlated with HLA-DR+CD4+ and CD8+ T-cell frequencies, and negatively associated with the expression of pro-inflammatory cytokines and CCR5. In contrast, the gut mucosa presented an anergic cytokine profile in relation to ANXA1 expression. In vitro stimulations with ANXA1 peptide resulted in decreased inflammatory response in PBMC but increased activation of gut lymphocytes. Our findings suggest that ANXA1 signaling is dysfunctional in SIV infection, and may contribute to chronic inflammation in periphery and with immune dysfunction in the gut mucosa. Thus, ANXA1 signaling may be a novel therapeutic target for the resolution of immune dysfunction in HIV infection. PMID:27484833

Minimizing tacrolimus decreases the risk of new-onset diabetes mellitus after liver transplantation.

PubMed

Song, Jiu-Lin; Gao, Wei; Zhong, Yan; Yan, Lu-Nan; Yang, Jia-Yin; Wen, Tian-Fu; Li, Bo; Wang, Wen-Tao; Wu, Hong; Xu, Ming-Qing; Chen, Zhe-Yu; Wei, Yong-Gang; Jiang, Li; Yang, Jian

2016-02-14

To investigate the impact of minimum tacrolimus (TAC) on new-onset diabetes mellitus (NODM) after liver transplantation (LT). We retrospectively analyzed the data of 973 liver transplant recipients between March 1999 and September 2014 in West China Hospital Liver Transplantation Center. Following the exclusion of ineligible recipients, 528 recipients with a TAC-dominant regimen were included in our study. We calculated and determined the mean trough concentration of TAC (cTAC) in the year of diabetes diagnosis in NODM recipients or in the last year of the follow-up in non-NODM recipients. A cutoff of mean cTAC value for predicting NODM 6 mo after LT was identified using a receptor operating characteristic curve. TAC-related complications after LT was evaluated by χ(2) test, and the overall and allograft survival was evaluated using the Kaplan-Meier method. Risk factors for NODM after LT were examined by univariate and multivariate Cox regression. Of the 528 transplant recipients, 131 (24.8%) developed NODM after 6 mo after LT, and the cumulative incidence of NODM progressively increased. The mean cTAC of NODM group recipients was significantly higher than that of recipients in the non-NODM group (7.66 ± 3.41 ng/mL vs 4.47 ± 2.22 ng/mL, P < 0.05). Furthermore, NODM group recipients had lower 1-, 5-, 10-year overall survival rates (86.7%, 71.3%, and 61.1% vs 94.7%, 86.1%, and 83.7%, P < 0.05) and allograft survival rates (92.8%, 84.6%, and 75.7% vs 96.1%, 91%, and 86.1%, P < 0.05) than the others. The best cutoff of mean cTAC for predicting NODM was 5.89 ng/mL after 6 mo after LT. Multivariate analysis showed that old age at the time of LT (> 50 years), hypertension pre-LT, and high mean cTAC (≥ 5.89 ng/mL) after 6 mo after LT were independent risk factors for developing NODM. Concurrently, recipients with a low cTAC (< 5.89 ng/mL) were less likely to become obese (21.3% vs 30.2%, P < 0.05) or to develop dyslipidemia (27.5% vs 44.8%, P <0.05), chronic kidney dysfunction (14.6% vs 22.7%, P < 0.05), and moderate to severe infection (24.7% vs 33.1%, P < 0.05) after LT than recipients in the high mean cTAC group. However, the two groups showed no significant difference in the incidence of acute and chronic rejection, hypertension, cardiovascular events and new-onset malignancy. A minimal TAC regimen can decrease the risk of long-term NODM after LT. Maintaining a cTAC value below 5.89 ng/mL after LT is safe and beneficial.

Cognitive performance of people with traumatic spinal cord injury: a cross-sectional study comparing people with subacute and chronic injuries.

PubMed

Molina, B; Segura, A; Serrano, J P; Alonso, F J; Molina, L; Pérez-Borrego, Y A; Ugarte, M I; Oliviero, A

2018-02-22

Cross-sectional study. To assess the impact of spinal cord injury (SCI) on cognitive function in individuals with subacute and chronic SCI. National Hospital for SCI patients (Spain). The present investigation was designed to determine the nature, pattern, and extent of cognitive deficits in a group of participants with subacute (n = 32) and chronic (n = 34) SCI, using a comprehensive battery of reliable and validated neuropsychological assessments to study a broad range of cognitive functions. Twenty-seven able-bodied subjects matched to the groups with SCI for age and educational level formed the control group. The neuropsychological assessment showed alterations in the domain of attention, processing speed, memory and learning, executive functions, and in recognition in participants with SCI. The prevalence of cognitive dysfunction in the chronic stage was also confirmed at the individual level. The comparison of the neuropsychological assessment between the groups with subacute and chronic SCI showed a worsening of cognitive functions in those with chronic SCI compared to the group with subacute SCI. In participants with SCI, cognitive dysfunctions are present in the subacute stage and worsen over time. From a clinical point of view, we confirmed the presence of cognitive dysfunction that may interfere with the first stage of rehabilitation which is the most intense and important. Moreover, cognitive dysfunction may be important beyond the end of the first stage of rehabilitation as it can affect an individual's quality of life and possible integration to society.

Association of N-Terminal Pro-B-Type Natriuretic Peptide with Left Ventricular Structure and Function in Chronic Kidney Disease (From the Chronic Renal Insufficiency Cohort [CRIC])

PubMed Central

Mishra, Rakesh K.; Li, Yongmei; Ricardo, Ana C.; Yang, Wei; Keane, Martin; Cuevas, Magdalena; Christenson, Robert; DeFilippi, Christopher; Chen, Jing; He, Jiang; Kallem, Radhakrishna R.; Raj, Dominic S.; Schelling, Jeffrey R.; Wright, Jackson; Go, Alan S.; Shlipak, Michael G.

2017-01-01

We evaluated the cross-sectional associations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) with cardiac structural and functional abnormalities in a cohort of chronic kidney disease (CKD) patients without clinical heart failure (HF), the Chronic Renal Insufficiency Cohort (n=3,232). Associations of NT-proBNP with echocardiographically determined left ventricular (LV) mass and LV systolic and diastolic function were evaluated by multivariable logistic and linear regression models. Reclassification of participants’ predicted risk of LV hypertrophy (LVH), systolic and diastolic dysfunction was performed using a category-free net reclassification improvement (NRI) index that compared a clinical model with and without NT-proBNP. The median (interquartile range) NT-proBNP was 126.6 pg/ml (55.5–303.7). The highest quartile of NT-proBNP was associated with nearly three-fold odds of LVH (odds ratio (OR) 2.7, 95% confidence interval (CI) 1.8–4.0) and LV systolic dysfunction (2.7, 1.7–4.5) and two-fold odds of diastolic dysfunction (2.0, 1.3–2.9) in the fully adjusted models. When evaluated alone as a screening test, NT-proBNP functioned modestly for the detection of LVH (area under the curve, AUC 0.66) and LV systolic dysfunction (AUC 0.62), and poorly for the detection of diastolic dysfunction (AUC 0.51). However, when added to the clinical model, NT-proBNP significantly reclassified participants’ likelihood of having LVH (NRI 0.14, 95% CI 0.13–0.15; p<0.001) and LV systolic dysfunction (0.28, 0.27–0.30; p<0.001), but not diastolic dysfunction (0.10, 0.10–0.11; p=0.07). In conclusion, in this large CKD cohort without HF, NT-proBNP had strong associations with prevalent LVH and LV systolic dysfunction. PMID:23178053

Polyglutamate directed coupling of bioactive peptides for the delivery of osteoinductive signals on allograft bone

PubMed Central

Culpepper, Bonnie K.; Bonvallet, Paul P.; Reddy, Michael S.; Ponnazhagan, Selvarangan; Bellis, Susan L.

2012-01-01

Allograft bone is commonly used as an alternative to autograft, however allograft lacks many osteoinductive factors present in autologous bone due to processing. In this study, we investigated a method to reconstitute allograft with osteoregenerative factors. Specifically, an osteoinductive peptide from collagen I, DGEA, was engineered to express a heptaglutamate (E7) domain, which binds the hydroxyapatite within bone mineral. Addition of E7 to DGEA resulted in 9× greater peptide loading on allograft, and significantly greater retention after a 5-day interval with extensive washing. When factoring together greater initial loading and retention, the E7 domain directed a 45-fold enhancement of peptide density on the allograft surface. Peptide-coated allograft was also implanted subcutaneously into rats and it was found that E7DGEA was retained in vivo for at least 3 months. Interestingly, E7DGEA peptides injected intravenously accumulated within bone tissue, implicating a potential role for E7 domains in drug delivery to bone. Finally, we determined that, as with DGEA, the E7 modification enhanced coupling of a bioactive BMP2-derived peptide on allograft. These results suggest that E7 domains are useful for coupling many types of bone-regenerative molecules to the surface of allograft to reintroduce osteoinductive signals and potentially advance allograft treatments. PMID:23182349

Mitochondrial Dysfunction and Oxidative Stress Promote Apoptotic Cell Death in the Striatum via Cytochrome c/Caspase-3 Signaling Cascade Following Chronic Rotenone Intoxication in Rats

PubMed Central

Lin, Tsu-Kung; Cheng, Ching-Hsiao; Chen, Shang-Der; Liou, Chia-Wei; Huang, Chi-Ren; Chuang, Yao-Chung

2012-01-01

Parkinson’s disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration. Evidence suggests that mitochondrial dysfunction may be linked to PD through a variety of different pathways, including free-radical generation and dysfunction of the mitochondrial Complex I activity. In Lewis rats, chronic systemic administration of a specific mitochondrial Complex I inhibitor, rotenone (3 mg/kg/day) produced parkinsonism-like symptoms. Increased oxidized proteins and peroxynitrite, and mitochondrial or cytosol translocation of Bim, Bax or cytochrome c in the striatum was observed after 2–4 weeks of rotenone infusion. After 28 days of systemic rotenone exposure, imunohistochemical staining for tyrosine hydroxylase indicated nigrostriatal dopaminergic neuronal cell degeneration. Characteristic histochemical (TUNEL or activated caspase-3 staining) or ultrastructural (electron microscopy) features of apoptotic cell death were present in the striatal neuronal cell after chronic rotenone intoxication. We conclude that chronic rotenone intoxication may enhance oxidative and nitrosative stress that induces mitochondrial dysfunction and ultrastructural damage, resulting in translocation of Bim and Bax from cytosol to mitochondria that contributes to apoptotic cell death in the striatum via cytochrome c/caspase-3 signaling cascade. PMID:22942730

The Prevalence of Olfactory Dysfunction in Chronic Rhinosinusitis

PubMed Central

Kohli, Preeti; Naik, Akash N.; Harruff, E. Emily; Nguyen, Shaun A.; Schlosser, Rodney J.; Soler, Zachary M.

2016-01-01

Objective Many studies have reported that olfactory dysfunction frequently occurs in chronic rhinosinusitis (CRS) populations; however, the prevalence and degree of olfactory loss has not been systematically studied. The aims of this study are to use combined data to report the prevalence of olfactory dysfunction and to calculate weighted averages of olfactory test scores in CRS patients. Data Sources A search was conducted in PubMed and Scopus, following the methods of Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Review Methods Studies reporting the prevalence of olfactory dysfunction using objective measures or olfactory test scores using validated scales were included. Results A total of 47 articles were included in systematic review and 35 in the pooled data analysis. The prevalence of olfactory dysfunction in chronic rhinosinusitis was found to be 30.0% using the Brief Smell Identification Test, 67.0% using the 40-item Smell Identification Test, and 78.2% using the total Sniffin’ Sticks score. Weighted averages ± standard deviation of olfactory test scores were 25.96±7.11 using the 40-item Smell Identification Test, 8.60±2.81 using the Brief Smell Identification Test, 21.96±8.88 using total Sniffin’ sticks score, 5.65±1.51 using Sniffin’ Sticks threshold, 9.21±4.63 using Sniffin’ Sticks discrimination, 9.47±3.92 using Sniffin’ Sticks Identification, and 8.90±5.14 using the questionnaire for olfactory disorders-negative statements. Conclusion In chronic rhinosinusitis populations, a significant percentage of patients experience olfactory dysfunction and mean olfactory scores are within the dysosmic range. PMID:27873345

Interleukin (IL)-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts1

PubMed Central

Iida, Shoichi; Tsuda, Hidetoshi; Tanaka, Toshiaki; Kish, Danielle D.; Abe, Toyofumi; Su, Charles A.; Abe, Ryo; Tanabe, Kazunari; Valujskikh, Anna; Baldwin, William M.; Fairchild, Robert L.

2016-01-01

Reperfusion of organ allografts induces a potent inflammatory response that directs rapid memory T cell, neutrophil and macrophage graft infiltration and their activation to express functions mediating graft tissue injury. The role of cardiac allograft IL-1 receptor signaling in this early inflammation and the downstream primary alloimmune response was investigated. When compared to complete MHC-mismatched wild type cardiac allografts, IL-1R−/− allografts had marked decreases in endogenous memory CD8 T cell and neutrophil infiltration and expression of proinflammatory mediators at early times after transplant whereas endogenous memory CD4 T cell and macrophage infiltration was not decreased. IL-1R−/− allograft recipients also had marked decreases in de novo donor-reactive CD8, but not CD4, T cell development to IFN-γ-producing cells. CD8 T cell-mediated rejection of IL-1R−/− cardiac allografts took 3 weeks longer than wild type allografts. Cardiac allografts from reciprocal bone marrow reconstituted IL-1R−/−/wild type chimeric donors indicated that IL-1R signaling on graft non-hematopoietic-derived, but not bone marrow-derived, cells is required for the potent donor-reactive memory and primary CD8 T cell alloimmune responses observed in response to wild type allografts. These studies implicate IL-1R-mediated signals by allograft parenchymal cells in generating the stimuli provoking development and elicitation of optimal alloimmune responses to the grafts. PMID:26856697

Revision of anterior cruciate ligament reconstruction with allografts in patients younger than 40 years old: a 2 to 4 year results.

PubMed

Pascual-Garrido, Cecilia; Carbo, L; Makino, A

2014-05-01

The purpose of this study is first to report the outcomes, at 4 years follow-up, in revision ACL surgery using allografts in patients younger than 40 years old, and then compared soft tissue allografts to bone tendon allografts. This retrospective study included 47 patients who underwent ACL revision surgery with fresh-frozen allografts. Patellar tendon allograft or tibialis anterior allograft was used. Twenty-seven patients undergoing ACL revision with patellar tendon allograft were compared retrospectively with twenty-two patients undergoing the same procedure with soft tissue tibialis anterior allograft. Lysholm, IKDC, and KT-1000 values were obtained preoperatively and postoperatively. The average patient follow-up was 4.6 years (±2.5). The mean age at time of the revision was 34 years old (±6.3). Overall, patients reported the overall condition of their knee as excellent or good in 85% of the patients (10 excellent, 33 good). Based on their experience, 85% would have the surgery again if they had the same problem in the other knee. Both subgroups experienced significant improvement in Lysholm, IKDC, and KT-1000 values, with no difference found between groups at final follow-up. Revision ACL with allografts has excellent and good results in 85% of patients younger than 40 years old. No statistical difference was seen between soft tissue (tibialis anterior) and patellar tendon allograft. IV.

Inhibition of Experimental Liver Cirrhosis in Mice by Telomerase Gene Delivery

NASA Astrophysics Data System (ADS)

Rudolph, Karl Lenhard; Chang, Sandy; Millard, Melissa; Schreiber-Agus, Nicole; DePinho, Ronald A.

2000-02-01

Accelerated telomere loss has been proposed to be a factor leading to end-stage organ failure in chronic diseases of high cellular turnover such as liver cirrhosis. To test this hypothesis directly, telomerase-deficient mice, null for the essential telomerase RNA (mTR) gene, were subjected to genetic, surgical, and chemical ablation of the liver. Telomere dysfunction was associated with defects in liver regeneration and accelerated the development of liver cirrhosis in response to chronic liver injury. Adenoviral delivery of mTR into the livers of mTR-/- mice with short dysfunctional telomeres restored telomerase activity and telomere function, alleviated cirrhotic pathology, and improved liver function. These studies indicate that telomere dysfunction contributes to chronic diseases of continual cellular loss-replacement and encourage the evaluation of ``telomerase therapy'' for such diseases.

PTH promotes allograft integration in a calvarial bone defect

PubMed Central

Sheyn, Dmitriy; Yakubovich, Doron Cohn; Kallai, Ilan; Su, Susan; Da, Xiaoyu; Pelled, Gadi; Tawackoli, Wafa; Cook-Weins, Galen; Schwarz, Edward M.; Gazit, Dan; Gazit, Zulma

2013-01-01

Allografts may be useful in craniofacial bone repair, although they often fail to integrate with the host bone. We hypothesized that intermittent administration of parathyroid hormone (PTH) would enhance mesenchymal stem cell recruitment and differentiation, resulting in allograft osseointegration in cranial membranous bones. Calvarial bone defects were created in transgenic mice, in which luciferase is expressed under the control of the osteocalcin promoter. The mice were given implants of allografts with or without daily PTH treatment. Bioluminescence imaging (BLI) was performed to monitor host osteprogenitor differentiation at the implantation site. Bone formation was evaluated with the aid of fluorescence imaging (FLI) and micro–computed tomography (μCT) as well as histological analyses. Reverse transcription polymerase chain reaction (RT-PCR) was performed to evaluate the expression of key osteogenic and angiogenic genes. Osteoprogenitor differentiation, as detected by BLI, in mice treated with an allograft implant and PTH was over 2-fold higher than those in mice treated with an allograft implant without PTH. FLI also demonstrated that the bone mineralization process in PTH-treated allografts was significantly higher than that in untreated allografts. The μCT scans revealed a significant increase in bone formation in Allograft + PTH–treated mice comparing to Allograft + PBS treated mice. The osteogenic genes osteocalcin (Oc/Bglap) and integrin binding sialoprotein (Ibsp) were upregulated in the Allograft + PTH–treated animals. In summary, PTH treatment enhances osteoprogenitor differentiation and augments bone formation around structural allografts. The precise mechanism is not clear, but we show that infiltration pattern of mast cells, associated with the formation of fibrotic tissue, in the defect site is significantly affected by the PTH treatment. PMID:24131143

Tanshinol suppresses cardiac allograft rejection in a murine model.

PubMed

Lu, Chuanjian; Zeng, Yu-Qun; Liu, Huazhen; Xie, Qingfeng; Xu, Shengmei; Tu, Kangsheng; Dou, Changwei; Dai, Zhenhua

2017-02-01

Achieving long-term cardiac allograft survival without continuous immunosuppression is highly desired in organ transplantation. Studies have shown that Salvia miltiorrhiza, an herb also known as danshen, improves microcirculation and is highly effective in treating coronary heart disease. Our objective is to determine whether tanshinol, an ingredient of danshen, improves cardiac allograft survival. Fully vascularized heterotopic heart transplantation was performed using BALB/c mice as donors and C57BL/6 mice as recipients, which were then treated with tanshinol and rapamycin. CD4 + FoxP3 + regulatory T cells (Tregs) were quantified by flow analyses, whereas CCL22 was measured by real-time polymerase chain reaction and Western blotting. We found that tanshinol significantly delayed cardiac allograft rejection. It promoted long-term allograft survival induced by rapamycin, a mammalian target-of-rapamycin (mTOR) inhibitor. Tanshinol increased CD4 + FoxP3 + Treg numbers in cardiac allografts, but not spleens and lymph nodes, of recipient mice by enhancing chemokine CCL22 expression in cardiac allografts, especially cardiac dendritic cells. In contrast, rapamycin increased Treg numbers in both lymphoid organs and allografts, suggesting that it generally expands Tregs. Moreover, Tregs induced by rapamycin plus tanshinol were more potent in suppressing T-cell proliferation in vitro than those from untreated recipients. Neutralizing CCL22 hindered CD4 + FoxP3 + Treg migration to cardiac allografts and reversed long-term allograft survival induced by tanshinol plus rapamycin. Tanshinol suppresses cardiac allograft rejection by recruiting CD4 + FoxP3 + Tregs to the graft, whereas rapamycin does so via expanding the Tregs. Thus, tanshinol cooperates with rapamycin to further extend cardiac allograft survival. Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Tendon allograft sterilized by peracetic acid/ethanol combined with gamma irradiation.

PubMed

Zhou, Mo; Zhang, Naili; Liu, Xiaoming; Li, Youchen; Zhang, Yumin; Wang, Xusheng; Li, Baoming; Li, Baoxing

2014-07-01

Research and clinical applications have demonstrated that the effects of tendon allografts are comparable to those of autografts when reconstructing injured tendons or ligaments, but allograft safety remains problematic. Sterilisation could eliminate or decrease the possibility of disease transmission, but current methods seldom achieve satisfactory sterilisation without affecting the mechanical properties of the tendon. Peracetic acid-ethanol in combination with low-dose gamma irradiation (PE-R) would inactivate potential deleterious microorganisms without affecting mechanical and biocompatible properties of tendon allograft. Controlled laboratory design. HIV, PPV, PRV and BVDV inactivation was evaluated. After verifying viral inactivation, the treated tendon allografts were characterised by optical microscopy, scanning electron microscopy and tensile testing, and the cytocompatibility was assessed with an MTT assay and by subcutaneous implantation. Effective and efficient inactivation of HIV, PPV, PRV and BVDV was observed. Histological structure and ultrastructure were unchanged in the treated tendon allograft, which also exhibited comparable biomechanical properties and good biocompatibility. The preliminary results confirmed our hypothesis and demonstrated that the PE-R tendon allograft has significant potential as an alternative to ligament/tendon reconstruction. Tendon allografts have been extensively used in ligament reconstruction and tendon repair. However, current sterilisation methods have various shortcomings, so PE-R has been proposed. This study suggests that PE-R tendon allograft has great potential as an alternative for ligament/tendon reconstruction. Sterilisation has been a great concern for tendon allografts. However, most sterilisation methods cannot inactivate viruses and bacteria without impairing the mechanical properties of the tendon allograft. Peracetic acid/ethanol with gamma irradiation can effectively inactivate viruses and bacteria. Meanwhile, tendon allografts sterilised by this method maintain their physiological tendon structure, biomechanical integrity and good compatibility.

In vitro comparison of the efficacy of TGF-β1 and PDGF-BB in combination with freeze-dried bone allografts for induction of osteogenic differentiation in MG-63 osteoblast-like cells.

PubMed

Vahabi, Surena; Torshabi, Maryam; Esmaeil Nejad, Azadeh

2016-12-01

Predictable regeneration of alveolar bone defects has always been a challenge in implant dentistry. Bone allografts are widely used bone substitutes with controversial osteoinductive activity. This in vitro study aimed to assess the osteogenic potential of some commercially available freeze-dried bone allografts supplemented with human recombinant platelet-derived growth factor-BB and transforming growth factor beta-1. Cell viability, mineralization, and osteogenic gene expression of MG-63 osteoblast-like cells were compared among the allograft alone, allograft/platelet-derived growth factor-BB, allograft/transforming growth factor beta-1, and allograft/platelet-derived growth factor-BB/transforming growth factor beta-1 groups. The methyl thiazol tetrazolium assay, real-time quantitative reverse transcription polymerase chain reaction and alizarin red staining were performed, respectively, for assessment of cell viability, differentiation, and mineralization at 24-72 h post treatment. The allograft with greater cytotoxic effect on MG-63 cells caused the lowest differentiation among the groups. In comparison with allograft alone, allograft/transforming growth factor beta-1, and allograft/transforming growth factor beta-1/platelet-derived growth factor-BB caused significant upregulation of bone sialoprotein and osteocalcin osteogenic mid-late marker genes, and resulted in significantly higher amounts of calcified nodules especially in mineralized non-cytotoxic allograft group. Supplementation of platelet-derived growth factor-BB alone in 5 ng/mL concentration had no significant effect on differentiation or mineralization markers. According to the results, transforming growth factor beta-1 acts synergistically with bone allografts to enhance the osteogenic differentiation potential. Therefore, this combination may be useful for rapid transformation of undifferentiated cells into bone-forming cells for bone regeneration. However, platelet-derived growth factor-BB supplementation did not support this synergistic ability to enhance osteogenic differentiation and thus, further investigations are required.

The character of gene expression of human periosteum used to form new tissue in allograft bone.

PubMed

Kemppainen, Jessica; Yu, Qing; Alexander, John; Jacquet, Robin; Scharschmidt, Thomas; Landis, William

2014-08-01

Of more than 2 million segmental bone defects repaired annually with bone autografts and allografts, 15-40% fail. Improving healing rates may be approached with tissue engineering and use of periosteum overlying an allograft. The present study documents gene expression in human periosteum-allograft constructs compared to allografts alone. Strips of human cadaveric periosteum (26 years, f, distal femur) were sutured about sterilized human femoral cortical strut bone allograft (54 years, m) segments. After construct incubation (M199 supplemented medium) for 8 d, constructs and allografts alone were implanted in nude mice. At 10 and 20 weeks, constructs (N = 4, each group) and allografts (N = 2, each group) were retrieved and placed in RNAlater for quantitative PCR to determine expression of human- and murine-specific genes relevant to remodeling. Specimens were frozen-ground to powders and RNA was extracted, purified, reverse-transcribed, and amplified. Ribosomal protein (P0) was used to normalize sample quantities. Fold change plots were generated following statistical analyses comparing 20- to 10-week gene expression data. Allografts alone yielded no human-specific gene expression. Notable fold changes of human-specific alkaline phosphatase, bone sialoprotein, type I collagen, decorin, RANKL, RANK, cathepsin K, and osteocalcin in 20-week compared to 10-week specimens were found. Murine-specific expression of genes indicative of host mouse vascularization (RANK, type I collagen) was detected in both allograft alone and periosteum-allograft samples. Gene data confirm viable periosteum in constructs after 20 weeks. Relatively higher fold-change values of RANK, RANKL and cathepsin K indicate activities of osteoclast precursors, osteoclasts and osteoblasts involved in allograft remodeling during implantation. All additional genes of interest indicate osteoblast activity in new bone matrix formation. Gene data are directly correlated with previous and present histology work. The results of this study suggest that further investigations could help to establish whether autologous periosteum-allograft constructs could be used for the repair of bone defects.

Dual pathology as a cause of proteinuria in the post-transplant period; report of a case.

PubMed

Tewari, Rohit; Mendonca, Satish; Nijhawan, Vijay

2016-01-01

Proteinuria is common after renal transplantation and affects between 35%-45% of patients during the same year as their transplant. We report a case of dual pathology in the renal allograft as a cause of severe proteinuria. A 38-year-old male presented with end-stage renal disease. He underwent live related renal allograft transplant. His immediate post-transplant period was unremarkable. He developed rise in serum creatinine (2.1 mg/dl) 6 months after transplant and was biopsied. He was diagnosed as a case of acute cellular rejection type Ib with suspicion for antibody mediated rejection. He was treated with methylprednisolone to which he showed a good response with return of serum creatinine to 1.6 mg/dl. Subsequently, he developed a nephrotic range proteinuria 6 months after this episode of rejection. Repeat biopsy was performed. He was diagnosed as a case of immune complex mediated glomerulonephritis (GN) (morphologically consistent with pattern of membranoproliferative glomerulonephritis) with chronic humoral rejection in the form of transplant glomerulopathy (TG). IHC for C4d and immunofluorescence studies were instrumental making the diagnosis. He was treated with steroids and rituximab to which he showed a good response with remission of proteinuria. This case highlights the importance of picking up dual pathology in an allograft biopsy to ensure appropriate therapy. The role of C4d and its correct interpretation is further highlighted, especially with regard to pattern (granular versus linear) and location (glomerular capillaries versus peritubular capillaries).

Dual pathology as a cause of proteinuria in the post-transplant period; report of a case

PubMed Central

Tewari, Rohit; Mendonca, Satish; Nijhawan, Vijay

2016-01-01

Proteinuria is common after renal transplantation and affects between 35%-45% of patients during the same year as their transplant. We report a case of dual pathology in the renal allograft as a cause of severe proteinuria. A 38-year-old male presented with end-stage renal disease. He underwent live related renal allograft transplant. His immediate post-transplant period was unremarkable. He developed rise in serum creatinine (2.1 mg/dl) 6 months after transplant and was biopsied. He was diagnosed as a case of acute cellular rejection type Ib with suspicion for antibody mediated rejection. He was treated with methylprednisolone to which he showed a good response with return of serum creatinine to 1.6 mg/dl. Subsequently, he developed a nephrotic range proteinuria 6 months after this episode of rejection. Repeat biopsy was performed. He was diagnosed as a case of immune complex mediated glomerulonephritis (GN) (morphologically consistent with pattern of membranoproliferative glomerulonephritis) with chronic humoral rejection in the form of transplant glomerulopathy (TG). IHC for C4d and immunofluorescence studies were instrumental making the diagnosis. He was treated with steroids and rituximab to which he showed a good response with remission of proteinuria. This case highlights the importance of picking up dual pathology in an allograft biopsy to ensure appropriate therapy. The role of C4d and its correct interpretation is further highlighted, especially with regard to pattern (granular versus linear) and location (glomerular capillaries versus peritubular capillaries). PMID:28197503

Comprehensive morphometric analysis of mononuclear cell infiltration during experimental renal allograft rejection.

PubMed

Hoffmann, Ute; Bergler, Tobias; Jung, Bettina; Steege, Andreas; Pace, Claudia; Rümmele, Petra; Reinhold, Stephan; Krüger, Bernd; Krämer, Bernhard K; Banas, Bernhard

2013-01-01

The role of specific subtypes of infiltrating cells in acute kidney allograft rejection is still not clear and was so far not examined by different analyzing methods under standardized conditions of an experimental kidney transplantation model. Immunohistochemical staining of CD3, CD20 and CD68 was performed in rat allografts, in syngeneically transplanted rats and in control rats with a test duration of 6 and 28 days. The detailed expression and localization of infiltrating cells were analyzed manually in different kidney compartments under light microscope and by the two different morphometric software programs. Data were correlated with the corresponding kidney function as well as with histopathological classification. The information provided by the morphometric software programs on the infiltration of the specific cell types after renal transplantation was in accordance with the manual analysis. Morphometric methods were solid to analyze reliably the induction of cellular infiltrates after renal transplantation. By manual analysis we could clearly demonstrate the detailed localization of the specific cell infiltrates in the different kidney compartments. Besides infiltration of CD3 and CD68 infiltrating cells, a robust infiltration of CD20 B-cells in allogeneically transplanted rats, even at early time points after transplantation was detected. Additionally an MHC class I expression could reliable be seen in allogeneically transplanted rats. The infiltration of B-cells and the reliable antigen presentation might act as a silent subclinical trigger for subsequent chronic rejection and premature graft loss. Copyright © 2012 Elsevier B.V. All rights reserved.

Bilateral Vestibular Dysfunction Associated With Chronic Exposure to Military Jet Propellant Type-Eight Jet Fuel

PubMed Central

Fife, Terry D.; Robb, Michael J. A.; Steenerson, Kristen K.; Saha, Kamala C.

2018-01-01

We describe three patients diagnosed with bilateral vestibular dysfunction associated with the jet propellant type-eight (JP-8) fuel exposure. Chronic exposure to aromatic and aliphatic hydrocarbons, which are the main constituents of JP-8 military aircraft jet fuel, occurred over 3–5 years’ duration while working on or near the flight line. Exposure to toxic hydrocarbons was substantiated by the presence of JP-8 metabolite n-hexane in the blood of one of the cases. The presenting symptoms were dizziness, headache, fatigue, and imbalance. Rotational chair testing confirmed bilateral vestibular dysfunction in all the three patients. Vestibular function improved over time once the exposure was removed. Bilateral vestibular dysfunction has been associated with hydrocarbon exposure in humans, but only recently has emphasis been placed specifically on the detrimental effects of JP-8 jet fuel and its numerous hydrocarbon constituents. Data are limited on the mechanism of JP-8-induced vestibular dysfunction or ototoxicity. Early recognition of JP-8 toxicity risk, cessation of exposure, and customized vestibular therapy offer the best chance for improved balance. Bilateral vestibular impairment is under-recognized in those chronically exposed to all forms of jet fuel. PMID:29867750

Bilateral Vestibular Dysfunction Associated With Chronic Exposure to Military Jet Propellant Type-Eight Jet Fuel.

PubMed

Fife, Terry D; Robb, Michael J A; Steenerson, Kristen K; Saha, Kamala C

2018-01-01

We describe three patients diagnosed with bilateral vestibular dysfunction associated with the jet propellant type-eight (JP-8) fuel exposure. Chronic exposure to aromatic and aliphatic hydrocarbons, which are the main constituents of JP-8 military aircraft jet fuel, occurred over 3-5 years' duration while working on or near the flight line. Exposure to toxic hydrocarbons was substantiated by the presence of JP-8 metabolite n -hexane in the blood of one of the cases. The presenting symptoms were dizziness, headache, fatigue, and imbalance. Rotational chair testing confirmed bilateral vestibular dysfunction in all the three patients. Vestibular function improved over time once the exposure was removed. Bilateral vestibular dysfunction has been associated with hydrocarbon exposure in humans, but only recently has emphasis been placed specifically on the detrimental effects of JP-8 jet fuel and its numerous hydrocarbon constituents. Data are limited on the mechanism of JP-8-induced vestibular dysfunction or ototoxicity. Early recognition of JP-8 toxicity risk, cessation of exposure, and customized vestibular therapy offer the best chance for improved balance. Bilateral vestibular impairment is under-recognized in those chronically exposed to all forms of jet fuel.

Biological properties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing

PubMed Central

Koob, Thomas J; Rennert, Robert; Zabek, Nicole; Massee, Michelle; Lim, Jeremy J; Temenoff, Johnna S; Li, William W; Gurtner, Geoffrey

2013-01-01

Human amnion/chorion tissue derived from the placenta is rich in cytokines and growth factors known to promote wound healing; however, preservation of the biological activities of therapeutic allografts during processing remains a challenge. In this study, PURION® (MiMedx, Marietta, GA) processed dehydrated human amnion/chorion tissue allografts (dHACM, EpiFix®, MiMedx) were evaluated for the presence of growth factors, interleukins (ILs) and tissue inhibitors of metalloproteinases (TIMPs). Enzyme-linked immunosorbent assays (ELISA) were performed on samples of dHACM and showed quantifiable levels of the following growth factors: platelet-derived growth factor-AA (PDGF-AA), PDGF-BB, transforming growth factor α (TGFα), TGFβ1, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), placental growth factor (PLGF) and granulocyte colony-stimulating factor (GCSF). The ELISA assays also confirmed the presence of IL-4, 6, 8 and 10, and TIMP 1, 2 and 4. Moreover, the relative elution of growth factors into saline from the allograft ranged from 4% to 62%, indicating that there are bound and unbound fractions of these compounds within the allograft. dHACM retained biological activities that cause human dermal fibroblast proliferation and migration of human mesenchymal stem cells (MSCs) in vitro. An in vivo mouse model showed that dHACM when tested in a skin flap model caused mesenchymal progenitor cell recruitment to the site of implantation. The results from both the in vitro and in vivo experiments clearly established that dHACM contains one or more soluble factors capable of stimulating MSC migration and recruitment. In summary, PURION® processed dHACM retains its biological activities related to wound healing, including the potential to positively affect four distinct and pivotal physiological processes intimately involved in wound healing: cell proliferation, inflammation, metalloproteinase activity and recruitment of progenitor cells. This suggests a paracrine mechanism of action for dHACM when used for wound healing applications. PMID:23902526

Accumulation of p53 is associated with tumour progression in cutaneous lesions of renal allograft recipients.

PubMed Central

Stark, L. A.; Arends, M. J.; McLaren, K. M.; Benton, E. C.; Shahidullah, H.; Hunter, J. A.; Bird, C. C.

1994-01-01

Renal allograft recipients suffer from a markedly increased susceptibility to premalignant and malignant cutaneous lesions. Although various aetiological factors have been implicated, little is known of the associated genetic events. In this study we initially employed immunocytochemical techniques to investigate the prevalence and localisation of accumulated p53 in over 200 cutaneous biopsies (including 56 squamous cell carcinomas) from renal allograft recipients and immunocompetent controls. In renal allograft recipients accumulated p53 was present in 24% of uninvolved skin samples, 14% of viral warts, 41% of premalignant keratoses, 65% of intraepidermal carcinomas and 56% of squamous cell carcinomas [squamous cell carcinoma and intraepidermal carcinoma differed significantly from uninvolved skin (P < 0.005) and viral warts (P < 0.01)]. A similar trend was revealed in immunocompetent patients (an older, chronically sun-exposed population) but with lower prevalence of p53 immunoreactivity: 25% of uninvolved skin samples, 0% of viral warts, 25% of keratoses, 53% of intraepidermal carcinomas and 53% of squamous cell carcinomas. These differences were not statistically significant. Morphologically, p53 immunoreactivity strongly associated with areas of epidermal dysplasia and the abundance of staining correlated positively with the severity of dysplasia. These data suggest that p53 plays a role in skin carcinogenesis and is associated with progression towards the invasive state. No correlation was observed between accumulated p53 and the presence of human papillomavirus (HPV) DNA in any of the lesions. Single-strand conformational polymorphism analysis (exons 5-8) was used to determine the frequency of mutated p53 in 28 malignancies with varying degrees of immunopositivity. p53 mutations were found in 5/9 (56%) malignancies with p53 staining in > 50% of cells, reducing to 1/6 (17%) where 10-50% of cells were positively stained and none where < 10% of cells were stained. These data imply that factors other than p53 gene mutation play a part in accumulation of p53 in skin cancers. Images Figure 2 Figure 3 PMID:7917913

Composite fatty acid ether amides suppress growth of liver cancer cells in vitro and in an in vivo allograft mouse model.

PubMed

Cao, Mengde; Prima, Victor; Nelson, David; Svetlov, Stanislav

2013-06-01

The heterogeneity of liver cancer, in particular hepatocellular carcinoma (HCC), portrays the requirement of multiple targets for both its treatment and prevention. Multifaceted agents, minimally or non-toxic for normal hepatocytes, are required to address the molecular diversity of HCC, including the resistance of putative liver cancer stem cells to chemotherapy. We designed and synthesized two fatty acid ethers of isopropylamino propanol, C16:0-AIP-1 and C18:1-AIP-2 (jointly named AIPs), and evaluated their anti-proliferative effects on the human HCC cell line Huh7 and the murine hepatoma cell line BNL 1MEA.7R.1, both in vitro and in an in vivo allograft mouse model. We found that AIP-1 and AIP-2 inhibited proliferation and caused cell death in both Huh7 and BNL 1MEA.7R.1 cells. Importantly, AIP-1 and AIP-2 were found to block the activation of putative liver cancer stem cells as manifested by suppression of clonal 'carcinosphere' development in growth factor-free and anchorage-free medium. The AIPs exhibited a relatively low toxicity against normal human or rat hepatocytes in primary cultures. In addition, we found that the AIPs utilized multifaceted pathways that mediate both autophagy and apoptosis in HCC, including the inhibition of AKTs and CAMK-1. In immune-competent mice, the AIPs significantly reduced BNL 1MEA.7R.1 cell-driven tumor allograft development, with a higher efficiency than sorafenib. A combination of AIP-1 + AIP-2 was most effective in reducing the tumor allograft incidence. AIPs represent a novel class of simple fatty acid derivatives that are effective against liver tumors via diverse pathways. They show a low toxicity towards normal hepatocytes. The addition of AIPs may represent a new avenue towards the management of chronic liver injury and, ultimately, the prevention and treatment of HCC.

Management of cytomegalovirus infection and disease in liver transplant recipients

PubMed Central

Bruminhent, Jackrapong; Razonable, Raymund R

2014-01-01

Cytomegalovirus (CMV) is one of the most common viral pathogens causing clinical disease in liver transplant recipients, and contributing to substantial morbidity and occasional mortality. CMV causes febrile illness often accompanied by bone marrow suppression, and in some cases, invades tissues including the transplanted liver allograft. In addition, CMV has been significantly associated with an increased predisposition to acute and chronic allograft rejection, accelerated hepatitis C recurrence, and other opportunistic infections, as well as reduced overall patient and allograft survival. To negate the adverse effects of CMV infection on transplant outcome, its prevention, whether through antiviral prophylaxis or preemptive therapy, is an essential component to the management of liver transplant recipients. Two recently updated guidelines have suggested that antiviral prophylaxis or preemptive therapy are similarly effective in preventing CMV disease in modest-risk CMV-seropositive liver transplant recipients, while antiviral prophylaxis is the preferred strategy over preemptive therapy for the prevention of CMV disease in high-risk recipients [CMV-seronegative recipients of liver allografts from CMV-seropositive donors (D+/R-)]. However, antiviral prophylaxis has only delayed the onset of CMV disease in many CMV D+/R- liver transplant recipients, and such occurrence of late-onset CMV disease was significantly associated with increased all-cause and infection-related mortality after liver transplantation. Therefore, a search for better strategies for prevention, such as prolonged duration of antiviral prophylaxis, a hybrid approach (antiviral prophylaxis followed by preemptive therapy), or the use of immunologic measures to guide antiviral prophylaxis has been suggested to prevent late-onset CMV disease. The standard treatment of CMV disease consists of intravenous ganciclovir or oral valganciclovir, and if feasible, reduction in pharmacologic immunosuppression. In one clinical trial, oral valganciclovir was as effective as intravenous ganciclovir for the treatment of mild to moderate CMV disease in solid organ (including liver) transplant recipients. The aim of this article is to provide a state-of-the art review of the epidemiology, diagnosis, prevention, and treatment of CMV infection and disease after liver transplantation. PMID:25018848

Use of polyvinylpyrrolidone-iodine solution for sterilisation and preservation improves mechanical properties and osteogenesis of allografts

NASA Astrophysics Data System (ADS)

Zhao, Yantao; Hu, Xiantong; Li, Zhonghai; Wang, Fuli; Xia, Yang; Hou, Shuxun; Zhong, Hongbin; Zhang, Feimin; Gu, Ning

2016-12-01

Allografts eliminate the disadvantages associated with autografts and synthetic scaffolds but are associated with a disease-transmission risk. Therefore, allograft sterilisation is crucial. We aimed to determine whether polyvinylpyrrolidone-iodine (PVP-I) can be used for sterilisation and as a new wet-preservation method. PVP-I-sterilised and preserved allografts demonstrated improved mechanical property, osteogenesis, and excellent microbial inhibition. A thigh muscle pouch model of nude mice showed that PVP-I-preserved allografts demonstrated better ectopic formation than Co60-sterilised allografts (control) in vivo (P < 0.05). Furthermore, the PVP-I-preserved group showed no difference between 24 h and 12 weeks of allograft preservation (P > 0.05). PVP-I-preserved allografts showed more hydrophilic surfaces and PVP-I-sterilised tendons showed higher mechanical strength than Co60-sterilised tendons (P < 0.05). The level of residual PVP-I was higher without washing and with prolonged preservation (P < 0.05). In vitro cellular tests showed that appropriate PVP-I concentration was nontoxic to preosteoblast cells, and cellular differentiation measured by alkaline phosphatase activity and osteogenic gene markers was enhanced (P < 0.05). Therefore, the improved biological performance of implanted allografts may be attributable to better surface properties and residual PVP-I, and PVP-I immersion can be a simple, easy method for allograft sterilisation and preservation.

IL-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts.

PubMed

Iida, Shoichi; Tsuda, Hidetoshi; Tanaka, Toshiaki; Kish, Danielle D; Abe, Toyofumi; Su, Charles A; Abe, Ryo; Tanabe, Kazunari; Valujskikh, Anna; Baldwin, William M; Fairchild, Robert L

2016-03-15

Reperfusion of organ allografts induces a potent inflammatory response that directs rapid memory T cell, neutrophil, and macrophage graft infiltration and their activation to express functions mediating graft tissue injury. The role of cardiac allograft IL-1 receptor (IL-1R) signaling in this early inflammation and the downstream primary alloimmune response was investigated. When compared with complete MHC-mismatched wild-type cardiac allografts, IL-1R(-/-) allografts had marked decreases in endogenous memory CD8 T cell and neutrophil infiltration and expression of proinflammatory mediators at early times after transplant, whereas endogenous memory CD4 T cell and macrophage infiltration was not decreased. IL-1R(-/-) allograft recipients also had marked decreases in de novo donor-reactive CD8, but not CD4, T cell development to IFN-γ-producing cells. CD8 T cell-mediated rejection of IL-1R(-/-) cardiac allografts took 3 wk longer than wild-type allografts. Cardiac allografts from reciprocal bone marrow reconstituted IL-1R(-/-)/wild-type chimeric donors indicated that IL-1R signaling on graft nonhematopoietic-derived, but not bone marrow-derived, cells is required for the potent donor-reactive memory and primary CD8 T cell alloimmune responses observed in response to wild-type allografts. These studies implicate IL-1R-mediated signals by allograft parenchymal cells in generating the stimuli-provoking development and elicitation of optimal alloimmune responses to the grafts. Copyright © 2016 by The American Association of Immunologists, Inc.

Graft-Derived CCL2 Increases Graft Injury During Antibody-Mediated Rejection of Cardiac Allografts

PubMed Central

Abe, Toyofumi; Su, Charles A.; Iida, Shoichi; Baldwin, William M.; Nonomura, Norio; Takahara, Shiro; Fairchild, Robert L.

2015-01-01

The pathogenic role of macrophages in antibody-mediated rejection (AMR) remains unclear. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is a potent chemotactic factor for monocytes and macrophages. The current studies used a murine model of AMR to investigate the role of graft-derived CCL2 in AMR and how macrophages may participate in antibody-mediated allograft injury. B6.CCR5−/−/CD8−/− recipients rejected MHC-mismatched wild type A/J allografts with high donor-reactive antibody titers and diffuse C4d deposition in the large vessels and myocardial capillaries, features consistent with AMR. In contrast, A/J.CCL2−/− allografts induced low donor-reactive antibody titers and C4d deposition at day 7 post-transplant. Decreased donor-reactive CD4 T cells producing IFN-γ were induced in response to A/J.CCL2−/− vs. wild type allografts. Consequently, A/J.CCL2−/− allograft survival was modestly but significantly longer than A/J allografts. Macrophages purified from wild type allografts expressed high levels of IL-1β and IL-12p40 and this expression and the numbers of classically activated macrophages were markedly reduced in CCL2-deficient allografts on day 7. The results indicate that allograft-derived CCL2 plays an important role in directing classically activated macrophages into allografts during AMR and that macrophages are important contributors to the inflammatory environment mediating graft tissue injury in this pathology, suggesting CCL2 as a therapeutic target for AMR. PMID:25040187

A prospective study on association of prostatic calcifications with sexual dysfunction in men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

PubMed

Zhao, Zhigang; Xuan, Xujun; Zhang, Jingwei; He, Jun; Zeng, Guohua

2014-10-01

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common debilitating condition of unclear etiology. Sexual dysfunction is an important component of the clinical phenotype of CP/CPPS. Patients often have prostatic calcifications, but a link to sexual dysfunction is unknown. The aim of this study was to evaluate the association of prostatic calcifications with sexual dysfunction in this condition. A total of 358 males with CP/CPPS were consecutively enrolled, and a prospectively maintained database of these patients was analyzed. Calcifications were diagnosed using ultrasound imaging of the prostate. Symptom severity was measured using the National Institutes of Health Chronic Prostatitis Symptom Index (CPSI). Sexual dysfunction was evaluated using the validated 15-item International Index of Erectile Function (IIEF-15) questionnaire and 5-item Premature Ejaculation Diagnostic Tool scales. The variables were compared between patients with prostatic calcifications and those without using the Student's t-test, Wilcoxon unpaired test, or chi-square test. Logistic regression models were developed to explore a possible association between prostatic calcifications and sexual dysfunction. Measurable calcifications in the prostate were found in 175 (48.9%) of the 358 patients. Patients with calcifications were more likely to have higher white blood cell counts or positive bacteria cultures in their prostatic fluid, longer symptoms duration, and lower scores for the total IIEF-15, IIEF-erectile function, and IIEF-intercourse satisfaction domains (P < 0.001 for each). However, the scores for CPSI, premature ejaculation, and IIEF-orgasmic function, IIEF-sexual desire, and IIEF-overall satisfaction domains were identical between men with and without calcifications (P > 0.05 for each). Furthermore, logistic regression analyses revealed that intraprostatic calcification is significantly associated with self-assessed erectile dysfunction (ED) (odds ratio:3.632, 95% confidence interval: 2.405-5.822, P < 0.001). Our results showed that prostatic calcifications are significantly associated with the presence of ED in CP/CPPS males. © 2014 International Society for Sexual Medicine.

21 CFR 862.1163 - Cardiac allograft gene expression profiling test system.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cardiac allograft gene expression profiling test... Chemistry Test Systems § 862.1163 Cardiac allograft gene expression profiling test system. (a) Identification. A cardiac allograft gene expression profiling test system is a device that measures the...

Management of Chronic Kidney Disease Patients in the Intensive Care Unit: Mixing Acute and Chronic Illness.

PubMed

De Rosa, Silvia; Samoni, Sara; Villa, Gianluca; Ronco, Claudio

2017-01-01

Patients with chronic kidney disease (CKD) are at high risk for developing critical illness and for admission to intensive care units (ICU). 'Critically ill CKD patients' frequently develop an acute worsening of renal function (i.e. acute-on-chronic, AoC) that contributes to long-term kidney dysfunction, potentially leading to end-stage kidney disease (ESKD). An integrated multidisciplinary effort is thus necessary to adequately manage the multi-organ damage of those kidney patients and contemporaneously reduce the progression of kidney dysfunction when they are critically ill. The aim of this review is to describe (1) the pathophysiological mechanisms underlying the development of AoC kidney dysfunction and its role in the progression toward ESKD; (2) the most common clinical presentations of critical illness among CKD/ESKD patients; and (3) the continuum of care for CKD/ESKD patients from maintenance hemodialysis/peritoneal dialysis to acute renal replacement therapy performed in ICU and, vice-versa, for AoC patients who develop ESKD. © 2017 S. Karger AG, Basel.

Interferon-γ-Mediated Allograft Rejection Exacerbates Cardiovascular Disease of Hyperlipidemic Murine Transplant Recipients

PubMed Central

Zhou, Jing; Qin, Lingfeng; Yi, Tai; Ali, Rahmat; Li, Qingle; Jiao, Yang; Li, Guangxin; Tobiasova, Zuzana; Huang, Yan; Zhang, Jiasheng; Yun, James J.; Sadeghi, Mehran M.; Giordano, Frank J.; Pober, Jordan S.; Tellides, George

2015-01-01

Rationale Transplantation, the most effective therapy for end-stage organ failure, is markedly limited by early-onset cardiovascular disease (CVD) and premature death of the host. The mechanistic basis of this increased CVD is not fully explained by known risk factors. Objective To investigate the role of alloimmune responses in promoting CVD of organ transplant recipients. Methods and Results We established an animal model of graft-exacerbated host CVD by combining murine models of atherosclerosis (apolipoprotein E-deficient recipients on standard diet) and of intra-abdominal graft rejection (heterotopic cardiac transplantation without immunosuppression). CVD was absent in normolipidemic hosts receiving allogeneic grafts and varied in severity among hyperlipidemic grafted hosts according to recipient-donor genetic disparities, most strikingly across an isolated major histocompatibility complex class II antigen barrier. Host disease manifested as increased atherosclerosis of the aorta that also involved the native coronary arteries and new findings of decreased cardiac contractility, ventricular dilatation, and diminished aortic compliance. Exacerbated CVD was accompanied by greater levels of circulating cytokines, especially interferon-γ and other Th1-type cytokines, and showed both systemic and intra-lesional activation of leukocytes, particularly T helper cells. Serologic neutralization of interferon-γ after allotransplantation prevented graft-related atherosclerosis, cardiomyopathy, and aortic stiffening in the host. Conclusions Our study reveals that sustained activation of the immune system due to chronic allorecognition exacerbates the atherogenic diathesis of hyperlipidemia and results in de novo cardiovascular dysfunction in organ transplant recipients. PMID:26399469

Preemptive treatment of early donor specific antibodies with IgA- and IgM-enriched intravenous human immunoglobulins in lung transplantation.

PubMed

Ius, Fabio; Verboom, Murielle; Sommer, Wiebke; Poyanmehr, Reza; Knoefel, Ann-Kathrin; Salman, Jawad; Kuehn, Christian; Avsar, Murat; Siemeni, Thierry; Erdfelder, Caroline; Hallensleben, Michael; Boethig, Dietmar; Schwerk, Nicolaus; Mueller, Carsten; Welte, Tobias; Falk, Christine; Haverich, Axel; Tudorache, Igor; Warnecke, Gregor

2018-05-02

This retrospective study presents our 4-year experience of preemptive treatment of early anti-HLA donor specific antibodies with IgA- and IgM-enriched immunoglobulins. We compared outcomes between patients with antibodies and treatment (case patients) and patients without antibodies (control patients). Records of patients transplanted at our institution between 03/2013 and 11/2017 were reviewed. The treatment protocol included one single 2g/kg immunoglobulin infusion followed by successive 0.5g/kg infusions for a maximum of 6 months, usually combined with a single dose of anti-CD20 antibody and, in case of clinical rejection or positive crossmatch, with plasmapheresis or immunoabsorption. Among the 598 transplanted patients, 128 (21%) patients formed the case group and 452 (76%) the control group. In 116 (91%) patients who completed treatment, 106 (91%) showed no antibodies at treatment end. Fourteen (13%) patients showed antibody recurrence thereafter. In case vs. control patients and at 4-year follow-up, respectively, graft survival (%) was 79 vs. 81 (p=0.59), freedom (%) from biopsy-confirmed rejection 57 vs. 53 (p=0.34) and from chronic lung allograft dysfunction 82 vs. 78 (p=0.83). After lung transplantation, patients with early donor specific antibodies and treated with IgA- and IgM-enriched immunoglobulins had 4-year graft survival similar to patients without antibodies and showed high antibody clearance. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

10 years of prophylaxis with nebulized liposomal amphotericin B and the changing epidemiology of Aspergillus spp. infection in lung transplantation.

PubMed

Peghin, Maddalena; Monforte, Victor; Martin-Gomez, Maria-Teresa; Ruiz-Camps, Isabel; Berastegui, Cristina; Saez, Berta; Riera, Jordi; Ussetti, Piedad; Solé, Juan; Gavaldá, Joan; Roman, Antonio

2016-01-01

The aim of this study was to assess the outcome and tolerability of prophylactic nebulized liposomal amphotericin B (n-LAB) in lung transplant recipients (LTR) and the changing epidemiology of Aspergillus spp. infection and colonization. We performed an observational study including consecutive LTR recipients (2003-2013) undergoing n-LAB prophylaxis lifetime. A total of 412 patients were included (mean postoperative follow-up 2.56 years; IQR 1.01-4.65). Fifty-three (12.8%) patients developed 59 Aspergillus spp. infections, and 22 invasive aspergillosis (overall incidence 5.3%). Since 2009, person-time incidence rates of Aspergillus spp. colonization and infection decreased (2003-2008, 0.19; 2009-2014, 0.09; P = 0.0007), but species with reduced susceptibility or resistance to amphotericin significantly increased (2003-2008, 38.1% vs 2009-2014, 58.1%; P = 0.039). Chronic lung allograft dysfunction (CLAD) was associated with Aspergillus spp. colonization and infection (HR 24.4, 95% CI 14.28-41.97; P = 0.00). Only 2.9% of patients presented adverse effects, and 1.7% required discontinuation. Long-term administration of prophylaxis with n-LAB has proved to be tolerable and can be used for preventing Aspergillus spp. infection in LTR. Over the last years, the incidence of Aspergillus spp. colonization and infection has decreased, but species with reduced amphotericin susceptibility or resistance are emerging. CLAD is associated with Aspergillus spp. colonization and infection. © 2015 Steunstichting ESOT.

Endothelial dysfunction in hemodialysis patients with failed renal transplants.

PubMed

Gorgulu, Numan; Yelken, Berna; Caliskan, Yasar; Elitok, Ali; Cimen, Arif Oguzhan; Yazici, Halil; Oflaz, Huseyin; Golcuk, Ebru; Ekmekci, Ahmet; Turkmen, Aydin; Yildiz, Alaattin; Sever, Mehmet Sukru

2010-01-01

Endothelial dysfunction (ED) is a common precursor and denominator of cardiovascular events including development of atherosclerosis. In this cross-sectional study, we aimed to investigate ED, measured by coronary flow reserve (CFR) in hemodialysis (nHD) patients who were never transplanted and patients with failed renal transplants restarting hemodialysis (fTx-HD). Forty nHD (24 males, mean age 39 ± 9 yr) and 43 fTx-HD patients (27 males, mean age 36 ± 9 yr) were included in the study. Clinical and biochemical parameters, including high-sensitive C-reactive protein (hs-CRP) levels were determined. Also, CFR measurements were used to evaluate ED. There were no significant differences regarding age, gender, smoking status, systolic and diastolic blood pressure levels, mean duration of HD treatment as well as Kt/V((urea)) values between the two groups. Time spent on dialysis in the nHD group and dialysis duration following failure of renal allograft in the fTx-HD group were similar. Serum creatinine, hemoglobin, hematocrit, calcium and phosphorus levels were similar between the two groups as well. When compared to nHD group, serum total cholesterol (139 ± 3 vs. 154 ± 3 mg/dL, p = 0.045), serum albumin (3.8 ± 0.3 g/dL vs. 4.1 ± 0.2 g/dL, p < 0.0001) and CFR (1.60 ± 0.2 vs. 1.75 ± 0.3, p = 0.028) levels were significantly lower, while serum hs-CRP levels (11 ± 15 mg/L vs. 3 ± 4 mg/L, p = 0.001) were significantly higher in the fTx-HD group. Serum hs-CRP negatively correlated (r = -0254, p = 0.021), while serum albumin positively correlated (r = 0402, p = 0.001) with CFR values. ED is more prominent in fTx-HD than the nHD patients. Inflammation, caused by failed renal allograft can be responsible for this abnormality. © 2009 John Wiley & Sons A/S.

Micro-organisms isolated from cadaveric samples of allograft musculoskeletal tissue.

PubMed

Varettas, Kerry

2013-12-01

Allograft musculoskeletal tissue is commonly used in orthopaedic surgical procedures. Cadaveric donors of musculoskeletal tissue supply multiple allografts such as tendons, ligaments and bone. The microbiology laboratory of the South Eastern Area Laboratory Services (SEALS, Australia) has cultured cadaveric allograft musculoskeletal tissue samples for bacterial and fungal isolates since 2006. This study will retrospectively review the micro-organisms isolated over a 6-year period, 2006-2011. Swab and tissue samples were received for bioburden testing and were inoculated onto agar and/or broth culture media. Growth was obtained from 25.1 % of cadaveric allograft musculoskeletal tissue samples received. The predominant organisms isolated were coagulase-negative staphylococci and coliforms, with the heaviest bioburden recovered from the hemipelvis. The rate of bacterial and fungal isolates from cadaveric allograft musculoskeletal tissue samples is higher than that from living donors. The type of organism isolated may influence the suitability of the allograft for transplant.

Subfractions of high-density lipoprotein (HDL) and dysfunctional HDL in chronic kidney disease patients.

PubMed

Rysz-Górzyńska, Magdalena; Banach, Maciej

2016-08-01

A number of studies have shown that chronic kidney disease (CKD) is associated with increased risk for cardiovascular disease (CVD). Chronic kidney disease is characterized by significant disturbances in lipoprotein metabolism, including differences in quantitative and qualitative content of high-density lipoprotein (HDL) particles. Recent studies have revealed that serum HDL cholesterol levels do not predict CVD in CKD patients; thus CKD-induced modifications in high-density lipoprotein (HDL) may be responsible for the increase in CV risk in CKD patients. Various methods are available to separate several subclasses of HDL and confirm their atheroprotective properties. However, under pathological conditions associated with inflammation and oxidation, HDL can progressively lose normal biological activities and be converted into dysfunctional HDL. In this review, we highlight the current state of knowledge on subfractions of HDL and HDL dysfunction in CKD.

Allograft update: the current status of tissue regulation, procurement, processing, and sterilization.

PubMed

McAllister, David R; Joyce, Michael J; Mann, Barton J; Vangsness, C Thomas

2007-12-01

Allografts are commonly used during sports medicine surgical procedures in the United States, and their frequency of use is increasing. Based on surgeon reports, it is estimated that more than 60 000 allografts were used in knee surgeries by members of the American Orthopaedic Society for Sports Medicine in 2005. In the United States, there are governmental agencies and other regulatory bodies involved in the oversight of tissue banks. In 2005, the Food and Drug Administration finalized its requirements for current good tissue practice and has mandated new rules regarding the "manufacture" of allogenic tissue. In response to well-publicized infections associated with the implantation of allograft tissue, some tissue banks have developed methods to sterilize allograft tissue. Although many surgeons have significant concerns about the safety of allografts, the majority believe that sterilized allografts are safe but that the sterilization process negatively affects tissue biology and biomechanics. However, most know very little about the principles of sterilization and the proprietary processes currently used in tissue banking. This article will review the current status of allograft tissue regulation, procurement, processing, and sterilization in the United States.

The safety of bone allografts used in dentistry: a review.

PubMed

Holtzclaw, Dan; Toscano, Nicholas; Eisenlohr, Lisa; Callan, Don

2008-09-01

Recent media reports concerning "stolen body parts" have shaken the public's trust in the safety of and the use of ethical practices involving human allografts. The authors provide a comprehensive review of the safety aspects of human bone allografts. The authors reviewed U.S. government regulations, industry standards, independent industry association guidelines, company guidelines and scientific articles related to the use of human bone allografts in the practice of dentistry published in the English language. The use of human bone allografts in the practice of dentistry involves the steps of procurement, processing, use and tracking. Rigorous donor screening and aseptic proprietary processing programs have rendered the use of human bone allografts safe and effective as a treatment option. When purchasing human bone allografts for the practice of dentistry, one should choose products accredited by the American Association of Tissue Banks for meeting uniformly high safety and quality control measures. Knowledge of human bone allograft procurement, processing, use and tracking procedures may allow dental clinicians to better educate their patients and address concerns about this valuable treatment option.

Treatment options for renal cell carcinoma in renal allografts: a case series from a single institution.

PubMed

Swords, Darden C; Al-Geizawi, Samer M; Farney, Alan C; Rogers, Jeffrey; Burkart, John M; Assimos, Dean G; Stratta, Robert J

2013-01-01

Renal cell carcinoma (RCC) is more common in renal transplant and dialysis patients than the general population. However, RCC in transplanted kidneys is rare, and treatment has previously consisted of nephrectomy with a return to dialysis. There has been recent interest in nephron-sparing procedures as a treatment option for RCC in allograft kidneys in an effort to retain allograft function. Four patients with RCC in allograft kidneys were treated with nephrectomy, partial nephrectomy, or radiofrequency ablation. All of the patients are without evidence of recurrence of RCC after treatment. We found nephron-sparing procedures to be reasonable initial options in managing incidental RCCs diagnosed in functioning allografts to maintain an improved quality of life and avoid immediate dialysis compared with radical nephrectomy of a functioning allograft. However, in non-functioning renal allografts, radical nephrectomy may allow for a higher chance of cure without the loss of transplant function. Consequently, radical nephrectomy should be utilized whenever the allograft is non-functioning and the patient's surgical risk is not prohibitive. © 2013 John Wiley & Sons A/S.

Automatic allograft bone selection through band registration and its application to distal femur.

PubMed

Zhang, Yu; Qiu, Lei; Li, Fengzan; Zhang, Qing; Zhang, Li; Niu, Xiaohui

2017-09-01

Clinical reports suggest that large bone defects could be effectively restored by allograft bone transplantation, where allograft bone selection acts an important role. Besides, there is a huge demand for developing the automatic allograft bone selection methods, as the automatic methods could greatly improve the management efficiency of the large bone banks. Although several automatic methods have been presented to select the most suitable allograft bone from the massive allograft bone bank, these methods still suffer from inaccuracy. In this paper, we propose an effective allograft bone selection method without using the contralateral bones. Firstly, the allograft bone is globally aligned to the recipient bone by surface registration. Then, the global alignment is further refined through band registration. The band, defined as the recipient points within the lifted and lowered cutting planes, could involve more local structure of the defected segment. Therefore, our method could achieve robust alignment and high registration accuracy of the allograft and recipient. Moreover, the existing contour method and surface method could be unified into one framework under our method by adjusting the lift and lower distances of the cutting planes. Finally, our method has been validated on the database of distal femurs. The experimental results indicate that our method outperforms the surface method and contour method.

28 CFR 79.61 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... the lung or pulmonary fibrosis means chronic inflammation and scarring of the pulmonary interstitium... Criteria for Claims by Ore Transporters § 79.61 Definitions. (a) Chronic renal disease means the chronic... resulting in chronic renal dysfunction. (j) Nonmalignant respiratory disease means fibrosis of the lung...

Impact of the pretransplant dialysis modality on kidney transplantation outcomes: a nationwide cohort study.

PubMed

Lin, Huan-Tang; Liu, Fu-Chao; Lin, Jr-Rung; Pang, See-Tong; Yu, Huang-Ping

2018-06-04

Most patients with uraemia must undergo chronic dialysis while awaiting kidney transplantation; however, the role of the pretransplant dialysis modality on the outcomes of kidney transplantation remains obscure. The objective of this study was to clarify the associations between the pretransplant dialysis modality, namely haemodialysis (HD) or peritoneal dialysis (PD), and the development of post-transplant de novo diseases, allograft failure and all-cause mortality for kidney-transplant recipients. Retrospective nationwide cohort study. Data retrieved from the Taiwan National Health Insurance Research Database. The National Health Insurance database was explored for patients who received kidney transplantation in Taiwan during 1998-2011 and underwent dialysis >90 days before transplantation. The pretransplant characteristics, complications during kidney transplantation and post-transplant outcomes were statistically analysed and compared between the HD and PD groups. Cox regression analysis was used to evaluate the HR of the dialysis modality on graft failure and all-cause mortality. The primary outcomes were long-term post-transplant death-censored allograft failure and all-cause mortality started after 90 days of kidney transplantation until the end of follow-up. The secondary outcomes were events during kidney transplantation and post-transplant de novo diseases adjusted by propensity score in log-binomial model. There were 1812 patients included in our cohort, among which 1209 (66.7%) and 603 (33.3%) recipients received pretransplant HD and PD, respectively. Recipients with chronic HD were generally older and male, had higher risks of developing post-transplant de novo ischaemic heart disease, tuberculosis and hepatitis C after adjustment. Pretransplant HD contributed to higher graft failure in the multivariate analysis (HR 1.38, p<0.05) after adjustment for the recipient age, sex, duration of dialysis and pretransplant diseases. There was no significant between-group difference in overall survival. Pretransplant HD contributed to higher risks of death-censored allograft failure after kidney transplantation when compared with PD. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Allograft tendon reconstruction of the anterior talofibular ligament and calcaneofibular Ligament in the treatment of chronic ankle instability.

PubMed

Wang, Weikai; Xu, Guo Hong

2017-04-08

The purpose was retrospectively to investigate functional and clinical outcomes after anterior talofibular ligament (ATFL) and calcaneofibular ligament (CFL) reconstruction using a single allograft. Patients with severe chronic lateral instability of the ankle underwent surgery after conservative treatment failed. Ultrasounds of the ankle were performed, and if the AFTL and CFL were completely torn without enough soft tissue for repair, the ligaments were reconstructed using allograft tendon. Outcomes were assessed by clinical examination, stress radiography, ultrasound, the American Orthopaedic Foot and Ankle Society score (AOFAS), and Karlsson Ankle Functional score (KAFS) before surgery and at final follow-up. Nineteen patients, ten men and nine women with mean age of 27.9 years (range, 19-41 years), underwent reconstruction. Mean follow-up was 30 months (range, 24-40 months). At final follow-up, all patients had returned to activity without instability, pain, or limited range of motion. On stress radiography, mean talar tilt angle decreased from 17.32° ± 3.58° before surgery to 4.16° ± 1.12° at follow-up (p < 0.001). Mean anterior drawer test (ADT) distance decreased from 9.79 ± 1.01 mm before surgery to 3.97 ± 0.99 mm at follow-up (p < 0.05). Mean AOFAS improved from 64.00 ± 18.43 to 90.32 ± 5.17 points (p < 0.001), and mean KAFS improved from 50.84 ± 16.73 to 90.89 ± 5.08 points (p < 0.001). Ultrasound showed the reconstructed ligaments maintained good continuity and excellent tension. No case of infection and immunological rejection was reported. This novel reconstruction technique takes into account the anatomical specialty of AFTL and CFL. This case series showed increased stability of the ankle in clinical and functional outcomes. The trial registration number (TRN) and date of registration: ChiCTR-ORC-17010796 , Mar 6th 2017. Retrospectively registered.

Mesenchymal Stem Cell Therapy Prevents Interstitial Fibrosis and Tubular Atrophy in a Rat Kidney Allograft Model

PubMed Central

Herrero, Esther; Torras, Joan; Ripoll, Elia; Flaquer, Maria; Gomà, Montse; Lloberas, Nuria; Anegon, Ignacio; Cruzado, Josep M.; Grinyó, Josep M.; Herrero-Fresneda, Immaculada

2012-01-01

In solid organ transplantation, mesenchymal stem cell (MSC) therapy is strongly emerging among other cell therapies due to the positive results obtained in vitro and in vivo as an immunomodulatory agent and their potential regenerative role. We aimed at testing whether a single dose of MSCs, injected at 11 weeks after kidney transplantation for the prevention of chronic mechanisms, enhanced regeneration and provided protection against the inflammatory and fibrotic processes that finally lead to the characteristic features of chronic allograft nephropathy (CAN). Either bone marrow mononuclear cells (BMCs) injection or no-therapy (NT) were used as control treatments. A rat kidney transplantation model of CAN with 2.5 h of cold ischemia was used, and functional, histological, and molecular parameters were assessed at 12 and 24 weeks after transplantation. MSC and BMC cell therapy preserves renal function at 24 weeks and abrogates proteinuria, which is typical of this model (NT24w: 68.9±26.5 mg/24 h, MSC24w: 16.6±2.3 mg/24 h, BMC24w: 24.1±5.3 mg/24 h, P<0.03). Only MSC-treated animals showed a reduction in interstitial fibrosis and tubular atrophy (NT24w: 2.3±0.29, MSC24w: 0.4±0.2, P<0.03), less T cells (NT: 39.6±9.5, MSC: 8.1±0.9, P<0.03) and macrophages (NT: 20.9±4.7, MSC: 5.9±1.7, P<0.05) infiltrating the parenchyma and lowered expression of inflammatory cytokines while increasing the expression of anti-inflammatory factors. MSCs appear to serve as a protection from injury development rather than regenerate the damaged tissue, as no differences were observed in Ki67 expression, and kidney injury molecule-1, Clusterin, NGAL, and hepatocyte growth factor expression were only up-regulated in nontreated animals. Considering the results, a single delayed MSC injection is effective for the long-term protection of kidney allografts. PMID:22494435

Hospital Resource Use with Donation after Cardiac Death Allografts in Liver Transplantation: A Matched Controlled Analysis from 2007 to 2011.

PubMed

Singhal, Ashish; Wima, Koffi; Hoehn, Richard S; Quillin, R Cutler; Woodle, E Steve; Paquette, Ian M; Paterno, Flavio; Abbott, Daniel E; Shah, Shimul A

2015-05-01

Although donation after cardiac death (DCD) liver allografts have been used to expand the donor pool, concerns exist regarding primary nonfunction and biliary complications. Our aim was to compare resource use and outcomes of DCD allografts with donation after brain death (DBD) liver allografts. Using a linkage between the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases, we identified 11,856 patients who underwent deceased donor liver transplantation (LT) from 2007 to 2011. Patients were divided into 2 cohorts based on type of allograft (DCD vs DBD). Matched pair analysis (n = 613 in each group) was used to compare outcomes of the 2 donor types. Donation after cardiac death allografts comprised 5.2% (n = 613) of all LTs in the studied cohort; DCD allograft recipients were healthier and had lower median Model of End-Stage Liver Disease (MELD) score (17 vs 19; p < 0.0001). Post LT, there was no significant difference in length of stay, perioperative mortality, and discharge to home rates. However, DCD allografts were associated with higher direct cost ($110,414 vs $99,543; p < 0.0001) and 30-day readmission rates (46.4% vs 37.1%; p < 0.0001). Matched analysis revealed that DCD allografts were associated with higher direct cost, readmission rates, and inferior graft survival. While confirming the previous reports of inferior graft survival associated with DCD allografts, this is the first national report to show increased financial and resource use associated with DCD compared with DBD allografts in a matched recipient cohort. Copyright © 2015 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Autograft versus nonirradiated allograft tissue for anterior cruciate ligament reconstruction: a systematic review.

PubMed

Mariscalco, Michael W; Magnussen, Robert A; Mehta, Divyesh; Hewett, Timothy E; Flanigan, David C; Kaeding, Christopher C

2014-02-01

An autograft has traditionally been the gold standard for anterior cruciate ligament reconstruction (ACLR), but the use of allograft tissue has increased in recent years. While numerous studies have demonstrated that irradiated allografts are associated with increased failure rates, some report excellent results after ACLR with nonirradiated allografts. The purpose of this systematic review was to determine whether the use of nonirradiated allograft tissue is associated with poorer outcomes when compared with autografts. Patients undergoing ACLR with autografts versus nonirradiated allografts will demonstrate no significant differences in graft failure risk, laxity on postoperative physical examination, or differences in patient-oriented outcome scores. Systematic review. A systematic review was performed to identify prospective or retrospective comparative studies (evidence level 1, 2, or 3) of autografts versus nonirradiated allografts for ACLR. Outcome data included graft failure based on clinical findings and instrumented laxity, postoperative laxity on physical examination, and patient-reported outcome scores. Studies were excluded if they did not specify whether the allograft had been irradiated. Quality assessment and data extraction were performed by 2 examiners. Nine studies comparing autografts and nonirradiated allografts were included. Six of the 9 studies compared bone-patellar tendon-bone (BPTB) autografts with BPTB allografts. Two studies compared hamstring tendon autografts to hamstring tendon allografts, and 1 study compared hamstring tendon autografts to tibialis anterior allografts. The mean patient age in 7 of 9 studies ranged from 24.5 to 32 years, with 1 study including only patients older than 40 years and another not reporting patient age. The mean follow-up duration was 24 to 94 months. Six of 9 studies reported clinical graft failure rates, 8 of 9 reported postoperative instrumented laxity measurements, 7 of 9 reported postoperative physical examination findings, and all studies reported patient-reported outcome scores. This review demonstrated no statistically significant difference between autografts and nonirradiated allografts in any outcome measure. No significant differences were found in graft failure rate, postoperative laxity, or patient-reported outcome scores when comparing ACLR with autografts to nonirradiated allografts in this systematic review. These findings apply to patients in their late 20s and early 30s. Caution is advised when considering extrapolation of these findings to younger, more active cohorts.

Nitric Oxide Bioavailability and Adiponectin Production in Chronic Systolic Heart Failure: Relation to Severity of Cardiac Dysfunction

PubMed Central

Tang, W.H. Wilson; Shrestha, Kevin; Tong, Wilson; Wang, Zeneng; Troughton, Richard W.; Borowski, Allen G.; Klein, Allan L.; Hazen, Stanley L.

2013-01-01

Adiponectin is an anti-inflammatory, anti-atherogenic adipokine elevated in heart failure (HF) that may protect against endothelial dysfunction by influencing underlying nitric oxide bioavailablity. In this study, we examine the relationship between plasma adiponectin levels and measures of nitric oxide bioavailability and myocardial performance in patients with chronic systolic HF. In 139 ambulatory patients with stable, chronic systolic HF (left ventricular [LV] ejection fraction ≤40%, New York Heart Association [NYHA] class I to IV), we measured plasma levels of adiponectin, asymmetric dimethylarginine (ADMA) and global arginine bioavailability (GABR), and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse events (all-cause mortality or cardiac transplantation) were prospectively tracked for a median of 39 months. Plasma adiponectin levels directly correlated with plasma ADMA levels (Spearman’s r=0.41, p<0.001) and NT-proBNP levels (r=0.55, p<0.001), inversely correlated with GABR (r= −0.39, p<0.001), and were not associated with hsCRP (p=0.81) or MPO (p=0.07). Interestingly, increased plasma adiponectin levels remained positively correlated with plasma ADMA levels only in patients with elevated NT-proBNP levels (r= 0.33, p=0.009). Higher plasma adiponectin levels were associated with worse LV diastolic dysfunction (rank sums p=0.002), RV systolic dysfunction (rank sums p=0.002), and RV diastolic dysfunction (rank sums p=0.011), but not after adjustment for plasma ADMA and NT-proBNP levels. Plasma adiponectin levels predicted increased risk of adverse clinical events (HR [95% CI]: 1.45 [1.02–2.07], p=0.038) but not after adjustment for plasma ADMA and NT-proBNP levels, or echocardiographic indices of diastolic or RV systolic dysfunction. In patients with chronic systolic HF, adiponectin production is more closely linked with nitric oxide bioavailability than inflammation, and appears to be more robust in the setting of cardiac dysfunction or elevated natriuretic peptide levels. PMID:23499315

Cervical spine dysfunctions in patients with chronic subjective tinnitus.

PubMed

Michiels, Sarah; De Hertogh, Willem; Truijen, Steven; Van de Heyning, Paul

2015-04-01

To assess, characterize, and quantify cervical spine dysfunction in patients with cervicogenic somatic tinnitus (CST) compared to patients suffering from other forms of chronic subjective non-pulsatile tinnitus. Cross-sectional study. Tertiary referral center. Consecutive adult patients suffering from chronic subjective non-pulsatile tinnitus were included. Ménière's disease, middle ear pathology, intracranial pathology, cervical spine surgery, whiplash trauma, temporomandibular dysfunction. Assessment comprises medical history, ENT examination with micro-otoscopy, audiometry, tinnitus assessment, temporomandibular and cervical spine investigation, and brain MRI. Patients were classified into CST and non-CST population. Cervical spine dysfunction was investigated using the Neck Bournemouth Questionnaire (NBQ) and clinical tests of the cervical spine, containing range of motion, pain provocation (adapted Spurling test, AST), and muscle tests (tenderness via trigger points, strength and endurance of deep neck flexors). Between-group analysis was performed. The prevalence of cervical spine dysfunction was described for the total group and for CST and non-CST groups. In total, 87 patients were included, of which 37 (43%) were diagnosed with CST. In comparison with the non-CST group, the CST group demonstrated a significantly higher prevalence of cervical spine dysfunction. In the CST group, 68% had a positive manual rotation test, 47% a positive AST, 49% a positive score on both, and 81% had positive trigger points. In the non-CST group, these percentages were 36, 18, 10, and 50%, respectively. Furthermore, 79% of the CST group had a positive NBQ versus 40% in the non-CST group. Significant differences between the both groups were found for all the aforementioned variables (all p < 0.005). Although a higher prevalence of neck dysfunction was found in the CST group, neck dysfunction is often in non-CST patients.

Evaluation of Right Ventricular Systolic Function in Chagas Disease Using Cardiac Magnetic Resonance Imaging.

PubMed

Moreira, Henrique T; Volpe, Gustavo J; Marin-Neto, José A; Ambale-Venkatesh, Bharath; Nwabuo, Chike C; Trad, Henrique S; Romano, Minna M D; Pazin-Filho, Antonio; Maciel, Benedito C; Lima, João A C; Schmidt, André

2017-03-01

Right ventricular (RV) impairment is postulated to be responsible for prominent systemic congestion in Chagas disease. However, occurrence of primary RV dysfunction in Chagas disease remains controversial. We aimed to study RV systolic function in patients with Chagas disease using cardiac magnetic resonance. This cross-sectional study included 158 individuals with chronic Chagas disease who underwent cardiac magnetic resonance. RV systolic dysfunction was defined as reduced RV ejection fraction based on predefined cutoffs accounting for age and sex. Multivariable logistic regression was used to verify the relationship of RV systolic dysfunction with age, sex, functional class, use of medications for heart failure, atrial fibrillation, and left ventricular systolic dysfunction. Mean age was 54±13 years, 51.2% men. RV systolic dysfunction was identified in 58 (37%) individuals. Although usually associated with reduced left ventricular ejection fraction, isolated RV systolic dysfunction was found in 7 (4.4%) patients, 2 of them in early stages of Chagas disease. Presence of RV dysfunction was not significantly different in patients with indeterminate/digestive form of Chagas disease (35.7%) compared with those with Chagas cardiomyopathy (36.8%) ( P =1.000). In chronic Chagas disease, RV systolic dysfunction is more commonly associated with left ventricular systolic dysfunction, although isolated and early RV dysfunction can also be identified. © 2017 American Heart Association, Inc.

[Epithelial dysfunction associated with pyo-inflammatory diseases of the ENT organs].

PubMed

Petukhova, N A

The modern concept of epithelial-endothelial dysfunction and epithelial-endothelial distress-syndrome associated with pyo-inflammatory ENT diseases is presented. It has provided a basis for the analysis of the initial stages of etiopathogenesis of acute and chronic inflammation in the ENT system including the mucous and associated lymphoid tissues as well as the Pirogov-Waldeyer limphopharyngeal ring making up the first protective barrier. The leading role of dysbiosis of synanthropic microflora and endotoxins of the Gram-negative bacteria in the mechanisms of regional responsiveness of the organism to the infection and chronic endotoxic aggression is demonstrated. The regional and synthetic mechanisms underlying the interaction between the external and internal media of the organism are subjected to the analysis with special reference to those operating in epithelium. The possible variants of the outcome of these processes are considered including both the recovery and the development of chronic inflammation. It has been proved that the exhaustion of the internal reserves for the stabilization of the epithelium-associated lymphoid tissue system including the Pirogov-Waldeyer limphopharyngeal ring leads to the formation of epithelial dysfunction as the initial stage of epithelial-endothelial dysfunction and epithelial-endothelial distress-syndrome. It is concluded that the modern concept of epithelial-endothelial dysfunction and epithelial-endothelial distress-syndrome is a fundamental interdisciplinary phenomenon.

Jaw Dysfunction Is Associated with Neck Disability and Muscle Tenderness in Subjects with and without Chronic Temporomandibular Disorders

PubMed Central

Silveira, A.; Gadotti, I. C.; Armijo-Olivo, S.; Biasotto-Gonzalez, D. A.; Magee, D.

2015-01-01

Purpose. Tender points in the neck are common in patients with temporomandibular disorders (TMD). However, the correlation among neck disability, jaw dysfunction, and muscle tenderness in subjects with TMD still needs further investigation. This study investigated the correlation among neck disability, jaw dysfunction, and muscle tenderness in subjects with and without chronic TMD. Participants. Forty females between 19 and 49 years old were included in this study. There were 20 healthy controls and 20 subjects who had chronic TMD and neck disability. Methods. Subjects completed the neck disability index and the limitations of daily functions in TMD questionnaires. Tenderness of the masticatory and cervical muscles was measured using an algometer. Results. The correlation between jaw disability and neck disability was significantly high (r = 0.915, P < 0.05). The correlation between level of muscle tenderness in the masticatory and cervical muscles with jaw dysfunction and neck disability showed fair to moderate correlations (r = 0.32–0.65). Conclusion. High levels of muscle tenderness in upper trapezius and temporalis muscles correlated with high levels of jaw and neck dysfunction. Moreover, high levels of neck disability correlated with high levels of jaw disability. These findings emphasize the importance of considering the neck and its structures when evaluating and treating patients with TMD. PMID:25883963

Jaw dysfunction is associated with neck disability and muscle tenderness in subjects with and without chronic temporomandibular disorders.

PubMed

Silveira, A; Gadotti, I C; Armijo-Olivo, S; Biasotto-Gonzalez, D A; Magee, D

2015-01-01

Tender points in the neck are common in patients with temporomandibular disorders (TMD). However, the correlation among neck disability, jaw dysfunction, and muscle tenderness in subjects with TMD still needs further investigation. This study investigated the correlation among neck disability, jaw dysfunction, and muscle tenderness in subjects with and without chronic TMD. Participants. Forty females between 19 and 49 years old were included in this study. There were 20 healthy controls and 20 subjects who had chronic TMD and neck disability. Subjects completed the neck disability index and the limitations of daily functions in TMD questionnaires. Tenderness of the masticatory and cervical muscles was measured using an algometer. The correlation between jaw disability and neck disability was significantly high (r = 0.915, P < 0.05). The correlation between level of muscle tenderness in the masticatory and cervical muscles with jaw dysfunction and neck disability showed fair to moderate correlations (r = 0.32-0.65). High levels of muscle tenderness in upper trapezius and temporalis muscles correlated with high levels of jaw and neck dysfunction. Moreover, high levels of neck disability correlated with high levels of jaw disability. These findings emphasize the importance of considering the neck and its structures when evaluating and treating patients with TMD.

Cost effectiveness of meniscal allograft for torn discoid lateral meniscus in young women.

PubMed

Ramme, Austin J; Strauss, Eric J; Jazrawi, Laith; Gold, Heather T

2016-09-01

A discoid meniscus is more prone to tears than a normal meniscus. Patients with a torn discoid lateral meniscus are at increased risk for early onset osteoarthritis requiring total knee arthroplasty (TKA). Optimal management for this condition is controversial given the up-front cost difference between the two treatment options: the more expensive meniscal allograft transplantation compared with standard partial meniscectomy. We hypothesize that meniscal allograft transplantation following excision of a torn discoid lateral meniscus is more cost-effective compared with partial meniscectomy alone because allografts will extend the time to TKA. A decision analytic Markov model was created to compare the cost effectiveness of two treatments for symptomatic, torn discoid lateral meniscus: meniscal allograft and partial meniscectomy. Probability estimates and event rates were derived from the scientific literature, and costs and benefits were discounted by 3%. One-way sensitivity analyses were performed to test model robustness. Over 25 years, the partial meniscectomy strategy cost $10,430, whereas meniscal allograft cost on average $4040 more, at $14,470. Partial meniscectomy postponed TKA an average of 12.5 years, compared with 17.30 years for meniscal allograft, an increase of 4.8 years. Allograft cost $842 per-year-gained in time to TKA. Meniscal allografts have been shown to reduce pain and improve function in patients with discoid lateral meniscus tears. Though more costly, meniscal allografts may be more effective than partial meniscectomy in delaying TKA in this model. Additional future long term clinical studies will provide more insight into optimal surgical options.

Spleen tyrosine kinase contributes to acute renal allograft rejection in the rat

PubMed Central

Ramessur Chandran, Sharmila; Tesch, Greg H; Han, Yingjie; Woodman, Naomi; Mulley, William R; Kanellis, John; Blease, Kate; Ma, Frank Y; Nikolic-Paterson, David J

2015-01-01

Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcγ-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague–Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation. PMID:25529862

Three-dimensional virtual bone bank system for selecting massive bone allograft in orthopaedic oncology.

PubMed

Wu, Zhigang; Fu, Jun; Wang, Zhen; Li, Xiangdong; Li, Jing; Pei, Yanjun; Pei, Guoxian; Li, Dan; Guo, Zheng; Fan, Hongbin

2015-06-01

Although structural bone allografts have been used for years to treat large defects caused by tumour or trauma, selecting the most appropriate allograft is still challenging. The objectives of this study were to: (1) describe the establishment of a visual bone bank system and workflow of allograft selection, and (2) show mid-term follow-up results of patients after allograft implantation. Allografts were scanned and stored in Digital Imaging and Communications in Medicine (DICOM) files. Then, image segmentation was conducted and 3D model reconstructed to establish a visual bone bank system. Based on the volume registration method, allografts were selected after a careful matching process. From November 2010 to June 2013, with the help of the Computer-assisted Orthopaedic Surgery (CAOS) navigation system, the allografts were implanted in 14 patients to fill defects after tumour resection. By combining the virtual bone bank and CAOS, selection time was reduced and matching accuracy was increased. After 27.5 months of follow-up, the mean Musculoskeletal Tumor Society (MSTS) 93 functional score was 25.7 ± 1.1 points. Except for two patients with pulmonary metastases, 12 patents were alive without evidence of disease at the time this report was written. The virtual bone bank system was helpful for allograft selection, tumour excision and bone reconstruction, thereby improving the safety and effectiveness of limb-salvage surgery.

Incidence of bacterial contamination and predisposing factors during bone and tendon allograft procurement.

PubMed

Terzaghi, Clara; Longo, Alessia; Legnani, Claudio; Bernasconi, Davide Paolo; Faré, Maristella

2015-03-01

The aim of this study was to analyze factors contributing to bacteriological contamination of bone and tendon allograft. Between 2008 and 2011, 2,778 bone and tendon allografts obtained from 196 organ and tissue donors or tissue donors only were retrospectively analysed. Several variables were taken into account: donor type (organ and tissue donors vs. tissue donor), cause of death, time interval between death and tissue procurement, duration of the procurement procedure, type of allografts, number of team members, number of trainees members, associated surgical procedures, positivity to haemoculture, type of procurement. The overall incidence of graft contamination was 23 %. The cause of death, the procurement time, the duration of procurement, the associated surgical procedures were not associated with increased risk of contamination. Significant effect on contamination incidence was observed for the number of staff members performing the procurement. In addition, our study substantiated significantly higher contamination rate among bone allografts than from tendon grafts. According to these observations, in order to minimize the contamination rate of procured musculoskeletal allografts, we recommend appropriate donor selection, use of standard sterile techniques, immediate packaging of each allograft to reduce graft exposure. Allograft procurement should be performed by a small surgical team.

Cost analysis of fresh-frozen femoral head allografts: is it worthwhile to run a bone bank?

PubMed

Benninger, E; Zingg, P O; Kamath, A F; Dora, C

2014-10-01

To assess the sustainability of our institutional bone bank, we calculated the final product cost of fresh-frozen femoral head allografts and compared these costs with the use of commercial alternatives. Between 2007 and 2010 all quantifiable costs associated with allograft donor screening, harvesting, storage, and administration of femoral head allografts retrieved from patients undergoing elective hip replacement were analysed. From 290 femoral head allografts harvested and stored as full (complete) head specimens or as two halves, 101 had to be withdrawn. In total, 104 full and 75 half heads were implanted in 152 recipients. The calculated final product costs were €1367 per full head. Compared with the use of commercially available processed allografts, a saving of at least €43 119 was realised over four-years (€10 780 per year) resulting in a cost-effective intervention at our institution. Assuming a price of between €1672 and €2149 per commercially purchased allograft, breakeven analysis revealed that implanting between 34 and 63 allografts per year equated to the total cost of bone banking. ©2014 The British Editorial Society of Bone & Joint Surgery.

Musculoskeletal allograft risks and recalls in the United States.

PubMed

Mroz, Thomas E; Joyce, Michael J; Steinmetz, Michael P; Lieberman, Isador H; Wang, Jeffrey C

2008-10-01

There have been several improvements to the US tissue banking industry over the past decade. Tissue banks had limited active government regulation until 1993, at which time the US Food and Drug Administration began regulatory oversight because of reports of disease transmission from allograft tissues. Reports in recent years of disease transmission associated with the use of allografts have further raised concerns about the safety of such implants. A retrospective review of allograft recall data was performed to analyze allograft recall by tissue type, reason, and year during the period from January 1994 to June 30, 2007. During the study period, more than 96.5% of all allograft tissues recalled were musculoskeletal. The reasons underlying recent musculoskeletal tissue recalls include insufficient or improper donor evaluation, contamination, recipient infection, and positive serologic tests. Infectious disease transmission following allograft implantation may occur if potential donors are not adequately evaluated or screened serologically during the prerecovery phase and if the implant is not sterilized before implantation.

International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010.

PubMed

Mehra, Mandeep R; Crespo-Leiro, Maria G; Dipchand, Anne; Ensminger, Stephan M; Hiemann, Nicola E; Kobashigawa, Jon A; Madsen, Joren; Parameshwar, Jayan; Starling, Randall C; Uber, Patricia A

2010-07-01

The development of cardiac allograft vasculopathy remains the Achilles heel of cardiac transplantation. Unfortunately, the definitions of cardiac allograft vasculopathy are diverse, and there are no uniform international standards for the nomenclature of this entity. This consensus document, commissioned by the International Society of Heart and Lung Transplantation Board, is based on best evidence and clinical consensus derived from critical analysis of available information pertaining to angiography, intravascular ultrasound imaging, microvascular function, cardiac allograft histology, circulating immune markers, non-invasive imaging tests, and gene-based and protein-based biomarkers. This document represents a working formulation for an international nomenclature of cardiac allograft vasculopathy, similar to the development of the system for adjudication of cardiac allograft rejection by histology.

Blood oxygenation level-dependent MRI for assessment of renal oxygenation

PubMed Central

Neugarten, Joel; Golestaneh, Ladan

2014-01-01

Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) has recently emerged as an important noninvasive technique to assess intrarenal oxygenation under physiologic and pathophysiologic conditions. Although this tool represents a major addition to our armamentarium of methodologies to investigate the role of hypoxia in the pathogenesis of acute kidney injury and progressive chronic kidney disease, numerous technical limitations confound interpretation of data derived from this approach. BOLD MRI has been utilized to assess intrarenal oxygenation in numerous experimental models of kidney disease and in human subjects with diabetic and nondiabetic chronic kidney disease, acute kidney injury, renal allograft rejection, contrast-associated nephropathy, and obstructive uropathy. However, confidence in conclusions based on data derived from BOLD MRI measurements will require continuing advances and technical refinements in the use of this technique. PMID:25473304

What Factors Influence the Biomechanical Properties of Allograft Tissue for ACL Reconstruction? A Systematic Review.

PubMed

Lansdown, Drew A; Riff, Andrew J; Meadows, Molly; Yanke, Adam B; Bach, Bernard R

2017-10-01

Allograft tissue is used in 22% to 42% of anterior cruciate ligament (ACL) reconstructions. Clinical outcomes have been inconsistent with allograft tissue, with some series reporting no differences in outcomes and others reporting increased risk of failure. There are numerous variations in processing and preparation that may influence the eventual performance of allograft tissue in ACL reconstruction. We sought to perform a systematic review to summarize the factors that affect the biomechanical properties of allograft tissue for use in ACL reconstruction. Many factors might impact the biomechanical properties of allograft tissue, and these should be understood when considering using allograft tissue or when reporting outcomes from allograft reconstruction. What factors affect the biomechanical properties of allograft tissue used for ACL reconstruction? We performed a systematic review to identify studies on factors that influence the biomechanical properties of allograft tissue through PubMed and SCOPUS databases. We included cadaveric and animal studies that reported on results of biomechanical testing, whereas studies on fixation, histologic evaluation, and clinical outcomes were excluded. There were 319 unique publications identified through the search with 48 identified as relevant to answering the study question. For each study, we recorded the type of tissue tested, parameters investigated, and the effects on biomechanical behavior, including load to failure and stiffness. Primary factors identified to influence allograft tissue properties were graft tissue type, sterilization methods (irradiation and chemical processing), graft preparation, donor parameters, and biologic adjuncts. Load to failure and graft stiffness varied across different tissue types, with nonlooped tibialis grafts exhibiting the lowest values. Studies on low-dose irradiation showed variable effects, whereas high-dose irradiation consistently produced decreased load to failure and stiffness values. Various chemical sterilization measures were also associated with negative effects on biomechanical properties. Prolonged freezing decreased load to failure, ultimate stress, and ultimate strain. Up to eight freeze-thaw cycles did not lead to differences in biomechanical properties of cadaveric grafts. Regional differences were noted in patellar tendon grafts, with the central third showing the highest load to failure and stiffness. Graft diameter strongly contributed to load-to-failure measurements. Age older than 40 years, and especially older than 65 years, negatively impacted biomechanical properties, whereas gender had minimal effect on the properties of allograft tissue. Biologic adjuncts show potential for improving in vivo properties of allograft tissue. Future clinical studies on allograft ACL reconstruction should investigate in vivo graft performance with standardized allograft processing and preparation methods that limit the negative effects on the biomechanical properties of tissue. Additionally, biologic adjuncts may improve the biomechanical properties of allograft tissue, although future preclinical and clinical studies are necessary to clarify the role of these treatments. Based on the findings of this systematic review that emphasize biomechanical properties of ACL allografts, surgeons should favor the use of central third patellar tendon or looped soft tissue grafts, maximize graft cross-sectional area, and favor grafts from donors younger than 40 years of age while avoiding grafts subjected to radiation doses > 20 kGy, chemical processing, or greater than eight freeze-thaw cycles.

The effect of endoscopic sinus surgery on symptoms of eustachian tube dysfunction.

PubMed

Stoikes, Nathaniel F N; Dutton, Jay M

2005-01-01

The symptom of eustachian tube dysfunction has been categorized as a "minor" symptom in chronic rhinosinusitis. The aim of this pilot study was to determine the frequency of otologic symptoms in patients with confirmed rhinosinusitis and the likelihood of its resolution in those patients undergoing endoscopic sinus surgery (ESS). Questionnaires were obtained from 168 patients who had undergone prior ESS over a 5-year period. Patients were asked to evaluate if they suffered from several different potential symptoms of eustachian tube dysfunction before ESS and whether that symptom changed postoperatively. Using the binomial test, 95% confidence intervals were determined for the following otologic symptoms of tubal dysfunction: "earfullness and congestion," "ear cracking and popping," "dizziness," and "ear pain. "ESS was found to have a significant treatment effect for the indicated otologic symptoms of tubal dysfunction. Tubal dysfunction, as manifested by otologic symptoms, is common in patients with chronic rhinosinusitis undergoing ESS. The classification of this as a "minor" symptom of rhinosinusitis needs to be reevaluated. These symptoms improve or resolve in the majority of patients undergoing ESS.

Obliterative portal venopathy: A histopathologic finding associated with chronic antibody-mediated rejection in pediatric liver allografts.

PubMed

Guerra, Marjorie-Anne R; Naini, Bita V; Scapa, Jason V; Reed, Elaine F; Busuttil, Ronald W; Cheng, Elaine Y; Farmer, Douglas G; Vargas, Jorge H; Venick, Robert S; McDiarmid, Sue V; Wozniak, Laura J

2018-03-01

The significance of post-transplant HLA DSA and chronic AMR in LT is an emerging field of study. Although OPV has previously been described as a histopathologic finding in DSA-positive adult LT recipients, it was not included in the recent Banff criteria for chronic AMR. Our aim was to describe the association between OPV and chronic AMR in pediatric LT recipients. A retrospective review of 67 liver biopsies performed between November 2014 and April 2016 in 45 pediatric LT recipients identified four patients with OPV. Clinical status, liver biochemistry, the presence of DSA, and available non-HLA antibody testing, as well as histopathologic features of chronic AMR, were assessed. All four patients with OPV had class II DSA and histopathologic features of chronic AMR based on the Banff criteria. Two patients were noted to have non-HLA antibodies. Three patients are undergoing treatment with IVIG but have persistent DSA. Two patients have graft failure and are awaiting retransplantation. In conclusion, OPV is a histopathologic finding associated with chronic AMR in pediatric LT recipients. Further studies are needed to elucidate whether OPV is reversible and/or amenable to medical therapy. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Increased Risk of Revision After Anterior Cruciate Ligament Reconstruction With Bone-Patellar Tendon-Bone Allografts Compared With Autografts.

PubMed

Maletis, Gregory B; Chen, Jason; Inacio, Maria C S; Love, Rebecca M; Funahashi, Tadashi T

2017-05-01

The use of allograft tissue for anterior cruciate ligament reconstruction (ACLR) remains controversial. To compare the risk of aseptic revision between bone-patellar tendon-bone (BPTB) autografts and BPTB allografts. Cohort study; Level of evidence, 2. A retrospective cohort study of prospectively collected data was conducted using the Kaiser Permanente ACLR Registry. A cohort of patients who underwent primary unilateral ACLR with BPTB autografts and BPTB allografts was identified. Aseptic revision was the endpoint. The type of graft and allograft processing method (nonprocessed, <1.8-Mrad, and ≥1.8-Mrad irradiation) were the exposures of interest evaluated. Age (≤21 and ≥22 years) was evaluated as an effect modifier. Analyses were adjusted for age, sex, and race. Kaplan-Meier curves and Cox proportional hazards models were employed. Hazard ratios (HRs) and 95% CIs are provided. The BPTB cohort consisted of 5586 patients: 3783 (67.7%) were male, 2359 (42.2%) were white, 1029 (18.4%) had allografts (nonprocessed: 155; <1.8 Mrad: 525; ≥1.8 Mrad: 288), and 4557 (81.6%) had autografts. The median age was 34.9 years (interquartile range [IQR], 25.4-44.0) for allograft cases and 22.0 years (IQR, 17.6-30.0) for autograft cases. The estimated cumulative revision rate at 2 years was 4.1% (95% CI, 2.9%-5.9%) for allografts and 1.7% (95% CI, 1.3%-2.2%) for autografts. BPTB allografts had a significantly higher adjusted risk of revision than BPTB autografts (HR, 4.54; 95% CI, 3.03-6.79; P < .001). This higher risk of revision was consistent with all allograft processing methods when compared with autografts and was also consistently higher in patients with allografts regardless of age. When BPTB allograft tissue was used for ACLR, an overall 4.54 times adjusted higher risk of revision was observed compared with surgery performed with a BPTB autograft. Whether the tissue was irradiated with either high- or low-dose radiation, chemically processed, or not processed at all made little difference in the risk of revision. The differences in the revision risk were also consistent in younger and older patients. Surgeons and patients should be aware of the increased risk of revision when a BPTB allograft is used for ACLR.

Belatacept: a novel biologic for maintenance immunosuppression after renal transplantation.

PubMed

Martin, Spencer T; Tichy, Eric M; Gabardi, Steven

2011-04-01

In the past decade, the availability of new immunosuppressive maintenance therapies for use in solid organ transplantation has remained limited. Patients and clinicians have relied on immunosuppressive drugs that require a significant amount of therapeutic monitoring and are associated with a variety of adverse effects that affect both quality of life and allograft function. Belatacept is an investigational intravenous biologic agent for long-term use in renal transplant recipients. The costimulatory pathway (signal 2) of T-cell activation and proliferation is produced by stimulation of the T-cell surface marker, CD28, and is essential to the immune system's cellular response and ability to recognize an allograft as foreign. Belatacept is a potent antagonist of B7-1 (CD80) and B7-2 (CD86) ligands present on antigen-presenting cells that are responsible for activation of CD28. Recent phase III trials describe various dosing strategies of belatacept versus a standard cyclosporine protocol in recipients of both living- and deceased-donor renal transplants, as well as in patients receiving kidneys transplanted from extended-criteria donors. Compared with cyclosporine, belatacept has been shown to be noninferior in both patient and allograft survival rates. However, the rate of biopsy-proven acute cellular rejection occurred more frequently in the belatacept groups. Also, compared with standard calcineurin-based regimens, the risk of posttransplant lymphoproliferative disorder is increased in patients receiving belatacept, with the greatest risk in transplant recipients who are Epstein-Barr virus seronegative before transplantation. However, this investigational immunosuppressive agent may avert common adverse effects experienced with standard immunosuppressive protocols including renal dysfunction, metabolic disorders, neurotoxicities, glucose abnormalities, and cosmetic effects. More data on the long-term risks of belatacept are needed to better define its role as immunosuppressive maintenance therapy. Aside from an increased risk of malignancy, belatacept's limited adverse-effect profile and convenient dosing strategy may make it an attractive option for immuno-suppressive maintenance for both the patient and clinician.

The effect of lung-size mismatch on mechanical ventilation tidal volumes after bilateral lung transplantation.

PubMed

Dezube, Rebecca; Arnaoutakis, George J; Reed, Robert M; Bolukbas, Servet; Shah, Ashish S; Orens, Jonathan B; Brower, Roy G; Eberlein, Michael

2013-03-01

Mechanical ventilation tidal volumes are usually set according to an estimate of patient size in millilitres (ml) per kilogram (kg) body weight. We describe the relationship between donor-recipient lung-size mismatch and postoperative mechanical ventilation tidal volumes according to recipient- and donor-predicted body weights in a cohort of bilateral lung transplant patients. A most-undersized (10 patients with lowest predicted total lung capacity [pTLC] ratio = pTLC-donor/pTLC-recipient), a most-oversized (10 patients with highest pTLC ratio) and best-matched subset (10 patients with predicted total lung capacity ratio closest to 1.0) were selected within a cohort of 70 patients. All tidal volumes during mechanical ventilation in the first 96 h after bilateral lung transplantation were recorded. Tidal volumes were expressed in ml and ml/kg-recipient-predicted body weights and ml/kg-donor-predicted body weights. Postoperative absolute tidal volumes (in ml) were comparable between subsets of patients with undersized, matched and oversized allografts (552 ± 103 vs 581 ± 107 vs 582 ± 104 ml), and tidal volumes in ml/kg-recipient-predicted body weights were also similar (8.8 ± 1.4 vs 9.3 ± 1.1 vs 9.8 ± 2.1). However, tidal volumes in ml/kg-donor-predicted body weights revealed significant differences between undersized, matched, and oversized subsets (11.4 ± 3.1 vs 9.4 ± 1.2 vs 8.1 ± 2.1, respectively; P < 0.05). Two patients developed primary graft dysfunction grade 3, both in the undersized subset. Four patients in the undersized group underwent tracheotomy (vs none in matched and one in oversized subset). During mechanical ventilation after bilateral lung transplantation, undersized allografts received relatively higher tidal volumes compared with oversized allografts when the tidal volumes were related to donor-predicted body weights.

Pre-transplant and post-transplant soluble CD30 for prediction and diagnosis of acute kidney allograft rejection.

PubMed

Nafar, Mohsen; Farrokhi, Farhat; Vaezi, Mohammad; Entezari, Amir-Ebrahim; Pour-Reza-Gholi, Fatemeh; Firoozan, Ahmad; Eniollahi, Behzad

2009-01-01

Serum levels of soluble CD30 (sCD30) have been considered as a predictor of acute kidney allograft rejection. We have evaluated the pre-transplant and post-transplant levels of sCD30 with the aim of determining its value in predicting and diagnosing kidney rejection. We measured sCD30 serum levels before kidney transplantation, 5 days post-operatively, and at creatinine elevation episodes. The predictive value of sCD30 for diagnosing acute rejection (AR) within the first 6 post-operative months was assessed in 203 kidney recipients from living donors. Pre-transplant and post-operative levels of serum sCD30 were 58.10 +/- 52.55 and 51.55 +/- 49.65 U/ml, respectively (P = 0.12). Twenty-three patients experienced biopsy-proven acute rejection, and 28 had acute allograft dysfunction due to non-immunologic diseases. The pre-transplant sCD30 level was not different between patients with and without AR. However, post-transplant sCD30 was higher in the AR group. The median serum level of post-transplant sCD30 was 52 U/ml in the AR group and 26.3 U/ml in a control group (P < 0.001). The relative changes of sCD30 on day 5 were higher in patients with AR (P = 0.003). Based on post-transplant sCD30 levels, we were able to differentiate between kidney recipients who experienced an AR within 6 months post-surgery and those without an AR (cutoff value 41 U/ml; sensitivity 70%; specificity 71.7%). The level of sCD30 during periods of elevated serum creatinine was not independently associated with the diagnosis of AR. Post-transplant sCD30 levels and their relative changes are higher in patients experiencing AR. We propose further studies on the post-transplant trend of this marker for the prediction of AR.

Recommendations for use of marginal donors in heart transplantation: Brazilian Association of Organs Transplantation guideline.

PubMed

Fiorelli, A I; Stolf, N A G; Pego-Fernandes, P M; Oliveira Junior, J L; Santos, R H B; Contreras, C A M; Filho, D D L; Dinkhuysen, J J; Moreira, M C V; Mejia, J A C; Castro, M C R

2011-01-01

The high prevalence of heart failure has increased the candidate list for heart transplantation; however, there is a shortage of viable donated organs, which is responsible for the high mortality of patients awaiting a transplantation. Because the marginal donor presents additional risk factors, it is not considered to be an ideal donor. The use of a marginal donor is only justified in situations when the risk of patient death due to heart disease is greater than that offered by the donor. These recommendations sought to expand the supply of donors, consequently increasing the transplant rate. We selected articles based on robust evidence to provide a substratum to develop recommendations for donors who exceed the traditional acceptance criteria. Recipient survival in the immediate postoperative period is intimately linked to allograft quality. Primary allograft failure is responsible for 38% to 40% of immediate deaths after heart transplantation: therefore; marginal donor selection must be more rigorous to not increase the surgical risk. The main donor risk factors with the respective evidence levels are: cancer in the donor (B), female donor (B), donor death due to hemorrhagic stroke (B), donor age above 50 years (relative risk [RR] = 1.5) (B), weight mismatch between donor and recipient < 0.8 (RR = 1.3) (B), ischemia > 240 minutes (RR = 1.2) (B), left ventricular dysfunction with ejection fraction below 45% (B), and use of high doses of vasoactive drugs (dopamine > 15 mg/kg·min) (B). Factors that impact recipient mortality are: age over 50 years (RR = 1.5); allograft harvest at a distance; adult recipient weighing more than 20% of the donor; high doses of vasoactive drugs (dopamine greater than 15 mg/kg·min) and ischemic time >4 hours. The use of a marginal donor is only justified when it is able to increase life expectancy compared with clinical treatment, albeit the outcomes are interior to those using an ideal donor. Copyright © 2011 Elsevier Inc. All rights reserved.

[The clinical manifestations and neurophysiological features of long-lasting paroxysmal vertigo:theanalysis of the original observations].

PubMed

Likhachev, S A; Mar'enko, I P

2015-01-01

The objective of the present study was to elucidate specific features of etiology and pathophysiology of recurring chronic vestibular dysfunction. It included 90 patients with this pathology of whom 24 (26.6%) presented with vascular compression of the vestibulocochlear nerve diagnosed by means of high-field MRI. This method revealed the high frequency of positionally-dependent vestibular dysfunction associated with neurovascular interactions. Analysis of the state of vestibular dysfunction during the attack-free periods demonstrated the signs of latent vestibular dysfunction in 20 (83.3%) patients. The results of the study provide additional information on the prevalence of vascular compression of the vestibulocochlear nerve in the patients presenting with recurrent chronic dizziness; moreover, they make it possible to evaluate the state of vestibular function and develop the new diagnostic criteria for vestibular paroxismia.

Outcomes of Renal Allograft Recipients With Hepatitis C.

PubMed

Carpio, R; Pamugas, G E; Danguilan, R; Que, E

2016-04-01

Studies on the effect of hepatitis C virus (HCV) infection showed decreased graft survival compared to HCV-negative matched patients. It was also identified as an independent risk factor for graft loss and mortality in kidney transplantation patients. This study was designed to evaluate the 10-year graft and patient outcomes of renal allograft recipients with HCV infection at the National Kidney and Transplant Institute. This is a retrospective study of patients who underwent renal transplantation with HCV infection and a group who were HCV-negative in the same post-transplantation period. Data were gathered from the in-patient and out-patient clinic records. Patient survival was significantly lower in the HCV-positive than in the HCV-negative group. The mean duration of patient survival was 154.95 (+4.95) months (12 years and 10 months) in HCV-negative patients compared to 141 (+6.52) months (11 years and 9 months) in the HCV-positive group (P = .05). Graft survival did not differ significantly between HCV-positive and HCV-negative recipients (P = .734). The mean duration of graft survival was 137 (+7.68) months (11 years and 5 months) in HCV-negative patients compared to 130 (+6.84) months (10 years and 10 months) in HCV-positive patients. Short- and long-term outcomes including biopsy-proven acute rejection, transplant glomerulopathy, chronic allograft nephropathy, renal function, and proteinuria were similar in both groups. Rejection, glomerulopathy, and renal function were similar in both groups. HCV progression was also observed in patients with detectable HCV-RNA 6 months before transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

Graft Immunocomplex Capture Fluorescence Analysis to Detect Donor-Specific Antibodies and HLA Antigen Complexes in the Allograft.

PubMed

Nakamura, Tsukasa; Ushigome, Hidetaka; Watabe, Kiyoko; Imanishi, Yui; Masuda, Koji; Matsuyama, Takehisa; Harada, Shumpei; Koshino, Katsuhiro; Iida, Taku; Nobori, Shuji; Yoshimura, Norio

2017-04-01

Immunocomplex capture fluorescence analysis (ICFA) is an attractive method to detect donor-specific anti-HLA antibodies (DSA) and HLA antigen complexes. Currently, antibody-mediated rejection (AMR) due to DSA is usually diagnosed by C4d deposition and serological DSA detection. Conversely, there is a discrepancy between these findings frequently. Thereupon, our graft ICFA technique may contribute to establish the diagnosis of AMR. Graft samples were obtained by a percutaneous needle biopsy. Then, the specimen was dissolved in PBS by the lysis buffer. Subsequently, HLA antigens were captured by anti-HLA beads. Then, DSA-HLA complexes were detected by PE-conjugated anti-human IgG antibodies, where DSA had already reacted with the allograft in vivo, analyzed by a Luminex system. A ratio (sample MFI/blank beads MFI) was calculated: ≥ 1.0 was determined as positive. We found that DSA-HLA complexes in the graft were successfully detected from only slight positive 1.03 to 79.27 in a chronic active AMR patient by graft ICFA. Next, positive graft ICFA had predicted the early phase of AMR (MFI ratio: 1.38) even in patients with no serum DSA. Finally, appropriate therapies for AMR deleted DSA deposition (MFI ratio from 0.3 to 0.7) from allografts. This novel application would detect early phase or incomplete pathological cases of AMR, which could lead to a correct diagnosis and initiation of appropriate therapies. Moreover, graft ICFA might address a variety of long-standing questions in terms of DSA. AMR: Antibody-mediated rejection; DSA: Donor-specific antibodies; ICFA: Immunocomplex capture fluorescence analysis.

Local Tacrolimus (FK506) Delivery for Prevention of Acute Rejection in the Nonhuman Primate Delayed Mixed Chimerism Vascularized Composite Allograft Tolerance Induction Protocol

DTIC Science & Technology

2016-10-01

Chimerism Vascularized Composite Allograft Tolerance Induction Protocol PRINCIPAL INVESTIGATORS: Dr. Curtis L. Cetrulo CONTRACTING ORGANIZATION...Tacrolimus (FK506) Delivery for Prevention of Acute Rejection in the Nonhuman Primate Delayed Mixed Chimerism Vascularized Composite Allograft Tolerance...tacrolimus, FK506, vascularized composite allografts , immune rejection, preclinical, transplant, nonhuman primate model, degradable polymer, tyrosine

Site-specific immunosuppression using a new formulation of topical cyclosporine A with polyethylene glycol-8 glyceryl caprylate/caprate.

PubMed

Tran, H S; Malli, D; Chrzanowski, F A; Puc, M M; Matthews, M S; Hewitt, C W

1999-05-15

Dermal application of immunosuppressants can be an effective means of achieving site-specific immunosuppression (SITE) on skin allografts in burn wound management and in the treatment of various immune skin disorders. We have previously reported success with topical cyclosporine A (tCsA) in the treatment of skin allograft rejection in rats. Using a new tCsA formulation with a penetration enhancer (PE), polyethylene glycol-8 (PEG-8) glyceryl caprylate/caprate (Labrasol, Gattefossé, St. Priest, France), in a trinary drug delivery system, we hypothesized that we would induce SITE and significantly delay rejection of dual skin allografts in rats. Dual rat skin allografts from Lewis x Brown-Norway (LBN) donors were grafted to Lewis (Lew) recipients. Experimental animals (EXP, n = 7) received a 10-day course of systemic cyclosporine (sCsA, 8 mg/kg/day) followed by topical application. One of the two allografts on each experimental animal received tCsA/PE application (5 mg/kg/day) until sacrifice (tCsA/PE-treated). The other allograft received vehicle only (vehicle-treated). Allogeneic controls (ALLO-CON, n = 9) received no sCsA or tCsA. First signs of rejection were determined based on the initial observation of erythema, hair loss, flakiness, and/or scabs. The mean time to rejection for ALLO-CON allografts was 6.3 +/- 0.7 days (t test, P = 0.0013); for vehicle-treated allografts, 12.3 +/- 3.8 days (paired t test, P = 0.0146); and for tCsA/PE-treated allografts, 25.6 +/- 5.4 days. The disparity of days to rejection between dual allografts in the ALLO-CON group was 0.0 +/- 0.0 day and that between the tCsA/PE- and vehicle-treated dual allografts was 13.3 +/- 3.9 days (t test, P = 0.0016). A new formulation of tCsA in a trinary drug delivery system is successful at delaying the onset of rejection in dual skin allografts in rats by SITE, and PEG-8 glyceryl caprylate/caprate may represent a potentially effective transdermal penetration enhancer. Copyright 1999 Academic Press.

Dual growth factor delivery from biofunctionalized allografts: Sequential VEGF and BMP-2 release to stimulate allograft remodeling.

PubMed

Sharmin, Farzana; McDermott, Casey; Lieberman, Jay; Sanjay, Archana; Khan, Yusuf

2017-05-01

Autografts have been shown to stimulate osteogenesis, osteoclastogenesis, and angiogenesis, and subsequent rapid graft incorporation. Large structural allografts, however, suffer from limited new bone formation and remodeling, both of which are directly associated with clinical failure due to non-unions, late graft fractures, and infections, making it a priority to improve large structural allograft healing. We have previously shown the osteogenic ability of a polymer-coated allograft that delivers bone morphogenetic protein-2 both in vitro and in vivo through both burst release and sustained release kinetics. In this study, we have demonstrated largely sequential delivery of bone morphogenetic protein-2 and vascular endothelial growth factor from the same coated allograft. Release data showed that loading both growth factors onto a polymeric coating with two different techniques resulted in short-term (95% release within 2 weeks) and long-term (95% release within 5 weeks) delivery kinetics. We have also demonstrated how released VEGF, traditionally associated with angiogenesis, can also provide a stimulus for allograft remodeling via resorption. Bone marrow derived mononuclear cells were co-cultured with VEGF released from the coated allograft and showed a statistically significant (p < 0.05) and dose dependent increase in the number of tartrate-resistant acid phosphatase-positive multinucleated osteoclasts. Functionality of these osteoclasts was assessed quantitatively and qualitatively by evaluating resorption pit area from both osteo-assay plates and harvested bone. Data indicated a statistically significant higher resorption area from the cells exposed to VEGF released from the allografts over controls (p < 0.05). These results indicate that by using different loading protocols temporal control can be achieved when delivering multiple growth factors from a polymer-coated allograft. Further, released VEGF can also stimulate osteoclastogenesis that may enhance allograft incorporation, and thus mitigate long-term clinical complications. © 2017 Orthopedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1086-1095, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Chronic inhibition of glycogen synthase kinase-3 protects against rotenone-induced cell death in human neuron-like cells by increasing BDNF secretion.

PubMed

Giménez-Cassina, Alfredo; Lim, Filip; Díaz-Nido, Javier

2012-12-07

Mitochondrial dysfunction is a common feature of many neurodegenerative disorders. Likewise, activation of glycogen synthase kinase-3 (GSK-3) has been proposed to play an important role in neurodegeneration. This multifunctional protein kinase is involved in a number of cellular functions and we previously showed that chronic inhibition of GSK-3 protects neuronal cells against mitochondrial dysfunction-elicited cell death, through a mechanism involving increased glucose metabolism and the translocation of hexokinase II (HKII) to mitochondria. Here, we sought to gain deeper insight into the molecular basis of this neuroprotection. We found that chronic inhibition of GSK-3, either genetically or pharmacologically, elicited a marked increase in brain-derived neurotrophic factor (BDNF) secretion, which in turn conferred resistance to mitochondrial dysfunction through subcellular re-distribution of HKII. These results define a molecular pathway through which chronic inhibition of GSK-3 may protect neuronal cells from death. Moreover, they highlight the potential benefits of enhanced neurotrophic factor secretion as a therapeutic approach to treat neurodegenerative diseases. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Resveratrol improves prostate fibrosis during progression of urinary dysfunction in chronic prostatitis.

PubMed

He, Yi; Zeng, Hui-Zhi; Yu, Yang; Zhang, Jia-Shu; Duan, Xingping; Zeng, Xiao-Na; Gong, Feng-Tao; Liu, Qi; Yang, Bo

2017-09-01

We investigated whether prostate fibrosis was associated with urinary dysfunction in chronic prostatitis (CP) and whether resveratrol improved urinary dysfunction and the underlying molecular mechanism. Rat model of CP was established via subcutaneous injections of DPT vaccine and subsequently treated with resveratrol. Bladder pressure and volume tests investigated the effect of resveratrol on urinary dysfunction in CP rats. Western blotting and immunohistochemical staining examined the expression level of C-kit/SCF and TGF-β/Wnt/β-catenin. Compared to the control group, the maximum capacity of the bladder, residual urine volume and maximum voiding pressure, the activity of C-kit/SCF and TGF-β/Wnt/β-catenin pathways were increased significantly in the CP group. Resveratrol treatment significantly improved these factors. CP induced significantly prostate fibrosis, which exhibits a close relationship with urinary dysfunction. Resveratrol improved fibrosis, which may be associated with the suppression of C-kit/SCF and TGF-β/Wnt/β-catenin pathway. Copyright © 2017 Elsevier B.V. All rights reserved.

Clinical application and viability of cryopreserved cadaveric skin allografts in severe burn: a retrospective analysis.

PubMed

Cleland, Heather; Wasiak, Jason; Dobson, Hannah; Paul, Michelle; Pratt, George; Paul, Eldho; Herson, Marisa; Akbarzadeh, Shiva

2014-02-01

Cadaveric cutaneous allografts are used in burns surgery both as a temporary bio-dressing and occasionally as definitive management of partial thickness burns. Nonetheless, limitations in the understanding of the biology of these grafts have meant that their role in burns surgery continues to be controversial. A review of all patients suffering 20% or greater total body surface area (TBSA) burns over an eight year period that received cadaveric allografts were identified. To investigate whether tissue viability plays a role in engraftment success, five samples of cryopreserved cadaveric cutaneous allograft processed at the Donor Tissue Bank of Victoria (DTBV) were submitted to our laboratory for viability analysis using two methods of Trypan Blue Exclusion and tetrazolium salt (MTT) assays. During the study period, 36 patients received cadaveric allograft at our institution. The average total burn surface area (TBSA) for this group of patients was 40% and all patients received cadaveric skin as a temporizing measure prior to definitive grafting. Cadaveric allograft was used in complicated cases such as wound contamination, where synthetic dressings had failed. Viability tests showed fewer than 30% viability in processed allografts when compared to fresh skin following the thawing process. However, the skin structure in the frozen allografts was histologically well preserved. Cryopreserved cutaneous cadaveric allograft has a positive and definite role as an adjunct to conventional dressing and grafting where available, particularly in patients with large TBSA burns. The low viability of cryopreserved specimens processed at DTBV suggests that cell viability in cadaveric allograft may not be essential for its clinical function as a wound dressing or even as permanent dermal substitute. Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.

Reducing the radiation sterilization dose improves mechanical and biological quality while retaining sterility assurance levels of bone allografts.

PubMed

Nguyen, Huynh; Cassady, Alan I; Bennett, Michael B; Gineyts, Evelyne; Wu, Andy; Morgan, David A F; Forwood, Mark R

2013-11-01

Bone allografts carry a risk of infection, so terminal sterilization by gamma irradiation at 25kGy is recommended; but is deleterious to bone quality. Contemporary bone banking significantly reduces initial allograft bioburden, questioning the need to sterilize at 25kGy. We inoculated allograft bone with Staphylococcus epidermidis and Bacillus pumilus, then exposed them to gamma irradiation at 0, 5, 10, 15, 20 and 25kGy. Mechanical and biological properties of allografts were also assessed. Our aim was to determine an optimal dose that achieves sterility assurance while minimizing deleterious effects on allograft tissue. 20-25kGy eliminated both organisms at concentrations from 10(1) to 10(3)CFU, while 10-15kGy sterilized bone samples to a bioburden concentration of 10(2)CFU. Irradiation did not generate pro-inflammatory bone surfaces, as evidenced by macrophage activation, nor did it affect attachment or proliferation of osteoblasts. At doses ≥10kGy, the toughness of cortical bone was reduced (P<0.05), and attachment and fusion of osteoclasts onto irradiated bone declined at 20 and 25kGy (P<0.05). There was no change in collagen cross-links, but a significant dose-response increase in denatured collagen (P<0.05). Our mechanical and cell biological data converge on 15kGy as a threshold for radiation sterilization of bone allografts. Between 5 and 15kGy, bone banks can undertake validation that provides allografts with an acceptable sterility assurance level, improving their strength and biocompatibility significantly. The application of radiation sterilization doses between 5 and 15kGy will improve bone allograft mechanical performance and promote integration, while retaining sterility assurance levels. Improved quality of allograft bone will promote superior clinical outcomes. © 2013.

Induction of MHC-mismatched Mouse Lung Allograft Acceptance with Combined Donor Bone Marrow: Lung Transplant using a 12-Hour Nonmyeloablative Conditioning Regimen

PubMed Central

Vulic, Ante; Panoskaltsis-Mortari, Angela; McDyer, John F.; Luznik, Leo

2016-01-01

Background Despite broad and intense conventional immunosuppression, long-term survival after lung transplantation lags behind that for other solid organ transplants, primarily because of allograft rejection. Therefore, new strategies to promote lung allograft acceptance are urgently needed. The purpose of the present study was to induce allograft tolerance with a protocol compatible with deceased donor organ utilization. Methods Using the MHC-mismatched mouse orthotopic lung transplant model, we investigated a conditioning regimen consisting of pretransplant T cell depletion, low dose total body irradiation and posttransplant (donor) bone marrow and splenocyte infusion followed by posttransplantation cyclophosphamide (PTTT-PTB/PTCy). Results Our results show that C57BL/6 recipients of BALB/c lung allografts undergoing this complete short-duration nonmyeloablative conditioning regimen had durable lung allograft acceptance. Mice that lacked 1 or more components of this regimen exhibited significant graft loss. Mechanistically, animals with lung allograft acceptance had established higher levels of donor chimerism, lymphocyte responses which were attenuated to donor antigens but maintained to third-party antigens, and clonal deletion of donor-reactive host Vβ T cells. Frequencies of Foxp3+ T regulatory cells were comparable in both surviving and rejected allografts implying that their perturbation was not a dominant cell-regulatory mechanism. Donor chimerism was indispensable for sustained tolerance, as evidenced by acute rejection of allografts in established chimeric recipients of PTTT-PTB/PTCy following a chimerism-ablating secondary recipient lymphocyte infusion. Conclusion Together, these data provide proof-of-concept for establishing lung allograft tolerance with tandem donor bone marrow transplantation (BMT) using a short-duration nonmyeloablative conditioning regimen and PTCy. PMID:27861294

Adipose Gene Expression Profile Changes With Lung Allograft Reperfusion.

PubMed

Diamond, Joshua M; Arcasoy, Selim; McDonnough, Jamiela A; Sonett, Joshua R; Bacchetta, Matthew; D'Ovidio, Frank; Cantu, Edward; Bermudez, Christian A; McBurnie, Amika; Rushefski, Melanie; Kalman, Laurel H; Oyster, Michelle; D'Errico, Carly; Suzuki, Yoshikazu; Giles, Jon T; Ferrante, Anthony; Lippel, Matthew; Singh, Gopal; Lederer, David J; Christie, Jason D

2017-01-01

Obesity is a risk factor for primary graft dysfunction (PGD), a form of lung injury resulting from ischemia-reperfusion after lung transplantation, but the impact of ischemia-reperfusion on adipose tissue is unknown. We evaluated differential gene expression in thoracic visceral adipose tissue (VAT) before and after lung reperfusion. Total RNA was isolated from thoracic VAT sampled from six subjects enrolled in the Lung Transplant Body Composition study before and after allograft reperfusion and quantified using the Human Gene 2.0 ST array. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed enrichment for genes involved in complement and coagulation cascades and Jak-STAT signaling pathways. Overall, 72 genes were upregulated and 56 genes were downregulated in the postreperfusion time compared with baseline. Long pentraxin-3, a gene and plasma protein previously associated with PGD, was the most upregulated gene (19.5-fold increase, p = 0.04). Fibronectin leucine-rich transmembrane protein-3, a gene associated with cell adhesion and receptor signaling, was the most downregulated gene (4.3-fold decrease, p = 0.04). Ischemia-reperfusion has a demonstrable impact on gene expression in visceral adipose tissue in our pilot study of nonobese, non-PGD lung transplant recipients. Future evaluation will focus on differential adipose tissue gene expression and the development of PGD after transplant. © Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.

Radiographic Outcomes Following Lateral Column Lengthening With a Porous Titanium Wedge.

PubMed

Gross, Christopher E; Huh, Jeannie; Gray, Joni; Demetracopoulos, Constantine; Nunley, James A

2015-08-01

Lateral column lengthening (LCL) is commonly utilized in treating stage II posterior tibialis tendon dysfunction. This study aimed to analyze the outcomes of LCL with porous titanium wedges compared to historic controls of iliac crest autograft and allograft. We hypothesized that the use of a porous titanium wedge would have radiographic improvement and union rates similar to those with the use of autograft and allograft in LCL. Between May 2009 and May 2014, 28 feet in 26 patients were treated with LCL using a porous titanium wedge. Of the 26 patients, 9 were males (34.6%). The average age for males was 43 years (range, 17.9-58.7), 48.7 years (range, 21-72.3) for females. Mean follow-up was 14.6 months. Radiographs were examined for correction of the flatfoot deformity and forefoot abduction. All complications were noted. Radiographically, the patients had a significant deformity correction in the anteroposterior talo-first metatarsal angle, talonavicular coverage angle, lateral talo-first metatarsal angle, and calcaneal pitch. All but 1 patient (96%) had bony incorporation of the porous titanium wedge. The average preoperative visual analog scale pain score was 5; all patients but 3 (12%) had improvements in their pain score, with a mean change of 3.4. LCL with porous titanium had low nonunion rates, improved radiographic correction, and pain relief. Level IV, case series. © The Author(s) 2015.

Liver transplantation using organs from deceased organ donors: a single organ transplant center experience.

PubMed

Han, Ming; Guo, Zhi-Yong; Zhao, Qiang; Wang, Xiao-Ping; Yuan, Xiao-Peng; Jiao, Xing-Yuan; Yang, Chun-Hua; Wang, Dong-Ping; Ju, Wei-Qiang; Wu, Lin-Wei; Hu, An-Bin; Tai, Qiang; Ma, Yi; Zhu, Xiao-Feng; He, Xiao-Shun

2014-08-01

In 2011, a pilot program for deceased organ donation was initiated in China. We describe the first successful series of liver transplants in the pilot program. From July 2011 to August 2012, our center performed 26 liver transplants from a pool of 29 deceased donors. All organ donation and allograft procurement were conducted according to the national protocol. The clinical data of donors and recipients were collected and summarized retrospectively. Among the 29 donors, 24 were China Category II donors (organ donation after cardiac death), and five were China Category III donors (organ donation after brain death followed by cardiac death). The recipients were mainly the patients with hepatocellular carcinoma. The one-year patient survival rate was 80.8% with a median follow-up of 422 (2-696) days. Among the five mortalities during the follow-up, three died of tumor recurrence. In terms of post-transplant complications, 9 recipients (34.6%) experienced early allograft dysfunction, 1 (3.8%) had non-anastomotic biliary stricture, and 1 (3.8%) was complicated with hepatic arterial thrombosis. None of these complications resulted in patient death. Notably, primary non-function was not observed in any of the grafts. With careful donor selection, liver transplant from deceased donors can be performed safely and plays a critical role in overcoming the extreme organ shortage in China.

Beta-Adrenergic Receptor Polymorphisms and Cardiac Graft Function in Potential Organ Donors

PubMed Central

Khush, K.K.; Pawlikowska, L.; Menza, R.L.; Goldstein, B.A.; Hayden, V.; Nguyen, J.; Kim, H.; Poon, A.; Sapru, A.; Matthay, M.A.; Kwok, P.Y.; Young, W.L.; Baxter-Lowe, L.A.; Zaroff, J.G.

2012-01-01

Prior studies have demonstrated associations between β-adrenergic receptor polymorphisms and left ventricular dysfunction—an important cause of allograft non-utilization for transplantation. We hypothesized that βAR polymorphisms predispose donor hearts to LV dysfunction after brain death. 1,043 organ donors managed from 2001-2006 were initially studied. The following βAR single nucleotide polymorphisms were genotyped: β1AR 1165C/G (Arg389Gly), β1AR 145A/G (Ser49Gly), β2AR 46G/A (Gly16Arg), and β2AR 79C/G (Gln27Glu). In multivariable regression analyses, the β2AR46 SNP was significantly associated with LV systolic dysfunction, with each minor allele additively decreasing the odds for LV ejection fraction<50%. The β1AR1165 and β2AR46 SNPs were associated with higher dopamine requirement during the donor management period: donors with the GG and AA genotypes had ORs of 2.64 (95% CI 1.52-4.57) and 2.70 (1.07-2.74) respectively for requiring >10 mcg/kg/min of dopamine compared to those with the CC and GG genotypes. However, no significant associations were found between βAR SNPs and cardiac dysfunction in 364 donors managed from 2007-2008, perhaps due to changes in donor management, lack of power in this validation cohort, or the absence of a true association. βAR polymorphisms may be associated with cardiac dysfunction after brain death, but these relationships require further study in independent donor cohorts. PMID:22994654

Allograft dendritic cell p40 homodimers activate donor-reactive memory CD8+ T cells

PubMed Central

Tsuda, Hidetoshi; Su, Charles A.; Tanaka, Toshiaki; Ayasoufi, Katayoun; Min, Booki; Valujskikh, Anna; Fairchild, Robert L.

2018-01-01

Recipient endogenous memory T cells with donor reactivity pose an important barrier to successful transplantation and costimulatory blockade–induced graft tolerance. Longer ischemic storage times prior to organ transplantation increase early posttransplant inflammation and negatively impact early graft function and long-term graft outcome. Little is known about the mechanisms enhancing endogenous memory T cell activation to mediate tissue injury within the increased inflammatory environment of allografts subjected to prolonged cold ischemic storage (CIS). Endogenous memory CD4+ and CD8+ T cell activation is markedly increased within complete MHC-mismatched cardiac allografts subjected to prolonged versus minimal CIS, and the memory CD8+ T cells directly mediate CTLA-4Ig–resistant allograft rejection. Memory CD8+ T cell activation within allografts subjected to prolonged CIS requires memory CD4+ T cell stimulation of graft DCs to produce p40 homodimers, but not IL-12 p40/p35 heterodimers. Targeting p40 abrogates memory CD8+ T cell proliferation within the allografts and their ability to mediate CTLA-4Ig–resistant allograft rejection. These findings indicate a critical role for memory CD4+ T cell–graft DC interactions to increase the intensity of endogenous memory CD8+ T cell activation needed to mediate rejection of higher-risk allografts subjected to increased CIS. PMID:29467328

Emulating Native Periosteum Cell Population and Subsequent Paracrine Factor Production To Promote Tissue Engineered Periosteum-Mediated Allograft Healing

PubMed Central

Hoffman, Michael D.

2015-01-01

Emulating autograft healing within the context of decellularized bone allografts has immediate clinical applications in the treatment of critical-sized bone defects. The periosteum, a thin, osteogenic tissue that surrounds bone, houses a heterogeneous population of stem cells and osteoprogenitors. There is evidence that periosteum-cell derived paracrine factors, specifically vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2), orchestrate autograft healing through host cell recruitment and subsequent tissue elaboration. In previous work, we demonstrated that the use of poly(ethylene glycol) (PEG) hydrogels as a tissue engineered (T.E.) periosteum to localize mesenchymal stem cells (MSCs) to the surface of decellularized bone enhances allograft healing and integration. Herein, we utilize a mixed population of 50:50 MSCs and osteoprogenitor cells to better mimic native periosteum cell population and paracrine factor production to further promote allograft healing. This mixed cell population was localized to the surface of decellularized allografts within degradable hydrogels and shown to expedite allograft healing. Specifically, bone callus formation and biomechanical graft-host integration are increased as compared to unmodified allografts. These results demonstrate the dual importance of periosteum-mediated paracrine factors orchestrating host cell recruitment as well as new bone formation while developing clinically translatable strategies for allograft healing and integration. PMID:25818449

Scabies in a bilateral hand allograft recipient: An additional mimicker of acute skin rejection in vascularized composite allotransplantation.

PubMed

Kanitakis, Jean; Morelon, Emmanuel

2017-06-01

Vascularized composite tissue allografts include skin, which frequently undergoes, in the early post-graft period, acute rejections. The diagnosis of acute rejection may be difficult as it can be mimicked by several dermatoses. We present a bilateral hand allograft recipient who developed, 16.5 years post-graft, cutaneous lesions raising suspicion about rejection. Physical examination and skin biopsy were diagnostic of scabies. This ectoparasitosis should be added in the list of dermatoses that can mimic allograft rejection in vascular composite allografts. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of L-carnitine.

PubMed

Marcovina, Santica M; Sirtori, Cesare; Peracino, Andrea; Gheorghiade, Mihai; Borum, Peggy; Remuzzi, Giuseppe; Ardehali, Hossein

2013-02-01

Mitochondria play important roles in human physiological processes, and therefore, their dysfunction can lead to a constellation of metabolic and nonmetabolic abnormalities such as a defect in mitochondrial gene expression, imbalance in fuel and energy homeostasis, impairment in oxidative phosphorylation, enhancement of insulin resistance, and abnormalities in fatty acid metabolism. As a consequence, mitochondrial dysfunction contributes to the pathophysiology of insulin resistance, obesity, diabetes, vascular disease, and chronic heart failure. The increased knowledge on mitochondria and their role in cellular metabolism is providing new evidence that these disorders may benefit from mitochondrial-targeted therapies. We review the current knowledge of the contribution of mitochondrial dysfunction to chronic diseases, the outcomes of experimental studies on mitochondrial-targeted therapies, and explore the potential of metabolic modulators in the treatment of selected chronic conditions. As an example of such modulators, we evaluate the efficacy of the administration of L-carnitine and its analogues acetyl and propionyl L-carnitine in several chronic diseases. L-carnitine is intrinsically involved in mitochondrial metabolism and function as it plays a key role in fatty acid oxidation and energy metabolism. In addition to the transportation of free fatty acids across the inner mitochondrial membrane, L-carnitine modulates their oxidation rate and is involved in the regulation of vital cellular functions such as apoptosis. Thus, L-carnitine and its derivatives show promise in the treatment of chronic conditions and diseases associated with mitochondrial dysfunction but further translational studies are needed to fully explore their potential. Copyright © 2013 Mosby, Inc. All rights reserved.

Replacement of the anterior cruciate ligament with a bone-ligament-bone anterior cruciate ligament allograft in dogs.

PubMed

Vasseur, P B; Rodrigo, J J; Stevenson, S; Clark, G; Sharkey, N

1987-06-01

Acute replacement of the canine anterior cruciate ligament (ACL) with a frozen, bone-ligament-bone anterior cruciate ligament preparation was studied using biochemical, immunologic, and biomechanical testing methods. Nine dogs were used for the study, six dogs received allografts and three received autografts. No tissue antigen matching was performed. All nine dogs were killed nine months after surgery. Necropsy examination revealed that the ACL was not present in three joints (one autograft, two allografts). The two autograft and four allograft ligaments available for mechanical testing sustained mean maximum loads that were 10% and 14%, respectively, of the mean maximum loads sustained by the contralateral ACL. Autoradiography indicated that cellular activity was more pronounced in the autograft specimens. Hydroxyproline uptake was 200% and 45% of normal in the autograft and allograft ligaments, respectively. Both autograft and allograft specimens were producing Type I collagen at the time of killing. Antidonor dog leukocyte antigen (DLA) antibody was detected in the synovial fluid taken at the time of killing from six of six dogs that received allografts and in zero of three dogs that received autografts.

Surgical treatment of infective endocarditis with aortic and tricuspid valve involvement using cryopreserved aortic and mitral valve allografts.

PubMed

Ostrovsky, Yury; Spirydonau, Siarhei; Shchatsinka, Mikalai; Shket, Aliaksandr

2015-05-01

Surgical treatment of infective and prosthetic endocarditis using allografts gives good results. Aortic allograft implantation is a common technique, while tricuspid valve replacement with a mitral allograft is very rare. Multiple valve disease in case of infective endocarditis is a surgical challenge as such patients are usually in a grave condition and results of surgical treatment are often unsatisfactory. In this article we describe a clinical case of successful surgical treatment in a patient with active infective endocarditis of aortic and tricuspid valve, complicated by an aortic-right ventricular fistula. The aortic valve and ascending aorta were replaced with a cryopreserved aortic allograft; the tricuspid valve was replaced with a cryopreserved mitral allograft. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Allograft replacement for absent native tissue.

PubMed

Chaudhury, Salma; Wanivenhaus, Florian; Fox, Alice J; Warren, Russell F; Doyle, Maureen; Rodeo, Scott A

2013-03-01

Structural instability due to poor soft tissue quality often requires augmentation. Allografts are important biological substitutes that are used for the symptomatic patient in the reconstruction of deficient ligaments, tendons, menisci, and osteochondral defects. Interest in the clinical application of allografts has arisen from the demand to obtain stable anatomy with restoration of function and protection against additional injury, particularly for high-demand patients who participate in sports. Traditionally, allografts were employed to reinforce weakened tissue. However, they can also be employed to substitute deficient or functionally absent tissue, particularly in the sports medicine setting. This article presents a series of 6 cases that utilized allografts to restore functionally deficient anatomic architecture, rather than just simply augmenting the degenerated or damaged native tissue. Detailed discussions are presented of the use of allografts as a successful treatment strategy to replace functionally weakened tissue, often after failed primary repairs.

Allograft Replacement for Absent Native Tissue

PubMed Central

Chaudhury, Salma; Wanivenhaus, Florian; Fox, Alice J.; Warren, Russell F.; Doyle, Maureen; Rodeo, Scott A.

2013-01-01

Context: Structural instability due to poor soft tissue quality often requires augmentation. Allografts are important biological substitutes that are used for the symptomatic patient in the reconstruction of deficient ligaments, tendons, menisci, and osteochondral defects. Interest in the clinical application of allografts has arisen from the demand to obtain stable anatomy with restoration of function and protection against additional injury, particularly for high-demand patients who participate in sports. Traditionally, allografts were employed to reinforce weakened tissue. However, they can also be employed to substitute deficient or functionally absent tissue, particularly in the sports medicine setting. Objective: This article presents a series of 6 cases that utilized allografts to restore functionally deficient anatomic architecture, rather than just simply augmenting the degenerated or damaged native tissue. Detailed discussions are presented of the use of allografts as a successful treatment strategy to replace functionally weakened tissue, often after failed primary repairs. PMID:24427387

Ionizing radiation regulates cardiac Ca handling via increased ROS and activated CaMKII.

PubMed

Sag, Can M; Wolff, Hendrik A; Neumann, Kay; Opiela, Marie-Kristin; Zhang, Juqian; Steuer, Felicia; Sowa, Thomas; Gupta, Shamindra; Schirmer, Markus; Hünlich, Mark; Rave-Fränk, Margret; Hess, Clemens F; Anderson, Mark E; Shah, Ajay M; Christiansen, Hans; Maier, Lars S

2013-11-01

Ionizing radiation (IR) is an integral part of modern multimodal anti-cancer therapies. IR involves the formation of reactive oxygen species (ROS) in targeted tissues. This is associated with subsequent cardiac dysfunction when applied during chest radiotherapy. We hypothesized that IR (i.e., ROS)-dependently impaired cardiac myocytes' Ca handling might contribute to IR-dependent cardiocellular dysfunction. Isolated ventricular mouse myocytes and the mediastinal area of anaesthetized mice (that included the heart) were exposed to graded doses of irradiation (sham 4 and 20 Gy) and investigated acutely (after ~1 h) as well as chronically (after ~1 week). IR induced a dose-dependent effect on myocytes' systolic function with acutely increased, but chronically decreased Ca transient amplitudes, which was associated with an acutely unaltered but chronically decreased sarcoplasmic reticulum (SR) Ca load. Likewise, in vivo echocardiography of anaesthetized mice revealed acutely enhanced left ventricular contractility (strain analysis) that declined after 1 week. Irradiated myocytes showed persistently increased diastolic SR Ca leakage, which was acutely compensated by an increase in SR Ca reuptake. This was reversed in the chronic setting in the face of slowed relaxation kinetics. As underlying cause, acutely increased ROS levels were identified to activate Ca/calmodulin-dependent protein kinase II (CaMKII). Accordingly, CaMKII-, but not PKA-dependent phosphorylation sites of the SR Ca release channels (RyR2, at Ser-2814) and phospholamban (at Thr-17) were found to be hyperphosphorylated following IR. Conversely, ROS-scavenging as well as CaMKII-inhibition significantly attenuated CaMKII-activation, disturbed Ca handling, and subsequent cellular dysfunction upon irradiation. Targeted cardiac irradiation induces a biphasic effect on cardiac myocytes Ca handling that is associated with chronic cardiocellular dysfunction. This appears to be mediated by increased oxidative stress and persistently activated CaMKII. Our findings suggest impaired cardiac myocytes Ca handling as a so far unknown mediator of IR-dependent cardiac damage that might be of relevance for radiation-induced cardiac dysfunction.

Productivity benefits of minimally invasive surgery in patients with chronic sacroiliac joint dysfunction.

PubMed

Saavoss, Josh D; Koenig, Lane; Cher, Daniel J

2016-01-01

Sacroiliac joint (SIJ) dysfunction is associated with a marked decrease in quality of life. Increasing evidence supports minimally invasive SIJ fusion as a safe and effective procedure for the treatment of chronic SIJ dysfunction. The impact of SIJ fusion on worker productivity is not known. Regression modeling using data from the National Health Interview Survey was applied to determine the relationship between responses to selected interview questions related to function and economic outcomes. Regression coefficients were then applied to prospectively collected, individual patient data in a randomized trial of SIJ fusion (INSITE, NCT01681004) to estimate expected differences in economic outcomes across treatments. Patients who receive SIJ fusion using iFuse Implant System(®) have an expected increase in the probability of working of 16% (95% confidence interval [CI] 11%-21%) relative to nonsurgical patients. The expected change in earnings across groups was US $3,128 (not statistically significant). Combining the two metrics, the annual increase in worker productivity given surgical vs nonsurgical care was $6,924 (95% CI $1,890-$11,945). For employees with chronic, severe SIJ dysfunction, minimally invasive SIJ fusion may improve worker productivity compared to nonsurgical treatment.

Blimp-1–mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis

PubMed Central

Cobb, Dustin A.; Bhadra, Rajarshi

2016-01-01

CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)–susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell–intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches. PMID:27481131

The enteroinsular axis and endocrine pancreatic function in chronic alcohol consumers: evidence for early beta-cell hypofunction.

PubMed

Patto, R J; Russo, E K; Borges, D R; Neves, M M

1993-09-01

Chronic alcohol consumers may have, as judged by functional criteria, exocrine as well as endocrine pancreatic dysfunction, the latter represented by a decreased insulin response to an oral glucose load. To investigate whether this decreased insulin response was due to an ethanol-induced beta-cell dysfunction or to an ethanol-induced dysfunction of the enteroinsular axis, we determined glucose, insulin, and C-peptide plasma concentrations following an oral and an intravenous glucose load in 16 healthy volunteer nonalcohol consumers and in 10 chronic alcohol consumers. In each group, total integrated response for glucose did not significantly change whether glucose was given orally or intravenously, indicating isoglycemic glucose loads. The total integrated response values for insulin in the alcoholic group following both glucose loads as well as C-peptide plasma concentrations were significantly lower than in the control group. Moreover, in both groups the insulin TIR values following the oral glucose load were significantly greater than the values obtained following the intravenous glucose load, indicating an incretin effect. These results indicate that the decreased insulin response observed in alcoholics was not caused by a dysfunction of the enteroinsular axis because it also occurred following an intravenous glucose load, but by an ethanol-induced beta-cell dysfunction because C-peptide and insulin were proportionally decreased in this group.

Association between plantar fascia vascularity and morphology and foot dysfunction in individuals with chronic plantar fasciitis.

PubMed

Chen, Hongying; Ho, Hok-Ming; Ying, Michael; Fu, Siu Ngor

2013-10-01

Single-cohort laboratory-based study. To identify whether plantar fascia vascularity and thickness are associated with foot pain and dysfunction in individuals with chronic plantar fasciitis. Background Altered plantar fascia vascularity and thickening of the fascia have been identified in individuals with chronic plantar fasciitis. Thirty-eight patients with chronic unilateral plantar fasciitis and 21 controls participated in this study. Proximal plantar fascia vascularization and thickness were assessed using ultrasound imaging, and pain and foot dysfunction were quantified with a visual analog scale and the Chinese version of the Foot Function Index, respectively. Paired t tests were used to assess the side-to-side differences in fascia thickness and vascularity index (VI) in the control and patient groups, and an unpaired t test was used to make comparisons with the patient group. Multiple regression analysis was performed to identify whether the VI and fascia thickness were associated with pain and foot dysfunction. There were significantly higher VI (mean ± SD, 2.4% ± 1.4%) and fascia thickness (5.0 ± 1.3 mm) values in the affected feet when compared with the unaffected feet in the patient group (VI, 1.4% ± 0.5%; fascia thickness, 3.3 ± 0.7 mm) and with the dominant side of the controls (VI, 1.6% ± 0.4%; fascia thickness, 2.9 ± 0.6 mm). After accounting for age, gender, body mass index, and duration of symptoms, the VI explained 13% and 33% of the variance in pain scores measured with a visual analog scale and the pain subscale of the Foot Function Index, respectively; the VI and fascia thickness explained 42% of the variance in the Foot Function Index. Individuals with unilateral chronic plantar fasciitis demonstrated significantly greater vascularity and thickened fascia on the affected side compared to the unaffected side and also to healthy controls. Fascia vascularity was associated independently with self-perceived pain, and both fascia vascularity and thickness were associated with foot dysfunction in patients with chronic plantar fasciitis. Public trials registry: Current Controlled Trials, ISRCTN49594569.

Clinical assessment and determinants of chronic allograft nephropathy in maintenance renal transplant patients.

PubMed

Grinyo, Josep M; Saval, Nuria; Campistol, Josep M

2011-11-01

Current knowledge about the natural history, treatment and physicians' perception of chronic allograft nephropathy (CAN) is limited. The present study evaluated the prevalence and determinants of CAN in renal transplant patients. Epidemiological, cross-sectional multi-centre study conducted in Spain. A total of 872 renal transplant recipients with a functioning graft and at least 2 years of post-transplant data on renal function were consecutively included. CAN diagnosis was recorded based on physician's clinical criteria and on laboratory criteria (serum creatinine ≥ 2 mg/dL and/or glomerular filtration rate ≤ 50 mL/min). The mean time from transplantation until the time of this study was 8.2 years. CAN was diagnosed in 35% of patients (n = 305) according to the physician's criteria (31% of whom with histological assessment) and in 55.5% (n = 482) according to laboratory objective criteria. An older donor age, lack of induction therapy, cyclosporine use, lower tacrolimus levels at 1 year, acute rejection, hypertension and worse initial renal function were associated with CAN development. Time from transplant to biopsy was greater in patients with anti-proteinuric treatment. Immunosuppression was modified in 46.9% of patients with CAN diagnosis [calcineurin inhibitor (CNI) reduction alone in 18.9% of cases; CNI reduction and mycophenolate modification in 17.8% and CNI reduction or withdrawal with introduction of proliferation signal inhibitors in 12.9%). After ~8 years from renal transplantation, 55.5% of patients presented CAN, which was considerably underestimated by physicians. An older donor age and less initial immunosuppression seemed to be related to CAN development.

Reliability of chronic allograft nephropathy diagnosis in sequential protocol biopsies.

PubMed

Serón, Daniel; Moreso, Francesc; Fulladosa, Xavier; Hueso, Miguel; Carrera, Marta; Grinyó, Josep M

2002-02-01

Chronic allograft nephropathy (CAN) progresses rapidly during the first few months and slowly thereafter. Although the presence of CAN in protocol renal biopsies is a predictor of outcome, the reliability of this diagnosis according to Banff criteria has not been characterized. Renal lesions were evaluated according to the Banff criteria in sequential protocol biopsies performed at 4 and 14 months in 310 biopsies obtained from 155 patients. CAN progressed from 40 to 53% (P=0.001) while serum creatinine remained stable (146 +/- 44 vs. 147 +/- 48 micromol/L, P=NS). Graft survival in patients with and without CAN in the first biopsy was 74 versus 91% (P < 0.05), and in the second biopsy 75 versus 94% (P < 0.05). In 54 patients (35%) no CAN was present in both biopsies, 39 (25%) showed progression to CAN, 19 (12%) showed regression of CAN, and 43 (28%) showed CAN in both biopsies. Graft survival was: 100%, 81.6%, 82.6% and 69.4%, respectively (P < 0.01). Assuming that CAN does not regress and sampling error is normally distributed, we estimated that 25% of biopsies cannot be properly classified. The increase in the incidence of CAN between the 4th and 14th month is lower than the proportion of misclassified biopsies. Thus, monitoring the progression of CAN by means of two sequential biopsies at 4 and 14 months is inaccurate. We suggest that progression of scarring be monitored by means of a donor and a protocol biopsy performed during the first year evaluated with a quantitative approach.

Post-transplant sCD30 and neopterin as predictors of chronic allograft nephropathy: impact of different immunosuppressive regimens.

PubMed

Weimer, R; Süsal, C; Yildiz, S; Staak, A; Pelzl, S; Renner, F; Dietrich, H; Daniel, V; Kamali-Ernst, S; Ernst, W; Padberg, W; Opelz, G

2006-08-01

Immunological monitoring for chronic allograft nephropathy (CAN) is of great potential interest. We assessed serum soluble CD30 (sCD30) together with in vitro Th2-type responses (IL-4, IL-10, CD4 helper activity) and neopterin in a prospective study of 84 renal transplant recipients with 2-year follow-up. Patients were randomized to CsA/Aza, CsA/MMF and Tacr/Aza, respectively, to analyze the effect of immunosuppression on posttransplant sCD30 and neopterin. ATG induction and acute rejections did not alter sCD30 levels whereas CMV disease was associated with transient upregulation of sCD30 (p = 0.003 at 4 months) and sustained upregulation of neopterin (corrected for graft function (Neo/CR) p = 0.005 at 2 years). Tacr versus CsA treatment proved to be an independent variable associated with downregulation of 1-year sCD30, which was positively related to Neo/CR (p = 0.007 and 0.01, respectively; logistic regression). Importantly, increased 1-year sCD30 and Neo/CR were associated with decreased glomerular filtration rate at 2 years (p = 0.02 and p < 0.0005, respectively) and evidence of CAN (p < 0.0005). High 1-year sCD30 could not be attributed to enhanced Th2-type responses and was not associated with HLA antibody formation. Our data suggest that elevated sCD30 and neopterin predict graft deterioration by CAN. Tacr effectively downregulates these responses and might be of advantage in patients with elevated sCD30 or neopterin.

Relevance of MICA and other non-HLA antibodies in clinical transplantation.

PubMed

Sumitran-Holgersson, Suchitra

2008-10-01

The clinical importance of HLA-specific antibodies for organ allograft outcome is well established. In the past few years, there has been an increasing interest in non-HLA antigens as targets of injury in organ transplant recipients. This increased interest has been spurred by the fact that HLA-identical kidney transplants also undergo immunological rejections. Polymorphisms within non-HLA genes associated with evoking an immune response to alloantigens are currently being studied for their association with transplant outcome. Non-HLA antigens, such as the polymorphic MHC class I-related chain A (MICA), expressed on endothelial cells have been implicated in the pathogenesis of hyperacute, acute and chronic organ allograft rejections. Use of endothelial cells as targets may clarify the specificities of other clinically relevant non-HLA antibodies in graft rejections. This review summarizes past and current knowledge of the clinical importance and specificities of non-HLA antibodies, and mechanisms by which these antibodies may contribute to graft destruction in clinical transplantation. The aims of current research into the role of non-HLA antigens and their genetics in predicting outcome are to develop an improved insight into the basic science of transplantation and to develop a risk or prognostic index for use in the clinical setting. Non-HLA antibody responses are receiving increasing interest in acute and chronic rejection and specificity, affinity, and pathogenicity need to be investigated to estimate their contribution. Undoubtedly, this will continue to be an area of interest in terms of fully understanding the role of non-HLA antigens as targets of immune-mediated injury and the potential for clinical intervention.

[The role of oxidative metabolism disturbance in the development of NO-related endothelial dysfunction during chronic hearth failure].

PubMed

Goishvili, N; Kakauridze, N; Sanikidze, T

2005-05-01

The aim of the work was to establish the oxidative metabolism changes and NO data in Chronic Hearth Failure (HF). 52 patients were included in the investigation, among them 37 patients with CHD and chronic HF (II-IV functional class by NIHA) and 17 without it (control group). For revealing of organism redox-status (ceruloplasmine, Fe3+-transfferine, Mn2+, methemoglobine) the blood paramagnetic centers was studied by electron paramagnetic resonance method. For revealing of blood free NO, the diethyldithiocarbamat (SIGMA) was used. In chronic HF the oxidative process intensification and organism compensate reaction reduction with low Fe3+-transferine levels, increased Mn2++, methaemoglobin and inactivation of erythrocytes membranes adrenergic receptors were revealed. In chronic HF the accumulation of reactive oxygen levels provoke NO transformation in peroxynitrote with following decreases of blood free NO and develop the endothelial dysfunction.

Antibody-Mediated Rejection of Single Class I MHC-Disparate Cardiac Allografts

PubMed Central

Hattori, Yusuke; Bucy, R. Pat; Kubota, Yoshinobu; Baldwin, William M.; Fairchild, Robert L.

2012-01-01

Murine CCR5−/− recipients produce high titers of antibody to complete MHC-mismatched heart and renal allografts. To study mechanisms of class I MHC antibody-mediated allograft injury, we tested the rejection of heart allografts transgenically expressing a single class I MHC disparity in wild-type C57BL/6 (H-2b) and B6.CCR5−/− recipients. Donor-specific antibody titers in CCR5−/− recipients were 30-fold higher than in wild-type recipients. B6.Kd allografts survived longer than 60 days in wild-type recipients whereas CCR5−/− recipients rejected all allografts within 14 days. Rejection was accompanied by infiltration of CD8 T cells, neutrophils, and macrophages and C4d deposition in the graft capillaries. B6.Kd allografts were rejected by CD8−/−/CCR5−/−, but not μMT−/−/CCR5−/−, recipients indicating the need for antibody but not CD8 T cells. Grafts retrieved at day 10 from CCR5−/− and CD8−/−/CCR5−/− recipients and from RAG-1−/− allograft recipients injected with anti-Kd antibodies expressed high levels of perforin, myeloperoxidase and CCL5 mRNA. These studies indicate that the continual production of anti-donor class I MHC antibody can mediate allograft rejection, that donor-reactive CD8 T cells synergize with the antibody to contribute to rejection, and that expression of three biomarkers during rejection can occur in the absence of this CD8 T cell activity. PMID:22578247

MicroRNA-10b downregulation mediates acute rejection of renal allografts by derepressing BCL2L11

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Xiaoyou; Dong, Changgui; Jiang, Zhengyao

Kidney transplantation is the major therapeutic option for end-stage kidney diseases. However, acute rejection could cause allograft loss in some of these patients. Emerging evidence supports that microRNA (miRNA) dysregulation is implicated in acute allograft rejection. In this study, we used next-generation sequencing to profile miRNA expression in normal and acutely rejected kidney allografts. Among 75 identified dysregulated miRNAs, miR-10b was the most significantly downregulated miRNAs in rejected allografts. Transfecting miR-10b inhibitor into human renal glomerular endothelial cells recapitulated key features of acute allograft rejection, including endothelial cell apoptosis, release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor α, interferon-γ, andmore » chemokine (C–C motif) ligand 2) and chemotaxis of macrophages whereas transfection of miR-10b mimics had opposite effects. Downregulation of miR-10b directly derepressed the expression of BCL2L11 (an apoptosis inducer) as revealed by luciferase reporter assay. Taken together, miR-10b downregulation mediates many aspects of disease pathogenicity of acute kidney allograft rejection. Restoring miR-10b expression in glomerular endothelial cells could be a novel therapeutic approach to reduce acute renal allograft loss. - Highlights: • miR-10b was the most downregulated microRNAs in acutely rejected renal allografts. • miR-10b downregulation triggered glomerular endothelial cell apoptosis. • miR-10b downregulation induced release of pro-inflammatory cytokines. • miR-10b downregulation derepressed its pro-apoptotic target BCL2L11.« less

The Influence of Liquids on the Mechanical Properties of Allografts in Bone Impaction Grafting.

PubMed

Putzer, David; Ammann, Christoph Gert; Coraça-Huber, Débora; Lechner, Ricarda; Schmölz, Werner; Nogler, Michael

2017-10-01

Allografts are used to compensate for bone defects resulting from revision surgery, tumor surgery, and reconstructive bone surgery. Although it is well known that the reduction of fat content of allografts increases mechanical properties, the content of liquids with a known grain size distribution has not been assessed so far. The aim of the study was to compare the mechanical properties of dried allografts (DA) with allografts mixed with a saline solution (ASS) and with allografts mixed with blood (AB) having a similar grain size distribution. Fresh-frozen morselized bone chips were cleaned chemically, sieved, and reassembled in specific portions with a known grain size distribution. A uniaxial compression was used to assess the yield limit, initial density, density at yield limit, and flowability of the three groups before and after compaction with a fall hammer apparatus. No statistically significant difference could be found for the yield limit between DA and ASS (p = 0.339) and between ASS and AB (p = 0.554). DA showed a statistically significant higher yield limit than AB (p = 0.022). Excluding the effect of the grain size distribution on the mechanical properties, it was shown that allografts have a lower yield limit when lipids are present. The liquid content of allografts seems to play an inferior role as no statistically significant difference could be found between DA and ASS. It is suggested, in accordance with other studies, to chemically clean allografts before implantation to reduce the contamination risk and the fat content.

Tolerance to Vascularized Composite Allografts in Canine Mixed Hematopoietic Chimeras

PubMed Central

Mathes, David W.; Hwang, Billanna; Graves, Scott S.; Edwards, James; Chang, Jeff; Storer, Barry E.; Butts-Miwongtum, Tiffany; Sale, George E.; Nash, Richard A.; Storb, Rainer.

2012-01-01

Background Mixed donor-host chimerism, established through hematopoietic cell transplantation (HCT), is a highly reproducible strategy for the induction of tolerance towards solid organs. Here, we ask whether a nonmyeloablative conditioning regimen establishing mixed donor-host chimerism leads to tolerance of highly antigenic vascularized composite allografts. Methods Stable mixed chimerism was established in dogs given a sublethal dose (1–2 Gy) total body irradiation before and a short course of immunosuppression after dog leukocyte antigen-identical marrow transplantation. Vascularized composite allografts from marrow donors were performed after a median of 36 (range 4-54) months after HCT. Results All marrow recipients maintained mixed donor-host hematopoietic chimerism and accepted composite tissue grafts for periods ranging between 52 and 90 weeks; in turn, marrow donors rejected vascularized composite allografts from their respective marrow recipients within 18–29 days. Biopsies of muscle and skin of vascularized composite allografts from mixed chimeras showed few infiltrating cells compared to extensive infiltrates in biopsies of vascularized composite allografts from marrow donors. Elevated levels of CD3+ FoxP3+ T-regulatory cells were found in skin and muscle of vascularized composite allografts of mixed chimeras compared to normal tissues. In mixed chimeras, increased numbers of T-regulatory cells were found in draining compared to non-draining lymph nodes of vascularized composite allografts. Conclusion These data suggest that nonmyeloablative HCT may form the basis for future clinical applications of solid organ transplantation and that T-regulatory cells may function towards maintenance of the vascularized composite allograft. PMID:22082819

Iliac Crest Bone Graft versus Local Autograft or Allograft for Lumbar Spinal Fusion: A Systematic Review.

PubMed

Tuchman, Alexander; Brodke, Darrel S; Youssef, Jim A; Meisel, Hans-Jörg; Dettori, Joseph R; Park, Jong-Beom; Yoon, S Tim; Wang, Jeffrey C

2016-09-01

Systematic review. To compare the effectiveness and safety between iliac crest bone graft (ICBG) and local autologous bone and allograft in the lumbar spine. A systematic search of multiple major medical reference databases identified studies evaluating spinal fusion in patients with degenerative joint disease using ICBG, local autograft, or allograft in the thoracolumbar spine. Six comparative studies met our inclusion criteria. A "low" strength of the overall body of evidence suggested no difference in fusion percentages in the lumbar spine between local autograft and ICBG. We found no difference in fusion percentages based on low evidence comparing allograft with ICBG autograft. There were no differences in pain or functional results comparing local autograft or allograft with ICBG autograft. Donor site pain and hematoma/seroma occurred more frequently in ICBG autograft group for lumbar fusion procedures. There was low evidence around the estimate of patients with donor site pain following ICBG harvesting, ranging from 16.7 to 20%. With respect to revision, low evidence demonstrated no difference between allograft and ICBG autograft. There was no evidence comparing patients receiving allograft with local autograft for fusion, pain, functional, and safety outcomes. In the lumbar spine, ICBG, local autograft, and allograft have similar effectiveness in terms of fusion rates, pain scores, and functional outcomes. However, ICBG is associated with an increased risk for donor site-related complications. Significant limitations exist in the available literature when comparing ICBG, local autograft, and allograft for lumbar fusion, and thus ICBG versus other fusion methods necessitates further investigation.

PBSCT is associated with poorer survival and increased chronic GvHD than BMT in Japanese paediatric patients with acute leukaemia and an HLA-matched sibling donor.

PubMed

Shinzato, Aki; Tabuchi, Ken; Atsuta, Yoshiko; Inoue, Masami; Inagaki, Jiro; Yabe, Hiromasa; Koh, Katsuyoshi; Kato, Koji; Ohta, Hideaki; Kigasawa, Hisato; Kitoh, Toshiyuki; Ogawa, Atsushi; Takahashi, Yoshiyuki; Sasahara, Yoji; Kato, Shun-Ichi; Adachi, Souichi

2013-09-01

Peripheral blood stem cells (PBSC) may be used as an alternative to bone marrow (BM) for allogeneic transplantation. Since peripheral blood stem cell bank from unrelated volunteer donor has been started in Japan, use of PBSC allografts may be increased. Therefore we surveyed the outcomes of Japanese leukemia children after PBSC and BM transplantation. This retrospective study compared the outcomes of 661 children (0-18 years) with acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML) who received their first allogeneic peripheral blood stem cell transplantation (PBSCT; n = 90) or bone marrow transplantation (BMT; n = 571) from HLA-matched siblings between January 1996 and December 2007. Neutrophil recovery was faster after PBSCT than after BMT (ALL: P < 0.0001; AML: P = 0.0002), as was platelet recovery (ALL: P = 0.0008; AML: P = 0.0848). However, the cumulative incidence of chronic graft-versus-host disease (GvHD) was higher after PBSCT than after BMT (ALL: 26.0% vs. 9.9%, P = 0.0066; AML: 41.6% vs. 11.1%, P < 0.0001). The 5-year disease-free survival (DFS) was lower after PBSCT than after BMT for ALL (40.6% vs. 57.1%, P = 0.0257). The 5-year overall survival (OS) was lower after PBSCT than after BMT for ALL (42.4% vs. 63.7%, P = 0.0032) and AML (49.8% vs. 71.8%, P = 0.0163). Multivariate analysis revealed the use of PBSC was a significant risk factor for DFS and OS. PBSCT and BMT did not differ in relapse rate, acute GvHD for ALL and AML, or in DFS for AML. PBSC allografts in Japanese children engraft faster but are associated with poorer survival and increased chronic GvHD. Copyright © 2013 Wiley Periodicals, Inc.

Neurocognitive Dysfunction in Systemic Lupus Erythematosus: Association with Antiphospholipid Antibodies, Disease Activity and Chronic Damage

PubMed Central

Conti, Fabrizio; Alessandri, Cristiano; Perricone, Carlo; Scrivo, Rossana; Rezai, Soheila; Ceccarelli, Fulvia; Spinelli, Francesca Romana; Ortona, Elena; Marianetti, Massimo; Mina, Concetta; Valesini, Guido

2012-01-01

Introduction Systemic lupus erythematosus (SLE) is characterized by frequent neuropsychiatric involvement, which includes cognitive impairment (CI). We aimed at assessing CI in a cohort of Italian SLE patients by using a wide range of neurocognitive tests specifically designed to evaluate the fronto-subcortical dysfunction. Furthermore, we aimed at testing whether CI in SLE is associated with serum autoantibodies, disease activity and chronic damage. Methods Fifty-eight consecutive patients were enrolled. Study protocol included data collection, evaluation of serum levels of ANA, anti-dsDNA, anti-cardiolipin, anti-β2-glycoprotein I, anti-P ribosomal, anti-endothelial cell, and anti-Nedd5 antibodies. SLEDAI-2000 and SLICC were used to assess disease activity and chronic damage. Patients were administered a test battery specifically designed to detect fronto-subcortical dysfunction across five domains: memory, attention, abstract reasoning, executive function and visuospatial function. For each patient, the raw scores from each test were compared with published norms, then transformed into Z scores (deviation from normal mean), and finally summed in the Global Cognitive Dysfunction score (GCDs). Results Nineteen percent of patients had mild GCDs impairment (GCDs 2–3), 7% moderate (GCDs 4–5) and 5% severe (GCDs≥6). The visuospatial domain was the most compromised (MDZs = −0.89±1.23). Anti-cardiolipin IgM levels were associated with visuospatial domain impairment (r = 0.331, P = 0.005). SLEDAI correlated with GCDs, and attentional and executive domains; SLICC correlated with GCDs, and with visuospatial and attentional domains impairment. Conclusions Anti-phospholipids, disease activity, and chronic damage are associated with cognitive dysfunction in SLE. The use of a wide spectrum of tests allowed for a better selection of the relevant factors involved in SLE cognitive dysfunction, and standardized neuropsychological testing methods should be used for routine assessment of SLE patients. PMID:22461897

76 FR 78216 - Organ Procurement and Transplantation Network

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-16

... composite tissue allograft; however, for the purposes of rulemaking, the Health Resources and Services..., Hand transplantation and vascularized composite tissue allografts in orthopaedics and traumatology... vascularized composite allografts, described below, within the definition of organs covered by the rules...

Minimizing tacrolimus decreases the risk of new-onset diabetes mellitus after liver transplantation

PubMed Central

Song, Jiu-Lin; Gao, Wei; Zhong, Yan; Yan, Lu-Nan; Yang, Jia-Yin; Wen, Tian-Fu; Li, Bo; Wang, Wen-Tao; Wu, Hong; Xu, Ming-Qing; Chen, Zhe-Yu; Wei, Yong-Gang; Jiang, Li; Yang, Jian

2016-01-01

AIM: To investigate the impact of minimum tacrolimus (TAC) on new-onset diabetes mellitus (NODM) after liver transplantation (LT). METHODS: We retrospectively analyzed the data of 973 liver transplant recipients between March 1999 and September 2014 in West China Hospital Liver Transplantation Center. Following the exclusion of ineligible recipients, 528 recipients with a TAC-dominant regimen were included in our study. We calculated and determined the mean trough concentration of TAC (cTAC) in the year of diabetes diagnosis in NODM recipients or in the last year of the follow-up in non-NODM recipients. A cutoff of mean cTAC value for predicting NODM 6 mo after LT was identified using a receptor operating characteristic curve. TAC-related complications after LT was evaluated by χ2 test, and the overall and allograft survival was evaluated using the Kaplan-Meier method. Risk factors for NODM after LT were examined by univariate and multivariate Cox regression. RESULTS: Of the 528 transplant recipients, 131 (24.8%) developed NODM after 6 mo after LT, and the cumulative incidence of NODM progressively increased. The mean cTAC of NODM group recipients was significantly higher than that of recipients in the non-NODM group (7.66 ± 3.41 ng/mL vs 4.47 ± 2.22 ng/mL, P < 0.05). Furthermore, NODM group recipients had lower 1-, 5-, 10-year overall survival rates (86.7%, 71.3%, and 61.1% vs 94.7%, 86.1%, and 83.7%, P < 0.05) and allograft survival rates (92.8%, 84.6%, and 75.7% vs 96.1%, 91%, and 86.1%, P < 0.05) than the others. The best cutoff of mean cTAC for predicting NODM was 5.89 ng/mL after 6 mo after LT. Multivariate analysis showed that old age at the time of LT (> 50 years), hypertension pre-LT, and high mean cTAC (≥ 5.89 ng/mL) after 6 mo after LT were independent risk factors for developing NODM. Concurrently, recipients with a low cTAC (< 5.89 ng/mL) were less likely to become obese (21.3% vs 30.2%, P < 0.05) or to develop dyslipidemia (27.5% vs 44.8%, P <0.05), chronic kidney dysfunction (14.6% vs 22.7%, P < 0.05), and moderate to severe infection (24.7% vs 33.1%, P < 0.05) after LT than recipients in the high mean cTAC group. However, the two groups showed no significant difference in the incidence of acute and chronic rejection, hypertension, cardiovascular events and new-onset malignancy. CONCLUSION: A minimal TAC regimen can decrease the risk of long-term NODM after LT. Maintaining a cTAC value below 5.89 ng/mL after LT is safe and beneficial. PMID:26877618

The role of imaging in diagnosing diseases of the distal radioulnar joint, triangular fibrocartilage complex, and distal ulna.

PubMed

Squires, Judy H; England, Eric; Mehta, Kaushal; Wissman, Robert D

2014-07-01

The purpose of this article is to review the anatomy, biomechanics, and multimodality imaging findings of common and uncommon distal radioulnar joint (DRUJ), triangular fibrocartilage complex, and distal ulna abnormalities. The DRUJ is a common site for acute and chronic injuries and is frequently imaged to evaluate chronic wrist pain, forearm dysfunction, and traumatic forearm injury. Given the complex anatomy of the wrist, the radiologist plays a vital role in the diagnosis of wrist pain and dysfunction.

Quercetin prevents chronic unpredictable stress induced behavioral dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress.

PubMed

Mehta, Vineet; Parashar, Arun; Udayabanu, Malairaman

2017-03-15

It is now evident that chronic stress is associated with anxiety, depression and cognitive dysfunction and very few studies have focused on identifying possible methods to prevent these stress-induced disorders. Previously, we identified abundance of quercetin in Urtica dioica extract, which efficiently attenuated stress related complications. Therefore, current study was designed to investigate the effect of quercetin on chronic unpredicted stress (CUS) induced behavioral dysfunction, oxidative stress and neuroinflammation in the mouse hippocampus. Animals were subjected to unpredicted stress for 21days, during which 30mg/kg quercetin was orally administered to them. Effect of CUS and quercetin treatment on animal behavior was assessed between day 22-26. Afterward, the hippocampus was processed to evaluate neuronal damage, oxidative and inflammatory stress. Results revealed that stressed animals were highly anxious (Elevated Plus Maze and Open Field), showed depressive-like behavior (sucrose preference task), performed poorly in short-term and long-term associative memory task (passive avoidance step-through task) and displayed reduced locomotion (open field). Quercetin alleviated behavioral dysfunction in chronically stressed animals. Compared to CUS, quercetin treatment significantly reduced anxiety, attenuated depression, improved cognitive dysfunction and normalized locomotor activity. Further, CUS elevated the levels of oxidative stress markers (TBARS, nitric oxide), lowered antioxidants (total thiol, catalase), enhanced expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1β and COX-2) in the hippocampus and damaged hippocampal neurons. Quercetin treatment significantly lowered oxidative and inflammatory stress and prevented neural damage. In conclusion, quercetin can efficiently prevent stress induced neurological complications by rescuing brain from oxidative and inflammatory stress. Copyright © 2017 Elsevier Inc. All rights reserved.

Frontal cortical mitochondrial dysfunction and mitochondria-related β-amyloid accumulation by chronic sleep restriction in mice.

PubMed

Zhao, Hongyi; Wu, Huijuan; He, Jialin; Zhuang, Jianhua; Liu, Zhenyu; Yang, Yang; Huang, Liuqing; Zhao, Zhongxin

2016-08-17

Mitochondrial dysfunction induced by mitochondria-related β-amyloid (Aβ) accumulation is increasingly being considered a novel risk factor for sporadic Alzheimer's disease pathophysiology. The close relationship between chronic sleep restriction (CSR) and cortical Aβ elevation was confirmed recently. By assessing frontal cortical mitochondrial function (electron microscopy manifestation, cytochrome C oxidase concentration, ATP level, and mitochondrial membrane potential) and the levels of mitochondria-related Aβ in 9-month-old adult male C57BL/6J mice subjected to CSR and as an environmental control (CO) group, we aimed to evaluate the association of CSR with mitochondrial dysfunction and mitochondria-related Aβ accumulation. In this study, frontal cortical mitochondrial dysfunction was significantly more severe in CSR mice compared with CO animals. Furthermore, CSR mice showed higher mitochondria-associated Aβ, total Aβ, and mitochondria-related β-amyloid protein precursor (AβPP) levels compared with CO mice. In the CSR model, mouse frontal cortical mitochondrial dysfunction was correlated with mitochondria-associated Aβ and mitochondria-related AβPP levels. However, frontal cortical mitochondria-associated Aβ levels showed no significant association with cortical total Aβ and mitochondrial AβPP concentrations. These findings indicated that CSR-induced frontal cortical mitochondrial dysfunction and mitochondria-related Aβ accumulation, which was closely related to mitochondrial dysfunction under CSR.

Electrocardiographic Characteristics of Potential Organ Donors and Associations with Cardiac Allograft Utilization

PubMed Central

Khush, Kiran K.; Menza, Rebecca; Nguyen, John; Goldstein, Benjamin A.; Zaroff, Jonathan G.; Drew, Barbara J.

2012-01-01

Background Current regulations require that all cardiac allograft offers for transplantation must include an interpreted 12-lead electrocardiogram (ECG). However, little is known about the expected ECG findings in potential organ donors, or the clinical significance of any identified abnormalities in terms of cardiac allograft function and suitability for transplantation. Methods and Results A single experienced reviewer interpreted the first ECG obtained after brainstem herniation in 980 potential organ donors managed by the California Transplant Donor Network from 2002-2007. ECG abnormalities were summarized, and associations between specific ECG findings and cardiac allograft utilization for transplantation were studied. ECG abnormalities were present in 51% of all cases reviewed. The most common abnormalities included voltage criteria for left ventricular hypertrophy (LVH), prolongation of the corrected QT interval (QTc), and repolarization changes (ST/T wave abnormalities). Fifty seven percent of potential cardiac allografts in this cohort were accepted for transplantation. LVH on ECG was a strong predictor of allograft non-utilization. No significant associations were seen between QTc prolongation, repolarization changes and allograft utilization for transplantation, after adjusting for donor clinical variables and echocardiographic findings. Conclusions We have performed the first comprehensive study of ECG findings in potential donors for cardiac transplantation. Many of the common ECG abnormalities seen in organ donors may result from the heightened state of sympathetic activation that occurs after brainstem herniation, and are not associated with allograft utilization for transplantation. PMID:22615333

Targeting Sirtuin-1 prolongs murine renal allograft survival and function

PubMed Central

Levine, Matthew H.; Wang, Zhonglin; Xiao, Haiyan; Jiao, Jing; Wang, Liqing; Bhatti, Tricia R.; Hancock, Wayne W.; Beier, Ulf H.

2016-01-01

Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3+ T-regulatory (Treg) cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3+ Treg suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1fl/flCD4cre) or mice treated with a Sirtuin-1 specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1fl/flCD4cre recipients showed markedly longer survival and improved kidney function. Sirt1fl/flCD4cre recipients exhibited donor specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell mediated rejection. However, effects on non-T cells that could adversely affect allograft survival and function merit consideration. PMID:27083279

IFN-γ Blocks CD4+CD25+ Tregs and Abolishes Immune Privilege of Minor Histocompatibility Mismatched Corneal Allografts

PubMed Central

Cunnusamy, Khrishen; Niederkorn, Jerry Y.

2014-01-01

Th1 CD4+ cells are believed to be the primary mediators of corneal allograft rejection. However, rejection of fully allogeneic C57BL/6 corneal allografts soared from 50% to 90% in both INF-γ−/− and anti-IFN-γ-treated BALB/c mice. In contrast, similar deficits in IFN-γ in BALB/c hosts enhanced immune privilege of BALB.B (minor histocompatibility antigen-matched, MHC-mismatched) and NZB (major histocompatibility complex-matched, minor histocompatibility antigen-mismatched) corneal allografts – decreasing rejection from 80% to ~20%. This effect of IFN-γ was independent of CD4+ T cell lineage commitment as both anti-IFN-γ-treated acceptor and rejector mice displayed a Th2 cytokine profile. The presence of IFN-γ prevented the generation of alloantigen-specific CD4+CD25+ Tregs in hosts receiving either MHC only mismatched BALB.B or minor only histocompatibility (minor H)-mismatched NZB corneal allografts. Tregs in these hosts, promoted corneal allograft survival by suppressing Th2 effector cells. By contrast, IFN-γ was necessary for the generation of CD4+CD25+ Tregs that prevented rejection of fully allogeneic C57BL/6 corneal allografts in BALB/c hosts. These findings suggest that MHC-matching in combination with blockade of IFN-γ holds promise as a means of enhancing corneal allograft survival. PMID:24119152

The effect of mesenchymal stem cell sheets on structural allograft healing of critical-sized femoral defects in mice

PubMed Central

Long, Teng; Zhu, Zhenan; Awad, Hani A.; Schwarz, Edward M.; Hilton, Matthew J.; Dong, Yufeng

2014-01-01

Structural bone allografts are widely used in the clinic to treat critical sized bone defects, despite lacking the osteoinductive characteristics of live autografts. To address this, we generated revitalized structural allografts wrapped with mesenchymal stem/progenitor cell (MSC) sheets, which were produced by expanding primary syngenic bone marrow derived cells on temperature-responsive plates, as a tissue engineered periosteum. In vitro assays demonstrated maintenance of the MSC phenotype in the sheets, suggesting that short-term culturing of MSC sheets is not detrimental. To test their efficacy in vivo, allografts wrapped with MSC sheets were transplanted into 4-mm murine femoral defects and compared to allografts with direct seeding of MSCs and allografts without cells. Evaluations consisted of x-ray plain radiography, 3D microCT, histology, and biomechanical testing at 4- and 6-weeks post-surgery. Our findings demonstrate that MSC sheets induce prolonged cartilage formation at the graft-host junction and enhanced bone callus formation, as well as graft-host osteointegration. Moreover, a large periosteal callus was observed spanning the allografts with MSC sheets, which partially mimics live autograft healing. Finally, biomechanical testing showed a significant increase in the structural and functional properties of MSC sheet grafted femurs. Taken together, MSC sheets exhibit enhanced osteogenicity during critical sized bone defect repair, demonstrating the feasibility of this tissue engineering solution for massive allograft healing. PMID:24393269

Estimating the usage of allograft in the treatment of major burns.

PubMed

Horner, C W M; Atkins, J; Simpson, L; Philp, B; Shelley, O; Dziewulski, P

2011-06-01

To assess the amount of allograft used in the past treatment of major burns and calculate a figure to guide estimation of the quantity of allograft required to treat future patients and aid resource planning. A retrospective observational study. Records of 143 patients treated with major burns at a regional centre, from January 2004 to November 2008 were accessed with biometric data and quantity of allograft used being recorded. This data was used to calculate an allograft index (cm² allograft used/burn surface area (cm²)) (AI) for each patient. 112 of the 143 patients had complete sets of data, of the 112, 89 patients survived the initial stay in hospital. For all data average AI=1.077 ± 0.090. AI varied according to burn % area with burns < 40% requiring 0.490 cm² allo/cm²burn, increasing in a logarithmic fashion (R²=0.995) for burn areas > 40%. The ability to estimate deceased donor skin requirements based on % body surface area affected is important in the care planning for patients with major burns. Our findings of 0.5 cm² allograft/cm² burn for injuries less than 40% TBSA, increasing to 1.82 cm² allograft/cm² burn for injuries up to 80% TBSA can be used for planning purposes for individual services and for burn disaster planning. Copyright © 2010 Elsevier Ltd and ISBI. All rights reserved.

Use of cultured human epidermal keratinocytes for allografting burns and conditions for temporary banking of the cultured allografts.

PubMed

Bolívar-Flores, J; Poumian, E; Marsch-Moreno, M; Montes de Oca, G; Kuri-Harcuch, W

1990-02-01

Five children who suffered burns clinically regarded as full skin thickness loss were grafted with cultured allogeneic skin from newborn prepuce. The wounds had remained open and infected without healing for about 20 days before the patients were received in the burn unit. To avoid losing surviving deep epidermal cells the wounds were débrided but not deeply excised and, a few days before allografting, they were washed with isodine solution and sterile water, and treated with silvadene cream application. All children received 76 cultured allografts of about 60 cm2 each. After allografting, the wounds were epithelized in 7-10 days and the allogeneic grafted skin began desquamation suggesting that the allograft did not 'take' permanently but was replaced by the newly formed skin. On the other hand, since allografting is an adequate therapy to provide early temporary coverage in extensively burned patients, we developed conditions for banking cultured skin to make it available for immediate use. The conditions described allow banking of the cultured grafts for 15-20 days with retention of clonal growth ability similar to that of unstored epithelia. The results show that cultured epidermal cells obtained from human newborn foreskin, when used as allografts for coverage of full skin or deep partial skin thickness burns, allow rapid epithelization of the burn wounds.

Utility of an allograft tendon for scoliosis correction via the costo-transverse foreman.

PubMed

Sun, Dong; McCarthy, Michael; Dooley, Adam C; Ramakrishnaiah, Raghu H; Shelton, R Shane; McLaren, Sandra G; Skinner, Robert A; Suva, Larry J; McCarthy, Richard E

2017-01-01

Current convex tethering techniques for treatment of scoliosis have centered on anterior convex staples or polypropylene tethers. We hypothesized that an allograft tendon tether inserted via the costo-transverse foramen would correct an established spinal deformity. In the pilot study, six 8-week-old pigs underwent allograft tendon tethering via the costo-transverse foreman or sham to test the strength of the transplanted tendon to retard spine growth. After 4 months, spinal deformity in three planes was induced in all animals with allograft tendons. In the treatment study, the allograft tendon tether was used to treat established scoliosis in 11 8-week-old pigs (spinal deformity > 50°). Once the deformity was observed (4 months) animals were assigned to either no treatment group or allograft tendon tether group and progression assessed by monthly radiographs. At final follow-up, coronal Cobb angle and maximum vertebral axial rotation of the treatment group was significantly smaller than the non-treatment group, whereas sagittal kyphosis of the treatment group was significantly larger than the non-treatment group. In sum, a significant correction was achieved using a unilateral allograft tendon spinal tether, suggesting that an allograft tendon tethering approach may represent a novel fusion-less procedure to correct idiopathic scoliosis. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:183-192, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

[The clinical use of cryopreserved human skin allografts for transplantation].

PubMed

Martínez-Flores, Francisco; Chacón-Gómez, María; Madinaveitia-Villanueva, Juan Antonio; Barrera-Lopez, Araceli; Aguirre-Cruz, Lucinda; Querevalu-Murillo, Walter

2015-01-01

The biological recovery of human skin allografts is the gold standard for preservation in Skin Banks. However, there is no worldwide consensus about specific allocation criteria for preserved human skin allografts with living cells. A report is presented on the results of 5 years of experience of using human skin allografts in burned patient in the Skin and Tissue Bank at the "Instituto Nacional de Rehabilitacion" The human skin allografts were obtained from multi-organ donors. processed and preserved at -80 °C for 12 months. Allocation criteria were performed according to blood type match, clinical history, and burned body surface. Up to now, the Skin and Tissue Bank at 'Instituto Nacional de Rehabilitacion" has processed and recovered 125,000 cm(2) of human skin allografts. It has performed 34 surgical implants on 21 burned patients. The average of burn body surface was 59.2%. More than two-thirds (67.7%) of recipients of skin allografts were matched of the same to type blood of the donor, and 66.6% survived after 126 days hospital stay. It is proposed to consider recipient's blood group as allocation criteria to assign tissue; and use human skin allografts on patiens affected with burns over 30% of body surface (according the "rule of the 9"). Copyright © 2015 Academia Mexicana de Cirugía A.C. Published by Masson Doyma México S.A. All rights reserved.

Current Status of Intestinal Transplantation in Children

PubMed Central

Reyes, Jorge; Bueno, Javier; Kocoshis, Samuel; Green, Mike; Abu-Elmagd, Kareem; Furukawa, Hiro; Barksdale, Edward M.; Strom, Sharon; Fung, John J.; Todo, Satoru; Irish, William; Starzl, Thomas E.

2010-01-01

Purpose A clinical trial of intestinal transplantation (Itx) under tacrolimus and prednisone immunosuppression was initiated in June 1990 in children with irreversible intestinal failure and who were dependent on total parenteral nutrition (TPN). Methods Fifty-five patients (28 girls, 27 boys) with a median age of 3.2 years (range, 0.5 to 18 years) received 58 intestinal transplants that included isolated small bowel (SB) (n = 17), liver SB (LSB) (n = 33), and multivisceral (MV) (n = 8) allografts. Nine patients also received bone marrow infusion, and there were 20 colonic allografts. Azathioprine, cyclophosphamide, or mycophenolate mofetil were used in different phases of the series. Indications for Itx included: gastroschisis(n = 14), volvulus (n = 13), necrotizing enterocolitis (n = 6), intestinal atresia (n = 8), chronic intestinal pseudoobstruction (n = 5), Hirschsprung’s disease (n = 4), microvillus inclusion disease (n = 3), multiple polyposis (n = 1), and trauma (n = 1). Results Currently, 30 patients are alive (patient survival, 55%; graft survival, 52%). Twenty-nine children with functioning grafts are living at home and off TPN, with a mean follow-up of 962 (range, 75 to 2,424) days. Immunologic complications have included liver allograft rejection (n = 18), intestinal allograft rejection (n = 52), posttransplant lymphoproliferative disease (n = 16), cytomegalovirus (n = 16) and graft-versus-host disease (n = 4). A combination of associated complications included intestinal perforation (n = 4), biliary leak (n = 3), bile duct stenosis (n = 1), intestinal leak (n = 6), dehiscence with evisceration (n = 4), hepatic artery thrombosis (n = 3), bleeding (n = 9), portal vein stenosis (n = 1), intraabdominal abscess (n = 11), and chylous ascites (n = 4). Graft loss occurred as a result of rejection (n = 8), infection (n = 12), technical complications (n = 8), and complications of TPN after graft removal (n = 3). There were four retransplants (SB, n = 1; LSB n = 3). Conclusions Intestinal transplantation is a valid therapeutic option for patients with intestinal failure suffering complications of TPN. The complex clinical and immunologic course of these patients is reflected in a higher complication rate as well as patient and graft loss than seen after heart, liver, and kidney transplantation, although better than after lung transplantation. PMID:9498395

Biological properties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing.

PubMed

Koob, Thomas J; Rennert, Robert; Zabek, Nicole; Massee, Michelle; Lim, Jeremy J; Temenoff, Johnna S; Li, William W; Gurtner, Geoffrey

2013-10-01

Human amnion/chorion tissue derived from the placenta is rich in cytokines and growth factors known to promote wound healing; however, preservation of the biological activities of therapeutic allografts during processing remains a challenge. In this study, PURION® (MiMedx, Marietta, GA) processed dehydrated human amnion/chorion tissue allografts (dHACM, EpiFix®, MiMedx) were evaluated for the presence of growth factors, interleukins (ILs) and tissue inhibitors of metalloproteinases (TIMPs). Enzyme-linked immunosorbent assays (ELISA) were performed on samples of dHACM and showed quantifiable levels of the following growth factors: platelet-derived growth factor-AA (PDGF-AA), PDGF-BB, transforming growth factor α (TGFα), TGFβ1, basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), placental growth factor (PLGF) and granulocyte colony-stimulating factor (GCSF). The ELISA assays also confirmed the presence of IL-4, 6, 8 and 10, and TIMP 1, 2 and 4. Moreover, the relative elution of growth factors into saline from the allograft ranged from 4% to 62%, indicating that there are bound and unbound fractions of these compounds within the allograft. dHACM retained biological activities that cause human dermal fibroblast proliferation and migration of human mesenchymal stem cells (MSCs) in vitro. An in vivo mouse model showed that dHACM when tested in a skin flap model caused mesenchymal progenitor cell recruitment to the site of implantation. The results from both the in vitro and in vivo experiments clearly established that dHACM contains one or more soluble factors capable of stimulating MSC migration and recruitment. In summary, PURION® processed dHACM retains its biological activities related to wound healing, including the potential to positively affect four distinct and pivotal physiological processes intimately involved in wound healing: cell proliferation, inflammation, metalloproteinase activity and recruitment of progenitor cells. This suggests a paracrine mechanism of action for dHACM when used for wound healing applications. ©2013 The Authors. International Wound Journal published by John Wiley & Sons Ltd and Medicalhelplines.com Inc.

The Role of Androgen Excess in Metabolic Dysfunction in Women : Androgen Excess and Female Metabolic Dysfunction.

PubMed

Escobar-Morreale, Héctor F

2017-01-01

Polycystic ovary syndrome (PCOS) is characterized by the association of androgen excess with chronic oligoovulation and/or polycystic ovarian morphology, yet metabolic disorders and classic and nonclassic cardiovascular risk factors cluster in these women from very early in life. This chapter focuses on the mechanisms underlying the association of PCOS with metabolic dysfunction, focusing on the role of androgen excess on the development of visceral adiposity and adipose tissue dysfunction.

Are levels of NT-proBNP and SDMA useful to determine diastolic dysfunction in chronic kidney disease and renal transplant patients?

PubMed

Memon, Lidija; Spasojevic-Kalimanovska, Vesna; Stanojevic, Natasa Bogavac; Kotur-Stevuljevic, Jelena; Simic-Ogrizovic, Sanja; Giga, Vojislav; Dopsaj, Violeta; Jelic-Ivanovic, Zorana; Spasic, Slavica

2013-11-01

The aim of the study was to determine the clinical usefulness of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and symmetric dimethylarginine (SDMA) for detection of renal and left ventricular (LV) diastolic dysfunction in chronic kidney disease (CKD) patients and renal transplant (RT) recipients. We included 98 CKD and 44 RT patients. We assessed LV function using pulsed-wave Doppler ultrasound. Diastolic dysfunction was defined when the E:A ratio was <1. Independent predictors of NT-proBNP levels were age, creatinine, and albumin in CKD patients and age and urea in RT patients. Determinants of SDMA in CKD patients were glomerular filtration rate (GFR) and NT-proBNP and creatinine in RT patients. In RT patients with diastolic dysfunction, NT-proBNP and SDMA were significantly higher than in patients without diastolic dysfunction (F = 7.478, P < 0.011; F = 2.631, P < 0.017). After adjustment for GFR, the differences were not seen. In CKD patients adjusted NT-proBNP and SDMA values for GFR were not significantly higher in patients with diastolic dysfunction than in patients without diastolic dysfunction. NT-proBNP is useful for detection of LV diastolic dysfunction in RT recipients. When evaluating both NT-proBNP and SDMA it is necessary to consider GFR as a confounding factor. © 2013 Wiley Periodicals, Inc.

Bone tissue engineering by way of allograft revitalization: mechanistic and mechanical investigations using a porcine model.

PubMed

Runyan, Christopher M; Ali, Samantha T; Chen, Wendy; Calder, Bennet W; Rumburg, Aaron E; Billmire, David A; Taylor, Jesse A

2014-05-01

"Allograft revitalization" is a process in which cadaveric bone is used to generate well-vascularized living bone. We had previously found that porcine allograft hemimandibles filled with autologous adipose-derived stem cells (ASCs) and recombinant human bone morphogenetic protein-2-soaked absorbable collagen sponge (rhBMP-2/ACS) were completely replaced by vascularized bone, provided the construct had been incubated within a periosteal envelope. The present study sought to deepen our understanding of allograft revitalization by investigating the individual contributions of ASCs and rhBMP-2 in the process and the mechanical properties of the revitalized allograft. Porcine allograft hemimandible constructs were implanted bilaterally into rib periosteal envelopes in 8 pigs. To examine the contributions of ASCs and rhBMP-2, the following groups were assessed: group 1, periosteum alone; group 2, periosteum+ASCs; group 3, periosteum+rhBMP-2/ACS; and group 4, periosteum+ASCs+rhBMP-2/ACS. After 8 weeks, the allograft constructs were harvested for micro-computed tomography (CT) and histologic analyses and 3-point bending to assess the strength. On harvesting, the constructs receiving rhBMP-2/ACS had significantly greater bone shown by micro-CT than those receiving periosteum only (51,463 vs. 34,310 mm3; P = .031). The constructs receiving ASCs had increased bone compared to group 1 (periosteum only), although not significantly (P = .087). The combination of rhBMP-2/ACS with ASCs produced bone (50,399 mm3) equivalent to that of the constructs containing rhBMP-2/ACS only. The 3-point bending tests showed no differences between the 4 groups and a nonimplanted allograft or native mandible (P = .586), suggesting the absence of decreased strength of the allograft bone when revitalized. These data have shown that rhBMP-2/ACS significantly stimulates new bone formation by way of allograft revitalization and that the revitalized allograft has equivalent mechanical strength to native bone. Copyright © 2014 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.

Vascularised free fibular flap in bone resection and reconstruction.

PubMed

Belt, P J; Dickinson, I C; Theile, D R B

2005-06-01

This paper compares allograft alone and in combination with vascularised free fibular flaps (FFF) to reconstruct long bone defects after tumour excision. We present 33 cases, 21 of these patients had reconstruction with an allograft alone as the initial procedure. Nine patients underwent reconstruction with FFF plus allograft plus iliac crest bone graft (ICG), two patients underwent reconstruction with a FFF and ICG and one patient underwent reconstruction with an allograft, a pedicled fibular flap and a FFF. The allograft was obtained from the Queensland Bone Bank and had been irradiated to 25 000Gy. In our experience (N=21) the complication rates with allograft alone were: delayed union 3, nonunion 7, fractured allograft 6, infection requiring resection of the allograft 3, other infections 2. The revision rate was 48% (10 cases of which five required a free fibular flap) and an average of 1.8 revision procedures were required. In the lower limb cases, the mean time to full weightbearing was 20 months and 40% were full weightbearing at 18 months. We felt that the high complication rate compared with other series may have been related to the irradiation of the graft. FFFs were used in 18 cases, 12 cases were primary reconstructions and six were revision reconstructions. The mean fibular length was 19.4 cm (range 10-29 cm). There were no flap losses and the FFF united at both ends of 11 of 12 primary reconstruction cases. One case had nonunion at one end, giving a union rate of 96% (23 of 24 junctions). When a FFF was used in combination with an allograft as a primary reconstruction, the allograft nonunion rate was 50% (five of 10 cases). The mean time to full weightbearing in the lower limb cases was 7.5 months and 100% were full weightbearing at 18 months. The FFF hastens time to full weightbearing but does not appear to affect the complication rates of allograft. The number of revision procedures required is reduced in the presence of a FFF and is the latter is a useful technique for the salvage of refractory cases.

Validation of 15 kGy as a radiation sterilisation dose for bone allografts manufactured at the Queensland Bone Bank: application of the VDmax 15 method.

PubMed

Nguyen, Huynh; Morgan, David A F; Sly, Lindsay I; Benkovich, Morris; Cull, Sharon; Forwood, Mark R

2008-06-01

ISO 11137-2006 (ISO 11137-2a 2006) provides a VDmax 15 method for substantiation of 15 kGy as radiation sterilisation dose (RSD) for health care products with a relatively low sample requirement. Moreover, the method is also valid for products in which the bioburden level is less than or equal to 1.5. In the literature, the bioburden level of processed bone allografts is extremely low. Similarly, the Queensland Bone Bank (QBB) usually recovers no viable organisms from processed bone allografts. Because bone allografts are treated as a type of health care product, the aim of this research was to substantiate 15 kGy as a RSD for frozen bone allografts at the QBB using method VDmax 15-ISO 11137-2: 2006 (ISO 11137-2e, Procedure for method VDmax 15 for multiple production batches. Sterilisation of health care products - radiation - part 2: establishing the sterilisation dose, 2006; ISO 11137-2f, Procedure for method VDmax 15 for a single production batch. Sterilisation of health care products - radiation - part 2: establishing the sterilisation dose, 2006). 30 femoral heads, 40 milled bone allografts and 40 structural bone allografts manufactured according to QBB standard operating procedures were used. Estimated bioburdens for each bone allograft group were used to calculate the verification doses. Next, 10 samples per group were irradiated at the verification dose, sterility was tested and the number of positive tests of sterility recorded. If the number of positive samples was no more than 1, from the 10 tests carried out in each group, the verification was accepted and 15 kGy was substantiated as RSD for those bone allografts. The bioburdens in all three groups were 0, and therefore the verification doses were 0 kGy. Sterility tests of femoral heads and milled bones were all negative (no contamination), and there was one positive test of sterility in the structural bone allograft. Accordingly, the verification was accepted. Using the ISO validated protocol, VDmax 15, 15 kGy was substantiated as RSD for frozen bone allografts manufactured at the QBB.

Increased Risk of Revision After Anterior Cruciate Ligament Reconstruction With Soft Tissue Allografts Compared With Autografts: Graft Processing and Time Make a Difference.

PubMed

Maletis, Gregory B; Chen, Jason; Inacio, Maria C S; Love, Rebecca M; Funahashi, Tadashi T

2017-07-01

The optimal graft for anterior cruciate ligament reconstruction (ACLR) remains controversial. To compare the risk of aseptic revision between bone-patellar tendon-bone (BPTB) autografts, hamstring autografts, and soft tissue allografts. Cohort study; Level of evidence, 2. Prospectively collected ACLR cases reconstructed with BPTB autografts, hamstring autografts, and soft tissue allografts were identified using the Kaiser Permanente ACLR Registry. Aseptic revision was the endpoint. The type of graft and allograft processing method (nonprocessed, <1.8-Mrad irradiation with and without chemical processing [Allowash or AlloTrue], ≥1.8-Mrad irradiation with and without chemical processing, and chemical processing alone [BioCleanse]) were the exposures evaluated. Analyses were adjusted for age, sex, and race. Kaplan-Meier curves and Cox proportional hazards models were employed. The cohort included 14,015 cases: there were 8924 (63.7%) male patients, there were 6397 (45.6%) white patients, 4557 (32.5%) ACLRs used BPTB autografts, 3751 ACLRs (26.8%) used soft tissue allografts, and 5707 (40.7%) ACLRs used hamstring autografts. The median age was 34.6 years for soft tissue allografts, 24.3 years for hamstring autografts, and 22.0 years for BPTB autografts. The crude nonadjusted revision rates were 85 (1.9%) in BPTB autograft cases, 132 (2.3%) in hamstring autograft cases, and 83 (2.2%) in soft tissue allograft cases. After adjusting for age, sex, and race, compared with hamstring autografts, a higher risk of revision was found with allografts with ≥1.8 Mrad without chemical processing after 2.5 years (hazard ratio [HR], 3.88; 95% CI, 1.48-10.12) and ≥1.8 Mrad with chemical processing after 1 year (HR, 3.43; 95% CI, 1.58-7.47) and with BioCleanse processed grafts at any time point (HR, 3.02; 95% CI, 1.40-6.50). Nonprocessed allografts and those irradiated with <1.8 Mrad with or without chemical processing were not found to have a different risk of revision compared with hamstring autografts. Compared with BPTB autografts, a higher risk of revision was seen with hamstring autografts (HR, 1.51; 95% CI, 1.15-1.99) and BioCleanse processed allografts (HR, 4.67; 95% CI, 2.15-10.16). Allografts irradiated with <1.8 Mrad with chemical processing (Allowash or AlloTrue) (HR, 2.19; 95% CI, 1.42-3.38) and without chemical processing (HR, 2.31; 95% CI, 1.40-3.82) had a higher risk of revision, as did allografts with ≥1.8 Mrad without chemical processing after 2 years (HR, 6.30; 95% CI, 3.18-12.48) and ≥1.8 Mrad with chemical processing (Allowash or AlloTrue) after 1 year (HR, 5.03; 95% CI, 2.30-11.00) compared with BPTB autografts. Nonprocessed allografts did not have a higher risk of revision compared with autografts. With the numbers available, direct comparisons between the specific allograft processing methods were not possible. When soft tissue allografts are used for ACLR, processing and time from surgery affect the risk of revision. Tissue processing has a significant effect on the risk of revision surgery, which is most profound with more highly processed grafts and increases with increasing follow-up time. Surgeons and patients need to be aware of the increased risks of revision with the various soft tissue allografts used for ACLR.

Histologic healing following tooth extraction with ridge preservation using mineralized versus combined mineralized-demineralized freeze-dried bone allograft: a randomized controlled clinical trial.

PubMed

Borg, Tyler D; Mealey, Brian L

2015-03-01

Mineralized and demineralized freeze-dried bone allografts (FDBAs) are used in alveolar ridge (AR) preservation; however, each material has advantages and disadvantages. Combinations of allografts aimed at capitalizing on the advantages each offers are available. To date, there is no evidence to indicate if a combination allograft is superior in this application. The primary objective of this study is to histologically evaluate and compare healing of non-molar extraction sites grafted with either mineralized FDBA or a 70:30 mineralized:demineralized FDBA combination allograft in AR preservation. The secondary objective is to compare dimensional changes in ridge height and width after grafting with these two materials. Forty-two patients randomized into two equal groups received ridge preservation with either 100% mineralized FDBA (active control group) or the combination 70% mineralized: 30% demineralized allograft (test group). Sites were allowed to heal for 18 to 20 weeks, at which time core biopsies were obtained and dental implants were placed. AR dimensions were evaluated at the time of extraction and at implant placement, including change in ridge width and change in buccal and lingual ridge height. Histomorphometric analysis was performed to determine percentage of vital bone, residual graft, and connective tissue/other non-bone components. There was no significant difference between groups in AR dimensional changes. Combination allograft produced increased vital bone percentage (36.16%) compared to the FDBA group (24.69%; P = 0.0116). The combination allograft also had a significantly lower mean percentage of residual graft particles (18.24%) compared to FDBA (27.04%; P = 0.0350). This study provides the first histologic evidence showing greater new bone formation with a combination mineralized/demineralized allograft compared to 100% mineralized FDBA in AR preservation in humans. Combination allograft results in increased vital bone formation while providing similar dimensional stability of the AR compared to FDBA alone in AR preservation.

A cost-effective method for femoral head allograft procurement for spinal arthrodesis: an alternative to commercially available allograft.

PubMed

Brown, Desmond A; Mallory, Grant W; Higgins, Dominique M; Abdulaziz, Mohammed; Huddleston, Paul M; Nassr, Ahmad; Fogelson, Jeremy L; Clarke, Michelle J

2014-07-01

A cost-effective procurement process for harvesting, storing, and using femoral head allografts is described. A brief review of the literature on the use of these allografts and a discussion of costs are provided. To describe a cost-effective method for the harvesting, storage, and use of femoral heads from patients undergoing total hip arthroplasty at our institution as a source of allograft bone. Spine fusion surgery uses a large proportion of commercially available bone grafts and bone substitutes. As the number of such surgical procedures performed in the United States continues to rise, these materials are at a historically high level of demand, which is projected to continue. Iliac crest bone autograft has historically been the standard of care, although this may be losing favor due to potential donor site morbidity. Although many substitutes are effective in promoting arthrodesis, their use is limited because of cost. Femoral heads are harvested under sterile conditions during total hip arthroplasty. The patient is tested per Food and Drug Administration regulations, and the tissue sample is cultured. The tissue is frozen and quarantined for a 6-month minimum pending repeat testing of donors and subsequently released for use. The relative cost-effectiveness of this tissue as a source of allograft bone is discussed. The average femoral head allograft is 54 to 56 mm in diameter and yields 50 cm of bone graft, with an average cost of US $435 for processing of the tissue resulting in a cost of US $8.70 per cm of allograft produced. Average production costs are significantly lower than those for other commonly available commercial bone grafts and substitutes. Femoral head allograft is a cost-effective alternative to commercially available allografts and bone substitutes. The method of procurement, storage, and use described could be adopted by other institutions in an effort to mitigate cost and increase supply. N/A.

Kidney Versus Islet Allograft Survival After Induction of Mixed Chimerism With Combined Donor Bone Marrow Transplantation.

PubMed

Oura, Tetsu; Ko, Dicken S C; Boskovic, Svjetlan; O'Neil, John J; Chipashvili, Vaja; Koulmanda, Maria; Hotta, Kiyohiko; Kawai, Kento; Nadazdin, Ognjenka; Smith, R Neal; Cosimi, A B; Kawai, Tatsuo

2016-01-01

We have previously reported successful induction of transient mixed chimerism and long-term acceptance of renal allografts in MHC mismatched nonhuman primates. In this study, we attempted to extend this tolerance induction approach to islet allografts. A total of eight recipients underwent MHC mismatched combined islet and bone marrow (BM) transplantation after induction of diabetes by streptozotocin. Three recipients were treated after a nonmyeloablative conditioning regimen that included low-dose total body and thymic irradiation, horse Atgam (ATG), six doses of anti-CD154 monoclonal antibody (mAb), and a 1-month course of cyclosporine (CyA) (Islet A). In Islet B, anti-CD8 mAb was administered in place of CyA. In Islet C, two recipients were treated with Islet B, but without ATG. The results were compared with previously reported results of eight cynomolgus monkeys that received combined kidney and BM transplantation (Kidney A) following the same conditioning regimen used in Islet A. The majority of kidney/BM recipients achieved long-term renal allograft survival after induction of transient chimerism. However, prolonged islet survival was not achieved in similarly conditioned islet/BM recipients (Islet A), despite induction of comparable levels of chimerism. In order to rule out islet allograft loss due to CyA toxicity, three recipients were treated with anti-CD8 mAb in place of CyA. Although these recipients developed significantly superior mixed chimerism and more prolonged islet allograft survival (61, 103, and 113 days), islet function was lost soon after the disappearance of chimerism. In Islet C recipients, neither prolonged chimerism nor islet survival was observed (30 and 40 days). Significant improvement of mixed chimerism induction and islet allograft survival were achieved with a CyA-free regimen that included anti-CD8 mAb. However, unlike the kidney allograft, islet allograft tolerance was not induced with transient chimerism. Induction of more durable mixed chimerism may be necessary for induction of islet allograft tolerance.

Allograft materials in phalloplasty: a comparative analysis.

PubMed

Solomon, Mark P; Komlo, Caroline; Defrain, Molly

2013-09-01

Allograft use has increased recently with the rising use of allograft materials in breast surgery. There are few data that compare the performance of the various allograft materials in this application, despite marketing efforts by the manufacturers to present one allograft material as superior to another. Phalloplasty is a procedure that uses allografts for penis girth augmentation. Preparation of these grafts differs with each manufacturer. We report our experience with 3 different types of allografts for this procedure. This allows for the comparison of these materials in their performance with a single model. Forty-seven patients who underwent penis girth enhancement with allograft material were reviewed. All patients underwent circumferential grafting to the shaft of the penis at the level of Buck's fascia. Graft materials included AlloDerm (n = 9), Belladerm (n = 20), and Repriza (n = 21). Charts were reviewed for material type, presence and type of infection, wound exposure, and graft loss with attention to the type of allograft material that was used. Follow-up ranged from 1 to 120 months with an average of 11.25 months. Infection, defined as an open wound with graft exposure, occurred in 20 (42%) of 47 patients. Of these, graft exposure only occurred in 17 (36%) patients, whereas 3 (6%) patients sustained total graft loss. Graft exposure or loss occurred in 3 patients who had AlloDerm, 9 patients with Belladerm, and 8 patients with Repriza. No patients with AlloDerm sustained graft loss, whereas 2 patients with Belladerm and 1 patient with Repriza sustained graft loss. There were no statistical differences among these graft types with regard to infection or graft loss. Three different brands of allograft material were used in 1 surgical procedure and followed up for their performance with regard to exposure and infection. In this model, there is no difference in the rate of infection in these materials despite their different methods of preparation. Implications of this fact are discussed in the approach surgeons should consider when using these materials.

Assessment of the relationship between ACE I/D gene polymorphism and renal allograft survival.

PubMed

Yang, Chun-Hua; Lu, Yi; Chen, Xue-Xia; Xian, Wen-Feng; Tu, Wei-Feng; Li, Hong-Yan

2015-12-01

The relationship between the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and renal allograft survival after renal transplantation from the published reports are still debatable. This study was performed to evaluate the relationship between the ACE I/D gene polymorphism and renal allograft survival after renal transplantation using meta-analysis. Eligible studies were identified from PubMed and Cochrane Library on 1 November 2014, and eligible studies were recruited and synthesized using a meta-analysis methodology. Twelve investigations were included in this meta-analysis for the assessment of the relationship between the ACE I/D gene polymorphism and renal allograft survival. In this meta-analysis, the ACE I/D gene polymorphism was not associated with renal allograft survival after renal transplantation for overall populations, Caucasians, Brazilians and Africans. Interestingly, the ACE D allele and DD genotype were associated with renal allograft survival after renal transplantation in the Asian population. ACE D allele and DD genotype were associated with renal allograft survival after renal transplantation in the Asian population. However, more studies should be performed to confirm this association. © The Author(s) 2015.

Long-term ocular consequences of sulfur mustard in seriously eye-injured war veterans.

PubMed

Ghasemi, Hassan; Ghazanfari, Tooba; Ghassemi-Broumand, Mohammad; Javadi, Mohammad Ali; Babaei, Mahmoud; Soroush, Mohammad Reza; Yaraee, Roya; Faghihzadeh, Soghrat; Poorfarzam, Shahriar; Owlia, Parviz; Naghizadeh, Mohammad Mehdi; Etezad-Razavi, Mohammad; Jadidi, Khosro; Naderi, Mostafa; Hassan, Zuhair Mohammad

2009-01-01

Sulfur mustard (SM) has been used as a dangerous chemical warfare agent since the early 20th century. Although many descriptive studies about SM-induced ocular injuries are present in the medical literature, few of them have been conducted over a large group with serious ocular involvement. This descriptive study was conducted on 149 severe SM-intoxicated war veterans. Ocular history, anterior and posterior segment findings using a slit lamp, and direct and indirect ophthalmoscopic findings were recorded. Severity of the disease was also recorded based on a chart of the Foundation of Martyrs and Veterans Affairs. Ocular complains included photophobia (73.2%), sense of decreased vision (72.5%), dry eye sensation (66.4%), foreign body sensation (61.1%), tearing (46.3%), and pain (43.0%). Slit lamp findings were meibomian gland dysfunction (MGD; 96%), blepharitis, punctal closure, trichiasis, tear break-up time, and tear meniscus layer abnormality (80% to 90%). Conjunctival disturbances included vascular abnormality, ischemia, hyperemia, subconjunctival fibrosis, and pterygium. Limbal changes were abnormal vessels, limbal tissue loss and pigment loss, and pannus formation. Corneal problems included epithelial and stromal disturbances, calcium deposition, and melting. The most frequent previous surgeries were punctal closure, lamellar keratoplasty (LK), and stem cell allograft. Severity of intoxication included mild (17%), moderate (25%), and severe (57%). Chronic blepharitis and decreased tear secretion are the 2 most important and influencing factors in progression of ocular problems in SM injuries. The more severe the initial exposure, percentage of disability, and duration of ocular involvement, the higher the likelihood of mustard gas keratopathy.

Stress Altered Stem Cells with Decellularized Allograft to Improve Rate of Nerve Regeneration

DTIC Science & Technology

2015-12-01

AWARD  NUMBER:      W81XWH-­13-­1-­0298   TITLE:    “Stress Altered Stem Cells with Decellularized Allograft to Improve Rate of Nerve Regeneration...Cells with Decellularized Allograft to Improve Rate of Nerve Regeneration 5b. GRANT NUMBER W81XWH-13-1-0298 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S... allograft , neural regeneration, stem cells, stress altered cells, peripheral nerve injury model, nerve graft 3 This comprehensive final report summarizes

Clinical Evaluation of Decellularized Nerve Allograft with Autologous Bone Marrow Stem Cells to Improve Peripheral Nerve Repair and Functional Outcomes

DTIC Science & Technology

2016-07-01

AWARD NUMBER: W81XWH-15-2-0026 TITLE: Clinical Evaluation of Decellularized Nerve Allograft With Autologous Bone Marrow Stem Cells To Improve...5b. GRANT NUMBER W81XWH-15-2-0026 CClinical Evaluation of Decellularized Nerve Allograft With Autologous Bone Marrow Stem Cells To Improve...co- treatments of a commercially available decellularized processed peripheral nerve allograft scaffold (Avance® Nerve Graft, AxoGen, Alachua FL) with

Clinical Evaluation of Decellularized Nerve Allograft with Autologous Bone Marrow Stem Cells to Improve Peripheral Nerve Repair and Functional Outcomes

DTIC Science & Technology

2017-07-01

AWARD NUMBER: W81XWH-15-2-0026 TITLE: Clinical Evaluation of Decellularized Nerve Allograft with Autologous Bone Marrow Stem Cells to Improve...of Decellularized Nerve Allograft with 5a. CONTRACT NUMBER Autologous Bone Marrow Stem Cells to Improve Peripheral Nerve 5b. GRANT NUMBER W81XWH...commercially available decellularized processed peripheral nerve allograft scaffold (Avance® Nerve Graft, AxoGen, Alachua FL) with autologous bone marrow

Sexual Abuse and Sexual Functioning in a Chronic Pelvic Pain Sample

ERIC Educational Resources Information Center

Randolph, Mary E.; Reddy, Diane M.

2006-01-01

Sexual abuse, particularly childhood sexual abuse, has been linked to chronic pelvic pain and to sexual dysfunction, though the sexual functioning of survivors of sexual abuse has not been studied in a chronic pain population. Sixty-three women with chronic pelvic pain completed measures of sexual function, sexual abuse, and pain. Using an index…

Cardiomyocyte dysfunction during the chronic phase of Chagas disease.

PubMed

Roman-Campos, Danilo; Sales-Júnior, Policarpo; Duarte, Hugo Leonardo; Gomes, Eneas Ricardo; Guatimosim, Silvia; Ropert, Catherine; Gazzinelli, Ricardo Tostes; Cruz, Jader Santos

2013-04-01

Chagas disease, which is caused by the parasite Trypanosoma cruzi, is an important cause of heart failure. We investigated modifications in the cellular electrophysiological and calcium-handling characteristics of an infected mouse heart during the chronic phase of the disease. The patch-clamp technique was used to record action potentials (APs) and L-type Ca2+ and transient outward K+ currents. [Ca2+]i changes were determined using confocal microscopy. Infected ventricular cells showed prolonged APs, reduced transient outward K+ and L-type Ca2+ currents and reduced Ca2+ release from the sarcoplasmic reticulum. Thus, the chronic phase of Chagas disease is characterised by cardiomyocyte dysfunction, which could lead to heart failure.

Cardiomyocyte dysfunction during the chronic phase of Chagas disease

PubMed Central

Roman-Campos, Danilo; Sales-Júnior, Policarpo; Duarte, Hugo Leonardo; Gomes, Eneas Ricardo; Guatimosim, Silvia; Ropert, Catherine; Gazzinelli, Ricardo Tostes; Cruz, Jader Santos

2013-01-01

Chagas disease, which is caused by the parasite Trypanosoma cruzi, is an important cause of heart failure. We investigated modifications in the cellular electrophysiological and calcium-handling characteristics of an infected mouse heart during the chronic phase of the disease. The patch-clamp technique was used to record action potentials (APs) and L-type Ca2+ and transient outward K+ currents. [Ca2+]i changes were determined using confocal microscopy. Infected ventricular cells showed prolonged APs, reduced transient outward K+ and L-type Ca2+ currents and reduced Ca2+ release from the sarcoplasmic reticulum. Thus, the chronic phase of Chagas disease is characterised by cardiomyocyte dysfunction, which could lead to heart failure. PMID:23579807

APOL1 Genotype and Kidney Transplantation Outcomes From Deceased African American Donors.

PubMed

Freedman, Barry I; Pastan, Stephen O; Israni, Ajay K; Schladt, David; Julian, Bruce A; Gautreaux, Michael D; Hauptfeld, Vera; Bray, Robert A; Gebel, Howard M; Kirk, Allan D; Gaston, Robert S; Rogers, Jeffrey; Farney, Alan C; Orlando, Giuseppe; Stratta, Robert J; Mohan, Sumit; Ma, Lijun; Langefeld, Carl D; Bowden, Donald W; Hicks, Pamela J; Palmer, Nicholette D; Palanisamy, Amudha; Reeves-Daniel, Amber M; Brown, W Mark; Divers, Jasmin

2016-01-01

Two apolipoprotein L1 gene (APOL1) renal-risk variants in donors and African American (AA) recipient race are associated with worse allograft survival in deceased-donor kidney transplantation (DDKT) from AA donors. To detect other factors impacting allograft survival from deceased AA kidney donors, APOL1 renal-risk variants were genotyped in additional AA kidney donors. The APOL1 genotypes were linked to outcomes in 478 newly analyzed DDKTs in the Scientific Registry of Transplant Recipients. Multivariate analyses accounting for recipient age, sex, race, panel-reactive antibody level, HLA match, cold ischemia time, donor age, and expanded criteria donation were performed. These 478 transplantations and 675 DDKTs from a prior report were jointly analyzed. Fully adjusted analyses limited to the new 478 DDKTs replicated shorter renal allograft survival in recipients of APOL1 2-renal-risk-variant kidneys (hazard ratio [HR], 2.00; P = 0.03). Combined analysis of 1153 DDKTs from AA donors revealed donor APOL1 high-risk genotype (HR, 2.05; P = 3 × 10), older donor age (HR, 1.18; P = 0.05), and younger recipient age (HR, 0.70; P = 0.001) adversely impacted allograft survival. Although prolonged allograft survival was seen in many recipients of APOL1 2-renal-risk-variant kidneys, follow-up serum creatinine concentrations were higher than that in recipients of 0/1 APOL1 renal-risk-variant kidneys. A competing risk analysis revealed that APOL1 impacted renal allograft survival, but not recipient survival. Interactions between donor age and APOL1 genotype on renal allograft survival were nonsignificant. Shorter renal allograft survival is reproducibly observed after DDKT from APOL1 2-renal-risk-variant donors. Younger recipient age and older donor age have independent adverse effects on renal allograft survival.

Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts.

PubMed

Kohei, Naoki; Tanaka, Toshiaki; Tanabe, Kazunari; Masumori, Naoya; Dvorina, Nina; Valujskikh, Anna; Baldwin, William M; Fairchild, Robert L

2016-06-01

While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) mice were transplanted with complete MHC-mismatched A/J kidney grafts, and intragraft inflammatory components were followed to rejection. B6.CCR5(-/-) and B6.CD8(-/-)/CCR5(-/-) recipients rejected kidney allografts by day 35, whereas 65% of allografts in wild-type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8(-/-)/CCR5(-/-) recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts

PubMed Central

Kohei, Naoki; Tanaka, Toshiaki; Tanabe, Kazunari; Masumori, Naoya; Dvorina, Nina; Valujskikh, Anna; Baldwin, William M.; Fairchild, Robert L.

2016-01-01

While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild type C57BL/6, B6.CCR5−/− and B6.CD8−/−/CCR5−/− mice were transplanted with complete MHC mismatched A/J kidney grafts and intra-graft inflammatory components were followed to rejection. B6.CCR5−/− and B6.CD8−/−/CCR5−/− recipients rejected kidney allografts by day 35 whereas 65% of allografts in wild type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5−/− and B6.CD8−/−/CCR5−/− recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8−/−/CCR5−/− recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts. PMID:27165816

Iliac Crest Bone Graft versus Local Autograft or Allograft for Lumbar Spinal Fusion: A Systematic Review

PubMed Central

Tuchman, Alexander; Brodke, Darrel S.; Youssef, Jim A.; Meisel, Hans-Jörg; Dettori, Joseph R.; Park, Jong-Beom; Yoon, S. Tim; Wang, Jeffrey C.

2016-01-01

Study Design  Systematic review. Objective  To compare the effectiveness and safety between iliac crest bone graft (ICBG) and local autologous bone and allograft in the lumbar spine. Methods  A systematic search of multiple major medical reference databases identified studies evaluating spinal fusion in patients with degenerative joint disease using ICBG, local autograft, or allograft in the thoracolumbar spine. Results  Six comparative studies met our inclusion criteria. A “low” strength of the overall body of evidence suggested no difference in fusion percentages in the lumbar spine between local autograft and ICBG. We found no difference in fusion percentages based on low evidence comparing allograft with ICBG autograft. There were no differences in pain or functional results comparing local autograft or allograft with ICBG autograft. Donor site pain and hematoma/seroma occurred more frequently in ICBG autograft group for lumbar fusion procedures. There was low evidence around the estimate of patients with donor site pain following ICBG harvesting, ranging from 16.7 to 20%. With respect to revision, low evidence demonstrated no difference between allograft and ICBG autograft. There was no evidence comparing patients receiving allograft with local autograft for fusion, pain, functional, and safety outcomes. Conclusion  In the lumbar spine, ICBG, local autograft, and allograft have similar effectiveness in terms of fusion rates, pain scores, and functional outcomes. However, ICBG is associated with an increased risk for donor site-related complications. Significant limitations exist in the available literature when comparing ICBG, local autograft, and allograft for lumbar fusion, and thus ICBG versus other fusion methods necessitates further investigation. PMID:27556001

Autograft versus Allograft for Cervical Spinal Fusion: A Systematic Review.

PubMed

Tuchman, Alexander; Brodke, Darrel S; Youssef, Jim A; Meisel, Hans-Jörg; Dettori, Joseph R; Park, Jong-Beom; Yoon, S Tim; Wang, Jeffrey C

2017-02-01

Systematic review. To compare the effectiveness and safety between iliac crest bone graft (ICBG), non-ICBG autologous bone, and allograft in cervical spine fusion. To avoid problems at the donor site, various allograft materials have been used as a substitute for autograft. However, there are still questions as to the comparative effectiveness and safety of cadaver allograft compared with autologous ICBG. A systematic search of multiple major medical reference databases was conducted to identify studies evaluating spinal fusion in patients with cervical degenerative disk disease using ICBG compared with non-ICBG autograft or allograft or non-ICBG autograft compared with allograft in the cervical spine. Radiographic fusion, patient-reported outcomes, and functional outcomes were the primary outcomes of interest. Adverse events were evaluated for safety. The search identified 13 comparative studies that met our inclusion criteria: 2 prospective cohort studies and 11 retrospective cohort studies. Twelve cohort studies compared allograft with ICBG autograft during anterior cervical fusion and demonstrated with a low evidence level of support that there are no differences in fusion percentages, pain scores, or functional results. There was insufficient evidence comparing patients receiving allograft with non-ICBG autograft for fusion, pain, revision, and functional and safety outcomes. No publications directly comparing non-ICBG autograft with ICBG were found. Although the available literature suggests ICBG and allograft may have similar effectiveness in terms of fusion rates, pain scores, and functional outcomes following anterior cervical fusion, there are too many limitations in the available literature to draw any significant conclusions. No individual study provided greater than class III evidence, and when evaluating the overall body of literature, no conclusion had better than low evidence support. A prospective randomized trial with adequate sample size to compare fusion rates, efficacy measures, costs, and safety is warranted.

Autograft versus Allograft for Cervical Spinal Fusion

PubMed Central

Brodke, Darrel S.; Youssef, Jim A.; Meisel, Hans-Jörg; Dettori, Joseph R.; Park, Jong-Beom; Yoon, S. Tim; Wang, Jeffrey C.

2017-01-01

Study Design Systematic review. Objective To compare the effectiveness and safety between iliac crest bone graft (ICBG), non-ICBG autologous bone, and allograft in cervical spine fusion. To avoid problems at the donor site, various allograft materials have been used as a substitute for autograft. However, there are still questions as to the comparative effectiveness and safety of cadaver allograft compared with autologous ICBG. Methods A systematic search of multiple major medical reference databases was conducted to identify studies evaluating spinal fusion in patients with cervical degenerative disk disease using ICBG compared with non-ICBG autograft or allograft or non-ICBG autograft compared with allograft in the cervical spine. Radiographic fusion, patient-reported outcomes, and functional outcomes were the primary outcomes of interest. Adverse events were evaluated for safety. Results The search identified 13 comparative studies that met our inclusion criteria: 2 prospective cohort studies and 11 retrospective cohort studies. Twelve cohort studies compared allograft with ICBG autograft during anterior cervical fusion and demonstrated with a low evidence level of support that there are no differences in fusion percentages, pain scores, or functional results. There was insufficient evidence comparing patients receiving allograft with non-ICBG autograft for fusion, pain, revision, and functional and safety outcomes. No publications directly comparing non-ICBG autograft with ICBG were found. Conclusion Although the available literature suggests ICBG and allograft may have similar effectiveness in terms of fusion rates, pain scores, and functional outcomes following anterior cervical fusion, there are too many limitations in the available literature to draw any significant conclusions. No individual study provided greater than class III evidence, and when evaluating the overall body of literature, no conclusion had better than low evidence support. A prospective randomized trial with adequate sample size to compare fusion rates, efficacy measures, costs, and safety is warranted. PMID:28451511

Sterilization with electron beam irradiation influences the biomechanical properties and the early remodeling of tendon allografts for reconstruction of the anterior cruciate ligament (ACL).

PubMed

Schmidt, Tanja; Hoburg, Arnd; Broziat, Christine; Smith, Mark D; Gohs, Uwe; Pruss, Axel; Scheffler, Sven

2012-08-01

Although allografts for anterior cruciate ligament (ACL) replacement have shown advantages compared to autografts, their use is limited due to the risk of disease transmission and the limitations of available sterilization methods. Gamma sterilization has shown detrimental effects on graft properties at the high doses required for sufficient pathogen inactivation. In our previous in vitro study on human patellar tendon allografts, Electron beam (Ebeam) irradiation showed less detrimental effects compared to gamma sterilization (Hoburg et al. in Am J Sports Med 38(6):1134-1140, 2010). To investigate the biological healing and restoration of the mechanical properties of a 34 kGy Ebeam treated tendon allograft twenty-four sheep underwent ACL replacement with either a 34 kGy Ebeam treated allograft or a non-sterilized fresh frozen allograft. Biomechanical testing of stiffness, ultimate failure load and AP-laxity as well as histological analysis to investigate cell, vessel and myofibroblast-density were performed after 6 and 12 weeks. Native sheep ACL and hamstring tendons (HAT, each n = 9) served as controls. The results of a previous study analyzing the remodeling of fresh frozen allografts (n = 12) and autografts (Auto, n = 18) with the same study design were also included in the analysis. Statistics were performed using Mann-Whitney U test followed by Bonferroni-Holm correction. Results showed significantly decreased biomechanical properties during the early remodeling period in Ebeam treated grafts and this was accompanied with an increased remodeling activity. There was no recovery of biomechanical function from 6 to 12 weeks in this group in contrast to the results observed in fresh frozen allografts and autografts. Therefore, high dose Ebeam irradiation investigated in this paper cannot be recommended for soft tissue allograft sterilization.

Radiation sterilization of tissue allografts: A review.

PubMed

Singh, Rita; Singh, Durgeshwer; Singh, Antaryami

2016-04-28

Tissue substitutes are required in a number of clinical conditions for treatment of injured and diseased tissues. Tissues like bone, skin, amniotic membrane and soft tissues obtained from human donor can be used for repair or reconstruction of the injured part of the body. Allograft tissues from human donor provide an excellent alternative to autografts. However, major concern with the use of allografts is the risk of infectious disease transmission. Therefore, tissue allografts should be sterilized to make them safe for clinical use. Gamma radiation has several advantages and is the most suitable method for sterilization of biological tissues. This review summarizes the use of gamma irradiation technology as an effective method for sterilization of biological tissues and ensuring safety of tissue allografts.

Radiation sterilization of tissue allografts: A review

PubMed Central

Singh, Rita; Singh, Durgeshwer; Singh, Antaryami

2016-01-01

Tissue substitutes are required in a number of clinical conditions for treatment of injured and diseased tissues. Tissues like bone, skin, amniotic membrane and soft tissues obtained from human donor can be used for repair or reconstruction of the injured part of the body. Allograft tissues from human donor provide an excellent alternative to autografts. However, major concern with the use of allografts is the risk of infectious disease transmission. Therefore, tissue allografts should be sterilized to make them safe for clinical use. Gamma radiation has several advantages and is the most suitable method for sterilization of biological tissues. This review summarizes the use of gamma irradiation technology as an effective method for sterilization of biological tissues and ensuring safety of tissue allografts. PMID:27158422

Differential effects of arginine methylation on diastolic dysfunction and disease progression in patients with chronic systolic heart failure

PubMed Central

Wilson Tang, Wai Hong; Tong, Wilson; Shrestha, Kevin; Wang, Zeneng; Levison, Bruce S.; Delfraino, Brian; Hu, Bo; Troughton, Richard W.; Klein, Allan L.; Hazen, Stanley L.

2008-01-01

Aims To investigate the association of arginine methylation with myocardial function and prognosis in chronic systolic heart failure patients. Methods and results Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), as well as N-mono-methylarginine (MMA) and methyl-lysine, were simultaneously measured by tandem mass spectrometry in 132 patients with chronic systolic heart failure with echocardiographic evaluation and follow-up. Increasing ADMA and SDMA levels were associated with elevated natriuretic peptide levels (both P < 0.001), and increasing SDMA levels were associated with worsening renal function (P < 0.001). Higher plasma levels of methylated arginine metabolites (but not methyl-lysine) were associated with the presence of left ventricular (LV) diastolic dysfunction (E/septal E′, Spearman's r = 0.31–0.36, P < 0.001). Patients taking beta-blockers had lower ADMA levels than those not taking beta-blockers [0.42 (0.33, 0.50) vs. 0.51 (0.40, 0.58), P < 0.001]. Only increasing ADMA levels were associated with advanced right ventricular (RV) systolic dysfunction. Elevated ADMA levels remained a consistent independent predictor of adverse clinical events (hazard ratio = 1.64, 95% CI: 1.20–2.22, P = 0.002). Conclusion In chronic systolic heart failure, accumulation of methylated arginine metabolites is associated with the presence of LV diastolic dysfunction. Among the methylated derivatives of arginine, ADMA provides the strongest independent prediction of disease progression and adverse long-term outcomes. PMID:18687662

[An adult with chronic active Epstein-Barr virus infection associated with repeated liver dysfunction].

PubMed

Endo, Tetsu; Mori, Yuki; Fukushi, Tsugumi; Yamaguchi, Kohei; Sato, Ken; Sakamoto, Juichi; Fukuda, Shinsaku; Wada, Ryuichi

2010-08-01

A 30-year-old woman with hepatitis for 5 months was admitted to our hospital. She had been given a diagnosis of liver dysfunction 2 years previously, and the hepatitis in this case was believed to be drug-induced. On admission, the patient was asymptomatic. Serologic tests for hepatitis A, B, and C were negative, and the laboratory results showed a WBC count of 7600/mm3 (lymphocytes, 85%), an AST level of 559 U/L, ALT level of 427 U/L, and EBV-DNA of 2.9x10(6) copies/microg DNA. Histopathological examination of the liver biopsy specimens revealed moderate lymphocyte infiltration in the sinusoids and positive Epstein-Barr-encoded RNA (EBER) -lymphocytes. Therefore, chronic active Epstein-Barr virus infection (CAEBV) was diagnosed. However, 9 months after the diagnosis she died of mycotic sepsis. We presume that the patient may have developed CAEBV at the prior diagnosis of liver dysfunction 2 years previously. Therefore, CAEBV associated with liver dysfunction should be considered during the differential diagnosis of patients showing persistent liver dysfunction.

Urothelial Dysfunction and Chronic Inflammation are Associated With Increased Bladder Sensation in Patients With Chronic Renal Insufficiency.

PubMed

Cheng, Sheng-Fu; Jiang, Yuan-Hong; Kuo, Hann-Chorng

2018-01-01

Chronic kidney disease (CKD) or end-stage renal disease (ESRD) patients usually have lower urinary tract symptoms, such as frequency and urgency. Additionally, they frequently suffer from urinary tract infections. This study investigated dysfunction and chronic inflammation of the bladder urothelium in ESRD/CKD patients. This study enrolled 27 patients with CKD (n=13) or ESRD (n=14) for urodynamic studies and bladder biopsies. Patients presented with detrusor underactivity (DU; n=8) or bladder oversensitivity (BO; n=19). Bladder biopsies were performed in these patients and in 20 controls. The bladder mucosa was examined for E-cadherin and zonula occludens-1 (ZO-1) expression, activated mast cell count (through tryptase staining), and urothelial apoptosis (through terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling [TUNEL]). The urodynamic parameters were also compared with variables regarding urothelial dysfunction. The bladder mucosa samples of ESRD and CKD patients revealed significantly higher mast cell counts, more urothelial apoptosis, and lower levels of ZO-1 expression than the control samples. E-cadherin expression was significantly reduced in ESRD/CKD patients with DU, but not in ESRD/CKD patients with BO. Increased mast cell and apoptotic cell counts were also associated with ESRD/CKD with BO. Less expression of ZO-1 and E-cadherin was significantly associated with increased bladder sensation and a small bladder capacity. Bladder urothelial dysfunction and chronic inflammation were present to a noteworthy extent in patients with ESRD or CKD. Increased inflammation and defective barrier function were more notable in ESRD/CKD bladders with BO than in those with DU. The clinical characteristics of these patients may involve urothelial pathophysiology.

Dysfunctional stress responses in chronic pain.

PubMed

Woda, Alain; Picard, Pascale; Dutheil, Frédéric

2016-09-01

Many dysfunctional and chronic pain conditions overlap. This review describes the different modes of chronic deregulation of the adaptive response to stress which may be a common factor for these conditions. Several types of dysfunction can be identified within the hypothalamo-pituitary-adrenal axis: basal hypercortisolism, hyper-reactivity, basal hypocortisolism and hypo-reactivity. Neuroactive steroid synthesis is another component of the adaptive response to stress. Dehydroepiandrosterone (DHEA) and its sulfated form DHEA-S, and progesterone and its derivatives are synthetized in cutaneous, nervous, and adipose cells. They are neuroactive factors that act locally. They may have a role in the localization of the symptoms and their levels can vary both in the central nervous system and in the periphery. Persistent changes in neuroactive steroid levels or precursors can induce localized neurodegeneration. The autonomic nervous system is another component of the stress response. Its dysfunction in chronic stress responses can be expressed by decreased basal parasympathethic activity, increased basal sympathetic activity or sympathetic hyporeactivity to a stressful stimulus. The immune and genetic systems also participate. The helper-T cells Th1 secrete pro-inflammatory cytokines such as IL-1-β, IL-2, IL-6, IL-8, IL-12, IFN-γ, and TNF-α, whereas Th2 secrete anti-inflammatory cytokines: IL-4, IL-10, IGF-10, IL-13. Chronic deregulation of the Th1/Th2 balance can occur in favor of anti- or pro-inflammatory direction, locally or systemically. Individual vulnerability to stress can be due to environmental factors but can also be genetically influenced. Genetic polymorphisms and epigenetics are the main keys to understanding the influence of genetics on the response of individuals to constraints. Copyright © 2016 Elsevier Ltd. All rights reserved.

Current Issues in the Evaluation and Treatment of Sexual Disturbance.

ERIC Educational Resources Information Center

Beutler, Larry E.

1986-01-01

Discusses causes of sexual disturbance, assessment of sexual dysfunction, treatment of sexual dysfunction, psychological issues associated with chronic physical illness and sexual behavior, theory and treatment in child molestation, and the psychosocial outcomes of sex reassignment surgery. (BL)

Effects of Particle Size and Porosity on In Vivo Remodeling of Settable Allograft Bone/Polymer Composites

PubMed Central

Prieto, Edna M.; Talley, Anne D.; Gould, Nicholas R.; Zienkiewicz, Katarzyna J.; Drapeau, Susan J.; Kalpakci, Kerem N.

2014-01-01

Established clinical approaches to treat bone voids include the implantation of autograft or allograft bone, ceramics, and other bone void fillers (BVFs). Composites prepared from lysine-derived polyurethanes and allograft bone can be injected as a reactive liquid and set to yield BVFs with mechanical strength comparable to trabecular bone. In this study, we investigated the effects of porosity, allograft particle size, and matrix mineralization on remodeling of injectable and settable allograft/polymer composites in a rabbit femoral condyle plug defect model. Both low viscosity (LV) and high viscosity (HV) grafts incorporating small (<105 μm) particles only partially healed at 12 weeks, and the addition of 10% demineralized bone matrix did not enhance healing. In contrast, composite grafts with large (105 – 500 μm) allograft particles healed at 12 weeks post-implantation, as evidenced by radial μCT and histomorphometric analysis. This study highlights particle size and surface connectivity as influential parameters regulating the remodeling of composite bone scaffolds. PMID:25581686