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Sample records for acute transplant rejection

  1. LATE ACUTE REJECTION IN LIVER TRANSPLANT: A SYSTEMATIC REVIEW

    PubMed Central

    NACIF, Lucas Souto; PINHEIRO, Rafael Soares; PÉCORA, Rafael Antônio de Arruda; DUCATTI, Liliana; ROCHA-SANTOS, Vinicius; ANDRAUS, Wellington; D'ALBUQUERQUE, Luiz Carneiro

    2015-01-01

    Introduction: Late acute rejection leads to worse patient and graft survival after liver transplantation. Aim: To analyze the reported results published in recent years by leading transplant centers in evaluating late acute rejection and update the clinical manifestations, diagnosis and treatment of liver transplantation. Method: Systematic literature review through Medline-PubMed database with headings related to late acute rejection in articles published until November 2013 was done. Were analyzed demographics, immunosuppression, rejection, infection and graft and patient survival rates. Results: Late acute rejection in liver transplantation showed poor results mainly regarding patient and graft survival. Almost all of these cohort studies were retrospective and descriptive. The incidence of late acute rejection varied from 7-40% in these studies. Late acute rejection was one cause for graft loss and resulted in different outcomes with worse patient and graft survival after liver transplant. Late acute rejection has been variably defined and may be a cause of chronic rejection with worse prognosis. Late acute rejection occurs during a period in which the goal is to maintain lower immunosuppression after liver transplantation. Conclusion: The current articles show the importance of late acute rejection. The real benefit is based on early diagnosis and adequate treatment at the onset until late follow up after liver transplantation. PMID:26537150

  2. Early diagnosis of acute postoperative renal transplant rejection

    SciTech Connect

    Tisdale, P.L.; Collier, B.D.; Kauffman, H.M.; Adams, M.B.; Isitman, A.T.; Hellman, R.S.; Rao, S.A.; Joestgen, T.; Krohn, L.

    1985-05-01

    A prospective evaluation of In-111 labeled autologous platelet scintigraphy for the early diagnosis of acute postoperative renal transplant rejection was undertaken. To date, 28 consecutive patients between 7 and 14 days post-op have been injected with 500..mu..Ci of In-111 platelets followed by imaging at 24 and 48 hours. Activity within the renal transplant exceeding activity in the adjacent iliac vessels was considered to be evidence of rejection, and both chemical evidence and clinical impression of rejection at 5 days after completion of imaging was accepted as proof of ongoing or incipient rejection at the time of scintigraphy. In addition, to visual inspection, independent quantitative analysis compared the area-normalized activity over the transplant with the adjacent iliac vessels (normal <1.0). For 5 patients, positive In-111 scintigraphy was present before convincing clinical evidence of rejection. In-111 platelet scintigraphy is useful not only to confirm the clinical diagnosis of rejection but also to establish the early, pre-clinical diagnosis of incipient acute postoperative renal transplant rejection.

  3. Pretransplant identification of acute rejection risk following kidney transplantation.

    PubMed

    Lebranchu, Yvon; Baan, Carla; Biancone, Luigi; Legendre, Christophe; Morales, José Maria; Naesens, Maarten; Thomusch, Oliver; Friend, Peter

    2014-02-01

    Lack of an accepted definition for 'high immunological risk' hampers individualization of immunosuppressive therapy after kidney transplantation. For recipient-related risk factors for acute rejection, the most compelling evidence points to younger age and African American ethnicity. Recipient gender, body mass, previous transplantation, and concomitant infection or disease do not appear to be influential. Deceased donation now has only a minor effect on rejection risk, but older donor age remains a significant predictor. Conventional immunological markers (human leukocyte antigen [HLA] mismatching, pretransplant anti-HLA alloantibodies, and panel reactive antibodies) are being reassessed in light of growing understanding about the role of donor-specific antibodies (DSA). At the time of transplant, delayed graft function is one of the most clear-cut risk factors for acute rejection. Extended cold ischemia time (≥ 24 h) may also play a contributory role. While it is not yet possible to establish conclusively the relative contribution of different risk factors for acute rejection after kidney transplantation, the available data point to variables that should be taken into account at the time of transplant. Together, these offer a realistic basis for planning an appropriate immunosuppression regimen in individual patients.

  4. Acute antibody-mediated rejection in kidney transplant recipients.

    PubMed

    Davis, Scott; Cooper, James E

    2017-01-01

    Antibody-mediated rejection has now been recognized as one of the most important causes of graft loss. Transplantation across HLA barriers and nonadherence can result in acute antibody-mediated rejection, which is associated with particularly worse graft outcomes. New technologies, including genomic studies and assays to detect and define donor-specific antibodies, have provided important insights into the pathophysiology and diagnosis of acute antibody-mediated rejection but have engendered many questions about the clinical application of these tests in the prognosis and prevention of this protean disease process. In this article, we review the pathophysiology of acute antibody-mediated rejection, the evolving diagnostic criteria, and specific challenges related to its prognosis, treatment, and prevention.

  5. Acute antibody-mediated rejection after intestinal transplantation

    PubMed Central

    Wu, Guo-Sheng; Cruz Jr, Ruy J; Cai, Jun-Chao

    2016-01-01

    AIM To investigate the incidence, risk factors and clinical outcomes of acute antibody-mediated rejection (ABMR) after intestinal transplantation (ITx). METHODS A retrospective single-center analysis was performed to identify cases of acute ABMR after ITx, based on the presence of donor-specific antibody (DSA), acute tissue damage, C4d deposition, and allograft dysfunction. RESULTS Acute ABMR was identified in 18 (10.3%) out of 175 intestinal allografts with an average occurrence of 10 d (range, 4-162) after ITx. All acute ABMR cases were presensitized to donor human leukocyte antigens class I and/or II antigens with a detectable DSA. A positive cross-match was seen in 14 (77.8%) cases and twelve of 18 patients (66.7%) produced newly-formed DSA following ITx. Histological characteristics of acute ABMR include endothelial C4d deposits, interstitial hemorrhage, and severe congestion with focal fibrin thrombin in the lamina propria capillaries. Multivariate analysis identified a liver-free graft and high level of panel reactive antibody as a significant independent risk factor. Despite initial improvement after therapy, eleven recipients (61.1%) lost transplant secondary to rejection. Of those, 9 (50%) underwent graft removal and 4 (22.2%) received second transplantation following acute ABMR. At an average follow-up of 32.3 mo (range, 13.3-76.4), 8 (44.4%) recipients died. CONCLUSION Our results indicate that acute ABMR is an important cause of intestine graft dysfunction, particularly in a liver-exclusive graft and survivors are at an increased risk of developing refractory acute rejection and chronic rejection. More effective strategies to prevent and manage acute ABMR are needed to improve outcomes. PMID:28058223

  6. Treatment of simultaneous acute antibody-mediated rejection and acute cellular rejection with alemtuzumab in kidney transplantation: a case report.

    PubMed

    Jirasiritham, S; Khunprakant, R; Techawathanawanna, N; Jirasiritham, Si; Mavichak, V

    2010-04-01

    This is a case report of a living related donor kidney transplantation using basiliximab induction and maintenance immunosuppression with cyclosporine, mycophenolate sodium, and steroid. On the second posttransplant day, the patient developed acute antibody-mediated rejection, which was treated with plasmapheresis and intravenous immunoglobulin (IVIG). Five days later, the graft had still not responded to the treatment. Another biopsy revealed additional acute cellular rejection (Banff IIA). As alemtuzumab can rapidly deplete T and B lymphocytes, monocytes, and natural killer cells, the patient was treated with alemtuzumab (30 mg subcutaneously) together with methylprednisolone (500 mg) and two more plasmaphereses. The kidney graft responded within 48 hours, producing more than 4 L of urine per day. The total lymphocyte decreased from 530/microL to 50/microL remaining in the 50 to 220/microL range. The patient received valgancyclovir and cotrimoxazole as infection prophylaxis. The kidney graft responded well to the rescue treatment and the patient was discharged with a serum creatinine of 1.1 mg/mL and has been uneventfully followed in the outpatient clinic for 8 months. Today, with the potent, effective, and selective immunosuppressive regimens, the rate and severity of acute cellular rejection in kidney transplantation has decreased in most centers. However, the rate of acute antibody-mediated rejection has increased to levels greater than those of acute cellular rejection in many centers. Acute antibody-mediated rejection is more difficult and expensive to treat successfully. The treatment of acute antibody-mediated rejection included plasmapheresis and IVIG. Herein we have reported a case of kidney transplantation simultaneously developing acute antibody-mediated and acute cellular rejection; the patient was successfully treated with alemtuzumab.

  7. Shotgun Proteomics Identifies Proteins Specific for Acute Renal Transplant Rejection

    SciTech Connect

    Sigdel, Tara K.; Kaushal, Amit; Gritsenko, Marina A.; Norbeck, Angela D.; Qian, Weijun; Xiao, Wenzhong; Camp, David G.; Smith, Richard D.; Sarwal, Minnie M.

    2010-01-04

    Acute rejection (AR) remains the primary risk factor for renal transplant outcome; development of non-invasive diagnostic biomarkers for AR is an unmet need. We used shotgun proteomics using LC-MS/MS and ELISA to analyze a set of 92 urine samples, from patients with AR, stable grafts (STA), proteinuria (NS), and healthy controls (HC). A total of 1446 urinary proteins were identified along with a number of NS specific, renal transplantation specific and AR specific proteins. Relative abundance of identified urinary proteins was measured by protein-level spectral counts adopting a weighted fold-change statistic, assigning increased weight for more frequently observed proteins. We have identified alterations in a number of specific urinary proteins in AR, primarily relating to MHC antigens, the complement cascade and extra-cellular matrix proteins. A subset of proteins (UMOD, SERPINF1 and CD44), have been further cross-validated by ELISA in an independent set of urine samples, for significant differences in the abundance of these urinary proteins in AR. This label-free, semi-quantitative approach for sampling the urinary proteome in normal and disease states provides a robust and sensitive method for detection of urinary proteins for serial, non-invasive clinical monitoring for graft rejection after

  8. A case of acute humoral rejection in liver transplantation: successful treatment with plasmapheresis and mycophenolate mofetil.

    PubMed

    Rostron, Anthony; Carter, Vaughan; Mutunga, Mbithe; Cavanagh, Gary; O'Suilleabhain, Criostoir; Burt, Alistair; Jaques, Bryon; Talbot, David; Manas, Derek

    2005-11-01

    We present a case of a 23-year-old female who underwent orthotopic liver transplantation (OLTx) for biliary atresia, 22 years after a failed Kasai operation. Unusually, her postoperative course was complicated by severe acute humoral rejection. In this case report, we discuss her management as well as the role of plasmapheresis in treating allograft dysfunction secondary to acute humoral rejection in liver transplant patients.

  9. [Wolff-Parkinson-White syndrome in a case of acute rejection of cardiac transplantation].

    PubMed

    Ollitrault, J; Daubert, J C; Ramée, M P; Ritter, P; Mabo, P; Leguerrier, A; Rioux, C; Logeais, Y

    1990-09-01

    A Wolff-Parkinson-White syndrome was observed during acute rejection in a patient who had undergone orthotopic cardiac transplantation. The sometimes intermittent nature of this syndrome could explain its postoperative appearance in this patient; the relationship with the episode of rejection is discussed.

  10. Flow cytometry crossmatching as a predictor of acute rejection in sensitized recipients of cadaveric renal transplants.

    PubMed

    O'Rourke, R W; Osorio, R W; Freise, C E; Lou, C D; Garovoy, M R; Bacchetti, P; Ascher, N L; Melzer, J S; Roberts, J P; Stock, P G

    2000-04-01

    Flow cytometry crossmatching (FCXM) was developed as a more sensitive assay than the standard complement-dependent cytotoxicity crossmatch (CDCXM) for the detection of anti-donor antibodies, that mediate hyperacute rejection and graft loss in the early post-transplant period in renal transplant recipients. The role of FCXM in predicting long-term clinical outcome in renal allograft recipients is unclear. This study examines the role of FCXM in predicting long-term clinical outcome in highly sensitized recipients of cadaveric renal transplants. All patients (n = 100) with peak panel reactive antibody (PRA) levels > 30%, who received cadaveric renal transplants between 1/1/'90 and 12/31/'95 at our institution, were divided into FCXM + and FCXM - groups. The incidence of acute rejection was determined for each group during the first yr after transplant. Graft survival rates at 1, 2, and 3 yr, and creatinine levels were also compared between groups. FCXM + patients experienced a higher incidence of acute rejection during the first yr after transplant (69 vs. 45%), and a higher percentage of FCXM + patients had more than one episode of acute rejection during the first yr after transplant (34 vs. 8%) when compared to FCXM - patients. There was no statistically significant difference in 1-, 2-, or 3-yr graft survival between FCXM + and FCXM - patients (76 vs. 83, 62 vs. 80, 62 vs. 72%, respectively). These results suggest that sensitized FCXM + cadaveric renal transplant recipients have a higher incidence of acute rejection episodes in the first yr after transplant. Given the association of multiple rejection episodes with poor long-term allograft survival, FCXM may be a useful predictor of long-term clinical outcome in this sub-group of renal transplant recipients.

  11. Reduction of Acute Rejection by Bone Marrow Mesenchymal Stem Cells during Rat Small Bowel Transplantation

    PubMed Central

    Zhang, Wen; Wu, Ben-Juan; Fu, Nan-Nan; Zheng, Wei-Ping; Don, Chong; Shen, Zhong-Yang

    2014-01-01

    Background Bone marrow mesenchymal stem cells (BMMSCs) have shown immunosuppressive activity in transplantation. This study was designed to determine whether BMMSCs could improve outcomes of small bowel transplantation in rats. Methods Heterotopic small bowel transplantation was performed from Brown Norway to Lewis rats, followed by infusion of BMMSCs through the superficial dorsal veins of the penis. Controls included rats infused with normal saline (allogeneic control), isogeneically transplanted rats (BN-BN) and nontransplanted animals. The animals were sacrificed after 1, 5, 7 or 10 days. Small bowel histology and apoptosis, cytokine concentrations in serum and intestinal grafts, and numbers of T regulatory (Treg) cells were assessed at each time point. Results Acute cellular rejection occurred soon after transplantation and became aggravated over time in the allogeneic control rats, with increase in apoptosis, inflammatory response, and T helper (Th)1/Th2 and Th17/Treg-related cytokines. BMMSCs significantly attenuated acute cellular rejection, reduced apoptosis and suppressed the concentrations of interleukin (IL)-2, IL-6, IL-17, IL-23, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ while upregulating IL-10 and transforming growth factor (TGF)-β expression and increasing Treg levels. Conclusion BMMSCs improve the outcomes of allogeneic small bowel transplantation by attenuating the inflammatory response and acute cellular rejection. Treatment with BMMSCs may overcome acute cellular rejection in small bowel transplantation. PMID:25500836

  12. The Association Between Broad Antigen HLA Mismatches, Eplet HLA Mismatches and Acute Rejection After Kidney Transplantation

    PubMed Central

    Do Nguyen, Hung Thanh; Wong, Germaine; Chapman, Jeremy R.; McDonald, Stephen P.; Coates, Patrick T.; Watson, Narelle; Russ, Graeme R.; D'Orsogna, Lloyd; Lim, Wai Hon

    2016-01-01

    Background Epitope matching, which evaluates mismatched amino acids within antigen-antibody interaction sites (eplets), may better predict acute rejection than broad antigen matching alone. We aimed to determine the association between eplet mismatches and acute rejection in kidney transplant recipients. Methods The association between eplet mismatches, broad antigen mismatches and acute rejection was assessed using adjusted Cox proportional hazard regression. Model discrimination for acute rejection was evaluated using the area under receiver operating characteristic curves. Results Of the 3,499 kidney transplant recipients from 2006 to 2011, the average (SD) number of broad antigen and eplet mismatches were 3.4 (1.7) and 22.8 (12.2), respectively. Compared with 0 to 2 eplet mismatches, the adjusted hazard ratio (HR) for acute rejection among those with 20 or greater eplet mismatches was 2.16 (95% confidence interval [CI], 1.33-3.52; P = 0.001). The adjusted area under the curve for broad antigen mismatches was 0.58 (95% CI, 0.56-0.61), similar to that for eplet mismatches (HR, 0.59; 95% CI, 0.56-0.61; P = 0.365). In recipients who were considered as low immunological risk (0-2 broad antigen HLA-ABDR mismatch), those with 20 or greater eplet mismatches experienced an increased risk of rejection compared to those with less than 20 mismatches (adjusted HR, 1.85; 95% CI, 1.11-3.08; P = 0.019). Conclusions Increasing number of eplet mismatches is associated with acute rejection in kidney transplant recipients. Consideration of eplet HLA mismatches may improve risk stratification for acute rejection in a selected group of kidney transplant candidates. PMID:27990485

  13. Cytokine levels in pleural fluid as markers of acute rejection after lung transplantation*

    PubMed Central

    de Camargo, Priscila Cilene León Bueno; Afonso, José Eduardo; Samano, Marcos Naoyuki; Acencio, Milena Marques Pagliarelli; Antonangelo, Leila; Teixeira, Ricardo Henrique de Oliveira Braga

    2014-01-01

    Our objective was to determine the levels of lactate dehydrogenase, IL-6, IL-8, and VEGF, as well as the total and differential cell counts, in the pleural fluid of lung transplant recipients, correlating those levels with the occurrence and severity of rejection. We analyzed pleural fluid samples collected from 18 patients at various time points (up to postoperative day 4). The levels of IL-6, IL-8, and VEGF tended to elevate in parallel with increases in the severity of rejection. Our results suggest that these levels are markers of acute graft rejection in lung transplant recipients. PMID:25210966

  14. The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients

    PubMed Central

    Hasanzamani, Boshra; Hami, Maryam; Zolfaghari, Vajihe; Torkamani, Mahtab; Ghorban Sabagh, Mahin; Ahmadi Simab, Saiideh

    2016-01-01

    Introduction: It is known that cytomegalovirus (CMV) infection is a common problem among kidney transplant patients. This infection can be increased morbidity and decreased graft survival. This problem has been associated with acute rejection too. Patients and Methods: One hundred and thirty renal transplant patients were included in a prospective, case-control study. The renal transplant patients were divided into two groups; patients group with CMV infection and control group without CMV infection. Serum CMV-IgG in all patients was positive (donor and recipients). None of patients had received anti-thymocyte-globulin and thymoglobulin. CMV infection was diagnosed by quantitative CMV-PCR (polymerase chain reaction) test (more than 500 copies/μg). Rejection episode was defined by kidney isotope scan or biopsy. Results: In the group of 66 CMV infection patients (41 male [62.1%] and 25 female [37.9%]) the incidence of graft rejection was 36%, however in the group of 64 control patients the incidence of graft rejection was 9.4 % (P < 0.005). Conclusion: CMV infection is important predisposing factor for acute allograft rejection after kidney transplantation. The results of this study suggests that the control of CMV infection could decrease episodes of acute kidney rejection. PMID:27471740

  15. Acute and chronic antibody-mediated rejection in pediatric kidney transplantation.

    PubMed

    Pape, Lars; Becker, Jan U; Immenschuh, Stephan; Ahlenstiel, Thurid

    2015-03-01

    Acute antibody-mediated rejection is a diagnostic challenge in renal transplantation medicine. However, it is an important diagnosis to make, since chronic antibody-mediated rejection (CAMR) is the main cause of long-term graft loss. Antibody-mediated rejection is diagnosed by detecting donor-specific antibodies (DSAs) in the blood in combination with observing typical histomorphological signs in kidney biopsy, as described in the Banff classification. Therapy is based on the removal of DSAs by administering intravenous immunoglobulins (IVIGs), plasmapheresis, or immunoadsorption. Reoccurrence of antibodies is diminished by the use of rituximab, increased immunosuppression, and in some cases additional experimental substances. A combination of these techniques has been shown to be successful in the majority of cases of acute and chronic antibody-mediated rejection. Routine DSA monitoring is warranted for early detection of antibody-mediated rejection.

  16. Graft irradiation in the treatment of acute rejection of renal transplants: a randomized study

    SciTech Connect

    Pilepich, M.V.; Anderson, C.B.; Etheredge, E.E.; Sicard, G.A.; Melzer, J.S.; Blum, J.

    1982-05-01

    A randomized study of graft irradiation in the treatment of acute rejection of renal transplants was conducted from 1978 to 1981. Patients developing clinical signs of an acute graft rejection received customary antirejection treatment in the form of intravenous administration of high-dose (1 gm per day) of methylprednisolone. They were at the same time randomized to either receive therapeutic irradiation (175 rad every other day to a total of 525 rad) or sham irradiation. Neither the patient nor the Transplant Service surgeons knew at any time whether the radiation treatment had been given. Eighty-three rejection episodes occurring in 64 grafts were entered into the study. Acute rejection was reversed in 84.5% of grafts in the control and 75% in the treated group. The incidence of recurrent rejection was higher in the treated group (66 vs. 46%) and graft survival was lower (22% vs. 54%). The study failed to demonstrate a beneficial effect of graft irradiation in the treatment of acute renal allograft rejection, when used in conjunction with high dose steriods.

  17. A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation

    PubMed Central

    Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A.; Gong, Yongquan; Fischbein, Michael P.; Robbins, Robert C.; Naesens, Maarten

    2013-01-01

    Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design. PMID:24127489

  18. A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation.

    PubMed

    Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A; Gong, Yongquan; Fischbein, Michael P; Robbins, Robert C; Naesens, Maarten; Butte, Atul J; Sarwal, Minnie M

    2013-10-21

    Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.

  19. Combined Detection of Serum IL-10, IL-17, and CXCL10 Predicts Acute Rejection Following Adult Liver Transplantation

    PubMed Central

    Kim, Nayoung; Yoon, Young-In; Yoo, Hyun Ju; Tak, Eunyoung; Ahn, Chul-Soo; Song, Gi-Won; Lee, Sung-Gyu; Hwang, Shin

    2016-01-01

    Discovery of non-invasive diagnostic and predictive biomarkers for acute rejection in liver transplant patients would help to ensure the preservation of liver function in the graft, eventually contributing to improved graft and patient survival. We evaluated selected cytokines and chemokines in the sera from liver transplant patients as potential biomarkers for acute rejection, and found that the combined detection of IL-10, IL-17, and CXCL10 at 1-2 weeks post-operation could predict acute rejection following adult liver transplantation with 97% specificity and 94% sensitivity. PMID:27498551

  20. Usefulness of liver stiffness measurement during acute cellular rejection in liver transplantation.

    PubMed

    Crespo, Gonzalo; Castro-Narro, Graciela; García-Juárez, Ignacio; Benítez, Carlos; Ruiz, Pablo; Sastre, Lydia; Colmenero, Jordi; Miquel, Rosa; Sánchez-Fueyo, Alberto; Forns, Xavier; Navasa, Miquel

    2016-03-01

    Liver stiffness measurement (LSM) is a useful method to estimate liver fibrosis and portal hypertension. The inflammatory process that takes place in post-liver transplant acute cellular rejection (ACR) may also increase liver stiffness. We aimed to explore the association between liver stiffness and the severity of ACR, as well as to assess the relationship between liver stiffness and response to rejection treatment in a prospective study that included 27 liver recipients with biopsy-proven ACR, 30 stable recipients with normal liver tests, and 30 hepatitis C virus (HCV)-infected LT recipients with histologically diagnosed HCV recurrence. Patients with rejection were stratified into 2 groups (mild and moderate/severe) according to the severity of rejection evaluated with the Banff score. Routine biomarkers and LSM with FibroScan were performed at the time of liver biopsy (baseline) and at 7, 30, and 90 days in patients with rejection and at baseline in control patients. Median baseline liver stiffness was 5.9 kPa in the mild rejection group, 11 kPa in the moderate/severe group (P = 0.001), 4.2 kPa in stable recipients (P = 0.02 versus mild rejection), and 13.6 kPa in patients with recurrent HCV (P = 0.17 versus moderate/severe rejection). The area under the receiver operator characteristic curve of LSM to discriminate mild versus moderate/severe ACR was 0.924, and a LSM value of 8.5 kPa yielded a positive predictive value of 100% to diagnose moderate/severe rejection. Liver stiffness improved in 7%, 21%, and 64% of patients with moderate/severe rejection at 7, 30, and 90 days. In conclusion, according to the results of this exploratory study, LSM is associated with the severity of ACR in liver transplantation and thus may be of help in its assessment.

  1. Pulmonary circulatory parameters as indices for the early detection of acute rejection after single lung transplantation.

    PubMed

    Yamamoto, H; Okada, M; Tobe, S; Tsuji, F; Ohbo, H; Nakamura, H; Yamashita, C

    1998-01-01

    We investigated the relationship between the changes in the pulmonary blood flow and histology during acute rejection following single lung transplantation. In single lung transplantation using adult mongrel dogs, immunosuppression with cyclosporine and azathioprine was discontinued after postoperative day 14 to induce rejection. Doppler flow probes were placed adjacent to the ascending aorta and the left pulmonary artery to measure the blood flow on a daily basis. In addition, chest roentgenograms were also examined daily. The pulmonary pressure was measured using a Swan-Ganz catheter prior to and following the induction of rejection. Open lung biopsies were performed when the left pulmonary artery flow decreased to half of the prerejection value. The pulmonary artery flow decreased to 14.3% of the aortic flow 5 days after the discontinuation of immunosuppression. The graft pulmonary vascular resistance increased significantly compared to the prerejection values (P < 0.001). This was not accompanied by any abnormalities on chest roentgenography. The histology was consistent, with marked perivascular lymphocytic infiltration with little alveolar or interstitial changes. During rejection, the increased pulmonary vascular resistance in the graft was probably the result of perivascular inflammatory cell infiltration, which was seen prior to changes on chest roentgenography. Changes in the left pulmonary artery flow and histology thus appear to be closely correlated in the early stages of acute rejection.

  2. Noninvasive assessment for acute allograft rejection in a rat lung transplantation model

    PubMed Central

    Takahashi, Ayuko; Hamakawa, Hiroshi; Sakai, Hiroaki; Zhao, Xiangdong; Chen, Fengshi; Fujinaga, Takuji; Shoji, Tsuyoshi; Bando, Toru; Wada, Hiromi; Date, Hiroshi

    2014-01-01

    Abstract After lung transplantation, early detection of acute allograft rejection is important not only for timely and optimal treatment, but also for the prediction of chronic rejection which is a major cause of late death. Many biological and immunological approaches have been developed to detect acute rejection; however, it is not well known whether lung mechanics correlate with disease severity, especially with pathological rejection grade. In this study, we examined the relationship between lung mechanics and rejection grade development in a rat acute rejection model using the forced oscillation technique, which provides noninvasive assessment of lung function. To this end, we assessed lung resistance and elastance (RL and EL) from implanted left lung of these animals. The perivascular/interstitial component of rejection severity grade (A‐grade) was also quantified from histological images using tissue fraction (TF; tissue + cell infiltration area/total area). We found that TF, RL, and EL increased according to A‐grade. There was a strong positive correlation between EL at the lowest frequency (Elow; EL at 0.5 Hz) and TF (r2 = 0.930). Furthermore, the absolute difference between maximum value of EL (Emax) and Elow (Ehet; Emax − Elow) showed the strong relationship with standard deviation of TF (r2 = 0.709), and A‐grade (Spearman's correlation coefficients; rs = 0.964, P < 0.0001). Our results suggest that the dynamic elastance as well as its frequency dependence have the ability to predict A‐grade. These indexes should prove useful for noninvasive detection and monitoring the progression of disease in acute rejection. PMID:25524280

  3. 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

  4. Genetic Polymorphism of Interferon Regulatory Factor 5 (IRF5) Correlates with Allograft Acute Rejection of Liver Transplantation

    PubMed Central

    Yu, Xiaobo; Wei, Bajin; Dai, Yifan; Zhang, Min; Wu, Jian; Xu, Xiao; Jiang, Guoping; Zheng, Shusen; Zhou, Lin

    2014-01-01

    Background Although liver transplantation is one of the most efficient curative therapies of end stage liver diseases, recipients may suffer liver graft loss opst-operation. IRF-5, a member of Interferon Regulatory Factors, functions as a key regulator in TLR4 cascade, and is capable of inducing inflammatory cytokines. Although TLR4 has been proved to contribute to acute allograft rejection, including after liver transplantation, the correlation between IRF5 gene and acute rejection has not been elucidated yet. Methods The study enrolled a total of 289 recipients, including 39 females and 250 males, and 39 recipients developed acute allograft rejection within 6 months post-transplantation. The allograft rejections were diagnosed by liver biopsies. Genome DNA of recipients was extracted from pre-operative peripheral blood. Genotyping of IRF-5, including rs3757385, rs752637 and rs11761199, was performed, followed by SNP frequency and Hardy-Weinberg equilibrium analysis. Results The genetic polymorphism of rs3757385 was found associated with acute rejection. G/G homozygous individuals were at higher risk of acute rejection, with a P value of 0.042 (OR = 2.34 (1.07–5.10)). Conclusions IRF5, which transcriptionally activates inflammatory cytokines, is genetically associated with acute rejection and might function as a risk factor for acute rejection of liver transplantations. PMID:24788560

  5. Increased Numbers of Circulating CD8 Effector Memory T Cells before Transplantation Enhance the Risk of Acute Rejection in Lung Transplant Recipients

    PubMed Central

    San Segundo, David; Ballesteros, María Ángeles; Naranjo, Sara; Zurbano, Felipe; Miñambres, Eduardo; López-Hoyos, Marcos

    2013-01-01

    The effector and regulatory T cell subpopulations involved in the development of acute rejection episodes in lung transplantation remain to be elucidated. Twenty-seven lung transplant candidates were prospectively monitored before transplantation and within the first year post-transplantation. Regulatory, Th17, memory and naïve T cells were measured in peripheral blood of lung transplant recipients by flow cytometry. No association of acute rejection with number of peripheral regulatory T cells and Th17 cells was found. However, effector memory subsets in acute rejection patients were increased during the first two months post-transplant. Interestingly, patients waiting for lung transplant with levels of CD8+ effector memory T cells over 185 cells/mm3 had a significant increased risk of rejection [OR: 5.62 (95% CI: 1.08-29.37), p=0.04]. In multivariate analysis adjusted for age and gender the odds ratio for rejection was: OR: 5.89 (95% CI: 1.08-32.24), p=0.04. These data suggest a correlation between acute rejection and effector memory T cells in lung transplant recipients. The measurement of peripheral blood CD8+ effector memory T cells prior to lung transplant may define patients at high risk of acute lung rejection. PMID:24236187

  6. A case of accelerated acute rejection after ABO-compatible living unrelated kidney transplantation.

    PubMed

    Matsuo, Nanae; Yamamoto, Hiroyasu; Kobayashi, Akimitsu; Yamamoto, Izumi; Mitome, Jun; Maruyama, Yukio; Hayakawa, Hiroshi; Miyazaki, Yoichi; Utsunomiya, Yasunori; Hosoya, Tatsuo; Yamaguchi, Yutaka

    2009-08-01

    A 59-yr-old Japanese woman with chronic renal failure caused by IgA nephropathy and antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis underwent kidney transplantation from a living unrelated spousal donor. The blood type was compatible, while the human leukocyte antigen (HLA) typing showed a 5/6 locus mismatch. She had become pregnant twice by her donor and had never received blood transfusions. Complement-dependent cytotoxicity cross-match, flow cytometry cross-match (FCXM), and flow panel reactive antibody (PRA) were negative. She initially underwent one week of immunosuppression with mycophenolate mofetil (MMF) and double filtration plasmapheresis (DFPP) immediately before transplantation to reduce the risk of antibody-mediated rejection. Induction therapy consisted of MMF, tacrolimus (TAC), methylprednisolone (MP), and basiliximab. The allograft function was excellent immediately after the operation. However, the urine output and platelet count declined rapidly on post-operative day (POD) 3, while the serum creatinine (sCr) and lactate dehydrogenase levels rose gradually. Subsequently, we could not detect the diastolic arterial flow on Doppler sonography. We diagnosed accelerated acute rejection and treated her with plasma exchange (PEX), intravenous MP pulse therapy, and rituximab. The first episode biopsy on POD 7 revealed acute vascular rejection and acute antibody-mediated rejection (Banff score AMR II). Her urinary excretion increased beginning on POD 13, while the sCr level decreased gradually and reached 0.9 mg/dL on POD 22. In our retrospective analysis, the LAB screen detected donor-specific antibody (DSA). This case suggested that, for successful kidney transplantation in highly sensitized recipients, such as husband-to-wife spousal kidney transplantation with a history of pregnancy, we should keep the risk of AMR in mind, even if the sensitive antibody detection tests are negative.

  7. Impact of combined acute rejection on BK virus-associated nephropathy in kidney transplantation.

    PubMed

    Kim, Yoon Jung; Jeong, Jong Cheol; Koo, Tai Yeon; Kwon, Hyuk Yong; Han, Miyeun; Jeon, Hee Jung; Ahn, Curie; Yang, Jaeseok

    2013-12-01

    BK virus-associated nephropathy (BKVAN) is one of the major causes of allograft dysfunction in kidney transplant (KT) patients. We compared BKVAN combined with acute rejection (BKVAN/AR) with BKVAN alone in KT patients. We retrospectively analyzed biopsy-proven BKVAN in KT patients from 2000 to 2011 at Seoul National University Hospital. Among 414 biopsies from 951 patients, biopsy-proven BKVAN was found in 14 patients. Nine patients had BKVAN alone, while 5 patients had both BKVAN and acute cellular rejection. BKVAN in the BKVAN alone group was detected later than in BKVAN/AR group (21.77 vs 6.39 months after transplantation, P=0.03). Serum creatinine at diagnosis was similar (2.09 vs 2.00 mg/dL). Histological grade was more advanced in the BKVAN/AR group (P=0.034). Serum load of BKV, dose of immunosuppressants, and tacrolimus level showed a higher tendency in the BKVAN alone group; however it was not statistically significant. After anti-rejection therapy, immunosuppression was reduced in the BKVAN/AR group. Renal functional deterioration over 1 yr after BKVAN diagnosis was similar between the two groups (P=0.665). These findings suggest that the prognosis of BKVAN/AR after anti-rejection therapy followed by anti-BKV therapy might be similar to that of BKVAN alone after anti-BKV therapy.

  8. Acute Rejection in Renal Transplant Patients of a Hospital in Bogota, Colombia

    PubMed Central

    García, P.; Huerfano, M; Rodríguez, M; Caicedo, A; Berrío, F; Gonzalez, C

    2016-01-01

    Background: Renal transplantation is the best treatment for end stage renal disease. Acute graft rejection is one of the main complications and may influence graft survival. Objective: To determine the incidence and features of acute cellular rejection (ACR) episodes confirmed by biopsy. Methods: We studied a cohort of 175 patients who underwent renal transplantation between 2004 and 2012 to determine the cumulative incidence of ACR confirmed by biopsy and to identify the associated risk factors using multivariate analysis. Results: The one-year patient survival was 96.6%; the graft survival was 93.7%. The incidence of ACR within one year was 14.3%, of which 46% were observed within 6 months following transplantation. The most frequently observed ACR type was 1B according to the Banff classification system (42%). A relationship between ACR and receipt of a kidney from expanded criteria donors was observed, both in univariate and adjusted multiple log-binomial regression analyses, but only 6.3% of patients received extended criteria donor kidneys. No other relationships between variables were found. Conclusion: ACR frequency in this study was similar to that of other cohorts reported previously. We need a bigger sample of renal transplants from expanded criteria donors, PRA and DSA test to support the results. PMID:27721962

  9. Acute antibody-mediated rejection after ABO-incompatible kidney transplantation treated successfully with antigen-specific immunoadsorption.

    PubMed

    Just, Søren Andreas; Marcussen, Niels; Sprogøe, Ulrik; Koefoed-Nielsen, Pernille; Bistrup, Claus

    2010-01-01

    ABO-incompatible kidney transplantation is possible after pre-treatment with rituximab, intravenous immunoglobulin and basiliximab combined with tacrolimus, mycophenolate mofetil and prednisolone. We report on the first patient treated with this protocol who developed acute antibody-mediated rejection (Banff grade II with IgG deposits) caused by ABO antibodies (anti-B). Anti-rejection treatment with anti-B-specific immunoadsorption, intravenous immunoglobulin and methylprednisolone efficiently cleared deposited IgG from the kidney allograft and re-established normal kidney function. We suggest that ABO-incompatible kidney transplantation complicated by acute antibody-mediated rejection, caused by ABO antibodies, may successfully be treated with this regime.

  10. Identification of Novel and Noninvasive Biomarkers of Acute Cellular Rejection After Liver Transplantation by Protein Microarray

    PubMed Central

    Okubo, Keita; Wada, Hiroshi; Tanaka, Atsushi; Eguchi, Hidetoshi; Hamaguchi, Masahide; Tomokuni, Akira; Tomimaru, Yoshito; Asaoka, Tadafumi; Hama, Naoki; Kawamoto, Koichi; Kobayashi, Shogo; Marubashi, Shigeru; Nagano, Hiroaki; Sakaguchi, Noriko; Nishikawa, Hiroyoshi; Doki, Yuichiro; Mori, Masaki; Sakaguchi, Shimon

    2016-01-01

    Background Acute cellular rejection (ACR) is one of the main factors in transplanted organ failure in liver transplantation. A precise marker for diagnosing or predicting rejection is not currently available; therefore, invasive liver biopsy is standard procedure. To develop a noninvasive method for precise diagnosis of ACR, we evaluated autoantibodies from patient sera as potential biomarkers using protein microarrays (seromics). Methods Sera from hepatitis C virus–positive ACR patients were compared to three hepatitis C virus cirrhosis control groups and healthy volunteers. The control groups consisted of 2 no-ACR groups obtained on postoperative day 28 and 1 year after transplantation and a preoperative group obtained 1 day before transplantation. For validation, we evaluated whether the candidate antibodies can distinguish ACR from other types of liver dysfunction after liver transplantation using enzyme-linked immunosorbent assay. Results Seromic analysis by weighted average difference (WAD) ranking and Mann-Whitney U test revealed a significant increase of 57 autoantibodies in the sera of ACR patients with liver dysfunction. Among the 57 candidates, autoantibodies to charged multivesicular body protein 2B, potassium channel tetramerization domain containing 14, voltage gated subfamily A regulatory beta subunit 3, and triosephosphate isomerase 1 were regarded as potential biomarkers of ACR after liver transplantation. Using 20 ACR patients with variable backgrounds for validation, the autoantibodies to charged multivesicular body protein 2B and triosephosphate isomerase 1 were significantly increased in ACR patients compared to other control groups. Conclusions A panel of autoantibodies identified by seromics as potential noninvasive biomarkers was clinically useful for diagnosing ACR after liver transplantation. PMID:27990483

  11. Lipoxygenase products in the urine correlate with renal function and body temperature but not with acute transplant rejection.

    PubMed

    Reinhold, Stephan W; Scherl, Thomas; Stölcker, Benjamin; Bergler, Tobias; Hoffmann, Ute; Weingart, Christian; Banas, Miriam C; Kollins, Dmitrij; Kammerl, Martin C; Krüger, Bernd; Kaess, Bernhard; Krämer, Bernhard K; Banas, Bernhard

    2013-02-01

    Acute transplant rejection is the leading cause of graft loss in the first months after kidney transplantation. Lipoxygenase products mediate pro- and anti-inflammatory actions and thus we aimed to correlate the histological reports of renal transplant biopsies with urinary lipoxygenase products concentrations to evaluate their role as a diagnostic marker. This study included a total of 34 kidney transplant recipients: 17 with an acute transplant rejection and 17 controls. LTE4, LTB4, 12-HETE and 15-HETE concentrations were measured by enzyme immunoassay. Urinary lipoxygenase product concentrations were not significantly changed during an acute allograft rejection. Nevertheless, LTB4 concentrations correlated significantly with the body temperature (P ≤ 0.05) 3 months after transplantation, and 12- and 15-HETE concentrations correlated significantly with renal function (P ≤ 0.05) 2 weeks after transplantation. In conclusion, our data show a correlation for LTB4 with the body temperature 3 months after transplantation and urinary 12- and 15-HETE concentrations correlate positively with elevated serum creatinine concentrations but do not predict acute allograft rejection.

  12. Successful Salvage Treatment of Resistant Acute Antibody-Mediated Kidney Transplant Rejection with Eculizumab.

    PubMed

    Khan, Saif A; Al-Riyami, Dawood; Al-Mula Abed, Yasser W; Mohammed, Saja; Al-Riyami, Marwa; Al-Lawati, Nabil M

    2016-08-01

    Antibody-mediated rejection (ABMR) jeopardises short- and long-term transplant survival and remains a challenge in the field of organ transplantation. We report the first use of the anticomplement agent eculizumab in Oman in the treatment of a 61-year-old female patient with ABMR following a living unrelated kidney transplant. The patient was admitted to the Sultan Qaboos University Hospital in Muscat, Oman, in 2013 on the eighth day post-transplantation with serum creatinine (Cr) levels of 400 µmol/L which continued to rise, necessitating haemodialysis. A biopsy indicated ABMR with acute cellular rejection. No improvement was observed following standard ABMR treatment and she continued to require dialysis. Five doses of eculizumab were administered over six weeks with a subsequent dramatic improvement in renal function. The patient became dialysis-free with serum Cr levels of 119 µmol/L within four months. This case report indicates that eculizumab is a promising agent in the treatment of ABMR.

  13. Cortical perfusion index: A predictor of acute rejection in transplanted kidneys

    SciTech Connect

    Atkins, H.L.; Oster, Z.H.; Anaise, D.; Wein, S.; Waltzer, W.; Gonder, A.; Cooch, E.; Rapaport, F.T.

    1985-05-01

    The presently available non-invasive methods for the diagnosis of acute rejection crisis (ARC) of renal transplants are not satisfactory. However, the need for such a test is of paramount clinical importance. A prospective study of 74 post-transplantation events in renal allograft recipients was performed. Clinical, surgical exploration and biopsy data were correlated with TC-99m DTPA scintigraphy using the following indices: Global perfusion index (GPI), cortical perfusion index (CPI), medullary perfusion index (MPI), the peak-to-plateau ratio (P/P), iliac artery peak to renal peak time (delta-P) and washout half-time (T1/2). Of the 74 events, 24 were proven to be due to acute rejection crisis (ARC), 13 were of ureteral obstruction, 18 various nephropathies and 19 in stable renal transplant function. The P/P, delta-P and T1/2 were not good predictors of ARC; the sensitivity was 79%, 79% and 80% respectively. The sensitivity of the GPI was 58% and the specificity was 87%. The cortical perfusion index rated better: specificity=84% and sensitivity=87%. However, the best indicator of ARC seemed to be the percent increase in cortical perfusion index over previous values obtained during stable graft function. Thus the sensitivity was found to be 91% and specificity was 96%. The difference between global and cortical perfusion indices reflects shunting of blood for cortex to medulla. This study suggest that the cortical perfusion index (CPI) and the percent increase in CPI can be used to non-invasively diagnose acute renal allograft rejection.

  14. Prediction of acute graft rejection in renal transplantation: the utility of cyclosporine blood concentrations.

    PubMed

    Grevel, J; Napoli, K L; Welsh, M S; Atkinson, N E; Kahan, B D

    1991-02-01

    While cyclosporine is recommended to be used only in conjunction with monitoring of its blood concentrations, the utility of these measurements in preventing treatment failure is not established. In a group of 52 patients trough levels and steady-state concentrations were monitored in serum and whole blood by specific (SP) and nonspecific (NS) assays (polyclonal radioimmunoassay, PR; fluorescence polarization immunoassay, FP; high-pressure liquid chromatography, HP). From as many as 10 determinations of trough level and steady state concentrations during the first 40 days after renal transplantation, the lowest measurement was selected. In the case of an acute rejection episode within that time period, only values until that event were considered. Trough level measurements in serum by PR/NS and by FP/NS and in whole blood by HP/SP were not significantly different between patients with and patients without rejection episodes. However, simultaneously measured steady-state values (serum/PR/NS and serum/FP/NS) were significantly lower in patients suffering from rejection (with rejection SS/serum/PR/NS mean = 127 ng/ml, SD = 41 ng/ml; without rejection mean = 163 ng/ml, SD = 60 ng/ml; P = 0.027, t test). This difference could not be demonstrated for steady state/whole blood/HP/SP measurements. A logistic regression analysis demonstrated that the probability of rejection can be decreased by up to 40% if steady state/serum/PR/NS or steady state/serum/FP/NS values never drop below 250 ng/ml early after renal transplantation.

  15. Early diagnosis of acute postoperative renal transplant rejection by indium-111-labeled platelet scintigraphy

    SciTech Connect

    Tisdale, P.L.; Collier, B.D.; Kauffman, H.M.; Adams, M.B.; Isitman, A.T.; Hellman, R.S.; Hoffmann, R.G.; Rao, S.A.; Joestgen, T.; Krohn, L.

    1986-08-01

    A prospective evaluation of /sup 111/In-labeled platelet scintigraphy (IPS) for the early diagnosis of acute postoperative renal transplant rejection (TR) was undertaken. The results of IPS were compared with in vitro biochemical tests, the clinical finding of graft tenderness, and combined (/sup 99m/Tc)DTPA and (/sup 131/I)orthoiodohippurate scintigraphy. With a sensitivity of 0.93 and a specificity of 0.95, IPS provided otherwise unavailable diagnostic information. Furthermore, postoperative IPS was a good predictor of long-term allograft survival.

  16. Donor and recipient genetic variants in NLRP3 associate with early acute rejection following kidney transplantation

    PubMed Central

    Dessing, Mark C.; Kers, Jesper; Damman, Jeffrey; Navis, Gerjan J.; Florquin, Sandrine; Leemans, Jaklien C.

    2016-01-01

    NLRP3 (NOD-like receptor family, pyrin domain containing 3) is a member of the inflammasome family and is of special interest in renal disease. Experimental studies have shown that Nlrp3 plays a significant role in the induction of renal damage and dysfunction in acute and chronic renal injury. However, the role of NLRP3 in human renal disease is completely unknown. From a retrospective cohort study, we determined in 1271 matching donor and recipient samples if several NLRP3 single nucelotide polymorphisms (SNPs) were associated with primary non-function (PNF), delayed graft function (DGF), biopsy-proven acute rejection (BPAR) and death-censored graft and patient survival. NLRP3 gain-of-function SNP (rs35829419) in donors was associated with an increased risk of BPAR while NLRP3 loss-of-function SNP (rs6672995) in the recipient was associated with a decreased risk of BPAR in the first year following renal transplantation (HR 1.91, 95% CI 1.38–2.64, P < 0.001 and HR 0.73, 95% CI 0.55–0.97, P = 0.03 resp.). NLRP3 SNPs in both donor and recipient were not associated with PNF, DGF, graft survival or patient survival. We conclude that genetic variants in the NLRP3 gene affect the risk of acute rejection following kidney transplantation. PMID:27819323

  17. Difficulties, guidelines and review of developing an acute rejection model after rat intestinal transplantation.

    PubMed

    Andres, Ane Miren; Santamaria, Monica; Hernandez-Oliveros, Francisco; Guerra, Laura; Lopez, Sergio; Stringa, Pablo; Vallejo, Maria Teresa; Largo, Carlota; Encinas, Jose Luis; Garcia de Las Heras, Maria Soledad; Lopez-Santamaria, Manuel; Tovar, Juan Antonio

    2016-05-01

    Experimental small bowel transplantation (SBT) in rats has been proven to be a useful tool for the study of ischemia-reperfusion and immunological aspects related to solid organ transplantation. However, the model is not completely refined, specialized literature is scarce and complex technical details are typically omitted or confusing. Most studies related to acute rejection (AR) use the orthotopic standard, with small sample sizes due to its high mortality, whereas those studying chronic rejection (CR) use the heterotopic standard, which allows longer term survival but does not exactly reflect the human clinical scenario. Various animal strains have been used, and the type of rejection and the timing of its analysis differ among authors. The double purpose of this study was to develop an improved unusual AR model of SBT using the heterotopic technique, and to elaborate a guide useful to implement experimental models for studying AR. We analyzed the model's technical details and expected difficulties in overcoming the learning curve for such a complex microsurgical model, identifying the potential problem areas and providing a step-by-step protocol and reference guide for future surgeons interested in the topic. We also discuss the historic and more recent options in the literature.

  18. Mycophenolate mofetil toxicity mimicking acute cellular rejection in a small intestinal transplant

    PubMed Central

    Apostolov, Ross; Asadi, Khashayar; Lokan, Julie; Kam, Ning; Testro, Adam

    2017-01-01

    Mycophenolate mofetil (MMF) is an important medication used for maintenance immunosuppression in solid organ transplants. A common gastrointestinal (GI) side effect of MMF is enterocolitis, which has been associated with multiple histological features. There is little data in the literature describing the histological effects of MMF in small intestinal transplant (SIT) recipients. We present a case of MMF toxicity in a SIT recipient, with histological changes in the donor ileum mimicking persistent acute cellular rejection (ACR). Concurrent biopsies of the patient’s native colon showed similar changes to those from the donor small bowel, suggesting a non-graft specific process, raising suspicion for MMF toxicity. The MMF was discontinued and complete resolution of these changes occurred over three weeks. MMF toxicity should therefore be considered as a differential diagnosis for ACR and graft-versus-host disease in SITs. PMID:28280702

  19. Perioperative infliximab application ameliorates acute rejection associated inflammation after intestinal transplantation.

    PubMed

    Pech, T; Finger, T; Fujishiro, J; Praktiknjo, M; Ohsawa, I; Abu-Elmagd, K; Limmer, A; Hirner, A; Kalff, J C; Schaefer, N

    2010-11-01

    As we have shown in the past, acute rejection-related TNF-α upregulation in resident macrophages in the tunica muscularis after small bowel transplantation (SBTx) results in local amplification of inflammation, decisively contributing to graft dysmotility. Therefore, the aim of this study is to investigate the effectiveness of the chimeric-monoclonal-anti-TNF-α antibody infliximab as perioperative single shot treatment addressing inflammatory processes during acute rejection early after transplantation. Orthotopic, isogenic and allogenic SBTx was performed in rats (BN-Lewis/BN-BN) with infliximab treatment. Vehicle and IV-immunoglobulin-treated animals served as controls. Animals were sacrificed after 24 and 168 h. Leukocyte infiltration was investigated in muscularis whole mounts by immunohistochemistry, mediator mRNA expression by Real-Time-RT-PCR, apoptosis by TUNEL and smooth muscle contractility in a standard organ bath. Both, infliximab and Sandoglobulin® revealed antiinflammatory effects. Infliximab resulted in significantly less leukocyte infiltration compared to allogenic controls and IV-immunoglobulin, which was accompanied by lower gene expression of MCP-1 (24 h), IFN-γ (168 h) and infiltration of CD8-positive cells. Smooth muscle contractility improved significantly after 24 h compared to all controls in infliximab treated animals accompanied by lower iNOS expression. Perioperative treatment with infliximab is a possible pharmaceutical approach to overcome graft dysmotility early after SBTx.

  20. Plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation.

    PubMed

    Furuya, Maiko; Yamamoto, Izumi; Kobayashi, Akimitsu; Nakada, Yasuyuki; Sugano, Naoki; Tanno, Yudo; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoyama, Keitaro; Yokoo, Takashi

    2014-06-01

    We report a case of plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. A 33-year-old man was admitted for an episode biopsy; he had a serum creatinine (S-Cr) level of 5.7 mg/dL 1 year following primary kidney transplantation. Histological features included two distinct entities: (1) a focal, aggressive tubulointerstitial inflammatory cell (predominantly plasma cells) infiltration with moderate tubulitis; and (2) inflammatory cell infiltration (including neutrophils) in peritubular capillaries. Substantial laboratory examination showed that the patient had donor-specific antibodies for DQ4 and DQ6. Considering both the histological and laboratory findings, we diagnosed him with plasma cell-rich rejection accompanied by acute antibody-mediated rejection. We started 3 days of consecutive steroid pulse therapy three times every 2 weeks for the former and plasma exchange with intravenous immunoglobulin (IVIG) for the latter histological feature. One month after treatment, a second allograft biopsy showed excellent responses to treatment for plasma cell-rich rejection, but moderate, acute antibody-mediated rejection remained. Therefore, we added plasma exchange with IVIG again. After treatment, allograft function was stable, with an S-Cr level of 2.8 mg/dL. This case report demonstrates the difficulty of the diagnosis of, and treatment for, plasma cell-rich rejection accompanied by acute antibody-mediated rejection in a patient with ABO-incompatible kidney transplantation. We also include a review of the related literature.

  1. Interleukin-28B rs12979860 C/T Polymorphism and Acute Cellular Rejection after Liver Transplantation

    PubMed Central

    Fereidooni, H.; Azarpira, N.; Yaghobi, R.; Vahdati, A.; Malek-Hoseini, S. A.

    2017-01-01

    Background: Interleukin-28 (IL-28B) rs12979860 C/T polymorphism is a known predictor of sustained virological response after antiviral treatment in hepatitis C. IL-28B affects the innate immune system as well as intrahepatic expression level of interferon-stimulated genes. Objective: To investigate the effect of recipient IL-28B polymorphism on occurrence of acute rejection after liver transplantation. Methods: 140 liver allograft recipients were selected. Acute rejection episodes were recorded in 39 patients (AR group); the remaining had normal graft function (non-AR group). 70 normal subjects were also studied as the control group. The IL-28B rs12979860 was genotyped through PCR-RFLP method. Results: No significant difference was found between AR and non-AR groups in terms of genotype and allele frequency. However, the CC genotype was significantly (p<0.001) more frequent in patients than in the control group; the C allele variants increased the risk of end-stage liver disease (OR: 2.60). Conclusion: Liver damage in association with the carriage of IL-28B C allele is associated with a higher likelihood of developing cirrhosis. PMID:28299025

  2. Effect of intestinal microbiota alteration on hepatic damage in rats with acute rejection after liver transplantation.

    PubMed

    Xie, Yirui; Chen, Huazhong; Zhu, Biao; Qin, Nan; Chen, Yunbo; Li, Zhengfeng; Deng, Min; Jiang, Haiyin; Xu, Xiangfei; Yang, Jiezuan; Ruan, Bing; Li, Lanjuan

    2014-11-01

    The previous studies all focus on the effect of probiotics and antibiotics on infection after liver transplantation. Here, we focus on the effect of gut microbiota alteration caused by probiotics and antibiotics on hepatic damage after allograft liver transplantation. Brown-Norway rats received saline, probiotics, or antibiotics via daily gavage for 3 weeks. Orthotopic liver transplantation (OLT) was carried out after 1 week of gavage. Alteration of the intestinal microbiota, liver function and histopathology, serum and liver cytokines, and T cells in peripheral blood and Peyer's patch were evaluated. Distinct segregation of fecal bacterial diversity was observed in the probiotic group and antibiotic group when compared with the allograft group. As for diversity of intestinal mucosal microbiota and pathology of intestine at 2 weeks after OLT, antibiotics and probiotics had a significant effect on ileum and colon. The population of Lactobacillus and Bifidobacterium in the probiotic group was significantly greater than the antibiotic group and the allograft group. The liver injury was significantly reduced in the antibiotic group and the probiotic group compared with the allograft group. The CD4/CD8 and Treg cells in Peyer's patch were decreased in the antibiotic group. The intestinal Treg cell and serum and liver TGF-β were increased markedly while CD4/CD8 ratio was significantly decreased in the probiotic group. It suggested that probiotics mediate their beneficial effects through increase of Treg cells and TGF-β and deduction of CD4/CD8 in rats with acute rejection (AR) after OLT.

  3. Exogenous Lipocalin 2 Ameliorates Acute Rejection in a Mouse Model of Renal Transplantation

    PubMed Central

    Ashraf, M. I.; Schwelberger, H. G.; Brendel, K. A.; Feurle, J.; Andrassy, J.; Kotsch, K.; Regele, H.; Pratschke, J.; Maier, H. T.

    2016-01-01

    Abstract Lipocalin 2 (Lcn2) is rapidly produced by damaged nephron epithelia and is one of the most promising new markers of renal injury, delayed graft function and acute allograft rejection (AR); however, the functional importance of Lcn2 in renal transplantation is largely unknown. To understand the role of Lcn2 in renal AR, kidneys from Balb/c mice were transplanted into C57Bl/6 mice and vice versa and analyzed for morphological and physiological outcomes of AR at posttransplantation days 3, 5, and 7. The allografts showed a steady increase in intensity of interstitial infiltration, tubulitis and periarterial aggregation of lymphocytes associated with a substantial elevation in serum levels of creatinine, urea and Lcn2. Perioperative administration of recombinant Lcn2:siderophore:Fe complex (rLcn2) to recipients resulted in functional and morphological amelioration of the allograft at day 7 almost as efficiently as daily immunosuppression with cyclosporine A (CsA). No significant differences were observed in various donor–recipient combinations (C57Bl/6 wild‐type and Lcn2−/−, Balb/c donors and recipients). Histochemical analyses of the allografts showed reduced cell death in recipients treated with rLcn2 or CsA. These results demonstrate that Lcn2 plays an important role in reducing the extent of kidney AR and indicate the therapeutic potential of Lcn2 in transplantation. PMID:26595644

  4. Activation of the transcription factor c-Jun in acute cellular and antibody-mediated rejection after kidney transplantation.

    PubMed

    Kobayashi, Akimitsu; Takahashi, Takamune; Horita, Shigeru; Yamamoto, Izumi; Yamamoto, Hiroyasu; Teraoka, Satoshi; Tanabe, Kazunari; Hosoya, Tatsuo; Yamaguchi, Yutaka

    2010-12-01

    c-Jun is a transcription factor that belongs to the activator protein-1 family of proteins. In human kidney disease, c-Jun is activated in glomerular and tubular cells and plays a major role in renal pathophysiology. However, the contribution of this pathway to renal allograft rejection has not been determined. We investigated whether c-Jun is activated in acute allograft rejection. c-Jun activation was assessed with immunohistochemistry using phospho-specific c-Jun antibodies in control human renal tissue and renal tissue from patients with acute cellular rejection, acute antibody-mediated rejection, and no rejection in the month after transplantation. In patients with acute cellular rejection, c-Jun activation was observed primarily in infiltrated T cells associated with tubulitis, interstitial cell infiltration, and endarteritis. The number of infiltrated phosphorylated c-Jun-positive cells in the tubules and interstitium was correlated with the Banff classification "t" and "i" scores. In patients with acute antibody-mediated rejection, c-Jun activation was observed in injured endothelial cells as well as in infiltrated cells, including macrophages, in the glomerular and peritubular capillaries. Furthermore, the serum creatinine levels and changes in serum creatinine from the previous year were significantly correlated with the total tubulointerstitial phosphorylated c-Jun-positive score (representing the number of positive nuclei in the tubules, interstitium, and peritubular capillaries). In conclusion, c-Jun was activated in acute antibody-mediated rejection and acute cellular rejection and was associated with reduced graft function. These findings suggest that c-Jun plays a key role in pathological events and may represent a novel therapeutic target in acute renal allograft rejection.

  5. Urinary granzyme A mRNA is a biomarker to diagnose subclinical and acute cellular rejection in kidney transplant recipients.

    PubMed

    van Ham, S Marieke; Heutinck, Kirstin M; Jorritsma, Tineke; Bemelman, Fréderike J; Strik, Merel C M; Vos, Wim; Muris, Jettie J F; Florquin, Sandrine; Ten Berge, Ineke J M; Rowshani, Ajda T

    2010-11-01

    The distinction between T-cell-mediated rejection (TCMR) and other causes of kidney transplant dysfunction such as tubular necrosis requires biopsy. Subclinical rejection (SCR), an established risk factor for chronic allograft dysfunction, can only be diagnosed by protocol biopsy. A specific non-invasive biomarker to monitor immunological graft status would facilitate diagnosis and treatment of common transplantation-related complications. To identify possible markers, we measured urinary mRNA levels of several cytolytic proteins by quantitative PCR. Our cohort of 70 renal transplant recipients had biopsy proven type I and type II TCMR, acute tubular necrosis, SCR, calcineurin inhibitor-toxicity, cytomegalovirus infection, and stable graft function with normal histology. Granzyme A (GzmA) mRNA was significantly higher in subclinical and acute cellular rejection compared to patients with stable grafts or those with tubular necrosis with 80% sensitivity and up to 100% specificity. Granzyme B and perforin mRNA levels could significantly discriminate acute rejection from stable or tubular necrosis, but were not significantly elevated during SCR. Importantly, only GzmA mRNA remained below detection limits from grafts that were stable and most with tubular necrosis. Hence, the presented data indicate that urinary GzmA mRNA levels may entail a diagnostic non-invasive biomarker to distinguish patients with subclinical and acute cellular rejection from those with tubular necrosis or stable grafts.

  6. 14-bp ins/del polymorphism and +3142C>G SNP of the HLA-G gene have a significant impact on acute rejection after liver transplantation.

    PubMed

    Thude, Hansjörg; Janssen, Maike; Sterneck, Martina; Nashan, Björn; Koch, Martina

    2016-12-01

    Expression of human leukocyte antigen G (HLA-G) has been associated with increased graft survival and decreased rejection episodes. It has been described that the HLA-G 14-base pair (bp) insertion/deletion (ins/del) (rs66554220) and +3142C>G (rs1063320) gene polymorphisms modify the expression level of HLA-G. The aim of the study was to investigate whether these HLA-G polymorphisms have an impact on acute rejection after liver transplantation. In total, 146 liver transplant recipients (57 with acute rejection and 89 without acute rejection) and 99 corresponding liver donors were genotyped for both polymorphisms. In liver transplantation the 14-bp ins/ins and the +3142GG genotypes are more frequent in recipients without rejection compared to recipients with rejection (3.5% vs. 31.5%, p=<0.001; 12.3% vs. 41.6%, p=<0.001) demonstrating an association with protection from acute rejection. In contrast, in liver donors we could not reveal an association. We conclude that 14-bp ins/ins and +3142GG genotypes of HLA-G in liver transplant recipients are of importance for prediction of acute rejection after liver transplantation. Thus genotyping of liver recipients for both polymorphisms might be useful to stratify liver transplant recipients according to the risk of acute liver transplant rejection.

  7. A Five-Gene Peripheral Blood Diagnostic Test for Acute Rejection in Renal Transplantation

    PubMed Central

    Li, Li; Khatri, Purveshkumar; Sigdel, Tara K.; Tran, Tim; Ying, Lihua; Vitalone, Matthew; Chen, Amery; Hsieh, Szu-chuan; Dai, Hong; Zhang, Meixia; Naesens, Maarten; Zarkhin, Valeriya; Sansanwal, Poonam; Chen, Rong; Mindrinos, Michael; Xiao, Wenzhong; Benfield, Mark; Ettenger, Robert; Dharnidharka, Vikas; Mathias, Robert; Portale, Anthony; McDonald, Ruth; Harmon, William; Kershaw, David; Vehaskari, V. Matti; Kamil, Elaine; Baluarte, H. Jorge; Warady, Brad; Davis, Ron; Butte, Atul J.; Salvatierra, Oscar; Sarwal, Minnie

    2012-01-01

    Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in gthe NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n=47) and validated on independent test-set (n=198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool. PMID:23009139

  8. Alemtuzumab Induction and Delayed Acute Rejection in Steroid-Free Simultaneous Pancreas-Kidney Transplant Recipients

    PubMed Central

    Bank, Jonna R.; Heidt, Sebastiaan; Moes, Dirk Jan A. R.; Roelen, Dave L.; Mallat, Marko J. K.; van der Boog, Paul J.M.; Vergunst, Manon; Jol-van der Zijde, Cornelia M.; Bredius, Robbert G. M.; Braat, Andries E.; Ringers, Jan; van Tol, Maarten J. D.; Claas, Frans H. J.; Reinders, Marlies E. J.; de Fijter, Johannes W.

    2017-01-01

    Background The optimal immunosuppressive regimen in simultaneous pancreas-kidney transplant (SPKT) recipients that prevents acute rejection episodes (AREs) and allows optimal outcome remains elusive. Methods This cohort study assessed incidence and time to AREs in 73 consecutive SPKT recipients receiving alemtuzumab induction and steroid-free maintenance with tacrolimus and mycophenolate mofetil. A cohort with single high-dose antithymocyte globulin (ATG; n = 85) and triple therapy served as controls. In addition, we provided mechanistic insights in AREs after alemtuzumab depletion, including composition and alloreactivity of lymphocytes (flow cytometry and mixed lymphocyte reaction) plasma alemtuzumab levels (enzyme-linked immunosorbent assay), and maintenance drug exposure. Results Overall number of AREs at 3 years was significantly lower with alemtuzumab versus ATG induction (26.0% vs 43.5%; adjusted hazard ratio, 0.38; P = 0.029). Most AREs (94.6%) with ATG occurred within the first month, whereas 84.2% of AREs with alemtuzumab occurred beyond 3 months. Patients with and without an ARE in the steroid-free alemtuzumab group showed no differences in composition of lymphocytes, or in alemtuzumab levels. Of note, more than two thirds of these AREs were preceded by empiric tacrolimus and/or mycophenolate mofetil dose adjustments due to viral infections, leukopenia, or gastrointestinal symptoms. Conclusions Alemtuzumab induction resulted in a significant lower incidence of AREs. Empiric dose adjustments beyond 3 months in the absence of steroids carry a significant risk for subsequent rejection in SPKT recipients. PMID:28349124

  9. A peripheral blood diagnostic test for acute rejection in renal transplantation.

    PubMed

    Li, L; Khatri, P; Sigdel, T K; Tran, T; Ying, L; Vitalone, M J; Chen, A; Hsieh, S; Dai, H; Zhang, M; Naesens, M; Zarkhin, V; Sansanwal, P; Chen, R; Mindrinos, M; Xiao, W; Benfield, M; Ettenger, R B; Dharnidharka, V; Mathias, R; Portale, A; McDonald, R; Harmon, W; Kershaw, D; Vehaskari, V M; Kamil, E; Baluarte, H J; Warady, B; Davis, R; Butte, A J; Salvatierra, O; Sarwal, M M

    2012-10-01

    Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in the NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n = 47) and validated on independent test-set (n = 198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.

  10. Association of cytotoxic T-lymphocyte antigen 4 +49A/G gene polymorphism with acute rejection risk in renal transplantation.

    PubMed

    Yang, Chun-Hua; Chen, Xue-Xia; Chen, Li; Zheng, Dong-Hua; Liu, Qiong-Shan; Xie, Wen-Feng

    2017-03-23

    The conclusions on the association between cytotoxic T-lymphocyte antigen 4 (CTLA4) +49A/G gene polymorphism and acute rejection risk in renal transplantation are still debated. This meta-analysis was performed to update the association between CTLA4 +49A/G and acute rejection risk in renal transplantation. The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. Fourteen reports were included into this meta-analysis for the association of CTLA4 A/G gene polymorphism and acute rejection risk in renal transplantation, consisting of 962 acute rejection patients and 2084 non-acute rejection controls. The association between CTLA4 G allele/GG genotype and acute rejection risk in renal transplantation was found in this meta-analysis (G allele: OR=1.21, 95% CI: 1.03-1.44, P=.02; GG genotype: OR=1.37, 95% CI: 1.10-1.69, P=.004). However, the AA genotype was not associated with acute rejection risk in renal transplantation. In conclusion, CTLA4 G allele/GG genotype is associated with the acute rejection risk in renal transplantation.

  11. Fiber optic probe enabled by surface-enhanced Raman scattering for early diagnosis of potential acute rejection of kidney transplant

    NASA Astrophysics Data System (ADS)

    Chi, Jingmao; Chen, Hui; Tolias, Peter; Du, Henry

    2014-06-01

    We have explored the use of a fiber-optic probe with surface-enhanced Raman scattering (SERS) sensing modality for early, noninvasive and, rapid diagnosis of potential renal acute rejection (AR) and other renal graft dysfunction of kidney transplant patients. Multimode silica optical fiber immobilized with colloidal Ag nanoparticles at the distal end was used for SERS measurements of as-collected urine samples at 632.8 nm excitation wavelength. All patients with abnormal renal graft function (3 AR episodes and 2 graft failure episodes) who were clinically diagnosed independently show common unique SERS spectral features in the urines collected just one day after transplant. SERS-based fiber-optic probe has excellent potential to be a bedside tool for early diagnosis of kidney transplant patients for timely medical intervention of patients at high risk of transplant dysfunction.

  12. Thallium kinetics in rat cardiac transplant rejection

    SciTech Connect

    Barak, J.H.; LaRaia, P.J.; Boucher, C.A.; Fallon, J.T.; Buckley, M.J.

    1988-04-01

    Cardiac transplant rejection is a very complex process involving both cellular and vascular injury. Recently, thallium imaging has been used to assess acute transplant rejection. It has been suggested that changes in thallium kinetics might be a sensitive indicator of transplant rejection. Accordingly, thallium kinetics were assessed in vivo in acute untreated rat heterotopic (cervical) transplant rejection. Male Lewis rats weighing 225-250 g received heterotopic heart transplants from syngeneic Lewis rats (group A; n = 13), or allogeneic Brown Norway rats (group B; n = 11). Rats were imaged serially on the 2nd and the 7th postoperative days. Serial cardiac thallium content was determined utilizing data collected every 150 sec for 2 hr. The data were fit to a monoexponential curve and the decay rate constant (/sec) derived. By day 7 all group B hearts had histological evidence of severe acute rejection, and demonstrated decreased global contraction. Group A hearts showed normal histology and contractility. However, thallium uptakes and washout of the two groups were the same. Peak thallium uptake of group B was +/- 3758 1166 counts compared with 3553 +/- 950 counts in the control group A (P = 0.6395); The 2-hr percentage of washout was 12.1 +/- 1.04 compared with 12.1 +/- 9.3 (P = 1.0000); and the decay constant was -0.00002065 +/- 0.00001799 compared with -0.00002202 +/- 0.00001508 (P = 0.8409). These data indicate that in vivo global thallium kinetics are preserved during mild-to-severe acute transplant rejection. These findings suggest that the complex cellular and extracellular processes of acute rejection limit the usefulness of thallium kinetics in the detection of acute transplant rejection.

  13. The relation between apoptosis of acinar cells and nitric oxide during acute rejection of pancreas transplantation in rats.

    PubMed

    Xiaoguang, Ni; Zhong, Liu; Hailong, Chen; Ping, Zhao; Xiaofeng, Bai; Fenglin, Guan

    2003-01-01

    Apoptosis is an important mechanism of immune-mediated graft damage. Nitric oxide (NO) generated by inducible NO synthase (iNOS) has been demonstrated to induce apoptosis. This study investigated whether apoptosis occurs during pancreas allograft rejection and examined the relationship of apoptosis of acinar cells and NO. The rats were divided into three groups: untreated isograft group, untreated allograft group and aminoguanidine (AG)-treated group. The pancreatic grafts were harvested on the post-transplantation day 3, 5 and 7 and were used to detect the histopathological rejection grade, the expression of iNOS and the apoptotic index (AI) of the graft. iNOS presented faint positive in the acinar cells of untreated isografts and did not change greatly after transplantation (P>0.05), the level of iNOS in the untreated allografts increased progressively (P<0.01) and at the same time point was significantly higher than that of untreated isograft group and AG-treated group (P<0.01). The transferase-mediated dUTP nick end labeling showed that the apoptotic cells were mainly acinar cells. A significant correlation between AI and iNOS was noted (P<0.01, r=0.611). Therefore, NO-mediated apoptosis of acinar cells plays an important role in acute rejection of pancreas transplantation, AG can mitigate the damage of pancreas allografts.

  14. Characterization of transfusion-elicited acute antibody-mediated rejection in a rat model of kidney transplantation.

    PubMed

    Huang, G; Wilson, N A; Reese, S R; Jacobson, L M; Zhong, W; Djamali, A

    2014-05-01

    Animal models of antibody-mediated rejection (ABMR) may provide important evidence supporting proof of concept. We elicited donor-specific antibodies (DSA) by transfusion of donor blood (Brown Norway RT1(n) ) into a complete mismatch recipient (Lewis RT1(l) ) 3 weeks prior to kidney transplantation. Sensitized recipients had increased anti-donor splenocyte IgG1, IgG2b and IgG2c DSA 1 week after transplantation. Histopathology was consistent with ABMR characterized by diffuse peritubular capillary C4d and moderate microvascular inflammation with peritubular capillaritis + glomerulitis > 2. Immunofluorescence studies of kidney allograft tissue demonstrated a greater CD68/CD3 ratio in sensitized animals, primarily of the M1 (pro-inflammatory) phenotype, consistent with cytokine gene analyses that demonstrated a predominant T helper (TH )1 (interferon-γ, IL-2) profile. Immunoblot analyses confirmed the activation of the M1 macrophage phenotype as interferon regulatory factor 5, inducible nitric oxide synthase and phagocytic NADPH oxidase 2 were significantly up-regulated. Clinical biopsy samples in sensitized patients with acute ABMR confirmed the dominance of M1 macrophage phenotype in humans. Despite the absence of tubulitis, we were unable to exclude the effects of T cell-mediated rejection. These studies suggest that M1 macrophages and TH 1 cytokines play an important role in the pathogenesis of acute mixed rejection in sensitized allograft recipients.

  15. Antibody-Mediated Lung Transplant Rejection

    PubMed Central

    Hachem, Ramsey

    2012-01-01

    Antibody-mediated rejection after lung transplantation remains enigmatic. However, emerging evidence over the past several years suggests that humoral immunity plays an important role in allograft rejection. Indeed, the development of donor-specific antibodies after transplantation has been identified as an independent risk factor for acute cellular rejection and bronchiolitis obliterans syndrome. Furthermore, cases of acute antibody-mediated rejection resulting in severe allograft dysfunction have been reported, and these demonstrate that antibodies can directly injure the allograft. However, the incidence and toll of antibody-mediated rejection are unknown because there is no widely accepted definition and some cases may be unrecognized. Clearly, humoral immunity has become an important area for research and clinical investigation. PMID:23002428

  16. Efficacy of Acute Cellular Rejection Treatment According to Banff Score in Kidney Transplant Recipients: A Systematic Review

    PubMed Central

    Lamarche, Caroline; Côté, Jean-Maxime; Sénécal, Lynne; Cardinal, Héloïse

    2016-01-01

    Background The poor prognosis classically associated with Banff grade 2 acute cell-mediated rejection (CMR) may be due to unrecognized antibody-mediated damage. We thus performed a systematic review of the literature to determine the rate of response to treatment in kidney transplant recipients with pure CMR, stratified by Banff class. Methods In addition to a manual search, databases interrogated included Excerpta Medica Database (EMBASE), Medical Literature Analysis and Retrieval System Online (MEDLINE), Evidence-Based Medicine (EBM) databases, Central, PubMed and CINAHL. Studies providing functional and/or histological response rates to the treatment of CMR rejection by Banff class (1997 or more recent) were included. Results Among the 746 articles identified, 5 articles were included in the final review. Two studies excluded some, and 2 excluded all features of antibody-mediated rejection, while providing data on functional recovery. The absence of functional recovery was reported in 4% of borderline, 15% for Banff grade 1A and IB pooled, 0% to 25% of Banff grade 1B alone, 11% to 20% of Banff grade 2A, and 38% of Banff grade 2B rejections. Conclusions The rate of functional recovery of pure Banff IIA CMR overlapped with that of Banff grade 1 CMR, whereas Banff grade 2B showed worse prognosis. There was important heterogeneity in the definition of response to treatment and paucity of data describing the histological response to treatment stratified by Banff class. There is a pressing need to standardize outcome metrics for the reversibility of rejection in kidney transplant recipients in order to design high-quality trials for novel therapeutic alternatives. PMID:27990480

  17. Association Between Cytokines and Their Receptor Antagonist Gene Polymorphisms and Clinical Risk Factors and Acute Rejection Following Renal Transplantation

    PubMed Central

    Ding, Siqing; Xie, Jianfei; Wan, Qiquan

    2016-01-01

    Background Acute rejection (AR) after renal transplantation affects both patient and graft survival. There is growing evidence of the genetic association between cytokine or its receptor antagonist and AR in solid organ transplantation. The objectives of this study were to investigate the role of recipient TNF β, IL-10, IL-1β, and IL-1 receptor antagonist (ra) gene polymorphism, as well as traditional clinical variables such as panel-reactive antibody (PRA) levels, donor type, and HLA mismatches in AR following renal transplantation. Material/Methods TNF β (+252A/G), IL-10 (−592A/C), IL-1β (−511C/T) and IL-1ra (86 bp VNTR) gene polymorphisms were determined in 195 renal allograft recipients with and without AR, using PCR. Both these genotypic variants and clinical risk factors were investigated for correlation with AR within the first year after renal transplantation. Results Patients with increased pre-transplant PRA levels (P<0.001) and donor type (P=0.012) were prone to the development of AR. After adjusting for all variables of P<0.2, a PRA level >10% (OR=4.515, 95% confidence intervals=1.738–11.727, P=0.002) and the receipt of a graft from a donation after cardiac death (DCD) donor (OR=2.437, 95% confidence intervals=1.047–5.673, P=0.039) remained significantly associated with AR in a multivariate logistic regression analysis. No correlation could be found between recipients with an episode and absence of acute rejection and the gene polymorphisms of these cytokines investigated in the present study. Conclusions This study shows that the presence of increased pre-transplant levels of PRA and the receipt of a graft from DCD donor other than cytokine gene polymorphisms are significant risk factors for AR in renal transplantation. To reduce the occurrence of AR, clinicians should take necessary measures to lower the PRA levels and pay more attention to patients who received a graft from a DCD donor. PMID:27913812

  18. A Novel Cardioprotective Agent in Cardiac Transplantation: Metformin Activation of AMP-Activated Protein Kinase Decreases Acute Ischemia-Reperfusion Injury and Chronic Rejection

    PubMed Central

    Chin, Jocelyn T.; Troke, Joshua J.; Kimura, Naoyuki; Itoh, Satoshi; Wang, Xi; Palmer, Owen P.; Robbins, Robert C.; Fischbein, Michael P.

    2011-01-01

    The main cause of mortality after the first year from cardiac transplantation is cardiac allograft vasculopathy (CAV), which leads to chronic rejection of the heart. To improve long-term outcomes in cardiac transplantation, treatments to prevent or diminish CAV are actively being researched. Ischemia-reperfusion (I-R) injury has been shown to be the strongest alloantigen-independent factor in the development of CAV. Here, we investigate the use of metformin in murine cardiac transplantation models as a novel cardioprotective agent to limit acute I-R injury and subsequent chronic rejection. We show that metformin treatment activates AMP-activated kinase (AMPK) in vitro and in vivo. In the acute transplantation model, metformin activation of AMPK resulted in significantly decreased apoptosis in cardiac allografts on postoperative day (POD) 1 and 8. In the chronic transplantation model, metformin pretreatment of allografts led to significantly improved graft function and significantly decreased CAV, as measured on POD 52. Taken together, our results in the acute and chronic rejection studies suggest a potential cardioprotective mechanism for metformin; we demonstrate a correlation between metformin-induced decrease in acute I-R injury and metformin-related decrease in chronic rejection. Thus, one of the ways by which metformin and AMPK activation may protect the transplanted heart from chronic rejection is by decreasing initial I-R injury inherent in donor organ preservation and implantation. Our findings suggest novel therapeutic strategies for minimizing chronic cardiac rejection via the use of metformin- and AMPK-mediated pathways to suppress acute I-R injury. PMID:22180679

  19. A novel cardioprotective agent in cardiac transplantation: metformin activation of AMP-activated protein kinase decreases acute ischemia-reperfusion injury and chronic rejection.

    PubMed

    Chin, Jocelyn T; Troke, Joshua J; Kimura, Naoyuki; Itoh, Satoshi; Wang, Xi; Palmer, Owen P; Robbins, Robert C; Fischbein, Michael P

    2011-12-01

    The main cause of mortality after the first year from cardiac transplantation is cardiac allograft vasculopathy (CAV), which leads to chronic rejection of the heart. To improve long-term outcomes in cardiac transplantation, treatments to prevent or diminish CAV are actively being researched. Ischemia-reperfusion (I-R) injury has been shown to be the strongest alloantigen-independent factor in the development of CAV. Here, we investigate the use of metformin in murine cardiac transplantation models as a novel cardioprotective agent to limit acute I-R injury and subsequent chronic rejection. We show that metformin treatment activates AMP-activated kinase (AMPK) in vitro and in vivo. In the acute transplantation model, metformin activation of AMPK resulted in significantly decreased apoptosis in cardiac allografts on postoperative day (POD) 1 and 8. In the chronic transplantation model, metformin pretreatment of allografts led to significantly improved graft function and significantly decreased CAV, as measured on POD 52. Taken together, our results in the acute and chronic rejection studies suggest a potential cardioprotective mechanism for metformin; we demonstrate a correlation between metformin-induced decrease in acute I-R injury and metformin-related decrease in chronic rejection. Thus, one of the ways by which metformin and AMPK activation may protect the transplanted heart from chronic rejection is by decreasing initial I-R injury inherent in donor organ preservation and implantation. Our findings suggest novel therapeutic strategies for minimizing chronic cardiac rejection via the use of metformin- and AMPK-mediated pathways to suppress acute I-R injury.

  20. The ratio of circulating regulatory T cells (Tregs)/Th17 cells is associated with acute allograft rejection in liver transplantation.

    PubMed

    Wang, Ying; Zhang, Min; Liu, Zhen-Wen; Ren, Wei-Guo; Shi, Yan-Chao; Sun, Yan-Ling; Wang, Hong-Bo; Jin, Lei; Wang, Fu-Sheng; Shi, Ming

    2014-01-01

    CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) and Th17 cells are known to be involved in the alloreactive responses in organ transplantation, but little is known about the relationship between Tregs and Th17 cells in the context of liver alloresponse. Here, we investigated whether the circulating Tregs/Th17 ratio is associated with acute allograft rejection in liver transplantation. In present study, thirty-eight patients who received liver transplant were enrolled. The patients were divided into two groups: acute allograft rejection group (Gr-AR) (n = 16) and stable allograft liver function group (Gr-SF) (n = 22). The frequencies of circulating Tregs and circulating Th17 cells, as well as Tregs/Th17 ratio were determined using flow cytometry. The association between Tregs/Th17 ratio and acute allograft rejection was then analyzed. Our results showed that the frequency of circulating Tregs was significantly decreased, whereas the frequency of circulating Th17 cells was significantly increased in liver allograft recipients who developed acute rejection. Tregs/Th17 ratio had a negative correlation with liver damage indices and the score of rejection activity index (RAI) after liver transplantation. In addition, the percentages of CTLA-4(+), HLA-DR(+), Ki67(+), and IL-10(+) Tregs were higher in Gr-SF group than in Gr-AR group. Our results suggested that the ratio of circulating Tregs/Th17 cells is associated with acute allograft rejection, thus the ratio may serve as an alternative marker for the diagnosis of acute rejection.

  1. Polymorphisms in the lectin pathway of complement activation influence the incidence of acute rejection and graft outcome after kidney transplantation.

    PubMed

    Golshayan, Déla; Wójtowicz, Agnieszka; Bibert, Stéphanie; Pyndiah, Nitisha; Manuel, Oriol; Binet, Isabelle; Buhler, Leo H; Huynh-Do, Uyen; Mueller, Thomas; Steiger, Jürg; Pascual, Manuel; Meylan, Pascal; Bochud, Pierre-Yves

    2016-04-01

    There are conflicting data on the role of the lectin pathway of complement activation and its recognition molecules in acute rejection and outcome after transplantation. To help resolve this we analyzed polymorphisms and serum levels of lectin pathway components in 710 consecutive kidney transplant recipients enrolled in the nationwide Swiss Transplant Cohort Study, together with all biopsy-proven rejection episodes and 1-year graft and patient survival. Functional mannose-binding lectin (MBL) levels were determined in serum samples, and previously described MBL2, ficolin 2, and MBL-associated serine protease 2 polymorphisms were genotyped. Low MBL serum levels and deficient MBL2 diplotypes were associated with a higher incidence of acute cellular rejection during the first year, in particular in recipients of deceased-donor kidneys. This association remained significant (hazard ratio 1.75, 95% confidence interval 1.18-2.60) in a Cox regression model after adjustment for relevant covariates. In contrast, there was no significant association with rates of antibody-mediated rejection, patient death, early graft dysfunction or loss. Thus, results in a prospective multicenter contemporary cohort suggest that MBL2 polymorphisms result in low MBL serum levels and are associated with acute cellular rejection after kidney transplantation. Since MBL deficiency is a relatively frequent trait in the normal population, our findings may lead to individual risk stratification and customized immunosuppression.

  2. [Sirolimus for rescue of recurrent acute rejection and diabetes mellitus after liver transplantation: report of one case].

    PubMed

    Roque, Jorge; Ríos, Gloria; Hepp, Juan; Humeres, Roberto; Ríos, Horacio; Herrera, José M; Rius, Montserrat

    2005-10-01

    Sirolimus (SRL) is a new immunosuppressive drug approved for renal transplantation, but is being used increasingly in orthotopic liver transplantation (OLT). Compared with the calcineurin inhibitors, SRL has different mechanisms of action and side effects profile. Thus, this drug offers significant potential advantages over other immunosuppressive agents. SRL does not cause glucose intolerance, hypertension or renal failure, but it may cause dyslipidemia, hepatic artery thrombosis, thrombocytopenia, anemia, leukopenia, oral mucosa ulcers, edema, arthralgias and wound complications. SRL inhibits the signal of interleukin 2 at a post-receptor level, inhibiting lymphocyte proliferation and fibroblast proliferation. It also has antineoplastic and antifungal effects. We report a 10 years old girl who underwent OLT, experiencing a biopsy-proven recurrent acute rejection (AR) in spite of using three immunosuppressive agents (tacrolimus, mofetil micofenolate and steroids). She developed diabetes mellitus as a consequence of the immunosuppressive therapy. She was rescued with SRL, not experiencing AR again. Mofetil micofenolate, steroids and insulin could be discontinued and tacrolimus doses were reduced, without experiencing severe complications. SRL is a new and safe immunosuppressive agent for rescue in patients with OLT and recurrent AR.

  3. Pre-Transplant Donor-Specific T-Cell Alloreactivity Is Strongly Associated with Early Acute Cellular Rejection in Kidney Transplant Recipients Not Receiving T-Cell Depleting Induction Therapy

    PubMed Central

    Crespo, Elena; Lucia, Marc; Cruzado, Josep M.; Luque, Sergio; Melilli, Edoardo; Manonelles, Anna; Lloberas, Nuria; Torras, Joan; Grinyó, Josep M.; Bestard, Oriol

    2015-01-01

    Preformed T-cell immune-sensitization should most likely impact allograft outcome during the initial period after kidney transplantation, since donor-specific memory T-cells may rapidly recognize alloantigens and activate the effector immune response, which leads to allograft rejection. However, the precise time-frame in which acute rejection is fundamentally triggered by preformed donor-specific memory T cells rather than by de novo activated naïve T cells is still to be established. Here, preformed donor-specific alloreactive T-cell responses were evaluated using the IFN-γ ELISPOT assay in a large consecutive cohort of kidney transplant patients (n = 90), to assess the main clinical variables associated with cellular sensitization and its predominant time-frame impact on allograft outcome, and was further validated in an independent new set of kidney transplant recipients (n = 67). We found that most highly T-cell sensitized patients were elderly patients with particularly poor HLA class-I matching, without any clinically recognizable sensitizing events. While one-year incidence of all types of biopsy-proven acute rejection did not differ between T-cell alloreactive and non-alloreactive patients, Receiver Operating Characteristic curve analysis indicated the first two months after transplantation as the highest risk time period for acute cellular rejection associated with baseline T-cell sensitization. This effect was particularly evident in young and highly alloreactive individuals that did not receive T-cell depletion immunosuppression. Multivariate analysis confirmed preformed T-cell sensitization as an independent predictor of early acute cellular rejection. In summary, monitoring anti-donor T-cell sensitization before transplantation may help to identify patients at increased risk of acute cellular rejection, particularly in the early phases after kidney transplantation, and thus guide decision-making regarding the use of induction therapy. PMID:25689405

  4. Association of Serum MiR-142-3p and MiR-101-3p Levels with Acute Cellular Rejection after Heart Transplantation

    PubMed Central

    Sukma Dewi, Ihdina; Hollander, Zsuzsanna; Lam, Karen K.; McManus, Janet-Wilson; Tebbutt, Scott J.; Ng, Raymond T.; Keown, Paul A.; McMaster, Robert W.; McManus, Bruce M.; Gidlöf, Olof; Öhman, Jenny

    2017-01-01

    Background Identifying non-invasive and reliable blood-derived biomarkers for early detection of acute cellular rejection in heart transplant recipients is of great importance in clinical practice. MicroRNAs are small molecules found to be stable in serum and their expression patterns reflect both physiological and underlying pathological conditions in human. Methods We compared a group of heart transplant recipients with histologically-verified acute cellular rejection (ACR, n = 26) with a control group of heart transplant recipients without allograft rejection (NR, n = 37) by assessing the levels of a select set of microRNAs in serum specimens. Results The levels of seven microRNAs, miR-142-3p, miR-101-3p, miR-424-5p, miR-27a-3p, miR-144-3p, miR-339-3p and miR-326 were significantly higher in ACR group compared to the control group and could discriminate between patients with and without allograft rejection. MiR-142-3p and miR-101-3p had the best diagnostic test performance among the microRNAs tested. Serum levels of miR-142-3p and miR-101-3p were independent of calcineurin inhibitor levels, as measured by tacrolimus and cyclosporin; kidney function, as measured by creatinine level, and general inflammation state, as measured by CRP level. Conclusion This study demonstrated two microRNAs, miR-142-3p and miR-101-3p, that could be relevant as non-invasive diagnostic tools for identifying heart transplant patients with acute cellular rejection. PMID:28125729

  5. Elevated CXCL10 (IP-10) in Bronchoalveolar Lavage Fluid is Associated with Acute Cellular Rejection Following Human Lung Transplantation

    PubMed Central

    Husain, Shahid; Resende, Mariangela R.; Rajwans, Nimerta; Zamel, Ricardo; Pilewski, Joseph M.; Crespo, Maria M; Singer, Lianne G.; McCurry, Kenneth R.; Kolls, Jay K.; Keshavjee, Shaf; Liles, W. Conrad

    2013-01-01

    Background CXCL10 (IP-10) is a potent chemoattractant for T cells that has been postulated to play arole in infection and acute cellular rejection (ACR) in animal models. We measured CXCL10 (IP-10) (and other cytokines previously implicated in the pathogenesis of ACR) in the bronchoalveolar lavage (BAL) of lung transplant recipients (LTRs) to determine the association between CXCL10 (IP-10) and ACR in LTRs. Methods In a prospective study of 85 LTRs, expression of cytokines (TNF, IFNγ, IL-6, IL-8, IL-15, IL-16, IL-17, CXCL10 (IP-10) and MCP-1 (CCL2)) in BAL samples (n=233) from patients with episodes of ACR (n=44), infection (Infect) (n=25), concomitant ‘Infect +ACR’ (n=10), and ‘No Infect & No ACR’ (n=154) were analyzed. Results The levels of both CXCL10 (IP-10) and IL-16 were significantly increased in histologically proven ACR, as compared to the ‘No Infect & No ACR’ group (CXCL10 [IP-10]: 107.0 vs. 31.9 pg/mL [p=0.001]; IL-16: 472.1 vs. 283.01 [p=0.01]).However, in a linear mixed effects model, significant association was found only between CXCL10 (IP-10)] and ACR. A 1-log increase of CXCL10 (IP-10) was associated with a 40% higher risk of ACR (OR 1.4; 95% CI 1.12-1.84). Conclusion Higher values of CXCL10 (IP-10) in BAL fluid are associated with ACR in LTRs suggesting a potential mechanistic role in the pathogenesis of ACR in LTRs. These results suggest that therapeutic strategies to inhibit CXCL10 (IP-10) and or its cognate receptor, CXCR3, warrant investigation to prevent and/or treat ACR in clinical lung transplantation. PMID:24025324

  6. The Effect of Histological CD20-Positive B Cell Infiltration in Acute Cellular Rejection on Kidney Transplant Allograft Survival

    PubMed Central

    Jiang, Yan; Wang, Rending; Wang, Huiping; Huang, Hongfeng; Peng, Wenhan; Qiu, Wenxian; Zhou, Jingyi

    2016-01-01

    Background. It is controversial whether lymphocyte infiltration exhibited in biopsy specimens is associated with transplant outcomes. This study focused on the effect of CD20-positive B cell infiltration in biopsy specimens from allografts with acute cellular rejection (ACR) in a Chinese population. Methods. Altogether, 216 patients transplanted from Sep. 2001 to Dec. 2014 with biopsy-proved ACR (Banff I or Banff II) were included in the analysis. Biopsies were immunostained for CD20 and C4d. Baseline information, serum creatinine and GFR before and after treatment, steroid resistance, response to treatment, graft loss, and survival were analyzed. Results. Eighty-three patients were classified into CD20-negative group, and 133 patients were classified into CD20-positive group. Significantly more CD20-negative patients (49/83, 59.0%) received steroid plus antibody therapy compared with the CD20-positive group (52/133, 39.1%) (P = 0.004). The response to treatment for ACR did not differ between these two groups. The CD20-positive group had less graft loss (18.8% versus 32.5%, P = 0.022) and a better graft survival rate. Further exploration of the infiltration degree suggested that it tended to be positively related to graft survival, but this did not reach statistical significance. Conclusion. CD20-positive B cell infiltration in renal allograft biopsies with ACR is associated with less steroid resistance and better graft survival. The presence of CD20-positive B cells is protective for renal allografts. PMID:28058267

  7. Artificial intelligence techniques: predicting necessity for biopsy in renal transplant recipients suspected of acute cellular rejection or nephrotoxicity.

    PubMed

    Hummel, A D; Maciel, R F; Sousa, F S; Cohrs, F M; Falcão, A E J; Teixeira, F; Baptista, R; Mancini, F; da Costa, T M; Alves, D; Rodrigues, R G D S; Miranda, R; Pisa, I T

    2011-05-01

    The gold standard for nephrotoxicity and acute cellular rejection (ACR) is a biopsy, an invasive and expensive procedure. More efficient strategies to screen patients for biopsy are important from the clinical and financial points of view. The aim of this study was to evaluate various artificial intelligence techniques to screen for the need for a biopsy among patients suspected of nephrotoxicity or ACR during the first year after renal transplantation. We used classifiers like artificial neural networks (ANN), support vector machines (SVM), and Bayesian inference (BI) to indicate if the clinical course of the event suggestive of the need for a biopsy. Each classifier was evaluated by values of sensitivity and area under the ROC curve (AUC) for each of the classifiers. The technique that showed the best sensitivity value as an indicator for biopsy was SVM with an AUC of 0.79 and an accuracy rate of 79.86%. The results were better than those described in previous works. The accuracy for an indication of biopsy screening was efficient enough to become useful in clinical practice.

  8. Impact of ABO Incompatibility on the Development of Acute Antibody-Mediated Rejection in Kidney Transplant Recipients Presensitized to HLA.

    PubMed

    Chung, Byung Ha; Joo, Yu Young; Lee, Jaesin; Kim, Hyung Duk; Kim, Ji-Il; Moon, In Sung; Choi, Bum Soon; Oh, Eun-Jee; Park, Cheol Whee; Kim, Yong-Soo; Yang, Chul Woo

    2015-01-01

    Whether the coexistence of anti-A/B antibody and donor specific anti-HLA antibody (HLA-DSA) has a synergistic impact on the development of acute antibody-mediated rejection (AAMR) in kidney transplant recipients (KTRs) is unclear. This study includes 92 KTRs who received a kidney from an ABO-incompatible (ABOi) donor or were presensitized to donor HLA (HLAs) and 292 controls (CONT). HLAs was defined as a crossmatch positivity or the presence of HLA-DSA. We compared the incidence of AAMR among ABOi (n = 58), ABOi+HLAs (n = 12), HLAs (n = 22), and CONT (n = 292) groups and evaluated the risk factors and antibody type (anti-A/B vs. HLA-DSA) responsible for AAMR. AAMR developed less frequently in ABOi and CONT than in the ABOi+HLAs or HLAs (P < 0.05 for all); however, there was no difference between the ABOi+HLAs and HLAs groups. AAMR developed more frequently with strong HLA-DSA at baseline; however, high baseline anti-A/B titer did not affect AAMR development. Strong baseline HLA-DSA was an independent predictor for AAMR, however the baseline anti-A/B titer was not. All four AAMR episodes in ABOi+HLAs were positive to HLA-DSA but not to anti-A/B. In conclusion, ABO incompatibility does not increase the risk for AAMR in HLAs KTRs.

  9. Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II

    PubMed Central

    Crespo-Leiro, Maria G.; Stypmann, Jörg; Schulz, Uwe; Zuckermann, Andreas; Mohacsi, Paul; Bara, Christoph; Ross, Heather; Parameshwar, Jayan; Zakliczyński, Michal; Fiocchi, Roberto; Hoefer, Daniel; Colvin, Monica; Deng, Mario C.; Leprince, Pascal; Elashoff, Barbara; Yee, James P.; Vanhaecke, Johan

    2016-01-01

    Aims A non-invasive gene-expression profiling (GEP) test for rejection surveillance of heart transplant recipients originated in the USA. A European-based study, Cardiac Allograft Rejection Gene Expression Observational II Study (CARGO II), was conducted to further clinically validate the GEP test performance. Methods and results Blood samples for GEP testing (AlloMap®, CareDx, Brisbane, CA, USA) were collected during post-transplant surveillance. The reference standard for rejection status was based on histopathology grading of tissue from endomyocardial biopsy. The area under the receiver operating characteristic curve (AUC-ROC), negative (NPVs), and positive predictive values (PPVs) for the GEP scores (range 0–39) were computed. Considering the GEP score of 34 as a cut-off (>6 months post-transplantation), 95.5% (381/399) of GEP tests were true negatives, 4.5% (18/399) were false negatives, 10.2% (6/59) were true positives, and 89.8% (53/59) were false positives. Based on 938 paired biopsies, the GEP test score AUC-ROC for distinguishing ≥3A rejection was 0.70 and 0.69 for ≥2–6 and >6 months post-transplantation, respectively. Depending on the chosen threshold score, the NPV and PPV range from 98.1 to 100% and 2.0 to 4.7%, respectively. Conclusion For ≥2–6 and >6 months post-transplantation, CARGO II GEP score performance (AUC-ROC = 0.70 and 0.69) is similar to the CARGO study results (AUC-ROC = 0.71 and 0.67). The low prevalence of ACR contributes to the high NPV and limited PPV of GEP testing. The choice of threshold score for practical use of GEP testing should consider overall clinical assessment of the patient's baseline risk for rejection. PMID:26746629

  10. Late acute humoral rejection in low-risk renal transplant recipients induced with an interleukin-2 receptor antagonist and maintained with standard therapy: preliminary communication.

    PubMed

    Morales, J; Contreras, L; Zehnder, C; Pinto, V; Elberg, M; Araneda, S; Herzog, C; Calabran, L; Aguiló, J; Ferrario, M; Buckel, E; Fierro, J A

    2011-01-01

    Low-risk renal transplant recipients treated with standard immunosuppressive therapy including interleukin-2 receptor (IL-2R) antagonist show a low incidence of early rejection episodes but few reports have examined the incidence and severity of late rejection processes. This study evaluated retrospectively cellular and antibody-mediated rejection (AMR) among 42 recipients selected because they showed low panel-reactive-antibodies, short cold ischemia time, no delayed graft function, and therapy including basiliximab (Simulect) induction. The mean observation time was 6.6 years. Sixty-seven percent of donors were deceased. Ten-year patient and death-censored graft survivals were 81% and 78%, respectively. Seven patients lost their kidneys due to nonimmunologic events. The seven recipients who experienced cellular rejection episodes during the first posttransplant year had them reversed with steroids. Five patients displayed late acute AMR causing functional deterioration in four cases including 1 graft loss. De novo sensitization occurred in 48% of recipients including patients without clinical rejection. In conclusion, long-term follow-up of kidney transplant recipients selected by a low immunologic risk showed a persistent risk of de novo sensitization evolving to acute AMR in 11% of cases. Although immunologic events were related to late immunosuppressive reduction, most graft losses were due to nonimmunologic factors.

  11. Subclinical antibody-mediated rejection due to anti-human-leukocyte-antigen-DR53 antibody accompanied by plasma cell-rich acute rejection in a patient with cadaveric kidney transplantation.

    PubMed

    Katsuma, Ai; Yamamoto, Izumi; Komatsuzaki, Yo; Niikura, Takahito; Kawabe, Mayuko; Okabayashi, Yusuke; Yamakawa, Takafumi; Katsumata, Haruki; Nakada, Yasuyuki; Kobayashi, Akimitsu; Tanno, Yudo; Miki, Jun; Yamada, Hiroki; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi

    2016-07-01

    A 56-year-old man who had undergone cadaveric kidney transplantation 21 months earlier was admitted to our hospital for a protocol biopsy; he had a serum creatinine level of 1.2 mg/dL and no proteinuria. Histological features showed two distinct entities: (i) inflammatory cell infiltration, in the glomerular and peritubular capillaries and (ii) focal, aggressive tubulointerstitial inflammatory cell infiltration, predominantly plasma cells, with mild tubulitis (Banff 13 classification: i2, t1, g2, ptc2, v0, ci1, ct1, cg0, cv0). Immunohistological studies showed mildly positive C4d immunoreactivity in the peritubular capillaries. The patient had donor specific antibody to human-leucocyte-antigen-DR53. We diagnosed him with subclinical antibody-mediated rejection accompanied by plasma cell-rich acute rejection. Both antibody-mediated rejection due to anti- human-leucocyte-antigen -DR53 antibodies and plasma cell-rich acute rejection are known to be refractory and have a poor prognosis. Thus, we started plasma exchange with intravenous immunoglobulin and rituximab for the former and 3 days of consecutive steroid pulse therapy for the latter. Three months after treatment, a follow-up allograft biopsy showed excellent responses to treatment for both histological features. This case report considers the importance of an early diagnosis and appropriate intervention for subclinical antibody-mediated rejection due to donor specific antibody to human-leucocyte-antigen-DR53 and plasma cell-rich acute rejection.

  12. Should IFN-γ, IL-17 and IL-2 be considered predictive biomarkers of acute rejection in liver and kidney transplant? Results of a multicentric study.

    PubMed

    Millán, O; Rafael-Valdivia, L; San Segundo, D; Boix, F; Castro-Panete, M J; López-Hoyos, M; Muro, M; Valero-Hervás, D; Rimola, A; Navasa, M; Muñoz, P; Miras, M; Andrés, A; Guirado, L; Pascual, J; Brunet, M

    2014-10-01

    Acute rejection (AR) remains a major challenge in organ transplantation, and there is a need for predictive biomarkers. In the present multicenter study, we prospectively examined a series of biomarkers in liver and kidney recipients. Intracellular expression of IFN-γ, IL-17 and IL-2 and IL-17 soluble production were evaluated both pre-transplantation and post-transplantation (1st and 2nd week, 1st, 2nd and 3rd month). 142 transplant patients (63 liver/79 kidney) were included in the study. Twenty-eight recipients (14 liver/14 kidney) developed AR. Pre- and post-transplantation intracellular expression of %IFN-γ(+) in CD4(+)CD69(+) and in CD8(+)CD69(+) and soluble IL17 identified liver and kidney transplant patients at high risk of AR. Pre-transplantation, %IL-2(+) in CD8(+)CD69(+) also identified kidney patients at high risk. We constructed pre- and post-transplantation risk prediction models, based on a composite panel of biomarkers, which could provide the basis for future studies and will be a useful tool for the selection and adjustment of immunosuppressive treatments.

  13. Three-Dimensional Self-Navigated T2 Mapping for the Detection of Acute Cellular Rejection After Orthotopic Heart Transplantation

    PubMed Central

    van Heeswijk, Ruud B.; Piccini, Davide; Tozzi, Piergiorgio; Rotman, Samuel; Meyer, Philippe; Schwitter, Juerg; Stuber, Matthias; Hullin, Roger

    2017-01-01

    Background T2 mapping is a magnetic resonance imaging technique measuring T2 relaxation time, which increases with the myocardial tissue water content. Myocardial edema is a component of acute cellular rejection (ACR) after heart transplantation. This pilot study compares in heart transplantation recipients a novel high resolution 3-dimensional (3D) T2-mapping technique with standard 2-dimensional (2D) T2-mapping for ACR detection. Methods Consecutive asymptomatic patients (n = 26) underwent both 3D T2 mapping and reference 2D T2 mapping magnetic resonance imaging on the day of endomyocardial biopsy (EMB). 3D T2 maps were obtained at an isotropic spatial resolution of 1.72 mm (voxel volume 5.1 mm3). 2D and 3D maps were matched anatomically, and maximum segmental T2 values were compared blinded to EMB results. In addition, all 3D T2 maps were rendered as 3D images and inspected for foci of T2 elevation. Results T2 values of segments from 2D and reformatted 3D T2 maps agreed (p > 0.5). The highest 2D segmental T2 values were 49.9 ± 4.0 ms (no ACR = 0R, n = 18), 48.9 ± 0.8 ms (mild ACR = 1R, n = 3), and 65.0 ms (moderate ACR = 2R). Rendered 3D T2 maps of cases with 1R showed foci with significantly elevated T2 signal (T2 = 58.2 ± 3.6 ms); 5 cases (28%) in the 0R group showed foci with increased T2 values (>2 SD above adjacent tissue) that were not visible on the 2D T2 maps. Conclusions This pilot study in a small cohort suggests equivalency of standard segmental analysis between 3D and 2D T2-mapping. 3D T2 mapping provides a spatial resolution that permits detection of foci with elevated T2 in patients with mild ACR.

  14. Evaluation of OKT3 monoclonal antibody and anti-thymocyte globulin in the treatment of steroid-resistant acute allograft rejection in pediatric renal transplants.

    PubMed

    Mochon, M; Kaiser, B; Palmer, J A; Polinsky, M; Flynn, J T; Caputo, G C; Baluarte, H J

    1993-06-01

    We reviewed the effectiveness of Muromonab-CD3 (OKT3) and anti-thymocyte globulin (ATG) in the treatment of corticosteroid-resistant acute renal allograft rejection in 49 transplanted children. Reversal of rejection was successful in 22 of 23 patients (96%) treated with OKT3 and 21 of 26 (81%) treated with ATG (P = NS). Re-rejection episodes occurred within 1 month of cessation of therapy in 9 of 22 patients treated with OKT3 but only in 2 of 21 who received ATG (P < 0.05). In the patients with re-rejection, 7 of the 9 patients originally given OKT3 and 1 of the 2 who received ATG responded to a repeat course of high-dose corticosteroids; thus, at 1 month post treatment, the incidence of graft loss due to initial rejection or re-rejection was 13% for the OKT3 and 23% for the ATG group (P = NS). Graft survival was similar at 6 months: 82% for OKT3- and 73% for ATG-treated patients (P = NS); 100% patient survival was noted in both groups. Mean calculated creatinine clearance prior to, during, and at 1 and 6 months post rejection was similar in the OKT3- and ATG-treated groups. Neutropenia and thrombocytopenia occurred more frequently in the ATG group, but there was no significant difference in infectious complications. Two patients developed high (> or = 1:1,000) OKT3 antibody titers. In our experience, children with corticosteroid-resistant acute renal allograft rejection treated with OKT3 and ATG had similar allograft survival and level of renal function at 1 and 6 months, and number of infectious complications post therapy.

  15. High frequency of central memory regulatory T cells allows detection of liver recipients at risk of early acute rejection within the first month after transplantation.

    PubMed

    Boix-Giner, Francisco; Millan, Olga; San Segundo, David; Muñoz-Cacho, Pedro; Mancebo, Esther; Llorente, Santiago; Rafael-Valdivia, Lourdes; Rimola, Antoni; Fábrega, Emilio; Mrowiec, Anna; Allende, Luis; Minguela, Alfredo; Bolarín, Jose M; Paz-Artal, Estela; López-Hoyos, Marcos; Brunet, Mercé; Muro, Manuel

    2016-02-01

    Several studies have analyzed the potential of T regulatory cells (Treg cells) as biomarkers of acute rejection (AR). The aim of the present multicenter study was to correlate the percentage of peripheral Treg cells in liver graft recipients drawn at baseline up to 12 months after transplantation with the presence of AR. The percentage of central memory (cm) Treg cells (CD4(+)CD25(high)CD45RO(+)CD62L(+)) was monitored at pre-transplant and at 1 and 2 weeks, and 1, 2, 3 and 6 months and 1 year post-transplantation. The same validation standard operating procedures were used in all participating centers. Fifteen patients developed AR (23.4%). Hepatitis C virus recurrence was observed in 16 recipients, who displayed low peripheral blood cmTreg levels compared with patients who did not. A steady increase of cmTregs was observed during the first month after transplantation with statistically significant differences between AR and non-AR patients. The high frequency of memory Treg cells allowed us to monitor rejection episodes during the first month post-transplantation. On the basis of these data, we developed a prediction model for assessing risk of AR that can provide clinicians with useful information for managing patients individually and customizing immunosuppressive therapies.

  16. High frequency of central memory regulatory T cells allows detection of liver recipients at risk of early acute rejection within the first month after transplantation

    PubMed Central

    Boix-Giner, Francisco; Millan, Olga; San Segundo, David; Muñoz-Cacho, Pedro; Mancebo, Esther; Llorente, Santiago; Rafael-Valdivia, Lourdes; Rimola, Antoni; Fábrega, Emilio; Mrowiec, Anna; Allende, Luis; Minguela, Alfredo; Bolarín, Jose M.; Paz-Artal, Estela; López-Hoyos, Marcos; Brunet, Mercé

    2016-01-01

    Several studies have analyzed the potential of T regulatory cells (Treg cells) as biomarkers of acute rejection (AR). The aim of the present multicenter study was to correlate the percentage of peripheral Treg cells in liver graft recipients drawn at baseline up to 12 months after transplantation with the presence of AR. The percentage of central memory (cm) Treg cells (CD4+CD25highCD45RO+CD62L+) was monitored at pre-transplant and at 1 and 2 weeks, and 1, 2, 3 and 6 months and 1 year post-transplantation. The same validation standard operating procedures were used in all participating centers. Fifteen patients developed AR (23.4%). Hepatitis C virus recurrence was observed in 16 recipients, who displayed low peripheral blood cmTreg levels compared with patients who did not. A steady increase of cmTregs was observed during the first month after transplantation with statistically significant differences between AR and non-AR patients. The high frequency of memory Treg cells allowed us to monitor rejection episodes during the first month post-transplantation. On the basis of these data, we developed a prediction model for assessing risk of AR that can provide clinicians with useful information for managing patients individually and customizing immunosuppressive therapies. PMID:26270267

  17. Th-17 Alloimmune Responses in Renal Allograft Biopsies From Recipients of Kidney Transplants Using Extended Criteria Donors During Acute T Cell-Mediated Rejection.

    PubMed

    Matignon, M; Aissat, A; Canoui-Poitrine, F; Grondin, C; Pilon, C; Desvaux, D; Saadoun, D; Barathon, Q; Garrido, M; Audard, V; Rémy, P; Lang, P; Cohen, J; Grimbert, P

    2015-10-01

    Although renal transplantation using expanded criteria donors has become a common practice, immune responses related to immunosenescence in those kidney allografts have not been studied yet in humans. We performed a retrospective molecular analysis of the T cell immune response in 43 kidney biopsies from patients with acute T cell-mediated rejection including 25 from recipients engrafted with a kidney from expanded criteria donor and 18 from recipients grafted with optimal kidney allograft. The clinical, transplant and acute T cell-mediated rejection characteristics of both groups were similar at baseline. The expression of RORγt, Il-17 and T-bet mRNA was significantly higher in the elderly than in the optimal group (p = 0.02, p = 0.036, and p = 0.01, respectively). Foxp3 mRNA levels were significantly higher in elderly patients experiencing successful acute T cell-mediated rejection reversal (p = 0.03). The presence of IL-17 mRNA was strongly associated with nonsuccessful reversal in elderly patients (p = 0.008). Patients with mRNA IL17 expression detection and low mRNA Foxp3 expression experienced significantly more treatment failure (87.5%) than patients with no mRNA IL17 expression and/or high mRNA Foxp3 expression (26.7%; p = 0.017). Our study suggests that the Th17 pathway is involved in pathogenesis and prognosis of acute T cell-mediated rejection in recipients of expanded criteria allograft.

  18. Early acute antibody-mediated rejection of a negative flow crossmatch 3rd kidney transplant with exclusive disparity at HLA-DP.

    PubMed

    Mierzejewska, Beata; Schroder, Paul M; Baum, Caitlin E; Blair, Annette; Smith, Connie; Duquesnoy, Rene J; Marrari, Marilyn; Gohara, Amira; Malhotra, Deepak; Kaw, Dinkar; Liwski, Robert; Rees, Michael A; Stepkowski, Stanislaw

    2014-08-01

    Donor-specific alloantibodies (DSA) to HLA-DP may cause antibody-mediated rejection (AMR), especially in re-transplants. We describe the immunization history of a patient who received 3 kidney transplants; the 3rd kidney was completely matched except at DPA1 and DPB1. Prior to the 3rd transplant, single antigen bead analysis (SAB) showed DSA reactivity against DPA1 shared by the 1st and 3rd donors, but B and T flow crossmatch (FXM) results were negative. Within 11 days the 3rd transplant underwent acute C4d+ AMR which coincided with the presence of complement (C1q)-binding IgG1 DSA against donor DPA1 and DPB1. Using HLAMatchmaker and SAB, we provide evidence that eplet (epitope) spreading on DPA1 and eplet sharing on differing DPB1 alleles of the 1st and 3rd transplants was associated with AMR. Since weak DSA to DPA1/DPB1 may induce acute AMR with negative FXM, donor DPA1/DPB1 high resolution typing should be considered in sensitized patients with DP-directed DSA.

  19. Monitoring Pharmacologically Induced Immunosuppression by Immune Repertoire Sequencing to Detect Acute Allograft Rejection in Heart Transplant Patients: A Proof-of-Concept Diagnostic Accuracy Study

    PubMed Central

    Valantine, Hannah A.; Penland, Lolita; Luikart, Helen; Strehl, Calvin; Cohen, Garrett; Khush, Kiran K.; Quake, Stephen R.

    2015-01-01

    Background It remains difficult to predict and to measure the efficacy of pharmacological immunosuppression. We hypothesized that measuring the B-cell repertoire would enable assessment of the overall level of immunosuppression after heart transplantation. Methods and Findings In this proof-of-concept study, we implemented a molecular-barcode-based immune repertoire sequencing assay that sensitively and accurately measures the isotype and clonal composition of the circulating B cell repertoire. We used this assay to measure the temporal response of the B cell repertoire to immunosuppression after heart transplantation. We selected a subset of 12 participants from a larger prospective cohort study (ClinicalTrials.gov NCT01985412) that is ongoing at Stanford Medical Center and for which enrollment started in March 2010. This subset of 12 participants was selected to represent post-heart-transplant events, with and without acute rejection (six participants with moderate-to-severe rejection and six without). We analyzed 130 samples from these patients, with an average follow-up period of 15 mo. Immune repertoire sequencing enables the measurement of a patient’s net state of immunosuppression (correlation with tacrolimus level, r = −0.867, 95% CI −0.968 to −0.523, p = 0.0014), as well as the diagnosis of acute allograft rejection, which is preceded by increased immune activity with a sensitivity of 71.4% (95% CI 30.3% to 94.9%) and a specificity of 82.0% (95% CI 72.1% to 89.1%) (cell-free donor-derived DNA as noninvasive gold standard). To illustrate the potential of immune repertoire sequencing to monitor atypical post-transplant trajectories, we analyzed two more patients, one with chronic infections and one with amyloidosis. A larger, prospective study will be needed to validate the power of immune repertoire sequencing to predict rejection events, as this proof-of-concept study is limited to a small number of patients who were selected based on several

  20. RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection

    PubMed Central

    Van Aelst, L. N. L.; Summer, G.; Li, S.; Gupta, S. K.; Heggermont, W.; De Vusser, K.; Carai, P.; Naesens, M.; Van Cleemput, J.; Van de Werf, F.; Vanhaecke, J.; Thum, T.; Waer, M.; Papageorgiou, A.‐P.; Schroen, B.

    2015-01-01

    Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR‐21, ‐142‐3p, ‐142‐5p, ‐146a, ‐146b, ‐155, ‐222, ‐223, and ‐494 increased during ACR in humans and mice, whereas miR‐149‐5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune‐related diseases. Interestingly, 33 of 70 transcripts function downstream of IL‐6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR‐155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR‐155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR‐155, and transcripts, in particular those related to the IL‐6 pathway, are promising therapeutic targets to prevent acute allograft rejection. PMID:26249758

  1. Preformed donor HLA-DP-specific antibodies mediate acute and chronic antibody-mediated rejection following renal transplantation.

    PubMed

    Jolly, E C; Key, T; Rasheed, H; Morgan, H; Butler, A; Pritchard, N; Taylor, C J; Clatworthy, M R

    2012-10-01

    Donor-specific HLA alloantibodies may cause acute and chronic antibody-mediated rejection (AMR) and significantly compromise allograft survival. The clinical relevance of antibodies directed against some HLA class II antigens, particularly HLA-DP, is less clear with conflicting reports on their pathogenicity. We report two patients with high levels of pretransplant donor-specific HLA-DP antibodies who subsequently developed recurrent acute AMR and graft failure. In both cases, there were no other donor-specific HLA alloantibodies, suggesting that the HLA-DP-specific antibodies may be directly pathogenic.

  2. Diagnostic Performance of Fas Ligand mRNA Expression for Acute Rejection after Kidney Transplantation: A Systematic Review and Meta-Analysis

    PubMed Central

    Ren, Haolin; Shi, Liping; Chen, Jie; Wu, Xun; Lai, Caiyong; Yu, Ganshen; Xu, Yin; Su, Zexuan

    2016-01-01

    Background The value of Fas ligand (FASL) as a diagnostic immune marker for acute renal rejection is controversial; this meta-analysis aimed to clarify the role of FASL in acute renal rejection. Methods The relevant literature was included by systematic searching the MEDLINE, EMBASE, and Cochrane Library databases. Accuracy data for acute rejection (AR) and potential confounding variables (the year of publication, area, sample source, quantitative techniques, housekeeping genes, fluorescence staining, sample collection time post-renal transplantation, and clinical classification of AR) were extracted after carefully reviewing the studies. Data were analyzed by Meta-DiSc 1.4, RevMan 5.0, and the Midas module in Stata 11.0 software. Results Twelve relevant studies involving 496 subjects were included. The overall pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, and diagnostic odds ratio, together with the 95% CI were 0.64 (0.57–0.70), 0.90 (0.85–0.93), 5.66 (3.51–9.11), 0.30 (0.16–0.54), and 30.63 (14.67–63.92), respectively. The area under the summary receiver operating characteristic curve (AUC) was 0.9389. Fagan’s nomogram showed that the probability of AR episodes in the kidney transplant recipient increased from 15% to 69% when FASL was positive, and was reduced to 4% when FASL was negative. No threshold effect, sensitivity analyses, meta-regression, and subgroup analyses based on the potential variables had a significant statistical change for heterogeneity. Conclusions Current evidence suggests the diagnostic potential for FASL mRNA detection as a reliable immune marker for AR in renal allograft recipients. Further large, multicenter, prospective studies are needed to validate the power of this test marker in the non-invasive diagnosis of AR after renal transplantation. PMID:27812144

  3. The kSORT Assay to Detect Renal Transplant Patients at High Risk for Acute Rejection: Results of the Multicenter AART Study

    PubMed Central

    Hsieh, Sue; Dai, Hong; Bestard, Oriol; Metes, Diana; Zeevi, Andrea; Gritsch, Albin; Cheeseman, Jennifer; Macedo, Camila; Peddy, Ram; Medeiros, Mara; Vincenti, Flavio; Asher, Nancy; Salvatierra, Oscar; Shapiro, Ron; Kirk, Allan; Reed, Elaine; Sarwal, Minnie M.

    2014-01-01

    Background Development of noninvasive molecular assays to improve disease diagnosis and patient monitoring is a critical need. In renal transplantation, acute rejection (AR) increases the risk for chronic graft injury and failure. Noninvasive diagnostic assays to improve current late and nonspecific diagnosis of rejection are needed. We sought to develop a test using a simple blood gene expression assay to detect patients at high risk for AR. Methods and Findings We developed a novel correlation-based algorithm by step-wise analysis of gene expression data in 558 blood samples from 436 renal transplant patients collected across eight transplant centers in the US, Mexico, and Spain between 5 February 2005 and 15 December 2012 in the Assessment of Acute Rejection in Renal Transplantation (AART) study. Gene expression was assessed by quantitative real-time PCR (QPCR) in one center. A 17-gene set—the Kidney Solid Organ Response Test (kSORT)—was selected in 143 samples for AR classification using discriminant analysis (area under the receiver operating characteristic curve [AUC] = 0.94; 95% CI 0.91–0.98), validated in 124 independent samples (AUC = 0.95; 95% CI 0.88–1.0) and evaluated for AR prediction in 191 serial samples, where it predicted AR up to 3 mo prior to detection by the current gold standard (biopsy). A novel reference-based algorithm (using 13 12-gene models) was developed in 100 independent samples to provide a numerical AR risk score, to classify patients as high risk versus low risk for AR. kSORT was able to detect AR in blood independent of age, time post-transplantation, and sample source without additional data normalization; AUC = 0.93 (95% CI 0.86–0.99). Further validation of kSORT is planned in prospective clinical observational and interventional trials. Conclusions The kSORT blood QPCR assay is a noninvasive tool to detect high risk of AR of renal transplants. Please see later in the article for the Editors' Summary PMID

  4. Is Duplex-Ultrasound a useful tool in defining rejection episodes in composite tissue allograft transplants?

    PubMed

    Loizides, Alexander; Kronberger, Irmgard-Elisabeth; Plaikner, Michaela; Gruber, Hannes

    2015-12-01

    Immunologic reactions in transplanted organs are in more or less all allograft patients detectable: clear parameters exist as e.g. in renal transplants where the clearance power reduces by rejection. On the contrary, in composite tissue allografts clear and objective indicators stating a rejection episode lack. We present the case of a hand-transplanted subject with signs of acute transplant rejection diagnosed by means of Duplex Ultrasound and confirmed by biopsy.

  5. Immuno-histological assessment of sub-clinical acute and borderline rejection in renal allograft recipients: Data from a transplant center in India.

    PubMed

    Badwal, Sonia; Kumar, Arun; Hooda, A K; Varma, P P

    2015-11-01

    This single-center study was carried out on living related and unrelated renal transplant recipients (RTRs) to evaluate the usefulness of surveillance biopsies in monitoring stable renal allografts using immuno-histological markers for immune-activation. This is a prospective, longitudinal study. Protocol biopsies of 60 RTRs with stable graft function were evaluated at three, six and 12 months post-transplant. Immuno-histological evaluation was carried out using immune-activation markers (perforins, granzyme and interleukin-2R), phenotypic markers (CD-3 and CD-20), viral markers and C4d. The demographic and clinical profile was recorded for each patient. All cases of acute sub-clinical rejection (SCR) were treated and borderline SCR cases were followed-up without treatment. SCR at three and six months post-transplant was evident in 16.7% and 3.7% of RTRs, respectively. Positive statistical association of SCR was seen with HLA-DR mismatches, whereas patients receiving induction therapy and tacrolimus-based immunosuppression exhibited a lower incidence of SCR. T cell phenotype with persistent expression of immune-activation markers exhibited positive statistical association with interstitial fibrosis and tubular atrophy at 12-month follow-up biopsy. The mean creatinine levels were significantly lower in the protocol biopsy group than the non-protocol biopsy group. No significant difference was found between the mean creatinine levels of the SCR group after treatment and the non-SCR cases within the protocol biopsy group. Early treatment of sub-clinical acute rejection leads to better functional outcomes. However, persistent immune-activation is associated with chronicity and may have implications on long-term graft survival.

  6. Imaging-based diagnosis of acute renal allograft rejection

    PubMed Central

    Thölking, Gerold; Schuette-Nuetgen, Katharina; Kentrup, Dominik; Pawelski, Helga; Reuter, Stefan

    2016-01-01

    Kidney transplantation is the best available treatment for patients with end stage renal disease. Despite the introduction of effective immunosuppressant drugs, episodes of acute allograft rejection still endanger graft survival. Since efficient treatment of acute rejection is available, rapid diagnosis of this reversible graft injury is essential. For diagnosis of rejection, invasive core needle biopsy of the graft is the “gold-standard”. However, biopsy carries the risk of significant graft injury and is not immediately feasible in patients taking anticoagulants. Therefore, a non-invasive tool assessing the whole organ for specific and fast detection of acute allograft rejection is desirable. We herein review current imaging-based state of the art approaches for non-invasive diagnostics of acute renal transplant rejection. We especially focus on new positron emission tomography-based as well as targeted ultrasound-based methods. PMID:27011915

  7. Mechanisms of chronic rejection in cardiothoracic transplantation

    PubMed Central

    Weiss, Matthew J.; Madsen, Joren C.; Rosengard, Bruce R.; Allan, James S.

    2010-01-01

    Despite significant improvements in early post-transplantation survival rates, long-term patient and graft survival have remained poor, due in large part to the vexing problem of chronic allograft rejection. Attempts to combat this problem with intensification of immunosuppression have led to concomitant increases in the rates of fatal malignancies and infections. In cardiac transplantation, chronic rejection is manifested primarily by a disease entity known as cardiac allograft vasculopathy, an occlusive narrowing of the coronary vessels. In lung transplantation, chronic rejection is typified by obliterative bronchiolitis, an airflow limiting narrowing of the bronchioles. From an immunologic standpoint, chronic rejection is believed to be the end result of repeated immune and non-immune insults to the graft. This review examines the pathophysiology of heart and lung chronic, with emphasis on both immune and non-immune causes. PMID:17981771

  8. Diagnostic criteria of antibody-mediated rejection in kidney transplants.

    PubMed

    Mosquera Reboredo, J M; Vázquez Martul, E

    2011-01-01

    The diagnosis and treatment of anti-donor antibody-mediated rejection or humoral rejection (ABMR) is one of the main discussions at the moment in kidney transplantation. The search for histopathological markers that help us to diagnose ABMR has been more problematic, in contrast to the histological expression of cellular or tubulointerstitial rejection. Although the relationship between post-transplant anti-donor antibodies and the allograft's prognosis has been a topic of discussion for a long time, led in the main by P.Terasaki, it was not until the beginning of 1990s when P. Halloran studied the humoral mechanisms of rejection in greater depth. Feutch described the importance of C4d deposits as a marker that shows a humoral mechanism of allograft rejection in 1993. As a result of many studies carried out, the Banff consensus group established some diagnostic histopathological criteria of acute (ABMR) in 2003. These have been modified slightly in later meetings of the group. Furthermore, in 2005 this same working group looked at the physiopathological mechanisms causing chronic allograft failure in more detail and established the criteria defining chronic humoral rejection. In this review, we are trying to update any useful histopathological criteria for diagnosing acute and chronic ABMR.

  9. Effect of deoxyspergualin on vascular rejection in canine kidney transplantation.

    PubMed

    Tanabe, K; Takahashi, K; Nemoto, K; Okada, M; Yasuo, M; Hayasaka, Y; Toma, H; Ota, K

    1994-08-01

    Deoxyspergualin (DSG), an analogue of spergualin produced by Bacillus laterosporus, has a strong immunosuppressive effect in various transplantation models. In this study, we investigated the effect of DSG on vascular rejection in canine kidney transplantation. To enhance vascular rejection, donor-specific blood transfusion (DST) was carried out on days 28, 21 and 14 preceding kidney transplantation. After DST, the donor kidney was transplanted to the recipient iliac fossa. The recipient animals were divided into five groups: namely, Group 1 (n = 7), no treatment; Group 2 (n = 6), DST only; Group 3 (n = 5), DSG only (treated with DSG intravenously at 1.2 mg./kg./day for the first 3 days after transplantation, 1.0 mg./kg./day for the following 3 days and 0.8 mg./kg./day for the following 8 days); Group 4 (n = 6), DST and DSG treatment (same protocol as Group 3); and Group 5 (n = 5), DST and cyclosporine (CsA) (treated with CsA orally at 10 mg./kg./day for 14 days after transplantation). In Group 2, DST treatment significantly reduced kidney graft survival time (8.6 +/- 2.2 days) compared with Group 1 (14.1 +/- 5.5 days). Despite DST, DSG treatment (Group 4) significantly prolonged graft survival time (29.5 +/- 2.6 days), whereas treatment with CsA (Group 5) did not prolong survival time (14.1 +/- 5.5 days) (Group 4 versus 5, p < 0.01). The onset of rejection was significantly delayed in Group 4 (22.1 +/- 2.7 days) compared with Groups 2 (5.7 +/- 2.4 days) and 5 (13.0 +/- 5.7 days) (p < 0.01). In contrast, the interval between rejection onset and animal death was significantly reduced in Groups 2 (3.0 +/- 0.6 days) and 5 (2.4 +/- 1.0 days) compared with Group 4 (7.3 +/- 1.7 days) (p < 0.01). These findings suggest that DSG successfully prevented humoral-type (accelerated acute-type) rejections. Histologically, nonDST groups (Groups 1 and 3) showed minimum vascular rejection. In contrast, all recipients in Group 2 showed severe vascular rejection, as did 80% of Cs

  10. Kidney transplant rejection and tissue injury by gene profiling of biopsies and peripheral blood lymphocytes.

    PubMed

    Flechner, Stuart M; Kurian, Sunil M; Head, Steven R; Sharp, Starlette M; Whisenant, Thomas C; Zhang, Jie; Chismar, Jeffrey D; Horvath, Steve; Mondala, Tony; Gilmartin, Timothy; Cook, Daniel J; Kay, Steven A; Walker, John R; Salomon, Daniel R

    2004-09-01

    A major challenge for kidney transplantation is balancing the need for immunosuppression to prevent rejection, while minimizing drug-induced toxicities. We used DNA microarrays (HG-U95Av2 GeneChips, Affymetrix) to determine gene expression profiles for kidney biopsies and peripheral blood lymphocytes (PBLs) in transplant patients including normal donor kidneys, well-functioning transplants without rejection, kidneys undergoing acute rejection, and transplants with renal dysfunction without rejection. We developed a data analysis schema based on expression signal determination, class comparison and prediction, hierarchical clustering, statistical power analysis and real-time quantitative PCR validation. We identified distinct gene expression signatures for both biopsies and PBLs that correlated significantly with each of the different classes of transplant patients. This is the most complete report to date using commercial arrays to identify unique expression signatures in transplant biopsies distinguishing acute rejection, acute dysfunction without rejection and well-functioning transplants with no rejection history. We demonstrate for the first time the successful application of high density DNA chip analysis of PBL as a diagnostic tool for transplantation. The significance of these results, if validated in a multicenter prospective trial, would be the establishment of a metric based on gene expression signatures for monitoring the immune status and immunosuppression of transplanted patients.

  11. Perturbations in the Urinary Exosome in Transplant Rejection

    SciTech Connect

    Sigdel, Tara K.; NG, Yolanda; Lee, Sangho; Nicora, Carrie D.; Qian, Weijun; Smith, Richard D.; Camp, David G.; Sarwal, Minnie M.

    2015-01-05

    Background: Urine exosomes, vesicles exocytosed into urine by all renal epithelial cell types, occur under normal physiologic and disease states. Exosome contents may mirror disease-specific proteome perturbations in kidney injury. Analysis methodologies for the exosomal fraction of the urinary proteome were developed and for comparing the urinary exosomal fraction versus unfractionated proteome for biomarker discovery. Methods: Urine exosomes were isolated by centrifugal filtration from mid-stream, second morning void, urine samples collected from kidney transplant recipients with and without biopsy matched acute rejection. The proteomes of unfractionated whole urine (Uw) and urine exosomes (Uexo) underwent mass spectrometry-based quantitative proteomics analysis. The proteome data were analyzed for significant differential protein abundances in acute rejection (AR). Results: Identifications of 1018 and 349 proteins, Uw and Uexo fractions, respectively, demonstrated a 279 protein overlap between the two urinary compartments with 25%(70) of overlapping proteins unique to Uexoand represented membrane bound proteins (p=9.31e-7). Of 349 urine exosomal proteins identified in transplant patients 220 were not previously identified in the normal urine exosomal fraction. Uexo proteins (11), functioning in the inflammatory / stress response, were more abundant in patients with biopsy-confirmed acute rejection, 3 of which were exclusive to Uexo. Uexo AR-specific biomarkers (8) were also detected in Uw, but since they were observed at significantly lower abundances in Uw, they were not significant for AR in Uw. Conclusions: A rapid urinary exosome isolation method and quantitative measurement of enriched Uexo proteins was applied. Urine proteins specific to the exosomal fraction were detected either in unfractionated urine (at low abundances) or by Uexo fraction analysis. Perturbed proteins in the exosomal compartment of urine collected from kidney transplant patients were

  12. Antimyosin imaging in cardiac transplant rejection

    SciTech Connect

    Johnson, L.L.; Cannon, P.J. )

    1991-09-01

    Fab fragments of antibodies specific for cardiac myosin have been labeled with indium-111 and injected intravenously into animals and into patients with heart transplants. The antibodies, developed by Khaw, Haber, and co-workers, localize in cardiac myocytes that have been damaged irreversibly by ischemia, myocarditis, or the rejection process. After clearance of the labeled antibody from the cardiac blood pool, planar imaging or single photon emission computed tomography is performed. Scintigrams reveal the uptake of the labeled antimyosin in areas of myocardium undergoing transplant rejection. In animal studies, the degree of antimyosin uptake appears to correlate significantly with the degree of rejection assessed at necropsy. In patients, the correlation between scans and pathologic findings from endomyocardial biopsy is not as good, possibly because of sampling error in the endomyocardial biopsy technique. The scan results at 1 year correlate with either late complications (positive) or benign course (negative). Current limitations of the method include slow blood clearance, long half-life of indium-111, and hepatic uptake. Overcoming these limitations represents a direction for current research. It is possible that from these efforts a noninvasive approach to the diagnosis and evaluation of cardiac transplantation may evolve that will decrease the number of endomyocardial biopsies required to evaluate rejection. This would be particularly useful in infants and children. 31 references.

  13. Testing the Efficacy of Contrast-Enhanced Ultrasound in Detecting Transplant Rejection Using a Murine Model of Heart Transplantation.

    PubMed

    Fischer, K; Ohori, S; Meral, F C; Uehara, M; Giannini, S; Ichimura, T; Smith, R N; Jolesz, F A; Guleria, I; Zhang, Y; White, P J; McDannold, N J; Hoffmeister, K; Givertz, M M; Abdi, R

    2016-12-23

    One of the key unmet needs to improve long-term outcomes of heart transplantation is to develop accurate, noninvasive, and practical diagnostic tools to detect transplant rejection. Early intragraft inflammation and endothelial cell injuries occur prior to advanced transplant rejection. We developed a novel diagnostic imaging platform to detect early declines in microvascular perfusion (MP) of cardiac transplants using contrast-enhanced ultrasonography (CEUS). The efficacy of CEUS in detecting transplant rejection was tested in a murine model of heart transplants, a standard preclinical model of solid organ transplant. As compared to the syngeneic groups, a progressive decline in MP was demonstrated in the allografts undergoing acute transplant rejection (40%, 64%, and 92% on days 4, 6, and 8 posttransplantation, respectively) and chronic rejection (33%, 33%, and 92% on days 5, 14, and 30 posttransplantation, respectively). Our perfusion studies showed restoration of MP following antirejection therapy, highlighting its potential to help monitor efficacy of antirejection therapy. Our data suggest that early endothelial cell injury and platelet aggregation contributed to the early MP decline observed in the allografts. High-resolution MP mapping may allow for noninvasive detection of heart transplant rejection. The data presented have the potential to help in the development of next-generation imaging approaches to diagnose transplant rejection.

  14. Disparate rates of acute rejection and donor-specific antibodies among high-immunologic risk renal transplant subgroups receiving antithymocyte globulin induction.

    PubMed

    Patel, Samir J; Suki, Wadi N; Loucks-DeVos, Jennifer; Graviss, Edward A; Nguyen, Duc T; Knight, Richard J; Kuten, Samantha A; Moore, Linda W; Teeter, Larry D; Gaber, Lillian W; Gaber, A Osama

    2016-08-01

    Lymphocyte-depleting induction lowers acute rejection (AR) rates among high-immunologic risk (HIR) renal transplant recipients, including African Americans (AAs), retransplants, and the sensitized. It is unclear whether different HIR subgroups experience similarly low rates of AR. We aimed to describe the incidence of AR and de novo donor-specific antibody (dnDSA) among HIR recipients categorized by age, race, or donor type. All received antithymocyte globulin (ATG) induction and triple maintenance immunosuppression. A total of 464 HIR recipients from 2007 to 2014 were reviewed. AR and dnDSA rates at 1 year for the entire population were 14% and 27%, respectively. AR ranged from 6.7% among living donor (LD) recipients to 30% in younger AA deceased donor (DD) recipients. De novo donor-specific antibody at 1 year ranged from 7% in older non-AA LD recipients to 32% in AAs. AA race remained as an independent risk factor for AR among DD recipients and for dnDSA among all HIR recipients. Development of both AR and dnDSA within the first year was associated with a 54% graft survival at 5 years and was an independent risk factor for graft loss. Despite utilization of recommended immunosuppression for HIR recipients, substantial disparities exist among subgroups, warranting further consideration of individualized immunosuppression in certain HIR subgroups.

  15. A truncated-dose regimen of daclizumab for prevention of acute rejection in kidney transplant recipients: a single-center experience.

    PubMed

    Soltero, Liliana; Carbajal, Hector; Sarkissian, Nadine; Khan, Abdul-Jabbar; Brennan, Stephen; Gonzalez, Juan M; Truong, Luan D; Suki, Wadi N

    2004-11-27

    Daclizumab can decrease the incidence of acute rejection (AR) in renal transplant (RTx) recipients. In this prospective study, 52 RTx patients were divided into two groups according to the dose of daclizumab: 1 mg/kg on day 0 and every 14 days for five doses (group 1, n = 30) or a truncated regimen of 2 mg/kg on day 0 and on the day of discharge (group 2, n = 22). The following variables were recorded: demographics; delayed graft function; AR at 3, 6, and 12 months; time to AR; chronic allograft nephropathy (CAN); and serum creatinine. The overall incidences of AR were 23% and 27% (P = 0.76) in groups 1 and 2, respectively, whereas at 6 months they were 21% and 18% (P = 1.0). Median time to AR was 10 days in group 1 and 94 days in group 2 (P = 0.09). The incidence of CAN was 6.6% in group 1 and 13% in group 2 (P = 0.63). These data suggest that the truncated dose of daclizumab is as effective as the standard regimen for AR prophylaxis.

  16. Platelets in Early Antibody-Mediated Rejection of Renal Transplants

    PubMed Central

    Kuo, Hsiao-Hsuan; Fan, Ran; Dvorina, Nina; Chiesa-Vottero, Andres

    2015-01-01

    Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses. PMID:25145937

  17. 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

  18. Chronic Renal Transplant Rejection and Possible Anti-Proliferative Drug Targets.

    PubMed

    Bhatti, Adnan Bashir; Usman, Muhammad

    2015-11-06

    The global prevalence of renal transplants is increasing with time, and renal transplantation is the only definite treatment for end-stage renal disease. We have limited the acute and late acute rejection of kidney allografts, but the long-term survival of renal tissues still remains a difficult and unanswered question as most of the renal transplants undergo failure within a decade of their transplantation. Among various histopathological changes that signify chronic allograft nephropathy (CAN), tubular atrophy, fibrous thickening of the arteries, fibrosis of the kidney interstitium, and glomerulosclerosis are the most important. Moreover, these structural changes are followed by a decline in the kidney function as well. The underlying mechanism that triggers the long-term rejection of renal transplants involves both humoral and cell-mediated immunity. T cells, with their related cytokines, cause tissue damage. In addition, CD 20+ B cells and their antibodies play an important role in the long-term graft rejection. Other risk factors that predispose a recipient to long-term graft rejection include HLA-mismatching, acute episodes of graft rejection, mismatch in donor-recipient age, and smoking. The purpose of this review article is the analyze current literature and find different anti-proliferative agents that can suppress the immune system and can thus contribute to the long-term survival of renal transplants. The findings of this review paper can be helpful in understanding the long-term survival of renal transplants and various ways to improve it.

  19. Chronic Renal Transplant Rejection and Possible Anti-Proliferative Drug Targets

    PubMed Central

    Usman, Muhammad

    2015-01-01

    The global prevalence of renal transplants is increasing with time, and renal transplantation is the only definite treatment for end-stage renal disease. We have limited the acute and late acute rejection of kidney allografts, but the long-term survival of renal tissues still remains a difficult and unanswered question as most of the renal transplants undergo failure within a decade of their transplantation. Among various histopathological changes that signify chronic allograft nephropathy (CAN), tubular atrophy, fibrous thickening of the arteries, fibrosis of the kidney interstitium, and glomerulosclerosis are the most important. Moreover, these structural changes are followed by a decline in the kidney function as well. The underlying mechanism that triggers the long-term rejection of renal transplants involves both humoral and cell-mediated immunity. T cells, with their related cytokines, cause tissue damage. In addition, CD 20+ B cells and their antibodies play an important role in the long-term graft rejection. Other risk factors that predispose a recipient to long-term graft rejection include HLA-mismatching, acute episodes of graft rejection, mismatch in donor-recipient age, and smoking. The purpose of this review article is the analyze current literature and find different anti-proliferative agents that can suppress the immune system and can thus contribute to the long-term survival of renal transplants. The findings of this review paper can be helpful in understanding the long-term survival of renal transplants and various ways to improve it. PMID:26677426

  20. UGT1A9 -275T>A/-2152C>T polymorphisms correlate with low MPA exposure and acute rejection in MMF/tacrolimus-treated kidney transplant patients.

    PubMed

    van Schaik, R H N; van Agteren, M; de Fijter, J W; Hartmann, A; Schmidt, J; Budde, K; Kuypers, D; Le Meur, Y; van der Werf, M; Mamelok, R; van Gelder, T

    2009-09-01

    Mycophenolate mofetil (MMF) is an immunosuppressive drug commonly used in the context of kidney transplantation. Exposure to the active metabolite mycophenolic acid (MPA) is associated with risk of allograft rejection. MPA pharmacokinetics varies between individuals, the potential cause being the presence of genetic polymorphisms in key enzymes. We genotyped 338 kidney transplant patients for UGT1A8, UGT1A9, UGT2B7, and MRP2 polymorphisms and recorded MPA exposure and biopsy-proven acute rejections (BPARs) during a 1-year follow-up. Tacrolimus-treated patients who were UGT1A9 -275T>A and/or -2152C>T carriers displayed a 20% lower MPA area under the concentration-time curve from 0 to 12 h (AUC(0-12)) (P = 0.012). UGT1A9*3 carriers displayed a 49% higher MPA AUC(0-12) when treated with tacrolimus and a 54% higher MPA AUC(0-12) when treated with cyclosporine (P < 0.005). Cyclosporine-treated UGT1A8*2/*2 (518GG) patients had an 18% higher MPA AUC(0-12) compared with noncarriers. Carrying the UGT1A9 -275T>A and/or -2152C>T polymorphism significantly predicted acute rejection in fixed-dose (FD) MMF-treated patients receiving tacrolimus (odds ratio 13.3, 95% confidence interval 1.1-162.3; P < 0.05). UGT1A9 -275T>A and/or -2152C>T genotyping may identify patients at risk of MPA underexposure and acute rejection when receiving treatment with MMF and tacrolimus.

  1. Acute pancreatitis, acute hepatitis and acute renal failure favourably resolved in two renal transplant recipients.

    PubMed

    Voiculescu, Mihai; Ionescu, Camelia; Ismail, Gener; Mandache, Eugen; Hortopan, Monica; Constantinescu, Ileana; Iliescu, Olguta

    2003-03-01

    Renal transplantation is often associated with severe complications. Except for acute rejection, infections and toxicity of immunosuppressive treatment are the most frequent problems observed after transplantation. Infections with hepatic viruses (HBV, HDV, HCV, HGV) and cytomegalic virus (CMV) are the main infectious complications after renal transplantation. Cyclosporine toxicity is not unusual for a patient with renal transplantation and is even more frequent for patients with hepatic impairment due to viral infections. The subjects of this report are two renal transplant recipients with acute pancreatitis, severe hepatitis and acute renal failure on graft, receiving immunosuppressive therapy for maintaining renal graft function

  2. Rejection is less common in children undergoing liver transplantation for hepatoblastoma.

    PubMed

    Ruth, N D; Kelly, D; Sharif, K; Morland, B; Lloyd, C; McKiernan, P J

    2014-02-01

    To compare the incidence of acute histologically proven rejection in children who have had a liver transplant for hepatoblastoma with a control group of children transplanted for biliary atresia (EHBA). A retrospective case notes based study was performed. Twenty patients were identified with hepatoblastoma who were transplanted at a single unit between 1991 and 2008. These were matched as closely as possible for age, gender, year of transplant and type of immunosuppression used to the control group transplanted for biliary atresia (n = 60). There was a significant decrease in rate of acute rejection as assessed by the rejection activity index (RAI) in the hepatoblastoma group (75% vs. 50%, respectively, p < 0.04). Chronic rejection was rare in both groups, but twice as common in the biliary atresia group. Equal levels of immunosuppression were achieved in both groups. Renal function was noted to be reduced one yr post-transplant in both groups, as previously reported. A modified immunosuppression regimen could be considered in children with hepatoblastoma undergoing liver transplantation.

  3. Organ transplant tissue rejection: detection and staging by fluorescence spectroscopy

    NASA Astrophysics Data System (ADS)

    MacAulay, Calum E.; Whitehead, Peter D.; McManus, Bruce; Zeng, Haishan; Wilson-McManus, Janet; MacKinnon, Nick; Morgan, David C.; Dong, Chunming; Gerla, Paul; Kenyon, Jennifer

    1998-07-01

    Patients receiving heart or other organ transplants usually require some level of anti-rejection drug therapy, most commonly cyclosporine. The rejection status of the organ must be monitored to determine the optimal anti-rejection drug therapy. The current method for monitoring post-transplant rejection status of heart transplant patients consists of taking biopsies from the right ventricle. In this work we have developed a system employing optical and signal-processing techniques that will allow a cardiologist to measure spectral changes associated with tissue rejection using an optical catheter probe. The system employs time gated illumination and detection systems to deal with the dynamic signal acquisition problems associated with in vivo measurements of a beating heart. Spectral data processing software evaluates and processes the data to produce a simple numerical score. Results of measurements made on 100 excised transplanted isograft and allograft rat hearts have demonstrated the ability of the system to detect the presence of rejection and to accurately correlate the spectroscopic results with the ISHLT (International Society for Heart and Lung Transplantation) stage of rejection determined by histopathology. In vivo measurements using a pig transplant model are now in process.

  4. Role of interleukin-17A in early graft rejection after orthotopic lung transplantation in mice

    PubMed Central

    Chen, Qi-Rui; Wang, Li-Feng; Xia, Si-Si; Zhang, Ya-Mei; Xu, Jiang-Nan

    2016-01-01

    Background The cellular and molecular mechanisms underlying lung allograft rejection remain poorly understood. We investigated the potential role of interleukin (IL)-17A in lung transplant rejection in a mouse model, because previous studies in clinical and rodent models have implicated IL-17A in both acute and chronic rejection. Methods To generate an orthotopic lung transplantation model, lungs from C57BL/6 or BALB/c mice were transplanted into C57BL/6 mice (isograft and allograft models, respectively). The effects of anti-IL-17A treatment in allograft recipients were investigated. The histological features and rejection status of isografts and allografts were assessed at 3, 7, and 28 days after transplantation, and differences in graft infiltrating cells and mRNA expression of relevant cytokines were quantified at 3 and 7 days after transplantation. Results As expected, isografts showed no obvious signs of rejection, whereas allografts exhibited minimal-to-mild rejection (grade A1–A2) by day 3 and moderate-to-severe rejection (grade A3–A4) by day 7, without evidence of obliterative bronchiolitis (OB). However, by 28 days, evidence of OB was observed in 67% (2/3) of allografts and severe rejection (grade A4) was observed in all. IL-17 mRNA expression in allografts was increased with rejection, and interferon (IFN)-γ and IL-6 mRNA expression levels followed a similar pattern. In contrast, IL-22 expression in allografts was only slightly increased. Antibody (Ab) neutralization of IL-17A diminished the signs of acute rejection at 7 days after transplantation in allografts, and this early protection was accompanied by a decrease in cellular stress according to histological evaluation, suggesting the involvement of IL-17A in the development of early post-transplantation lesions. Conclusions Our data indicate that IL-17A is important in the pathophysiology of allograft rejection, and neutralization of IL-17A is a potential therapeutic strategy to preventing lung

  5. The Potential of MicroRNAs as Novel Biomarkers for Transplant Rejection

    PubMed Central

    Kawakita, Satoru; Everly, Matthew

    2017-01-01

    The control of gene expression by microRNAs (miRNAs, miR) influences many cellular functions, including cellular differentiation, cell proliferation, cell development, and functional regulation of the immune system. Recently, miRNAs have been detected in serum, plasma, and urine and circulating miR profiles have been associated with a variety of diseases. Rejection is one of the major causes of allograft failure and preventing and treating acute rejection are the central task for clinicians working with transplant patients. Invasive biopsies used in monitoring rejection are burdensome and risky to transplant patients. Novel and easily accessible biomarkers of acute rejection could make it possible to detect rejection earlier and make more fine-tuned calibration of immunosuppressive or new target treatment possible. In this review, we discuss whether circulating miRNA can serve as an early noninvasive diagnostic biomarker and an expression fingerprint of allograft rejection and transplant failure. Understanding the regulatory interplay of relevant miRNAs and the rejecting allograft will result in a better understanding of the molecular pathophysiology of alloimmune injury. PMID:28191475

  6. Association of GSTO2 (N142D) Genetic Polymorphism and Acute Rejection of Liver

    PubMed Central

    Khosravi, M.; Saadat, I.; Karimi, M. H.; Malek Hosseini, S. A.

    2016-01-01

    Background: Acute rejection is the main problem in liver transplantation that occurs in the first days or months of transplantation. It includes histological and cellular rejection. Acute histological rejection is confirmed by biopsy. Glutathione S-transferase family is the most important genes in phase II detoxification working in xenobiotic and drug metabolism. GSTO2 is one of the members of this family. GSTO2 (N142D) polymorphism may influence metabolism of immunosuppressive drugs. Objective: To determine if GSTO2 polymorphism has association with acute liver rejection. Methods: The present study included 120 patients with histological-proven acute liver rejection and 182 patients without acute rejection. Both groups were matched for sex and age. To determine variants of GSTO2, we used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: There was a significant association between the GSTO2 genotype and acute liver rejection (NN: OR: 3.642, 95% CI: 1.179–5.444) and (ND: OR: 2.533, 95% CI: 1.672–8.149) compared to those with DD geneotype. Conclusion: Recipients with either NN or ND genotype for GSTO2 are more likely to develop acute liver rejection compared to those with DD genotype. PMID:27721965

  7. Detection of cardiac transplant rejection with radiolabeled lymphocytes. [Rats

    SciTech Connect

    Bergmann, S.R.; Lerch, R.A.; Carlson, E.M.; Saffitz, J.E.; Sobel, B.E.

    1982-03-01

    To determine whether rejections of cardiac transplants could be detected specifically and non-invasively by lymphocytes labeled with indium-111 (111In), we studied 36 allogeneic and 14 isogeneic heterotopic cardiac transplants in rats. Allogeneic grafts accumulated autologous 111In-lymphocytes, detectable scintigraphically 24 hours after i.v. injection of the labeled cells. At the time of peak histologic rejection, the allogeneic grafts accumulated 92. +/- 4.8 times more activity than the native hearts (determined by well counting). The tissue-to-blood ratio in the rejecting transplants was 3.7 +/- 2.2; total uptake by the graft was 2.9 +/- 2.1% of the injected dose. Autoradiography confirmed that graft radioactivity was associated with labeled lymphocytes. In contrast, isogeneic grafts showed no signs of rejection and did not accumulate radioactivity. Because conventionally isolated and labeled lymphocytes are often contaminated with platelets, we prepared both 111In-platelets and purified 111In-lymphocytes for use in additional experiments. Allogeneic grafts accumulated platelets and purified lymphocytes independently. Thus, deposition of immunologically active cells in the rejecting graft representing specific pathophysiologic events can be detected. The results suggest that rejection of cardiac transplants can be detected noninvasively, potentially facilitating objective early clinical detection of rejection and titration of antirejection therapy.

  8. Plasma-Derived C1 Esterase Inhibitor for Acute Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized Double-Blind Placebo-Controlled Pilot Study.

    PubMed

    Montgomery, R A; Orandi, B J; Racusen, L; Jackson, A M; Garonzik-Wang, J M; Shah, T; Woodle, E S; Sommerer, C; Fitts, D; Rockich, K; Zhang, P; Uknis, M E

    2016-05-16

    Antibody-mediated rejection (AMR) is typically treated with plasmapheresis (PP) and intravenous immunoglobulin (standard of care; SOC); however, there is an unmet need for more effective therapy. We report a phase 2b, multicenter double-blind randomized placebo-controlled pilot study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to SOC for AMR. Eighteen patients received 20 000 units of C1 INH or placebo (C1 INH n = 9, placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or study drug-related serious adverse events occurred. While the study's primary end point, a difference between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated a trend toward sustained improvement in renal function. Six-month biopsies performed in 14 subjects (C1 INH = 7, placebo = 7) showed no transplant glomerulopathy (TG) (PTC+cg≥1b) in the C1 INH group, whereas 3 of 7 placebo subjects had TG. Endogenous C1 INH measured before and after PP demonstrated decreased functional C1 INH serum concentration by 43.3% (p < 0.05) for both cohorts (C1 INH and placebo) associated with PP, although exogenous C1 INH-treated patients achieved supraphysiological levels throughout. This new finding suggests that C1 INH replacement may be useful in the treatment of AMR.

  9. Reviewing the pathogenesis of antibody-mediated rejection and renal graft pathology after kidney transplantation.

    PubMed

    Morozumi, Kunio; Takeda, Asami; Otsuka, Yasuhiro; Horike, Keiji; Gotoh, Norihiko; Narumi, Shunji; Watarai, Yoshihiko; Kobayashi, Takaaki

    2016-07-01

    The clinicopathological context of rejection after kidney transplantation was well recognized. Banff conferences greatly contributed to elucidate the pathogenesis and to establish the pathologic criteria of rejection after kidney transplantation. The most important current problem of renal transplantation is de novo donor-specific antibody (DSA) production leading chronic rejection and graft loss. Microvascular inflammation is considered as a reliable pathological marker for antibody-mediated rejection (AMR) in the presence of DSA. Electron microscopic study allowed us to evaluate early changes in peritubular capillaries in T-lymphocyte mediated rejection and transition to antibody-mediated rejection. Severe endothelial injuries with edema and activated lymphocyte invaded into subendothelial space with early multi-layering of peritubular capillary basement membrane suggest T-lymphocyte mediated rejection induce an unbounded chain of antibody-mediated rejection. The risk factors of AMR after ABO-incompatible kidney transplantation are important issues. Anti-ABO blood type antibody titre of IgG excess 32-fold before transplant operation is the only predictable factor for acute AMR. Characteristics of chronic active antibody-mediated rejection (CAAMR) are one of the most important problems. Light microscopic findings and C4d stain of peritubular capillary and glomerular capillary are useful diagnostic criteria of CAAMR. Microvascular inflammation, double contour of glomerular capillary and thickening of peritubular capillary basement are good predictive factors of the presence of de novo DSA. C4d stain of linear glomerular capillary is a more sensitive marker for CAAMR than positive C4d of peritubular capillary. Early and sensitive diagnostic attempts of diagnosing CAAMR are pivotal to prevent chronic graft failure.

  10. Diagnosis of Rejection by Analyzing Ventricular Late Potentials in Heart Transplant Patients

    PubMed Central

    Mendes, Vítor Nogueira; Pereira, Telmo Santos; Matos, Vítor Azevedo

    2016-01-01

    Background Heart transplant rejection originates slow and fragmented conduction. Signal-averaged ECG (SAECG) is a stratification method in the risk of rejection. Objective To develop a risk score for rejection, using SAECG variables. Methods We studied 28 transplant patients. First, we divided the sample into two groups based on the occurrence of acute rejection (5 with rejection and 23 without). In a second phase, we divided the sample considering the existence or not of rejection in at least one biopsy performed on the follow-up period (rejection pm1: 18 with rejection and 10 without). Results On conventional ECG, the presence of fibrosis was the only criterion associated with acute rejection (OR = 19; 95% CI = 1.65-218.47; p = 0.02). Considering the rejection pm1, an association was found with the SAECG variables, mainly with RMS40 (OR = 0.97; 95% CI = 0.87-0.99; p = 0.03) and LAS40 (OR = 1.06; 95% IC = 1.01-1.11; p = 0.03). We formulated a risk score including those variables, and evaluated its discriminative performance in our sample. The presence of fibrosis with increasing of LAS40 and decreasing of RMS40 showed a good ability to distinguish between patients with and without rejection (AUC = 0.82; p < 0.01), assuming a cutoff point of sensitivity = 83.3% and specificity = 60%. Conclusion The SAECG distinguished between patients with and without rejection. The usefulness of the proposed risk score must be demonstrated in larger follow-up studies. PMID:26815311

  11. Abdominal Wall Transplantation: Skin as a Sentinel Marker for Rejection.

    PubMed

    Gerlach, U A; Vrakas, G; Sawitzki, B; Macedo, R; Reddy, S; Friend, P J; Giele, H; Vaidya, A

    2016-06-01

    Abdominal wall transplantation (AWTX) has revolutionized difficult abdominal closure after intestinal transplantation (ITX). More important, the skin of the transplanted abdominal wall (AW) may serve as an immunological tool for differential diagnosis of bowel dysfunction after transplant. Between August 2008 and October 2014, 29 small bowel transplantations were performed in 28 patients (16 male, 12 female; aged 41 ± 13 years). Two groups were identified: the solid organ transplant (SOT) group (n = 15; 12 ITX and 3 modified multivisceral transplantation [MMVTX]) and the SOT-AWTX group (n = 14; 12 ITX and 2 MMVTX), with the latter including one ITX-AWTX retransplantation. Two doses of alemtuzumab were used for induction (30 mg, 6 and 24 h after reperfusion), and tacrolimus (trough levels 8-12 ng/mL) was used for maintenance immunosuppression. Patient survival was similar in both groups (67% vs. 61%); however, the SOT-AWTX group showed faster posttransplant recovery, better intestinal graft survival (79% vs. 60%), a lower intestinal rejection rate (7% vs. 27%) and a lower rate of misdiagnoses in which viral infection was mistaken and treated as rejection (14% vs. 33%). The skin component of the AW may serve as an immune modulator and sentinel marker for immunological activity in the host. This can be a vital tool for timely prevention of intestinal graft rejection and, more important, avoidance of overimmunosuppression in cases of bowel dysfunction not related to graft rejection.

  12. Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs.

    PubMed

    Sánchez-Fueyo, Alberto; Strom, Terry B

    2011-01-01

    Transplantation of organs between genetically different individuals of the same species causes a T cell-mediated immune response that, if left unchecked, results in rejection and graft destruction. The potency of the alloimmune response is determined by the antigenic disparity that usually exists between donors and recipients and by intragraft expression of proinflammatory cytokines in the early period after transplantation. Studies in animal models have identified many molecules that, when targeted, inhibit T-cell activation. In addition, some of these studies have shown that certain immunologic interventions induce transplantation tolerance, a state in which the allograft is specifically accepted without the need for chronic immunosuppression. Tolerance is an important aspect of liver transplantation, because livers have a unique microenvironment that promotes tolerance rather than immunity. In contrast to the progress achieved in inducing tolerance in animal models, patients who receive transplanted organs still require nonspecific immunosuppressant drugs. The development of calcineurin inhibitors has reduced the acute rejection rate and improved short-term, but not long-term, graft survival. However, long-term use of immunosuppressive drugs leads to nephrotoxicity and metabolic disorders, as well as manifestations of overimmunosuppression such as opportunistic infections and cancers. The status of pharmacologic immunosuppression in the clinic is therefore not ideal. We review recently developed therapeutic strategies to promote tolerance to transplanted livers and other organs and diagnostic tools that might be used to identify patients most likely to accept or reject allografts.

  13. Prediction of acute cardiac rejection by changes in left ventricular volumes

    SciTech Connect

    Novitzky, D.; Cooper, D.K.; Boniaszczuk, J.

    1988-11-01

    Sixteen patients underwent heart transplantation (11 orthotopic, five heterotopic). Monitoring for acute rejection was by both endomyocardial biopsy (EMB) and multigated equilibrium blood pool scanning with technetium 99m-labelled red blood cells. From the scans information was obtained on left ventricular volumes (stroke, end-diastolic, and end-systolic), ejection fraction, and heart rate. Studies (208) were made in the 16 patients. There was a highly significant correlation between the reduction in stroke volume and end-diastolic volume (and a less significant correlation in end-systolic volume) and increasing acute rejection seen on EMB. Heart rate and ejection fraction did not correlate with the development of acute rejection. Correlation of a combination of changes in stroke volume and end-diastolic volume with EMB showed a sensitivity of 85% and a specificity of 96%. Radionuclide scanning is therefore a useful noninvasive tool for monitoring acute rejection.

  14. Heavy Proteinuria as a Manifestation of Acute Allograft Rejection Presenting Early after Kidney Transplantation: A Retrospective, Single-Center Case Series

    DTIC Science & Technology

    2009-01-01

    Abstract: The differential diagnosis of heavy proteinuria presenting early after kidney transplantation has generally included de novo or recurrent...SUPPLEMENTARY NOTES 14. ABSTRACT The differential diagnosis of heavy proteinuria presenting early after kidney transplantation has generally included de novo...Deceased Donor 1 IgA Nephropathy 9 days 100mg% dipstick 1.5 5.8 Urine dip negative 1.5 0.5 gm/Kg/d x 5d 5 53 F AA Deceased Donor 2 Membranous

  15. Challenges inherent to the diagnosis of antibody-mediated rejection in lung transplantation

    PubMed Central

    Chin, Nicholas; Westall, Glen; Paraskeva, Miranda; Ciciulla, John; Cantwell, Linda; Snell, Greg

    2015-01-01

    A bilateral sequential lung transplant was performed on a young female with cystic fibrosis-related bronchiectasis. She had negative prospective T- and B-cell crossmatch, and no known donor-specific antibodies. Post-transplantation, she developed bilateral pulmonary infiltrates of uncertain etiology, compounded by persistent tachycardia and questionable medication adherence. Despite aggressive intervention for suspected cellular rejection with high-dose intravenous corticosteroid, immunoglobulin, and anti-thymocyte globulin, her condition deteriorated to ultimately require ventilatory support. The eventual discovery of eplet donor-recipient mismatches on related DQB1 alleles raised the diagnosis of antibody-mediated rejection. Before plasmapheresis could be instituted, the patient rapidly succumbed to respiratory failure. Postmortem examination confirmed features of atypical allograft rejection, without evidence of classic acute cellular rejection. This is an unconventional case of antibody-mediated lung allograft rejection – an entity that is currently a difficult diagnostic and therapeutic challenge. Prevention of donor-specific antibodies by correct donor-recipient matching, and optimizing adherence post-transplantation are most important. PMID:25802749

  16. Increased T cell glucose uptake reflects acute rejection in lung grafts

    PubMed Central

    Chen, Delphine L.; Wang, Xingan; Yamamoto, Sumiharu; Carpenter, Danielle; Engle, Jacquelyn T.; Li, Wenjun; Lin, Xue; Kreisel, Daniel; Krupnick, Alexander S.; Huang, Howard J.; Gelman, Andrew E.

    2013-01-01

    Although T cells are required for acute lung rejection, other graft-infiltrating cells such as neutrophils accumulate in allografts and are also high glucose utilizers. Positron emission tomography (PET) with the glucose probe [18F]fluorodeoxyglucose ([18F]FDG) has been employed to image solid organ acute rejection, but the sources of glucose utilization remain undefined. Using a mouse model of orthotopic lung transplantation, we analyzed glucose probe uptake in the grafts of syngeneic and allogeneic recipients with or without immunosuppression treatment. Pulmonary microPET scans demonstrated significantly higher [18F]FDG uptake in rejecting allografts when compared to transplanted lungs of either immunosuppressed or syngeneic recipients. [18F]FDG uptake was also markedly attenuated following T cell depletion therapy in lung recipients with ongoing acute rejection. Flow-cytometric analysis using the fluorescent deoxyglucose analog 2-NBDG revealed that T cells, and in particular CD8+ T cells, were the largest glucose utilizers in acutely rejecting lung grafts followed by neutrophils and antigen presenting cells. These data indicate that imaging modalities tailored toward assessing T cell metabolism may be useful in identifying acute rejection in lung recipients PMID:23927673

  17. The role of complement in antibody-mediated rejection in kidney transplantation.

    PubMed

    Stegall, Mark D; Chedid, Marcio F; Cornell, Lynn D

    2012-11-01

    Over the past decade, several studies have suggested that the complement system has an active role in both acute and chronic allograft rejection. These studies have been facilitated by improved techniques to detect antibody-mediated organ rejection, including immunohistological staining for C4d deposition in the allograft and solid-phase assays that identify donor-specific alloantibodies (DSAs) in the serum of transplant recipients. Studies with eculizumab, a humanized monoclonal antibody directed against complement component C5, have shown that activation of the terminal complement pathway is necessary for the development of acute antibody-mediated rejection in recipients of living-donor kidney allografts who have high levels of DSAs. The extent to which complement activation drives chronic antibody-mediated injury leading to organ rejection is less clear. In chronic antibody-mediated injury, early complement activation might facilitate chemotaxis of inflammatory cells into the allograft in a process that later becomes somewhat independent of DSA levels and complement factors. In this Review, we discuss the different roles that the complement system might have in antibody-mediated allograft rejection, with specific emphasis on renal transplantation.

  18. Severe antibody-mediated rejection following IVIG infusion in a kidney transplant recipient with BK-virus nephropathy.

    PubMed

    Mainra, R; Xu, Q; Chibbar, R; Hassan, A; Shoker, A

    2013-06-01

    Intravenous immune-globulin (IVIG) use in renal transplantation has increased, with common uses including desensitization, treatment of antibody mediated rejection and adjunctive therapy for BK virus nephropathy. Although considered generally safe, potential side effects can occur in up to 23% of patients including acute kidney injury. We present a case of an unexpected cause of acute kidney injury in a renal transplant recipient following IVIG infusion. A 48-year-old nonsensitized female with end stage renal disease secondary to polycystic kidney disease received a deceased donor kidney transplant. The initial post-transplant period was unremarkable however at three years post-transplant the patient develops BK virus nephropathy. Despite a reduction in immunosuppression, graft function worsened and IVIG infusion was commenced. Immediately following the IVIG infusion, the patient develops anuric acute kidney injury necessitating hemodialysis. Renal transplant biopsy performed before and after the IVIG infusion revealed the de novo development of acute antibody mediated rejection and donor specific antibodies in the serum. Anti-HLA and donor-specific antibodies were also confirmed in a diluted sample of the IVIG preparation. We argue that the anti-HLA antibodies present in the IVIG caused an acute antibody mediated rejection in this previously nonsensitized female.

  19. Accurate diagnosis of renal transplant rejection by indium-111 platelet imaging despite postoperative cyclosporin therapy

    SciTech Connect

    Collier, B.D.; Adams, M.B.; Kauffman, H.M.; Trembath, L.; Hoffmann, R.G.; Tisdale, P.L.; Rao, S.A.; Hellman, R.S.; Isitman, A.T.

    1988-08-01

    Previous reports indicate that In-111 platelet scintigraphy (IPS) is a reliable test for the early diagnosis of acute post-operative renal transplant rejection (TR). However, the recent introduction of cyclosporin for post-transplantation immunosuppression requires that the diagnostic efficacy of IPS once again be established. Therefore, a prospective IPS study of 73 post-operative renal transplant recipients was conducted. Fourty-nine patients received cyclosporin and 24 patients did not receive this drug. Between these two patient groups, there were no significant differences in the diagnostic sensitivities (0.86 vs 0.80) and specificities (0.93 vs 0.84) with which TR was identified. We conclude that during the first two weeks following renal transplantation the cyclosporin treatment regimen used at our institution does not limit the reliability of IPS as a test for TR.

  20. B Lymphocytes Differentially Influence Acute and Chronic Allograft Rejection in Mice1

    PubMed Central

    DiLillo, David J.; Griffiths, Robert; Seshan, Surya V.; Magro, Cynthia M.; Ruiz, Phillip; Coffman, Thomas M.; Tedder, Thomas F.

    2013-01-01

    The relative contributions of B lymphocytes and plasma cells during allograft rejection remain unclear. Therefore, the effects of B cell depletion on acute cardiac rejection, chronic renal rejection, and skin graft rejection were compared using CD20 or CD19 mAbs. Both CD20 and CD19 mAbs effectively depleted mature B cells, while CD19 mAb treatment depleted plasmablasts and some plasma cells. B cell depletion did not affect acute cardiac allograft rejection, although CD19 mAb treatment prevented allograft-specific IgG production. Strikingly, CD19 mAb treatment significantly reduced renal allograft rejection and abrogated allograft-specific IgG development, while CD20 mAb treatment did not. By contrast, B cell depletion exacerbated skin allograft rejection and augmented the proliferation of adoptively transferred alloantigen-specific CD4+ T cells, demonstrating that B cells can also negatively regulate allograft rejection. Thereby, B cells can either positively or negatively regulate allograft rejection depending on the nature of the allograft and the intensity of the rejection response. Moreover, CD19 mAb may represent a new approach for depleting both B cells and plasma cells to concomitantly impair T cell activation, inhibit the generation of new allograft-specific Abs, or reduce preexisting allograft-specific Ab levels in transplant patients. PMID:21248259

  1. Acute Pancreatitis after Kidney Transplantation

    PubMed Central

    Tabakovic, Mithat; Salkic, Nermin N.; Bosnjic, Jasmina; Alibegovic, Ervin

    2012-01-01

    Acute pancreatitis is a rare but life-threatening complication in patients with transplanted kidney. The incidence of acute pancreatitis after kidney transplantation ranges from 2% to 7%, with mortality rate between 50 and 100%. We report a case of a female patient aged 46 years, developing an interstitial acute pancreatitis 8 years following a renal transplantation. The specific aethiological factor was not clearly established, although possibility of biliary pancreatitis with spontaneous stone elimination and/or medication-induced pancreatitis remains the strongest. Every patient after renal transplantation with an acute onset of abdominal pain should be promptly evaluated for presence of pancreatitis with a careful application of the most appropriate diagnostic procedure for each individual patient. PMID:23259142

  2. Noninvasive monitoring of infection and rejection after lung transplantation

    PubMed Central

    De Vlaminck, Iwijn; Martin, Lance; Kertesz, Michael; Patel, Kapil; Kowarsky, Mark; Strehl, Calvin; Cohen, Garrett; Luikart, Helen; Neff, Norma F.; Okamoto, Jennifer; Nicolls, Mark R.; Cornfield, David; Weill, David; Valantine, Hannah; Khush, Kiran K.; Quake, Stephen R.

    2015-01-01

    The survival rate following lung transplantation is among the lowest of all solid-organ transplants, and current diagnostic tests often fail to distinguish between infection and rejection, the two primary posttransplant clinical complications. We describe a diagnostic assay that simultaneously monitors for rejection and infection in lung transplant recipients by sequencing of cell-free DNA (cfDNA) in plasma. We determined that the levels of donor-derived cfDNA directly correlate with the results of invasive tests of rejection (area under the curve 0.9). We also analyzed the nonhuman cfDNA as a hypothesis-free approach to test for infections. Cytomegalovirus is most frequently assayed clinically, and the levels of CMV-derived sequences in cfDNA are consistent with clinical results. We furthermore show that hypothesis-free monitoring for pathogens using cfDNA reveals undiagnosed cases of infection, and that certain infectious pathogens such as human herpesvirus (HHV) 6, HHV-7, and adenovirus, which are not often tested clinically, occur with high frequency in this cohort. PMID:26460048

  3. Changing Paradigms in the Management of Rejection in Kidney Transplantation

    PubMed Central

    Maier, Mirela; Takano, Tomoko; Sapir-Pichhadze, Ruth

    2017-01-01

    Purpose of review: P4 medicine denotes an evolving field of medicine encompassing predictive, preventive, personalized, and participatory medicine. Using the example of kidney allograft rejection because of donor-recipient incompatibility in human leukocyte antigens, this review outlines P4 medicine’s relevance to the various stages of the kidney transplant cycle. Sources of information: A search for English articles was conducted in Medline via OvidSP (up to August 18, 2016) using a combination of subject headings (MeSH) and free text in titles, abstracts, and author keywords for the concepts kidney transplantation and P4 medicine. The electronic database search was expanded further on particular subject headings. Findings: Available histocompatibility methods exemplify current applications of the predictive and preventive domains of P4 medicine in kidney transplant recipients’ care. Pharmacogenomics are discussed as means to facilitate personalized immunosuppression regimens and promotion of active patient participation as a means to improve adherence. Limitations: For simplicity, this review focuses on rejection. P4 medicine, however, should more broadly address health concerns in kidney transplant recipients, including competing outcomes such as infections, malignancies, and cardiovascular disease. This review highlights how biomarkers to evaluate these competing outcomes warrant validation and standardization prior to their incorporation into clinical practice. Implications: Consideration of all 4 domains of the P4 medicine framework when caring for and/or studying kidney transplant recipients has the potential of increasing therapeutic efficiency, minimizing adverse effects, decreasing health care costs, and maximizing wellness. Technologies to gauge immune competency, immunosuppression requirements, and early/reversible immune-mediated injuries are required to optimize kidney transplant care. PMID:28270929

  4. Pulmonary capillaritis: a possible histologic form of acute pulmonary allograft rejection.

    PubMed

    Badesch, D B; Zamora, M; Fullerton, D; Weill, D; Tuder, R; Grover, F; Schwarz, M I

    1998-04-01

    Acute rejection after lung transplantation occurs commonly and is usually characterized histologically by a perivascular mononuclear infiltrate. We report five cases of pulmonary capillaritis with a histologic appearance distinct from typical rejection, occurring in patients ranging in age from 18 to 45 years, with a variety of underlying diseases including alpha1 antitrypsin deficiency, pulmonary hypertension, cystic fibrosis, and rheumatoid arthritis. Four of the five patients had alveolar hemorrhage histologically, and two had frank hemoptysis. Time of onset ranged from 3 weeks to many months after transplantation. Three cases were fulminant, and there were two deaths. In only one case, with methicillin-resistant Staphylococcus aureus bronchitis, could infection be established. All were treated with intensification of immunosuppressive therapy. Plasmapheresis was carried out in two cases and coincided with temporary improvement, but its efficacy was questionable because of concurrent immunosuppressive therapy. Two had recurrent biopsy-proven acute rejection within 6 weeks of treatment, and one had recurrent severe pulmonary hemorrhage that abated with total lymphoid irradiation. Our experience suggests that pulmonary capillaritis in lung transplant recipients can be an acute, fatal illness with the potential for recurrence in the survivors. We speculate that it represents a form of acute vascular rejection. Early pathologic diagnosis and aggressive immunosuppressive therapy are recommended. Although a humoral component was not documented, the possible response to plasmapheresis requires continued evaluation.

  5. Eculizumab to treat antibody-mediated rejection in a 7-year-old kidney transplant recipient.

    PubMed

    Chehade, Hassib; Rotman, Samuel; Matter, Maurice; Girardin, Eric; Aubert, Vincent; Pascual, Manuel

    2015-02-01

    We report on successful early eculizumab administration to treat acute antibody-mediated rejection (ABMR) in a highly sensitized kidney transplant recipient. The recipient is a 7-year-old boy who received, 6 months after a desensitization protocol with monthly intravenous immunoglobulin infusion, a second kidney transplant in the presence of low donor-specific antibodies (DSAs). Both pretransplant lymphocytotoxic and flow cytometric crossmatch were negative. Allograft function recovered promptly, with excellent initial function. On postoperative day (POD) 4, the child developed significant proteinuria with an acute rise in serum creatinine. Allograft biopsy showed severe acute ABMR. Intravenous eculizumab (600 mg), preceded by a single session of plasmapheresis, was administered on POD 5 and 12 along with a 4-day thymoglobulin course. After the first dose of eculizumab, a strikingly rapid normalization of allograft function with a decrease in proteinuria occurred. However, because circulating DSA levels remained elevated, the child received 3 doses of intravenous immunoglobulin (POD 15, 16, and 17), with a significant subsequent decrease in DSA levels. At 9 months after transplant, the child continues to maintain excellent allograft function with undetectable circulating DSA levels. This unique case highlights the potential efficacy of using early eculizumab to rapidly reverse severe ABMR in pediatric transplantation, and therefore it suggests a novel therapeutic approach to treat acute ABMR.

  6. Magnetic Nanoparticles in-vivo Detection of Transplant Rejection

    NASA Astrophysics Data System (ADS)

    Flynn, E. R.; Bryant, H. C.; Larson, R. S.; Sergatskov, D. A.

    2006-03-01

    Superparamagnetic nanoparticles are being used to develop methodology for the in-vivo detection and imaging of immune system attacks on transplanted organs. The signature for impending rejection of a transplant is enhanced presence of T-cells. Magnetic nanoparticles coated with specific antibodies (CD-2 and CD-3) will target and attach to these T-cells. Approximately 3 .10^5 nanoparticles can attach to each cell. When a pulsed external magnetic field is applied to the decorated cells for a fraction of a second, magnetic moments of the nanoparticles aligned with the field. After the pulse is switched off, the net magnetic moment decays over several seconds by the Nèel mechanism. The resulting magnetic remanence field (typically 10-11 T) is measured using a multi-channel SQUID array. We present the data from live T-cells placed in realistic kidney phantom. The detection sensitivity was ˜2.10^3 T-cells - a small fraction of the number actually invading the rejected transplant. The 7-channel SQUID array allows us to image the cell clusters with a few millimeters resolution.

  7. Novel Multivariate Methods for Integration of Genomics and Proteomics Data: Applications in a Kidney Transplant Rejection Study

    PubMed Central

    Günther, Oliver P.; Shin, Heesun; Ng, Raymond T.; McMaster, W. Robert; McManus, Bruce M.; Keown, Paul A.; Tebbutt, Scott. J.

    2014-01-01

    Abstract Multi-omics research is a key ingredient of data-intensive life sciences research, permitting measurement of biological molecules at different functional levels in the same individual. For a complete picture at the biological systems level, appropriate statistical techniques must however be developed to integrate different ‘omics’ data sets (e.g., genomics and proteomics). We report here multivariate projection-based analyses approaches to genomics and proteomics data sets, using the case study of and applications to observations in kidney transplant patients who experienced an acute rejection event (n=20) versus non-rejecting controls (n=20). In this data sets, we show how these novel methodologies might serve as promising tools for dimension reduction and selection of relevant features for different analytical frameworks. Unsupervised analyses highlighted the importance of post transplant time-of-rejection, while supervised analyses identified gene and protein signatures that together predicted rejection status with little time effect. The selected genes are part of biological pathways that are representative of immune responses. Gene enrichment profiles revealed increases in innate immune responses and neutrophil activities and a depletion of T lymphocyte related processes in rejection samples as compared to controls. In all, this article offers candidate biomarkers for future detection and monitoring of acute kidney transplant rejection, as well as ways forward for methodological advances to better harness multi-omics data sets. PMID:25387159

  8. Use of a SQUID array to detect T-cells with magnetic nanoparticles in determining transplant rejection

    NASA Astrophysics Data System (ADS)

    Flynn, Edward R.; Bryant, H. C.; Bergemann, Christian; Larson, Richard S.; Lovato, Debbie; Sergatskov, Dmitri A.

    2007-04-01

    Acute rejection in organ transplant is signaled by the proliferation of T-cells that target and kill the donor cells requiring painful biopsies to detect rejection onset. An alternative non-invasive technique is proposed using a multi-channel superconducting quantum interference device (SQUID) magnetometer to detect T-cell lymphocytes in the transplanted organ labeled with magnetic nanoparticles conjugated to antibodies specifically attached to lymphocytic ligand receptors. After a magnetic field pulse, the T-cells produce a decaying magnetic signal with a characteristic time of the order of a second. The extreme sensitivity of this technique, 10 5 cells, can provide early warning of impending transplant rejection and monitor immune-suppressive chemotherapy.

  9. Inflammatory triggers of acute rejection of organ allografts

    PubMed Central

    Mori, Daniel N.; Kreisel, Daniel; Fullerton, James N.; Gilroy, Derek W.; Goldstein, Daniel R.

    2014-01-01

    Summary Solid organ transplantation is a vital therapy for end stage diseases. Decades of research has established that the components of the adaptive immune system are critical for transplant rejection, but the role of the innate immune system in organ transplantation is just emerging. Accumulating evidence indicates that the innate immune system is activated at the time of organ implantation by the release of endogenous inflammatory triggers. This review discusses the nature of these triggers in organ transplantation and also potential mediators that may enhance inflammation resolution after organ implantation. PMID:24517430

  10. Inhibition of αvβ6 promotes acute renal allograft rejection in nonhuman primates.

    PubMed

    Lo, D J; Farris, A B; Song, M; Leopardi, F; Anderson, D J; Strobert, E A; Ramakrishnan, S; Turgeon, N A; Mehta, A K; Turnbull, B; Maroni, B; Violette, S M; Kirk, A D

    2013-12-01

    The integrin αvβ6 activates latent transforming growth factor-β (TGF-β) within the kidney and may be a target for the prevention of chronic allograft fibrosis after kidney transplantation. However, TGF-β also has known immunosuppressive properties that are exploited by calcineurin inhibitors (CNIs); thus, the net benefit of αvβ6 inhibition remains undetermined. To assess the acute impact of interference with αvβ6 on acute rejection, we tested a humanized αvβ6-specific monoclonal antibody (STX-100) in a randomized, double-blinded, placebo-controlled nonhuman primate renal transplantation study to evaluate whether αvβ6 blockade alters the risk of acute rejection during CNI-based immunosuppression. Rhesus monkeys underwent renal allotransplantation under standard CNI-based maintenance immunosuppression; 10 biopsy-confirmed rejection-free animals were randomized to receive weekly STX-100 or placebo. Animals treated with STX-100 experienced significantly decreased rejection-free survival compared to placebo animals (p = 0.049). Immunohistochemical analysis confirmed αvβ6 ligand presence, and αvβ6 staining intensity was lower in STX-100-treated animals (p = 0.055), indicating an apparent blockade effect of STX-100. LAP, LTBP-1 and TGF-β were all decreased in animals that rejected on STX-100 compared to those that rejected on standard immunosuppression alone, suggesting a relevant effect of αvβ6 blockade on local TGF-β. These data caution against the use of αvβ6 blockade to achieve TGF-β inhibition in kidney transplantation.

  11. [Neurologic complications induced by the treatment of the acute renal allograft rejection with the monoclonal antibody OKT3].

    PubMed

    Fernández, O; Romero, F; Bravo, M; Burgos, D; Cabello, M; González-Molina, M

    1993-10-01

    The treatment of the acute renal allograft rejection with the monoclonal antibody orthoclone OKT3 produces both systemic and neurologic alterations. In a series of 21 patients with an acute renal allograft rejection treated with this monoclonal antibody, 20 with a renal allograft transplantation and one with a renal and pancreatic allograft transplantation, 29% referred headache associated with fever and vomiting, and 14.2% presented severe neurological alterations induced by the treatment. We stress the need to know these secondary effects to differentiate them from other central nervous system disorders, particularly those of infectious origin.

  12. The medullary pyramid index: an objective assessment of prominence in renal transplant rejection.

    PubMed

    Fried, A M; Woodring, J H; Loh, F K; Lucas, B A; Kryscio, R J

    1983-12-01

    Prominence of the medullary pyramids at sonography has been considered a sign of renal transplant rejection. A search of the literature reveals no previously published objective assessment of this phenomenon. Medullary pyramids of 67 normal kidneys, 53 nonrejecting transplanted kidneys, and 71 transplanted kidneys in rejection were measured. The area of the pyramid was related to the thickness of the overlying renal cortex by a "medullary pyramid index" (MPI): MPI (formula; see text) The median MPI was 4.17 for normal kidneys, 6.0 for nonrejecting transplanted kidneys, and 7.50 for transplanted kidneys in rejection. The results are significantly different (P = 0.0001) for all possible pairs. Overlap between rejection and nonrejection distributions is, however, considerable, rendering the discriminatory value of an individual observation quite low (0.69). Prominence of the medullary pyramids is therefore of very limited predictive value in the determination of transplant rejection in an individual patient.

  13. Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients.

    PubMed

    Halloran, Philip F; Chang, Jessica; Famulski, Konrad; Hidalgo, Luis G; Salazar, Israel D R; Merino Lopez, Maribel; Matas, Arthur; Picton, Michael; de Freitas, Declan; Bromberg, Jonathan; Serón, Daniel; Sellarés, Joana; Einecke, Gunilla; Reeve, Jeff

    2015-07-01

    The prevalent renal transplant population presents an opportunity to observe the adaptive changes in the alloimmune response over time, but such studies have been limited by uncertainties in the conventional biopsy diagnosis of T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR). To circumvent these limitations, we used microarrays and conventional methods to investigate rejection in 703 unselected biopsies taken 3 days to 35 years post-transplant from North American and European centers. Using conventional methods, we diagnosed rejection in 205 biopsy specimens (28%): 67 pure TCMR, 110 pure ABMR, and 28 mixed (89 designated borderline). Using microarrays, we diagnosed rejection in 228 biopsy specimens (32%): 76 pure TCMR, 124 pure ABMR, and 28 mixed (no borderline). Molecular assessment confirmed most conventional diagnoses (agreement was 90% for TCMR and 83% for ABMR) but revealed some errors, particularly in mixed rejection, and improved prediction of failure. ABMR was strongly associated with increased graft loss, but TCMR was not. ABMR became common in biopsy specimens obtained >1 year post-transplant and continued to appear in all subsequent intervals. TCMR was common early but progressively disappeared over time. In 108 biopsy specimens obtained 10.2-35 years post-transplant, TCMR defined by molecular and conventional features was never observed. We conclude that the main cause of kidney transplant failure is ABMR, which can present even decades after transplantation. In contrast, TCMR disappears by 10 years post-transplant, implying that a state of partial adaptive tolerance emerges over time in the kidney transplant population.

  14. Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence.

    PubMed

    Sellarés, J; de Freitas, D G; Mengel, M; Reeve, J; Einecke, G; Sis, B; Hidalgo, L G; Famulski, K; Matas, A; Halloran, P F

    2012-02-01

    We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow-up period (median 31.4 months). Failure was rare after T-cell-mediated rejection and acute kidney injury and common after antibody-mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody-mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T-cell-mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody-mediated or mixed rejection and also underscores the major role of nonadherence.

  15. Acute T cell-mediated rejection accompanied by C4d-negative acute antibody-mediated rejection and cell debris in tubulus: A case report.

    PubMed

    Takamura, Tsuyoshi; Yamamoto, Izumi; Nakada, Yasuyuki; Katsumata, Haruki; Yamakawa, Takafumi; Furuya, Maiko; Mafune, Aki; Kobayashi, Akimitsu; Tanno, Yudo; Miki, Jun; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi

    2015-07-01

    Herein, we report a complicated case of acute T-cell-mediated rejection (ACR) accompanied by C4d-negative acute antibody-mediated rejection (AMR) and cell debris in tubulus. A 32 year-old male was admitted for an episode biopsy with a serum creatinine (S-Cr) level of 1.83 mg/dL and pyuria (20-29 white blood cells per high power field) 49 days following kidney transplantation. Histological features included three distinct entities, mainly, in one of the three specimens: 1) focal aggressive tubulointerstitial inflammatory cell infiltration with moderate tubulitis, 2) inflammatory cell infiltration in peritubular capillaries (including neutrophils) and glomerular capillaries, and 3) cell debris consisting mainly of neutrophils in tubulus. Laboratory examination revealed evidence of non-human leukocyte antigen donor-specific antibodies. However, urinary culture and gram staining were negative. Considering both the histological and laboratory findings, the patient was diagnosed with ACR accompanied by C4d-negative AMR and suspicion of a urinary tract infection (UTI). The patient was treated for three consecutive days with steroid pulse therapy. The patient's S-Cr level decreased to ~1.5 mg/dL following treatment and did not increase thereafter. A second biopsy 133 days following kidney transplantation showed an excellent response to treatment and revealed no evidence of rejection. This case report demonstrates the difficulty in the diagnosis of, and therapy for, the complicated pathological findings of ACR, AMR and suspicion of a UTI.

  16. Total lymphoid irradiation in heart transplantation: Adjunctive treatment for recurrent rejection

    SciTech Connect

    Frist, W.H.; Winterland, A.W.; Gerhardt, E.B.; Merrill, W.H.; Atkinson, J.B.; Eastburn, T.E.; Stewart, J.R.; Eisert, D.R. )

    1989-12-01

    In the face of recurrent heart transplant graft rejection refractory to all conventional immunotherapy, retransplantation is customary treatment. The case of a heart transplant recipient unsuitable for retransplantation whose recurrent rejection was successfully treated with postoperative total lymphoid irradiation is described.

  17. Magnetic resonance imaging of the transplanted pediatric heart as a potential predictor of rejection

    PubMed Central

    Greenway, Steven C; Dallaire, Frederic; Kantor, Paul F; Dipchand, Anne I; Chaturvedi, Rajiv R; Warade, Monali; Riesenkampff, Eugenie; Yoo, Shi-Joon; Grosse-Wortmann, Lars

    2016-01-01

    AIM To evaluate cardiac magnetic resonance imaging (CMR) as a non-invasive tool to detect acute cellular rejection (ACR) in children after heart transplant (HT). METHODS Thirty pediatric HT recipients underwent CMR at the time of surveillance endomyocardial biopsy (EMB) and results were compared to 14 non-transplant controls. Biventricular volumes, ejection fractions (EFs), T2-weighted signal intensities, native T1 times, extracellular volumes (ECVs) and presence of late gadolinium enhancement (LGE) were compared between patients and controls and between patients with International Society of Heart and Lung Transplantation (ISHLT) grade ≥ 2R rejection and those with grade 0/1R. Heart rate (HR) and brain natriuretic peptide (BNP) were assessed as potential biomarkers. RESULTS Significant ACR (ISHLT grade ≥ 2R) was an infrequent event in our population (5/30, 17%). Ventricular volumes, EFs, LGE prevalence, ECVs, native T1 times, T2 signal intensity ratios, HR and BNP were not associated with the presence of ≥ 2R ACR. CONCLUSION In this pilot study CMR did not reliably identify ACR-related changes in pediatric HT patients. PMID:28058227

  18. Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants.

    PubMed

    Halloran, P F; Merino Lopez, M; Barreto Pereira, A

    2016-03-01

    The key lesions in antibody-mediated kidney transplant rejection (ABMR) are microcirculation inflammation (peritubular capillaritis and/or glomerulitis lesions, abbreviated "pg") and glomerular double contours (cg lesions). We used these features to explore subphenotypes in 164 indication biopsies with ABMR-related diagnoses: 137 ABMR (109 pure and 28 mixed with T cell-mediated rejection [TCMR]) and 27 transplant glomerulopathy (TG), identified from prospective multicenter studies. The lesions indicated three ABMR subphenotypes: pgABMR, cgABMR, and pgcgABMR. Principal component analysis confirmed these subphenotypes and showed that TG can be reclassified as pgcgABMR (n = 17) or cgABMR (n = 10). ABMR-related biopsies included 45 pgABMR, 90 pgcgABMR, and 25 cgABMR, with four unclassifiable. Dominating all time intervals was the subphenotype pgcgABMR. The pgABMR subphenotype presented earliest (median <2 years), frequently mixed with TCMR, and was most associated with nonadherence. The cgABMR subphenotype presented late (median 9 years). Subphenotypes differed in their molecular changes, with pgABMR having the most histologic-molecular discrepancies (i.e. potential errors). Donor-specific antibody (DSA) was not identified in 29% of pgcgABMR and 46% of cgABMR, but failure rates and molecular findings were similar to cases where DSA was known to be positive. Thus, ABMR presents distinct subphenotypes, early pg-dominant, late cg-dominant, and combined pgcg phenotype, differing in time, molecular features, accompanying TCMR, HLA antibody, and probability of nonadherence.

  19. Acute Kidney Allograft Rejection Precipitated by Lenalidomide Treatment for Multiple Myeloma.

    PubMed

    Lum, Erik L; Huang, Edmund; Bunnapradist, Suphamai; Pham, Thu; Danovitch, Gabriel

    2017-02-09

    Patients who develop malignancy after kidney transplantation typically undergo a reduction in immunosuppression and referral to an oncologist for chemotherapeutic considerations for the management of their malignancy. Traditional cytotoxic chemotherapy agents can result in kidney transplant injury, but the decision about which agents to be used has largely been determined by oncologists without the involvement of nephrologists. More recently, several classes of drugs with immunomodulatory actions have been approved for the treatment of cancer, including multiple myeloma. Activation of the immune system against malignant cells may have unintended consequences in solid-organ transplant recipients, who require suppression of the immune system to avoid transplant rejection. In this report, we present a case of acute kidney transplant rejection in a 65-year-old woman following administration of the newer immunomodulatory agent lenalidomide for the treatment of multiple myeloma. A greater awareness of the mechanisms of newly introduced chemotherapy agents and discussion with the treating oncologist and patient are paramount in caring for patients who develop malignancy following transplantation.

  20. Prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation

    PubMed Central

    Tannuri, Ana Cristina Aoun; Lima, Fabiana; de Mello, Evandro Sobroza; Tanigawa, Ryan Yukimatsu; Tannuri, Uenis

    2016-01-01

    OBJECTIVE: Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation. METHODS: Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups. RESULTS: Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01). CONCLUSION: The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection. PMID:27166772

  1. Treatment Options and Strategies for Antibody Mediated Rejection after Renal Transplantation

    PubMed Central

    Levine, Matthew H.

    2011-01-01

    Antibody mediated rejection is a significant clinical problem encountered in a subset of renal transplant recipients. This type of rejection has a variable pathogenesis from the presence of donor specific antibodies with no overt disease to immediate hyperacute rejection and many variations between. Antibody mediated rejection is more common in human leukocyte antigen sensitized patients. In general, transplant graft survival after antibody mediated rejection is jeopardized, with less than 50% graft survival 5 years after this diagnosis. A variety of agents have been utilized singly and in combinations to treat antibody mediated rejection with differing results and significant research efforts are being placed on developing new targets for intervention. These same agents have been used in desensitization protocols with some success. In this review, we describe the biology of antibody mediated rejection, review the available agents to treat this form of rejection, and highlight areas of ongoing and future research into this difficult clinical problem. PMID:21940179

  2. PD1-Expressing T Cell Subsets Modify the Rejection Risk in Renal Transplant Patients

    PubMed Central

    Pike, Rebecca; Thomas, Niclas; Workman, Sarita; Ambrose, Lyn; Guzman, David; Sivakumaran, Shivajanani; Johnson, Margaret; Thorburn, Douglas; Harber, Mark; Chain, Benny; Stauss, Hans J.

    2016-01-01

    We tested whether multi-parameter immune phenotyping before or after renal ­transplantation can predict the risk of rejection episodes. Blood samples collected before and weekly for 3 months after transplantation were analyzed by multi-parameter flow cytometry to define 52 T cell and 13 innate lymphocyte subsets in each sample, producing more than 11,000 data points that defined the immune status of the 28 patients included in this study. Principle component analysis suggested that the patients with histologically confirmed rejection episodes segregated from those without rejection. Protein death 1 (PD-1)-expressing subpopulations of regulatory and conventional T cells had the greatest influence on the principal component segregation. We constructed a statistical tool to predict rejection using a support vector machine algorithm. The algorithm correctly identified 7 out of 9 patients with rejection, and 14 out of 17 patients without rejection. The immune profile before transplantation was most accurate in determining the risk of rejection, while changes of immune parameters after transplantation were less accurate in discriminating rejection from non-rejection. The data indicate that pretransplant immune subset analysis has the potential to identify patients at risk of developing rejection episodes, and suggests that the proportion of PD1-expressing T cell subsets may be a key indicator of rejection risk. PMID:27148254

  3. Postoperative rebound of antiblood type antibodies and antibody-mediated rejection after ABO-incompatible living-related kidney transplantation.

    PubMed

    Ishida, Hideki; Kondo, Tsunenori; Shimizu, Tomokazu; Nozaki, Taiji; Tanabe, Kazunari

    2015-03-01

    The purpose of this study is to examine whether postoperative antiblood type antibody rebound is attributed to kidney allograft rejection in ABO blood type-incompatible (ABO-I) living-related kidney transplantation (KTx). A total of 191 ABO-I recipients who received ABO-I living-related KTx between 2001 and 2013 were divided into two groups: Group 1 consisted of low rebound [(≦1:32), N = 170] and Group 2 consisted of high rebound [(≧1:64), N = 21], according to the levels of the rebounded antiblood type antibodies within 1 year after transplantation. No prophylactic treatment for rejection was administered for elevated antiblood type antibodies, regardless of the levels of the rebounded antibodies. Within 1 year after transplantation, T-cell-mediated rejection was observed in 13 of 170 recipients (13/170, 8%) in Group 1 and in 2 of 21 recipients (2/21, 10%) in Group 2 (Groups 1 vs. 2, P = 0.432). Antibody-mediated rejection was observed in 15 of 170 recipients (15/170, 9%) and 2 of 21 recipients (2/21, 10%) in Groups 1 and 2, respectively (P = 0.898). In this study, we found no correlation between the postoperative antiblood type antibody rebound and the incidence of acute rejection. We concluded that no treatment is necessary for rebounded antiblood type antibodies.

  4. The role of indium-111 antimyosin (Fab) imaging as a noninvasive surveillance method of human heart transplant rejection

    SciTech Connect

    De Nardo, D.; Scibilia, G.; Macchiarelli, A.G.; Cassisi, A.; Tonelli, E.; Papalia, U.; Gallo, P.; Antolini, M.; Pitucco, G.; Reale, A. )

    1989-09-01

    The identification of rejection after heart transplantation in patients receiving cyclosporine immunosuppressive therapy requires the endomyocardial biopsy, an invasive method associated with a finite morbidity. To evaluate the role of indium-111 antimyosin (Fab) scintigraphy as a noninvasive surveillance method of heart transplant rejection, the Fab fragment of murine monoclonal antimyosin antibodies labeled with indium-111 was administered intravenously in 30 scintigraphic studies to 10 consecutive heart transplant recipients. Endomyocardial biopsy specimens were obtained 72 hours after each scintigraphic study. Nineteen scintigraphic studies had negative findings; no false negative finding was obtained. Eleven antimyosin scintigraphic studies had positive findings, and in these studies endomyocardial biopsy revealed mild rejection in two cases, moderate acute rejection with myocyte necrosis in two cases, myocyte necrosis as a consequence of ischemic injury in six cases, and possibly cytotoxic damage in one case. Antimyosin scintigraphy may represent a reliable screening method for the surveillance of heart transplant patients. In the presence of a negative finding from antimyosin scintigraphy, it may be possible to avoid endomyocardial biopsy. Conversely, in patients who have a positive finding from antimyosin scintigraphy, the endomyocardial biopsy is mandatory to establish the definitive diagnosis by histologic examination of the myocardium.

  5. Acute leukaemia following renal transplantation.

    PubMed

    Subar, M; Gucalp, R; Benstein, J; Williams, G; Wiernik, P H

    1996-03-01

    Four renal transplant patients on immunosuppressive therapy who presented with acute myeloid leukaemia are described. In two cases, azathioprine may have played an important role as a cofactor in leukaemogenesis. In a third case, the alkylating agent cyclophosphamide may have contributed. All patients were treated for leukaemia with full doses of cytotoxic chemotherapy and, in each case, a functioning renal allograft was preserved throughout the treatment despite attenuation of immunosuppressive therapy. Three patients achieved complete remission. Of the three, one is surviving at 2 years and two expired during the pancytopenic phase of their treatment with no active leukaemia present, and with intact renal function. As increasing expertise in the field of organ transplantation allows patients to survive longer, such patients' exposure to immunosuppressive and potentially leukaemogenic drugs is prolonged. The risk of secondary neoplasia has been previously documented in this population. Two of the four cases reported here suffered from polycystic kidney disease as their underlying condition. While this report suggests that the leukaemias are related to renal transplantation, we cannot rule out an association with the underlying disease which led to the transplant. This report further suggests that the leukaemia that develops in such patients may respond to standard therapy, and that such treatment does not compromise the transplanted kidney.

  6. A severe Mycoplasma pneumoniae pneumonia inducing an acute antibody-mediated pulmonary graft rejection

    PubMed Central

    Démir, Sarah; Saison, Julien; Sénéchal, Agathe; Mornex, Jean-Francois

    2017-01-01

    A 40-year-old cystic fibrosis woman with a history of double-lung transplantation 2 years previously was admitted for a progressive respiratory distress. Physical examination revealed fever (39°C) and diffuse bilateral lung crackles. Laboratory findings included severe hypoxemia and inflammatory syndrome. Bronchoalveolar lavage and serological test were positive for mycoplasma pneumonia. As the patient did not improve after 3 days of antibiotics and donor-specific HLA antibodies had been detected, an acute antibody-mediated graft rejection was treated with high-dose corticosteroids, plasma exchange, intravenous immunoglobulin, and rituximab. The patient rapidly improved. Unfortunately, 6 months after this episode, she developed a bronchiolitis obliterans syndrome with a dependence to noninvasive ventilator leading to the indication of retransplantation. This case illustrates the possible relationship between infection and humoral rejection. These two diagnoses should be promptly investigated and systematically treated in lung transplant recipients. PMID:28144069

  7. Noninvasive detection of human cardiac transplant rejection with indium-111 antimyosin (Fab) imaging

    SciTech Connect

    Frist, W.; Yasuda, T.; Segall, G.; Khaw, B.A.; Strauss, H.W.; Gold, H.; Stinson, E.; Oyer, P.; Baldwin, J.; Billingham, M.

    1987-11-01

    Diagnosis of rejection after cardiac transplantation is currently made by right ventricular endomyocardial biopsy. To evaluate antimyosin imaging as a noninvasive means of detecting human cardiac rejection, the Fab fragment of murine monoclonal antimyosin antibodies was labeled with indium-111 and given intravenously to 18 patients (age 45 +/- 12 years) in 20 studies 7 days to 9 years after transplantation. Endomyocardial biopsy specimens were obtained at the time of each imaging study. Eight patients had positive scans confirmed by biopsy as rejection, and eight patients had negative scans and no evidence of rejection on biopsy. Discordance was observed in four studies, two with positive scans and no rejection on biopsy and two with negative scans and positive biopsy. The sensitivity, specificity, and overall accuracy of the technique were each 80%. Imaging with radiolabeled antimyosin antibody Fab fragments may be of value in the noninvasive identification of rejection in the cardiac transplant recipient.

  8. Immunity of fungal infections alleviated graft reject in liver transplantation compared with non-fungus recipients

    PubMed Central

    Xing, Tonghai; Zhong, Lin; Lin, Lihui; Qiu, Guoqiang; Peng, Zhihai

    2015-01-01

    Objective: To evaluate of the immune tolerance in adult LT recipients with Invasive fungal infections (IFIs). Methods: 109 consecutive LT recipients who received LT were included. Percentage of T subsets (CD4+CD25hiCD127- T cells, CD4+CD25loCD45RA+ T cells, CD4+CD25loCD45RA- and CD4+CD45RA-CD45RO+ T cells populations), levels of cytokines (IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IFN-γ, IL-12p70, IL-17, TNF-α, TNF-β and GM-CSF) were detected by FACS and Bioplex in peripheral blood. Biopsy specimens were fixed, monoclonal antibodies against CD4, Foxp3 and IL-17 were applied to the above sections and FISH was performed. Results: The risk of acute rejection was decreased in fungal infected liver transplant recipients comparing with non-fungal infected group. CD4+CD25hiCD127T cell population was increased in peripheral blood and memory CD4+CD45RA-CD45RO+ T cell population decreased. There was significant lower levels observed in naïve CD4+CD25loCD45RA+ and CD4+CD25loCD45RA- T cell populations in fungal infected liver transplant. Moreover, IL-2, IL-6, IL-10 and GM-CSF were decreased. However, no significant difference with IL-4 and IL-8 in serum in two infected LT recipients. Conclusion: The incidence of graft rejection in liver transplantation recipients with fungal infections was lower than the non-fungal group. It is important to assess the risk during pretransplant and postoperation for liver transplantation. PMID:26045766

  9. Expression of decoy receptor 3 in kidneys is associated with allograft survival after kidney transplant rejection.

    PubMed

    Weng, Shuo-Chun; Shu, Kuo-Hsiung; Wu, Ming-Ju; Wen, Mei-Chin; Hsieh, Shie-Liang; Chen, Nien-Jung; Tarng, Der-Cherng

    2015-09-03

    Decoy receptor 3 (DcR3) expression in kidneys has been shown to predict progression of chronic kidney disease. We prospectively investigated a cohort comprising 96 renal transplant recipients (RTRs) undergoing graft kidney biopsies. Computer-assisted quantitative immunohistochemical staining value of DcR3 in renal tubular epithelial cells (RTECs) was used to determine the predictive role of DcR3 in kidney disease progression. The primary end point was doubling of serum creatinine and/or graft failure. A multivariate Cox proportional hazards model was used to assess the risk of DcR3 expression in rejected kidney grafts toward the renal end point. In total, RTRs with kidney allograft rejection were evaluated and the median follow-up was 30.9 months. The greater expression of DcR3 immunoreactivity in RTECs was correlated with a higher rate of the histopathological concordance of acute T cell-mediated rejection. Compared with 65 non-progressors, 31 progressors had higher DcR3 expression (HDE) regardless of the traditional risk factors. Cox regression analysis showed HDE was significantly associated with the risk of renal end point with a hazard ratio of 3.19 (95% confidence interval, 1.40 to 7.27; P = 0.006) after adjusting for other variables. In repetitive biopsies, HDE in tissue showed rapid kidney disease progression due to persistent inflammation.

  10. Graft-infiltrating host dendritic cells play a key role in organ transplant rejection

    PubMed Central

    Zhuang, Quan; Liu, Quan; Divito, Sherrie J.; Zeng, Qiang; Yatim, Karim M.; Hughes, Andrew D.; Rojas-Canales, Darling M.; Nakao, A.; Shufesky, William J.; Williams, Amanda L.; Humar, Rishab; Hoffman, Rosemary A.; Shlomchik, Warren D.; Oberbarnscheidt, Martin H.; Lakkis, Fadi G.; Morelli, Adrian E.

    2016-01-01

    Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells. We show that donor DCs that accompany heart or kidney grafts are rapidly replaced by recipient DCs. The DCs originate from non-classical monocytes and form stable, cognate interactions with effector T cells in the graft. Eliminating recipient DCs reduces the proliferation and survival of graft-infiltrating T cells and abrogates ongoing rejection or rejection mediated by transferred effector T cells. Therefore, host DCs that infiltrate transplanted organs sustain the alloimmune response after T-cell activation has already occurred. Targeting these cells provides a means for preventing or treating rejection. PMID:27554168

  11. 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

  12. A retrospective analysis of the use of caspofungin in recipients of liver transplant with a modified high index of suspicion for fungal infection. A critical review of mortality, acute cellular rejection, infections, and changes in the liver function tests while on caspofungin.

    PubMed

    Doria, Cataldo; Bodzin, Adam S; Vaccino, Silvia; Daskalakis, Constantine; Krawitz, Steven; Ramirez, Carlo B

    2011-01-01

    comparable (p = 0.540), and both better than no preventive treatment at all (OR = 0.15, p = 0.049, for caspofungin versus no preventive treatment; OR = 0.29, p = 0.085, for other antifungal versus no preventive treatment). Caspofungin appears to be an effective preventive agent against fungal infections when used in recipients of liver transplant designated as high risk for fungal infection. Usage of caspofungin in these patients does not carry an apparent increase in risk of death or acute cellular rejection, although we observed a significantly higher risk of AEs, especially acute renal failure (p = 0.001), in patients who received this agent.

  13. Mouse model of alloimmune-induced vascular rejection and transplant arteriosclerosis.

    PubMed

    Enns, Winnie; von Rossum, Anna; Choy, Jonathan

    2015-05-17

    Vascular rejection that leads to transplant arteriosclerosis (TA) is the leading representation of chronic heart transplant failure. In TA, the immune system of the recipient causes damage of the arterial wall and dysfunction of endothelial cells and smooth muscle cells. This triggers a pathological repair response that is characterized by intimal thickening and luminal occlusion. Understanding the mechanisms by which the immune system causes vasculature rejection and TA may inform the development of novel ways to manage graft failure. Here, we describe a mouse aortic interposition model that can be used to study the pathogenic mechanisms of vascular rejection and TA. The model involves grafting of an aortic segment from a donor animal into an allogeneic recipient. Rejection of the artery segment involves alloimmune reactions and results in arterial changes that resemble vascular rejection. The basic technical approach we describe can be used with different mouse strains and targeted interventions to answer specific questions related to vascular rejection and TA.

  14. Antibody-mediated rejection, T cell-mediated rejection, and the injury-repair response: new insights from the Genome Canada studies of kidney transplant biopsies.

    PubMed

    Halloran, Philip F; Reeve, Jeff P; Pereira, Andre B; Hidalgo, Luis G; Famulski, Konrad S

    2014-02-01

    Prospective studies of unselected indication biopsies from kidney transplants, combining conventional assessment with molecular analysis, have created a new understanding of transplant disease states and their outcomes. A large-scale Genome Canada grant permitted us to use conventional and molecular phenotypes to create a new disease classification. T cell-mediated rejection (TCMR), characterized histologically or molecularly, has little effect on outcomes. Antibody-mediated rejection (ABMR) manifests as microcirculation lesions and transcript changes reflecting endothelial injury, interferon-γ effects, and natural killer cells. ABMR is frequently C4d negative and has been greatly underestimated by conventional criteria. Indeed, ABMR, triggered in some cases by non-adherence, is the major disease causing failure. Progressive dysfunction is usually attributable to specific diseases, and pure calcineurin inhibitor toxicity rarely explains failure. The importance of ABMR argues against immunosuppressive drug minimization and stands as a barrier to tolerance induction. Microarrays also defined the transcripts induced by acute kidney injury (AKI), which correlate with reduced function, whereas histologic changes of acute tubular injury do not. AKI transcripts are induced in kidneys with late dysfunction, and are better predictors of failure than fibrosis and inflammation. Thus progression reflects ongoing parenchymal injury, usually from identifiable diseases such as ABMR, not destructive fibrosis.

  15. Risk of antibody-mediated rejection in kidney transplant recipients with anti-HLA-C donor-specific antibodies.

    PubMed

    Aubert, O; Bories, M-C; Suberbielle, C; Snanoudj, R; Anglicheau, D; Rabant, M; Martinez, F; Scemla, A; Legendre, C; Sberro-Soussan, R

    2014-06-01

    Anti-HLA donor-specific antibodies (DSAs) cause acute and chronic antibody-mediated rejection (AMR). However, the clinical relevance of anti-HLA-C antibodies remains unclear. We evaluated the clinical relevance of the presence of anti-HLA-C DSA at day 0 in renal transplant recipients. In this retrospective, case-controlled study, 608 patients who underwent kidney transplantation between August 2008 and March 2012 were screened for the presence of isolated anti-HLA-C DSA at day 0. A total of 22 renal transplant recipients were selected and followed for a period of 1 year. AMR was classified according to the Banff classification. The 22 patients were compared with 88 immunized patients. Acute AMR was diagnosed in six patients (27.3%). The median level of DSA at day 0 was 1179 (530-17,941). The mean fluorescence intensity in the anti-C group was 4966 (978-17,941) in the AMR group and 981 (530-8012) in the group of patients without AMR. Acute AMR was diagnosed less frequently in the 88 immunized individuals (9.1%) than in the DSA anti-C group (p = 0.033). The level of DSA at day 0 was predictive for AMR (p = 0.017). Patients with a high level of pretransplant anti-HLA-C DSAs are likely to develop acute AMR during the first year after transplantation.

  16. Analysis of leukocyte activation during acute rejection of pulmonary allografts in noninfected and cytomegalovirus-infected rats.

    PubMed

    Steinmüller, C; Steinhoff, G; Bauer, D; You, X M; Denzin, H; Franke-Ullmann, G; Hausen, B; Bruggemann, C; Wagner, T O; Lohmann-Matthes, M L; Emmendörffer, A

    1997-01-01

    After human lung transplantation acute rejection and cytomegalovirus (CMV) infections may occur, probably contributing to the development of chronic rejection. We established a model of subacute allograft rejection in rats to analyze leukocyte activation and effects of a CMV infection. Histoincompatible lung transplants (BN/LEW) without immunosuppression (group A) and lungs of initially immunosuppressed animals (group B) were analyzed. The production of inflammatory mediators (interleukin-6, tumor necrosis factor alpha, nitric oxides) and the expression of MHC class II antigens by alveolar and lung tissue macrophages were significantly enhanced during the alloresponse. In recipients without immunosuppression (group A) allograft necrosis was detected by day 6, whereas group B allografts were fully rejected by day 25. In allografts of immunosuppressed, CMV-infected animals (group C) the CMV infection was clearly aggravated and the number of activated lung tissue macrophages was increased when compared with noninfected allografts or isografts. The subacute model provides the advantage of allowing us to study mechanisms of acute rejection without the effects of reperfusion injury. Furthermore these findings underline the role of inflammatory mediators produced by macrophages during rejection.

  17. Doppler tissue imaging for assessing left ventricular diastolic dysfunction in heart transplant rejection

    PubMed Central

    Stengel, S; Allemann, Y; Zimmerli, M; Lipp, E; Kucher, N; Mohacsi, P; Seiler, C

    2001-01-01

    OBJECTIVE—To test the hypothesis that diastolic mitral annular motion velocity, as determined by Doppler tissue imaging and left ventricular diastolic flow propagation velocity, is related to the histological degree of heart transplant rejection according to the International Society of Heart and Lung Transplantation (ISHLT).
METHODS—In 41 heart transplant recipients undergoing 151 myocardial biopsies, the following Doppler echocardiographic measurements were performed within one hour of biopsy: transmitral and pulmonary vein flow indices; mitral annular motion velocity indices; left ventricular diastolic flow propagation velocity.
RESULTS—Late diastolic mitral annular motion velocity (ADTI) and mitral annular systolic contraction velocity (SCDTI) were higher in patients with ISHLT < IIIA than in those with ISHLT ⩾ IIIA (ADTI, 8.8 cm/s v 7.7 cm/s (p = 0.03); SCDTI, 19.3 cm/s v 9.3 cm/s (p < 0.05)). Sensitivity and specificity of ADTI < 8.7 cm/s (the best cut off value) in predicting significant heart transplant rejection were 82% and 53%, respectively. Early diastolic mitral annular motion velocity (EDTI) and flow propagation velocity were not related to the histological degree of heart transplant rejection.
CONCLUSIONS—Doppler tissue imaging of the mitral annulus is useful in diagnosing heart transplant rejection because a high late diastolic mitral annular motion velocity can reliably exclude severe rejection. However, a reduced late diastolic mitral annular motion velocity cannot predict severe rejection reliably because it is not specific enough.


Keywords: heart transplant rejection; diastolic function; Doppler tissue imaging; echocardiography PMID:11559685

  18. Effective therapy for acute antibody-mediated rejection with mild chronic changes: case report and review of the literature.

    PubMed

    Gheith, Osama; Al-Otaibi, Torki; Nampoory, Narayanan; Halim, Medhat; Nair, Prasad; Saied, Tarek; Al-Waheeb, Salah; Muzeirei, Ibraheem; Ibraheim, Mona

    2012-08-01

    To reduce the long-term toxicities of immunosuppressant drugs, corticosteroid-sparing and calcineurin-inhibitor-sparing immunosuppression protocols have become increasingly popular in managing kidney transplant recipients. The most vexing clinical condition caused by antibodies in organ transplants is antibody-mediated rejection. Limitations of the current antibody-mediated rejection therapies include (1) antibody-mediated rejection reversal tends to be gradual rather than prompt, (2) expense, (3) rejection reversal rates below 80%, (4) common appearance of chronic rejection after antibody-mediated rejection treatment, and (5) long-term persistence of donor specific antibodies after therapy. Because these limitations may be due to a lack of effects on mature plasma cells, the effects of bortezomib on mature plasma cells may represent a quantum advance in antihumoral therapy. Our experiences represent the first clinical use of bortezomib as an antihumoral agent in renal allograft recipients in Kuwait. We present 2 cases with resistant-acute antibody-mediated rejection to the standard therapies that were managed successfully with bortezomib.

  19. Effector Mechanisms of Rejection

    PubMed Central

    Moreau, Aurélie; Varey, Emilie; Anegon, Ignacio; Cuturi, Maria-Cristina

    2013-01-01

    Organ transplantation appears today to be the best alternative to replace the loss of vital organs induced by various diseases. Transplants can, however, also be rejected by the recipient. In this review, we provide an overview of the mechanisms and the cells/molecules involved in acute and chronic rejections. T cells and B cells mainly control the antigen-specific rejection and act either as effector, regulatory, or memory cells. On the other hand, nonspecific cells such as endothelial cells, NK cells, macrophages, or polymorphonuclear cells are also crucial actors of transplant rejection. Last, beyond cells, the high contribution of antibodies, chemokines, and complement molecules in graft rejection is discussed in this article. The understanding of the different components involved in graft rejection is essential as some of them are used in the clinic as biomarkers to detect and quantify the level of rejection. PMID:24186491

  20. MicroRNA-10b downregulation mediates acute rejection of renal allografts by derepressing BCL2L11

    SciTech Connect

    Liu, Xiaoyou; Dong, Changgui; Jiang, Zhengyao; Wu, William K.K.; Chan, Matthew T.V.; Zhang, Jie; Li, Haibin; Qin, Ke; Sun, Xuyong

    2015-04-10

    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, and 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.

  1. Tacrolimus confers lower acute rejection rates and better renal allograft survival compared to cyclosporine

    PubMed Central

    Kamel, Mahmoud; Kadian, Manish; Srinivas, Titte; Taber, David; Posadas Salas, Maria Aurora

    2016-01-01

    AIM To compare the impact of tacrolimus (FK) and cyclosporine (CYA) on acute rejection and graft survival and to assess the predominant causes of graft loss between patients receiving these two calcineurin inhibitors (CNIs). METHODS Retrospective review of 1835 patients who received a kidney transplant (KTX) between 1999-2012. Patients were grouped based on initial CNI utilized: 1195 in FK group, 640 in CYA group. Data on baseline characteristics, clinical outcomes, and causes of graft loss in both groups were analyzed. RESULTS Cumulative acute rejection rates were 14% in the FK vs 24% in the CYA group. Despite more marginal donor characteristics in the FK group, these patients had better graft survival rates compared to the CYA group. Three and five year graft survival rates were 88% and 84% respectively in the FK group compared to 79% and 70% respectively in the CYA group (P < 0.001). After multivariate analysis, which controlled for confounders, FK use was a strong predictor for lower acute rejection rates [odds ratio (OR) 0.60, 95%CI: 0.45-0.79] and better renal allograft survival (OR 0.740, 95%CI: 0.58-0.94). Death with a functioning graft was the most common cause of graft loss in both groups. Common causes of death included cardiovascular disease, infections, and malignancies. Chronic allograft nephropathy was also found to be an important cause of graft loss, being more prevalent in the CYA group. CONCLUSION The use of FK-based maintenance immunosuppression therapy is associated with a significantly lower rate of acute rejection and better graft survival compared to CYA-based regimen. Individualizing immunosuppression through risk-stratified CNI choice may lead to improved outcomes across all spectra of KTX patients. PMID:28058220

  2. Quantification of C4d deposition and hepatitis C virus RNA in tissue in cases of graft rejection and hepatitis C recurrence after liver transplantation

    PubMed Central

    Song, Alice Tung Wan; de Mello, Evandro Sobroza; Alves, Venâncio Avancini Ferreira; Cavalheiro, Norma de Paula; Melo, Carlos Eduardo; Bonazzi, Patricia Rodrigues; Tengan, Fatima Mitiko; Freire, Maristela Pinheiro; Barone, Antonio Alci; D'Albuquerque, Luiz Augusto Carneiro; Abdala, Edson

    2015-01-01

    Histology is the gold standard for diagnosing acute rejection and hepatitis C recurrence after liver transplantation. However, differential diagnosis between the two can be difficult. We evaluated the role of C4d staining and quantification of hepatitis C virus (HCV) RNA levels in liver tissue. This was a retrospective study of 98 liver biopsy samples divided into four groups by histological diagnosis: acute rejection in patients undergoing liver transplant for hepatitis C (RejHCV+), HCV recurrence in patients undergoing liver transplant for hepatitis C (HCVTx+), acute rejection in patients undergoing liver transplant for reasons other than hepatitis C and chronic hepatitis C not transplanted (HCVTx-). All samples were submitted for immunohistochemical staining for C4d and HCV RNA quantification. Immunoexpression of C4d was observed in the portal vessels and was highest in the HCVTx- group. There was no difference in C4d expression between the RejHCV+ and HCVTx+ groups. However, tissue HCV RNA levels were higher in the HCVTx+ group samples than in the RejHCV+ group samples. Additionally, there was a significant correlation between tissue and serum levels of HCV RNA. The quantification of HCV RNA in liver tissue might prove to be an efficient diagnostic test for the recurrence of HCV infection. PMID:25742264

  3. Differentiation between Acute Skin Rejection in Allotransplantation and T-Cell Mediated Skin Inflammation Based on Gene Expression Analysis

    PubMed Central

    Wolfram, Dolores; Morandi, Evi M.; Eberhart, Nadine; Hautz, Theresa; Hackl, Hubert; Zelger, Bettina; Riede, Gregor; Wachter, Tanja; Dubrac, Sandrine; Ploner, Christian; Pierer, Gerhard; Schneeberger, Stefan

    2015-01-01

    Advances in microsurgical techniques and immunosuppressive medication have rendered transplantation of vascularized composite allografts possible, when autologous tissue is neither available nor sufficient for reconstruction. However, skin rejection and side effects of long-term immunosuppression still remain a major hurdle for wide adoption of this excellent reconstructive technique. Histopathologic changes during acute skin rejection in vascular composite allotransplantation often mimic inflammatory skin disorders and are hard to distinguish. Hence, the identification of diagnostic and therapeutic markers specific for skin rejection is of particular clinical need. Here we present novel markers allowing for early differentiation between rejection in hind limb allotransplantation and contact hypersensitivity. Assessment of Ccl7, Il18, and Il1b expression is most indicative of distinguishing skin rejection from skin inflammatory disorders. Gene expression levels varied significantly across skin types and regions, indicating localization specific mechanism of leukocyte migration and infiltration. Expression of Il12b, Il17a, and Il1b gene expression levels differed significantly between rejection and inflammation, independent of the skin type. In synopsis of the RNA expression profile and previously assessed protein expression, the Il1 family appears as a promising option for accurate skin rejection diagnosis and, as a following step, for development of novel rejection treatments. PMID:25756043

  4. Changes in the action potential and transient outward potassium current in cardiomyocytes during acute cardiac rejection in rats

    PubMed Central

    Luo, Wenqi; Jia, Yixin; Zheng, Shuai; Li, Yan; Han, Jie

    2017-01-01

    Background Acute cardiac rejection contributes to the changes in the electrophysiological properties of grafted hearts. However, the electrophysiological changes of cardiomyocytes during acute cardiac rejection are still unknown. An understanding of the electrophysiological mechanisms of cardiomyocytes could improve the diagnosis and treatment of acute cardiac rejection. So it is important to characterize the changes in the action potential (AP) and the transient outward potassium current (Ito) in cardiomyocytes during acute cardiac rejection. Methods Heterotopic heart transplantation was performed in allogeneic [Brown Norway (BN)-to-Lewis] and isogeneic (BN-to-BN) rats. Twenty models were established in each group. Ten recipients were sacrificed at the 2nd day and the other ten recipients were sacrificed at the 4th day after the operation in each group. Histopathological examinations of the grafted hearts were performed in half of the recipients in each group randomly. The other half of the grafted hearts were excised rapidly and enzymatically dissociated to obtain single cardiomyocytes. The AP and Ito current were recorded using the whole cell patch-clamp technique. Results Forty grafted hearts were successfully harvested and used in experiments. Histologic examination showed mild rejection at the 2nd day and moderate rejection at the 4th day in the allogeneic group after cardiac transplantation, while no evidence of histologic lesions of rejection were observed in the isogeneic group. Compared with the isogeneic group, the action potential duration (APD) of cardiomyocytes in the allogeneic group was significantly prolonged (APD90 was 49.28±5.621 mV in the isogeneic group and 88.08±6.445 mV in the allogeneic group at the 2nd day, P=0.0016; APD90 was 59.34±5.183 mV in the isogeneic group and 104.0±9.523 mV in the allogeneic group at the 4th day, P=0.0064). The current density of Ito was significantly decreased at the 4th day after cardiac transplantation

  5. EKTACHEM bilirubin fraction Bc as a predictor of liver transplant rejection.

    PubMed

    Cox, C J; Valdiserri, R O; Zerbe, T R; Genter, J L

    1987-10-01

    Bilirubin fractions Bc and DELTA, not routinely available prior to the EKTACHEM Chemistry Analyzer and its slide methodology, were studied in an outpatient population of liver transplant recipients. A preliminary evaluation by the authors has shown that direct bilirubin (DBILI) levels in the normal range consist almost exclusively of DELTA (protein-bound conjugated bilirubin), while at elevated DBILI levels, an increasing amount of Bc (non-protein-bound conjugated bilirubin) is measured as well. The present study evaluated the clinical significance of Bc in the serum of 80 liver transplant recipients as a means of identifying episodes of rejection. Each patient was classified into rejection or nonrejection categories based on clinical status, liver biopsy results, and/or response to therapy. Eighteen patients were classified as experiencing an episode of rejection during the period of this study. Fourteen of these (77.8%) had Bc levels that ranged from 0.1 to 6.8 mg/dl. Sixty two patients were classified in the nonrejection category. Fourteen (22.6%) of these patients had Bc levels that ranged from 0.1 to 0.6 mg/dl. In our outpatient liver transplant recipients with Bc greater than or equal to 0.1 mg/dl, the relative risk of rejection (% of rejection patients with Bc/% of nonrejection patients with Bc) was 3.44. This value indicates that Bc determination may be a helpful adjunct in the assessment of rejection.

  6. ACUTE CONSTRICTIVE PERICARDITIS FOLLOWING LUNG TRANSPLANTATION FOR LYMPHANGIOLEIOMYOMATOSIS: A CASE REPORT

    PubMed Central

    Billings, Martha E.; Mulligan, Michael; Raghu, Ganesh

    2009-01-01

    Lymphangioleiomyomatosis (LAM) is a rare cystic progressive lung disease with many extra-pulmonary manifestations which may complicate allograft function after transplantation. We present a LAM patient, one-year status-post bilateral lung transplant, with new dyspnea and declining spirometry without rejection, infection or recurrence. Investigation revealed acute constrictive pericarditis which has not previously been reported in LAM lung transplant patients. This represents a novel complication likely due to progression of extra-pulmonary LAM that should be considered in LAM transplant patients with dyspnea. PMID:19134542

  7. Molecular diagnosis of antibody-mediated rejection in human kidney transplants.

    PubMed

    Sellarés, J; Reeve, J; Loupy, A; Mengel, M; Sis, B; Skene, A; de Freitas, D G; Kreepala, C; Hidalgo, L G; Famulski, K S; Halloran, P F

    2013-04-01

    Antibody-mediated rejection is the major cause of kidney transplant failure, but the histology-based diagnostic system misses most cases due to its requirement for C4d positivity. We hypothesized that gene expression data could be used to test biopsies for the presence of antibody-mediated rejection. To develop a molecular test, we prospectively assigned diagnoses, including C4d-negative antibody-mediated rejection, to 403 indication biopsies from 315 patients, based on histology (microcirculation lesions) and donor-specific HLA antibody. We then used microarray data to develop classifiers that assigned antibody-mediated rejection scores to each biopsy. The transcripts distinguishing antibody-mediated rejection from other conditions were mostly expressed in endothelial cells or NK cells, or were IFNG-inducible. The scores correlated with the presence of microcirculation lesions and donor-specific antibody. Of 45 biopsies with scores>0.5, 39 had been diagnosed as antibody-mediated rejection on the basis of histology and donor-specific antibody. High scores were also associated with unanimity among pathologists that antibody-mediated rejection was present. The molecular score also strongly predicted future graft loss in Cox regression analysis. We conclude that microarray assessment of gene expression can assign a probability of ABMR to transplant biopsies without knowledge of HLA antibody status, histology, or C4d staining, and predicts future failure.

  8. Alpha-1-antitrypsin for the improvement of autoimmunity and allograft rejection in beta cell transplantation.

    PubMed

    Ye, Jian; Liao, Yu-Ting; Jian, You-Qiang; Zhang, Xiao-Dan; Wei, Pei; Qi, Hui; Deng, Chun-Yan; Li, Fu-Rong

    2013-02-01

    Islet transplantation offers hope for patients with type 1 diabetes, which is an autoimmune disease. However, islet transplant recipients must overcome two obstacles in both allograft rejection and autoimmune reaction. Alpha-1-antitrypsin (a1-proteinase inhibitor, AAT) possesses anti-inflammatory properties, reduces cytokine-mediated islet damage, and induces specific immune tolerance. In this study, an insulinoma cell line, NIT-1, was transfected with human AAT (hAAT), named NIT-hAAT, and was transplanted to the left renal subcapsular spaces of 7-week-old female non-obese diabetic (NOD) mice (n=22). Cyclophosphamide(CY) was administered to synchronize and accelerate the development of diabetes. Thus, the immunosuppressive and cytoprotective activity of hAAT in β-cell transplantation was investigated. NIT-hAAT has immunomodulatory properties, which delay the onset of autoimmune diabetes, reduce diabetes incidence, inhibit insulitis and β-cell apoptosis, and dampen transplant site inflammation. We propose that NIT-hAAT has a dual function by improving islet autoimmunity and protecting transplanted β-cells from allograft rejection. However, the low expression of hAAT in vivo results in the inability of NIT-hAAT to induce long-term specific immune tolerance and to completely block allograft rejection.

  9. Noninvasive detection of rejection of transplanted hearts with indium-111-labeled lymphocytes

    SciTech Connect

    Eisen, H.J.; Eisenberg, S.B.; Saffitz, J.E.; Bolman, R.M. 3d.; Sobel, B.E.; Bergmann, S.R.

    1987-04-01

    To determine whether cardiac transplant rejection can be detected noninvasively with indium-111 (/sup 111/In)-labeled lymphocytes, we studied 11 dogs with thoracic heterotopic cardiac transplants without immunosuppression and five dogs with transplants treated with cyclosporine (10 mg/kg/day) and prednisone (1 mg/kg/day). All were evaluated sequentially with gamma scintigraphy after administration of 150 to 350 muCi of autologous /sup 111/In-lymphocytes. Technetium-99m-labeled red blood cells (1 to 3 mCi) were used for correction of radioactivity in the blood pool attributable to circulating labeled lymphocytes. Lymphocyte infiltration was quantified as the ratio of indium in the myocardium of the transplant or native heart compared with that in blood (indium excess, IE). Results were correlated with mechanical and electrical activity of allografts and with histologic findings in sequential biopsy specimens. In untreated dogs (n = 11), IE was 15.5 +/- 7.0 (SD) in transplanted hearts undergoing rejection and 0.4 +/- 1.1 in native hearts on the day before animals were killed. In dogs treated with cyclosporine and prednisone (n = 5), IE was minimal in allografts during the course of immunosuppression (0.8 +/- 0.4) and increased to 22.9 +/- 11.1 after immunosuppression was stopped. Scintigraphic criteria of rejection (IE greater than 2 SD above that in native hearts) correlated with results of biopsies indicative of rejection and appeared before electrophysiologic or mechanical manifestations of dysfunction. Thus infiltration of labeled lymphocytes in allografts, indicative of rejection, is detectable noninvasively by gamma scintigraphy and provides a sensitive approach potentially applicable to clinical monitoring for early detection of rejection and guidance for titration of immunosuppressive measures.

  10. A Higher Risk of Acute Rejection of Human Kidney Allografts Can Be Predicted from the Level of CD45RC Expressed by the Recipients’ CD8 T Cells

    PubMed Central

    Ordonez, Laurence; Bernard, Isabelle; Chabod, Marianne; Augusto, Jean-François; Lauwers-Cances, Valerie; Cristini, Christelle; Cuturi, Maria-Cristina; Subra, Jean-François; Saoudi, Abdelhadi

    2013-01-01

    Although transplantation is the common treatment for end-stage renal failure, allograft rejection and marked morbidity from the use of immunosuppressive drugs remain important limitations. A major challenge in the field is to identify easy, reliable and noninvasive biomarkers allowing the prediction of deleterious alloreactive immune responses and the tailoring of immunosuppressive therapy in individuals according to the rejection risk. In this study, we first established that the expression of the RC isoform of the CD45 molecule (CD45RC) on CD4 and CD8 T cells from healthy individuals identifies functionally distinct alloreactive T cell subsets that behave differently in terms of proliferation and cytokine secretion. We then investigated whether the frequency of the recipients CD45RC T cell subsets before transplantation would predict acute graft rejection in a cohort of 89 patients who had undergone their first kidney transplantation. We showed that patients exhibiting more than 54.7% of CD8 CD45RChigh T cells before transplantation had a 6 fold increased risk of acute kidney graft rejection. In contrast, the proportions of CD4 CD45RC T cells were not predictive. Thus, a higher risk of acute rejection of human kidney allografts can be predicted from the level of CD45RC expressed by the recipients’ CD8 T cells. PMID:23894540

  11. Eculizumab for Treatment of Refractory Antibody-Mediated Rejection in Kidney Transplant Patients: A Single-Center Experience.

    PubMed

    Yelken, B; Arpalı, E; Görcin, S; Kocak, B; Karatas, C; Demiralp, E; Turkmen, A

    2015-01-01

    Antibody-mediated rejection (AMR) is responsible for up to 20%-30% of acute rejection episodes after kidney transplantation. In several cases, conventional therapies including plasmapheresis, intravenous immunoglobulin, and anti-CD20 therapy can resolve AMR successfully. But in some cases the load of immunoglobulins that can activate complement cascade may submerge the routine desensitization therapy and result in the formation of membrane attack complexes. Eculizumab, a monoclonal antibody against C5, was reported to be an option in cases with severe AMR that are resistant to conventional therapy. Here, we present 8 cases that were resistant to conventional therapy and in which eculizumab was given as a salvage treatment. Given the bad prognosis for renal transplants displaying acute injury progressing rapidly to cortical necrosis on the biopsy, the prompt use of eculizumab could have the advantage of immediate effects by stopping cellular injury. This can provide a therapeutic window to allow conventional treatment modalities to be effective and prevent early graft loss.

  12. Probable C4d-negative accelerated acute antibody-mediated rejection due to non-HLA antibodies.

    PubMed

    Niikura, Takahito; Yamamoto, Izumi; Nakada, Yasuyuki; Kamejima, Sahoko; Katsumata, Haruki; Yamakawa, Takafumi; Furuya, Maiko; Mafune, Aki; Kobayashi, Akimitsu; Tanno, Yudo; Miki, Jun; Yamada, Hiroki; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi

    2015-07-01

    We report a case of probable C4d-negative accelerated acute antibody-mediated rejection due to non-HLA antibodies. A 44 year-old male was admitted to our hospital for a kidney transplant. The donor, his wife, was an ABO minor mismatch (blood type O to A) and had Gitelman syndrome. Graft function was delayed; his serum creatinine level was 10.1 mg/dL at 3 days after transplantation. Open biopsy was performed immediately; no venous thrombosis was observed during surgery. Histology revealed moderate peritubular capillaritis and mild glomerulitis without C4d immunoreactivity. Flow cytometric crossmatching was positive, but no panel-reactive antibodies against HLA or donor-specific antibodies (DSAbs) to major histocompatibility complex class I-related chain A (MICA) were detected. Taken together, we diagnosed him with probable C4d-negative accelerated antibody-mediated rejection due to non-HLA, non-MICA antibodies, the patient was treated with steroid pulse therapy (methylprednisolone 500 mg/day for 3 days), plasma exchange, intravenous immunoglobulin (40 g/body), and rituximab (200 mg/body) were performed. Biopsy at 58 days after transplantation, at which time S-Cr levels were 1.56 mg/dL, found no evidence of rejection. This case, presented with a review of relevant literature, demonstrates that probable C4d-negative accelerated acute AMR can result from non-HLA antibodies.

  13. Gene expression profiling for monitoring graft rejection in heart transplant recipients.

    PubMed

    Crespo-Leiro, M G; Paniagua-Martín, M J; Hermida-Prieto, M; Castro-Beiras, A

    2009-01-01

    Heart transplantation is a life-prolonging therapy for many patients with stage D heart failure and other forms of advanced heart disease. However, graft rejection and/or immunosuppression-related side effects are major causes of morbidity and death among heart transplant patients. Graft rejection monitoring remains a challenge. It would be desirable to be able to detect rejection early enough and specifically enough to prevent allograft dysfunction without unnecessary overimmunosuppression. Hitherto, the main technique employed in monitoring the rejection status of a transplanted heart has been endomyocardial biopsy (EMB), which allows rejection to be screened for and monitored on the basis of the extent and distribution of lymphocytic infiltrates and associated myocardial damage. However, EMB has significant limitations: it is invasive, its sensitivity is limited by sampling efficacy, and it suffers from considerable between-observer variability. Although many noninvasive techniques have been investigated, none so far has proved able to match the performance of EMB. Currently, a multiparametric approach is employed that comprises clinical examination for signs or symptoms of heart failure, EMBs, drug level monitoring, allograft function tests (mainly echocardiographic studies), and screening for allograft vasculopathy. Gene expression profiling may be a promising tool for this purpose.

  14. Functional abnormalities of sinusoidal endothelial cells in rats with acute liver rejection.

    PubMed

    Yokoi, Y; Nakamura, S; Muro, H; Baba, S

    1994-01-01

    The purpose of this study was to determine the changes of hepatic sinusoidal endothelial cell (SEC) function in acute liver rejection with respect to receptor-mediated endocytosis. Orthotopic rat liver transplantation was performed in Lewis rats grafted with DA livers and in Lewis rats grafted with Lewis livers as rejectors and controls, respectively. Animals were killed at 1, 3, 5, 7, and 10 days after the operation. Fc receptors (FcRs) were histochemically stained on frozen liver sections by applying peroxidase-antiperoxidase IgG complex as a ligand, and the FcR activity, i.e., capacity of binding the ligands represented by the FcR staining intensity, was semiquantitatively analyzed as an indicator of SEC function. The serum level of hyaluronic acid, which is specifically cleared from the circulation by receptor-mediated SEC endocytosis, was also assayed, along with the total serum bilirubin. Three days after the operation, the SECs of rejectors showed a significantly weaker FcR staining intensity of about half the value of that seen in the controls (P < 0.05), and staining disappeared after 5 days (P < 0.01). The decrease of FcR staining intensity, i.e., FcR activity, showed a correlation with elevation of the serum hyaluronic acid level (r = -0.77; P < 0.001). Histological evidence of endothelialitis and a significant elevation of total serum bilirubin (P < 0.01) were also present at 3 and 5 days, respectively. These results suggest that impairment of the endocytic function of SECs occurs at an earlier phase of acute liver rejection when compared with development of abnormalities of traditional indicators. Determination of receptor-mediated SEC endocytic functions may thus provide useful information for the early diagnosis of acute rejection.

  15. A Probabilistic Approach to Histologic Diagnosis of Antibody-Mediated Rejection in Kidney Transplant Biopsies.

    PubMed

    Halloran, P F; Famulski, K S; Chang, J

    2017-01-01

    Histologic diagnosis of antibody-mediated rejection (ABMR) in kidney transplant biopsies uses lesion score cutoffs such as 0 versus >0 rather than actual scores and requires donor-specific antibody (DSA); however, cutoffs lose information, and DSA is not always reliable. Using microarray-derived molecular ABMR scores as a histology-independent estimate of ABMR in 703 biopsies, we reassessed criteria for ABMR to determine relative importance of various lesions, the utility of equations using actual scores rather than cutoffs, and the potential for diagnosing ABMR when DSA is unknown or negative. We confirmed that the important features for ABMR diagnosis were peritubular capillaritis (ptc), glomerulitis (g), glomerular double contours, DSA and C4d staining, but we questioned some features: arterial fibrosis, vasculitis, acute tubular injury, and sum of ptc+g scores. Regression equations using lesion scores predicted molecular ABMR more accurately than score cutoffs (area under the curve 0.85-0.86 vs. 0.75). DSA positivity improved accuracy, but regression equations predicted ABMR with moderate accuracy when DSA was unknown. Some biopsies without detectable DSA had high probability of ABMR by regression, although most had HLA antibody. We concluded that regression equations using lesion scores plus DSA maximized diagnostic accuracy and can estimate probable ABMR when DSA is unknown or undetectable.

  16. Suppressor of cytokine signaling (SOCS) 1 is down-regulated in renal transplant recipients with rejection.

    PubMed

    Wu, Tsai-Hung; Lee, Hui-Ting; Lai, Chien-Chih; Yang, An-Hang; Loong, Che-Chuan; Wang, Hsin-Kai; Yu, Chia-Li; Tsai, Chang-Youh

    2016-09-01

    The role of suppressor of cytokine signaling (SOCS) in maintaining the immunotolerance of renal allograft is unknown. To clarify this, peripheral blood mononuclear cells (PBMCs) from renal transplant patients with or without rejection were analyzed for the expression of SOCS family proteins by cell culture, immunoblot, flowcytometry and quantitative reverse transcription-polymerase chain reaction (qPCR). Patients with renal graft rejection expressed lower levels of SOCS1 while those without rejection showed a higher SOCS1 expression in the PBMC either on stimulation or not. In addition, SOCS1 was constitutively expressed in normal individuals as well as renal transplant patients with graft tolerance while patients with rejection exhibited down-regulation of the SOCS1 but not SOCS3. The qPCR tests and flowcytometric measurements have also showed that the reduction of SOCS1 expression in rejection could be quantitatively evaluated. These results have suggested that down-regulation of SOCS1 may be regarded as a biomarker for early detection of renal allograft rejection.

  17. ACUTE APENDICITIS IN LIVER TRANSPLANT RECIPIENTS

    PubMed Central

    da FONSECA-NETO, Olival Cirilo Lucena; LIMA, Heloise Caroline de Souza; de MELO, Paulo Sérgio Vieira; LEMOS, Roberto; LEITÃO, Laércio; AMORIM, Américo Gusmão; LACERDA, Cláudio Moura

    2016-01-01

    Background : Appendicitis is a common cause of emergency surgery that in the population undergoing organ transplantation presents a rare incidence due to late diagnosis and treatment. Aim : To report the occurrence of acute appendicitis in a cohort of liver transplant recipients. Methods : Retrospective analysis in a period of 12 years among 925 liver transplants, in witch five cases of acute appendicitis were encountered. Results : Appendicitis occurred between three and 46 months after liver transplantation. The age ranged between 15 and 58 years. There were three men and two women. The clinical presentations varied, but not discordant from those found in non-transplanted patients. Pain was a symptom found in all patients, in two cases well located in the right iliac fossa (40%). Two patients had symptoms characteristic of peritoneal irritation (40%) and one patient had abdominal distention (20%). All patients were submitted to laparotomies. In 20% there were no complications. In 80% was performed appendectomy complicated by suppuration (40%) or perforation (40%). Superficial infection of the surgical site occurred in two patients, requiring clinical management. The hospital stay ranged from 48 h to 45 days. Conclusion : Acute appendicitis after liver transplantation is a rare event being associated with a high rate of drilling, due to delays in diagnosis and therapy, and an increase in hospital stay. PMID:27120736

  18. Inducible expression of indoleamine 2,3-dioxygenase attenuates acute rejection of tissue-engineered lung allografts in rats.

    PubMed

    Ebrahimi, Ammar; Kardar, Gholam Ali; Teimoori-Toolabi, Ladan; Toolabi, LadanTeimoori; Ghanbari, Hossein; Sadroddiny, Esmaeil

    2016-01-15

    Lung disease remains one of the principal causes of death worldwide and the incidence of pulmonary diseases is increasing. Complexity in treatments and shortage of donors leads us to develop new ways for lung disease treatment. One promising strategy is preparing engineered lung for transplantation. In this context, employing new immunosuppression strategies which suppresses immune system locally rather than systemic improves transplant survival. This tends to reduce the difficulties in transplant rejection and the systemic impact of the use of immunosuppressive drugs which causes side effects such as serious infections and malignancies. In our study examining the immunosuppressive effects of IDO expression, we produced rat lung tissues with the help of decellularized tissue, differentiating medium and rat mesenchymal stem cells. Transduction of these cells by IDO expressing lentiviruses provided inducible and local expression of this gene. To examine immunosuppressive properties of IDO expression by these tissues, we transplanted these allografts into rats and, subsequently, evaluated cytokine expression and histopathological properties. Expression of inflammatory cytokines IFNγ and TNFα were significantly downregulated in IDO expressing allograft. Moreover, acute rejection score of this experimental group was also lower comparing other two groups and mRNA levels of FOXP3, a regulatory T cell marker, upregulated in IDO expressing group. However, infiltrating lymphocyte counting did not show significant difference between groups. This study demonstrates that IDO gene transfer into engineered lung allograft tissues significantly attenuates acute allograft damage suggesting local therapy with IDO as a strategy to reduce the need for systemic immunosuppression and, thereby, its side effects.

  19. Rationale and design of the RIACT–study: a multi-center placebo controlled double blind study to test the efficacy of RItuximab in Acute Cellular tubulointerstitial rejection with B-cell infiltrates in renal Transplant patients: study protocol for a randomized controlled trial

    PubMed Central

    2012-01-01

    Background Acute kidney allograft rejection is a major cause for declining graft function and has a negative impact on the long-term graft survival. The majority (90%) of acute rejections are T-cell mediated and, therefore, the anti-rejection therapy targets T-cell-mediated mechanisms of the rejection process. However, there is increasing evidence that intragraft B-cells are also important in the T-cell-mediated rejections. First, a significant proportion of patients with acute T-cell-mediated rejection have B-cells present in the infiltrates. Second, the outcome of these patients is inferior, which has been related to an inferior response to the conventional anti-rejection therapy. Third, treatment of these patients with an anti-CD20 antibody (rituximab) improves the allograft outcome as reported in single case observations and in one small study. Despite the promise of these observations, solid evidence is required before incorporating this treatment option into a general treatment recommendation. Methods/Design The RIACT study is designed as a randomized, double-blind, placebo-controlled, parallel group multicenter Phase III study. The study examines whether rituximab, in addition to the standard treatment with steroid-boli, leads to an improved one-year kidney allograft function, compared to the standard treatment alone in patients with acute T-cell mediated tubulointerstitial rejection and significant B-cell infiltrates in their biopsies. A total of 180 patients will be recruited. Discussion It is important to clarify the relevance of anti-B cell targeting in T-cell mediated rejection and answer the question whether this novel concept should be incorporated in the conventional anti-rejection therapy. Trial registration Clinical trials gov. number: NCT01117662 PMID:23101480

  20. Combining Theoretical and Experimental Techniques to Study Murine Heart Transplant Rejection

    PubMed Central

    Arciero, Julia C.; Maturo, Andrew; Arun, Anirudh; Oh, Byoung Chol; Brandacher, Gerald; Raimondi, Giorgio

    2016-01-01

    The quality of life of organ transplant recipients is compromised by complications associated with life-long immunosuppression, such as hypertension, diabetes, opportunistic infections, and cancer. Moreover, the absence of established tolerance to the transplanted tissues causes limited long-term graft survival rates. Thus, there is a great medical need to understand the complex immune system interactions that lead to transplant rejection so that novel and effective strategies of intervention that redirect the system toward transplant acceptance (while preserving overall immune competence) can be identified. This study implements a systems biology approach in which an experimentally based mathematical model is used to predict how alterations in the immune response influence the rejection of mouse heart transplants. Five stages of conventional mouse heart transplantation are modeled using a system of 13 ordinary differential equations that tracks populations of both innate and adaptive immunity as well as proxies for pro- and anti-inflammatory factors within the graft and a representative draining lymph node. The model correctly reproduces known experimental outcomes, such as indefinite survival of the graft in the absence of CD4+ T cells and quick rejection in the absence of CD8+ T cells. The model predicts that decreasing the translocation rate of effector cells from the lymph node to the graft delays transplant rejection. Increasing the starting number of quiescent regulatory T cells in the model yields a significant but somewhat limited protective effect on graft survival. Surprisingly, the model shows that a delayed appearance of alloreactive T cells has an impact on graft survival that does not correlate linearly with the time delay. This computational model represents one of the first comprehensive approaches toward simulating the many interacting components of the immune system. Despite some limitations, the model provides important suggestions of

  1. Monitoring of Human Uterus Transplantation With Cervical Biopsies: A Provisional Scoring System for Rejection.

    PubMed

    Mölne, J; Broecker, V; Ekberg, J; Nilsson, O; Dahm-Kähler, P; Brännström, M

    2016-11-21

    Until now, absolute uterine factor infertility has been the major untreatable form of female infertility. Uterus transplantation has recently proven to be the first successful treatment for absolute uterine factor infertility, with demonstration of live births. In this study, live donation uterus transplantation was performed in nine women. In total, 163 cervical biopsies (149 protocol, 14 follow-up) were taken to detect histopathological signs of rejection. Based on experience from animal experiments, we used a three-grade scoring system to evaluate biopsies systematically. Nine episodes of rejection were diagnosed in five patients: grade 1 in six episodes, grade 2 in two episodes, and grade 3 in one episode. Treatment decisions were based on histopathology, and all rejection episodes were reversed after treatment. The biopsies were reviewed retrospectively, and immunohistochemistry was performed to characterize the inflammatory infiltrates. A borderline category was introduced to avoid overtreatment of patients. Based on our review of all biopsies, we put forward a simple grading system for monitoring of rejection and to guide immunosuppressive treatment in uterus transplantation.

  2. Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options.

    PubMed

    Kim, Miae; Martin, Spencer T; Townsend, Keri R; Gabardi, Steven

    2014-07-01

    Antibody-mediated rejection (AMR), also known as B-cell-mediated or humoral rejection, is a significant complication after kidney transplantation that carries a poor prognosis. Although fewer than 10% of kidney transplant patients experience AMR, as many as 30% of these patients experience graft loss as a consequence. Although AMR is mediated by antibodies against an allograft and results in histologic changes in allograft vasculature that differ from cellular rejection, it has not been recognized as a separate disease process until recently. With an improved understanding about the importance of the development of antibodies against allografts as well as complement activation, significant advances have occurred in the treatment of AMR. The standard of care for AMR includes plasmapheresis and intravenous immunoglobulin that remove and neutralize antibodies, respectively. Agents targeting B cells (rituximab and alemtuzumab), plasma cells (bortezomib), and the complement system (eculizumab) have also been used successfully to treat AMR in kidney transplant recipients. However, the high cost of these medications, their use for unlabeled indications, and a lack of prospective studies evaluating their efficacy and safety limit the routine use of these agents in the treatment of AMR in kidney transplant recipients.

  3. Acute graft-versus-host disease in pancreas transplantation: a comparison of two case presentations and a review of the literature.

    PubMed

    Weinstein, Adam; Dexter, David; KuKuruga, Debra L; Philosophe, Benjamin; Hess, John; Klassen, David

    2006-07-15

    As a complication of solid organ transplantation, acute graft-versus-host disease (GVHD) is most associated with small bowel and liver transplants. We present two cases of acute GVHD following pancreas transplantation. Case 1 was a 27-year-old female who underwent cadaveric pancreas transplant 9 months after a successful live donor kidney transplant. Case 2 was a 38-year-old male who received a simultaneous cadaveric pancreas and live donor kidney transplant. Both patients presented within 30 days of transplant with nonspecific symptoms. Rejection and infection were ruled out. Both subjects had progressive decline in mentation associated with pancytopenia and hyperbilirubinemia. Rash was not present until late in their hospital course. Skin biopsies demonstrated mixed chimerism with pancreas donor DNA diagnostic of GVHD. Acute GVHD is a rare, often fatal, complication of pancreas transplantation, and its presentation appears to differ from acute GVHD associated with stem cell transplantation.

  4. Evaluation of In-111 labeled lymphocytes in an acute rejection model

    SciTech Connect

    Schauwecker, D.S.; Leapman, S.B.; Siddiqui, A.R.; Filo, R.S.; Smith, P.G.; Forney, M.N.

    1983-01-01

    Four days after surgery, canine renal allografts were studied with 290-500 microCi of In-111/10(8) lymphocytes. All transplants were visualized, implying that it may not be necessary to harvest large numbers of lymphocytes from immunosuppressed patients. On the day of renal transplant, a second set of dogs were injected with 80-150 microCi of In-111/10(8) lymphocytes. No delayed visualization could be seen 2-4 days later when rejection commenced. Cellular damage, even at this lower level of labeling, may require injection of labeled lymphocytes after the onset of the rejection process in order to visualize the rejection organ.

  5. Chronic rejection after combined liver and small bowel transplantation in a child with chronic intestinal pseudo-obstruction: a case report.

    PubMed

    Giovanelli, M; Gupte, G L; Sharif, K; Mayer, D A; Mirza, D F

    2008-06-01

    An 11-year-old boy with irreversible intestinal failure secondary to chronic intestinal pseudo-obstruction (CIPO) and intestinal failure-associated liver disease (IFALD) underwent a combined en bloc reduced liver and small bowel transplantation. He was discharged home after 9 weeks on full oral intake without requiring intravenous nutritional or fluid supplementation. The first episode of mild acute rejection, which occurred 18 months after transplantation, was successfully treated with steroids. An episode of rotavirus gastroenteritis led to severe exfoliative rejection of the bowel graft, which was resistant to steroid and Infliximab treatment but responded to OKT3. There was associated Epstein-Barr virus viremia with no evidence of posttransplant lymphoproliferative disease. Another episode of moderate to severe acute liver rejection occurred 5 months later. At the same time, multiple biliary strictures were diagnosed and treated. Persistent clinical symptoms of abdominal pain and increased stomal output as well as atrophy of the ileal mucosa on several biopsies, suggested the possibility of chronic rejection (CR). A second combined whole liver and small bowel transplant was performed. The diagnosis of CR was confirmed on histology of the explanted graft. The postoperative course was severely complicated and 71 days after the retransplantation, the boy died because of respiratory failure and multiorgan failure. In summary, intestinal transplantation can be successfully performed in children with CIPO, giving them the opportunity to be free from total parenteral nutrition. As survival following intestinal transplantation continues to improve, the problem of CR has become increasingly important and the only treatment available is retransplantation, which is associated with poor outcomes.

  6. Treatment of acute antibody-mediated rejection using bortezomib: a case report.

    PubMed

    Sin, Yong-Hun; Kim, Yong-Jin; Oh, Joon Seok; Lee, Jin Ho; Kim, Seong Min; Kim, Joong Kyung

    2015-07-01

    Here we report the successful treatment of acute antibody-mediated rejection (AMR) with bortezomib. Bortezomib rescue treatment was administered after a 42-year-old woman failed to respond to steroid pulse and plasmapheresis with intravenous immunoglobulin (IVIG). The patient underwent a second renal transplantation with a deceased donor kidney. She was treated pre-operatively with rituximab (200 mg/body) and underwent plasmapheresis twice (day-1 and operation day) because ELISA screening revealed that her pre-operative peak panel reactive antibody (PRA) composition was 100% class I and 100% class II and 15 times of cross-match positive history during the waiting period for transplantation. The patients received induction therapy with Simulect (an IL-2-blocking agent). A 1-hour protocol biopsy revealed C4d-positivity and mild peritubular capillary inflammation. This was suggestive of early AMR-associated changes. After transplantation, the patient underwent plasmaphereses (nine times) with low-dose IVIG (2 mg/kg). Despite this treatment regimen, serum creatinine levels increased to 3.4 mg/dL on post-transplant day 15. A second graft biopsy was performed, which showed overt AMR with glomerulitis, peritubular capillary inflammation and no C4d deposition. On post-operative day (POD) 22, treatment with four doses of bortezomib (1.3 mg/m(2) ) was initiated with the patient's consent. On POD 55, renal function had recovered and serum creatinine was 1.5 mg/dL. In summary, bortezomib was administered as a rescue treatment for a patient who developed AMR that was refractory to a combination of plasmaphereses with low-dose IVIG and preemptive administration of rituximab.

  7. Transfusion Induced Bone Marrow Transplant Rejection Due to Minor Histocompatibility Antigens

    PubMed Central

    Patel, Seema R; Zimring, James C

    2014-01-01

    Traditionally, alloimmunization to transfused blood products has focused exclusively upon recipient antibodies recognizing donor alloantigens present on the cell surface. Accordingly, the immunological sequelae of alloimmunization have been antibody mediated effects (i.e. hemolytic transfusion reactions, platelet refractoriness, anti-HLA and anti-HNA effects, etc.). However, in addition to the above sequelae, there is also a correlation between the number of antecedent transfusions in humans and the rate of bone marrow transplant (BMT) rejection - under reduced intensity conditioning with HLA matched or HLA identical marrow. BMT of this nature is the only existing cure for a series of non-malignant hematological diseases (e.g. sickle cell disease, thalassemias, etc.); however, rejection remains a clinical problem. It has been hypothesized that transfusion induces subsequent BMT rejection through immunization. Studies in animal models have observed the same effect and have demonstrated that transfusion induced BMT rejection can occur in response to alloimmunization. However, unlike traditional antibody responses, sensitization in this case results in cellular immune effects, involving populations such as T cell or NK cells. In this case, rejection occurs in the absence of alloantibodies, and would not be detected by existing immune-hematological methods. We review human and animal studies in light of the hypothesis that, for distinct clinical populations, enhanced rejection of BMT may be an unappreciated adverse consequence of transfusion which current blood bank methodologies are unable to detect. PMID:24090731

  8. Simultaneous diagnosis and gene therapy of immuno-rejection in rat allogeneic heart transplantation model using a T-cell-targeted theranostic nanosystem.

    PubMed

    Guo, Yu; Chen, Wenjie; Wang, Weiwei; Shen, Jun; Guo, Ruomi; Gong, Faming; Lin, Shudong; Cheng, Du; Chen, Guihua; Shuai, Xintao

    2012-12-21

    As the final life-saving treatment option for patients with terminal organ failure, organ transplantation is far from an ideal solution. The concomitant allograft rejection, which is hardly detectable especially in the early acute rejection (AR) period characterized by an intense cellular and humoral attack on donor tissue, greatly affects the graft survival and results in rapid graft loss. Based on a magnetic resonance imaging (MRI)-visible and T-cell-targeted multifunctional polymeric nanocarrier developed in our lab, effective co-delivery of pDNA and superparamagnetic iron oxide nanoparticles into primary T cells expressing CD3 molecular biomarker was confirmed in vitro. In the heart transplanted rat model, this multifunctional nanocarrier showed not only a high efficiency in detecting post-transplantation acute rejection but also a great ability to mediate gene transfection in T cells. Upon intravenous injection of this MRI-visible polyplex of nanocarrier and pDNA, T-cell gathering was detected at the endocardium of the transplanted heart as linear strongly hypointense areas on the MRI T(2)*-weighted images on the third day after cardiac transplantation. Systematic histological and molecular biology studies demonstrated that the immune response in heart transplanted rats was significantly suppressed upon gene therapy using the polyplex bearing the DGKα gene. More excitingly, the therapeutic efficacy was readily monitored by noninvasive MRI during the treatment process. Our results revealed the great potential of the multifunctional nanocarrier as a highly effective imaging tool for real-time and noninvasive monitoring and a powerful nanomedicine platform for gene therapy of AR with high efficiency.

  9. PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection.

    PubMed

    Tanaka, Katsunori; Albin, Monica J; Yuan, Xueli; Yamaura, Kazuhiro; Habicht, Antje; Murayama, Takaya; Grimm, Martin; Waaga, Ana Maria; Ueno, Takuya; Padera, Robert F; Yagita, Hideo; Azuma, Miyuki; Shin, Tahiro; Blazar, Bruce R; Rothstein, David M; Sayegh, Mohamed H; Najafian, Nader

    2007-10-15

    The PD-1:PDL pathway plays an important role in regulating alloimmune responses but its role in transplantation tolerance is unknown. We investigated the role of PD-1:PDL costimulatory pathway in peripheral and a well established model of central transplantation tolerance. Early as well as delayed blockade of PDL1 but not PDL2 abrogated tolerance induced by CTLA4Ig in a fully MHC-mismatched cardiac allograft model. Accelerated rejection was associated with a significant increase in the frequency of IFN-gamma-producing alloreactive T cells and expansion of effector CD8(+) T cells in the periphery, and a decline in the percentage of Foxp3(+) graft infiltrating cells. Similarly, studies using PDL1/L2-deficient recipients confirmed the results with Ab blockade. Interestingly, while PDL1-deficient donor allografts were accepted by wild-type recipients treated with CTLA4Ig, the grafts developed severe chronic rejection and vasculopathy when compared with wild-type grafts. Finally, in a model of central tolerance induced by mixed allogeneic chimerism, engraftment was not abrogated by PDL1/L2 blockade. These novel data demonstrate the critical role of PDL1 for induction and maintenance of peripheral transplantation tolerance by its ability to alter the balance between pathogenic and regulatory T cells. Expression of PDL1 in donor tissue is critical for prevention of in situ graft pathology and chronic rejection.

  10. [Immunosuppressive treatment after kidney transplant: the frontier of chronic antibody-mediated rejection].

    PubMed

    Biancone, Luigi; Lavacca, Antonio; Beltramo, Silvia; Ariaudo, Claudia; Gallo, Ester; Segoloni, Giuseppe Paolo

    2012-01-01

    The recognition of antibody-mediated rejection as an important factor in the reduction of long-term renal graft survival represents a new challenge to the immunosuppressive strategies of recent years, which have been quite successful in reducing the acute rejection rates as well as the side effects of pharmacological immunosuppression. The search for an effective treatment of chronic anti-donor antibody disease has been pursued mostly through limited single-center experiences and therefore in a dispersed fashion, without leading to the definition of a consolidated approach. The most frequently used pharmacological approaches stem from the experience of antibody-mediated acute rejection. In this review we will critically analyze the results reported so far of various intervention strategies and we will discuss future pharmacological novelties targeting the humoral immune response.

  11. Late antibody-mediated rejection by de novo donor HLA-DP-specific antibody after renal transplantation: a case report.

    PubMed

    Cippà, Pietro E; Gaspert, Ariana; Etter, Christoph; Guenduez, Zehra; Ferrari-Lacraz, Sylvie; Rüsi, Barbara; Fehr, Thomas

    2014-05-01

    The role of donor HLA-DP-specific antibodies after renal transplantation is controversial, and only preformed HLA-DP-specific antibodies have been shown to mediate rejection. Here we present a case of late humoral rejection mediated by de novo donor HLA-DP-specific antibodies in a non-sensitized recipient. This unique case demonstrates the pathogenic role of de novo anti-DP antibodies and suggests that HLA-DP matching might be relevant for renal transplantation.

  12. Acute Rejection Phenotypes in the Current Era of Immunosuppression: A Single-Center Analysis

    PubMed Central

    Wehmeier, Caroline; Amico, Patrizia; Hirt-Minkowski, Patricia; Georgalis, Argyrios; Höenger, Gideon; Menter, Thomas; Mihatsch, Michael; Burkhalter, Felix; Steiger, Juerg; Dickenmann, Michael; Hopfer, Helmut; Schaub, Stefan

    2017-01-01

    Background Besides ‘definitive rejection’, the Banff classification includes categories for ‘suspicious for rejection’ phenotypes. The aim of this study was to determine the frequency and phenotypes of rejection episodes in 316 consecutive renal transplants from 2009 to 2014 grouped into patients without/with pretransplant HLA-DSA (ptDSAneg, n = 251; ptDSApos, n = 65). Methods All adequate indication (n = 125) and surveillance biopsies (n = 538) performed within the first year posttransplant were classified according to the current Banff criteria. Results ‘Suspicious for rejection’ phenotypes were 3 times more common than ‘definitive rejection’ phenotypes in biopsies from ptDSAneg patients (35% vs 11%) and equally common in biopsies from ptDSApos patients (25% vs 27%). In both groups, ‘suspicious for rejection’ phenotypes were more frequent in surveillance than in indication biopsies (28% vs 16% in ptDSAneg patients, and 37% vs 29% in ptDSApos patients). ‘Borderline changes: ‘Suspicious' for acute T-cell mediated rejection’ (91%) were the dominant ‘suspicious for rejection’ phenotype in ptDSAneg patients, whereas ‘borderline changes’ (58%) and ‘suspicious for acute/active antibody-mediated rejection’ (42%) were equally frequent in biopsies from ptDSApos patients. Inclusion of ‘suspicious for rejection’ phenotypes increased the 1-year incidence of clinical (ptDSAneg patients: 18% vs 8%, P = 0.0005; ptDSApos patients: 24% vs 18%, P = 0.31) and (sub)clinical rejection (ptDSAneg patients: 59% vs 22%, P < 0.0001; ptDSApos patients: 68% vs 40%, P = 0.004). Conclusions ‘Suspicious for rejection’ phenotypes are very common in the current era and outnumber the frequency of ‘definitive rejection’ within the first year posttransplant. PMID:28361120

  13. Biological mechanism analysis of acute renal allograft rejection: integrated of mRNA and microRNA expression profiles

    PubMed Central

    Huang, Shi-Ming; Zhao, Xia; Zhao, Xue-Mei; Wang, Xiao-Ying; Li, Shan-Shan; Zhu, Yu-Hui

    2014-01-01

    Objectives: Renal transplantation is the preferred method for most patients with end-stage renal disease, however, acute renal allograft rejection is still a major risk factor for recipients leading to renal injury. To improve the early diagnosis and treatment of acute rejection, study on the molecular mechanism of it is urgent. Methods: MicroRNA (miRNA) expression profile and mRNA expression profile of acute renal allograft rejection and well-functioning allograft downloaded from ArrayExpress database were applied to identify differentially expressed (DE) miRNAs and DE mRNAs. DE miRNAs targets were predicted by combining five algorithm. By overlapping the DE mRNAs and DE miRNAs targets, common genes were obtained. Differentially co-expressed genes (DCGs) were identified by differential co-expression profile (DCp) and differential co-expression enrichment (DCe) methods in Differentially Co-expressed Genes and Links (DCGL) package. Then, co-expression network of DCGs and the cluster analysis were performed. Functional enrichment analysis for DCGs was undergone. Results: A total of 1270 miRNA targets were predicted and 698 DE mRNAs were obtained. While overlapping miRNA targets and DE mRNAs, 59 common genes were gained. We obtained 103 DCGs and 5 transcription factors (TFs) based on regulatory impact factors (RIF), then built the regulation network of miRNA targets and DE mRNAs. By clustering the co-expression network, 5 modules were obtained. Thereinto, module 1 had the highest degree and module 2 showed the most number of DCGs and common genes. TF CEBPB and several common genes, such as RXRA, BASP1 and AKAP10, were mapped on the co-expression network. C1R showed the highest degree in the network. These genes might be associated with human acute renal allograft rejection. Conclusions: We conducted biological analysis on integration of DE mRNA and DE miRNA in acute renal allograft rejection, displayed gene expression patterns and screened out genes and TFs that may

  14. European Transplant Registry of Senior Renal Transplant Recipients on Advagraf

    ClinicalTrials.gov

    2016-08-11

    Graft Failure; Death; Acute Rejection of Renal Transplant; Infections; Bone Disease; Post Transplant Diabetes Mellitus; Quality of Life; HLA Antibody Production; Cardiovascular Risk Factors; Non-HLA Antibody Production

  15. Tacrolimus in preventing transplant rejection in Chinese patients – optimizing use

    PubMed Central

    Li, Chuan-Jiang; Li, Liang

    2015-01-01

    Tacrolimus is a product of fermentation of Streptomyces, and belongs to the family of calcineurin inhibitors. It is a widely used immunosuppressive drug for preventing solid-organ transplant rejection. Compared to cyclosporine, tacrolimus has greater immunosuppressive potency and a lower incidence of side effects. It has been accepted as first-line treatment after liver and kidney transplantation. Tacrolimus has specific features in Chinese transplant patients; its in vivo pharmacokinetics, treatment regimen, dose and administration, and adverse-effect profile are influenced by multiple factors, such as genetics and the spectrum of primary diseases in the Chinese population. We reviewed the clinical experience of tacrolimus use in Chinese liver- and kidney-transplant patients, including the pharmacology of tacrolimus, the immunosuppressive effects of tacrolimus versus cyclosporine, effects of different factors on tacrolimus metabolism on Chinese patients, personalized medicine, clinical safety profile, and patient satisfaction and adherence. This article provides guidance for the rational and efficient use of tacrolimus in Chinese organ-transplant patients. PMID:25609922

  16. Transplant rejection

    MedlinePlus

    ... Fleisher TA, Shearer WT, et al, eds. Clinical Immunology. 4th ed. Philadelphia, PA: Elsevier; 2013:chap 81. Read More Graft-versus-host disease Immune response Transfusion reaction - hemolytic Review Date 4/30/2015 Updated by: Laura J. ...

  17. 75 FR 32490 - Issues in the Development of Medical Products for the Prophylaxis and/or Treatment of Acute...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-08

    ... Prophylaxis and/or Treatment of Acute Antibody Mediated Rejection in Kidney Transplant Recipients; Public... prophylaxis and/or treatment of acute antibody mediated rejection (AMR) in kidney transplant recipients....

  18. Intravenous mesenchymal stem cells prevented rejection of allogeneic corneal transplants by aborting the early inflammatory response.

    PubMed

    Oh, Joo Youn; Lee, Ryang Hwa; Yu, Ji Min; Ko, Jung Hwa; Lee, Hyun Ju; Ko, Ah Young; Roddy, Gavin W; Prockop, Darwin J

    2012-11-01

    Mesenchymal stem/progenitor cells (MSCs) were reported to enhance the survival of cellular and organ transplants. However, their mode of action was not established. We here used a mouse model of corneal allotransplantation and demonstrated that peri-transplant intravenous (i.v.) infusion of human MSCs (hMSCs) decreased the early surgically induced inflammation and reduced the activation of antigen-presenting cells (APCs) in the cornea and draining lymph nodes (DLNs). Subsequently, immune rejection was decreased, and allograft survival was prolonged. Quantitative assays for human GAPDH revealed that <10 hMSCs out of 1 × 10(6) injected cells were recovered in the cornea 10 hours to 28 days after i.v. infusion. Most of hMSCs were trapped in lungs where they were activated to increase expression of the gene for a multifunctional anti-inflammatory protein tumor necrosis factor-α stimulated gene/protein 6 (TSG-6). i.v. hMSCs with a knockdown of TSG-6 did not suppress the early inflammation and failed to prolong the allograft survival. Also, i.v. infusion of recombinant TSG-6 reproduced the effects of hMSCs. Results suggest that hMSCs improve the survival of corneal allografts without engraftment and primarily by secreting TSG-6 that acts by aborting early inflammatory responses. The same mechanism may explain previous reports that MSCs decrease rejection of other organ transplants.

  19. Minor histocompatibility antigens on transfused leukoreduced units of red blood cells induce bone marrow transplant rejection in a mouse model.

    PubMed

    Desmarets, Maxime; Cadwell, Chantel M; Peterson, Kenneth R; Neades, Renee; Zimring, James C

    2009-09-10

    When successful, human leukocyte antigen (HLA)-matched bone marrow transplantation with reduced-intensity conditioning is a cure for several nonmalignant hematologic disorders that require chronic transfusion, such as sickle cell disease and aplastic anemia. However, there are unusually high bone marrow transplant (BMT) rejection rates in these patients. Rejection correlates with the number of transfusions before bone marrow transplantation, and it has been hypothesized that preimmunization to antigens on transfused blood may prime BMT rejection. Using a novel mouse model of red blood cell (RBC) transfusion and major histocompatibility complex-matched bone marrow transplantation, we report that transfusion of RBC products induced BMT rejection across minor histocompatibility antigen (mHA) barriers. It has been proposed that contaminating leukocytes are responsible for transfusion-induced BMT rejection; however, filter leukoreduction did not prevent rejection in the current studies. Moreover, we generated a novel transgenic mouse with RBC-specific expression of a model mHA and demonstrated that transfusion of RBCs induced a CD8(+) T-cell response. Together, these data suggest that mHAs on RBCs themselves are capable of inducing BMT rejection. Cellular immunization to mHAs is neither monitored nor managed by current transfusion medicine practice; however, the current data suggest that mHAs on RBCs may represent an unappreciated and significant consequence of RBC transfusion.

  20. Successful Treatment of Plasma Cell-Rich Acute Rejection Using Pulse Steroid Therapy Alone: A Case Report

    PubMed Central

    Nakada, Yasuyuki; Yamamoto, Izumi; Kawabe, Mayuko; Yamakawa, Takafumi; Katsuma, Ai; Katsumata, Haruki; Mafune, Aki; Kobayashi, Akimitsu; Koike, Yusuke; Yamada, Hiroki; Miki, Jun; Tanno, Yudo; Ohkido, Ichiro; Tsuboi, Nobuo; Yokoyama, Keitaro; Yamamoto, Hiroyasu; Yokoo, Takashi

    2017-01-01

    Despite the recent development of immunosuppressive agents, plasma cell-rich acute rejection (PCAR) has remained refractory to treatment. Herein, we report an unusual case of PCAR that responded well to pulse steroid therapy alone. A 47-year-old man was admitted for a protocol biopsy three months after kidney transplantation, with a stable serum creatinine level of 1.6 mg/dL. Histological examination showed focal aggressive tubulointerstitial inflammatory cell infiltration of predominantly polyclonal mature plasma cells, leading to our diagnosis of PCAR. Three months following three consecutive days of high-dose methylprednisolone (mPSL) therapy, an allograft biopsy performed for therapy evaluation showed persistent PCAR. We readministered mPSL therapy and successfully resolved the PCAR. Although PCAR generally develops more than six months after transplantation, we diagnosed this case early, at three months after transplantation, with focally infiltrated PCAR. This case demonstrates the importance of early diagnosis and prompt treatment of PCAR to manage the development and severity of allograft rejection. PMID:28168079

  1. The Perfect Storm: HLA Antibodies, Complement, FcγRs and Endothelium in Transplant Rejection

    PubMed Central

    Thomas, Kimberly A.; Valenzuela, Nicole M.; Reed, Elaine F.

    2015-01-01

    The pathophysiology of antibody-mediated rejection (AMR) in solid organ transplants is multi-faceted and predominantly caused by antibodies directed against polymorphic donor human leukocyte antigens (HLA). Despite the clearly detrimental impact of HLA antibodies (HLA-Ab) on graft function and survival, the prevention, diagnosis and treatment of AMR remain a challenge. Histological manifestations of AMR reflect signatures of HLA-Ab-triggered injury, specifically endothelial changes, recipient leukocytic infiltrate, and complement deposition. We review the interconnected mechanisms of HLA-Ab-mediated injury that might synergize in a “perfect storm” of inflammation. Characterization of antibody features that are critical for effector functions may help identify HLA-Ab more likely to cause rejection. We also highlight recent advancements that may pave the way for new, more effective therapeutics. PMID:25801125

  2. Asymptomatic Antibody-mediated Rejection After Heart Transplantation Predicts Poor Outcomes

    PubMed Central

    Wu, Grace W.; Kobashigawa, Jon A.; Fishbein, Michael C.; Patel, Jignesh K.; Kittleson, Michelle M.; Reed, Elaine F.; Kiyosaki, Krista K.; Ardehali, Abbas

    2013-01-01

    Background Antibody-mediated rejection (AMR) has been associated with poor outcome after heart transplantation. The diagnosis of AMR usually includes endomyocardial biopsy findings of endothelial cell swelling, intravascular macrophages, C4d+ staining, and associated left ventricular dysfunction. The significance of AMR findings in biopsy specimens of asymptomatic heart transplant patients (normal cardiac function and no symptoms of heart failure) is unclear. Methods Between July 1997 and September 2001, AMR was found in the biopsy specimens of 43 patients. Patients were divided into 2 groups: asymptomatic AMR (AsAMR, n = 21) and treated AMR (TxAMR with associated left ventricular dysfunction, n = 22). For comparison, a control group of 86 contemporaneous patients, without AMR, was matched for age, gender, and time from transplant. Outcomes included 5-year actuarial survival and development of cardiac allograft vasculopathy (CAV). Patients were considered to have AMR if they had ≥ 1 endomyocardial biopsy specimen positive for AMR. Results The 5-year actuarial survival for the AsAMR (86%), TxAMR (68%), and control groups (79%) was not significantly different (p = 0.41). Five-year freedom from CAV (≥ 30% stenosis in any vessel) was AsAMR, 52%; TxAMR, 68%; and control, 79%. Individually, freedom from CAV was significantly lower in the AsAMR group compared with the control group (p = 0.02). There was no significant difference between AsAMR vs TxAMR and TxAMR vs control for CAV. Conclusions Despite comparable 5-year survival with controls after heart transplantation, AsAMR rejection is associated with a greater risk of CAV. Trials to treat AsAMR to alter outcome are warranted. PMID:19416767

  3. Atypical HUS associated with severe, unexpected antibody-mediated rejection post kidney transplant.

    PubMed

    Stevenson, Sarah; Mallett, Andrew; Oliver, Kimberley; Hyland, Valentine; Hawley, Carmel; Malmanche, Theo; Isbel, Nicole

    2014-04-01

    We present a case of an unsensitized patient with end-stage kidney disease secondary to atypical haemolytic uremic syndrome (aHUS) with mutations in CD46/MCP and CFH who developed severe, intractable antibody-mediated rejection (ABMR) unresponsive to therapy post kidney transplantation. There were no haematological features of thrombotic microangiopathy. The patient received standard induction therapy and after an initial fall in serum creatinine, severe ABMR developed in the setting of urosepsis. Despite maximal therapy with thymoglobulin, plasma exchange and methylprednisolone, rapid graft loss resulted and transplant nephrectomy was performed. Luminex at 4 weeks showed a new DSA and when repeated after nephrectomy showed antibodies to each of the 5 mismatched antigens with high MFI. The rate of recurrence of disease in patients with aHUS referred for transplantation is 50% and is associated with a high rate of graft loss. It is dependent in part on the nature of the mutation with circulating factors CFH and CFI more likely to cause recurrent disease than MCP which is highly expressed in the kidney. There is increasing interest in the role of complement in the development and propagation of ABMR via terminal complement activation. This case suggesting that dysregulation of the alternative complement pathway within the transplant kidney may have contributed to the severe AMR. Very little is known about the impact of complement dysregulation and the development of anti HLA antibodies however the strength of HLA antibody formation was prominent in this case.

  4. Chronic transplantation immunity in newts: temperature susceptibility of an effector phase in allo-skin graft rejection.

    PubMed

    Kinefuchi, Kenjiroh; Kushida, Yoshihiro; Johnouchi, Masato; Shimizu, Yuiko; Ohneda, Hikaru; Fujii, Masato; Hosono, Masamichi

    2011-07-01

    Urodele amphibians are unique due to their greatly reduced immune responsiveness compared to bony fishes, which show acute immune responsiveness. In newts, the mean survival time of allogenic skin grafts in the transplantation immunity was 48.8 ± 8.3 days at 25°C, suggesting that it occurs in a chronic manner. The graft rejection process was categorized into three stages: a latent stage with frequent blood circulation, or the immune induction phase; a vascular stoppage stage with dominant infiltrating cells of T cells; and a rejection stage showing the change of the dominant cells to monocytes/macrophages, probably as effector cells, tetntatively referred to as the immune effector phase. The immune induction phase is susceptible to the cyclophosphamide (CY) mitosis inhibitor, but not to a temperature shift from 18 to 27°C, while the immune effector phase is susceptible to temperature shifts, but not CY-treatment, although the temperature shift failed to shorten the graft survival time to less than 25 days, which nearly equals that of the secondary set of grafts where the lack of complete blood circulation is remarkable and graft rejection is resistant to CY-treatment. In contrast, a very low temperature (5-10°C) completely prevented effector generation in newts; in frogs, however, it is reported that such low temperatures did not prevent the generation of effectors. Taken together, these data suggest that chronic responses in newts are due to effector cells other than cytotoxic T cells; possible effector cells are discussed.

  5. Acute oxalate nephropathy following kidney transplantation: Report of three cases

    PubMed Central

    Taheri, Diana; Gheissari, Alaleh; Shaabani, Pooria; Tabibian, Seyed Reza; Mortazavi, Mojgan; Seirafian, Shiva; Merrikhi, Alireza; Fesharakizadeh, Mehdi; Dolatkhah, Shahaboddin

    2015-01-01

    Calcium oxalate (CaOx) crystal deposition is a common finding immediately after kidney transplantation. However, small depositions of CaOx could be benign while extensive depositions lead to poor graft outcome. Here we report three cases with end-stage renal disease (ESRD), bilateral nephrolithiasis, and unknown diagnosis of primary hyperoxaluria (PH) who underwent a renal transplant and experienced an early-onset graft failure. Although an acute rejection was suspected, renal allograft biopsies and subsequent allograft nephrectomies showed extensive CaOx deposition, which raised a suspicion of PH. Even though increased urinary excretion of CaOx was found in all patients, this diagnosis could be confirmed with further tests including genetic study and metabolic assay. In conclusion, massive CaOx deposition in kidney allograft is an important cause of poor allograft survival and needs special management. Furthermore, our cases suggest patients with ESRD and a history of nephrolithiasis should be screened for elevated urinary oxalate excretion and rule out of PH. PMID:26664431

  6. Antibody-mediated rejection in pediatric kidney transplantation: pathophysiology, diagnosis, and management.

    PubMed

    Ng, Yolanda W; Singh, Manpreet; Sarwal, Minnie M

    2015-04-01

    Kidney transplant is the preferred treatment of pediatric end-stage renal disease. One of the most challenging aspects of pediatric kidney transplant is the prevention and treatment of antibody-mediated rejection (ABMR), which is one of the main causes of graft dysfunction and early graft loss. Most challenges are similar to those faced in adult kidney transplants; however, factors unique to the pediatric realm include naivety of the immune system and the small number of studies and randomized controlled trials available when considering pharmacological treatment options. Here, we present a case of ABMR in a pediatric patient and a review of the pathophysiology, diagnosis, and management of ABMR. ABMR in pediatric kidney transplant continues to be a frustrating condition to treat because (1) there still remain many unidentified potential antigens leading to ABMR, (2) children and adults are at different stages of their immune system development, and, thus, (3) the full pathophysiology of alloimmunity is still not completely understood, and (4) the efficacy and safety of treatment in adults may not be directly translated to children. As we continue to gain a better understanding towards the precise alloimmune mechanism that drives a particular ABMR, we can also improve pharmacotherapeutic choices. With continued research, they will become more precise in treating a particular mechanism versus using a broad scope of immunosuppression such as steroids. However, there is much more to be uncovered, such as identifying more non-human leukocyte antigens and their role in alloimmunity, determining the exact mechanism of adults achieving complete operational tolerance, and understanding the difference between pediatric and adult transplant recipients. Making strides towards a better understanding of these mechanisms will lead to continued efficacy and safety in treatment of pediatric ABMR.

  7. Maximum entropy, fractal dimension and lacunarity in quantification of cellular rejection in myocardial biopsy of patients submitted to heart transplantation

    NASA Astrophysics Data System (ADS)

    Neves, L. A.; Oliveira, F. R.; Peres, F. A.; Moreira, R. D.; Moriel, A. R.; de Godoy, M. F.; Murta Junior, L. O.

    2011-03-01

    This paper presents a method for the quantification of cellular rejection in endomyocardial biopsies of patients submitted to heart transplant. The model is based on automatic multilevel thresholding, which employs histogram quantification techniques, histogram slope percentage analysis and the calculation of maximum entropy. The structures were quantified with the aid of the multi-scale fractal dimension and lacunarity for the identification of behavior patterns in myocardial cellular rejection in order to determine the most adequate treatment for each case.

  8. Detection of Donor-Derived Microparticles in the Peripheral Blood of a Hand Transplant Recipient During Rejection

    PubMed Central

    Kim, Joseph Y.; Kelesidis, Theodoros; Yang, Otto O.

    2017-01-01

    Background Microparticles (MPs) are released from the plasma membrane of activated or dying cells and bear surface molecules from those cells. We examined whether donor-derived MPs in the peripheral blood of the recipient could serve as a marker of tissue damage due to rejection of a transplanted hand. Methods Platelet-free plasma from the recipient of the transplanted hand was analyzed for MPs bearing the donor-specific HLA molecule A*02 using flow cytometry. Rejection status of the transplanted hand was monitored by histopathology of skin punch biopsies. Results Donor-specific MPs expressing HLA A*02 were quantifiable in the peripheral blood of the recipient. Levels of these MPs increased with worsening rejection of the transplanted hand. Conclusions These findings demonstrate the ability to detect donor specific MPs through staining of graft cell-specific HLA and promote further investigation into the potential utility of flow cytometry for donor-derived MPs as a noninvasive tool to assess rejection in solid organ transplantation patients.

  9. Identification of microRNAs involved in acute rejection and spontaneous tolerance in murine hepatic allografts

    PubMed Central

    Morita, Miwa; Chen, Jiajie; Fujino, Masayuki; Kitazawa, Yusuke; Sugioka, Atsushi; Zhong, Liang; Li, Xiao-Kang

    2014-01-01

    Graft acceptance without the need for immunosuppressive drugs is the ultimate goal of transplantation therapy. In murine liver transplantation, allografts are accepted across major histocompatibility antigen complex barriers without the use of immunosuppressive drugs and constitute a suitable model for research on immunological rejection and tolerance. MicroRNA (miRNA) has been known to be involved in the immunological responses. In order to identify mRNAs in spontaneous liver allograft tolerance, miRNA expression in hepatic allografts was examined using this transplantation model. According to the graft pathological score and function, miR-146a, 15b, 223, 23a, 27a, 34a and 451 were upregulated compared with the expression observed in the syngeneic grafts. In contrast, miR-101a, 101b and 148a were downregulated. Our results demonstrated the alteration of miRNAs in the allografts and may indicate the role of miRNAs in the induction of tolerance after transplantation. Furthermore, our data suggest that monitoring the graft expression of novel miRNAs may allow clinicians to differentiate between rejection and tolerance. A better understanding of the tolerance inducing mechanism observed in murine hepatic allografts may provide a therapeutic strategy for attenuating allograft rejection. PMID:25323448

  10. Microarray diagnosis of antibody-mediated rejection in kidney transplant biopsies: an international prospective study (INTERCOM).

    PubMed

    Halloran, P F; Pereira, A B; Chang, J; Matas, A; Picton, M; De Freitas, D; Bromberg, J; Serón, D; Sellarés, J; Einecke, G; Reeve, J

    2013-11-01

    In a reference set of 403 kidney transplant biopsies, we recently developed a microarray-based test that diagnoses antibody-mediated rejection (ABMR) by assigning an ABMR score. To validate the ABMR score and assess its potential impact on practice, we performed the present prospective INTERCOM study (clinicaltrials.gov NCT01299168) in 300 new biopsies (264 patients) from six centers: Baltimore, Barcelona, Edmonton, Hannover, Manchester and Minneapolis. We assigned ABMR scores using the classifier created in the reference set and compared it to conventional assessment as documented in the pathology reports. INTERCOM documented uncertainty in conventional assessment: In 41% of biopsies where ABMR features were noted, the recorded diagnoses did not mention ABMR. The ABMR score correlated with ABMR histologic lesions and donor-specific antibodies, but not with T cell-mediated rejection lesions. The agreement between ABMR scores and conventional assessment was identical to that in the reference set (accuracy 85%). The ABMR score was more strongly associated with failure than conventional assessment, and when the ABMR score and conventional assessment disagreed, only the ABMR score was associated with early progression to failure. INTERCOM confirms the need to reduce uncertainty in the diagnosis of ABMR, and demonstrates the potential of the ABMR score to impact practice.

  11. Expanding the antibody-mediated component of plasma cell-rich acute rejection: A case series

    PubMed Central

    Uppin, M. S.; Gudithi, S.; Taduri, G.; Prayaga, A. K.; Raju, S. B.

    2016-01-01

    Renal allograft rejection is mediated by T-cells (T-cell mediated rejection) or by donor-specific antibodies (DSAs) (antibody mediated rejection, ABMR). Plasma cell-rich acute rejection (PCAR) is a unique entity due to its peculiar morphology and poor prognostic behavior. All allograft biopsies done at our center from January 2013 to October 2014 were reviewed, and seven were identified with a diagnosis of PCAR with antibody mediated rejection (ABMR). The allograft biopsies were classified as per the Banff 2007 schema. Immunohistochemistry with C4d, SV 40, CD3, CD20, CD138, kappa and lambda light chain was performed. Total 210 allograft biopsies were performed in the study period of which seven biopsies (3.3%) were diagnosed as PCAR with ABMR. All these were late ABMRs (more than 6 months) with median posttransplant duration of 17 months. The allograft biopsy showed features of PCAR along with glomerulitis, peritubular capillaritis, and positive C4d. DSA was positive in six patients. All the patients were treated with standard therapeutic measures of acute cellular rejection (ACR) and ABMR including steroids, plasma exchange, rituximab and intravenous immunoglobulins. All the patients had persistent graft dysfunction or graft loss on follow-up. PMID:27194831

  12. Endothelial Cells in Antibody-Mediated Rejection of Kidney Transplantation: Pathogenesis Mechanisms and Therapeutic Implications

    PubMed Central

    Wang, Shuo; Wang, Jina; Yang, Cheng; Xu, Ming

    2017-01-01

    Antibody-mediated rejection (AMR) has been identified as a main obstacle for stable immune tolerance and long survival of kidney allografts. In spite of new insights into the underlying mechanisms of AMR, accurate diagnosis and efficient treatment are still challenges in clinical practice. Endothelium is the first barrier between recipients' immune systems and grafts in vascularized organ transplants. Considering that endothelial cells express a number of antigens that can be attacked by various allo- and autoantibodies, endothelial cells act as main targets for the recipients' humoral immune responses. Importantly, emerging evidence has shown that endothelial cells in transplants could also initiate protective mechanisms in response to immune injuries. A better understanding of the role of endothelial cells during the pathogenesis of AMR might provide novel therapeutic targets. In the present review, we summarize the antigens expressed by endothelial cells and also discuss the activation and accommodation of endothelial cells as well as their clinical implications. Collectively, the progress discussed in this review indicates endothelial cells as promising targets to improve current diagnosis and therapeutic regimens for AMR. PMID:28255564

  13. Endothelial Cells in Antibody-Mediated Rejection of Kidney Transplantation: Pathogenesis Mechanisms and Therapeutic Implications.

    PubMed

    Wang, Shuo; Zhang, Chao; Wang, Jina; Yang, Cheng; Xu, Ming; Rong, Ruiming; Zhu, Tongyu; Zhu, Dong

    2017-01-01

    Antibody-mediated rejection (AMR) has been identified as a main obstacle for stable immune tolerance and long survival of kidney allografts. In spite of new insights into the underlying mechanisms of AMR, accurate diagnosis and efficient treatment are still challenges in clinical practice. Endothelium is the first barrier between recipients' immune systems and grafts in vascularized organ transplants. Considering that endothelial cells express a number of antigens that can be attacked by various allo- and autoantibodies, endothelial cells act as main targets for the recipients' humoral immune responses. Importantly, emerging evidence has shown that endothelial cells in transplants could also initiate protective mechanisms in response to immune injuries. A better understanding of the role of endothelial cells during the pathogenesis of AMR might provide novel therapeutic targets. In the present review, we summarize the antigens expressed by endothelial cells and also discuss the activation and accommodation of endothelial cells as well as their clinical implications. Collectively, the progress discussed in this review indicates endothelial cells as promising targets to improve current diagnosis and therapeutic regimens for AMR.

  14. Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic transplantation therapy of leukemia and lymphoma.

    PubMed

    Fowler, D H; Gress, R E

    2000-07-01

    Allogeneic stem cell transplantation (SCT) represents a curative treatment option for patients with leukemia and lymphoma. T lymphocytes contained in the allograft mediate a graft-versus-leukemia (GVL) effect and prevent graft rejection; however, T cells also initiate graft-versus-host disease (GVHD). Identification of T cell populations which mediate a GVL effect and prevent rejection with reduced GVHD will likely improve transplantation outcome. T cells exist in four functionally-defined populations, the CD4+, Th1/Th2 and CD8+, Tc1/Tc2 subsets. Th1-type CD4 cells primarily secrete type I cytokines (IL-2 and IFN-gamma), whereas Th2 cells secrete type II cytokines (IL-4, IL-5, and IL-10). Similarly, the CD8+ Tc1 and Tc2 cells differentially secrete the type I and type II cytokines, respectively. In addition to cytokine secretion, Tc1 and Tc2 populations mediate cytolytic effects, with Tc1 cells utilizing both perforin- and fas-based killing pathways, whereas Tc2 cells primarily utilize perforin-mediated cytolysis. In murine transplantation models of graft rejection, GVHD, and GVL effects, we have evaluated such functional T cell subsets for their ability to differentially mediate and regulate transplantation responses. These studies demonstrate that donor Th2 cells do not initiate acute GVHD, and can regulate the GVHD mediated by unmanipulated donor T cells without impairing alloengraftment. Additional experiments have shown that allospecific donor Tc2 cells result in reduced GVHD, and mediate a significant GVL effect. Thirdly, we have demonstrated that non-host reactive Tc2 cells with veto-like activity can potently abrogate marrow rejection independent of GVHD. Together, these results demonstrate that functionally-defined donor Th2 and Tc2 populations play an important role in the regulation of GVHD, the prevention of graft rejection, and the mediation of GVL effects, and suggest that utilization of Th2 and Tc2 cells in clinical allogeneic SCT may have potential

  15. Quantitative Evaluation of Acute Renal Transplant Dysfunction with Low-Dose Three-dimensional MR Renography

    PubMed Central

    Zhang, Jeff L.; Rusinek, Henry; Chandarana, Hersh; Vivier, Pierre-Hugues; Babb, James S.; Diflo, Thomas; John, Devon G.; Benstein, Judith A.; Barisoni, Laura; Stoffel, David R.; Lee, Vivian S.

    2011-01-01

    Purpose: To assess prospectively the ability of quantitative low-dose three-dimensional magnetic resonance (MR) renography to help identify the cause of acute graft dysfunction. Materials and Methods: This HIPAA-compliant study was approved by the institutional review board, and written informed consent was obtained. Between December 2001 and May 2009, sixty patients with transplanted kidneys (41 men and 19 women; mean age, 49 years; age range, 22–71 years) were included. Thirty-one patients had normal function and 29 had acute dysfunction due to acute rejection (n = 12), acute tubular necrosis (ATN) (n = 8), chronic rejection (n = 6), or drug toxicity (n = 3). MR renography was performed at 1.5 T with three-dimensional gradient-echo imaging. With use of a multicompartment renal model, the glomerular filtration rate (GFR) and the mean transit time (MTT) of the tracer for the vascular compartment (MTTA), the tubular compartment (MTTT), and the collecting system compartment (MTTC) were calculated. Also derived was MTT for the whole kidney (MTTK = MTTA + MTTT + MTTC) and fractional MTT of each compartment (MTTA/K = MTTA/MTTK, MTTT/K = MTTT/MTTK, MTTC/K = MTTC/MTTK). These parameters were compared in patients in the different study groups. Statistical analysis was performed by using analysis of covariance. Results: There were significant differences in GFR and MTTK between the acute dysfunction group (36.4 mL/min ± 20.8 [standard deviation] and 177.1 seconds ± 46.8, respectively) and the normal function group (65.9 mL/min ± 27.6 and 140.5 seconds ± 51.8, respectively) (P < .001 and P = .004). The MTTA/K was significantly higher in the acute rejection group (mean, 12.7% ± 2.9) than in the normal function group (mean, 8.3% ± 2.2; P < .001) or in the ATN group (mean, 7.1% ± 1.4; P < .001). The MTTT/K was significantly higher in the ATN group (mean, 83.2% ± 9.2) than in the normal function group (mean, 72.4% ± 10.2; P = .031) or in the acute rejection group

  16. A type I interferon signature characterizes chronic antibody-mediated rejection in kidney transplantation.

    PubMed

    Rascio, Federica; Pontrelli, Paola; Accetturo, Matteo; Oranger, Annarita; Gigante, Margherita; Castellano, Giuseppe; Gigante, Maddalena; Zito, Anna; Zaza, Gianluigi; Lupo, Antonio; Ranieri, Elena; Stallone, Giovanni; Gesualdo, Loreto; Grandaliano, Giuseppe

    2015-09-01

    Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss. To uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of peripheral blood mononuclear cells (PBMCs) and, separately, of CD4(+) T lymphocytes isolated from CAMR patients, compared to kidney transplant recipients with normal graft function and histology. We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls), and 8 transplant recipients with clinical and histological evidence of interstitial fibrosis/tubular atrophy. Messenger RNA and microRNA profiling of PBMCs and CD4(+) T lymphocytes was performed using Agilent microarrays in eight randomly selected patients per group from CAMR and control subjects. Results were evaluated statistically and by functional pathway analysis (Ingenuity Pathway Analysis) and validated in the remaining subjects. In PBMCs, 45 genes were differentially expressed between the two groups, most of which were up-regulated in CAMR and were involved in type I interferon signalling. In the same patients, 16 microRNAs were down-regulated in CAMR subjects compared to controls: four were predicted modulators of six mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signalling. To further confirm this result, we investigated the transcriptomic profiles of CD4(+) T lymphocytes in an independent group of patients, observing that the activation of type I interferon signalling was a specific hallmark of CAMR. In addition, in CAMR patients, we detected a reduction of circulating BDCA2(+) dendritic cells, the natural type I interferon-producing cells, and their recruitment into the graft along with increased expression of MXA, a type I interferon-induced protein, at the tubulointerstitial and vascular level. Finally, interferon alpha mRNA expression was significantly increased in CAMR compared to control

  17. Thiopurine methyltransferase activity and its relationship to the occurrence of rejection episodes in paediatric renal transplant recipients treated with azathioprine

    PubMed Central

    Dervieux, T; Médard, Y; Baudouin, V; Maisin, A; Zhang, D; Broly, F; Loirat, C; Jacqz-Aigrain, E

    1999-01-01

    Aims Azathioprine is a prodrug commonly used in combination therapy to prevent allograft rejection after renal transplantation. After conversion to 6-mercaptopurine, the drug is metabolized into 6-thioguanine nucleotides (6-TGN) and catabolized by thiopurine methyltransferase (TPMT), an enzyme under monogenic control. The aim of this study was to evaluate the inter- and intraindividual variability of red blood cell thiopurine methyltransferase and 6-TGN concentrations and their relationship to the clinical effects of azathioprine in paediatric patients. Methods In the present study, the interand intraindividual variations in red blood cell TPMT activity and 6-TGN concentrations and their relationship to the actions of azathioprine were evaluated during the first year after renal transplantation in 22 paediatric patients. Results 6-TGN concentration reached steady-state values after 6 months and correlated negatively with TPMT activity (P=0.004). Initial TPMT activity (median: 20.8 nmol h−1 ml−1, range 7.8–34.6) and 6-TGN concentration at steady-state (median: 80 pmol 8×108–1 cells, range not detected to 366) were not related to the occurrence of rejection episodes during the period of the study. In contrast, TPMT activity and the percentage difference in TPMT activity from the day of transplantation determined at month 1 were higher in the patients with rejection episodes by comparison with those that did not reject during the first 3 months or the first year following transplantation (P<0.005). Conclusions We report a relationship between TPMT activity and occurrence of rejection in paediatric kidney transplant patients undergoing azathioprine therapy. These data suggest a link between high red blood cell TPMT activity and poor clinical outcome probably caused by rapid azathioprine catabolism. PMID:10594482

  18. Endothelial induction of fgl2 contributes to thrombosis during acute vascular xenograft rejection.

    PubMed

    Ghanekar, Anand; Mendicino, Michael; Liu, Hao; He, Wei; Liu, Mingfeng; Zhong, Robert; Phillips, M James; Levy, Gary A; Grant, David R

    2004-05-01

    Thrombosis is a prominent feature of acute vascular rejection (AVR), the current barrier to survival of pig-to-primate xenografts. Fibrinogen-like protein 2 (fgl2/fibroleukin) is an inducible prothrombinase that plays an important role in the pathogenesis of fibrin deposition during viral hepatitis and cytokine-induced fetal loss. We hypothesized that induction of fgl2 on the vascular endothelium of xenografts contributes to thrombosis associated with AVR. We first examined fgl2 as a source of procoagulant activity in the pig-to-primate combination. The porcine fgl2 (pfgl2) was cloned and its chromosomal locus was identified. Recombinant pfgl2 protein expressed in vitro was detected on the cell surface and generated thrombin from human prothrombin. Studies of pig-to-baboon kidney xenografts undergoing AVR in vivo revealed induction of pfgl2 expression on graft vascular endothelial cells (ECs). Cultured porcine ECs activated by human TNF-alpha in vitro demonstrated induction of pfgl2 expression and enhanced activation of human prothrombin. The availability of gene-targeted fgl2-deficient mice allowed the contribution of fgl2 to the pathogenesis of AVR to be directly examined in vivo. Hearts heterotopically transplanted from fgl2(+/+) and fgl2(+/-) mice into Lewis rats developed AVR with intravascular thrombosis associated with induction of fgl2 in graft vascular ECs. In contrast, xenografts from fgl2(-/-) mice were devoid of thrombosis. These observations collectively suggest that induction of fgl2 on the vascular endothelium plays a role in the pathogenesis of AVR-associated thrombosis. Manipulation of fgl2, in combination with other interventions, may yield novel strategies by which to overcome AVR and extend xenograft survival.

  19. Acute Kidney Disease After Liver and Heart Transplantation.

    PubMed

    Rossi, Ana P; Vella, John P

    2016-03-01

    After transplantation of nonrenal solid organs, an acute decline in kidney function develops in the majority of patients. In addition, a significant number of nonrenal solid organ transplant recipients develop chronic kidney disease, and some develop end-stage renal disease, requiring renal replacement therapy. The incidence varies depending on the transplanted organ. Acute kidney injury after nonrenal solid organ transplantation is associated with prolonged length of stay, cost, increased risk of death, de novo chronic kidney disease, and end-stage renal disease. This overview focuses on the risk factors for posttransplant acute kidney injury after liver and heart transplantation, integrating discussion of proteinuria and chronic kidney disease with emphasis on pathogenesis, histopathology, and management including the use of mechanistic target of rapamycin inhibition and costimulatory blockade.

  20. The Effect of ABO Blood Incompatibility on Corneal Transplant Failure in Conditions with Low Risk of Graft Rejection

    PubMed Central

    Dunn, Steven P.; Stark, Walter J.; Doyle Stulting, R.; Lass, Jonathan H.; Sugar, Alan; Pavilack, Mark A.; Smith, Patricia W.; Tanner, Jean Paul; Dontchev, Mariya; Gal, Robin L.; Beck, Roy W.; Kollman, Craig; Mannis, Mark J.; Holland, Edward J.

    2009-01-01

    Purpose To determine whether corneal graft survival over a five-year follow-up period was affected by ABO blood type compatibility in participants in the Cornea Donor Study undergoing corneal transplantation principally for Fuchs’ dystrophy or pseudophakic corneal edema, conditions at low risk for graft rejection. Design Multi-center prospective, double-masked, clinical trial Methods ABO blood group compatibility was determined for 1,002 donors and recipients. During a five-year follow-up period, episodes of graft rejection were documented, and graft failures were classified as to whether or not they were due to immunologic rejection. Endothelial cell density was determined by a central reading center for a subset of subjects. Results ABO donor-recipient incompatibility was not associated with graft failure due to any cause including graft failure due to rejection, or with the occurrence of a rejection episode. The five-year cumulative incidence of graft failure due to rejection was 6% for recipients with ABO recipient-donor compatibility and 4% for those with ABO incompatibility (hazard ratio 0.65, 95% confidence interval 0.33 to 1.25, p=0.20). The five-year incidence for a definite rejection episode, irrespective of whether graft failure ultimately occurred, was 12% for ABO compatible compared with 8% for ABO incompatible cases (p=0.09). Among clear grafts at five years, percent loss of endothelial cells was similar in ABO compatible and incompatible cases. Conclusions In patients undergoing penetrating keratoplasty for Fuchs’ dystrophy or pseudophakic corneal edema, ABO matching is not indicated since ABO incompatibility does not increase the risk of transplant failure due to graft rejection. PMID:19056078

  1. Pathologic studies of acute rejection of mismatched feline musculocutaneous flaps. Effect of cyclosporine and prednisolone.

    PubMed

    Gregory, C R; Gourley, I M; Ferreira, H; Moore, P F; Imondi, K A; Patz, J D; Gregory, T A; Pedersen, N C

    1991-06-01

    The gracilis musculocutaneous flap was developed as an allograft model to study acute rejection and immunosuppression in the cat. Twelve adult cats received a MLC incompatible flap. Six of the cats received cyclosporine oral solution and prednisolone (0.5 mg/kg/24 hr) for 100 days and six cats were not treated. Trough whole-blood levels of cyclosporine in the treatment group were maintained at approximately 750 ng/ml for 70 days, then 500 ng/ml for the remaining 30 days. Three flaps failed due to technical problems; 5 flaps were studied in the treatment group and 4 in the untreated group. All 5 flaps in the treatment group survived the 100 day treatment period and were rejected 30 +/- 26 days following cessation of treatment. Prior to discontinuation of treatment, with the exception of one cat, inflammatory changes associated with rejection were not observed in biopsy specimen. The flaps in the untreated group survived 13 +/- 1.5 days. Histopathologic examination of the flaps revealed little difference in the appearance of acute rejection and rejection after cessation of therapy. The most prominent lesion was a vasculitis with extensive perivascular lymphohistocytic inflammation. The lymphoid infiltrates consisted predominantly of T cells of both major classes (CD4 and CD8). Full-thickness epidermal necrosis and subsequent bacterial invasion followed vascular compromise.

  2. Acute renal failure in liver transplant patients: Indian study.

    PubMed

    Naik, Pradeep; Premsagar, B; Mallikarjuna, M

    2015-01-01

    The acute renal failure is the frequent medical complication observed in liver transplant patients. The objective of this study was to determine the cause of acute renal failure in post liver transplant patients. A total of 70 patients who underwent (cadaveric 52, live 18) liver transplantation were categorized based on clinical presentation into two groups, namely hepatorenal failure (HRF, n = 29), and Hepatic failure (HF, n = 41). All the patients after the liver transplant had received tacrolimus, mycophenolate and steroids. We analyzed the modification of diet in renal disease, (MDRD) serum urea, creatinine and albumin before and after 5th and 30th day of liver transplant and data was categorized into survivors and non-survivors group. In HRF survivor group, serum creatinine, and urea levels were high and, albumin, MDRD were low in pre- transplant and reached to normal levels on 30th day of post transplant, and 79.3 % of patients in this group showed resumption of normal kidney function. On the contrary in HRF nonsurvivor group, we did not observed any significant difference and 20.7 % of patients showed irreversible changes after the liver transplant. In HF survivor group, 82.9 % of liver failure patients did not show any deviation in serum creatinine, urea, albumin and MDRD, whereas in HF non survivor group, 17.1 % of liver failure patients who had HCV positive before the transplant developed acute renal failure. The levels of creatinine, urea, albumin and MDRD were normal before the transplant and on day 30th, the levels of albumin and MDRD were significantly low whereas serum urea, creatinine levels were high. In conclusion, based on these observations, an diagnosis and treatment of Acute renal failure is important among the liver transplantation cases in the early postoperative period.

  3. Bortezomib-based treatment of acute antibody-mediated rejection: a case report.

    PubMed

    Wang, Q; Li, X L; Xu, X G; Shi, B Y; Zhang, Z M; Li, Z L; Han, Y; Zhou, W Q; Chen, C Q; Cai, M; Zhang, X

    2015-12-22

    Antibody-mediated rejection (AMR) is an important factor affecting survival after renal transplantation. A highly selective proteasome inhibitor, bortezomib, clears activated plasma cells from the body and has important therapeutic effect on AMR. We investigated the effects of bortezomib on AMR in a patient after a second renal transplant. Biopsy confirmed the diagnosis of mixed cellular rejection and AMR. Bortezomib was administered on day 1 (1.3 mg/m(2)), day 4 (1.0 mg/m(2)), and day 8 (1.0 mg/m(2)). On the same days, 250 mg methylprednisolone was administered once, and cyclosporine dose (5 mg·kg(-1)·day(-1)) was reduced by 50%. Oral mycophenolate mofetil and steroid were withdrawn on day 1 of bortezomib treatment. Intermittent double-filtration plasmapheresis was also performed. We monitored parameters, including T lymphocyte subsets, CD139 and CD19 expression, panel reactive antibody (PRA), and serum creatinine concentration. At follow-up 6 months after bortezomib treatment, we observed: 1) serum creatinine stabilized at 130 μM from a peak level of 337 μM; 2) PRA decreased from a maximum of 66.7 to 0%; 3) blood plasma cell percentage rebounded after significantly decreasing following the first dose of bortezomib; 4) in renal allograft biopsy, immunohistochemical staining for C4d shifted from strongly positive to negative, and cellular rejection shifted from type IIA to borderline; and 5) adverse effects such as platelet suppression, hypotension, and grade 3 peripheral neuropathy emerged. Bortezomib effectively treated antibody-mediated renal transplantation rejection in this case study, but clinical trials with large sample sizes are still needed to explore clinical safety and tolerability.

  4. How to Recondition Ex Vivo Initially Rejected Donor Lungs for Clinical Transplantation: Clinical Experience from Lund University Hospital

    PubMed Central

    Lindstedt, Sandra; Eyjolfsson, Atli; Koul, Bansi; Wierup, Per; Pierre, Leif; Gustafsson, Ronny; Ingemansson, Richard

    2011-01-01

    A major problem in clinical lung transplantation is the shortage of donor lungs. Only about 20% of donor lungs are accepted for transplantation. We have recently reported the results of the first six double lung transplantations performed with donor lungs reconditioned ex vivo that had been deemed unsuitable for transplantation by the Scandiatransplant, Eurotransplant, and UK Transplant organizations because the arterial oxygen pressure was less than 40 kPa. The three-month survival of patients undergoing transplant with these lungs was 100%. One patient died due to sepsis after 95 days, and one due to rejection after 9 months. Four recipients are still alive and well 24 months after transplantation, with no signs of bronchiolitis obliterans syndrome. The donor lungs were reconditioned ex vivo in an extracorporeal membrane oxygenation circuit using STEEN solution mixed with erythrocytes, to dehydrate edematous lung tissue. Functional evaluation was performed with deoxygenated perfusate at different inspired fractions of oxygen. The arterial oxygen pressure was significantly improved in this model. This ex vivo evaluation model is thus a valuable addition to the armamentarium in increasing the number of acceptable lungs in a donor population with inferior arterial oxygen pressure values, thereby, increasing the lung donor pool for transplantation. In the following paper we present our clinical experience from the first six patients in the world. We also present the technique we used in detail with flowchart. PMID:21876780

  5. Acute lobar nephronia in renal transplant: Gallium-67 scintigraphy for diagnosis and therapy monitoring

    PubMed Central

    Othman, Saleh

    2015-01-01

    A 33 years old female patient with chronic renal transplant rejection proved by MAG3, ultrasound and graft biopsy presented with abdominal pain and fever. Part of her work up included gallium-67 scan which revealed diffuse abnormal graft uptake with multifocal areas of marked uptake. Findings were interpreted as acute lobar nephronia. Repeat gallium scan two weeks after intravenous antibiotic therapy showed significant response reflected by resolution of most of focal areas of increased uptake which was parallel to clinical improvement. PMID:26170574

  6. Hematopoietic stem cell transplantation from alternative sources in adults with high-risk acute leukemia.

    PubMed

    Aversa, Franco; Reisner, Yair; Martelli, Massimo F

    2004-01-01

    Since 75% of patients with high-risk acute leukemia do not have a human leukocyte antigen (HLA)-identical sibling, alternative sources for hematopoietic stem cell transplantation (HSCT) are matched unrelated donors (MUD), unrelated umbilical cord blood (UD-UCB) and one HLA haplotype mismatched family members (haploidentical). The chance of finding a suitable donor in the international voluntary donor registries is limited by frequency of the HLA phenotype and the time required to identify the right donor from a potential panel, to establish eligibility and to harvest the cells. In adult MUD recipients, event-free survival ranges up to 50% and refers only to patients who undergo transplant, without taking into account those who do not find a donor. Umbilical cord blood offers the advantages of easy procurement, the absence of risks to donors, the reduced risk of transmitting infections, immediate availability of cryopreserved samples and acceptance of mismatches at two of the six antigens. Although UD-UCB transplantation is a viable option for children, it is seldom considered for adults. The great divergency between body weight and the number of hematopoietic cells in a standard cord blood unit, particularly if associated with a two-antigen mismatch, increases the risk of graft failure and delays hematopoietic reconstitution. Work on full-haplotype mismatched transplants has been proceeding for over 20 years. Originally, outcome in leukemia patients was disappointing because of high incidence of severe graft-vs.-host disease in T-replete transplants and high rejection rates in T-cell-depleted transplants. The breakthrough came with the use of a megadose of T-cell-depleted progenitor cells after a high-intensity conditioning regimen. Treating end-stage patients inevitably confounded clinical outcome in the early pilot studies. Today, high-risk acute leukemia patients are treated at less advanced stages of disease, receive a reasonably well tolerated conditioning

  7. Liver transplantation in acute liver failure: A challenging scenario

    PubMed Central

    Mendizabal, Manuel; Silva, Marcelo Oscar

    2016-01-01

    Acute liver failure is a critical medical condition defined as rapid development of hepatic dysfunction associated with encephalopathy. The prognosis in these patients is highly variable and depends on the etiology, interval between jaundice and encephalopathy, age, and the degree of coagulopathy. Determining the prognosis for this population is vital. Unfortunately, prognostic models with both high sensitivity and specificity for prediction of death have not been developed. Liver transplantation has dramatically improved survival in patients with acute liver failure. Still, 25% to 45% of patients will survive with medical treatment. The identification of patients who will eventually require liver transplantation should be carefully addressed through the combination of current prognostic models and continuous medical assessment. The concerns of inaccurate selection for transplantation are significant, exposing the recipient to a complex surgery and lifelong immunosuppression. In this challenging scenario, where organ shortage remains one of the main problems, alternatives to conventional orthotopic liver transplantation, such as living-donor liver transplantation, auxiliary liver transplant, and ABO-incompatible grafts, should be explored. Although overall outcomes after liver transplantation for acute liver failure are improving, they are not yet comparable to elective transplantation. PMID:26819519

  8. A refractory case of subclinical antibody-mediated rejection due to anti-HLA-DQ antibody in a kidney transplant patient.

    PubMed

    Fujimoto, Toshinari; Nakada, Yasuyuki; Yamamoto, Izumi; Kobayashi, Akimitsu; Tanno, Yudo; Yamada, Hiroki; Miki, Jun; Ohkido, Ichiro; Tsuboi, Nobuo; Yamamoto, Hiroyasu; Yokoo, Takashi

    2015-07-01

    We herein report a refractory case of subclinical antibody-mediated rejection (AMR) due to anti-HLA-DQ antibody in a kidney transplant patient. A 45-year-old man was admitted for a protocol biopsy; he had a serum creatinine (S-Cr) level of 1.8 mg/dL 3 years following primary kidney transplantation. Histological examination revealed moderate to severe inflammatory cell infiltration in the peritubular capillaries. Thorough laboratory examination showed that the patient had donor-specific antibodies (DSAbs) to DR9 and DQ9. Considering both the histological and laboratory findings, we diagnosed acute antibody-mediated rejection. The patient underwent 3 days of consecutive steroid pulse therapy, intravenous immunoglobulin (IVIG), and plasma exchange. We also administered rituximab (200 mg/body). Six months after the treatment, a second allograft biopsy revealed the progression of interstitial fibrosis and tubular atrophy and persistence of mild peritubular capillaritis. Further analysis showed that the anti-DR9 antibodies had disappeared, but that the mean fluorescence intensity value of the anti-DQ9 antibodies had increased. Therefore, we repeated the plasma exchange and IVIG. Allograft function was stable throughout the course of treatment, and the S-Cr level remained at 1.8 mg/dL. This case report demonstrates the difficulty of treating AMR due to the presence of anti-DQ DSAbs and the necessity for subsequent therapies in refractory cases.

  9. [Role of biomarkers in the differential diagnosis of acute respiratory failure in the immediate postoperative period of lung transplantation].

    PubMed

    Ruano, L; Sacanell, J; Roman, A; Rello, J

    2013-01-01

    Lung transplant recipients are at high risk of suffering many complications during the immediate postoperative period, such as primary graft dysfunction, acute graft rejection or infection. The most common symptom is the presence of acute respiratory failure, and the use of biomarkers could be useful for establishing an early diagnosis of these conditions. Different biomarkers have been studied, but none have proven to be the gold standard in the differential diagnosis of acute respiratory failure. This paper offers a review of the different biomarkers that have been studied in this field.

  10. Better understanding of transplant glomerulopathy secondary to chronic antibody-mediated rejection.

    PubMed

    Remport, Adam; Ivanyi, Bela; Mathe, Zoltan; Tinckam, Kathryn; Mucsi, Istvan; Molnar, Miklos Z

    2015-11-01

    Transplant glomerulopathy (TG) is generally accepted to result from repeated episodes of endothelial activation, injury and repair, leading to pathological abnormalities of double contouring or multi-layering of the glomerular basement membrane. TG is a major sequel of chronic active antibody-mediated rejection (cABMR), from pre-existing or de novo anti-HLA antibodies. Hepatitis C infection, thrombotic microangiopathy or other factors may also contribute to TG development. TG prevalence is 5-20% in most series, reaching 55%, in some high-risk cohorts, and is associated with worse allograft outcomes. Despite its prevalence and clinical significance, few well-studied treatment options have been proposed. Similar to desensitization protocols, plasmapheresis with or without immunoabsorption, high-dose intravenous immunoglobulin, rituximab, bortezomib and eculizumab have been proposed in the treatment of TG due to cABMR individually or in various combinations. Robust clinical trials are urgently needed to address this major cause of allograft loss. This review summarizes the current knowledge of the epidemiology, etiology, pathology, and the preventive and treatment options for TG secondary to cABMR.

  11. Significance and Suppression of Redundant IL17 Responses in Acute Allograft Rejection by Bioinformatics Based Drug Repositioning of Fenofibrate

    PubMed Central

    Okamura, Homare; Hsieh, Szu-Chuan; Gong, Yongquan; Sarwal, Minnie M.

    2013-01-01

    Despite advanced immunosuppression, redundancy in the molecular diversity of acute rejection (AR) often results in incomplete resolution of the injury response. We present a bioinformatics based approach for identification of these redundant molecular pathways in AR and a drug repositioning approach to suppress these using FDA approved drugs currently available for non-transplant indications. Two independent microarray data-sets from human renal allograft biopsies (n = 101) from patients on majorly Th1/IFN-y immune response targeted immunosuppression, with and without AR, were profiled. Using gene-set analysis across 3305 biological pathways, significant enrichment was found for the IL17 pathway in AR in both data-sets. Recent evidence suggests IL17 pathway as an important escape mechanism when Th1/IFN-y mediated responses are suppressed. As current immunosuppressions do not specifically target the IL17 axis, 7200 molecular compounds were interrogated for FDA approved drugs with specific inhibition of this axis. A combined IL17/IFN-y suppressive role was predicted for the antilipidemic drug Fenofibrate. To assess the immunregulatory action of Fenofibrate, we conducted in-vitro treatment of anti-CD3/CD28 stimulated human peripheral blood cells (PBMC), and, as predicted, Fenofibrate reduced IL17 and IFN-γ gene expression in stimulated PMBC. In-vivo Fenofibrate treatment of an experimental rodent model of cardiac AR reduced infiltration of total leukocytes, reduced expression of IL17/IFN-y and their pathway related genes in allografts and recipients’ spleens, and extended graft survival by 21 days (p<0.007). In conclusion, this study provides important proof of concept that meta-analyses of genomic data and drug databases can provide new insights into the redundancy of the rejection response and presents an economic methodology to reposition FDA approved drugs in organ transplantation. PMID:23437201

  12. Myocardial Gene Expression Profiling to Predict and Identify Cardiac Allograft Acute Cellular Rejection: The GET-Study

    PubMed Central

    Bodez, Diane; Hocini, Hakim; Tchitchek, Nicolas; Tisserand, Pascaline; Benhaiem, Nicole; Barau, Caroline; Kharoubi, Mounira; Guellich, Aziz; Guendouz, Soulef; Radu, Costin; Couetil, Jean-Paul; Ghaleh, Bijan; Dubois-Randé, Jean-Luc; Teiger, Emmanuel; Hittinger, Luc

    2016-01-01

    Aims Serial invasive endomyocardial biopsies (EMB) remain the gold standard for acute cellular rejection (ACR) diagnosis. However histological grading has several limitations. We aimed to explore the value of myocardial Gene Expression Profiling (GEP) for diagnosing and identifying predictive biomarkers of ACR. Methods A case-control study nested within a retrospective heart transplant patients cohort included 126 patients with median (IQR) age 50 (41–57) years and 111 (88%) males. Among 1157 EMB performed, 467 were eligible (i.e, corresponding to either ISHLT grade 0 or ≥3A), among which 36 were selected for GEP according to the grading: 0 (CISHLT, n = 13); rejection ≥3A (RISHLT, n = 13); 0 one month before ACR (BRISHLT, n = 10). Results We found 294 genes differentially expressed between CISHLT and RISHLT, mainly involved in immune activation, and inflammation. Hierarchical clustering showed a clear segregation of CISHLT and RISHLT groups and heterogeneity of GEP within RISHLT. All EMB presented immune activation, but some RISHLT EMB were strongly subject to inflammation, whereas others, closer to CISHLT, were characterized by structural modifications with lower inflammation level. We identified 15 probes significantly different between BRISHLT and CISHLT, including the gene of the muscular protein TTN. This result suggests that structural alterations precede inflammation in ACR. Linear Discriminant Analysis based on these 15 probes was able to identify the histological status of every 36 samples. Conclusion Myocardial GEP is a helpful method to accurately diagnose ACR, and predicts rejection one month before its histological occurrence. These results should be considered in cardiac allograft recipients’ care. PMID:27898719

  13. Blood cyclosporin concentrations and the short-term risk of lung rejection following heart-lung transplantation.

    PubMed Central

    Best, N G; Trull, A K; Tan, K K; Hue, K L; Spiegelhalter, D J; Gore, S M; Wallwork, J

    1992-01-01

    1. The relationship between blood cyclosporin concentration (CyACb) and a patient's risk of organ rejection following heart-lung (HL) transplantation was investigated. 2. Longitudinal data were collected for 90 days post-operation for 31 HL transplant recipients. Following exploratory analysis, a multiple logistic regression model with a binary outcome variable representing presence or absence of lung rejection (as defined on biopsy findings and/or intention to treat) in the next 5 days was fitted to the data. 3. A significant interaction between time post-transplant and CyACb was found. During weeks 1-3, the relative risk (RR) of rejection per unit increase in log(e) (5-day mean CyACb) was reduced: RR = 0.29, 95% confidence interval (CI) = (0.12, 0.72). After 3 post-operative weeks, this trend was reversed: RR = 1.61, 95% CI = (0.96, 2.70). Increases in cyclosporin dose (CyAD) and in coefficient of variation (CV) for both CyAD and CyACb over the previous 10 days significantly increased the risk of rejection: RR per unit increase in log(e) (5-day mean CyAD) = 2.72, 95% CI = (1.18, 6.25); RR per increase of 10% (i.e. from, say, 20% to 30%) in the CV for CyAD = 1.20, 95% CI = (1.07, 1.36); RR if the CV for CyACb > 40% = 1.51, 95% CI = (1.01, 2.27). Administration of high dose steroids in the previous 5 days was found to protect against further rejection: RR if steroid treatment was given = 0.23, 95% CI = (0.13, 0.38).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1493084

  14. Dual Role of Natural Killer Cells on Graft Rejection and Control of Cytomegalovirus Infection in Renal Transplantation

    PubMed Central

    López-Botet, Miguel; Vilches, Carlos; Redondo-Pachón, Dolores; Muntasell, Aura; Pupuleku, Aldi; Yélamos, José; Pascual, Julio; Crespo, Marta

    2017-01-01

    Allograft rejection constitutes a major complication of solid organ transplantation requiring prophylactic/therapeutic immunosuppression, which increases susceptibility of patients to infections and cancer. Beyond the pivotal role of alloantigen-specific T cells and antibodies in the pathogenesis of rejection, natural killer (NK) cells may display alloreactive potential in case of mismatch between recipient inhibitory killer-cell immunoglobulin-like receptors (KIRs) and graft HLA class I molecules. Several studies have addressed the impact of this variable in kidney transplant with conflicting conclusions; yet, increasing evidence supports that alloantibody-mediated NK cell activation via FcγRIIIA (CD16) contributes to rejection. On the other hand, human cytomegalovirus (HCMV) infection constitutes a risk factor directly associated with the rate of graft loss and reduced host survival. The levels of HCMV-specific CD8+ T cells have been reported to predict the risk of posttransplant infection, and KIR-B haplotypes containing activating KIR genes have been related with protection. HCMV infection promotes to a variable extent an adaptive differentiation and expansion of a subset of mature NK cells, which display the CD94/NKG2C-activating receptor. Evidence supporting that adaptive NKG2C+ NK cells may contribute to control the viral infection in kidney transplant recipients has been recently obtained. The dual role of NK cells in the interrelation of HCMV infection with rejection deserves attention. Further phenotypic, functional, and genetic analyses of NK cells may provide additional insights on the pathogenesis of solid organ transplant complications, leading to the development of biomarkers with potential clinical value. PMID:28261220

  15. Clinical transplantation of individualized recipient serum-adapted cornea reduces the risk of graft rejection after keratoplasty.

    PubMed

    Thanos, Solon; Gatzioufas, Zissis; Schallenberg, Maurice; König, Simone; Meyer-Rüsenberg, Hans-Werner; Busse, Holger

    2013-01-01

    Corneal diseases cause severe visual impairment that necessitates corneal transplantation and frequently repetitive procedures due to graft rejection. We tested the hypothesis that exposure of donor corneas to recipient serum-derived factors during eye banking triggers a preoperative adaptation that is beneficial for postoperative tolerance. Donor corneas were incubated in a medium containing human serum (HS) obtained in each case from the prospective graft recipient in order to individually expose the donor cornea to the recipient's serum. All recipient serum-adapted corneas (RSACs) fulfilled the clinical criteria required by the national law and were transplanted successfully. The postoperative ophthalmological examination extended up to 8 years. All RSACs were tolerated by their recipients and did not cause postoperative complications and no rejection. Proteomic analysis of corneas cultivated in culture medium containing either fetal calf serum (FCS) that is routinely used for cornea banking or HS revealed different patterns of proteins. HS-cultured corneas showed a greater proteomic similarity with native human corneas than did the FCS-cultured corneas, indicating a differential nutrification of the cultured corneal tissue by HS-derived factors. The clinical results show for the first time that postoperative complications such as tissue intolerance and graft rejection might be managed if the corneal tissue is individually adapted to the recipient's serum trophic factors. This new donor tissue treatment procedure offers incontrovertible advantages and could be adapted for low-risk eyes as well as other transplantable tissues.

  16. Inducible costimulatory molecule deficiency induced imbalance of Treg and Th17/Th2 delays rejection reaction in mice undergoing allogeneic tracheal transplantation

    PubMed Central

    Xu, Jingsong; Wu, Yu; Wang, Guifang; Qin, Yanghua; Zhu, Li; Tang, Gusheng; Shen, Qian

    2014-01-01

    Objective: This study aimed to investigate the role of inducible costimulatory molecule (ICOS) pathway in the rejection reaction of mice undergoing allogeneic tracheal transplantation. Methods: The bronchus was separated from wide-type (WT) BalB/c mice and transplanted into WT BalB/c mice, C57 mice and icos-/- mice to prepare the obliterative bronchiolitis (OB) animal model. The transplanted bronchus was pathologically examined; flow cytometry was done to detect the T cell subsets and activity of the bronchus and spleen of recipient mice. Results: 21 d after transplantation, evident rejection reaction was observed and the proportion of Th2 and Th17 cells increased significantly in the bronchus and spleen in C57 mice receiving allogeneic tracheal transplantation when compared with mice with autologous transplantation, but the proportion of Treg cells was comparable between them. When compared with WT BalB/c mice, the proportion of Th2, Th17 and Treg cells reduced markedly and rejection reaction was attenuated in icos-/- mice receiving tracheal transplantation, although rejection reaction was still noted. Conclusion: icos knockout may delay the rejection reaction after tracheal transplantation, which might be ascribed to the imbalance among Th2, Th17 and Treg cells. PMID:25628788

  17. Acute thrombosis of a transplanted renal artery after gastric ulcer bleeding in a patient with a long-term well-functioning renal allograft

    PubMed Central

    Wu, Chung-Kuan; Leu, Jyh-Gang; Wei, Cheng-Chun; Hsieh, Shih-Chung

    2016-01-01

    Abstract Background: Acute thrombosis of a transplanted renal artery is a serious vascular complication following renal allograft transplantation, which usually occurs within the first month after transplantation and often results in graft loss. It rarely occurs beyond the first month, except in a rejected kidney or in a kidney with high-grade transplant renal artery stenosis. Result: A 65-year-old male with a history of type 2 diabetes mellitus, hypertension, pulmonary tuberculosis, and end-stage renal disease was previously treated with hemodialysis (HD). He received a kidney transplant and had a well-functioning graft for 2 years. He presented to our emergency department with gastric ulcer bleeding and received treatment involving an endoscopic submucosal epinephrine injection, a proton pump inhibitor, and blood transfusions. Nine days later, he complained of sudden lower abdominal pain and had acute anuric kidney failure. Renal ultrasonography revealed an absence of blood flow to the allograft kidney. Renal artery angiogram demonstrated complete occlusion of the transplanted renal artery. After thrombectomy and percutaneous transluminal angioplasty (PTA) with stent placement, 60% stenosis of the proximal renal artery with distal perfusion was noted. However, his graft function did not improve, and he received HD again. Histopathology of the transplanted kidney revealed ischemic tubular nephropathy with focal infarction without rejection. Conclusion: This is the first case of acute thrombosis of the transplanted renal artery following gastric ulcer bleeding in a patient with a long-term well-functioning graft kidney. PMID:27472705

  18. Immunosuppressive Total Lymphoid Irradiation-Based Reconditioning Regimens Enable Engraftment After Graft Rejection or Graft Failure in Patients Treated With Allogeneic Hematopoietic Stem Cell Transplantation

    SciTech Connect

    Heinzelmann, Frank; Lang, Peter J.; Ottinger, Hellmut; Faul, Christoph; Bethge, Wolfgang; Handgretinger, Rupert; Bamberg, Michael; Belka, Claus

    2008-02-01

    Purpose: To retrospectively evaluate the efficacy of total lymphoid irradiation (TLI)-based reconditioning regimens in patients with graft failure or graft rejection after allogeneic hematopoietic stem cell transplantation. Methods and Materials: The results of 14 patients (7 adults and 7 children) with a variety of hematologic malignant diseases treated with a TLI-based reconditioning regimen with 7-Gy single-dose application plus anti-T-lymphocyte antibody OKT3 (n = 11) and/or antithymocyte globulin (n = 7)/fludarabine (n = 9), followed by an infusion of peripheral blood stem cells (n = 13) or bone marrow stem cells (n = 1) from related or unrelated donors, were retrospectively analyzed. Results: Of the 14 recipients, the data from 11 were evaluable for engraftment after TLI-based reconditioning because 3 adults died early (at Day 2, 5, and 15) after the second transplantation of infectious complications. Engraftment in 4 adults was seen after a median of 12 days (range, 10-18) and occurred after a median of 10 days (range, 9-32) in the 7 children. TLI-based reconditioning was well-tolerated with no severe toxicity. The median overall survival and disease-free survival for the whole cohort was 140 days (range, 5-1,268). After a median follow-up of 681 days, the disease-free survival and overall survival rate was 85.7% and 85.7%, respectively, in the children. Despite engraftment in the 4 remaining adults, 1 died of fatal graft-vs.-host disease, 1 of infectious complications, 1 of disease relapse, and 1 of acute respiratory distress syndrome. Conclusions: In patients with graft failure or graft rejection after allogeneic hematopoietic stem cell transplantation, TLI-based reconditioning regimens allow sustained engraftment, paralleled by a favorable toxicity profile, potentially leading to long-term survival.

  19. Antibody-mediated rejection in heart transplant recipients: potential efficacy of B-cell depletion and antibody removal.

    PubMed

    Bierl, Charlene; Miller, Barry; Prak, Eline Luning; Gasiewski, Allison; Kearns, Jane; Tsai, Donald; Jessup, Mariell; Kamoun, Malek

    2006-01-01

    We present four patients with late AMR following cardiac transplantation, which was associated with de novo post-transplant anti-HLA class II antibody production. All patients had negative anti-HLA class I and class II antibodies prior to transplantation (as assessed by sensitive Flow PRA bead assays) and had a negative retrospective T- and B-cell flow cytometric cross-match. Upon presentation with late graft rejection due to AMR, all patients were treated with rituximab and serial plasmapheresis with IVIg plus triple-drug immunosuppression therapy. Despite initial responses to therapy, relapses occurred in all of the patients and necessitated prolonged or multiple hospital admissions and second transplants in two cases. Post-transplant serum antibody monitoring did not prove to be predictive of treatment success or failure. Serum anti-HLA antibodies should be monitored after heart transplantation. We recommend an assessment of anti-HLA antibodies following a decline in immunosuppressant drug levels or in the presence of heart failure symptoms. Anti-HLA antibody detection should be performed using very sensitive techniques such as microparticle-based assays.

  20. Autologous stem cell transplantation versus alternative allogeneic donor transplants in adult acute leukemias.

    PubMed

    Claude Gorin, Norbert

    2016-04-01

    The availability of alternative sources of stem cells including most recently T-replete haploidentical marrow or peripheral blood, and the increasing use of reduced-intensity conditioning (RIC), renders feasible an allogeneic transplant to almost all patients with acute leukemia up to 70 years of age. Autologous stem cell transplantation (ASCT) for consolidation of complete remission (CR), however, offers in some circumstances an alternative option. Although associated with a higher relapse rate, autologous transplant benefits from a lower non-relapse mortality, the absence of graft-versus-host disease (GVHD), and a better quality of life for long-term survivors. The recent use of intravenous busulfan (IVBU) with high-dose melphalan, better monitoring of minimal residual disease (MRD), and maintenance therapy post autografting bring new interest. Few retrospective studies compared the outcome following alternative donor versus autologous transplants for remission consolidation. Genoidentical and phenoidentical allogeneic stem cell transplantations are undisputed gold standards, but there are no data showing the superiority of alternative allogeneic donor over autologous transplantation, at the time of undetectable MRD, in patients with good- and intermediate-1 risk acute myelocytic leukemia (AML) in first complete remission (CR1), acute promyelocytic leukemia in second complete remission (CR2), and Philadelphia chromosome-positive (Ph(+)) acute lymphocytic leukemia (ALL).

  1. Presentation and Outcomes of C4d-Negative Antibody-Mediated Rejection After Kidney Transplantation.

    PubMed

    Orandi, B J; Alachkar, N; Kraus, E S; Naqvi, F; Lonze, B E; Lees, L; Van Arendonk, K J; Wickliffe, C; Bagnasco, S M; Zachary, A A; Segev, D L; Montgomery, R A

    2016-01-01

    The updated Banff classification allows for the diagnosis of antibody-mediated rejection (AMR) in the absence of peritubular capillary C4d staining. Our objective was to quantify allograft loss risk in patients with consistently C4d-negative AMR (n = 51) compared with C4d-positive AMR patients (n = 156) and matched control subjects without AMR. All first-year posttransplant biopsy results from January 2004 through June 2014 were reviewed and correlated with the presence of donor-specific antibody (DSA). C4d-negative AMR patients were not different from C4d-positive AMR patients on any baseline characteristics, including immunologic risk factors (panel reactive antibody, prior transplant, HLA mismatch, donor type, DSA class, and anti-HLA/ABO-incompatibility). C4d-positive AMR patients were significantly more likely to have a clinical presentation (85.3% vs. 54.9%, p < 0.001), and those patients presented substantially earlier posttransplantation (median 14 [interquartile range 8-32] days vs. 46 [interquartile range 20-191], p < 0.001) and were three times more common (7.8% vs 2.5%). One- and 2-year post-AMR-defining biopsy graft survival in C4d-negative AMR patients was 93.4% and 90.2% versus 86.8% and 82.6% in C4d-positive AMR patients, respectively (p = 0.4). C4d-negative AMR was associated with a 2.56-fold (95% confidence interval, 1.08-6.05, p = 0.033) increased risk of graft loss compared with AMR-free matched controls. No clinical characteristics were identified that reliably distinguished C4d-negative from C4d-positive AMR. However, both phenotypes are associated with increased graft loss and thus warrant consideration for intervention.

  2. Post-Transplant Membranous Nephropathy Associated with Chronic Active Antibody-Mediated Rejection and Hepatitis C Infection after Deceased Donor Renal Transplantation.

    PubMed

    Doke, Tomohito; Sato, Waichi; Takahashi, Kazuo; Hayashi, Hiroki; Koide, Sigehisa; Sasaki, Hitomi; Kusaka, Mamoru; Shiroki, Ryoichi; Hoshinaga, Kiyotaka; Takeda, Asami; Yuzawa, Yukio; Hasegawa, Midori

    2016-01-01

    A 53-year-old woman who had undergone deceased donor kidney transplantation twice, at 35 and 43 years of age, presented with renal impairment. She was infected with hepatitis C virus (HCV). The histology of the graft kidney revealed post-transplant membranous nephropathy (MN) with podocytic infolding and antibody-mediated rejection (AMR). IgG subclass staining showed fine granular deposits of IgG1 and IgG3, but not IgG4, in the glomerular capillary walls. Panel reactive antibody scores for human leukocyte antigen class I and class II were 92.67% and 66.68%, respectively. Thus, this case of post-transplanted MN was considered to be associated with AMR and HCV infection.

  3. Endoscopic biopsy of islet transplants in the gastric submucosal space provides evidence of islet graft rejection in diabetic pigs

    PubMed Central

    Tanaka, Takayuki; Fujita, Minoru; Bottino, Rita; Piganelli, Jon D.; McGrath, Kevin; Li, Jiang; Lee, Whayoung; Iwase, Hayato; Wijkstrom, Martin; Bertera, Suzanne; Long, Cassandra; Landsittel, Douglas; Haruma, Ken; Cooper, David K.C.; Hara, Hidetaka

    2016-01-01

    ABSTRACT Transplantation of islets into the gastric submucosal space (GSMS) has several advantages (e.g., avoidance of the instant blood-mediated inflammatory response [IBMIR], ability to biopsy). The aim of this study was to determine whether endoscopic biopsy of islet allografts transplanted into the GSMS in diabetic pigs can provide histopathological and immunohistochemical information that correlates with the clinical course (e.g.,, blood glucose level, insulin requirement). Islet allografts (Group1: 10,000 kIEq /kg [n = 4]; Group2: 15,000 kIEq /kg [n = 2]) were transplanted into the GSMS of diabetic pigs under immunosuppression. In Group2, the anti-oxidant, BMX-001 was applied during preservation, isolation, and culture of the islets, and at the time of transplantation. Endoscopic biopsies of the islet grafts were obtained one or 2 weeks after transplantation, and histopathological features were compared with the clinical course (e.g., blood glucose, insulin requirement). In Group1, in the absence of anti-oxidant therapy, most of the islets became fragmented, and there was no reduction in exogenous insulin requirement. In Group2, with an increased number of transplanted islets in the presence of BMX-001, more healthy insulin-positive islet masses were obtained at biopsy and necropsy (4 weeks), and these correlated with reductions in both blood glucose level and insulin requirement. In all cases, inflammatory cell infiltrates were present. After islet transplantation into the GSMS, endoscopic biopsy can provide information on graft rejection, which would be an immense advantage in clinical islet transplantation. PMID:26857703

  4. CD8 T-cell recognition of acquired alloantigen promotes acute allograft rejection

    PubMed Central

    Harper, Simon J. F.; Ali, Jason M.; Wlodek, Elizabeth; Negus, Marg C.; Harper, Ines G.; Chhabra, Manu; Qureshi, M. Saeed; Mallik, Mekhola; Bolton, Eleanor; Bradley, J. Andrew; Pettigrew, Gavin J.

    2015-01-01

    Adaptive CD8 T-cell immunity is the principal arm of the cellular alloimmune response, but its development requires help. This can be provided by CD4 T cells that recognize alloantigen “indirectly,” as self-restricted allopeptide, but this process remains unexplained, because the target epitopes for CD4 and CD8 T-cell recognition are “unlinked” on different cells (recipient and donor antigen presenting cells (APCs), respectively). Here, we test the hypothesis that the presentation of intact and processed MHC class I alloantigen by recipient dendritic cells (DCs) (the “semidirect” pathway) allows linked help to be delivered by indirect-pathway CD4 T cells for generating destructive cytotoxic CD8 T-cell alloresponses. We show that CD8 T-cell–mediated rejection of murine heart allografts that lack hematopoietic APCs requires host secondary lymphoid tissue (SLT). SLT is necessary because within it, recipient dendritic cells can acquire MHC from graft parenchymal cells and simultaneously present it as intact protein to alloreactive CD8 T cells and as processed peptide alloantigen for recognition by indirect-pathway CD4 T cells. This enables delivery of essential help for generating cytotoxic CD8 T-cell responses that cause rapid allograft rejection. In demonstrating the functional relevance of the semidirect pathway to transplant rejection, our findings provide a solution to a long-standing conundrum as to why SLT is required for CD8 T-cell allorecognition of graft parenchymal cells and suggest a mechanism by which indirect-pathway CD4 T cells provide help for generating effector cytotoxic CD8 T-cell alloresponses at late time points after transplantation. PMID:26420874

  5. Acute cardiac tamponade: an unusual cause of acute renal failure in a renal transplant recipient.

    PubMed

    Nampoory, Naryanan; Gheith, Osama; Al-Otaibi, Torki; Halim, Medhat; Nair, Prasad; Said, Tarek; Mosaad, Ahmed; Al-Sayed, Zakareya; Alsayed, Ayman; Yagan, Jude

    2015-04-01

    We report a case of slow graft function in a renal transplant recipient caused by uremic acute pericardial effusion with tamponade. Urgent pericardiocentesis was done with an improvement in blood pressure, immediate diuresis, and quick recovery of renal function back to baseline. Pericardial tamponade should be included in consideration of causes of type 1 cardiorenal syndrome in renal transplant recipients.

  6. Sinusoidal endotheliitis as a histological parameter for diagnosing acute liver allograft rejection

    PubMed Central

    Shi, Yu; Dong, Kun; Zhang, Yu-Guo; Michel, René P; Marcus, Victoria; Wang, Yu-Yue; Chen, Yu; Gao, Zu-Hua

    2017-01-01

    AIM To investigated the feasibility of using sinusoidal endotheliitis (SE) as a histological marker for liver allograft rejection. METHODS We compared the histological features of 88 liver allograft biopsies with acute cellular rejection (ACR) and 59 cases with no evidence of ACR. SE was scored as: (1) focal linear lifting up of the endothelial cells by lymphocytes with no obvious damage to adjacent hepatocytes; (2) focal disruption of the endothelial lining by a cluster of subendothelial lymphocytes (a group of > 3 lymphocytes); and (3) severe confluent endotheliitis with hemorrhage and adjacent hepatocyte loss. RESULTS The sensitivity and specificity of SE was 81% and 85%, respectively. Using SE as the only parameter, the positive predictive value for ACR (PPV) was 0.89, whereas the negative predictive value for ACR (NPV) was 0.75. The correlation between RAI and SE was moderate (R = 0.44, P < 0.001) (Figure 3A), whereas it became strong (R = 0.65, P < 0.001) when correlating SE with the venous endotheliitis activity index only. CONCLUSION Our data suggest that SE scoring could be a reliable and reproducible supplemental parameter to the existing Banff schema for diagnosing acute liver allograft rejection. PMID:28223723

  7. Difference in outcomes after antibody-mediated rejection between abo-incompatible and positive cross-match transplantations.

    PubMed

    Couzi, Lionel; Manook, Miriam; Perera, Ranmith; Shaw, Olivia; Ahmed, Zubir; Kessaris, Nicos; Dorling, Anthony; Mamode, Nizam

    2015-10-01

    Graft survival seems to be worse in positive cross-match (HLAi) than in ABO-incompatible (ABOi) transplantation. However, it is not entirely clear why these differences exist. Sixty-nine ABOi, 27 HLAi and 10 combined ABOi+HLAi patients were included in this retrospective study, to determine whether the frequency, severity and the outcome of active antibody-mediated rejection (AMR) were different. Five-year death-censored graft survival was better in ABOi than in HLAi and ABOi+HLAi patients (99%, 69% and 64%, respectively, P = 0.0002). Features of AMR were found in 38%, 95% and 100% of ABOi, HLAi and ABOi+HLAi patients that had a biopsy, respectively (P = 0.0001 and P = 0.001). After active AMR, a declining eGFR and graft loss were observed more frequently in HLAi and HLAi+ABOi than in ABOi patients. The poorer prognosis after AMR in HLAi and ABOi+HLAi transplantations was not explained by a higher severity of histological lesions or by a less aggressive treatment. In conclusion, ABOi transplantation offers better results than HLAi transplantation, partly because AMR occurs less frequently but also because outcome after AMR is distinctly better. HLAi and combined ABOi+HLAi transplantations appear to have the same outcome, suggesting there is no synergistic effect between anti-A/B and anti-HLA antibodies.

  8. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia

    PubMed Central

    Zhang, Mei-Jie; Bacigalupo, Andrea A.; Bashey, Asad; Appelbaum, Frederick R.; Aljitawi, Omar S.; Armand, Philippe; Antin, Joseph H.; Chen, Junfang; Devine, Steven M.; Fowler, Daniel H.; Luznik, Leo; Nakamura, Ryotaro; O’Donnell, Paul V.; Perales, Miguel-Angel; Pingali, Sai Ravi; Porter, David L.; Riches, Marcie R.; Ringdén, Olle T. H.; Rocha, Vanderson; Vij, Ravi; Weisdorf, Daniel J.; Champlin, Richard E.; Horowitz, Mary M.; Fuchs, Ephraim J.; Eapen, Mary

    2015-01-01

    We studied adults with acute myeloid leukemia (AML) after haploidentical (n = 192) and 8/8 HLA-matched unrelated donor (n = 1982) transplantation. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate, and posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88 received reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737 received reduced intensity conditioning regimens. In the myeloablative setting, day 30 neutrophil recovery was lower after haploidentical compared with matched unrelated donor transplants (90% vs 97%, P = .02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96% (P = .25). In the myeloablative setting, 3-month acute grade 2-4 (16% vs 33%, P < .0001) and 3-year chronic GVHD (30% vs 53%, P < .0001) were lower after haploidentical compared with matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% vs 28% (P = .05) and 34% vs 52% (P = .002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI, 36-54) and 50% (95% CI, 47-53) after haploidentical and matched unrelated donor transplants (P = .38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI, 35-56) and 44% (95% CI, 0.40-47) (P = .71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation. PMID:26130705

  9. Renal allograft rejection: sonography and scintigraphy

    SciTech Connect

    Singh, A.; Cohen, W.N.

    1980-07-01

    A total of 30 renal allograft patients who had sonographic B scanning and radionuclide studies of the transplant was studied as to whether: (1) the allograft rejection was associated with any consistent and reliable sonographic features and (2) the sonograms complemented the radionuclide studies. Focal areas of decreased parenchymal echogenicity were the most striking and consistent sonographic finding in chymal echogenicity were the most striking and consistens sonographic finding in allograft rejection. This was observed in most of the patients exhibiting moderate or severe rejection, but was frequently absent with mild rejection. Areas of decreased parenchymal echogenicity were not seen during episodes of acute tubular necrosis. Therefore, sonography showing zones of decreased parenchymal echogenicity was complementary to radionuclide studies in the diagnosis of allograft rejection versus acute tubular necrosis. Corticomedullary demarcation was difficult to interpret because of technical variables, and was inconsistently related to rejection in this series.

  10. Transplanting Kidneys from Deceased Donors With Severe Acute Kidney Injury.

    PubMed

    Heilman, R L; Smith, M L; Kurian, S M; Huskey, J; Batra, R K; Chakkera, H A; Katariya, N N; Khamash, H; Moss, A; Salomon, D R; Reddy, K S

    2015-08-01

    Our aim was to determine outcomes with transplanting kidneys from deceased donors with acute kidney injury, defined as a donor with terminal serum creatinine ≥2.0 mg/dL, or a donor requiring acute renal replacement therapy. We included all patients who received deceased donor kidney transplant from June 2004 to October 2013. There were 162 AKI donor transplant recipients (21% of deceased donor transplants): 139 in the standard criteria donor (SCD) and 23 in the expanded criteria donor (ECD) cohort. 71% of the AKI donors had stage 3 (severe AKI), based on acute kidney injury network (AKIN) staging. Protocol biopsies were done at 1, 4, and 12 months posttransplant. One and four month formalin-fixed paraffin embedded (FFPE) biopsies from 48 patients (24 AKI donors, 24 non-AKI) underwent global gene expression profiling using DNA microarrays (96 arrays). DGF was more common in the AKI group but eGFR, graft survival at 1 year and proportion with IF/TA>2 at 1 year were similar for the two groups. At 1 month, there were 898 differentially expressed genes in the AKI group (p-value <0.005; FDR <10%), but by 4 months there were no differences. Transplanting selected kidneys from deceased donors with AKI is safe and has excellent outcomes.

  11. Recurrence of Acute Page Kidney in a Renal Transplant Allograft

    PubMed Central

    Zayas, Carlos; Mulloy, Laura; Jagadeesan, Muralidharan

    2016-01-01

    Acute Page Kidney (APK) phenomenon is a rare cause of secondary hypertension, mediated by activation of renin-angiotensin-aldosterone system (RAAS). Timely intervention is of great importance to prevent any end organ damage from hypertension. We present a unique case of three episodes of APK in the same renal transplant allograft. PMID:27725836

  12. Recurrence of Acute Page Kidney in a Renal Transplant Allograft.

    PubMed

    Kapoor, Rajan; Zayas, Carlos; Mulloy, Laura; Jagadeesan, Muralidharan

    2016-01-01

    Acute Page Kidney (APK) phenomenon is a rare cause of secondary hypertension, mediated by activation of renin-angiotensin-aldosterone system (RAAS). Timely intervention is of great importance to prevent any end organ damage from hypertension. We present a unique case of three episodes of APK in the same renal transplant allograft.

  13. Transplant Outcomes for Children with Hypodiploid Acute Lymphoblastic Leukemia

    PubMed Central

    Mehta, Parinda A.; Zhang, Mei-Jie; Eapen, Mary; He, Wensheng; Seber, Adriana; Gibson, Brenda; Camitta, Bruce M.; Kitko, Carrie L.; Dvorak, Christopher C.; Nemecek, Eneida R.; Frangoul, Haydar A.; Abdel-Azim, Hisham; Kasow, Kimberly A.; Lehmann, Leslie; Vicent, Marta Gonzalez; Diaz Pérez, Miguel A.; Ayas, Mouhab; Qayed, Muna; Carpenter, Paul A.; Jodele, Sonata; Lund, Troy C.; Leung, Wing H.; Davies, Stella M.

    2015-01-01

    Children with hypodiploid acute lymphoblastic leukemia (ALL) have inferior outcomes despite intensive risk adapted chemotherapy regimens. We describe 78 children with hypodiploid ALL who underwent hematopoietic stem cell transplant (HSCT) between 1990 and 2010. Thirty nine (50%) patients had ≤ 43 chromosomes, 12 (15%) had 44 chromosomes and 27 (35%) had 45 chromosomes. Forty three (55%) patients were transplanted in first remission (CR1) while 35 (45%) were transplanted in ≥CR2. Twenty nine patients (37%) received a graft from a related donor and 49 (63%) from an unrelated donor. All patients received a myeloablative conditioning regimen. The 5-year probabilities of leukemia-free survival (LFS), overall survival (OS), relapse, and treatment related mortality (TRM) for the entire cohort were 51%, 56%, 27% and 22% respectively. Multivariate analysis confirmed that mortality risks were higher for patients transplanted in CR2 (HR 2.16, p=0.05), with chromosome number ≤43 (HR 2.15, p=0.05) and for those transplanted in the first decade of the study period (HR 2.60, p=0.01). Similarly, treatment failure risks were higher with chromosome number ≤43 (HR 2.28, p=0.04) and the earlier transplant period (HR 2.51, p=0.01). Although survival is better with advances in donor selection and supportive care, disease-related risk factors significantly influence transplantation outcomes. PMID:25865650

  14. Dynamic MRI-based computer aided diagnostic systems for early detection of kidney transplant rejection: A survey

    NASA Astrophysics Data System (ADS)

    Mostapha, Mahmoud; Khalifa, Fahmi; Alansary, Amir; Soliman, Ahmed; Gimel'farb, Georgy; El-Baz, Ayman

    2013-10-01

    Early detection of renal transplant rejection is important to implement appropriate medical and immune therapy in patients with transplanted kidneys. In literature, a large number of computer-aided diagnostic (CAD) systems using different image modalities, such as ultrasound (US), magnetic resonance imaging (MRI), computed tomography (CT), and radionuclide imaging, have been proposed for early detection of kidney diseases. A typical CAD system for kidney diagnosis consists of a set of processing steps including: motion correction, segmentation of the kidney and/or its internal structures (e.g., cortex, medulla), construction of agent kinetic curves, functional parameter estimation, diagnosis, and assessment of the kidney status. In this paper, we survey the current state-of-the-art CAD systems that have been developed for kidney disease diagnosis using dynamic MRI. In addition, the paper addresses several challenges that researchers face in developing efficient, fast and reliable CAD systems for the early detection of kidney diseases.

  15. β-Cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection.

    PubMed

    El Khatib, M M; Sakuma, T; Tonne, J M; Mohamed, M S; Holditch, S J; Lu, B; Kudva, Y C; Ikeda, Y

    2015-05-01

    Protection of β cells from autoimmune destruction potentially cures type 1 diabetes mellitus (T1D). During antigen presentation, interactions between cytotoxic T-lymphocyte antigen-4 (CTLA4) and B7 molecules, or programmed death 1 (PD1) and its ligand PDL1, negatively regulate immune responses in a non-redundant manner. Here we employed β-cell-targeted adeno-associated virus serotype 8 (AAV8)-based vectors to overexpress an artificial PDL1-CTLA4Ig polyprotein or interleukin 10 (IL10). β-Cell-targeted expression of PDL1-CTLA4Ig or IL10 preserved β-cell mass and protected NOD mice from T1D development. When NOD mice were treated with vectors at early onset of hyperglycemia, PDL1-CTLA4Ig or IL10 alone failed to normalize the early onset of hyperglycemia. When drug-induced diabetic mice received major histocompatibility complex (MHC)-matched allo-islets, with or without pretreatment of the PDL1-CTLA4Ig-expressing vector, PDL1-CTLA4Ig-expressing islets were protected from rejection for at least 120 days. Similarly, transplantation of PDL1-CTLA4Ig-expressing MHC-matched islets into mice with established T1D resulted in protection of allo-islets from acute rejection, although islet grafts were eventually rejected. Thus the present study demonstrates the potent immuno-suppressive effects of β-cell-targeted PDL1-CTLA4Ig overexpression against T1D development and allo-islet rejection. The gene-based simultaneous inhibition of PD1 and CTLA4 pathways provides a unique strategy for immunosuppression-free tissue/organ transplantation, especially in the setting of no established autoimmunity.

  16. Novel insights into pretransplant allosensitization in heart transplant recipients in the contemporary era of immunosuppression and rejection surveillance.

    PubMed

    Svobodova, Eva; Gazdic, Tomas; Kubanek, Milos; Vymetalova, Jevgenija; Voska, Ludek; Kment, Martin; Lanska, Vera; Kolesar, Libor; Urban, Marian; Netuka, Ivan; Pirk, Jan; Melenovsky, Vojtech; Kautzner, Josef; Slavcev, Antonij; Malek, Ivan

    2016-01-01

    Solid-phase assays (SPA) have facilitated detection and definition of antibodies to human leukocyte antigens (HLA) and major histocompatibility complex class I chain-related antigen A (MICA). However, clinical consequences of pretransplant SPA results in heart transplantation have been studied insufficiently in the current era of immunosuppression and rejection surveillance. Pretransplant sera, panel-reactive antibodies (PRA), pretransplant crossmatch, and clinical data were retrospectively analyzed in 264 adult heart transplant recipients. The specificity of HLA and MICA antibodies and C1q-binding activity of donor-specific antibodies (DSA) were defined using SPA. Pretransplant HLA antibodies were detected in 57 (22%) individuals, in 28 individuals (11%); these antibodies were DSA after transplant. Preformed DSA and elevated peak PRA were independent predictors of pathologic AMR, which occurred in 19 individuals (7%). The increasing number of DSA and the cumulative mean fluorescence intensity of DSA were associated with AMR. C1q-binding assay was a suboptimal predictor of AMR in our cohort. Pretransplant allosensitization and MICA antibodies were related neither to impaired graft survival nor to other adverse clinical events during a median follow-up of 39 months. Identification of preformed DSA by SPA, in addition to PRA monitoring, may predict AMR in the contemporary era of heart transplantation.

  17. Knockdown of toll-like receptor 4 signaling pathways ameliorate bone graft rejection in a mouse model of allograft transplantation

    PubMed Central

    Hsieh, Jeng-Long; Shen, Po-Chuan; Wu, Po-Ting; Jou, I-Ming; Wu, Chao-Liang; Shiau, Ai-Li; Wang, Chrong-Reen; Chong, Hao-Earn; Chuang, Shu-Han; Peng, Jia-Shiou; Chen, Shih-Yao

    2017-01-01

    Non-union occurring in structural bone grafting is a major problem in allograft transplantation because of impaired interaction between the host and graft tissue. Activated toll-like receptor (TLR) induces inflammatory cytokines and chemokines and triggers cell-mediated immune responses. The TLR-mediated signal pathway is important for mediating allograft rejection. We evaluated the effects of local knockdown of the TLR4 signaling pathway in a mouse segmental femoral graft model. Allografts were coated with freeze-dried lentiviral vectors that encoded TLR4 and myeloid differentiation primary response gene 88 (MyD88) short-hairpin RNA (shRNA), which were individually transplanted into the mice. They were assessed morphologically, radiographically, and histologically for tissue remodeling. Union occurred in autografted but not in allografted mice at the graft and host junctions after 4 weeks. TLR4 and MyD88 expression was up-regulated in allografted mice. TLR4 and MyD88 shRNAs inhibited TLR4 and MyD88 expression, which led to better union in the grafted sites. More regulatory T-cells in the draining lymph nodes suggested inflammation suppression. Local inhibition of TLR4 and MyD88 might reduce immune responses and ameliorate allograft rejection. PMID:28393847

  18. BAT2 and BAT3 polymorphisms as novel genetic risk factors for rejection after HLA-related stem cell transplantation

    PubMed Central

    Piras, Ignazio Stefano; Angius, Andrea; Andreani, Marco; Testi, Manuela; Lucarelli, Guido; Floris, Matteo; Marktel, Sarah; Ciceri, Fabio; La Nasa, Giorgio; Fleischhauer, Katharina; Roncarolo, Maria Grazia; Bulfone, Alessandro

    2014-01-01

    The genetic background of donor and recipient is an important factor determining the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We applied a whole genome analysis to investigate genetic variants - other than HLA class I and II - associated with negative outcome after HLA-identical sibling allo-HSCT in a cohort of 110 β-Thalassemic patients. We identified two single nucleotide polymorphisms in BAT2 (A/G) and BAT3 (T/C) genes, SNP rs11538264 and SNP rs10484558, both located in the HLA class III region, in strong Linkage Disequilibrium between each other (R2=0.92). When considered as single SNP, none of them reached a significant association with graft rejection (nominal P < 0.00001 for BAT2 SNP rs11538264, and P < 0.0001 for BAT3 SNP rs10484558). Whereas, the BAT2/BAT3 A/C haplotype was present at significantly higher frequency in patients who rejected as compared to those with functional graft (30.0% vs. 2.6%, nominal P = 1.15×10−8; and adjusted P = 0.0071). The BAT2/BAT3 polymorphisms and specifically the A/C haplotype may represent novel immunogenetic factor associated with graft rejection in patients undergoing allo-HSCT. PMID:25111513

  19. Bortezomib in the treatment of antibody-mediated rejection in pediatric kidney transplant recipients: A multicenter Midwest Pediatric Nephrology Consortium study.

    PubMed

    Kizilbash, Sarah; Claes, Donna; Ashoor, Isa; Chen, Ashton; Jandeska, Sara; Matar, Raed Bou; Misurac, Jason; Sherbotie, Joseph; Twombley, Katherine; Verghese, Priya

    2017-05-01

    Antibody-mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody-mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy-proven antibody-mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients. Thirty-three patients received bortezomib for antibody-mediated rejection at nine pediatric kidney transplant centers. Ninety percent of patients received intravenous immunoglobulin, 78% received plasmapheresis, and 78% received rituximab. After a median follow-up of 15 months, 65% of patients had a functioning graft. The estimated glomerular filtration rate improved or stabilized in 61% and 36% of patients at 3 and 12 months post-bortezomib, respectively. The estimated glomerular filtration rate at diagnosis significantly predicted estimated glomerular filtration rate at 12 months after adjusting for chronic histologic changes (P .001). Fifty-six percent of patients showed an at least 25% reduction in the mean fluorescence intensity of the immune-dominant donor-specific antibody, 1-3 months after the first dose of bortezomib. Non-life-threatening side effects were documented in 21 of 33 patients. Pediatric kidney transplant recipients tolerated bortezomib without life-threatening side effects. Bortezomib may stabilize estimated glomerular filtration rate for 3-6 months in pediatric kidney transplant recipients with antibody-mediated rejection.

  20. T-cell-replete haploidentical transplantation versus autologous stem cell transplantation in adult acute leukemia: a matched pair analysis.

    PubMed

    Gorin, Norbert-Claude; Labopin, Myriam; Piemontese, Simona; Arcese, William; Santarone, Stella; Huang, He; Meloni, Giovanna; Ferrara, Felicetto; Beelen, Dietrich; Sanz, Miguel; Bacigalupo, Andrea; Ciceri, Fabio; Mailhol, Audrey; Nagler, Arnon; Mohty, Mohamad

    2015-04-01

    Adult patients with acute leukemia in need of a transplant but without a genoidentical donor are usually considered upfront for transplantation with stem cells from any other allogeneic source, rather than autologous stem cell transplantation. We used data from the European Society for Blood and Marrow Transplantation and performed a matched pair analysis on 188 T-cell-replete haploidentical and 356 autologous transplants done from January 2007 to December 2012, using age, diagnosis, disease status, cytogenetics, and interval from diagnosis to transplant as matching factors. "Haploidentical expert" centers were defined as having reported more than five haploidentical transplants for acute leukemia (median value for the study period). The median follow-up was 28 months. Multivariate analyses, including type of transplant categorized into three classes ("haploidentical regular", "haploidentical expert" and autologous), conditioning intensity (reduced intensity versus myeloablative conditioning) and the random effect taking into account associations related to matching, showed that non-relapse mortality was higher following haploidentical transplants in expert (HR: 4.7; P=0.00004) and regular (HR: 8.98; P<10(-5)) centers. Relapse incidence for haploidentical transplants was lower in expert centers (HR:0.39; P=0.0003) but in regular centers was similar to that for autologous transplants. Leukemia-free survival and overall survival rates were higher following autologous transplantation than haploidentical transplants in regular centers (HR: 1.63; P=0.008 and HR: 2.31; P=0.0002 respectively) but similar to those following haploidentical transplants in expert centers. We conclude that autologous stem cell transplantation should presently be considered as a possible alternative to haploidentical transplantation in regular centers that have not developed a specific expert program.

  1. Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibody-mediated rejection: a pilot study.

    PubMed

    Bachelet, Thomas; Nodimar, Celine; Taupin, Jean-Luc; Lepreux, Sebastien; Moreau, Karine; Morel, Delphine; Guidicelli, Gwendaline; Couzi, Lionel; Merville, Pierre

    2015-05-01

    Outcome of patients with transplant glomerulopathy (TG) is poor. Using B-cell targeting molecules represent a rational strategy to treat TG during chronic antibody-mediated rejection. In this pilot study, 21 patients with this diagnosis received four doses of intravenous immunoglobulins and two doses of rituximab (IVIG/RTX group). They were retrospectively compared with a untreated control group of 10 patients. At 24 months post-biopsy, graft survival was similar and poor between the treated and the untreated group, 47% vs. 40%, respectively, p = 0.69. This absence of response of IVIG/RTX treatment was observed, regardless the phenotype of TG. Baseline estimated glomerular filtration rate (eGFR) and decline in eGFR during the first six months after the treatment were risk factors associated with 24-month graft survival. The IVIG/RTX therapy had a modest effect on the kinetics of donor-specific alloantibodies at M24, compared to the untreated group, not associated with an improvement in graft survival. The mean number of adverse events per patient was higher in the IVIG/RTX group than in the control group (p = 0.03). Taken together, IVIG/RTX treatment for severe TG during chronic antibody-mediated rejection does not seem to change the natural history of TG and is associated with a high incidence of adverse events.

  2. Physalins B, F and G, seco-steroids purified from Physalis angulata L., inhibit lymphocyte function and allogeneic transplant rejection.

    PubMed

    Soares, M B P; Brustolim, D; Santos, L A; Bellintani, M C; Paiva, F P; Ribeiro, Y M; Tomassini, T C B; Ribeiro Dos Santos, R

    2006-03-01

    Physalis angulata is a solanaceae widely used in folk medicine in various tropical countries in the world. We have previously described that seco-steroids (physalins) purified from P. angulata are potent inhibitors of macrophage activation, blocking the production of pro-inflammatory cytokines and LPS-induced lethality. Herein we investigated the immunomodulatory activities of these substances in lymphocyte proliferation and cytokine production and in transplantation. The addition of physalins B, F or G to concanavalin A-activated splenocyte cultures induced a concentration-dependent inhibition of proliferation. Physalin B also inhibited IL-2 production by Con A-activated spleen cells. The addition of 2 mug/ml physalin B to mixed lymphocyte reaction (MLR) caused a 100% inhibition of proliferation. More importantly, treatment of mice with physalin B, F or G prevented the rejection of allogeneic heterotopic heart transplant. Our results demonstrate the suppressive activity of physalins B, F and G in lymphocyte function and indicate the potential use of physalins as immunosuppressive agents for treatments of pathologies in which inhibition of immune responses is desired.

  3. The molecular landscape of antibody-mediated kidney transplant rejection: evidence for NK involvement through CD16a Fc receptors.

    PubMed

    Venner, J M; Hidalgo, L G; Famulski, K S; Chang, J; Halloran, P F

    2015-05-01

    The recent recognition that antibody-mediated rejection (ABMR) is the major cause of kidney transplant loss creates strong interest in its pathogenesis. We used microarray analysis of kidney transplant biopsies to identify the changes in pure ABMR. We found that the ABMR transcript changes in the initial Discovery Set were strongly conserved in a subsequent Validation Set. In the Combined Set of 703 biopsies, 2603 transcripts were significantly changed (FDR < 0.05) in ABMR versus all other biopsies. In cultured cells, the transcripts strongly associated with ABMR were expressed in endothelial cells, e.g. cadherins CDH5 and CDH13; IFNG-treated endothelial cells, e.g. phospholipase PLA1A and chemokine CXCL11; or NK cells, e.g. cytotoxicity molecules granulysin (GNLY) and FGFBP2. Other ABMR transcripts were expressed in normal kidney but not cell lines, either increased e.g. Duffy chemokine receptor (DARC) or decreased e.g. sclerostin (SOST). Pathway analysis of ABMR transcripts identified angiogenesis, with roles for angiopoietin and vascular endothelial growth factors; leukocyte-endothelial interactions; and NK signaling, including evidence for CD16a Fc receptor signaling elements shared with T cells. These data support a model of ABMR involving injury-repair in the microcirculation induced by cognate recognition involving antibody and CD16a, triggering IFNG release and antibody-dependent NK cell-mediated cytotoxicity.

  4. Relationship between European Mitochondrial Haplogroups and Chronic Renal Allograft Rejection in Patients with Kidney Transplant

    PubMed Central

    JIMÉNEZ-SOUSA, María Angeles; TAMAYO, Eduardo; GUZMÁN-FULGENCIO, María; FERNÁNDEZ-RODRÍGUEZ, Amanda; HEREDIA-RODRIGUEZ, María; GARCÍA-ÁLVAREZ, Mónica; BERMEJO-MARTIN, Jesús F; PINEDA-TENOR, Daniel; RUIZ-GRANADO, Patricia; ALVAREZ-FUENTE, Elisa; GÓMEZ-SANCHEZ, Esther; GÓMEZ-HERRERAS, José I; RESINO, Salvador

    2014-01-01

    Mitochondrial DNA variants may contribute to differences in mitochondrial function, leading to an altered immune system. The aim of this study was to analyze the relationship between mtDNA haplogroups and the development of chronic allograft dysfunction in patients with kidney transplant. A retrospective observational study was carried out on 261 patients who received kidney transplant (114 had stable transplant and 147 patients developed chronic allograft dysfunction). DNA samples were genotyped for 14 mtDNA polymorphisms by using Sequenom's MassARRAY platform (San Diego, CA, USA). Only European white patients within the N macro-cluster were included. Patients with haplogroups V (odds ratio (OR)=0.32; p=0.037) and J (OR=0.36; p=0.038) showed lower odds for developing CRAD than patients with haplogroup H. After adjusting for the most significant variables, haplogroups V and J tended to statistical significance (p=0.091 and p=0.067 respectively). This is a preliminary study in which mtDNA haplogroups seem to be implicated in susceptibility or protection for developing chronic allograft dysfunction. PMID:25170295

  5. Concise Review: Mechanisms Behind Apoptotic Cell-Based Therapies Against Transplant Rejection and Graft versus Host Disease.

    PubMed

    Morelli, Adrian E; Larregina, Adriana T

    2016-05-01

    The main limitations to the success of transplantation are the antigraft response developed by the recipient immune system, and the adverse side effects of chronic immunosuppression. Graft-versus-host disease (GVHD) triggered by donor-derived T lymphocytes against the recipient tissues is another serious obstacle in the field of hematopoietic stem cell transplantation. Several laboratories have tested the possibility of promoting antigen (Ag)-specific tolerance for therapy of graft rejection, GVHD, and autoimmune disorders, by developing methodologies that mimic the mechanisms by which the immune system maintains peripheral tolerance in the steady state. It has been long recognized that the silent clearance of cells undergoing apoptosis exerts potent immune-regulatory effects and provides apoptotic cell-derived Ags to those Ag-presenting cells (APCs) that internalize them, in particular macrophages and dendritic cells. Therefore, in situ-targeting of recipient APCs by systemic administration of leukocytes in early apoptosis and bearing donor Ags represents a relatively simple approach to control the antidonor response against allografts. Here, we review the mechanisms by which apoptotic cells are silently cleared by phagocytes, and how such phenomenon leads to down-regulation of the innate and adaptive immunity. We discuss the evolution of apoptotic cell-based therapies from murine models of organ/tissue transplantation and GVHD, to clinical trials. We make emphasis on potential limitations and areas of concern of apoptotic cell-based therapies, and on how other immune-suppressive therapies used in the clinics or tested experimentally likely also function through the silent clearance of apoptotic cells by the immune system. Stem Cells 2016;34:1142-1150.

  6. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

    PubMed

    Vyas, Paresh; Appelbaum, Frederick R; Craddock, Charles

    2015-01-01

    Allogeneic stem cell transplantation is an increasingly important treatment option in the management of adult acute myeloid leukemia (AML). The major causes of treatment failure remain disease relapse and treatment toxicity. In this review, Dr Vyas presents an overview of important recent data defining molecular factors associated with treatment failure in AML. He also identifies the emerging importance of leukemia stem cell biology in determining both response to therapy and relapse risk in AML. Dr Appelbaum discusses advances in the design and delivery of both myeloablative and reduced-intensity conditioning regimens, highlighting novel strategies with the potential to improve outcome. Dr Craddock discusses the development of both novel conditioning regimens and post-transplantation strategies aimed at reducing the risk of disease relapse.

  7. Reprint of: Allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

    PubMed

    Vyas, Paresh; Appelbaum, Frederick R; Craddock, Charles

    2015-02-01

    Allogeneic stem cell transplantation is an increasingly important treatment option in the management of adult acute myeloid leukemia (AML). The major causes of treatment failure remain disease relapse and treatment toxicity. In this review, Dr Vyas presents an overview of important recent data defining molecular factors associated with treatment failure in AML. He also identifies the emerging importance of leukemia stem cell biology in determining both response to therapy and relapse risk in AML. Dr Appelbaum discusses advances in the design and delivery of both myeloablative and reduced-intensity conditioning regimens, highlighting novel strategies with the potential to improve outcome. Dr Craddock discusses the development of both novel conditioning regimens and post-transplantation strategies aimed at reducing the risk of disease relapse.

  8. Propylthiouracil-induced acute liver failure: role of liver transplantation.

    PubMed

    Carrion, Andres F; Czul, Frank; Arosemena, Leopoldo R; Selvaggi, Gennaro; Garcia, Monica T; Tekin, Akin; Tzakis, Andreas G; Martin, Paul; Ghanta, Ravi K

    2010-01-01

    Propylthiouracil- (PTU-) induced hepatotoxicity is rare but potentially lethal with a spectrum of liver injury ranging from asymptomatic elevation of transaminases to fulminant hepatic failure and death. We describe two cases of acute hepatic failure due to PTU that required liver transplantation. Differences in the clinical presentation, histological characteristics, and posttransplant management are described as well as alternative therapeutic options. Frequent monitoring for PTU-induced hepatic dysfunction is strongly advised because timely discontinuation of this drug and implementation of noninvasive therapeutic interventions may prevent progression to liver failure or even death.

  9. Drawing networks of rejection - a systems biological approach to the identification of candidate genes in heart transplantation.

    PubMed

    Cadeiras, Martin; von Bayern, Manuel; Sinha, Anshu; Shahzad, Khurram; Latif, Farhana; Lim, Wei Keat; Grenett, Hernan; Tabak, Esteban; Klingler, Tod; Califano, Andrea; Deng, Mario C

    2011-04-01

    Technological development led to an increased interest in systems biological approaches to characterize disease mechanisms and candidate genes relevant to specific diseases. We suggested that the human peripheral blood mononuclear cells (PBMC) network can be delineated by cellular reconstruction to guide identification of candidate genes. Based on 285 microarrays (7370 genes) from 98 heart transplant patients enrolled in the Cardiac Allograft Rejection Gene Expression Observational study, we used an information-theoretic, reverse-engineering algorithm called ARACNe (algorithm for the reconstruction of accurate cellular networks) and chromatin immunoprecipitation assay to reconstruct and validate a putative gene PBMC interaction network. We focused our analysis on transcription factor (TF) genes and developed a priority score to incorporate aspects of network dynamics and information from published literature to supervise gene discovery. ARACNe generated a cellular network and predicted interactions for each TF during rejection and quiescence. Genes ranked highest by priority score included those related to apoptosis, humoural and cellular immune response such as GA binding protein transcription factor (GABP), nuclear factor of κ light polypeptide gene enhancer in B-cells (NFκB), Fas (TNFRSF6)-associated via death domain (FADD) and c-AMP response element binding protein. We used the TF CREB to validate our network. ARACNe predicted 29 putative first-neighbour genes of CREB. Eleven of these (37%) were previously reported. Out of the 18 unknown predicted interactions, 14 primers were identified and 11 could be immunoprecipitated (78.6%). Overall, 75% (n= 22) inferred CREB targets were validated, a significantly higher fraction than randomly expected (P < 0.001, Fisher's exact test). Our results confirm the accuracy of ARACNe to reconstruct the PBMC transcriptional network and show the utility of systems biological approaches to identify possible molecular targets

  10. Acute Kidney Injury in Hematopoietic Stem Cell Transplantation: A Review

    PubMed Central

    Gupta, Mohit; Manu, Gurusidda; Kwatra, Shivani; Owusu, Osei-Tutu

    2016-01-01

    Hematopoietic stem cell transplantation (HSCT) is a highly effective treatment strategy for lymphoproliferative disorders and bone marrow failure states including aplastic anemia and thalassemia. However, its use has been limited by the increased treatment related complications, including acute kidney injury (AKI) with an incidence ranging from 20% to 73%. AKI after HSCT has been associated with an increased risk of mortality. The incidence of AKI reported in recipients of myeloablative allogeneic transplant is considerably higher in comparison to other subclasses mainly due to use of cyclosporine and development of graft-versus-host disease (GVHD) in allogeneic groups. Acute GVHD is by itself a major independent risk factor for the development of AKI in HSCT recipients. The other major risk factors are sepsis, nephrotoxic medications (amphotericin B, acyclovir, aminoglycosides, and cyclosporine), hepatic sinusoidal obstruction syndrome (SOS), thrombotic microangiopathy (TMA), marrow infusion toxicity, and tumor lysis syndrome. The mainstay of management of AKI in these patients is avoidance of risk factors contributing to AKI, including use of reduced intensity-conditioning regimen, close monitoring of nephrotoxic medications, and use of alternative antifungals for prophylaxis against infection. Also, early identification and effective management of sepsis, tumor lysis syndrome, marrow infusion toxicity, and hepatic SOS help in reducing the incidence of AKI in HSCT recipients. PMID:27885340

  11. Two-Stage, In Silico Deconvolution of the Lymphocyte Compartment of the Peripheral Whole Blood Transcriptome in the Context of Acute Kidney Allograft Rejection

    PubMed Central

    Shannon, Casey P.; Balshaw, Robert; Ng, Raymond T.; Wilson-McManus, Janet E.; Keown, Paul; McMaster, Robert; McManus, Bruce M.; Landsberg, David; Isbel, Nicole M.; Knoll, Greg; Tebbutt, Scott J.

    2014-01-01

    Acute rejection is a major complication of solid organ transplantation that prevents the long-term assimilation of the allograft. Various populations of lymphocytes are principal mediators of this process, infiltrating graft tissues and driving cell-mediated cytotoxicity. Understanding the lymphocyte-specific biology associated with rejection is therefore critical. Measuring genome-wide changes in transcript abundance in peripheral whole blood cells can deliver a comprehensive view of the status of the immune system. The heterogeneous nature of the tissue significantly affects the sensitivity and interpretability of traditional analyses, however. Experimental separation of cell types is an obvious solution, but is often impractical and, more worrying, may affect expression, leading to spurious results. Statistical deconvolution of the cell type-specific signal is an attractive alternative, but existing approaches still present some challenges, particularly in a clinical research setting. Obtaining time-matched sample composition to biologically interesting, phenotypically homogeneous cell sub-populations is costly and adds significant complexity to study design. We used a two-stage, in silico deconvolution approach that first predicts sample composition to biologically meaningful and homogeneous leukocyte sub-populations, and then performs cell type-specific differential expression analysis in these same sub-populations, from peripheral whole blood expression data. We applied this approach to a peripheral whole blood expression study of kidney allograft rejection. The patterns of differential composition uncovered are consistent with previous studies carried out using flow cytometry and provide a relevant biological context when interpreting cell type-specific differential expression results. We identified cell type-specific differential expression in a variety of leukocyte sub-populations at the time of rejection. The tissue-specificity of these differentially

  12. High proportion of CD95(+) and CD38(+) in cultured CD8(+) T cells predicts acute rejection and infection, respectively, in kidney recipients.

    PubMed

    Mancebo, Esther; Castro, María José; Allende, Luís M; Talayero, Paloma; Brunet, Mercè; Millán, Olga; Guirado, Luís; López-Hoyos, Marcos; San Segundo, David; Rodrigo, Emilio; Muñoz, Pedro; Boix Giner, Francisco; Llorente Viñas, Santiago; Muro-Amador, Manuel; Paz-Artal, Estela

    2016-02-01

    The aim of this study was to find noninvasive T-cell markers able to predict rejection or infection risk after kidney transplantation. We prospectively examined T-lymphocyte subsets after cell culture stimulation (according to CD38, CD69, CD95, CD40L, and CD25 expression) in 79 first graft recipients from four centers, before and after transplantation. Patients were followed up for one year. Patients who rejected within month-1 (n=10) showed high pre-transplantation and week-1 post-transplantation percentages of CD95(+), in CD4(+) and CD8(+) T-cells (P<0.001 for all comparisons). These biomarkers conferred independent risk for early rejection (HR:5.05, P=0.061 and HR:75.31, P=0.004; respectively). The cut-off values were able to accurately discriminate between rejectors and non-rejectors and Kaplan-Meier curves showed significantly different free-of-rejection time rates (P<0.005). Patients who rejected after the month-1 (n=4) had a higher percentage of post-transplantation CD69(+) in CD8(+) T-cells than non-rejectors (P=0.002). Finally, patients with infection (n=41) previously showed higher percentage of CD38(+) in CD8(+) T-cells at all post-transplantation times evaluated, being this increase more marked in viral infections. A cut-off of 59% CD38(+) in CD8(+) T-cells at week-1, week-2 and month-2 reached 100% sensitivity for the detection of subsequent viral infections. In conclusion, predictive biomarkers of rejection and infection risk after transplantation were detected that could be useful for the personalized care of kidney recipients.

  13. [Current status and development of kidney transplantation].

    PubMed

    Kirste, G

    1993-01-01

    Since the first successful procedure in 1954 kidney transplantation has become a standard therapy of end stage renal disease. The knowledge of immunoregulation and immune response of the body has enabled people to recognize acute rejection of organs. HLA-testing and organ exchange on basis of HLA-compatibility are extremely important for a successful kidney transplantation. A shortage of organs is limiting the further increase of transplantations. Chronic rejection is in most cases the reason for late graft failure. Further investigations to develop new immunosuppressive drugs and to clarify immunological processes underlying chronic rejections are necessary in the future.

  14. Acute promyelocytic leukemia after renal transplant and filgrastim treatment for neutropenia

    PubMed Central

    Krause, John R.

    2016-01-01

    Prolonged immunosuppression in solid organ transplant recipients has been considered a risk for developing opportunistic infections and malignancies. Acute leukemia is a rare complication. We report a case of acute promyelocytic leukemia (APL) (FAB M3) after cadaveric renal transplant for focal segmental glomerulosclerosis in a 24-year-old woman. Her immunosuppressive therapy included tacrolimus, mycophenolate mofetil, and prednisone. Approximately 2 years after transplant, she became pancytopenic, prompting administration of filgrastim. A few doses caused a markedly increased blast count, resulting in a diagnosis of APL. She was successfully treated with all-trans-retinoic acid and arsenic trioxide. Myeloproliferative neoplasms after organ transplant or due to filgrastim are rare. PMID:27695174

  15. Infections in intestinal and multivisceral transplant recipients.

    PubMed

    Timpone, Joseph G; Girlanda, Raffaele; Rudolph, Lauren; Fishbein, Thomas M

    2013-06-01

    Intestinal and multivisceral transplantation has become an effective treatment option for patients with intestinal failure. More potent immunosuppressive therapy has resulted in a decreased incidence of acute rejection and has improved patient survival. However, infectious complications can cause significant morbidity both before and after transplantation. In comparison with other solid organ transplant recipients, these patients experience higher rates of acute allograft rejection, thus requiring higher levels of immunosuppression and escalating the risk of infection. This article reviews the most common infectious disease complications encountered, and proposes a potential temporal association for types of infections in this patient population.

  16. Nonapoptotic cell death in acute kidney injury and transplantation.

    PubMed

    Linkermann, Andreas

    2016-01-01

    Acute tubular necrosis causes a loss of renal function, which clinically presents as acute kidney failure (AKI). The biochemical signaling pathways that trigger necrosis have been investigated in detail over the past 5 years. It is now clear that necrosis (regulated necrosis, RN) represents a genetically driven process that contributes to the pathophysiology of AKI. RN pathways such as necroptosis, ferroptosis, parthanatos, and mitochondrial permeability transition-induced regulated necrosis (MPT-RN) may be mechanistically distinct, and the relative contributions to overall organ damage during AKI in living organisms largely remain elusive. In a synchronized manner, some necrotic programs induce the breakdown of tubular segments and multicellular functional units, whereas others are limited to killing single cells in the tubular compartment. Importantly, the means by which a renal cell dies may have implications for the subsequent inflammatory response. In this review, the recent advances in the field of renal cell death in AKI and key enzymes that might serve as novel therapeutic targets will be discussed. As a consequence of the interference with RN, the immunogenicity of dying cells in AKI in renal transplants will be diminished, rendering inhibitors of RN indirect immunosuppressive agents.

  17. Patterns of Early Rejection in Renal Retransplantation: A Single-Center Experience

    PubMed Central

    Fu, Cheng; Lin, Kailin; Wang, Zhiqiang; Guo, Hui; Chen, Song; Lin, Zhengbin; Chen, Zhishui

    2016-01-01

    It has been reported that kidney retransplant patients had high rates of early acute rejection due to previous sensitization. In addition to the acute antibody-mediated rejection (ABMR) that has received widespread attention, the early acute T-cell-mediated rejection (TCMR) may be another important issue in renal retransplantation. In the current single-center retrospective study, we included 33 retransplant patients and 90 first transplant patients with similar protocols of induction and maintenance therapy. Analysis focused particularly on the incidence and patterns of early acute rejection episodes, as well as one-year graft and patient survival. Excellent short-term clinical outcomes were obtained in both groups, with one-year graft and patient survival rates of 93.9%/100% in the retransplant group and 92.2%/95.6% in the first transplant group. Impressively, with our strict immunological selection and desensitization criteria, the retransplant patients had a very low incidence of early acute ABMR (6.1%), which was similar to that in the first transplant patients (4.4%). However, a much higher rate of early acute TCMR was observed in the retransplant group than in the first transplant group (30.3% versus 5.6%, P < 0.001). Acute TCMR that develops early after retransplantation should be monitored in order to obtain better transplant outcomes. PMID:28058265

  18. 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.

  19. Gallium-67 imaging in human heart transplantation: correlation with endomyocardial biopsy

    SciTech Connect

    Meneguetti, J.C.; Camargo, E.E.; Soares, J. Jr.; Bellotti, G.; Bocchi, E.; Higuchi, M.L.; Stolff, N.; Hironaka, F.H.; Buchpiguel, C.A.; Pileggi, F.

    1987-05-01

    Endomyocardial biopsy seems to be the most accurate method to use for diagnosis and follow-up of acute rejection of the transplanted heart. This investigation compared a noninvasive procedure, gallium-67 imaging, with endomyocardial biopsy in the detection of acute rejection in heart transplantation. Seven male patients (aged 41 to 54 years) sequentially had 46 gallium-67 scintigrams and 46 endomyocardial biopsies between 1 week and 8 months after transplantation. Both studies were obtained in the same day, 48 hours after the administration of an intravenous injection of gallium-67 citrate. Cardiac uptake was graded as negative, mild, moderate, and marked according to an increasing count ratio with rib and sternal uptakes. Histologic findings were graded as negative, mild acute rejection, moderate acute rejection, severe acute rejection, resolving rejection, and nonspecific reaction. Negative biopsies were not found with moderate uptake, and neither moderate nor severe acute rejection were found with negative scintigrams. Imaging sensitivity was 83% with 17% false negatives and 9% false positives. Of seven studies with moderate uptake, five showed moderate acute rejection, and the patients had specific therapy with a decline in uptake, which correlated with resolving rejection. It is conceivable that in the future this technique may be used as a screening procedure for sequential endomyocardial biopsies in the follow-up of heart transplant patients.

  20. C1q binding is not an independent risk factor for kidney allograft loss after an acute antibody-mediated rejection episode: a retrospective cohort study.

    PubMed

    Moktefi, Anissa; Parisot, Juliette; Desvaux, Dominique; Canoui-Poitrine, Florence; Brocheriou, Isabelle; Peltier, Julie; Audard, Vincent; Kofman, Tomek; Suberbielle, Caroline; Lang, Philippe; Rondeau, Eric; Grimbert, Philippe; Matignon, Marie

    2017-03-01

    After kidney transplantation, C4d is an incomplete marker of acute antibody-mediated rejection (AMR) and C1q-binding donor-specific antibodies (DSA) have been associated with allograft survival. However, the impact on allograft survival of C1q+ DSA after clinical AMR has not been studied yet. We analysed retrospectively in clinical AMR C4d staining and C1q-binding impact on allograft survival. We compared clinical, histological and serological features of C4d- and C4d+ AMR, C1q+ and C1q- DSA AMR and analysed C4d and C1q-binding impact on allograft survival. Among 500 for-cause kidney allograft biopsies, 48 fulfilled AMR criteria. C4d+ AMR [N = 18 (37.5%)] have significantly higher number class I DSA (P = 0.02), higher microvascular score (P = 0.02) and more transplant glomerulopathy (P = 0.04). C1q+ AMR [N = 20 (44%)] presented with significantly more class I and class II DSA (P = 0.005 and 0.04) and C4d+ staining (P = 0.01). Graft losses were significantly higher in the C4d+ group (P = 0.04) but similar in C1q groups. C4d+ but not C1q+ binding was an independent risk factor for graft loss [HR = 2.65; (1.11-6.34); P = 0.028]. In our cohort of clinical AMR, C4d+ staining but not C1q+ binding is an independent risk factor for graft loss. Allograft loss and patient survival were similar in C1q+ and C1q- AMR.

  1. Different regulatory and cytotoxic CD4+ T lymphocyte profiles in renal transplants with antibody-mediated chronic rejection or long-term good graft function.

    PubMed

    Giaretta, Fulvia; Bussolino, Stefania; Beltramo, Silvia; Fop, Fabrizio; Rossetti, Maura; Messina, Maria; Cantaluppi, Vincenzo; Ranghino, Andrea; Basso, Elisa; Camussi, Giovanni; Segoloni, Giuseppe Paolo; Biancone, Luigi

    2013-01-01

    Comparative analysis of the different subsets of CD4(+) T-lymphocytes may provide hints on the immunologic mechanisms operating in the long-term fate of a kidney transplant. We analyzed peripheral regulatory CD4(+) T cells (Tregs) and CD4(+) cytotoxic T lymphocytes (CTLs) in antibody-mediated chronic rejection (AMCR), in middle-term kidney transplants (2-4 years, MTKT) with good graft function and rejection-free history, in long-term kidney transplants (>15 years, LTKT) and in normal healthy subjects (NHS). Transplant groups with good prognosis (MTKT and LTKT) displayed a significant lower amount of CD4(+)CD25(high) T lymphocytes than NHS, with a trend of a higher percentage in AMCR than in MTKT and LTKT. However, CD4(+)CD25(high) Foxp3(+) cells were significantly higher in LTKT and MTKT than AMCR. Characterization of CD4(+)CD25(high) T cells showed a marked increase of intracellular CTLA-4 in the AMCR group in respect to the other transplant groups, while the expression of the surface molecule seemed to follow a reverse trend. In addition, CD27, a costimulatory receptor involved in long-term T cell survival and prevention of immune tolerance, is significantly reduced in CD4(+)CD25(high) and CD4(+)Foxp3(+) T cells in the LTKT in respect to the other transplant groups. CD4(+)CD25(high)CD45RO(+) and CD4(+)Foxp3(+)CD45RO(+) regulatory T cells with memory function were increased in LTKT compared to NHS and for the latter also in AMCR group. Finally, CD4(+)CTLs that were quantified on the basis of granzyme A expression, were more represented in AMCR patients in comparison to the other groups. Strikingly, CD27 in the CD4(+)CTLs was suppressed in LTKT and MTKT and markedly expressed in AMCR group. No significant differences in the expression of CD28 were observed among different groups. In conclusion, different profiles of Tregs and CD4(+)CTL populations correlate with different long-term conditions of kidney-transplanted patients, suggesting their role in the development

  2. Bridging therapies and liver transplantation in acute liver failure, 10 years of MARS experience from Finland.

    PubMed

    Kantola, T; Ilmakunnas, M; Koivusalo, A-M; Isoniemi, H

    2011-01-01

    Acute liver failure is a life-threatening condition in the absence of liver transplantation option. The aetiology of liver failure is the most important factor determining the probability of native liver recovery and prognosis of the patient. Extracorporeal liver assist devices like MARS (Molecular Adsorbent Recirculating System) may buy time for native liver recovery or serve as bridging therapy to liver transplantation, with reduced risk of cerebral complications. MARS treatment may alleviate hepatic encephalopathy even in patients with a completely necrotic liver. Taking this into account, better prognostic markers than hepatic encephalopathy should be used to assess the need for liver transplantation in acute liver failure.

  3. Allogeneic hematopoietic cell transplantation in adult patients with acute lymphoblastic leukemia.

    PubMed

    Marks, David I; Alonso, Laura; Radia, Rohini

    2014-12-01

    This review discusses the use of prognostic factors, patient and donor selection, choice of conditioning regimens, and timing of transplant. It also describes the management of Philadelphia-positive acute lymphocytic leukemia (ALL) and central nervous system disease. All aggressively treated adults with ALL should be considered for allogeneic transplantation and tissue typed at diagnosis. We further suggest that eligible patients be entered into clinical trials (that incorporate transplantation); these unselected prospective outcome data are essential to evaluate the true value of allogeneic transplantation in adults with ALL.

  4. Acute stimulation of transplanted neurons improves motoneuron survival, axon growth, and muscle reinnervation.

    PubMed

    Grumbles, Robert M; Liu, Yang; Thomas, Christie M; Wood, Patrick M; Thomas, Christine K

    2013-06-15

    Few options exist for treatment of pervasive motoneuron death after spinal cord injury or in neurodegenerative diseases such as amyotrophic lateral sclerosis. Local transplantation of embryonic motoneurons into an axotomized peripheral nerve is a promising approach to arrest the atrophy of denervated muscles; however, muscle reinnervation is limited by poor motoneuron survival. The aim of the present study was to test whether acute electrical stimulation of transplanted embryonic neurons promotes motoneuron survival, axon growth, and muscle reinnervation. The sciatic nerve of adult Fischer rats was transected to mimic the widespread denervation seen after disease or injury. Acutely dissociated rat embryonic ventral spinal cord cells were transplanted into the distal tibial nerve stump as a neuron source for muscle reinnervation. Immediately post-transplantation, the cells were stimulated at 20 Hz for 1 h. Other groups were used to control for the cell transplantation and stimulation. When neurons were stimulated acutely, there were significantly more neurons, including cholinergic neurons, 10 weeks after transplantation. This led to enhanced numbers of myelinated axons, reinnervation of more muscle fibers, and more medial and lateral gastrocnemius muscles were functionally connected to the transplant. Reinnervation reduced muscle atrophy significantly. These data support the concept that electrical stimulation rescues transplanted motoneurons and facilitates muscle reinnervation.

  5. Tacrolimus rescue in liver transplant patients with refractory rejection or intolerance or malabsorption of cyclosporine. The US Multicenter FK506 Liver Study Group.

    PubMed

    Klein, A

    1999-11-01

    Tacrolimus is an effective immunosuppressant in the rescue of liver allograft patients in whom conventional immunosuppression failed. Efficacy and safety were examined in a multicenter trial of liver transplant recipients converted to tacrolimus because of rejection despite cyclosporine (CyA) therapy or intolerance to CyA. Six hundred seventy-seven patients were enrolled onto the study; 475 patients for rejection, 197 patients for intolerance, and 5 patients treated compassionately. The mean daily dose of tacrolimus was less in the intolerance (Int) patients throughout the study: 0.22 versus 0.17 mg/kg at 1 week and 0.14 versus 0.11 mg/kg at 24 months in rejection (Rej) and Int patients, respectively. Mean blood levels paralleled dosing in both groups, but were greater in the Rej patients (10.7 v 8.3 ng/mL at 18 months). Kaplan-Meier estimates of patient and graft survival were similar in the two groups. Patient survival rates were 80.1% and 81.5%, and graft survival rates were 72.7% and 73.9% at 24 months in the Rej and Int patients, respectively. Most adverse events occurred with a similar incidence in the two groups. Those with a 4% or greater incidence were fever, viral hepatitis, and pneumonia. The incidence of sepsis, gastrointestinal hemorrhage, kidney failure, and convulsion was greater in the Int group. The incidence of abnormal liver function test results, hyperglycemia, headache, and abnormal kidney function was greater in the Rej group. Mean liver function test results decreased with time postrescue in both groups. Mean serum creatinine level increased from baseline to 18 months postrescue in both groups (1.44 to 1.51 mg/dL for Int patients, 1.14 to 1.48 mg/dL for Rej patients). We conclude tacrolimus is safe and effective rescue in liver transplant recipients with rejection or CyA intolerance.

  6. Thoracic organ transplantation: laboratory methods.

    PubMed

    Patel, Jignesh K; Kobashigawa, Jon A

    2013-01-01

    Although great progress has been achieved in thoracic organ transplantation through the development of effective immunosuppression, there is still significant risk of rejection during the early post-transplant period, creating a need for routine monitoring for both acute antibody and cellular mediated rejection. The currently available multiplexed, microbead assays utilizing solubilized HLA antigens afford the capability of sensitive detection and identification of HLA and non-HLA specific antibodies. These assays are being used to assess the relative strength of donor specific antibodies; to permit performance of virtual crossmatches which can reduce the waiting time to transplantation; to monitor antibody levels during desensitization; and for heart transplants to monitor antibodies post-transplant. For cell mediated immune responses, the recent development of gene expression profiling has allowed noninvasive monitoring of heart transplant recipients yielding predictive values for acute cellular rejection. T cell immune monitoring in heart and lung transplant recipients has allowed individual tailoring of immunosuppression, particularly to minimize risk of infection. While the current antibody and cellular laboratory techniques have enhanced the ability to manage thoracic organ transplant recipients, future developments from improved understanding of microchimerism and graft tolerance may allow more refined allograft monitoring techniques.

  7. Successful living donor liver transplantation for acute liver failure after acetylsalicylic acid overdose.

    PubMed

    Shirota, Tomoki; Ikegami, Toshihiko; Sugiyama, Satoshi; Kubota, Kouji; Shimizu, Akira; Ohno, Yasunari; Mita, Atsuyoshi; Urata, Koichi; Nakazawa, Yuichi; Kobayashi, Akira; Iwaya, Mai; Miyagawa, Shinichi

    2015-04-01

    A 20-year-old woman was admitted to an emergency hospital after ingesting 66 g of acetylsalicylic acid in a suicide attempt. Although she was treated with gastric lavage, oral activated charcoal, and intravenous hydration with sodium bicarbonate, her hepatic and renal function gradually deteriorated and serum amylase levels increased. Steroid pulse therapy, plasma exchange, and continuous hemodiafiltration did not yield any improvement in her hepatic or renal function, and she was transferred to our hospital for living donor liver transplantation. Nine days after drug ingestion, she developed hepatic encephalopathy: thus, we diagnosed the patient with acute liver failure with hepatic coma accompanied by acute pancreatitis due to the overdose of acetylsalicylic acid. Living donor liver transplantation was immediately performed using a left lobe graft from the patient's mother. Following transplantation, the patient's renal and hepatic function and consciousness improved, and she was discharged. In this report, we describe a rare case of acetylsalicylic acid-induced acute liver failure with acute hepatic coma and concomitant acute pancreatitis and acute renal failure, which were treated successfully with emergency living donor liver transplantation.

  8. Acute Myeloid Leukaemia of Donor Cell Origin Developing 17 Years after Allogenic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukaemia

    PubMed Central

    Jiménez, Pilar; Alvarez, J. Carlos; Garrido, Pilar; Lorente, J. Antonio; Palacios, Jorge; Ruiz-Cabello, Francisco

    2012-01-01

    Donor cell leukaemia (DCL) is a rare complication of allogenic hematopoietic cell transplantation (HCT). We report the case of a female patient with acute promyelocytic leukaemia (APL), FAB type M3, who developed acute myeloid leukaemia (AML) type M5 of donor origin 17 years after allogenic bone marrow transplantation (BMT) from her HLA-matched sister. Morphology and immunophenotyping showed differences with the initial leukaemia, and short tandem repeat (STR) analysis confirmed donor-type haematopoiesis. Interphase fluorescence in situ hybridisation (FISH) showed an 11q23 deletion. Given that the latency period between transplant and development of leukaemia was the longest reported to date, we discuss the mechanisms underlying delayed leukaemia onset. PMID:23675279

  9. Endovascular Treatment of Acute Portal Vein Thrombosis After Liver Transplantation in a Child

    SciTech Connect

    Carnevale, Francisco Cesar Borges, Marcus Vinicius; Moreira, Airton Mota; Cerri, Giovanni Guido; Maksoud, Joao Gilberto

    2006-06-15

    Although operative techniques in hepatic transplantation have reduced the time and mortality on waiting lists, the rate of vascular complications associated with these techniques has increased. Stenosis or thrombosis of the portal vein is an infrequent complication, and if present, surgical treatment is considered the traditional management. This article describes a case of acute portal vein thrombosis after liver transplantation from a living donor to a child managed by percutaneous techniques.

  10. Pentostatin and Lymphocyte Infusion in Preventing Graft Rejection in Patients Who Have Undergone Donor Stem Cell Transplant

    ClinicalTrials.gov

    2016-02-29

    Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Graft Versus Host Disease; Hodgkin Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma; Plasma Cell Myeloma; Waldenstrom Macroglobulinemia

  11. Lung Transplantation

    MedlinePlus

    ... are used to treat people who have severe COPD Cystic fibrosis Idiopathic pulmonary fibrosis Alpha-1 antitrypsin deficiency Pulmonary hypertension Complications of lung transplantation include rejection of the transplanted lung and infection. NIH: National Heart, Lung, and Blood Institute

  12. Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice

    PubMed Central

    Kashiyama, Noriyuki; Miyagawa, Shigeru; Fukushima, Satsuki; Kawamura, Takuji; Kawamura, Ai; Yoshida, Shohei; Harada, Akima; Watabe, Tadashi; Kanai, Yasukazu; Toda, Koichi; Hatazawa, Jun; Sawa, Yoshiki

    2016-01-01

    Allogeneic transplantation (Tx) of induced pluripotent stem cells (iPSCs) is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET) imaging targets translocator protein (TSPO), which is highly expressed on mitochondrial membrane, especially in activated macrophage. N,N-diethyl-2-[4-(2-fluoroethoxy) phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714) is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs) of allogeneic origin may be quantitated using 18F-DPA-714-PET imaging study. iPSC-CM cell-sheets of C57BL/6 mice origin were transplanted on the surface of the left ventricle (LV) of C57BL/6 mice as a syngeneic cell-transplant model (syngeneic Tx group), or Balb/c mice as an allogeneic model (allogeneic Tx group). 18F-DPA-714-PET was used to determine the uptake ratio, calculated as the maximum standardized uptake value in the anterior and septal wall of the LV. The uptake ratio was significantly higher in the allogeneic Tx group than in the syngeneic group or the sham group at days 7 and day 10 after the cell transplantation. In addition, the immunochemistry showed significant presence of CD68 and CD3-positive cells at day 7 and 10 in the transplanted graft of the allogeneic Tx group. The expression of TSPO, CD68, IL-1 beta, and MCP-1 was significantly higher in the allogeneic Tx group than in the syngeneic Tx and the sham groups at day 7. The 18F-DPA-714-PET imaging study enabled quantitative visualization of the macrophages-mediated immune rejection of

  13. Usefulness of Diastolic Strain Measurements in Predicting Elevated Left Ventricular Filling Pressure and Risk of Rejection or Coronary Artery Vasculopathy in Pediatric Heart Transplant Recipients.

    PubMed

    Lu, Jimmy C; Magdo, H Sonali; Yu, Sunkyung; Lowery, Ray; Aiyagari, Ranjit; Zamberlan, Mary; Gajarski, Robert J

    2016-05-01

    In pediatric heart transplant recipients, elevated pulmonary capillary wedge pressure (PCWP) is associated with rejection and coronary artery vasculopathy. This study aimed to evaluate which echocardiographic parameters track changes in PCWP and predict adverse outcomes (rejection or coronary artery vasculopathy). This prospective single-center study enrolled 49 patients (median 11.4 years old, interquartile range 7.4 to 16.5) at time of cardiac catheterization and echocardiography. Median follow-up was 2.4 years (range 1.2 to 3.1 years), with serial testing per clinical protocol. Ratio of early mitral inflow to annular velocity (E/E'), left atrial (LA) distensibility, peak LA systolic strain, E/left ventricular (LV) diastolic strain, and E/LV diastolic strain rate were measured from echocardiograms. Increase in PCWP ≥3 mm Hg was associated with changes in LA distensibility, E/E', and E/LV diastolic strain, with highest area under the receiver operating characteristic curve for E/LV diastolic strain (0.76). In 9 patients who subsequently developed rejection or coronary artery vasculopathy, E/LV diastolic strain rate at baseline differed from patients without events (median 57.0 vs 43.6, p = 0.02). On serial studies, only change in LV ejection fraction differed in patients with events (median -10% vs -1%, p = 0.01); decrease in LV ejection fraction of -19% had a specificity of 100% and sensitivity of 44%. In conclusion, LV diastolic strain and strain rate measurements can track changes in PCWP and identify patients at risk for subsequent rejection or coronary artery vasculopathy. Further studies are necessary to confirm these data in a larger cohort.

  14. Allograft loss from acute Page kidney secondary to trauma after kidney transplantation.

    PubMed

    Takahashi, Kazuhiro; Prashar, Rohini; Putchakayala, Krishna G; Kane, William J; Denny, Jason E; Kim, Dean Y; Malinzak, Lauren E

    2017-02-24

    We report a rare case of allograft loss from acute Page kidney secondary to trauma that occurred 12 years after kidney transplantation. A 67-year-old Caucasian male with a past surgical history of kidney transplant presented to the emergency department at a local hospital with left lower abdominal tenderness. He recalled that his cat, which weighs 15 lbs, jumped on his abdomen 7 d prior. On physical examination, a small tender mass was noticed at the incisional site of the kidney transplant. He was producing a normal amount of urine without hematuria. His serum creatinine level was slightly elevated from his baseline. Computer tomography revealed a large subscapular hematoma around the transplant kidney. The patient was observed to have renal trauma grade II at the hospital over a period of three days, and he was finally transferred to a transplant center after his urine output significantly decreased. Doppler ultrasound demonstrated an extensive peri-allograft hypoechoic area and abnormal waveforms with absent arterial diastolic flow and a patent renal vein. Despite surgical decompression, the allograft failed to respond appropriately due to the delay in surgical intervention. This is the third reported case of allograft loss from acute Page kidney following kidney transplantation. This case reinforces that kidney care differs if the kidney is solitary or a transplant. Early recognition and aggressive treatments are mandatory, especially in a case with Doppler signs that are suggestive of compression.

  15. Allograft loss from acute Page kidney secondary to trauma after kidney transplantation

    PubMed Central

    Takahashi, Kazuhiro; Prashar, Rohini; Putchakayala, Krishna G; Kane, William J; Denny, Jason E; Kim, Dean Y; Malinzak, Lauren E

    2017-01-01

    We report a rare case of allograft loss from acute Page kidney secondary to trauma that occurred 12 years after kidney transplantation. A 67-year-old Caucasian male with a past surgical history of kidney transplant presented to the emergency department at a local hospital with left lower abdominal tenderness. He recalled that his cat, which weighs 15 lbs, jumped on his abdomen 7 d prior. On physical examination, a small tender mass was noticed at the incisional site of the kidney transplant. He was producing a normal amount of urine without hematuria. His serum creatinine level was slightly elevated from his baseline. Computer tomography revealed a large subscapular hematoma around the transplant kidney. The patient was observed to have renal trauma grade II at the hospital over a period of three days, and he was finally transferred to a transplant center after his urine output significantly decreased. Doppler ultrasound demonstrated an extensive peri-allograft hypoechoic area and abnormal waveforms with absent arterial diastolic flow and a patent renal vein. Despite surgical decompression, the allograft failed to respond appropriately due to the delay in surgical intervention. This is the third reported case of allograft loss from acute Page kidney following kidney transplantation. This case reinforces that kidney care differs if the kidney is solitary or a transplant. Early recognition and aggressive treatments are mandatory, especially in a case with Doppler signs that are suggestive of compression. PMID:28280700

  16. [Acute renal failure secondary to hepatic veno-occlusive disease in a bone marrow transplant patient].

    PubMed

    Borrego, F J; Viedma, G; Pérez del Barrio, P; Gil, J M; de Santis-Scoccia, C; Ramírez Huerta, J M; Alcalá, A; Pérez Bañasco, V

    2003-01-01

    Acute renal failure following bone marrow transplantation is a frequent complication with an incidence ranging 15-30% and with high rates of morbidity and mortality. Numerous potential etiologies can be implicated as chemotherapy regimen, use of nephrotoxic antibiotics, sepsis-induced damage, cyclosporine toxicity and other especific pathologies as graft-v-host disease or veno-occlusive disease of the liver. We report the case of a 41-year-old man who underwent autologous peripheral blood stem cell transplantation and developed and acute renal failure secondary to a fatal veno-occlusive disease of the liver. Incidence, potential predisposing factors, outcome and possibilities of treatment are reviewed.

  17. Rational rejection? The ethical complications of assessing organ transplant candidates in the United Kingdom and the United States.

    PubMed

    Cherkassky, Lisa

    2010-09-01

    The practice of allocating scarce organs in medicine is an ethical minefield. Due to the organ shortage, organ procurement agencies in both the United Kingdom and the United States are placed in the unenviable position of having to choose a limited number of patients to compete equally for life-saving treatment. They do this by composing multidisciplinary transplant teams, which must evaluate transplant candidates and their complex range of personal, medical, environmental, psychiatric and financial characteristics. During the candidate assessment process, such teams may often be torn between their moral duty to save those who are most in need, considerations of efficiency, and the battle against forming moral judgments about particular candidates. Several ethical approaches can be adopted by transplant teams during the decision-making process, but do these ideologies provide adequate justification for their sometimes controversial decisions? This article provides a detailed examination of the ethical principles available to transplant teams in the United Kingdom and the United States, and the effect that these principles have on assessment procedures, organ allocation protocols, transplant candidates and their prospects.

  18. Endovascular Management of Acute Enteric Bleeding from Pancreas Transplant

    SciTech Connect

    Semiz-Oysu, Aslihan; Cwikiel, Wojciech

    2007-04-15

    Arterioenteric fistula is a rare but serious complication of enteric drained pancreas transplant, which may lead to massive gastrointestinal bleeding. We present 3 patients with failed enteric drained pancreas transplants and massive gastrointestinal bleeding secondary to arterioenteric fistula. One patient was treated by embolization and the 2 others by stent graft placement. Bleeding was successfully controlled in all cases, at follow up of 5 days, 8 months, and 12 months, respectively. One patient died 24 days after embolization, of unknown causes.

  19. Myoglobin cast nephropathy in a kidney transplant patient with normal creatine kinase.

    PubMed

    Oliveira da Fonseca, Elissa; Jittirat, Arksarapuk; Birdwell, Kelly A; Fogo, Agnes B

    2015-04-01

    Delayed graft function in kidney transplant recipients is a known complication associated with increased risk of acute rejection and reduced transplant survival after 1 year. There are multiple risk factors, including prolonged cold ischemia time, donor age, and cause of donor's death. Major causes of delayed graft function are acute kidney injury in the donor, often from prolonged terminal ischemia, reflected by acute tubular injury in the recipient. However, the differential diagnosis of delayed graft function includes acute rejection, recurrence of the primary glomerular diseases, and other less commonly encountered conditions. A transplant kidney biopsy usually is required to elucidate the correct cause and initiate the right treatment, which is crucial for transplant survival. We report a case of a transplant recipient who developed delayed graft function due to an uncommon cause. After correct diagnosis, the patient's transplant function improved.

  20. An acute negative bystander effect of γ-irradiated recipients on transplanted hematopoietic stem cells.

    PubMed

    Shen, Hongmei; Yu, Hui; Liang, Paulina H; Cheng, Haizi; XuFeng, Richard; Yuan, Youzhong; Zhang, Peng; Smith, Clayton A; Cheng, Tao

    2012-04-12

    Ultimate success of hematopoietic stem cell transplantation (HSCT) depends not only on donor HSCs themselves but also on the host environment. Total body irradiation is a component in various host conditioning regimens for HSCT. It is known that ionizing radiation exerts "bystander effects" on nontargeted cells and that HSCs transplanted into irradiated recipients undergo proliferative exhaustion. However, whether irradiated recipients pose a proliferation-independent bystander effect on transplanted HSCs is unclear. In this study, we found that irradiated mouse recipients significantly impaired the long-term repopulating ability of transplanted mouse HSCs shortly (∼ 17 hours) after exposure to irradiated hosts and before the cells began to divide. There was an increase of acute cell death associated with accelerated proliferation of the bystander hematopoietic cells. This effect was marked by dramatic down-regulation of c-Kit, apparently because of elevated reactive oxygen species. Administration of an antioxidant chemical, N-acetylcysteine, or ectopically overexpressing a reactive oxygen species scavenging enzyme, catalase, improved the function of transplanted HSCs in irradiated hosts. Together, this study provides evidence for an acute negative, yet proliferation-independent, bystander effect of irradiated recipients on transplanted HSCs, thereby having implications for HSCT in both experimental and clinical scenarios in which total body irradiation is involved.

  1. [Mesenchymal stromal cells transplantation in acute and chronic pancreatitis in rats].

    PubMed

    Lazebnik, L B; Trubitsyna, I E; Agafonov, M A; Kniazev, O V; Liundup, A V

    2011-01-01

    Before using MSC transplantation in the clinic to conduct preclinical studies MSCs to animals with acute and chronic pancreatitis. Work out the timing and dose of MSCs. The rationale of MSCs transplantation for the regeneration of damaged pancreatic tissue. The essence of the experiments is to establish the existence of common pathogenetic mechanisms for the development of pathological processes and sanogenesis toxic damage of pancreatic tissue. The study was work out in the rat model of acute and chronic pancreatitis, to explore beneficial and adverse effects of allogeneic stem cells for regenerative-reduction processes. For cell transplantation using allogenic stromal cell fraction of bone marrow, the cell suspension was injected at a dose of 2 x 10(6) and 5 x 10(6) cells.

  2. Intestinal and multivisceral transplantation

    PubMed Central

    Meira, Sérgio Paiva; Guardia, Bianca Della; Evangelista, Andréia Silva; Matielo, Celso Eduardo Lourenço; Neves, Douglas Bastos; Pandullo, Fernando Luis; Felga, Guilherme Eduardo Gonçalves; Alves, Jefferson André da Silva; Curvelo, Lilian Amorim; Diaz, Luiz Gustavo Guedes; Rusi, Marcela Balbo; Viveiros, Marcelo de Melo; de Almeida, Marcio Dias; Epstein, Marina Gabrielle; Pedroso, Pamella Tung; Salvalaggio, Paolo; Meirelles, Roberto Ferreira; Rocco, Rodrigo Andrey; de Almeida, Samira Scalso; de Rezende, Marcelo Bruno

    2015-01-01

    Intestinal transplantation has shown exceptional growth over the past 10 years. At the end of the 1990’s, intestinal transplantation moved out of the experimental realm to become a routine practice in treating patients with severe complications related to total parenteral nutrition and intestinal failure. In the last years, several centers reported an increasing improvement in survival outcomes (about 80%), during the first 12 months after surgery, but long-term survival is still a challenge. Several advances led to clinical application of transplants. Immunosuppression involved in intestinal and multivisceral transplantation was the biggest gain for this procedure in the past decade due to tacrolimus, and new inducing drugs, mono- and polyclonal anti-lymphocyte antibodies. Despite the advancement of rigid immunosuppression protocols, rejection is still very frequent in the first 12 months, and can result in long-term graft loss. The future of intestinal transplantation and multivisceral transplantation appears promising. The major challenge is early recognition of acute rejection in order to prevent graft loss, opportunistic infections associated to complications, post-transplant lymphoproliferative disease and graft versus host disease; and consequently, improve results in the long run. PMID:25993080

  3. Acute renal graft-versus-host disease in a murine model of allogeneic bone marrow transplantation.

    PubMed

    Schmid, Peter M; Bouazzaoui, Abdellatif; Schmid, Karin; Birner, Christoph; Schach, Christian; Maier, Lars S; Holler, Ernst; Endemann, Dierk H

    2017-03-23

    Acute kidney injury (AKI) is a very common complication after allogeneic bone marrow transplantation (BMT) and associated with poor prognosis. Generally kidneys are assumed to be no direct target of Graft-versus-Host Disease (GvHD), and renal impairment is often attributed to several other factors occurring in the early phase after BMT. Our study aimed to prove the existence of renal GvHD in a fully MHC-mismatched model of BALB/c mice conditioned and transplanted according to two different intensity protocols. Syngeneically transplanted and untreated animals served as controls. 4 weeks after transplantation, allogeneic animals developed acute GvHD that was more pronounced in the high-intensity protocol (HIP) group than in the low-intensity protocol (LIP) group. Urea and creatinine as classic serum markers of renal function could not verify renal impairment 4 weeks after BMT. Creatinine levels were even reduced as a result of catabolic metabolism and loss of muscle mass due to acute GvHD. Proteinuria, albuminuria, and urinary N-acetyl-beta-Dglucosaminidase (NAG) levels were measured as additional renal markers before and after transplantation. Albuminuria and NAG were only significantly increased after allogeneic transplantation, correlating with disease severity between HIP and LIP animals. Histological investigations of the kidneys showed renal infiltration of T-cells and macrophages with endarteriitis, interstitial nephritis, tubulitis, and glomerulitis. T-cells consisted of CD4+, CD8+, and FoxP3+ cells. Renal expression analysis of allogeneic animals showed increases in indoleamine-2,3 dioxygenase (IDO), different cytokines (TNFα, IFN-γ, IL-1α, IL2, IL-6, and IL-10), and adhesion molecules (ICAM-1 and VCAM-1), resembling findings from other tissues in acute GvHD. In summary, our study supports the entity of renal GvHD with histological features suggestive of cell-mediated renal injury. Albuminuria and urinary NAG levels may serve as early markers of renal

  4. The role of extracorporeal photopheresis in the management of cutaneous T-cell lymphoma, graft-versus-host disease and organ transplant rejection: a consensus statement update from the UK Photopheresis Society.

    PubMed

    Alfred, Arun; Taylor, Peter C; Dignan, Fiona; El-Ghariani, Khaled; Griffin, James; Gennery, Andrew R; Bonney, Denise; Das-Gupta, Emma; Lawson, Sarah; Malladi, Ram K; Douglas, Kenneth W; Maher, Tracey; Guest, Julie; Hartlett, Laura; Fisher, Andrew J; Child, Fiona; Scarisbrick, Julia J

    2017-02-21

    Extracorporeal photopheresis (ECP) has been used for over 35 years in the treatment of erythrodermic cutaneous T-cell lymphoma (CTCL) and over 20 years for chronic and acute graft-versus-host disease (GvHD) and solid organ transplant rejection. ECP for CTCL and GvHD is available at specialised centres across the UK. The lack of prospective randomised trials in ECP led to the development of UK Consensus Statements for patient selection, treatment schedules, monitoring protocols and patient assessment criteria for ECP. The recent literature has been reviewed and considered when writing this update. Most notably, the national transition from the UVAR XTS(®) machine to the new CELLEX machine for ECP with dual access and a shorter treatment time has led to relevant changes in these schedules. This consensus statement updates the previous statement from 2007 on the treatment of CTCL and GvHD with ECP using evidence based medicine and best medical practise and includes guidelines for both children and adults.

  5. Giardia lamblia infection after pancreas-kidney transplantation.

    PubMed

    Kristensen, Ann Abkjaer; Horneland, Rune; Birn, Henrik; Svensson, My

    2016-01-18

    Infection is a common complication of solid organ transplantation. It is associated with an increased risk of acute cellular rejection and loss of graft function. The most common infections are due to bacteria and viruses, including transmission of cytomegalovirus from donor to recipient. In the past years, an increasing number of parasitic infections have been documented in transplant recipients. We describe the first reported case of intestinal Giardia lamblia transmission following simultaneous pancreas and kidney transplantation.

  6. Determination of urinary and serum beta-glucuronidase and alkaline phosphatase in various renal disease and kidney rejection transplanted patients.

    PubMed

    Refaie, M O; Abo-Zaid, H; Gomma, N A; Aboul-Enein, H Y

    2000-05-01

    Beta-glucuronidase (beta-Glu) and alkaline phosphatase (ALP) were evaluated in serum and urine in 50 subjects classified into five equal groups. Group I was control healthy subjects, while groups II, III, IV, and V were patients with nephritic syndrome, pyelonephritis, kidney rejection, and end-stage renal disease, respectively. Urinary beta-Glu was significantly elevated in all four groups; while serum enzyme showed no change. On the other hand, serum ALP showed a significant elevation in all abnormal groups. Accordingly, urinary beta-Glu and serum ALP could be used as diagnostic markers for various renal diseases.

  7. Fatal hepatic failure associated with graft rejection following reduced-intensity stem-cell transplantation for chronic idiopathic myelofibrosis (CIMF).

    PubMed

    Miyakoshi, Shigesaburo; Kami, Masahiro; Kishi, Yukiko; Murashige, Naoko; Yuji, Koichiro; Kusumi, Eiji; Matsumura, Tomoko; Onishi, Yasushi; Kobayashi, Kazuhiko; Kim, Sung-Won; Hamaki, Tamae; Takaue, Yoichi; Taniguchi, Shuichi

    2004-12-01

    A 54-year-old man with chronic idiopathic myelofibrosis (CIMF) underwent RIST. His clinical course had been uneventful until day 60, when splenomegaly reappeared. Hepatic dysfunction developed on day 75. Recipient-type hematopoiesis increased to 51% on day 90. After rapid tapering of cyclosporin, serum levels of AST and ALP normalized in parallel with recovery of complete chimerism on day 134. Yet, jaundice progressed. He died of liver failure on day 176. Postmortem examination revealed neither GVHD nor VOD. Graft rejection following RIST for CIMF may lead to fatal hepatic damage through extramedullary hematopoiesis in the liver or cytokine-mediated immune dysregulations.

  8. Post-transplant hepatic complications: Imaging findings

    PubMed Central

    Drudi, F.M.; Pagliara, E.; Cantisani, V.; Arduini, F.; D'Ambrosio, U.; Alfano, G.

    2007-01-01

    Transplantation is considered definitive therapy for acute or chronic irreversible pathologies of the liver, and the increased survival rates are mainly due to improved immunosuppressive therapies and surgical techniques. However, early diagnosis of possible graft dysfunction is crucial to liver graft survival. Diagnostic imaging plays an important role in the evaluation of the liver before and after transplant and in the detection of complications such as vascular and biliary diseases, acute and chronic rejection and neoplastic recurrence. Integrated imaging using color-Doppler, CT, MRI and traditional x-ray reach a high level of sensitivity and specificity in the management of transplanted patients. PMID:23395917

  9. Renal transplantation in developing countries.

    PubMed

    Akoh, Jacob A

    2011-07-01

    Patients with established renal failure, living in developing countries, face many obstacles including lack of access to transplantation centers, quality and safety issues, and exploittation associated with transplant tourism. This review aims to determine the state and outcome of renal transplantation performed in developing countries and to recommend some solutions. The lack of suitable legislation and infrastructure has prevented growth of deceased donor programs; so, living donors have continued to be the major source of transplantable kidneys. Transplant tourism and commercial kidney transplants are associated with a high incidence of surgical complications, acute rejection and invasive infection, which cause major morbidity and mortality. Developing transplant services worldwide has many benefits - improving the results of transplantation as they would be performed legally, increasing the donor pool, making transplant tourism unnecessary and granting various governments the moral courage to fight unacceptable practices. A private-public partnership underpinned by transparency, public audit and accountability is a prerequisite for effective transplant services in the developing world. Finally, lack of dialysis facilities coupled with better outcomes in patients spending <6 months on dialysis prior to transplantation favor pre-emptive transplantation in developing countries.

  10. Pathological and MR-DWI study of the acute hepatic injury model after stem cell transplantation

    PubMed Central

    Shang, Quan-Liang; Xiao, En-Hua; Zhou, Qi-Chang; Luo, Jian-Guang; Wu, Hai-Jun

    2011-01-01

    AIM: To investigate apparent diffusion coefficient (ADC) values as an indication of reconditioning of acute hepatic injury (AHI) after allogeneic mononuclear bone marrow cell (MBMC) transplantation. METHODS: Three groups were used in our study: a cell transplantation group (n = 21), transplantation control group (n = 21) and normal control group (n = 10). AHI model rabbits in the cell transplantation group were injected with 5 mL of MBMC suspension at multiple sites in the liver and the transplantation controls were injected with 5 mL D-Hanks solution. At the end of the 1st, 2nd and 4th wk, 7 rabbits were randomly selected from the cell transplantation group and transplantation control group for magnetic resonance diffusion-weighted imaging (MR-DWI) and measurement of the mean ADC values of injured livers. After MR-DWI examination, the rabbits were sacrificed and the livers subjected to pathological examination. Ten healthy rabbits from the normal control group were used for MR-DWI examination and measurement of the mean ADC value of normal liver. RESULTS: At all time points, the liver pathological scores from the cell transplantation group were significantly lower than those in the transplantation control group (27.14 ± 1.46 vs 69.29 ± 6.16, 22.29 ± 2.29 vs 57.00 ± 1.53, 19.00 ± 2.31 vs 51.86 ± 6.04, P = 0.000). The mean ADC values of the cell transplantation group were significantly higher than the transplantation control group ((1.07 ± 0.07) × 10-3 mm2/s vs (0.69 ± 0.05) × 10-3 mm2/s, (1.41 ± 0.04) × 10-3 mm2/s vs (0.84 ± 0.06) × 10-3 mm2/s, (1.68 ± 0.04) × 10-3 mm2/s vs (0.86 ± 0.04) × 10-3 mm2/s, P = 0.000). The pathological scores of the cell transplantation group and transplantation control group gradually decreased. However, their mean ADC values gradually increased to near that of the normal control. At the end of the 1st wk, the mean ADC values of the cell transplantation group and transplantation control group were significantly lower

  11. Intestinal transplantation: a review.

    PubMed

    Desai, Chirag Sureshchandra; Khan, Khalid Mahmood; Girlanda, Raffaele; Fishbein, Thomas M

    2012-09-01

    Parenteral nutrition is a life-saving therapy for patients with intestinal failure. Intestinal transplantation is now recognized as a treatment for patients who develop complications of parenteral nutrition and in whom attempts at intestinal rehabilitation have failed. Patients with parenteral nutrition related liver disease will require a liver graft typically part of a multivisceral transplant. Isolated intestinal transplants are more commonly performed in adults while multivisceral transplants are most commonly performed in infants. Isolated intestinal transplants have the best short-term outcome, with over 80 % survival at 1 year. Patients requiring multivisceral transplants have a high rate of attrition with a 1 year survival less than 70 %. Prognostic factors for a poor outcome include patient hospitalization at the time of transplant and donor age greater than 40 years while systemic sepsis and acute rejection are the major determinant of early postoperative outcome. For patients surviving the first year the outcome of transplantation of the liver in addition to intestine affords some survival advantage though long-term outcome does not yet match other abdominal organs. Outcomes for intestinal retransplantation are poor as a result of immunology and patient debility. Overall intestinal transplantation continues to develop and is a clear indication with cost and quality of life advantages in patients with intestinal failure that do not remain stable on parenteral nutrition.

  12. Cortical necrosis in a renal transplant

    SciTech Connect

    Blumhardt, R.; Growcock, G.; Lasher, J.C.

    1983-07-01

    The /sup 99m/Tc-DTPA renogram is a well extabished noninvasive method for evaluating and following transplanted kidneys. The examination is useful in distinguishing rejection from acute tubular necrosis as well as demonstrating several less common complications such as vascular occlusion, urinary extravasation, obstruction, and lymphocele. A previously unreported condition involving a transplant kidney (i.e., renal cortical necrosis) is described which was diagnosed with renal scintigraphy in combination with sonography.

  13. Power-Pulse Thrombolysis and Stent Recanalization for Acute Post-Liver Transplant Iliocaval Venous Thrombosis

    SciTech Connect

    Baccin, Carlos E.; Haskal, Ziv J.

    2008-07-15

    Postoperative inferior vena cava (IVC) thrombosis is a potentially lethal complication in a liver transplant recipient. We report the case of a 57-year-old liver transplant recipient, who developed acute, postoperative, markedly symptomatic complete IVC, ilial-femoral-caval, and left renal vein thrombosis. After treatment with power-pulse tissue plasminogen activator thrombolysis, thrombectomy, and stent placement, the IVC and iliac veins were successfully recanalized. At 2.5-year imaging and laboratory follow-up, the IVC, iliac, and renal veins remained patent and graft function was preserved.

  14. Acute kidney injury and post-reperfusion syndrome in liver transplantation

    PubMed Central

    Umbro, Ilaria; Tinti, Francesca; Scalera, Irene; Evison, Felicity; Gunson, Bridget; Sharif, Adnan; Ferguson, James; Muiesan, Paolo; Mitterhofer, Anna Paola

    2016-01-01

    In the past decades liver transplantation (LT) has become the treatment of choice for patients with end stage liver disease (ESLD). The chronic shortage of cadaveric organs for transplantation led to the utilization of a greater number of marginal donors such as older donors or donors after circulatory death (DCD). The improved survival of transplanted patients has increased the frequency of long-term complications, in particular chronic kidney disease (CKD). Acute kidney injury (AKI) post-LT has been recently recognized as an important risk factor for the occurrence of de novo CKD in the long-term outcome. The onset of AKI post-LT is multifactorial, with pre-LT risk factors involved, including higher Model for End-stage Liver Disease score, more sever ESLD and pre-existing renal dysfunction, either with intra-operative conditions, in particular ischaemia reperfusion injury responsible for post-reperfusion syndrome (PRS) that can influence recipient’s morbidity and mortality. Post-reperfusion syndrome-induced AKI is an important complication post-LT that characterizes kidney involvement caused by PRS with mechanisms not clearly understood and implication on graft and patient survival. Since pre-LT risk factors may influence intra-operative events responsible for PRS-induced AKI, we aim to consider all the relevant aspects involved in PRS-induced AKI in the setting of LT and to identify all studies that better clarified the specific mechanisms linking PRS and AKI. A PubMed search was conducted using the terms liver transplantation AND acute kidney injury; liver transplantation AND post-reperfusion syndrome; acute kidney injury AND post-reperfusion syndrome; acute kidney injury AND DCD AND liver transplantation. Five hundred seventy four articles were retrieved on PubMed search. Results were limited to title/abstract of English-language articles published between 2000 and 2015. Twenty-three studies were identified that specifically evaluated incidence, risk factors

  15. Expression of nestin after renal transplantation in the rat.

    PubMed

    Skwirba, Michael; Zakrzewicz, Anna; Atanasova, Srebrena; Wilker, Sigrid; Fuchs-Moll, Gabriele; Müller, Dieter; Padberg, Winfried; Grau, Veronika

    2014-10-01

    Chronic allograft injury (CAI) limits the long-term success of renal transplantation. Nestin is a marker of progenitor cells, which probably contribute to its pathogenesis. We hypothesize that nestin is induced by ischemia/reperfusion injury and acute rejection, main risk factors for CAI. Syngeneic renal transplantation was performed in Lewis rats and allogeneic transplantation in the Fischer 344 to Lewis strain combination, which results in reversible acute rejection and in CAI in the long-run. The Dark Agouti to Lewis rat strain combination was used to study fatal acute rejection. In untreated kidneys, nestin immunoreactivity was detected in glomeruli and in very few interstitial or microvascular cells. Syngeneic transplantation induced nestin expression within 4 days, which decreased until day 9 and returned to control levels on day 42. Nestin expression was strong during acute rejection and still detected during the pathogenesis of CAI on day 42. Nestin-positive cells were identified as endothelial cells and interstitial fibroblast-like cells co-expressing alpha-smooth muscle actin. A sub-population of them expressed proliferating cell nuclear antigen. In conclusion, nestin is induced in renal grafts by ischemia/reperfusion injury and acute rejection. It is expressed by proliferating myofibroblasts and endothelial cells and probably contributes to the pathogenesis of CAI.

  16. Association of high HLA-E expression during acute cellular rejection and numbers of HLA class I leader peptide mismatches with reduced renal allograft survival.

    PubMed

    Guberina, Hana; Rebmann, Vera; Wagner, Bettina; da Silva Nardi, Fabiola; Dziallas, Phillip; Dolff, Sebastian; Bienholz, Anja; Wohlschlaeger, Jeremias; Bankfalvi, Agnes; Heinemann, Falko M; Witzke, Oliver; Zoet, Yvonne M; Claas, Frans H J; Horn, Peter A; Kribben, Andreas; Doxiadis, Ilias I N

    2017-03-01

    Non-classical Human Leukocyte Antigen (HLA)-E preferentially presents leader peptides derived from classical HLA-class I molecules. HLA-E can trigger opposed immune responses by interacting with inhibitory NKG2A or by activating NKG2C receptors on NK and T-cells. We studied the impact of HLA-E on renal allograft survival during acute cellular rejection. HLA-E expression was up-regulated in acute cellular rejection (ACR) biopsies (n=12) compared to biopsies from 13 renal allografts with no rejection-signs. HLA-E up-regulation was correlated with numbers of HLA-class I leader peptide mismatches (p=0.04). CD8+ and CD56+ infiltrating cells correlated with HLA-E expression (p<0.0001 and p=0.0009, respectively). Activating NKG2C receptor dominated on effector cells in biopsies and peripheral blood during ACR potentially allowing HLA-E-mediated immune activation. Moreover, HLA-E expression correlated with deterioration in renal allograft function (p<0.008) and reduced allograft survival (p=0.002). Our findings provide evidence that during renal allograft rejection HLA-E along with high numbers of mismatched HLA-class I leader peptides might represent additional targets for immune-activating responses.

  17. A Critical Analysis of Rejection in Vascularized Composite Allotransplantation: Clinical, Cellular and Molecular Aspects, Current Challenges, and Novel Concepts

    PubMed Central

    Sarhane, Karim A.; Tuffaha, Sami H.; Broyles, Justin M.; Ibrahim, Amir E.; Khalifian, Saami; Baltodano, Pablo; Santiago, Gabriel F.; Alrakan, Mohammed; Ibrahim, Zuhaib

    2013-01-01

    Advances in microsurgical techniques and immunomodulatory protocols have contributed to the expansion of vascularized composite allotransplantation (VCA) with very encouraging immunological, functional, and cosmetic results. Rejection remains however a major hurdle that portends serious threats to recipients. Rejection features in VCA have been described in a number of studies, and an international consensus on the classification of rejection was established. Unfortunately, current available diagnostic methods carry many shortcomings that, in certain cases, pose a great diagnostic challenge to physicians especially in borderline rejection cases. In this review, we revisit the features of acute skin rejection in hand and face transplantation at the clinical, cellular, and molecular levels. The multiple challenges in diagnosing rejection and in defining chronic and antibody-mediated rejection in VCA are then presented, and we finish by analyzing current research directions and novel concepts aiming at improving available diagnostic measures. PMID:24324470

  18. Sex Related Differences in the Risk of Antibody-Mediated Rejection and Subsequent Allograft Vasculopathy Post-Heart Transplantation: A Single-Center Experience

    PubMed Central

    Grupper, Avishay; Nestorovic, Emilija M.; Daly, Richard C.; Milic, Natasa M.; Joyce, Lyle D.; Stulak, John M.; Joyce, David L.; Edwards, Brooks S.; Pereira, Naveen L.; Kushwaha, Sudhir S.

    2016-01-01

    Background Pregnancies may result in antibodies against HLA, a risk factor for antibody-mediated rejection (AMR) and subsequent cardiac allograft vasculopathy (CAV) after heart transplantation (HTx). The aim of this study was to evaluate sex differences in the incidence of AMR events and subsequent risk of CAV among HTx recipients. Methods The study comprised 160 patients (51 [32%] women) who underwent HTx in 2008 to 2014. The cumulative effect of AMR events was calculated by AMR score (sum of myocardial biopsy grading divided by number of biopsies taken during 3 years post-HTx). Results Females had higher levels of anti-HLA I antibodies pre-HTx compared to males which was associated with a history of pregnancies, total number of children and with a higher AMR score at 6 months post-HTx (P < 0.05). Women demonstrated a significant increase in the total incidence of AMR events (27 vs. 7%, P = 0.001) and in AMR scores at 6, 12, 24 and 36 months post-HTx compared to men (P < 0.05). There were no differences in cellular rejection between the groups. A history of AMR events was associated with a significantly increased risk of severe CAV onset (hazard ratio, 7.0; 95% confidence interval, 1.5-31.5; P = 0.012). Conclusions Women are at higher risk for AMR post-HTx which subsequently increases their risk for CAV. Females recipients may benefit from closer surveillance to identify AMR at an earlier stage post-HTx, and targeted immunosuppressive therapy to attenuate the development of CAV. PMID:27795988

  19. Indium-111-monoclonal antimyosin antibody studies after the first year of heart transplantation. Identification of risk groups for developing rejection during long-term follow-up and clinical implications

    SciTech Connect

    Ballester, M.; Obrador, D.; Carrio, I.; Auge, J.M.; Moya, C.; Pons-Llado, G.; Caralps-Riera, J.M. )

    1990-12-01

    The long-term clinical course and results of biopsies in 21 patients studied with monoclonal antimyosin antibodies more than 12 months after heart transplantation according to the presence and degree of antimyosin-antibody uptake is described. Eighteen men and three women aged 20-52 years (39 +/- 9 years) were studied with antimyosin antibodies 12-40 months (mean, 22 +/- 9 months) after heart transplantation, and followed for a mean of 18 months (10-28 months). The number of biopsies performed during follow-up was 102. Results showed normal antimyosin-antibody studies in nine patients and abnormal studies in 12 patients. Myocyte damage was identified in 18 of the 102 biopsies (17.6%), one in the normal antimyosin-antibody group of patients and 17 in those patients with myocardial antimyosin-antibody uptake. Patients who developed rejection comprised 11% and 67% of each respective group; the mean number of rejection episodes per patient was 0.11 +/- 0.33 and 1.41 +/- 1.41, respectively (p less than 0.01). A trend was noted by which higher heart-to-lung ratios were associated with greater probability of rejection. Conclusively, (1) antimyosin-antibody studies performed after more than 1 year after heart transplantation indicate the presence and level of rejection activity, (2) groups of patients at risk for developing rejection at biopsy during long-term follow-up may be detected by antimyosin-antibody study, and (3) surveillance for rejection and the degree of immunosuppression should be tailored to meet individual patient needs.

  20. Bilateral trans-humeral arm transplantation: result at 2 years.

    PubMed

    Cavadas, P C; Ibáñez, J; Thione, A; Alfaro, L

    2011-05-01

    Unilateral and bilateral hand transplantations have been performed worldwide with good mid-term functional results. An above-elbow bilateral transplantation was performed in a 29-year-old male patient from a fully HLA-mismatched donor. Alemtuzumab induction and steroid-free maintenance immunosuppression with tacrolimus and mycophenolate was used. Due to acute rejection, steroids were introduced at 6 months. Three acute rejection episodes occurred, one treated with alemtuzumab. New-onset diabetes after transplant, dyslipemia and worsening of previous high blood pressure required treatment. At 26 months post-transplantation, the patient has excellent elbow active movement, active flexion and extension of the thumb and fingers, useful sensation and a gainful job. Based on the functional results of the case reported, bilateral trans-humeral transplantation could be a viable treatment for selected bilateral above-elbow amputees.

  1. Anesthesia management of surgery for sigmoid perforation and acute peritonitis patient following heart transplantation: case report.

    PubMed

    Yang, Xu-Li; Dai, Shu-Hong; Zhang, Juan; Zhang, Jing; Liu, Yan-Jun; Yang, Yan; Sun, Yu-E; Ma, Zheng-Liang; Gu, Xiao-Ping

    2015-01-01

    Here we described a case in which a patient underwent emergency laparotomy for acute peritonitis and sigmoid perforation under general anesthesia with a history of heart transplantation. A good knowledge in the physiology of the transplanted heart is critical for effective and safe general anesthesia. We chose etomidate that have a weaker impact on cardiovascular function plus propofol for induction, and propofol plus cisatracurium for maintenance with intermittently analgesics and vasoactive drugs to facilitate the anesthesia. In addition, fluid input, electrolyte and acid-base balance were well adjusted during the whole procedure. The patient was in good condition after the surgery. In this case report we are aiming to provide some guidance for those scheduled for non-cardiac surgery after heart transplant.

  2. Anesthesia management of surgery for sigmoid perforation and acute peritonitis patient following heart transplantation: case report

    PubMed Central

    Yang, Xu-Li; Dai, Shu-Hong; Zhang, Juan; Zhang, Jing; Liu, Yan-Jun; Yang, Yan; Sun, Yu-E; Ma, Zheng-Liang; Gu, Xiao-Ping

    2015-01-01

    Here we described a case in which a patient underwent emergency laparotomy for acute peritonitis and sigmoid perforation under general anesthesia with a history of heart transplantation. A good knowledge in the physiology of the transplanted heart is critical for effective and safe general anesthesia. We chose etomidate that have a weaker impact on cardiovascular function plus propofol for induction, and propofol plus cisatracurium for maintenance with intermittently analgesics and vasoactive drugs to facilitate the anesthesia. In addition, fluid input, electrolyte and acid-base balance were well adjusted during the whole procedure. The patient was in good condition after the surgery. In this case report we are aiming to provide some guidance for those scheduled for non-cardiac surgery after heart transplant. PMID:26379997

  3. Determining donor-specific antibody C1q-binding ability improves the prediction of antibody-mediated rejection in human leucocyte antigen-incompatible kidney transplantation.

    PubMed

    Malheiro, Jorge; Tafulo, Sandra; Dias, Leonídio; Martins, La Salete; Fonseca, Isabel; Beirão, Idalina; Castro-Henriques, António; Cabrita, António

    2017-04-01

    Detrimental impact of preformed donor-specific antibodies (DSAs) against human leucocyte antigens on outcomes after kidney transplantation are well documented, however, the value of their capacity to bind complement for predicting antibody-mediated rejection (AMR) and graft survival still needs to be confirmed. We aimed to study DSA characteristics (strength and C1q binding) that might distinguish harmful DSA from clinically irrelevant ones. We retrospectively studied 60 kidney-transplanted patients with preformed DSA detected by single antigen bead (SAB) assays (IgG and C1q kits), from a cohort of 517 kidney graft recipients (124 with detectable anti-HLA antibodies). Patients were divided into DSA strength (MFI < vs. ≥ 15 000) and C1q-binding ability. AMR frequency was high (30%) and it increased with DSA strength (P = 0.002) and C1q+ DSA (P < 0.001). The performance of DSA C1q-binding ability as a predictor of AMR was better than DSA strength (diagnostic odds ratio 16.3 vs. 6.4, respectively). Furthermore, a multivariable logistic regression showed that C1q+ DSA was a risk factor for AMR (OR = 16.80, P = 0.001), while high MFI DSAs were not. Graft survival was lower in high MFI C1q+ DSA in comparison with patients with C1q- high or low MFI DSA (at 6 years, 38%, 83% and 80%, respectively; P = 0.001). Both DSA strength and C1q-binding ability assessment seem valuable for improving pretransplant risk assessment. Since DSA C1q-binding ability was a better predictor of AMR and correlated with graft survival, C1q-SAB may be a particularly useful tool.

  4. Family directed umbilical cord blood banking for acute leukemia: usage rate in hematopoietic stem cell transplantation.

    PubMed

    Screnci, M; Murgi, E; Tamburini, A; Pecci, M R; Ballatore, G; Cusanno, A; Valle, V; Luciani, P; Corona, F; Girelli, G

    2015-04-01

    Family-directed umbilical cord blood (UCB) collection and banking is indicated in women delivering healthy babies who already have a member of their own family with a disease potentially treatable with an allogeneic hematopoietic stem cell (HSCs) transplantation (HSCT). The rapid availability of UCB is an important issue in HSCs procurement particularly for recipients with acute leukemia who urgently need HSCT. The aims of this study were to assess the usage rate of family UCB collections directed to patients with acute leukemia and to investigate the factors influencing the usage rate. A total of 113 families were enrolled, 118 UCB units were successfully collected and one collection failed due to emergency occurred during delivery. Among these, 7 collections were required for children who were in urgent need of a transplant: three HLA-matched units were successfully transplanted, respectively after 2, 5 and 6 months from collection; three collections resulted HLA-mismatched, while HLA-typing is pending for one unit. The remaining collections were mostly required for potential future use, among these units only one was transplanted in a HLA compatible sibling after 3 years and 4 months from collection. After a median time of storage of 8.5 years (range 0.1-20 years) a total of 4/118 (3.4 %) collection has been transplanted. During this time interval, considering only patients who have had the need of a transplant, the main factor influencing low utilization rate of UCB collections was due to HLA disparity, indeed among typed UCB unit mostly (77 %) resulted HLA mismatched with the intended recipient.

  5. Early post-transplant urinary IP-10 expression after kidney transplantation is predictive of short- and long-term graft function.

    PubMed

    Matz, M; Beyer, J; Wunsch, D; Mashreghi, M-F; Seiler, M; Pratschke, J; Babel, N; Volk, H-D; Reinke, P; Kotsch, K

    2006-05-01

    The early identification of renal transplant recipients at enhanced risk of developing acute and subclinical rejection would allow individualized adjustment of immunosuppression before functional graft injury occurs and would exclude these patients from drug-weaning studies. Protein and reverse transcriptase-polymerase chain reaction-based analyses of candidate markers in urine open the opportunity to closely monitor kidney-transplanted patients non-invasively. The chemokine interferon-inducible protein 10 (IP-10; CXCL10) might be an interesting candidate to uncover ongoing immune processes within the graft. Urine samples from kidney-transplanted recipients were retrospectively analyzed for IP-10 mRNA and protein expression. IP-10 levels were correlated with the incidence of acute rejection episodes proven by histology and long-term graft function assessed by the glomerular filtration rate 6 months post transplantation. IP-10 expression in urine identified patients with ongoing acute rejection episodes several days before a biopsy was indicated by rising serum creatinine levels. Most importantly, elevated levels of urinary IP-10 protein within the first four postoperative weeks were predictive of graft function at 6 months even in the absence of acute rejection. These data reveal a correlation between elevated IP-10 expression in urine at early time points post-transplantation and intragraft immune activation that leads to acute rejection and compromised long-term graft function.

  6. Determinants of graft survival in pediatric and adolescent live donor kidney transplant recipients: a single center experience.

    PubMed

    El-Husseini, Amr A; Foda, Mohamed A; Shokeir, Ahmed A; Shehab El-Din, Ahmed B; Sobh, Mohamed A; Ghoneim, Mohamed A

    2005-12-01

    To study the independent determinants of graft survival among pediatric and adolescent live donor kidney transplant recipients. Between March 1976 and March 2004, 1600 live donor kidney transplants were carried out in our center. Of them 284 were 20 yr old or younger (mean age 13.1 yr, ranging from 5 to 20 yr). Evaluation of the possible variables that may affect graft survival were carried out using univariate and multivariate analyses. Studied factors included age, gender, relation between donor and recipient, original kidney disease, ABO blood group, pretransplant blood transfusion, human leukocyte antigen (HLA) matching, pretransplant dialysis, height standard deviation score (SDS), pretransplant hypertension, cold ischemia time, number of renal arteries, ureteral anastomosis, time to diuresis, time of transplantation, occurrence of acute tubular necrosis (ATN), primary and secondary immunosuppression, total dose of steroids in the first 3 months, development of acute rejection and post-transplant hypertension. Using univariate analysis, the significant predictors for graft survival were HLA matching, type of primary urinary recontinuity, time to diuresis, ATN, acute rejection and post-transplant hypertension. The multivariate analysis restricted the significance to acute rejection and post-transplant hypertension. The independent determinants of graft survival in live-donor pediatric and adolescent renal transplant recipients are acute rejection and post-transplant hypertension.

  7. Successful Hematopoietic Cell Transplantation in a Patient With X-linked Agammaglobulinemia and Acute Myeloid Leukemia

    PubMed Central

    Abu-Arja, Rolla F.; Chernin, Leah R.; Abusin, Ghada; Auletta, Jeffery; Cabral, Linda; Egler, Rachel; Ochs, Hans D.; Torgerson, Troy R.; Lopez-Guisa, Jesus; Hostoffer, Robert W.; Tcheurekdjian, Haig; Cooke, Kenneth R.

    2016-01-01

    X-linked agammaglobulinemia (XLA) is a primary immunodeficiency characterized by marked reduction in all classes of serum immunoglobulins and the near absence of mature CD19+ B-cells. Although malignancy has been observed in patients with XLA, we present the first reported case of acute myeloid leukemia (AML) in a patient with XLA. We also demonstrate the complete correction of the XLA phenotype following allogeneic hematopoietic cell transplantation for treatment of the patient’s leukemia. PMID:25900577

  8. Acute parkinsonian syndrome with demyelinating leukoencephalopathy in bone marrow transplant recipients.

    PubMed

    Lockman, L A; Sung, J H; Krivit, W

    1991-01-01

    A syndrome of rigidity, bradykinesia, spasticity, and often myoclonus and dementia developed acutely in 5 patients who had undergone successful engraftment of bone marrow transplants for the treatment of various hematologic diseases. Magnetic resonance imaging demonstrated widespread changes in white matter; brain biopsy disclosed mild demyelination associated with active phagocytosis of myelin. One patient, who was not treated, remains severely demented. Patients treated with very high-dose methylprednisolone had complete clinical recovery.

  9. Deceased donor kidney transplantation from donors with acute renal failure due to rhabdomyolysis.

    PubMed

    Mekeel, K L; Moss, A A; Mulligan, D C; Chakkera, H A; Hamawi, K; Mazur, M J; Heilman, R L; Reddy, K S

    2009-07-01

    With the current shortage of solid organs for transplant, the transplant community continues to look for ways to increase the number of organ donors, including extending the criteria for donation. In rhabdomyolysis, the byproducts of skeletal muscle breakdown leak into the circulation resulting in acute renal failure in up to 30% of patients. In nonbrain dead patients, this condition is reversible and most patients recover full renal function. Seven potential donors had rhabdomyolysis with acute renal failure as evidenced by the presence of urine hemoglobin, plasma creatinine kinase levels of greater than five times the normal and elevated creatinine. One donor required dialysis. At our institution, 10 kidneys were transplanted from the seven donors. Two grafts had immediate function, five grafts experienced slow graft function and three grafts had delayed graft function requiring hemodialysis. At a mean of 8.7 months posttransplant (2.4-25.2 months), all patients have good graft function, are off dialysis and have a mean creatinine of 1.3 (0.7-1.8). In conclusion, our experience suggests that rhabdomyolysis with acute renal failure should not be a contraindication for donation, although recipients may experience slow or delayed graft function.

  10. Direct label-free electrical immunodetection of transplant rejection protein biomarker in physiological buffer using floating gate AlGaN/GaN high electron mobility transistors.

    PubMed

    Tulip, Fahmida S; Eteshola, Edward; Desai, Suchita; Mostafa, Salwa; Roopa, Subramanian; Evans, Boyd; Islam, Syed Kamrul

    2014-06-01

    Monokine induced by interferon gamma (MIG/CXCL9) is used as an immune biomarker for early monitoring of transplant or allograft rejection. This paper demonstrates a direct electrical, label-free detection method of recombinant human MIG with anti-MIG IgG molecules in physiologically relevant buffer environment. The sensor platform used is a biologically modified GaN-based high electron mobility transistor (HEMT) device. Biomolecular recognition capability was provided by using high affinity anti-MIG monoclonal antibody to form molecular affinity interface receptors on short N-hydroxysuccinimide-ester functionalized disulphide (DSP) self-assembled monolayers (SAMs) on the gold sensing gate of the HEMT device. A floating gate configuration has been adopted to eliminate the influences of external gate voltage. Preliminary test results with the proposed chemically treated GaN HEMT biosensor show that MIG can be detected for a wide range of concentration varying from 5 ng/mL to 500 ng/mL.

  11. Acute myeloid leukemia of a primary hepatic carcinoma patient after liver transplantation: a case report and literature review

    PubMed Central

    Wu, Wen-Jun; Dong, Meng-Meng; Chen, Yun; He, Jing-Song; Huang, He; Cai, Zhen

    2015-01-01

    Living donor liver transplantation (LDLT) is an important means to treat end-stage liver disease. Although effective immunosuppressant medication greatly assists the survival of patients, it is likely to promote infections and cancer. Acute leukemia (AL) is a rare complication after LDLT and up to now only 1 case of post-transplantation AL has occurred in our liver transplantation center after more than 1,600 LDLT interventions since 1993. In the present report, we describe a rare case of subsequent acute myeloid leukemia (AML), 27 months after LDLT and review the literature of this infrequent complication. PMID:26722593

  12. Bacterial Infections, Alloimmunity, and Transplantation Tolerance

    PubMed Central

    Ahmed, Emily B.; Daniels, Melvin; Alegre, Maria-Luisa; Chong, Anita S.

    2010-01-01

    Transplantation of solid organs across histocompatibility barriers in the absence of immunosuppression is invariably followed by acute allograft rejection. Although several immunosuppressive regimens have been developed to prevent allograft rejection, these global immunosuppressive agents effectively inhibit all T cells leaving the host vulnerable to infections. Thus a major goal in transplantation immunology is to induce donor-specific tolerance that results in the extended suppression of allograft-specific immune responses, while leaving the remainder of the immune system competent to fight infections and malignancies. Initial successes in identifying approaches that successfully induce transplantation tolerance in experimental models have led to a newer research focus of identifying potential barriers to the induction of such tolerance as well as events that may reverse established allograft tolerance. Both clinical and experimental studies have identified bacterial infections as a possible trigger of allograft rejection. Recently, experimental models of transplantation tolerance have identified that bacterial signals can promote acute allograft rejection either by preventing the induction of transplantation tolerance or by reversing tolerance after it has been stably established. This review summarizes experimental and clinical literature supporting the hypothesis that bacterial infections and innate immunity can qualitatively and quantitatively alter adaptive alloreactivity through effects on innate immune responses. PMID:21126661

  13. Graft vasculopathy in clinical hand transplantation.

    PubMed

    Kaufman, C L; Ouseph, R; Blair, B; Kutz, J E; Tsai, T M; Scheker, L R; Tien, H Y; Moreno, R; Ozyurekoglu, T; Banegas, R; Murphy, E; Burns, C B; Zaring, R; Cook, D F; Marvin, M R

    2012-04-01

    Allogeneic hand transplantation is now a clinical reality. While results have been encouraging, acute rejection rates are higher than in their solid-organ counterparts. In contrast, chronic rejections, as defined by vasculopathy and/or fibrosis and atrophy of skin and other tissues, as well as antibody mediated rejection, have not been reported in a compliant hand transplant recipient. Monitoring vascularized composite allograft (VCA) hand recipients for rejection has routinely involved punch skin biopsies, vascular imaging and graft appearance. Our program, which has transplanted a total of 6 hand recipients, has experience which challenges these precepts. We present evidence that the vessels, both arteries and veins may also be a primary target of rejection in the hand. Two of our recipients developed severe intimal hyperplasia and vasculopathy early post-transplant. An analysis of events and our four other patients has shown that the standard techniques used for surveillance of rejection (i.e. punch skin biopsies, DSA and conventional vascular imaging studies) are inadequate for detecting the early stages of vasculopathy. In response, we have initiated studies using ultrasound biomicroscopy (UBM) to evaluate the vessel wall thickness. These findings suggest that vasculopathy should be a focus of frequent monitoring in VCA of the hand.

  14. The value of needle renal allograft biopsy. I. A retrospective study of biopsies performed during putative rejection episodes.

    PubMed Central

    Matas, A J; Sibley, R; Mauer, M; Sutherland, D E; Simmons, R L; Najarian, J S

    1983-01-01

    Following renal transplantation, immunosuppression is usually increased to treat presumed rejection episodes. However, a) many conditions mimic rejection in the post-transplant period, and b) many rejection episodes are irreversible. As increased immunosuppressive therapy is associated with an increased risk of infection, it would be ideal to limit antirejection therapy to only the rejection episodes that are reversible. The role of percutaneous allograft biopsy was studied as an aid to decide which patients to treat for rejection, to limit unnecessary immunosuppression and to predict allograft survival. One hundred thirty-five patients with suspected rejection underwent 206 allograft biopsies without complication. Two hundred four biopsies were available for study. Biopsies were coded on a 1-4 scale (minimal, mild, moderate, severe) for acute and chronic tubulointerstitial infiltrate and vascular rejection, as well as no rejection (e.g., recurrence of original disease). Treatment decisions were made on the basis of the biopsy combined with clinical data. All patients have been followed two years and outcome correlated with biopsy findings (death, nephrectomy, and return to dialysis defined as kidney loss). The results were the following: 1) biopsies represented changes within the kidney. Of 16 kidneys removed within one month of biopsy, no nephrectomy specimen showed less rejection than that seen on biopsy. 2) Eighty-one biopsies (39.7%) led to tapering or not increasing immunosuppression (either no rejection, minimal rejection, or irreversible changes). 3) Kidneys having either severe acute or chronic vascular rejection (less than 30% function at three months) had significantly (p less than 0.05) decreased survival three to 24 months postbiopsy than those with minimal or mild vascular rejection or tubulointerstitial infiltrate (83% function at three months). 4) Kidneys with moderate chronic vascular rejection and those with severe acute tubulointerstitial

  15. Derivation of a Predictive Model for Graft Loss Following Acute Kidney Injury in Kidney Transplant Recipients

    PubMed Central

    Molnar, Amber O.; van Walraven, Carl; Fergusson, Dean; Garg, Amit X.; Knoll, Greg

    2017-01-01

    Background: Acute kidney injury (AKI) is common in the kidney transplant population. Objective: To derive a multivariable survival model that predicts time to graft loss following AKI. Design: Retrospective cohort study using health care administrative and laboratory databases. Setting: Southwestern Ontario (1999-2013) and Ottawa, Ontario, Canada (1996-2013). Patients: We included first-time kidney only transplant recipients who had a hospitalization with AKI 6 months or greater following transplant. Measurements: AKI was defined using the Acute Kidney Injury Network criteria (stage 1 or greater). The first episode of AKI was included in the analysis. Graft loss was defined by return to dialysis or repeat kidney transplant. Methods: We performed a competing risk survival regression analysis using the Fine and Gray method and modified the model into a simple point system. Graft loss with death as a competing event was the primary outcome of interest. Results: A total of 315 kidney transplant recipients who had a hospitalization with AKI 6 months or greater following transplant were included. The median (interquartile range) follow-up time was 6.7 (3.3-10.3) years. Graft loss occurred in 27.6% of the cohort. The final model included 6 variables associated with an increased risk of graft loss: younger age, increased severity of AKI, failure to recover from AKI, lower baseline estimated glomerular filtration rate, increased time from kidney transplant to AKI admission, and receipt of a kidney from a deceased donor. The risk score had a concordance probability of 0.75 (95% confidence interval [CI], 0.69-0.82). The predicted 5-year risk of graft loss fell within the 95% CI of the observed risk more than 95% of the time. Limitations: The CIs of the estimates were wide, and model overfitting is possible due to the limited sample size; the risk score requires validation to determine its clinical utility. Conclusions: Our prognostic risk score uses commonly available

  16. Cost-effectiveness and clinical outcomes of double versus single cord blood transplantation in adults with acute leukemia in France.

    PubMed

    Labopin, Myriam; Ruggeri, Annalisa; Gorin, Norbert Claude; Gluckman, Eliane; Blaise, Didier; Mannone, Lionel; Milpied, Noel; Yakoub-Agha, Ibrahim; Deconinck, Eric; Michallet, Mauricette; Fegueux, Nathalie; Socié, Gerard; Nguyen, Stephanie; Cahn, Jean Yves; de Revel, Thierry; Garnier, Federico; Faucher, Catherine; Taright, Namik; Kenzey, Chantal; Volt, Fernanda; Bertrand, Dominique; Mohty, Mohamad; Rocha, Vanderson

    2014-03-01

    Double cord blood transplantation extends the use of cord blood to adults for whom a single unit is not available, but the procedure is limited by its cost. To evaluate outcomes and cost-effectiveness of double compared to single cord blood transplantation, we analyzed 134 transplants in adults with acute leukemia in first remission. Transplants were performed in France with reduced intensity or myeloablative conditioning regimens. Costs were estimated from donor search to 1 year after transplantation. A Markov decision analysis model was used to calculate quality-adjusted life-years and cost-effectiveness ratio within 4 years. The overall survival at 2 years after single and double cord blood transplants was 42% versus 62%, respectively (P=0.03), while the leukemia-free-survival was 33% versus 53%, respectively (P=0.03). The relapse rate was 21% after double transplants and 42% after a single transplant (P=0.006). No difference was observed for non-relapse mortality or chronic graft-versus-host-disease. The estimated costs up to 1 year after reduced intensity conditioning for single and double cord blood transplantation were € 165,253 and €191,827, respectively. The corresponding costs after myeloablative conditioning were € 192,566 and € 213,050, respectively. Compared to single transplants, double cord blood transplantation was associated with supplementary costs of € 21,302 and € 32,420 up to 4 years, but with increases in quality-adjusted life-years of 0.616 and 0.484, respectively, and incremental cost-effectiveness ratios of € 34,581 and €66,983 in the myeloablative and reduced intensity conditioning settings, respectively. Our results showed that for adults with acute leukemia in first complete remission in France, double cord transplantation is more cost-effective than single cord blood transplantation, with better outcomes, including quality-adjusted life-years.

  17. Pretransplant NPM1 MRD levels predict outcome after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia.

    PubMed

    Kayser, S; Benner, A; Thiede, C; Martens, U; Huber, J; Stadtherr, P; Janssen, J W G; Röllig, C; Uppenkamp, M J; Bochtler, T; Hegenbart, U; Ehninger, G; Ho, A D; Dreger, P; Krämer, A

    2016-07-29

    The objective was to evaluate the prognostic impact of pre-transplant minimal residual disease (MRD) as determined by real-time quantitative polymerase chain reaction in 67 adult NPM1-mutated acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-eight of the 67 patients had a FLT3-ITD (42%). Median age at transplantation was 54.7 years, median follow-up for survival from time of allografting was 4.9 years. At transplantation, 31 patients were in first, 20 in second complete remission (CR) and 16 had refractory disease (RD). Pre-transplant NPM1 MRD levels were measured in 39 CR patients. Overall survival (OS) for patients transplanted in CR was significantly longer as compared to patients with RD (P=0.004), irrespective of whether the patients were transplanted in first or second CR (P=0.74). There was a highly significant difference in OS after allogeneic HSCT between pre-transplant MRD-positive and MRD-negative patients (estimated 5-year OS rates of 40 vs 89%; P=0.007). Multivariable analyses on time to relapse and OS revealed pre-transplant NPM1 MRD levels >1% as an independent prognostic factor for poor survival after allogeneic HSCT, whereas FLT3-ITD had no impact. Notably, outcome of patients with pre-transplant NPM1 MRD positivity >1% was as poor as that of patients transplanted with RD.

  18. Absence of Intragraft B Cells in Rejection Biopsies After Rituximab Induction Therapy: Consequences for Clinical Outcome

    PubMed Central

    van den Hoogen, Martijn W.F.; Steenbergen, Eric J.; Baas, Marije C.; Florquin, Sandrine; Hilbrands, Luuk B.

    2017-01-01

    Background The pathophysiological role of intragraft B cells during renal allograft rejection is unclear. Methods We studied B-cell infiltration during acute rejection in 53 patients who participated in a clinical trial in which adult renal transplant patients were randomized between a single intraoperative dose of rituximab (375 mg/m2) or placebo as induction therapy. Two independent pathologists scored all biopsies in a blinded fashion according to the Banff classification and scored for the presence of B cells and plasma cells using CD79a and CD138 as markers. Results The majority of acute rejections were T cell–mediated. The proportion of acute rejections with an antibody-mediated component tended to be lower in rituximab-treated patients (4/23, 17.4%) than in placebo-treated patients (11/30, 36.7%; P = 0.14). Biopsies of rituximab-treated patients had significantly lower scores for B cells (0.00; range, 0.00-0.50 vs 1.70; range, 0.60-3.30; P < 0.0001) and plasma cells (0.10; range, 0.00-1.90 vs 0.40; range, 0.00-7.50; P = 0.006). During acute rejection, intragraft clusters of B cells were not observed after rituximab induction therapy. However, the depletion of intragraft B cells during acute rejection did not affect steroid resistance, proteinuria, graft function at 2 years follow-up, or patient and graft survival at a median follow-up of 4.1 years (range, 2.0-6.2 years). Conclusions These data do not support a harmful influence of intragraft B cells present during acute allograft rejection on the clinical course within the first few years after renal transplantation.

  19. Cardiac transplantation in children.

    PubMed

    Zuberbuhler, J R; Fricker, F J; Griffith, B P

    1989-05-01

    Heart transplantation is becoming an accepted treatment for children with irreversible and profoundly disabling cardiomyopathy. The risk is much higher when there is underlying congenital heart disease, and even moderately elevated pulmonary vascular resistance is a contraindication to orthotopic heart transplantation. Heterotopic or heart-lung transplantation may be considered in patients with elevated pulmonary vascular resistance. In a few centers, heart transplantation is being performed as an alternative to palliative surgical procedures in children with hypoplastic left heart syndrome. Chronic immune suppression is necessary in all patients postoperatively. Cyclosporine and prednisone are the mainstays of therapy, and azathioprine is often added to the regimen. ATG is used prophylactically in the immediate postoperative period and acute rejection episodes are treated with pulses of prednisone, ATG, or OKT3. Infection continues to be a major problem, and the chronic long-term effects of both rejection and the drugs used to treat it, especially cyclosporine, are also very important. Coronary artery disease and lymphoproliferative disease are causes of death, and hypertension and decreased renal function are present in almost all survivors. The shortage of donor hearts is becoming a progressively more important problem and may affect selection criteria in the future. On the positive side, most children can return to age-appropriate activities following transplantation and they seem to tolerate their chronic illness and its attendant repeated invasive procedures surprisingly well.

  20. A case of Clostridium difficile infection complicated by acute respiratory distress syndrome treated with fecal microbiota transplantation.

    PubMed

    Kim, Ji Eun; Gweon, Tae-Geun; Yeo, Chang Dong; Cho, Young-Seok; Kim, Gi Jun; Kim, Jae Young; Kim, Jong Wook; Kim, Hyunho; Lee, Hye Won; Lim, Taeseok; Ham, Hyoju; Oh, Hyun Jin; Lee, Yeongbok; Byeon, Jaeho; Park, Sung Soo

    2014-09-21

    Acute respiratory distress syndrome is a life-threatening disorder caused mainly by pneumonia. Clostridium difficile infection (CDI) is a common nosocomial diarrheal disease. Disruption of normal intestinal flora by antibiotics is the main risk factor for CDI. The use of broad-spectrum antibiotics for serious medical conditions can make it difficult to treat CDI complicated by acute respiratory distress syndrome. Fecal microbiota transplantation is a highly effective treatment in patients with refractory CDI. Here we report on a patient with refractory CDI and acute respiratory distress syndrome caused by pneumonia who was treated with fecal microbiota transplantation.

  1. Desensitization: Overcoming the Immunologic Barriers to Transplantation

    PubMed Central

    Choi, Jua; Vo, Ashley; Peng, Alice; Jordan, Stanley C.

    2017-01-01

    HLA (Human Leucocyte Antigen) sensitization is a significant barrier to successful kidney transplantation. It often translates into difficult crossmatch before transplant and increased risk of acute and chronic antibody mediated rejection after transplant. Over the last decade, several immunomodulatory therapies have emerged allowing for increased access to kidney transplantation for the immunologically disadvantaged group of HLA sensitized end stage kidney disease patients. These include IgG inactivating agents, anti-cytokine antibodies, costimulatory molecule blockers, complement inhibitors, and agents targeting plasma cells. In this review, we discuss currently available agents for desensitization and provide a brief analysis of data on novel biologics, which will likely improve desensitization outcomes, and have potential implications in treatment of antibody mediated rejection. PMID:28127571

  2. Acute bacterial sternoclavicular osteomyelitis in a long-term renal transplant recipient

    PubMed Central

    Dounousi, Evangelia; Duni, Anila; Xiromeriti, Sofia; Pappas, Charalambos; Siamopoulos, Kostas C

    2016-01-01

    Kidney transplantation is the treatment of choice for a significant number of patients with end-stage renal disease. Although immunosuppression therapy improves graft and patient’s survival, it is a major risk factor for infection following kidney transplantation altering clinical manifestations of the infectious diseases and complicating both the diagnosis and management of renal transplant recipients (RTRs). Existing literature is very limited regarding osteomyelitis in RTRs. Sternoclavicular osteomyelitis is rare and has been mainly reported after contiguous spread of infection or direct traumatic seeding of the bacteria. We present an interesting case of acute, bacterial sternoclavicular osteomyelitis in a long-term RTR. Blood cultures were positive for Streptococcus mitis, while the portal entry site was not identified. Magnetic resonance imaging of the sternoclavicluar region and a three-phase bone scan were positive for sternoclavicular osteomyelitis. Eventually, the patient was successfully treated with Daptomycin as monotherapy. In the presence of immunosuppression, the transplant physician should always remain alert for opportunistic pathogens or unusual location of osteomyelitis. PMID:27358791

  3. Lipid raft facilitated ligation of K-{alpha}1-tubulin by specific antibodies on epithelial cells: Role in pathogenesis of chronic rejection following human lung transplantation

    SciTech Connect

    Tiriveedhi, Venkataswarup; Angaswamy, Nataraju; Weber, Joseph; Mohanakumar, T.

    2010-08-20

    Research highlights: {yields} Addition of KAT Abs (+) sera to NHBE culture causes upregulation of growth factors. {yields} Cholesterol depletion causes down regulation of growth factor expression. {yields} Cholesterol depletion is accompanied by loss of membrane bound caveolin. {yields} Thus, we demonstrate lipid raft are critical for efficient ligation of the KAT Abs. -- Abstract: Long term function of human lung allografts is hindered by development of chronic rejection manifested as Bronchiolitis Obliterans Syndrome (BOS). We have previously identified the development of antibodies (Abs) following lung transplantation to K-{alpha}1-tubulin (KAT), an epithelial surface gap junction cytoskeletal protein, in patients who develop BOS. However, the biochemical and molecular basis of the interactions and signaling cascades mediated by KAT Abs are yet to be defined. In this report, we investigated the biophysical basis of the epithelial cell membrane surface interaction between KAT and its specific Abs. Towards this, we analyzed the role of the lipid raft-domains in the membrane interactions which lead to cell signaling and ultimately increased growth factor expression. Normal human bronchial epithelial (NHBE) cells, upon specific ligation with Abs to KAT obtained either from the serum of BOS(+) patients or monoclonal KAT Abs, resulted in upregulation of growth factors VEGF, PDGF, and bFGF (6.4 {+-} 1.1-, 3.2 {+-} 0.9-, and 3.4 {+-} 1.1-fold increase, respectively) all of which are important in the pathogenesis of BOS. To define the role for lipid raft in augmenting surface interactions, we analyzed the changes in the growth factor expression pattern upon depletion and enrichment with lipid raft following the ligation of the epithelial cell membranes with Abs specific for KAT. NHBE cells cultured in the presence of {beta}-methyl cyclodextran ({beta}MCD) had significantly reduced growth factor expression (1.3 {+-} 0.3, vs {beta}MCD untreated being 6.4 {+-} 1.1-fold

  4. Clinical Significance of HLA-DQ Antibodies in the Development of Chronic Antibody-Mediated Rejection and Allograft Failure in Kidney Transplant Recipients.

    PubMed

    Lee, Hyeyoung; Min, Ji Won; Kim, Ji-Il; Moon, In-Sung; Park, Ki-Hyun; Yang, Chul Woo; Chung, Byung Ha; Oh, Eun-Jee

    2016-03-01

    With the development of the single antigen beads assay, the role of donor specific alloantibody (DSA) against human leukocyte antigens in kidney transplantation (KT) has been highlighted. This study aimed to investigate the clinical significance of DQ-DSA detected at renal allograft biopsy. We evaluated 263 KT recipients who underwent allograft biopsy and DSA detection at the same time. Among them, 155 patients who were nonsensitized before transplantation were selected to investigate the role of de-novo DQ-DSA. Both the total and nonsensitized subgroup was categorized into 4 groups each according to DSA results as: DQ only, DQ + non-DQ, non-DQ, and no DSA. In the total patient group, post-KT DSA was positive in 79 (30.0%) patients and DQ-DSA was most prevalent (64.6%). In the nonsensitized subgroup, de-novo DSAs were detected in 45 (29.0%) patients and DQ-DSA was also most prevalent (73.3%). The DQ only group showed a significantly longer post-KT duration compared to the other groups (P < 0.05). The overall incidence of antibody-mediated rejection (AMR) was 17.9%. B-DSA, DR-DSA, and DQ-DSA were associated with AMR (P < 0.05), but in the analysis for chronic AMR, only DQ-DSA showed significance in both the total and the nonsensitized subgroup (P < 0.05). On comparison of Banff scores among groups, those representing humoral immunity were significantly dominant in all DSA positive groups compared to the no DSA group (P < 0.05), and higher scores of markers representing chronic tissue injury were more frequently detected in the groups with DQ-DSA. The worst postbiopsy survival was seen in the DQ + non-DQ group of the total patient group, and patients with de-novo DQ-DSA showed poorer graft survival in the nonsensitized subgroup compared to the no DSA group (P < 0.05). In the multivariate analysis, de-novo DQ-DSA was the only significant risk factor associated with late allograft failure (P < 0.05). Our study is the first to demonstrate

  5. Unrelated Cord Blood Transplantation for Acute Leukemia Diagnosed in the First Year of Life: Outcomes and Risk Factor Analysis.

    PubMed

    Ruggeri, Annalisa; Volt, Fernanda; Locatelli, Franco; Michel, Gerard; Diaz de Heredia, Cristina; Abecasis, Manuel; Zecca, Marco; Vora, Ajay; Yakouben, Karima; O'Brien, Tracey A; Giardino, Stefano; Cornish, Jacqueline; Rocha, Vanderson; Peters, Christina; Bader, Peter; Gluckman, Eliane; Dalle, Jean Hugues

    2017-01-01

    Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% ± 3% and of 4-year chronic GVHD was 13% ± 2%. CIF of 1-year transplant-related mortality was 23% ± 3% and of 4-year relapse was 27% ± 3%. Leukemia-free-survival (LFS) at 4 years was 50% ± 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL.

  6. [Liver transplantation and pregnancy].

    PubMed

    Goarin, A-C; Homer, L

    2010-11-01

    Management during their sexual life of patients with a liver transplantation is a more or less common situation depending centers. Based on literature review, a focus on management of recipient women was conducted, from contraception to pregnancy, describing the complications related to the status of transplant recipient, but also those that may be related to immunosuppressive agents. If fertility and access to contraception are only slightly modified by graft, complications related to graft or immunosuppressive drugs can affect the pregnancy. On the maternal side, hypertension and preeclampsia are more common, as well as renal dysfunction, iatrogenic diabetes and bacterial or viral infections, acute rejection and graft loss do not appear to be influenced by pregnancy. The fetus is also exposed to risks such as induced prematurity and IUGR. Pregnancy in recipients of hepatic grafts therefore requires joint follow-up by transplant specialist and perinatologist, which leads in most cases to successful outcome for mother and child.

  7. Takotsubo Cardiomyopathy: A Cardiac Syndrome Mimicking Acute Myocardial Infarction in a Liver Transplant Recipient

    PubMed Central

    Anders, Maria M; Comignani, Pablo D; Couce, Rocio; Prini, Nadia; Zerega, Alina R; Santopinto, Mariano; Devetach, Gustavo; Quinonez, Emilio G; Goldaracena, Nicolas; McCormack, Lucas; Mastai, Ricardo C

    2011-01-01

    Takotsubo cardiomyopathy (TTC) is a rare clinical syndrome defined as a profound but reversible left ventricular dysfunction in the absence of coronary artery disease. We describe the clinical features and management of TC manifesting in the postoperative period in a patient undergoing liver transplantation. Two days after surgery, the patient developed clinical features of acute myocardial infarction. Ecochardiography revealed hypokinesis of the left ventricle. Coronary angiography revealed normal arteries without any stenosis or obstruction. The patient required vasopressor and inotropic support. The placement of intra-aortic balloon pump had a beneficial effect on the management of heart failure. The patient had a complete recovery of cardiac function 40 days after surgery. TC is a possible occurrence after liver transplant. Awareness of this condition is essential as early diagnosis and prompt management can save the patient’s life.

  8. Acute pulmonary involvement by paracoccidiodomycosis disease immediately after kidney transplantation: Case report and literature review.

    PubMed

    Radisic, Marcelo V; Linares, Laura; Afeltra, Javier; Pujato, Natalia; Vitale, Roxana G; Bravo, Martin; Dotta, Ana C; Casadei, Domingo H

    2017-04-01

    Paracoccidioides brasiliensis is the cause of paracoccidioidomycosis, one of the most important systemic mycoses in Latin America. Human disease has been observed in a limited geographic and ecological niche, and it is attributed to exposure to the fungus in soil. Most primary infections are subclinical, as the infection is contained by the host mainly through cell-mediated immune response. However, as the fungus has the ability to survive in a dormant state for long periods, an impairment of the immune response may lead to reactivation and clinical disease. Surprisingly, paracoccidioidomycosis has rarely been reported in transplanted patients. The aim of this communication is to report a case occurring in a kidney recipient in an acute clinical form immediately after transplantation, and to review the available information on previously reported cases.

  9. Small Bowel Transplant

    PubMed Central

    2003-01-01

    velocity with no catch-up growth. The quality of life after SBT was reported to be comparable to that of patients on home enteral nutrition. A study found that while the parents of pediatric SBT recipients reported significant limitations in the physical and psychological well being of the children compared with normal school children, the pediatric SBT recipients themselves reported a quality of life similar to other school children. Survival was found to be better in transplants performed since 1991. Patient survival was associated with the type of organ transplanted with better survival in isolated small bowel recipients. Adverse Events Despite improvement in patient and graft survival rates, small bowel transplant is still associated with significant mortality and morbidity. Infection with subsequent sepsis is the leading cause of death (51.3%). Bacterial, fungal and viral infections have all been reported. The most common viral infections are cytomegalorvirus (18-40%) and Epstein-Barr virus. The latter often led to ß-cell post-transplant lymphoproliferative disease. Graft rejection is the second leading cause of death after SBT (10.4%) and is responsible for 57% of graft removal. Acute rejection rates ranged from 51% to 83% in the major programs. Most of the acute rejection episodes were mild and responded to steroids and OKT3. Antilymphocyte therapy was needed in up to 27% of patients. Isolated small bowel allograft and positive lymphocytotoxic cross-match were found to be risk factors for acute rejection. Post-transplant lymphoproliferative disease occurred in 21% of SBT recipients and accounted for 7% of post-transplant mortality. The frequency was higher in pediatric recipients (31%) and in adults receiving composite visceral allografts (25%). The allograft itself is often involved in post-transplant lymphoproliferative disease. The reported incidence of host versus graft disease varied widely among centers (0% - 14%). Surgical complications were reported to

  10. Concerns about human hand transplantation in the 21st century.

    PubMed

    Jones, Neil F

    2002-09-01

    The decision to perform a human hand transplant was justified perhaps on less than an ideal scientific basis-only approximately 60 rat limb transplants and 2 primate limb transplants have survived for longer than 200 days and only 8 of 19 pig limb osteomyocutaneous transplants showed no signs of rejection at 90 days. It seems unlikely that the survival of a human hand transplant will be any better than the survival of a kidney transplant, which has a half-life of approximately 7.5 to 9.5 years. Fourteen hand transplants, however, have now been performed in 11 humans with the skin component of 1 remaining viable up to 3 years after surgery. Intermittent episodes of acute rejection seem to have been relatively simple to reverse by temporarily increasing the dose of immunosuppressive agents and steroids. Chronic rejection has occurred in 1 patient, necessitating re-amputation of the transplanted hand. Active range of motion of the digits has been surprisingly better than would have been expected based on previous results of replantation, but return of sensibility has been less than optimal. The immunosuppression has been well tolerated without any major medical problems or life-threatening episodes, but some patients have developed chronic viral and fungal infections and several have developed posttransplant diabetes. Extrapolating from the previous experience of solid-organ transplants, chronic immunosuppression may predispose a hand transplant patient to an 80% chance of developing an infection, a 20% potential risk of developing posttransplant diabetes, and a 4% to 18% potential risk of developing a malignancy. Even though there is universal agreement that composite tissue allograft transplantation will become the ultimate reconstructive option, no one can predict the eventual role of hand transplantation in the future, but perhaps an international database of these hand transplant patients should be established so that independent reviewers can more objectively

  11. Key issues in transplant tourism.

    PubMed

    Akoh, Jacob A

    2012-02-24

    Access to organ transplantation depends on national circumstances, and is partly determined by the cost of health care, availability of transplant services, the level of technical capacity and the availability of organs. Commercial transplantation is estimated to account for 5%-10% (3500-7000) of kidney transplants performed annually throughout the world. This review is to determine the state and outcome of renal transplantation associated with transplant tourism (TT) and the key challenges with such transplantation. The stakeholders of commercial transplantation include: patients on the waiting lists in developed countries or not on any list in developing countries; dialysis funding bodies; middlemen, hosting transplant centres; organ-exporting countries; and organ vendors. TT and commercial kidney transplants are associated with a high incidence of surgical complications, acute rejection and invasive infection which cause major morbidity and mortality. There are ethical and medical concerns regarding the management of recipients of organs from vendors. The growing demand for transplantation, the perceived failure of altruistic donation in providing enough organs has led to calls for a legalised market in organ procurement or regulated trial in incentives for donation. Developing transplant services worldwide has many benefits - improving results of transplantation as they would be performed legally, increasing the donor pool and making TT unnecessary. Meanwhile there is a need to re-examine intrinsic attitudes to TT bearing in mind the cultural and economic realities of globalisation. Perhaps the World Health Organization in conjunction with The Transplantation Society would set up a working party of stakeholders to study this matter in greater detail and make recommendations.

  12. Key issues in transplant tourism

    PubMed Central

    Akoh, Jacob A

    2012-01-01

    Access to organ transplantation depends on national circumstances, and is partly determined by the cost of health care, availability of transplant services, the level of technical capacity and the availability of organs. Commercial transplantation is estimated to account for 5%-10% (3500-7000) of kidney transplants performed annually throughout the world. This review is to determine the state and outcome of renal transplantation associated with transplant tourism (TT) and the key challenges with such transplantation. The stakeholders of commercial transplantation include: patients on the waiting lists in developed countries or not on any list in developing countries; dialysis funding bodies; middlemen, hosting transplant centres; organ-exporting countries; and organ vendors. TT and commercial kidney transplants are associated with a high incidence of surgical complications, acute rejection and invasive infection which cause major morbidity and mortality. There are ethical and medical concerns regarding the management of recipients of organs from vendors. The growing demand for transplantation, the perceived failure of altruistic donation in providing enough organs has led to calls for a legalised market in organ procurement or regulated trial in incentives for donation. Developing transplant services worldwide has many benefits - improving results of transplantation as they would be performed legally, increasing the donor pool and making TT unnecessary. Meanwhile there is a need to re-examine intrinsic attitudes to TT bearing in mind the cultural and economic realities of globalisation. Perhaps the World Health Organization in conjunction with The Transplantation Society would set up a working party of stakeholders to study this matter in greater detail and make recommendations. PMID:24175191

  13. Long-term outcome following heart transplantation: current perspective.

    PubMed

    Wilhelm, Markus J

    2015-03-01

    Heart transplantation keeps its leading position in the treatment of end-stage heart failure (HF). Survival rates and functional status following heart transplantation are excellent, particularly if compared to medical therapy. The process of acute and chronic transplant rejection, however, and the sequelae of immunosuppression, such as infection, malignancy and renal insufficiency, prevents even better results. Therapy with current mechanical circulatory support devices is associated with improving outcome and may become competitive to heart transplantation, at least in selected patients. But long-term results are not yet available.

  14. Clinical neurology in lung transplantation.

    PubMed

    Wigfield, Christopher H; Love, Robert B

    2014-01-01

    Lung transplantation is the only established therapeutic option for several end-stage respiratory diseases. Limited mostly by lack of suitable allografts, the results have measurably improved over the last decade. Numerous surgical and pharmaceutical improvements have had positive impact on outcomes. The potential for critical care issues and the need for interdisciplinary management remains paramount. Cardiac, renal, and metabolic complications are frequently encountered in the acute postoperative phase. Allograft rejection and infectious diseases as well as problems related to immunosuppressive regimen are seen later after lung transplantation. Neurologic manifestations with a range of etiologies are discussed here in this context.

  15. Secondary surgery for functional improvement after hand transplantation.

    PubMed

    Cavadas, Pedro C; Ibañez, Javier; Thione, Alessandro

    2011-10-01

    Unilateral and bilateral hand transplantations have been performed worldwide with good midterm functional results. The role of secondary surgery to improve function in the patients with hand transplant has not been uniformly agreed upon. A series of 10 secondary procedures were performed in 5 surgeries on 3 patients with bilateral upper extremity transplantation. There was 1 incidence of acute rejection after 1 procedure. The functional improvement was evaluated subjectively by the patients as substantial. Secondary procedures can upgrade function after hand transplantation and provide unique opportunities for deep-tissue biopsies. The proinflammatory stimulus of the surgery can theoretically precipitate an acute rejection. The pharmacologic interference of some immunosuppressive drugs with wound healing should also be considered.

  16. The pathological implications of heart transplantation: experience with 50 cases in a single center.

    PubMed

    Ishibashi-Ueda, Hatsue; Ikeda, Yoshihiko; Matsuyama, Taka-Aki; Ohta-Ogo, Keiko; Sato, Takuma; Seguchi, Osamu; Yanase, Masanobu; Fujita, Tomoyuki; Kobayashi, Junjiro; Nakatani, Takeshi

    2014-09-01

    Heart transplantation started in Japan in 1999. Since then, 50 transplants have been performed at our center. We performed histopathological analyses of the 50 explanted hearts and the post-transplant biopsy specimens. The median age of recipients was 39 years. The primary diseases before transplant were idiopathic dilated cardiomyopathy in 33 patients (66%), hypertrophic cardiomyopathy in seven (14%), restrictive cardiomyopathy in one, arrhythmogenic right ventricular cardiomyopathy in one, and secondary cardiomyopathy in eight (16%). Before transplantation, 47 patients (94%) had left ventricular assist devices. No severe cardiovascular failure due to allograft rejection occurred. The post-transplant survival rate was 97.6% at 1 year and 93.1% at 10 years. One recipient was lost to sepsis from myelodysplastic syndrome in the fourth year, one died of multiple organ failure and peritonitis 8 months after transplant. Another patient died of recurrent post-transplant lymphoproliferative disorders (PTLD). Mild cardiac dysfunction occurred in seven recipients in the early postoperative period. Moderate acute cellular rejection occurred in six patients (12%), and antibody-mediated rejection occurred in three (6%). The number of heart transplants performed in Japan is very small. However, the outstanding 10-year survival rate is due to donor evaluation and post-transplant care resulting in low grade rejection. Pathological evaluation has also greatly contributed to the results.

  17. Effect of Graft Source on Unrelated Donor Haemopoietic Stem-Cell Transplantation in Adults with Acute Leukemia: A Retrospective Analysis

    PubMed Central

    Eapen, Mary; Rocha, Vanderson; Sanz, Guillermo; Scaradavou, Andromachi; Zhang, Mei-Jie; Arcese, William; Sirvent, Anne; Champlin, Richard E.; Chao, Nelson; Gee, Adrian P.; Isola, Luis; Laughlin, Mary J.; Marks, David I.; Nabhan, Samir; Ruggeri, Annalisa; Soiffer, Robert; Horowitz, Mary M.; Gluckman, Eliane; Wagner, John E.

    2011-01-01

    SUMMARY Background Umbilical cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPC) or bone marrow (BM), especially when a HLA-matched adult unrelated donor is not available. Methods In order to establish the appropriateness of current graft selection practices, we retrospectively compared leukemia-free survival and other outcomes for each graft source in patients aged >16 years transplanted for acute leukemia using Cox regression. Data were available on 1525 patients transplanted between 2002 and 2006 using UCB (n=165), PBPC (n=888) and BM (n=472). UCB units were matched at HLA-A and B at antigen level and DRB1 at allele level (n=10) or mismatched at one (n=40) or two antigens (n=115). PBPC and BM grafts from unrelated adult donors were matched for allele-level HLA-A, B, C and DRB1 (n=632; n=332) or mismatched at one locus (n=256; n=140). Findings Leukemia-free survival after UCB transplantation was comparable to that observed after 8/8 and 7/8 allele-matched PBPC or BM transplantation. Transplant-related mortality, however, was higher after UCB transplantation compared to 8/8 allele-matched PBPC (HR 1.62, p<0.01) or BM (HR 1.69, p<0.01). Grades 2–4 acute and chronic graft-versus-host disease were lower in UCB recipients compared to allele-matched PBPC (HR 0.57, p<0.01 and HR 0.38, p<0.01, respectively), while chronic and not acute graft-versus-host disease was lower after UCB compared to allele-matched BM transplantation (HR 0.63, p=0.01). Interpretation Together, these data support the use of UCB for adults with acute leukemia when an HLA-matched unrelated adult donor is lacking and when transplant is urgently needed. PMID:20558104

  18. Association of HLA-G promoter and 14-bp insertion-deletion variants with acute allograft rejection and end-stage renal disease.

    PubMed

    Misra, M K; Prakash, S; Kapoor, R; Pandey, S K; Sharma, R K; Agrawal, S

    2013-11-01

    The aim of this study was to investigate the HLA-G 14-bp insertion/deletion (I/D) polymorphism among end-stage renal disease (ESRD) patients. Cytomegalovirus (CMV) infection, acute allograft rejection (AR) and overall survival after renal transplantation was investigated in 300 ESRD patients and 302 age, sex and ethnicity-matched controls. Sequencing was performed to evaluate the impact of HLA-G promoter region single-nucleotide polymorphisms (SNPs) whereas semi-quantitative PCR method was used to determine the probable HLA-G expression pattern among ESRD and AR cases. Further, soluble human leukocyte antigen (HLA)-G (sHLA-G) expression levels were compared in AR vs non-AR cases in the light of HLA-G 14-bp I/D polymorphism. Increased risk was found for 14-bp D/D (deletion-DD) genotype and 14-bp D allele [DD: odds ratio (OR) = 1.46, 95% confidence interval (CI) = 1.03-2.06, P value = 0.0358; D: OR = 1.29, 95% CI = 1.03-1.62, P value = 0.0277], respectively for ESRD and CMV infection (DD: OR = 2.70, 95% CI = 1.45-5.05, P value = 0.0021; D: OR = 1.94, 95% CI = 1.22-3.08, P value = 0.0052). Nearly fourfold (OR = 3.62, 95%CI = 1.61-8.14, p = 0.0039) risk was observed for 14-bp I/I (insertion-II) genotype for AR. Survival analysis showed increased overall survival (OS) (AR or death) for 14-bp D/D genotype. HLA-G promoter region sequencing was carried out among 60 ESRD patients and 100 normal controls which showed increased risk for -964 G>A, -725 C>G/T and -486 A>C SNPs. -964 G>A and -725 C>G/T SNPs showed risk association for AR patients. High level of HLA-G transcripts was observed among non-AR patients. Further soluble HLA-G (sHLA-G) showed increased levels in ESRD patients (mean ± SEM; 62.16 ± 2.43 U/ml) as compared to controls (mean ± SEM; 21.06 ± 3.89 U/ml) (P = <0.0001). The 14-bp I/I, 14-bp I/D and 14-bp D/D genotypes showed significantly higher levels of sHLA-G among non-AR as

  19. Role of NK, NKT cells and macrophages in liver transplantation

    PubMed Central

    Fahrner, René; Dondorf, Felix; Ardelt, Michael; Settmacher, Utz; Rauchfuss, Falk

    2016-01-01

    Liver transplantation has become the treatment of choice for acute or chronic liver disease. Because the liver acts as an innate immunity-dominant organ, there are immunological differences between the liver and other organs. The specific features of hepatic natural killer (NK), NKT and Kupffer cells and their role in the mechanism of liver transplant rejection, tolerance and hepatic ischemia-reperfusion injury are discussed in this review. PMID:27468206

  20. Micro and Nanoparticle Drug Delivery Systems for Preventing Allotransplant Rejection

    PubMed Central

    Fisher, James D.; Acharya, Abhinav P.; Little, Steven R.

    2015-01-01

    Despite decades of advances in transplant immunology, tissue damage caused by acute allograft rejection remains the primary cause of morbidity and mortality in the transplant recipient. Moreover, the long-term sequelae of lifelong immunosuppression leaves patients at risk for developing a host of other deleterious conditions. Controlled drug delivery using micro- and nanoparticles (MNPs) is an effective way to deliver higher local doses of a given drug to specific tissues and cells while mitigating systemic effects. Herein, we review several descriptions of MNP immunotherapies aimed at prolonging allograft survival. We also discuss developments in the field of biomimetic drug delivery that use MNP constructs to induce and recruit our bodies' own suppressive immune cells. Finally, we comment on the regulatory pathway associated with these drug delivery systems. Collectively, it is our hope the studies described in this review will help to usher in a new era of immunotherapy in organ transplantation. PMID:25937032

  1. Overview of marrow transplantation

    SciTech Connect

    Thomas, E.D.

    1985-12-01

    Bone marrow transplantation is now an accepted form of therapy for many hematologic disorders including aplastic anemia, genetically determined diseases and malignant diseases, particularly leukemia, and for rescue of patients given intensive chemoradiotherapy for malignant disease. The donor may be a healthy identical twin, a family member or even an unrelated person. Selection is made on the basis of human leukocyte antigen tissue typing. Intensive chemoradiotherapy is used to suppress patients' immune systems to facilitate engraftment and destroy diseased marrow. Transfusion of platelets, erythrocytes and granulocytes (or all of these), antibiotic coverage and protection from infection are necessary during the pancytopenic period. Survival rates vary considerably depending on a patient's disease, clinical state and age. Patients with aplastic anemia transplanted early in the course of their disease have a survival rate of approximately 80%. Patients with acute lymphoblastic leukemia are usually transplanted in a second or subsequent remission and have a survival rate of 25% to 40%. Patients with acute nonlymphoblastic leukemia in remission have survivals ranging from 45% to 70%. More than 200 patients in the chronic phase of chronic granulocytic leukemia have been transplanted with survival ranging from 50% to 70%. Complications of marrow transplantation include marrow graft rejection, graft-versus-host disease, immunologic insufficiency and the possibility of recurrence of the leukemia. 14 references.

  2. Acute disseminated encephalomyelitis in two renal transplant patients: is there a role for Epstein-Barr virus reactivation?

    PubMed

    Caucheteux, N; Maarouf, A; Daelman, L; Toupance, O; Lavaud, S; Tourbah, A

    2013-08-01

    Acute disseminated encephalomyelitis (ADEM) is a rare inflammatory demyelinating disease of the central nervous system, usually occurring after a vaccination or infectious disease. It has been exceptionally described in transplanted patients. The pathophysiology remains incompletely understood. We report the clinical, biological and magnetic resonance imaging (MRI) presentation and evolution of two kidney-transplanted patients with ADEM associated with local Epstein-Barr virus (EBV) reactivation. ADEM may occur in transplanted patients with favorable evolution. Its pathophysiology is uncertain, and the implication of EBV is discussed.

  3. Early liver transplantation for patients with acute alcoholic hepatitis: public views and the effects on organ donation.

    PubMed

    Stroh, G; Rosell, T; Dong, F; Forster, J

    2015-06-01

    Patients with severe acute alcoholic hepatitis may not survive to fulfill the standard 6 months of abstinence and counseling prior to transplantation. A prospective study demonstrated that early liver transplantation in such patients improved 2 year survival from 23% to 71% and only 3 of 26 patients returned to drinking after 1140 days; graft function was unaffected. Nonetheless, this treatment protocol may raise public concerns and affect organ donation rates. A total of 503 participants took a survey made available at an online crowdsourcing marketplace. The survey measured attitudes on liver transplantation generally and early transplantation for this patient population, in addition to measuring responses to nine vignettes describing fictional candidates. The majority of respondents (81.5%, n = 410) was at least neutral toward early transplantation for these patients; only a minority (26.3%) indicated that transplantation in any vignette would make them hesitant to donate their organs. Middle-aged patients with good social support and financial stability were viewed most favorably (p < 0.001). Age was considered the most important selection factor and financial stability the least important factor (each p < 0.001). Results indicate early transplantation for carefully selected patients with acute alcoholic hepatitis may not be as controversial to the public as previously thought.

  4. Reduced-intensity conditioning allogeneic hematopoietic-cell transplantation for older patients with acute myeloid leukemia

    PubMed Central

    Goyal, Gaurav; Gundabolu, Krishna; Vallabhajosyula, Saraschandra; Silberstein, Peter T.; Bhatt, Vijaya Raj

    2016-01-01

    Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft-versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis. RIC regimens, intermediate in intensity between NMA and myeloablative regimens, can cause prolonged myelosuppresion and usually require stem cell support. A few retrospective and prospective studies suggest a possibility of lower risk of relapse with myeloablative HCT in fit older patients with lower HCT comorbidity index; however, RIC and NMA HCTs have an important role in less-fit patients and those with significant comorbidities because of lower TRM. Whether early tapering of immunosuppression, monitoring of minimal residual disease, and post-transplant maintenance therapy can improve the outcomes of RIC and NMA HCT in elderly patients will require prospective trials. PMID:27247754

  5. Markers of coagulation activation and acute kidney injury in patients after hematopoietic cell transplantation

    PubMed Central

    Hingorani, Sangeeta R; Seidel, Kristy; Pao, Emily; Lawler, Rick; McDonald, George B.

    2015-01-01

    Acute kidney injury (AKI) is common after hematopoietic cell transplant (HCT). The etiology of AKI is unknown because biopsies are rarely performed. The pathophysiology of injury is inferred from clinical data. Thrombotic microangiopathy (TMA) is often invoked as the cause of renal injury. Patients > 2 years undergoing their first HCT at Fred Hutchinson Cancer Research Center (FHCRC) participated in this study. We prospectively measured plasma markers of coagulation activation, (PAI-1 and tPA) and fibrinolyis (D-dimer) weekly in 149 patients during the first 100 days post-transplant. Cox proportional hazards modeling was used to determine associations between these markers and AKI (doubling of baseline serum creatinine). Kruskal-Wallis test was used to determine associations between day 100 urinary albumin to creatinine ratios (ACR) and these markers. Thirty one percent of patients developed AKI. Though elevations in these markers occurred frequently, neither PAI-1 nor tPA were associated with development of AKI. D-dimer was associated with a slightly increased risk of AKI (RR=1.76; p-value 0.04). None of these markers were associated with micro- or macroalbuminuria at day 100. The lack of an association with AKI suggests that endothelial injury in the form of TMA is not a common cause of AKI early after transplant. PMID:25665045

  6. Survival improvements in adolescents and young adults after myeloablative allogeneic transplantation for acute lymphoblastic leukemia.

    PubMed

    Wood, William A; Lee, Stephanie J; Brazauskas, Ruta; Wang, Zhiwei; Aljurf, Mahmoud D; Ballen, Karen K; Buchbinder, David K; Dehn, Jason; Freytes, Cesar O; Lazarus, Hillard M; Lemaistre, Charles F; Mehta, Paulette; Szwajcer, David; Joffe, Steven; Majhail, Navneet S

    2014-06-01

    Adolescents and young adults (AYAs, ages 15 to 40 years) with cancer have not experienced survival improvements to the same extent as younger and older patients. We compared changes in survival after myeloablative allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL) among children (n = 981), AYAs (n = 1218), and older adults (n = 469) who underwent transplantation over 3 time periods: 1990 to 1995, 1996 to 2001, and 2002 to 2007. Five-year survival varied inversely with age group. Survival improved over time in AYAs and paralleled that seen in children; however, overall survival did not change over time for older adults. Survival improvements were primarily related to lower rates of early treatment-related mortality in the most recent era. For all cohorts, relapse rates did not change over time. A subset of 222 AYAs between the ages of 15 and 25 at 46 pediatric or 49 adult centers were also analyzed to describe differences by center type. In this subgroup, there were differences in transplantation practices among pediatric and adult centers, although HCT outcomes did not differ by center type. Survival for AYAs undergoing myeloablative allogeneic HCT for ALL improved at a similar rate as survival for children.

  7. Stabilization of estimated glomerular filtration rate in kidney transplantation from deceased donors with acute kidney injuries

    PubMed Central

    Wiwattanathum, Punlop; Ingsathit, Atiporn; Kantachuvesiri, Surasak; Arpornsujaritkun, Nuttapon; Tirapanich, Wiwat; Sumethkul, Vasant

    2016-01-01

    AIM To evaluate and compare the outcomes of kidney transplant (KT) from deceased donors among standard criteria, acute kidney injury (AKI) and expanded criteria donors (ECDs). METHODS This retrospective study included 111 deceased donor kidney transplant recipients (DDKT). Deceased donors were classified as standard criteria donor (SCD), AKI donor and ECD. AKI was diagnosed and classified based on change of serum Cr by acute kidney injury network (AKIN) criteria. Primary outcome was one-year estimated glomerular filtration rate (eGFR) calculated from Cr by CKD-EPI. Multivariate regression analysis was done by adjusting factors such as type of DDKT, %Panel-reactive antibodies, cold ischemic time, the presence of delayed graft function and the use of induction therapy. Significant factors that can affect the primary outcomes were then identified. RESULTS ECD group had a significantly lower eGFR at one year (33.9 ± 17.3 mL/min) when compared with AKI group (56.6 ± 23.9) and SCD group (63.6 ± 19.9) (P < 0.001). For AKI group, one-year eGFR was also indifferent among AKIN stage 1, 2 or 3. Patients with AKIN stage 3 had progressive increase of eGFR from 49.6 ± 27.2 at discharge to 61.9 ± 29.0 mL/min at one year. From Kaplan-Meier analysis, AKI donor showed better two-year graft survival than ECD (100% vs 88.5%, P = 0.006). Interestingly, AKI group had a stable eGFR at one and two year. The two-year eGFR of AKI group was not significantly different from SCD group (56.6 ± 24.5 mL/min vs 58.6 ± 23.2 mL/min, P = 0.65). CONCLUSION Kidney transplantations from deceased donors with variable stage of acute kidney injuries were associated with favorable two-year allograft function. The outcomes were comparable with KT from SCD. This information supports the option that deceased donors with AKI are an important source of organ for kidney transplantation even in the presence of stage 3 AKI. PMID:28058222

  8. Biomarkers of delayed graft function as a form of acute kidney injury in kidney transplantation

    PubMed Central

    Malyszko, Jolanta; Lukaszyk, Ewelina; Glowinska, Irena; Durlik, Magdalena

    2015-01-01

    Renal transplantation ensures distinct advantages for patients with end-stage kidney disease. However, in some cases early complications can lead to allograft dysfunction and consequently graft loss. One of the most common early complications after kidney transplantation is delayed graft function (DGF). Unfortunately there is no effective treatment for DGF, however early diagnosis of DGF and therapeutic intervention (eg modification of immunosuppression) may improve outcome. Therefore, markers of acute kidney injury are required. Creatinine is a poor biomarker for kidney injury due principally to its inability to help diagnose early acute renal failure and complete inability to help differentiate among its various causes. Different urinary and serum proteins have been intensively investigated as possible biomarkers in this setting. There are promising candidate biomarkers with the ability to detect DGF. We focused on emerging biomarkers of DGF with NGAL is being the most studied followed by KIM-1, L-FABP, IL-18, and others. However, large randomized studies are needed to establish the value of new, promising biomarkers, in DGF diagnosis, prognosis and its cost-effectiveness. PMID:26175216

  9. YKL-40 in allogeneic hematopoietic cell transplantation after acute myeloid leukemia and myelodysplastic syndrome

    PubMed Central

    Kornblit, Brian; Wang, Tao; Lee, Stephanie J.; Spellman, Stephen R.; Zhu, Xiaochun; Fleischhauer, Katharina; Müller, Carlheinz; Verneris, Michael R.; Müller, Klaus; Johansen, Julia S.; Vindelov, Lars; Garred, Peter

    2016-01-01

    YKL-40, also called chitinase3-like-1 protein, is an inflammatory biomarker which has been associated with disease severity in inflammatory and malignant diseases, including acute myeloid leukemia (AML), multiple myeloma and lymphomas. The objective of the current study was to assess the prognostic value of pre-transplant recipient and donor plasma YKL-40 concentrations in patients with AML (n=624) or myelodysplastic syndrome (MDS) (n=157) treated with allogeneic hematopoietic cell transplantation (HCT). In recipients, the plasma YKL-40 concentrations were increased when the HCT-comorbidity index was ≥5 (p=0.028). There were no significant associations between plasma YKL-40 concentrations in recipients and any outcome measures. In donors with YKL-40 plasma concentrations above the age adjusted 95th percentile a trend towards increased grade II-IV acute graft versus host disease in recipients was observed (adjusted hazard ratio 1.39 (95% confidence interval 1.00–1.94), P=0.050), with no significant associations with overall survival, treatment-related mortality or relapse. In conclusion, our study shows that YKL-40 does not aid risk stratification of patients undergoing allogeneic HCT, but suggests that YKL-40 may aid donor selection when multiple, otherwise equal, donors are available. PMID:27427920

  10. Imaging mouse lung allograft rejection with 1H MRI

    PubMed Central

    Guo, Jinbang; Huang, Howard J.; Wang, Xingan; Wang, Wei; Ellison, Henry; Thomen, Robert P.; Gelman, Andrew E.; Woods, Jason C.

    2014-01-01

    Purpose To demonstrate that longitudinal, non-invasive monitoring via MRI can characterize acute cellular rejection (ACR) in mouse orthotopic lung allografts. Methods Nineteen Balb/c donor to C57BL/6 recipient orthotopic left lung transplants were performed, further divided into control-Ig vs anti-CD4/anti-CD8 treated groups. A two-dimensional multi-slice gradient-echo pulse sequence synchronized with ventilation was used on a small-animal MR scanner to acquire proton images of lung at post-operative days 3, 7 and 14, just before sacrifice. Lung volume and parenchymal signal were measured, and lung compliance was calculated as volume change per pressure difference between high and low pressures. Results Normalized parenchymal signal in the control-Ig allograft increased over time, with statistical significance between day 14 and day 3 post transplantation (0.046→0.789, P < 0.05), despite large inter-mouse variations; this was consistent with histopathologic evidence of rejection. Compliance of the control-Ig allograft decreased significantly over time (0.013→0.003, P < 0.05), but remained constant in mice treated with anti-CD4/anti-CD8 antibodies. Conclusion Lung allograft rejection in individual mice can be monitored by lung parenchymal signal changes and by lung compliance through MRI. Longitudinal imaging can help us better understand the time course of individual lung allograft rejection and response to treatment. PMID:24954886

  11. Pre-transplantation minimal residual disease with cytogenetic and molecular diagnostic features improves risk stratification in acute myeloid leukemia

    PubMed Central

    Oran, Betül; Jorgensen, Jeff L.; Marin, David; Wang, Sa; Ahmed, Sairah; Alousi, Amin M.; Andersson, Borje S.; Bashir, Qaiser; Bassett, Roland; Lyons, Genevieve; Chen, Julianne; Rezvani, Katy; Popat, Uday; Kebriaei, Partow; Patel, Keyur; Rondon, Gabriela; Shpall, Elizabeth J.; Champlin, Richard E.

    2017-01-01

    Our aim was to improve outcome prediction after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia by combining cytogenetic and molecular data at diagnosis with minimal residual disease assessment by multicolor flow-cytometry at transplantation. Patients with acute myeloid leukemia in first complete remission in whom minimal residual disease was assessed at transplantation were included and categorized according to the European LeukemiaNet classification. The primary outcome was 1-year relapse incidence after transplantation. Of 152 patients eligible, 48 had minimal residual disease at the time of their transplant. Minimal residual disease-positive patients were older, required more therapy to achieve first remission, were more likely to have incomplete recovery of blood counts and had more adverse risk features by cytogenetics. Relapse incidence at 1 year was higher in patients with minimal residual disease (32.6% versus 14.4%, P=0.002). Leukemia-free survival (43.6% versus 64%, P=0.007) and overall survival (48.8% versus 66.9%, P=0.008) rates were also inferior in patients with minimal residual disease. In multivariable analysis, minimal residual disease status at transplantation independently predicted 1-year relapse incidence, identifying a subgroup of intermediate-risk patients, according to the European LeukemiaNet classification, with a particularly poor outcome. Assessment of minimal residual disease at transplantation in combination with cytogenetic and molecular findings provides powerful independent prognostic information in acute myeloid leukemia, lending support to the incorporation of minimal residual disease detection to refine risk stratification and develop a more individualized approach during hematopoietic stem cell transplantation. PMID:27540139

  12. Transplantation of Endothelial Cells to Mitigate Acute and Chronic Radiation Injury to Vital Organs.

    PubMed

    Rafii, Shahin; Ginsberg, Michael; Scandura, Joseph; Butler, Jason M; Ding, Bi-Sen

    2016-08-01

    Current therapeutic approaches for treatment of exposure to radiation involve the use of antioxidants, chelating agents, recombinant growth factors and transplantation of stem cells (e.g., hematopoietic stem cell transplantation). However, exposure to high-dose radiation is associated with severe damage to the vasculature of vital organs, often leading to impaired healing, tissue necrosis, thrombosis and defective regeneration caused by aberrant fibrosis. It is very unlikely that infusion of protective chemicals will reverse severe damage to the vascular endothelial cells (ECs). The role of irradiated vasculature in mediating acute and chronic radiation syndromes has not been fully appreciated or well studied. New approaches are necessary to replace and reconstitute ECs in organs that are irreversibly damaged by radiation. We have set forth the novel concept that ECs provide paracrine signals, also known as angiocrine signals, which not only promote healing of irradiated tissue but also direct organ regeneration without provoking fibrosis. We have developed innovative technologies that enable manufacturing and banking of human GMP-grade ECs. These ECs can be transplanted intravenously to home to and engraft to injured tissues where they augment organ repair, while preventing maladaptive fibrosis. In the past, therapeutic transplantation of ECs was not possible due to a shortage of availability of suitable donor cell sources and preclinical models, a lack of understanding of the immune privilege of ECs, and inadequate methodologies for expansion and banking of engraftable ECs. Recent advances made by our group as well as other laboratories have breached the most significant of these obstacles with the development of technologies to manufacture clinical-scale quantities of GMP-grade and human ECs in culture, including genetically diverse reprogrammed human amniotic cells into vascular ECs (rAC-VECs) or human pluripotent stem cells into vascular ECs (iVECs). This

  13. Transplantation of Endothelial Cells to Mitigate Acute and Chronic Radiation Injury to Vital Organs

    PubMed Central

    Rafii, Shahin; Ginsberg, Michael; Scandura, Joseph; Butler, Jason M.; Ding, Bi-Sen

    2016-01-01

    Current therapeutic approaches for treatment of exposure to radiation involve the use of antioxidants, chelating agents, recombinant growth factors and transplantation of stem cells (e.g., hematopoietic stem cell transplantation). However, exposure to high-dose radiation is associated with severe damage to the vasculature of vital organs, often leading to impaired healing, tissue necrosis, thrombosis and defective regeneration caused by aberrant fibrosis. It is very unlikely that infusion of protective chemicals will reverse severe damage to the vascular endothelial cells (ECs). The role of irradiated vasculature in mediating acute and chronic radiation syndromes has not been fully appreciated or well studied. New approaches are necessary to replace and reconstitute ECs in organs that are irreversibly damaged by radiation. We have set forth the novel concept that ECs provide paracrine signals, also known as angiocrine signals, which not only promote healing of irradiated tissue but also direct organ regeneration without provoking fibrosis. We have developed innovative technologies that enable manufacturing and banking of human GMP-grade ECs. These ECs can be transplanted intravenously to home to and engraft to injured tissues where they augment organ repair, while preventing maladaptive fibrosis. In the past, therapeutic transplantation of ECs was not possible due to a shortage of availability of suitable donor cell sources and preclinical models, a lack of understanding of the immune privilege of ECs, and inadequate methodologies for expansion and banking of engraftable ECs. Recent advances made by our group as well as other laboratories have breached the most significant of these obstacles with the development of technologies to manufacture clinical-scale quantities of GMP-grade and human ECs in culture, including genetically diverse reprogrammed human amniotic cells into vascular ECs (rAC-VECs) or human pluripotent stem cells into vascular ECs (iVECs). This

  14. A case of chronic antibody-mediated rejection in the making.

    PubMed

    Bravou, Vasiliki; Galliford, Jack; McLean, Adam; Willicombe, Michelle; Taube, David; Cook, Herbert T; Roufosse, Candice

    2013-10-01

    A kidney transplant recipient developed chronic antibody-mediated rejection (ABMR) with clinically significant transplant glomerulopathy while under careful clinical monitoring. The patient developed a de novo donor-specific antibody (DSA) posttransplantation, and a protocol renal biopsy showed C4d deposition with no histological evidence of rejection. Subsequently he developed peritubular capillary basement membrane multilayering, with negative C4d and DSA. Finally, he developed proteinuria and transplant glomerulopathy, with reappearance of DSA and C4d. Despite having a de novo antibody and progressive antibody-mediated damage, this patient under close histological and serological surveillance did not fulfill Banff criteria for acute or chronic ABMR until his disease was advanced. This case illustrates the limitations of current Banff criteria in this setting, due to the fluctuating nature of DSA and C4d staining.

  15. Transplantation of Kidneys From Donors With Acute Kidney Injury: Friend or Foe?

    PubMed

    Boffa, C; van de Leemkolk, F; Curnow, E; Homan van der Heide, J; Gilbert, J; Sharples, E; Ploeg, R J

    2017-02-01

    The gap between supply and demand in kidney transplantation has led to increased use of marginal kidneys; however, kidneys with acute kidney injury are often declined/discarded. To determine whether this policy is justified, we analyzed outcomes of donor kidneys with acute kidney injury (AKI) in a large UK cohort. A retrospective analysis of the UK Transplant Registry evaluated deceased donors between 2003 and 2013. Donors were classified as no AKI, or AKI stage 1-3 according to Acute Kidney Injury Network (AKIN) criteria. Relationship of AKI with delayed graft function/primary nonfunction (DGF/PNF), estimated glomerular filtration rate (eGFR), and graft-survival at 90 days and 1 year was analyzed. There were 11 219 kidneys (1869 [17%] with AKI) included. Graft failure at 1 year is greater for donors with AKI than for those without (graft survival 89% vs. 91%, p = 0.02; odds ratio (OR) 1.20 [95% confidence interval (CI): 1.03-1.41]). DGF rates increase with donor AKI stage (p < 0.005), and PNF rates are significantly higher for AKIN stage 3 kidneys (9% vs. 4%, p = 0.04) Analysis of association between AKI and recipient eGFR suggests a risk of inferior eGFR with AKI versus no AKI (p < 0.005; OR 1.25 [95% CI: 1.08-1.31]). We report a small reduction in 1-year graft-survival of kidneys from donors with AKI. We conclude that AKI stage 1 or 2 kidneys should be used; however, caution is advised for AKI stage 3 donors.

  16. RIFLE criteria and hepatic function in the assessment of acute renal failure in liver transplantation.

    PubMed

    Tinti, F; Umbro, I; Meçule, A; Rossi, M; Merli, M; Nofroni, I; Corradini, S Ginanni; Poli, L; Pugliese, F; Ruberto, F; Berloco, P B; Mitterhofer, A P

    2010-05-01

    Renal dysfunction in cirrhotic patients is primary related to disturbances of circulatory function, triggered by portal hypertension with chronic intrarenal vasoconstriction and hypoperfusion. Pretransplant renal function is an important factor implicated in the development of acute renal failure (ARF) after liver transplantation (OLT), but other factors mostly related to liver function seem to influence the development of ARF. The Acute Dialysis Quality Initiative workgroup developed the RIFLE classification to define ARF. We sought to evaluate the incidence of ARF among patients undergoing OLT, to evaluate the association of ARF with pre-OLT renal and hepatic functions, and to evaluate the influence of ARF on chronic kidney disease (CKD) at 1 month post-OLT. Clinical, renal, hepatic function, and donor risk index data of 24 patients who underwent deceased donor OLT were collected before transplantation, in the perioperative period and in the first month post-OLT. ARF occurred in 37.5% of patients with 56% developing the R grade and 44% the I grade; no patient showed the F grade. An association was observed between ARF and a higher Model for End-Stage Liver Disease (MELD) score and between ARF and a reduced pre-OLT serum albumin. No association was noted between ARF and other pre-OLT parameters. In cirrhotic patients serum creatinine is a bias for renal function assessment and the Modification of Diet in Renal Disease formula overestimates GFR. Post-OLT CKD was present in 6.7% of patients without ARF and in 44.4% of patients with ARF. The R grade developed more frequently among patients with viral cirrhosis. The association of ARF with MELD and hypoalbuminemia may be the result of a close relationship between renal and hepatic functions among cirrhotic patients. Post-OLT CKD may be the result of unrecognized, preexisting CKD and/or the effects of not fully resolved acute damage to an injured kidney.

  17. Implementation and results of a new ECMO program for lung transplantation and acute respiratory distress

    PubMed Central

    Roman, Eduardo San; Venuti, María Sofía; Ciarrocchi, Nicolás Marcelo; Ceballos, Ignacio Fernández; Gogniat, Emiliano; Villarroel, Sonia; Carini, Federico Carlos; Giannasi, Sergio Eduardo

    2015-01-01

    Objective The development of the extracorporeal membrane oxygenation in Latin America represents a challenge in this specialty field. The objective of this article was to describe the results of a new extracorporeal membrane oxygenation program in an intensive care unit. Methods This retrospective cohort study included 22 patients who required extracorporeal membrane oxygenation and were treated from January 2011 to June 2014. The baseline characteristics, indications, duration of the condition, days on mechanical ventilation, days in the intensive care unit, complications, and hospital mortality were evaluated. Results Fifteen patients required extracorporeal membrane oxygenation after lung transplantation, and seven patients required oxygenation due to acute respiratory distress. All transplanted patients were weaned from extracorporeal membrane oxygenation with a median duration of 3 days (Interquartile range - IQR: 2 - 5), were on mechanical ventilation for a median of 15.5 days (IQR: 3 - 25), and had an intensive care unit stay of 31.5 days (IQR: 19 - 53) and a median hospital stay of 60 days (IQR: 36 - 89) with 20% mortality. Patients with acute respiratory distress had a median oxygenation membrane duration of 9 days (IQR: 3 - 14), median mechanical ventilation time of 25 days (IQR: 13 - 37), a 31 day stay in therapy (IQR: 11 - 38), a 32 day stay in the hospital (IQR: 11 - 41), and 57% mortality. The main complications were infections (80%), acute kidney failure (43%), bleeding at the surgical site and at the site of cannula placement (22%), plateletopenia (60%), and coagulopathy (30%). Conclusion In spite of the steep learning curve, we considered this experience to be satisfactory, with results and complications comparable to those reported in the literature. PMID:26340153

  18. Seizure Treatment in Transplant Patients

    PubMed Central

    Shepard, Paul W.

    2013-01-01

    Opinion statement Solid organ transplantation is frequently complicated by a spectrum of seizure types, including single partial-onset or generalized tonic-clonic seizures, acute repetitive seizures or status epilepticus, and sometimes the evolution of symptomatic epilepsy. There is currently no specific evidence involving the transplant patient population to guide the selection, administration, or duration of antiepileptic drug (AED) therapy, so familiarity with clinical AED pharmacology and application of sound judgment are necessary for successful patient outcomes. An initial detailed search for symptomatic seizure etiologies, including metabolic, infectious, cerebrovascular, and calcineurin inhibitor treatment-related neuro-toxic complications such as posterior reversible encephalopathy syndrome (PRES), is imperative, as underlying central nervous system disorders may impose additional serious risks to cerebral or general health if not promptly detected and appropriately treated. The mainstay for post-transplant seizure management is AED therapy directed toward the suspected seizure type. Unfavorable drug interactions could place the transplanted organ at risk, so choosing an AED with limited interaction potential is also crucial. When the transplanted organ is dysfunctional or vulnerable to rejection, AEDs without substantial hepatic metabolism are favored in post-liver transplant patients, whereas after renal transplantation, AEDs with predominantly renal elimination may require dosage adjustment to prevent adverse effects. Levetiracetam, gabapentin, pregabalin, and lacosamide are drugs of choice for treatment of partial-onset seizures in post-transplant patients given their efficacy spectrum, generally excellent tolerability, and lack of drug interaction potential. Levetiracetam is the drug of choice for primary generalized seizures in post-transplant patients. When intravenous drugs are necessary for acute seizure management, benzodiazepines and

  19. The influence of socioeconomic deprivation on outcomes in pancreas transplantation.

    PubMed

    Khalid, Usman; Laftsidis, Prodromos; Chapman, Dawn; Stephens, Michael R; Asderakis, Argiris

    2015-05-01

    Socioeconomic deprivation is an important factor in determining poor health and is associated with a higher prevalence of many chronic diseases including diabetes and renal failure, with poorer outcomes of their treatments. The influence of deprivation on outcomes following pancreas transplantation has not previously been reported. The Welsh Index of Multiple Deprivation was used to assess the influence of socioeconomic deprivation on outcomes for 119 consecutive pancreas transplant recipients from a single center in the United Kingdom, transplanted between 2004 and 2013. Outcomes measured were rate of acute rejection and graft survival. Thirty-five (29.4%) patients experienced at least one episode of acute rejection following their transplant. Rejection rates in least deprived were 37% and most deprived 24% (p = 0.29). Within the individual domains, rejection rate was higher for the "physical environment" domain (least deprived 40% vs. most deprived 17% (p = 0.053). Five-year graft survival for least and most deprived groups was 75% and 88%, respectively (log-rank test p-value 0.24). This study has not demonstrated any significant differences in outcomes following pancreas transplantation in Wales in relation to socioeconomic deprivation with the exception possibly of the "physical environment" domain. Further studies with larger patient population or concentrating on physical environment deprivation would be of interest.

  20. Maternal compared with paternal donor kidneys are associated with poorer graft outcomes after kidney transplantation.

    PubMed

    Lim, Wai H; McDonald, Stephen P; Coates, Patrick T; Chapman, Jeremy R; Russ, Graeme R; Wong, Germaine

    2016-03-01

    Noninherited maternal human leukocyte antigens may be less detrimental on allograft outcomes after kidney transplantation compared with noninherited paternal antigens, but this association in the era of modern immunosuppression remains unknown. Here we determine the association between parental donor kidneys, acute rejection, and graft failure in primary live-donor parental kidney transplant recipients using data from the Australia and New Zealand Dialysis and Transplant Registry between 1997 and 2012. Of the 1139 recipients followed for a median of 7.2 years (8588 person-years), 652 received kidneys from maternal donors. Compared with paternal donor kidneys, maternal donor kidneys were associated with a significantly increased risk of acute rejection (adjusted odds ratio 1.54; 95% confidence interval [CI], 1.14-2.07) and significant overall graft loss. The latter was confined to recipients who have experienced acute rejection (adjusted hazard ratio 1.60; 95%CI, 1.05-2.43) but not in those who did not experience acute rejection. Thus, our study suggests that recipients of maternal donor kidneys have a greater risk of rejection and graft loss. Hence, clinicians and patients should be cognizant of this association when determining which of the 2 parental donors is most suitable for transplantation.

  1. Raised serum levels of cachectin/tumor necrosis factor alpha in renal allograft rejection

    PubMed Central

    1987-01-01

    A sensitive radioimmunoassay was used for monitoring serum levels of endogenous cachectin/tumor necrosis factor alpha (TNF) in 10 renal transplant recipients. Acute allograft rejections were associated with marked elevations of circulating TNF. The peak levels of TNF (median 140 pg/ml) were in the same concentration range as previously reported in parasitic infections. The results show that the release of TNF into circulation is an early event in renal allograft rejection and that raised levels of TNF in man can also be induced by noninfectious stimuli. PMID:3309124

  2. Immunoglobulin therapy for plasma cell-rich rejection in the renal allograft.

    PubMed

    Adrogue, Horacio E; Soltero, Liliana; Land, Geoffrey A; Ramanathan, Venkataraman; Truong, Luan D; Suki, Wadi N

    2006-08-27

    Plasma cell-rich acute rejection (PCAR) is associated with poor allograft outcome in renal transplantation. Previous studies report a graft half-life of six months after a single PCAR episode. However, the management of this condition is unclear. Intravenous immunoglobulin (IVIG) therapy, by virtue of its immunomodulating properties, and its influence on B-cell maturation into plasma cells, may be a good candidate for reversing this type of rejection. We report four episodes of PCAR in two patients who responded well to IVIG with improvement in renal function.

  3. Heterotopic Auxiliary Rat Liver Transplantation With Flow-regulated Portal Vein Arterialization in Acute Hepatic Failure

    PubMed Central

    Schleimer, Karina; Kalder, Johannes; Grommes, Jochen; Jalaie, Houman; Tawadros, Samir; Greiner, Andreas; Jacobs, Michael; Kokozidou, Maria

    2014-01-01

    In acute hepatic failure auxiliary liver transplantation is an interesting alternative approach. The aim is to provide a temporary support until the failing native liver has regenerated.1-3 The APOLT-method, the orthotopic implantation of auxiliary segments- averts most of the technical problems. However this method necessitates extensive resections of both the native liver and the graft.4 In 1998, Erhard developed the heterotopic auxiliary liver transplantation (HALT) utilizing portal vein arterialization (PVA) (Figure 1). This technique showed promising initial clinical results.5-6 We developed a HALT-technique with flow-regulated PVA in the rat to examine the influence of flow-regulated PVA on graft morphology and function (Figure 2). A liver graft reduced to 30 % of its original size, was heterotopically implanted in the right renal region of the recipient after explantation of the right kidney.  The infra-hepatic caval vein of the graft was anastomosed with the infrahepatic caval vein of the recipient. The arterialization of the donor’s portal vein was carried out via the recipient’s right renal artery with the stent technique. The blood-flow regulation of the arterialized portal vein was achieved with the use of a stent with an internal diameter of 0.3 mm. The celiac trunk of the graft was end-to-side anastomosed with the recipient’s aorta and the bile duct was implanted into the duodenum. A subtotal resection of the native liver was performed to induce acute hepatic failure. 7 In this manner 112 transplantations were performed. The perioperative survival rate was 90% and the 6-week survival rate was 80%. Six weeks after operation, the native liver regenerated, showing an increase in weight from 2.3±0.8 g to 9.8±1 g. At this time, the graft’s weight decreased from 3.3±0.8 g to 2.3±0.8 g. We were able to obtain promising long-term results in terms of graft morphology and function. HALT with flow-regulated PVA reliably bridges acute hepatic failure

  4. Secondary Philadelphia chromosome and erythrophagocytosis in a relapsed acute myeloid leukemia after hematopoietic cell transplantation

    PubMed Central

    Kelemen, Katalin; Galani, Komal; Conley, Christopher R.; Greipp, Patricia T.

    2015-01-01

    The acquisition of Philadelphia chromosome (Ph) as a secondary change during the course of hematopoietic malignancies is rare and is associated with poor prognosis. Few cases of secondary Ph have been reported after hematopoietic cell transplantation (HCT). A secondary Ph at relapse is of clinical importance because it provides a therapeutic target for tyrosine kinase inhibitors along with or in replacement of chemotherapy. We describe a case of relapsed acute myeloid leukemia after HCT that developed a BCR/ABL-1 translocation along with erythrophagocytosis by blasts as a secondary change at the time of relapse. The progression of this patient's myeloid neoplasm from myelodysplastic syndrome to acute myeloid leukemia and relapsed AML after HCT was accompanied by a stepwise cytogenetic evolution: a deletion 20q abnormality subsequently acquired deletion 7q and, finally, at relapse after HCT, a secondary Ph was gained. The relationship between the secondary Ph and the erythrophagocytosis by blasts is not clear. We review the possible pathogenesis and cytogenetic associations of erythrophagocytosis by blasts, a rare feature in acute leukemias. PMID:25074248

  5. Serial profile of vitamins and trace elements during the acute phase of allogeneic stem cell transplantation.

    PubMed

    Nannya, Yasuhito; Shinohara, Akihito; Ichikawa, Motoshi; Kurokawa, Mineo

    2014-03-01

    Currently, we utilize vitamins and trace elements formulations that are not prepared specifically for patients receiving hematopoietic stem cell transplantation (HSCT), and adequacy of this strategy has not been evaluated. We prospectively measured blood level of vitamins and trace elements in 15 patients once per week at 6 time points around the acute phase of allogeneic HSCT. We provided standard nutrition support, including administration of parenteral nutrition with vitamin and trace elements formulation in case of impairment of oral intake. Most patients had vitamin B1 deficiency from the start of preparative regimens. Vitamin C deficiency was prominent throughout the acute phase of HSCT and this was significantly associated with high inflammatory markers, C-reactive protein and ferritin. Remarkable vitamin K overload associated with administration of parenteral supplementation and ferritin overload caused by repeated transfusions was observed. Moderate deficiency of zinc was at least partially linked to gastrointestinal loss by diarrhea. We revealed several features of vitamin and trace element status in the acute phase of HSCT and provided a basis for attempts to improve the nutritional condition in HSCT recipients.

  6. [Development of acute myeloid leukemia from donor cells after allogeneic peripheral blood stem cell transplantation in a female patient with acute monoblastic leukemia].

    PubMed

    2011-01-01

    Development of leukemia from donor cells is a rare complication of allogeneic blood stem cells (BSC). The paper describes a case of evolving acute myeloid leukemia of a graft in a patient with resistant acute monoblastic leukemia after related allogeneic peripheral BSC transplantation. The rarity of this complication, difficulties in providing evidence for the donor origin of a leukemic clone demonstrate a need for all-round careful dynamic assessment of the hematopoietic system after allogeneic transplantation, by applying the current cytogenetic (fluorescence in situ hybridization) and molecular (hypervariable genomic region amplification test using the polymerase chain reaction, hypervariable number of tandem repeats (VNTR), and short number of tandem repeats (STR)) techniques, which permits errors to be avoided in the assessment of a clinical situation and in the diagnosis of leukemia from donor cells. There is no developed policy for treatment of acute graft-versus-leukemia.

  7. Lymphocyte-depleting induction therapy lowers the risk of acute rejection in African American pediatric kidney transplant recipients.

    PubMed

    Crowson, Cole N; Reed, Rhiannon D; Shelton, Brittany A; MacLennan, Paul A; Locke, Jayme E

    2017-02-01

    The use of lymphocyte-depleting induction immunosuppression has been associated with a reduction in risk of AR after KT among adult recipients, particularly among high-risk subgroups such as AAs. However, data on induction regimen and AR risk are lacking among pediatric KT recipients. We examined outcomes among 7884 first-time pediatric KT recipients using SRTR data (2000-2014). Characteristics were compared across race using Wilcoxon rank-sum tests for continuous and chi-square tests for categorical variables. Risk of AR was estimated using modified Poisson regression, stratified by recipient race, adjusting for recipient age, gender, BMI, primary diagnosis, number of HLA mismatches, maintenance immunosuppression, and donor type. Risk of AR within 1 year was lower in AA recipients receiving lymphocyte-depleting induction (ATG or alemtuzumab; RR, 0.66; 95% CI, 0.52-0.83 P < .001) compared to AA recipients receiving anti-IL-2 receptor antibody induction. This difference was not seen in non-AA recipients receiving lymphocyte-depleting induction (RR, 0.93; 95% CI, 0.81-1.06, P = .26) compared to IL-2 induction. These findings support a role for lymphocyte-depleting induction agents in AA pediatric patients undergoing KT and continued use of IL-2 inhibitor induction in non-AA pediatric KT recipients.

  8. Preventing Rejection

    MedlinePlus

    ... Support Groups Patient Resources Newsroom Minorities AFTER THE TRANSPLANT Medications Staying Healthy Recovery Resources Lifestyle Changes Pregnancy Cancer PEDIATRIC Addressing Children's Needs Coping With Anxiety Helping Your Child Adjust Camps Resources LIVING DONATION ...

  9. Comparison of magnetic resonance imaging and radionuclide imaging in the evaluation of renal transplant failure

    SciTech Connect

    Goldsmith, M.S.; Tanasescu, D.E.; Waxman, A.D.; Crues, J.V. III

    1988-04-01

    Magnetic resonance imaging (MRI) was compared with radionuclide scintigraphy (RNS) in 16 patients with renal transplants undergoing renal failure to determine which modality could best discriminate between rejection, acute tubular necrosis (ATN), and cyclosporin nephrotoxicity (CN). Although all rejecting transplants had reduced corticomedullary differentiation (CMD) on T1-weighted MR images, four of five cases of ATN had appearances that could not be distinguished from rejection. A normal CMD suggests nonrejection, but diminished CMD is nonspecific. Tc-99m DTPA/I-131 hippuran RNS was superior to MRI in differentiating rejection from ATN. Although ATN and CN have similar RNS patterns, this distinction can usually be made based on the clinical time course. Other potential uses of MRI in the evaluation of the renal transplants are discussed.

  10. Transplant immunology for non-immunologist.

    PubMed

    Heeger, Peter S; Dinavahi, Rajani

    2012-01-01

    Transplantation is the treatment of choice for end-stage kidney, heart, lung, and liver disease. Short-term outcomes in solid-organ transplantation are excellent, but long-term outcomes remain suboptimal. Advances in immune suppression and human leukocyte antigen matching techniques have reduced the acute rejection rate to <10%. Chronic allograft injury remains problematic and is in part immune-mediated. This injury is orchestrated by a complex adaptive and innate immune system that has evolved to protect the organism from infection, but, in the context of transplantation, could result in allograft rejection. Such chronic injury is partially mediated by anti-human leukocyte antigen antibodies. Severe rejections have largely been avoided by the development of tissue-typing techniques and crossmatch testing, which are discussed in detail. Further advances in the understanding of T- and B-cell immunology have led to the development of new immunomodulatory therapies directed at prolonging allograft survival, including those that decrease antibody production as well as those that remove antibodies from circulation. Further application of these immunomodulatory therapies has allowed expansion of the donor pool in some cases by permitting ABO-incompatible transplantation and transplantation in patients with preformed antibodies. Although vast improvements have been made in allograft survival, patients must remain on lifetime immunosuppression. Withdrawal of immunosuppression almost always ultimately leads to allograft rejection. The ultimate dream of transplant biologists is the induction of tolerance, where immune function remains intact but the allograft is not rejected in the face of withdrawn immunosuppression. This, however, has remained a significant challenge in human studies.

  11. The Effect of Different Glycaemic States on Renal Transplant Outcomes

    PubMed Central

    Depczynski, Barbara; O'Sullivan, Anthony J.; Luxton, Grant; Mangos, George

    2016-01-01

    Background. Optimal glycaemic targets following transplantation are unknown. Understanding the impact of DM and posttransplant diabetes mellitus (PTDM) may improve patient and graft survival in transplant recipients. Aim. To determine the perioperative and one-year outcomes after renal transplantation and whether these outcomes are affected by preexisting DM, PTDM, or glycaemia during transplant admission. Method. Adult recipients of renal transplants from a single centre over 5.5 years were retrospectively reviewed. Measured outcomes during transplant admission included glycaemia and complications (infective complications, acute rejection, and return to dialysis) and, at 12 months, glycaemic control and complications (cardiovascular complication, graft failure). Results. Of 148 patients analysed, 29 (19.6%) had DM and 27 (18.2%) developed PTDM. Following transplantation, glucose levels were higher in patients with DM and PTDM. DM patients had a longer hospital stay, had more infections, and were more likely return to dialysis. PTDM patients had increased rates of acute rejection and return to dialysis. At 1 year after transplant, there were more cardiovascular complications in DM patients compared to those without DM. Conclusions. Compared to patients without DM, patients with DM or PTDM are more likely to suffer from complications perioperatively and at 12 months. Perioperative glycaemia is associated with graft function and may be a modifiable risk. PMID:28053992

  12. Iron overload in patients with acute leukemia or MDS undergoing myeloablative stem cell transplantation.

    PubMed

    Armand, Philippe; Kim, Haesook T; Rhodes, Joanna; Sainvil, Marie-Michele; Cutler, Corey; Ho, Vincent T; Koreth, John; Alyea, Edwin P; Hearsey, Doreen; Neufeld, Ellis J; Fleming, Mark D; Steen, Hanno; Anderson, Damon; Kwong, Raymond Y; Soiffer, Robert J; Antin, Joseph H

    2011-06-01

    Patients with hematologic malignancies undergoing allogeneic stem cell transplantation (HSCT) commonly have an elevated serum ferritin prior to HSCT, which has been associated with increased mortality after transplantation. This has led to the suggestion that iron overload is common and deleterious in this patient population. However, the relationship between serum ferritin and parenchymal iron overload in such patients is unknown. We report a prospective study of 48 patients with acute leukemia (AL) or myelodysplastic syndromes (MDS) undergoing myeloablative HSCT, using magnetic resonance imaging (MRI) to estimate liver iron content (LIC) and cardiac iron. The median (and range) pre-HSCT value of serum ferritin was 1549 ng/mL (20-6989); serum hepcidin, 59 ng/mL (10-468); labile plasma iron, 0 LPI units (0.0-0.9). Eighty-five percent of patients had hepatic iron overload (HIO), and 42% had significant HIO (LIC ≥5.0 mg/gdw). Only 1 patient had cardiac iron overload. There was a strong correlation between pre-HSCT serum ferritin and estimated LIC (r = .75), which was mostly dependent on prior transfusion history. Serum hepcidin was appropriately elevated in patients with HIO. Labile plasma iron elevation was rare. A regression calibration analysis supported the hypothesis that elevated pre-HSCT LIC is significantly associated with inferior post-HSCT survival. These results contribute to our understanding of the prevalence, mechanism, and consequences of iron overload in HSCT.

  13. Nimesulide-induced severe hemolytic anemia and acute liver failure leading to liver transplantation.

    PubMed

    Rodrigo, L; de Francisco, R; Pérez-Pariente, J M; Cadahia, V; Tojo, R; Rodriguez, M; Lucena, Ma I; Andrade, R J

    2002-11-01

    We present the case of a 63-year-old woman who had undergone 7 months of treatment with Nimesulide (100 mg/b.i.d.) for symptomatic osteoarthritis. The patient was admitted to our unit with a clinical picture of progressive jaundice over 3 weeks. Clinical and analytical studies revealed acute liver failure, this being confirmed by liver biopsy, which showed submassive necrosis. Serological tests for different viral agents causing hepatitis were all negative. In addition, she presented a picture of severe haemolytic anaemia resistant to several treatments and needed multiple transfusions. Twenty-three days after admission, the patient presented hepatic encephalopathy and received an orthotopic liver transplant on day 25. The evolution after transplantation was good and the patient continues in good health with no evidence of haemolysis almost 2 years later. Liver toxicity due to Nimesulide is well known, but to our knowledge the occurrence of haemolytic anaemia has not been related to this drug previously. For these reasons, Nimesulide has been restricted or removed from the market in several countries in recent months.

  14. Risk factors of acute kidney injury after orthotopic liver transplantation in China

    PubMed Central

    Zongyi, Yin; Baifeng, Li; Funian, Zou; Hao, Li; Xin, Wang

    2017-01-01

    In this study, we determined the risk factors for acute kidney injury (AKI) following orthotopic liver transplantation (OLT) in China. We collected 5074 donation after cardiac death (DCD) OLT recipients who underwent surgery between January 1, 2010, and December 31, 2015, in 86 academic hospitals or transplant centers in China. Univariate and multivariate analyses were used to investigate the criticality of donor, graft, or recipient variables in the development of post-OLT AKI. In all, 4482 patients were included (median age, 49.31 years). Post-OLT AKI occurred in 3.97% patients, and 73.6% of all OLT patients were male. The 1- and 5-year cumulative survival rates (CSRs) of the AKI group were 33.95% and 25.24%, respectively, compared with 86.34% and 70.05%, respectively, of the non-AKI group (P < 0.001). The independent risk factors for post-OLT AKI were blood loss, cold ischemia time, warm ischemia time, preoperative serum creatinine, the treatment period with dopamine, overexposure to calcineurin inhibitor, and combined mycophenolate mofetil use (P < 0.05). These had a high prediction accuracy for post-OLT AKI (area under the curve [AUC] = 0.740). PMID:28134286

  15. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia.

    PubMed

    Dhédin, Nathalie; Huynh, Anne; Maury, Sébastien; Tabrizi, Reza; Beldjord, Kheira; Asnafi, Vahid; Thomas, Xavier; Chevallier, Patrice; Nguyen, Stéphanie; Coiteux, Valérie; Bourhis, Jean-Henri; Hichri, Yosr; Escoffre-Barbe, Martine; Reman, Oumedaly; Graux, Carlos; Chalandon, Yves; Blaise, Didier; Schanz, Urs; Lhéritier, Véronique; Cahn, Jean-Yves; Dombret, Hervé; Ifrah, Norbert

    2015-04-16

    Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.

  16. Acute fatty liver of pregnancy -- an underlying condition for herpes simplex type 2 fulminant hepatitis necessitating liver transplantation.

    PubMed

    Luzar, B; Ferlan-Marolt, V; Poljak, M; Sojar, V; Stanisavljević, D; Bukovac, T; Markovic, S

    2005-05-01

    The infrequent occurrence of herpes simplex virus (HSV) hepatitis in healthy women in comparison with the high prevalence of HSV infections suggests that, in addition to deranged immunity, an underlying condition in the liver might be necessary to develop HSV hepatitis. We report the case of a 28-year-old pregnant woman in the 28 (th) week of gestation. Following HSV type 2 infection of the uterine cervix, acute liver failure developed, necessitating urgent liver transplantation. In addition to fulminant HSV type 2 hepatitis, the explanted liver also showed the histological features of acute fatty liver of pregnancy. The presented case suggests a possible pathogenetic role of acute fatty liver of pregnancy in the development of fulminant HSV hepatitis following recurrent infection with HSV in healthy pregnant women. We believe that early histopathological diagnosis, followed by specific antiviral treatment and liver transplantation in selected patients may improve the clinical outcome of otherwise almost uniformly fatal HSV hepatitis.

  17. Outcomes of acute leukemia patients transplanted with naive T cell–depleted stem cell grafts

    PubMed Central

    Bleakley, Marie; Heimfeld, Shelly; Loeb, Keith R.; Jones, Lori A.; Chaney, Colette; Seropian, Stuart; Gooley, Ted A.; Sommermeyer, Franziska; Riddell, Stanley R.; Shlomchik, Warren D.

    2015-01-01

    BACKGROUND. Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT). In mice, naive T cells (TN) cause more severe GVHD than memory T cells (TM). We hypothesized that selective depletion of TN from human allogeneic peripheral blood stem cell (PBSC) grafts would reduce GVHD and provide sufficient numbers of hematopoietic stem cells and TM to permit hematopoietic engraftment and the transfer of pathogen-specific T cells from donor to recipient, respectively. METHODS. In a single-arm clinical trial, we transplanted 35 patients with high-risk leukemia with TN-depleted PBSC grafts following conditioning with total body irradiation, thiotepa, and fludarabine. GVHD prophylactic management was with tacrolimus immunosuppression alone. Subjects received CD34-selected PBSCs and a defined dose of TM purged of CD45RA+ TN. Primary and secondary objectives included engraftment, acute and chronic GVHD, and immune reconstitution. RESULTS. All recipients of TN-depleted PBSCs engrafted. The incidence of acute GVHD was not reduced; however, GVHD in these patients was universally corticosteroid responsive. Chronic GVHD was remarkably infrequent (9%; median follow-up 932 days) compared with historical rates of approximately 50% with T cell–replete grafts. TM in the graft resulted in rapid T cell recovery and transfer of protective virus-specific immunity. Excessive rates of infection or relapse did not occur and overall survival was 78% at 2 years. CONCLUSION. Depletion of TN from stem cell allografts reduces the incidence of chronic GVHD, while preserving the transfer of functional T cell memory. TRIAL REGISTRATION. ClinicalTrials.gov (NCT 00914940). FUNDING. NIH, Burroughs Wellcome Fund, Leukemia and Lymphoma Society, Damon Runyon Cancer Research Foundation, and Richard Lumsden Foundation. PMID:26053664

  18. Improving results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia in first complete remission: an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

    PubMed Central

    Giebel, Sebastian; Labopin, Myriam; Socié, Gerard; Beelen, Dietrich; Browne, Paul; Volin, Liisa; Kyrcz-Krzemien, Slawomira; Yakoub-Agha, Ibrahim; Aljurf, Mahmoud; Wu, Depei; Michallet, Mauricette; Arnold, Renate; Mohty, Mohamad; Nagler, Arnon

    2017-01-01

    Allogeneic hematopoietic cell transplantation is widely used to treat adults with high-risk acute lymphoblastic leukemia. The aim of this study was to analyze whether the results changed over time and to identify prognostic factors. Adult patients treated between 1993 and 2012 with myeloablative allogeneic hematopoietic cell transplantation from HLA matched sibling (n=2681) or unrelated (n=2178) donors in first complete remission were included. For transplantations from sibling donors performed between 2008 and 2012, 2-year probabilities of overall survival were: 76% (18–25 years old), 69% (26–35 and 36–45 years old) and 60% (46–55 years old). Among recipients of transplantations from unrelated donors, the respective survival rates were 66%, 70%, 61%, and 62%. In comparison with the 1993–2007 period, significant improvements were observed for all age groups except for the 26–35-year old patients. In a multivariate model, transplantations performed between 2008 and 2012, when compared to 1993–2007, were associated with significantly reduced risks of non-relapse mortality (Hazard Ratio 0.77, P=0.00006), relapse (Hazard Ratio 0.85, P=0.007), treatment failure (Hazard Ratio 0.81, P<0.00001), and overall mortality (Hazard Ratio 0.79, P<0.00001). In the analysis restricted to transplantations performed between 2008 and 2012, the use of total body irradiation-based conditioning was associated with reduced risk of relapse (Hazard Ratio 0.48, P=0.004) and treatment failure (Hazard Ratio 0.63, P=0.02). We conclude that results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia improved significantly over time. Total body irradiation should be considered as the preferable type of myeloablative conditioning. PMID:27686376

  19. Can a combined screening/treatment programme prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies: study protocol for the multicentre randomised controlled OuTSMART trial

    PubMed Central

    2014-01-01

    Background Renal transplantation is the best treatment for kidney failure, in terms of length and quality of life and cost-effectiveness. However, most transplants fail after 10 to 12 years, consigning patients back onto dialysis. Damage by the immune system accounts for approximately 50% of failing transplants and it is possible to identify patients at risk by screening for the presence of antibodies against human leukocyte antigens. However, it is not clear how best to treat patients with antibodies. This trial will test a combined screening and treatment protocol in renal transplant recipients. Methods/Design Recipients >1 year post-transplantation, aged 18 to 70 with an estimated glomerular filtration rate >30 mL/min will be randomly allocated to blinded or unblinded screening arms, before being screened for the presence of antibodies. In the unblinded arm, test results will be revealed. Those with antibodies will have biomarker-led care, consisting of a change in their anti-rejection drugs to prednisone, tacrolimus and mycophenolate mofetil. In the blinded arm, screening results will be double blinded and all recruits will remain on current therapy (standard care). In both arms, those without antibodies will be retested every 8 months for 3 years. The primary outcome is the 3-year kidney failure rate for the antibody-positive recruits, as measured by initiation of long-term dialysis or re-transplantation, predicted to be approximately 20% in the standard care group but <10% in biomarker-led care. The secondary outcomes include the rate of transplant dysfunction, incidence of infection, cancer and diabetes mellitus, an analysis of adherence with medication and a health economic analysis of the combined screening and treatment protocol. Blood samples will be collected and stored every 4 months and will form the basis of separately funded studies to identify new biomarkers associated with the outcomes. Discussion We have evidence that the biomarker-led care

  20. Challenges in renal transplantation in Yemen.

    PubMed

    El-Nono, Ibrahiem H; Telha, Khaled A; Al-Alimy, Gamil M; Ghilan, Abdulilah M; Abu Asba, Nagieb W; Al-Zkri, Abdo M; Al-Adimi, Abdulilah M; Al-Ba'adani, Tawfiq H

    2015-02-16

    Background Renal replacement therapy was first introduced in Yemen in 1978 in the form of hemodialysis. Twenty years later, the first renal transplantation was performed. Kidney transplantations were started in socially and financially challenging circumstances in Yemen in 1998. A structured program was established and has been functioning regularly since 2005. A pediatric transplantation program was started in 2011. Material and Methods This was a prospective study of 181 transplants performed at the Urology and Nephrology Center between May 1998 and 2012. All transplants were from living related donors. The immunosuppressive protocol consisted initially of double therapy with steroid and mycophenolate mofetil (MMF). Subsequently, triple therapy with addition of a calcineurin inhibitor was introduced. Primary graft function was achieved in 176 (97.2%) recipients. Results Cold ischemia time was 48-68 min. Episodes of acute rejection in 12 patients were treated with high-dose steroids. Anti-thymocyte globulin (ATG) was used in cases of vascular or steroid-resistant rejection in 2 patients. The post-transplant complications, either surgical or medical, were comparable to those recorded in the literature. Conclusions Renal transplantation is a good achievement in our country. The patients and graft survival rates are comparable to other reports.

  1. Pediatric Liver Transplantation: Our Experiences

    PubMed Central

    Basturk, Ahmet; Yılmaz, Aygen; Sayar, Ersin; Dinçhan, Ayhan; Aliosmanoğlu, İbrahim; Erbiş, Halil; Aydınlı, Bülent; Artan, Reha

    2016-01-01

    Objective: The aim of our study was to evaluate our liver transplant pediatric patients and to report our experience in the complications and the long-term follow-up results. Materials and Methods: Patients between the ages of 0 and 18 years, who had liver transplantation in the organ transplantation center of our university hospital between 1997 and 2016, were included in the study. The age, sex, indications for the liver transplantation, complications after the transplantation, and long-term follow-up findings were retrospectively evaluated. The obtained results were analyzed with statistical methods. Results: In our organ transplantation center, 62 pediatric liver transplantations were carried out since 1997. The mean age of our patients was 7.3 years (6.5 months–17 years). The 4 most common reasons for liver transplantation were: Wilson’s disease (n=10; 16.3%), biliary atresia (n=9; 14.5%), progressive familial intrahepatic cholestasis (n=8; 12.9%), and cryptogenic cirrhosis (n=7; 11.3%). The mortality rate after transplantation was 19.6% (12 of the total 62 patients). The observed acute and chronic rejection rates were 34% and 4.9%, respectively. Thrombosis (9.6%) was observed in the hepatic artery (4.8%) and portal vein (4.8%). Bile leakage and biliary stricture rates were 31% and 11%, respectively. 1-year and 5-year survival rates of our patients were 87% and 84%, respectively. Conclusion: The morbidity and mortality rates in our organ transplantation center, regarding pediatric liver transplantations, are consistent with the literature. PMID:28149148

  2. Rejected applications

    PubMed Central

    2014-01-01

    Objective: To review membership application materials (especially rejected applications) to the American Academy of Neurology (AAN) during its formative years (1947–1953). Methods: Detailed study of materials in the AAN Historical Collection. Results: The author identified 73 rejected applications. Rejected applicants (71 male, 2 female) lived in 25 states. The largest number was for the Associate membership category (49). These were individuals “in related fields who have made and are making contributions to the field of neurology.” By contrast, few applicants to Active membership or Fellowship status were rejected. The largest numbers of rejectees were neuropsychiatrists (19), neurosurgeons (16), and psychiatrists (14). Conclusion: The AAN, established in the late 1940s, was a small and politically vulnerable organization. A defining feature of the fledgling society was its inclusiveness; its membership was less restrictive than that of the older American Neurological Association. At the same time, the society needed to preserve its core as a neurologic society rather than one of psychiatry or neurosurgery. Hence, the balance between inclusiveness and exclusive identity was a difficult one to maintain. The Associate membership category, more than any other, was at the heart of this issue of self-definition. Associate members were largely practitioners of psychiatry or neurosurgery. Their membership was a source of consternation and was to be carefully been held in check during these critical formative years. PMID:24944256

  3. The Impact of Hospital/Surgeon Volume on Acute Renal Failure and Mortality in Liver Transplantation: A Nationwide Cohort Study

    PubMed Central

    Cheng, Chih-Wen; Liu, Fu-Chao; Lin, Jr-Rung; Tsai, Yung-Fong; Chen, Hsiu-Pin; Yu, Huang-Ping

    2016-01-01

    The aim of this study was to assess whether the case volume of surgeons and hospitals affects the rates of postoperative complications and survival after liver transplantation. This population-based retrospective cohort study included 2938 recipients of liver transplantation performed between 1998 and 2012, enrolled from the Taiwan National Health Insurance Research Database. They were divided into two groups, according to the cumulative case volume of their operating surgeons and the case volume of their hospitals. The duration of intensive care unit stay and post-transplantation hospitalization, postoperative complications, and mortality were analyzed. The results showed that, in the low and high case volume surgeons groups, respectively, acute renal failure occurred at the rate of 14.11% and 5.86% (p<0.0001), and the overall mortality rates were 19.61% and 12.44% (p<0.0001). In the low and high case volume hospital groups, respectively, acute renal failure occurred in 11% and 7.11% of the recipients (p = 0.0004), and the overall mortality was 18.44% and 12.86% (p<0.0001). These findings suggest that liver transplantation recipients operated on higher case volume surgeons or in higher case volume hospitals have a lower rate of acute renal failure and mortality. PMID:27706183

  4. 15-Deoxyspergualin: a newly developed immunosuppressive agent and its mechanism of action and clinical effect: a review. Japan Collaborative Transplant Study Group for NKT-01.

    PubMed

    Amemiya, H

    1996-08-01

    15-Deoxyspargualin (DSG) is a synthetic analogue of spergualin isolated from the culture filtrate of Bacillus laterosporus. It shows a strong immunosuppressive effect by antiproliferating action inhibiting the IL-2-stimulated maturation of T cells from the G0/G1 phases to the S and G2/M phases. Hsc70, a constitutive member of Hsp70 was identified as the immunophilin of DSG by Nadlar et al. In allogeneic transplantation of rat heart and dog kidney, DSG was definitely proved to prevent rejection and to rescue ongoing rejection. Our multicenter clinical trials on DSG showed that the percent efficacy to reverse acute rejection was 70-80%, and 600 days graft survival was 90% in the cases effectively treated with DSG at acute rejections. The combined use of DSG with methylprednisolone to treat acute rejection and the use of DSG to treat rejections in chronic phases were reported as the beneficial uses of DSG.

  5. Intestinal Transplant Inflammation: the Third Inflammatory Bowel Disease.

    PubMed

    Kroemer, Alexander; Cosentino, Christopher; Kaiser, Jason; Matsumoto, Cal S; Fishbein, Thomas M

    2016-11-01

    Intestinal transplantation is the most immunologically complex of all abdominal organ transplants. Understanding the role both humoral and innate and adaptive cellular immunity play in intestinal transplantation is critical to improving outcomes and increasing indications for patients suffering from intestinal failure. Recent findings highlighting the impact of donor-specific antibodies on intestinal allografts, the role of NOD2 as a key regulator of intestinal immunity, the protective effects of innate lymphoid cells, and the role of Th17 in acute cellular rejection are reviewed here.

  6. Umbilical cord blood transplantation from unrelated donors in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

    PubMed Central

    Piñana, José Luis; Sanz, Jaime; Picardi, Alessandra; Ferrá, Christelle; Martino, Rodrigo; Barba, Pere; Gonzalez-Vicent, Marta; Pascual, María Jesús; Martín, Carmen; Verdeguer, Amparo; de Heredia, Cristina Diaz; Montesinos, Pau; Ribera, José-María; Sanz, Miguel; Arcese, William; Sanz, Guillermo

    2014-01-01

    There are very few disease-specific studies focusing on outcomes of umbilical cord blood transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia. We report the outcome of 45 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia who underwent myeloablative single unit cord blood transplantation from unrelated donors within the GETH/GITMO cooperative group. Conditioning regimens were based on combinations of thiotepa, busulfan, cyclophospamide or fludarabine, and antithymocyte globulin. At the time of transplantation, 35 patients (78%) were in first complete remission, four (8%) in second complete remission and six (14%) in third or subsequent response. The cumulative incidence of myeloid engraftment was 96% at a median time of 20 days and significantly better for patients receiving higher doses of CD34+ cells. The incidence of acute grade II–IV graft-versus-host disease was 31%, while that of overall chronic graft-versus-host disease was 53%. Treatment-related mortality was 17% at day +100 and 31% at 5 years. The 5-year relapse, event-free survival and overall survival rates were 31%, 36% and 44%, respectively. Although the event-free and overall survival rates in patients without BCR/ABL transcripts detectable at time of transplant were better than those in whom BCR/ABL transcripts were detected (46% versus 24% and 60% versus 30%, respectively) these differences were not statistically significant in the univariate analysis (P=0.07). These results demonstrate that umbilical cord blood transplantation from unrelated donors can be a curative treatment for a substantial number of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. PMID:24097633

  7. Transplantation of adipose derived mesenchymal stem cells for acute thoracolumbar disc disease with no deep pain perception in dogs

    PubMed Central

    Kim, Yongsun; Lee, Seung Hoon; Kim, Wan Hee

    2016-01-01

    Thirty-four dogs with no deep pain perception due to acute thoracolumbar intervertebral disc disease underwent decompression surgery within 1 week of diagnosis. All dogs underwent hemilaminectomy. Adipose derived mesenchymal stem cells (AD-MSCs) were transplanted into the injured spinal cord parenchyma for the AD-MSCs transplant dogs. Long-term outcome was evaluated at the end of the follow-up period (> 6 months). AD-MSCs combination treatment showed better recovery outcomes compared to decompression surgery alone. These results indicate that this stem cell therapy is a potential therapeutic strategy to overcome the limitations of treatment for spinal cord injury in clinical medicine. PMID:27051350

  8. Acute liver failure due to zinc phosphide containing rodenticide poisoning: Clinical features and prognostic indicators of need for liver transplantation.

    PubMed

    Saraf, Vivek; Pande, Supriya; Gopalakrishnan, Unnikrishnan; Balakrishnan, Dinesh; Menon, Ramachandran N; Sudheer, O V; Dhar, Puneet; Sudhindran, S

    2015-07-01

    Zinc phosphide (ZnP) containing rodenticide poisoning is a recognized cause of acute liver failure (ALF) in India. When standard conservative measures fail, the sole option is liver transplantation. Records of 41 patients admitted to a single centre with ZnP-induced ALF were reviewed to identify prognostic indicators for requirement of liver transplantation. Patients were analyzed in two groups: group I (n = 22) consisted of patients who either underwent a liver transplant (n = 14) or died without a transplant (n = 8); group II (n = 19) comprised those who survived without liver transplantation. International normalized ratio (INR) in group I was 9 compared to 3 in group II (p < 0.001). Encephalopathy occurred only in group I. Model for End-Stage Liver Disease (MELD) score in group I was 41 compared to 24 in group II (p < 0.001). MELD score of 36 (sensitivity of 86.7 %, specificity of 90 %) or a combination of INR of 6 and encephalopathy (sensitivity of 100 %, specificity of 83 %) were the best indicators of mortality. Such patients should undergo urgent liver transplantation.

  9. Secondary Philadelphia chromosome and erythrophagocytosis in a relapsed acute myeloid leukemia after hematopoietic cell transplantation.

    PubMed

    Kelemen, Katalin; Galani, Komal; Conley, Christopher R; Greipp, Patricia T

    2014-06-01

    The acquisition of the Philadelphia chromosome (Ph) as a secondary change during the course of hematopoietic malignancies is rare and is associated with poor prognosis. Few cases of secondary Ph have been reported after hematopoietic cell transplantation (HCT). A secondary Ph at relapse is of clinical importance because it provides a therapeutic target for tyrosine kinase inhibitors along with or in replacement of chemotherapy. We describe a case of relapsed acute myeloid leukemia (AML) after HCT that developed a BCR-ABL1 translocation along with erythrophagocytosis by blasts as a secondary change at the time of relapse. The progression of this patient's myeloid neoplasm from myelodysplastic syndrome to AML to relapsed AML after HCT was accompanied by a stepwise cytogenetic evolution: A deletion 20q abnormality subsequently acquired a deletion 7q and, finally, at relapse after HCT, a secondary Ph was gained. The relationship between the secondary Ph and the erythrophagocytosis by blasts is not clear. We review the possible pathogenesis and cytogenetic associations of erythrophagocytosis by blasts, a rare feature in acute leukemias.

  10. Mycophenolate mofetil suspension in pediatric renal transplantation: three-year data from the tricontinental trial.

    PubMed

    Höcker, Britta; Weber, Lutz T; Bunchman, Timothy; Rashford, Michelle; Tönshoff, Burkhard

    2005-08-01

    Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adult solid organ transplant recipients, but data in children and adolescents are scarce. This prospective, multicenter, open-labeled, single-arm study investigated the efficacy and safety of an MMF-based immunosuppressive regimen in 100 pediatric renal transplant recipients over a 3-yr period of time. Three age groups were formed (<6 yr, n = 33; 6 to <12 yr, n = 34; 12-18 yr, n = 33). Basic immunosuppression consisted of MMF (600 mg/m(2) b.i.d), cyclosporin A microemulsion and corticosteroids. Seventy-three percent of patients were given anti-lymphocyte antibody induction therapy, of whom 74% received anti-thymocyte globulin. Patient and graft survival 3 yr after transplantation amounted to 98 and 95%, respectively. Twenty-five percent of all patients suffered a biopsy-proven acute rejection episode in the first 6 month post-transplant. Children undergoing induction therapy exhibited a numerically lower rejection rate (21 vs. 37%, p = 0.11). Three years after transplantation, the acute rejection rate added up to 30% (26% with induction therapy vs. 41% without induction therapy, p = 0.21). The number of patients with acute rejection was lowest in the youngest age group (18%), in comparison with 39% in the 6 to <12 yr and 33% in the 12-18 yr age group, respectively. For the entire patient population, the rate of patients who withdrew prematurely because of adverse events was low (12%). The present study shows that MMF therapy in pediatric renal transplant recipients leads to an excellent patient and graft survival 3 yr post-transplant with an acceptable safety profile.

  11. Combination Chemotherapy With or Without Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia

    ClinicalTrials.gov

    2016-09-09

    Adult Acute Lymphoblastic Leukemia in Remission; Adult B Acute Lymphoblastic Leukemia; Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34;q11.2); BCR-ABL1; Adult L1 Acute Lymphoblastic Leukemia; Adult L2 Acute Lymphoblastic Leukemia; Adult T Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

  12. Immune Complex Mediated Glomerulonephritis with Acute Thrombotic Microangiopathy following Newly Detected Hepatitis B Virus Infection in a Kidney Transplant Recipient.

    PubMed

    Salter, Tracey; Burton, Hannah; Douthwaite, Sam; Newsholme, William; Horsfield, Catherine; Hilton, Rachel

    2016-01-01

    Hepatitis B virus (HBV) presents a risk to patients and staff in renal units. To minimise viral transmission, there are international and UK guidelines recommending HBV immunisation for patients commencing renal replacement therapy (RRT) and HBV surveillance in kidney transplant recipients. We report the case of a 56-year-old male who was immunised against HBV before starting haemodialysis. He received a deceased donor kidney transplant three years later, at which time there was no evidence of HBV infection. After a further six years he developed an acute kidney injury; allograft biopsy revealed an acute thrombotic microangiopathy (TMA) with glomerulitis, peritubular capillaritis, and C4d staining. Due to a "full house" immunoprofile, tests including virological screening were undertaken, which revealed acute HBV infection. Entecavir treatment resulted in an improvement in viral load and kidney function. HBV genotyping demonstrated a vaccine escape mutant, suggesting "past resolved" infection that reactivated with immunosuppression, though posttransplant acquisition cannot be excluded. This is the first reported case of acute HBV infection associated with immune complex mediated glomerulonephritis and TMA. Furthermore, it highlights the importance of HBV surveillance in kidney transplant recipients, which although addressed by UK guidelines is not currently practiced in all UK units.

  13. Immune Complex Mediated Glomerulonephritis with Acute Thrombotic Microangiopathy following Newly Detected Hepatitis B Virus Infection in a Kidney Transplant Recipient

    PubMed Central

    Burton, Hannah; Douthwaite, Sam; Newsholme, William; Horsfield, Catherine

    2016-01-01

    Hepatitis B virus (HBV) presents a risk to patients and staff in renal units. To minimise viral transmission, there are international and UK guidelines recommending HBV immunisation for patients commencing renal replacement therapy (RRT) and HBV surveillance in kidney transplant recipients. We report the case of a 56-year-old male who was immunised against HBV before starting haemodialysis. He received a deceased donor kidney transplant three years later, at which time there was no evidence of HBV infection. After a further six years he developed an acute kidney injury; allograft biopsy revealed an acute thrombotic microangiopathy (TMA) with glomerulitis, peritubular capillaritis, and C4d staining. Due to a “full house” immunoprofile, tests including virological screening were undertaken, which revealed acute HBV infection. Entecavir treatment resulted in an improvement in viral load and kidney function. HBV genotyping demonstrated a vaccine escape mutant, suggesting “past resolved” infection that reactivated with immunosuppression, though posttransplant acquisition cannot be excluded. This is the first reported case of acute HBV infection associated with immune complex mediated glomerulonephritis and TMA. Furthermore, it highlights the importance of HBV surveillance in kidney transplant recipients, which although addressed by UK guidelines is not currently practiced in all UK units. PMID:27800206

  14. Acute Neurological Illness in a Kidney Transplant Recipient Following Infection With Enterovirus-D68: An Emerging Infection?

    PubMed

    Wali, R K; Lee, A H; Kam, J C; Jonsson, J; Thatcher, A; Poretz, D; Ambardar, S; Piper, J; Lynch, C; Kulkarni, S; Cochran, J; Djurkovic, S

    2015-12-01

    We report the first case of enterovirus-D68 infection in an adult living-donor kidney transplant recipient who developed rapidly progressive bulbar weakness and acute flaccid limb paralysis following an upper respiratory infection. We present a 45-year-old gentleman who underwent pre-emptive living-donor kidney transplantation for IgA nephropathy. Eight weeks following transplantation, he developed an acute respiratory illness from enterovirus/rhinovirus that was detectable in nasopharyngeal (NP) swabs. Within 24 h of onset of respiratory symptoms, the patient developed binocular diplopia which rapidly progressed to multiple cranial nerve dysfunctions (acute bulbar syndrome) over the next 24 h. Within the next 48 h, asymmetric flaccid paralysis of the left arm and urinary retention developed. While his neurological symptoms were evolving, the Centers for Disease Control reported that the enterovirus strain from the NP swabs was, in fact, Enterovirus-D68 (EV-D68). Magnetic resonance imaging of the brain demonstrated unique gray matter and anterior horn cell changes in the midbrain and spinal cord, respectively. Constellation of these neurological symptoms and signs was suggestive for postinfectious encephalomyelitis (acute disseminated encephalomyelitis [ADEM]) from EV-D68. Treatment based on the principles of ADEM included intensive physical therapy and other supportive measures, which resulted in a steady albeit slow improvement in his left arm and bulbar weakness, while maintaining stable allograft function.

  15. In Vivo T Cell Depletion with Myeloablative Regimens on Outcomes after Cord Blood Transplantation for Acute Lymphoblastic Leukemia in Children.

    PubMed

    Ponce, Doris M; Eapen, Mary; Sparapani, Rodney; O'Brien, Tracey A; Chan, Ka Wah; Chen, Junfang; Craddock, John; Schultz, Kirk R; Wagner, John E; Perales, Miguel-Angel; Barker, Juliet N

    2015-12-01

    The inclusion of antithymocyte globulin (ATG) in cord blood transplantation is controversial. We evaluated outcomes according to ATG inclusion in 297 children and adolescents with acute lymphoblastic leukemia (ALL) who received myeloablative total body irradiation-based conditioning and either single-unit (74%) or double-unit (26%) grafts. Ninety-two patients (31%) received ATG and 205 (69%) did not. ATG recipients were more likely to be cytomegalovirus seronegative. The incidences of day 100 grades II to IV acute graft-versus-host disease (GVHD; 30% versus 54%, P = .0002) and chronic GVHD (22% versus 43%, P = .0008) were lower with ATG compared with non-ATG regimens. However, day 100 grades III to IV acute GVHD was comparable (11% versus 17%, P = .15). The 3-year incidences of transplant-related mortality (16% versus 17%, P = .98), relapse (17% versus 27%, P = .12), and leukemia-free survival (66% versus 55%, P = .23) in ATG and non-ATG recipients were similar. There were no differences in viral reactivation between treatment groups (60% versus 58%, P = .83). Therefore, the data suggest that incorporation of ATG with myeloablative conditioning regimens may be useful in reducing the risk of acute and chronic GVHD without any deleterious effect on transplant-related mortality, relapse, or leukemia-free survival in children and adolescents with ALL.

  16. Haploidentical bone marrow transplantation in Mexico.

    PubMed

    Vázquez-Meraz, José Eugenio; Arellano-Galindo, José; Mendoza-García, Emma; Jiménez-Hernández, Elva; Martínez Avalos, Armando; Velázquez Guadarrama, Norma; Mejía Arangure, Juan Manuel

    2012-11-01

    Haploidentical hematopoietic cell transplantation using CD34(+) cells depleted of T lymphocytes by the CliniMACS is a treatment for hematological malignancy. We report on four Mexican children, three with acute lymphocytic leukemia and one with chronic myelocytic leukemia, who was transplanted with 12 × 10(6) CD34(+) stem cells/kg body weight (98% of purity) with a follow-up of 9½ years. The engraftment was successful in three of the four children. All showed cytomegalovirus reactivation, and one died because of graft rejection and infectious complication. The risk of infections was a major problem.

  17. [Antibody-mediated rejection of renal allograft and the update Banff classification 2013].

    PubMed

    Honsová, Eva

    2015-01-01

    The view on the role of donor-specific antibodies in organ transplantation has been changed during the last several decades. Today, it is considered that the majority of cases of the late renal allograft dysfunction and loss are caused by the presence of donor-specific antibodies to HLA antigens. The real breakthrough in the diagnosis of antibody-mediated rejection was represented by the discovery of C4d, which enabled the determination of the diagnostic criteria of acute and later chronic antibody-mediated rejection. Although detection of C4d has been the cornerstone in the diagnosis of antibody-mediated rejection for over 10 years, it has become clear that some cases with similar morphological and clinical features do not have detectable C4d. Outcomes of key studies concerning presence of donor specific antibodies and morphological features in the graft biopsy samples resulted in the modification of Banff classification of 2013, which includes integrating C4d negative antibody-mediated rejection and also that acute vascular rejection (v1, v2) can be a part of the antibody-mediated rejection.

  18. Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver

    PubMed Central

    Yasuda, Makiko; Erwin, Angelika L; Liu, Lawrence U; Balwani, Manisha; Chen, Brenden; Kadirvel, Senkottuvelan; Gan, Lin; Fiel, M Isabel; Gordon, Ronald E; Yu, Chunli; Clavero, Sonia; Arvelakis, Antonios; Naik, Hetanshi; Martin, L David; Phillips, John D; Anderson, Karl E; Sadagoparamanujam, Vaithamanithi M; Florman, Sander S; Desnick, Robert J

    2015-01-01

    Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of hydroxymethylbilane (HMB) synthase. Symptomatic individuals experience life-threatening acute neurovisceral attacks that are precipitated by factors that induce the hepatic expression of 5-aminolevulinic acid synthase 1 (ALAS1), resulting in the marked accumulation of the putative neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Here, we provide the first detailed description of the biochemical and pathologic alterations in the explanted liver of an AIP patient who underwent orthotopic liver transplantation (OLT) due to untreatable and debilitating chronic attacks. After OLT, the recipient’s plasma and urinary ALA and PBG rapidly normalized, and her attacks immediately stopped. In the explanted liver, (a) ALAS1 mRNA and activity were elevated approximately ~3- and 5-fold, and ALA and PBG concentrations were increased ~3- and 1,760-fold, respectively; (b) uroporphyrin III concentration was elevated; (c) microsomal heme content was sufficient, and representative cytochrome P450 activities were essentially normal; (d) HMB synthase activity was approximately half-normal (~42%); (e) iron concentration was slightly elevated; and (f) heme oxygenase I mRNA was increased approximately three-fold. Notable pathologic findings included nodular regenerative hyperplasia, previously not reported in AIP livers, and minimal iron deposition, despite the large number of hemin infusions received before OLT. These findings suggest that the neurovisceral symptoms of AIP are not associated with generalized hepatic heme deficiency and support the neurotoxicity of ALA and/or PBG. Additionally, they indicate that substrate inhibition of hepatic HMB synthase activity by PBG is not a pathogenic mechanism in acute attacks. PMID:26062020

  19. Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome.

    PubMed

    Pusic, Iskra; Choi, Jaebok; Fiala, Mark A; Gao, Feng; Holt, Matthew; Cashen, Amanda F; Vij, Ravi; Abboud, Camille N; Stockerl-Goldstein, Keith E; Jacoby, Meghan A; Uy, Geoffrey L; Westervelt, Peter; DiPersio, John F

    2015-10-01

    Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m(2)/day × 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which ≤ 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the

  20. First Case Report of Acute Renal Failure After Mesh-Plug Inguinal Hernia Repair in a Kidney Transplant Recipient

    PubMed Central

    Veroux, Massimiliano; Ardita, Vincenzo; Zerbo, Domenico; Caglià, Pietro; Palmucci, Stefano; Sinagra, Nunziata; Giaquinta, Alessia; Veroux, Pierfrancesco

    2016-01-01

    Abstract Acute renal failure due to ureter compression after a mesh-plug inguinal repair in a kidney transplant recipient has not been previously reported to our knowledge. A 62-year-old man, who successfully underwent kidney transplantation from a deceased donor 6 years earlier, was admitted for elective repair of a direct inguinal hernia. The patient underwent an open mesh-plug repair of the inguinal hernia with placement of a plug in the preperitoneal space. We did not observe the transplanted ureter and bladder during dissection of the inguinal canal. Immediately after surgery, the patient became anuric, and a graft sonography demonstrated massive hydronephrosis. The serum creatinine level increased rapidly, and the patient underwent an emergency reoperation 8 hours later. During surgery, we did not identify the ureter but, immediately after plug removal, urine output increased progressively. We completed the hernia repair using the standard technique, without plug interposition, and the postoperative course was uneventful with complete resolution of graft dysfunction 3 days later. Furthermore, we reviewed the clinical features of complications related to inguinal hernia surgery. An increased risk of urological complications was reported recently in patients with a previous prosthetic hernia repair undergoing kidney transplantation, mainly due to the mesh adhesion to surrounding structures, making the extraperitoneal dissection during the transplant surgery very challenging. Moreover, older male kidney transplant recipients undergoing an inguinal hernia repair may be at higher risk of graft dysfunction due to inguinal herniation of a transplanted ureter. Mesh-plug inguinal hernia repair is a safe surgical technique, but this unique case suggests that kidney transplant recipients with inguinal hernia may be at higher risk of serious urological complications. Surgeons must be aware of the graft and ureter position before proceeding with hernia repair. A prompt

  1. Multi-state analysis illustrates treatment success after stem cell transplantation for acute myeloid leukemia followed by donor lymphocyte infusion.

    PubMed

    Eefting, Matthias; de Wreede, Liesbeth C; Halkes, Constantijn J M; von dem Borne, Peter A; Kersting, Sabina; Marijt, Erik W A; Veelken, Hendrik; Putter, Hein; Schetelig, Johannes; Falkenburg, J H Frederik

    2016-04-01

    In the field of hematopoietic stem cell transplantation, the common approach is to focus outcome analyses on time to relapse and death, without assessing the impact of post-transplant interventions. We investigated whether a multi-state model would give insight into the events after transplantation in a cohort of patients who were transplanted using a strategy including scheduled donor lymphocyte infusions. Seventy-eight consecutive patients who underwent myeloablative T-cell depleted allogeneic stem cell transplantation for acute myeloid leukemia or myelodysplastic syndrome were studied. We constructed a multi-state model to analyze the impact of donor lymphocyte infusion and graft-versus-host disease on the probabilities of relapse and non-relapse mortality over time. Based on this model we introduced a new measure for outcome after transplantation which we called 'treatment success': being alive without relapse and immunosuppression for graft-versus-host disease. All relevant clinical events were implemented into the multi-state model and were denoted treatment success or failure (either transient or permanent). Both relapse and non-relapse mortality were causes of failure of comparable magnitude. Whereas relapse was the dominant cause of failure from the transplantation state, its rate was reduced after graft-versus-host disease, and especially after donor lymphocyte infusion. The long-term probability of treatment success was approximately 40%. This probability was increased after donor lymphocyte infusion. Our multi-state model helps to interpret the impact of post-transplantation interventions and clinical events on failure and treatment success, thus extracting more information from observational data.

  2. Unraveling the Role of Allo-Antibodies and Transplant Injury

    PubMed Central

    Matsuda, Yoshiko; Sarwal, Minnie M.

    2016-01-01

    Alloimmunity driving rejection in the context of solid organ transplantation can be grossly divided into mechanisms predominantly driven by either T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), though the co-existence of both types of rejections can be seen in a variable number of sampled grafts. Acute TCMR can generally be well controlled by the establishment of effective immunosuppression (1, 2). Acute ABMR is a low frequency finding in the current era of blood group and HLA donor/recipient matching and the avoidance of engraftment in the context of high-titer, preformed donor-specific antibodies. However, chronic ABMR remains a major complication resulting in the untimely loss of transplanted organs (3–10). The close relationship between donor-specific antibodies and ABMR has been revealed by the highly sensitive detection of human leukocyte antigen (HLA) antibodies (7, 11–15). Injury to transplanted organs by activation of humoral immune reaction in the context of HLA identical transplants and the absence of donor specific antibodies (17–24), strongly suggest the participation of non-HLA (nHLA) antibodies in ABMR (25). In this review, we discuss the genesis of ABMR in the context of HLA and nHLA antibodies and summarize strategies for ABMR management. PMID:27818660

  3. Escaping from Rejection

    PubMed Central

    Lynch, Raymond J.; Platt, Jeffrey L.

    2009-01-01

    Summary Those engaged in clinical transplantation and transplantation immunology have always taken as a central objective the elucidation of means to prevent graft rejection by the recipient immune system. Conceptually, such mechanisms stem from the concept of Paul Ehrlich that all organisms can selectively avoid autotoxicity; i.e. they exhibit horror autotoxicus. Some mechanisms of horror autotoxicus now understood. T lymphocytes and B lymphocytes recognize foreign antigens but not some auto-antigens. Clonal deletion generates lacunae in what is otherwise a virtually limitless potential to recognize antigens. We call this mechanism structural tolerance. Where imperfections in structural tolerance allow self-recognition, the full activation of lymphocytes and generation of effector activity depends on delivery of accessory signals generated by infection and/or injury. The absence of accessory signals prevents or even suppresses immunological responses. We call this dichotomy of responsiveness conditional tolerance. When, despite structural and conditional tolerance, effector activity perturbs autologous cells, metabolism changes in ways that protect against injury. We use the term accommodation to refer to this acquired protection against injury. Structural and conditional tolerance and accommodation overlap in such a way that potentially toxic products can be generated to control microorganisms and neutralize toxins without overly damaging adjacent cells. The central challenge in transplantation, then, should be the orchestration of structural and conditional tolerance and accommodation in such a way that toxic products can still be generated for defense while preserving graft function and survival. Since the earliest days of transplantation, immunobiologists have sought means by which to prevent recognition and rejection of foreign tissue. The goal of these strategies is the retention of recipient immune function while selectively avoiding graft injury. While

  4. Early detection of biliary complications and graft rejection in a non-RH Identitical liver transplant recipient from a non-heart-beating donor: a case report.

    PubMed

    Turiño-Luque, J; Zambudio-Carroll, N; Muffak-Granero, K; Villegas-Herrera, T; Garrote-Lara, D; Ferrón-Orihuela, J-A

    2012-09-01

    Because of a shortage of organs, non-heart-beating donors have been proposed to be a possible source of grafts for orthotopic liver transplantation. Herein, we have presented a blood group A+ patient with primary biliary cirrhosis, who underwent orthotopic liver transplantation from a non-heart-beating blood group A- donor. On day 5 after transplantation the patient displayed a low hemoglobin levels as well as an increased total bilirubin with progressive encephalopathy, hypotension, and oligoanuria on day 11. The patient responded to steroid treatment. We assume the main cause of organ dysfunction was a passenger lymphocyte syndrome (ABO-Rh incompatibility). Biliary complications were detected at a 6-month follow-up visit by increased hepatic enzymes. We thus concluded that it is useful to take Rh group into account.

  5. What Health Educators Should Know about Pediatric Heart Transplant Recipients.

    ERIC Educational Resources Information Center

    Duitsman, Dalen

    1996-01-01

    This article provides background information on heart transplantation in general, focusing on pediatric heart transplantation and offering suggestions for teachers regarding the unique concerns of students with heart transplants (exercise, physical appearance, immunosuppressive medications, transplant rejection, infection, and psychological…

  6. Therapy-related acute myeloid leukemia and myelodysplastic syndrome after hematopoietic cell transplantation for lymphoma.

    PubMed

    Yamasaki, S; Suzuki, R; Hatano, K; Fukushima, K; Iida, H; Morishima, S; Suehiro, Y; Fukuda, T; Uchida, N; Uchiyama, H; Ikeda, H; Yokota, A; Tsukasaki, K; Yamaguchi, H; Kuroda, J; Nakamae, H; Adachi, Y; Matsuoka, K-I; Nakamura, Y; Atsuta, Y; Suzumiya, J

    2017-04-03

    Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P<0.001). Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT were high-stage risk at HCT (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or involved field radiotherapy (P=0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.Bone Marrow Transplantation advance online publication, 3 April 2017; doi:10.1038/bmt.2017.52.

  7. Management and prevention of post-transplant malignancies in kidney transplant recipients

    PubMed Central

    Stallone, Giovanni; Infante, Barbara; Grandaliano, Giuseppe

    2015-01-01

    The central issue in organ transplantation remains suppression of allograft rejection. Thus, the development of immunosuppressive drugs has been the key to successful allograft function. The increased immunosuppressive efficiency obtained in the last two decades in kidney transplantation dramatically reduced the incidence of acute rejection. However, the inevitable trade-off was an increased rate of post-transplant infections and malignancies. Since the incidence of cancer in immunosuppressed transplant recipients becomes greater over time, and the introduction of new immunosuppressive strategies are expected to extend significantly allograft survival, the problem might grow exponentially in the near future. Thus, cancer is becoming a major cause of morbidity and mortality in patients otherwise successfully treated by organ transplantation. There are at least four distinct areas requiring consideration, which have a potentially serious impact on recipient outcome after transplantation: (i) the risk of transmitting a malignancy to the recipient within the donor organ; (ii) the problems of previously diagnosed and treated malignancy in the recipient; (iii) the prevention of de novo post-transplant malignant diseases and (iv) the management of these complex and often life-threatening clinical problems. In this scenario, the direct and indirect oncogenic potential of immunosuppressive therapy should be always carefully considered. PMID:26413294

  8. Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients 2014 Data Report: Intestine.

    PubMed

    Cai, Junchao; Wu, Guosheng; Qing, Annie; Everly, Matthew; Cheng, Elaine; Terasaki, Paul

    2014-01-01

    As of September 19, 2014, 2441 cases of intestinal transplantation have been performed in 46 centers (2400 deceased, 41 living). Eight centers did more than 100 transplants. Annual case numbers peaked in 2007 (N = 198) and steadily decreased to 109 cases in 2013. Short gut syndrome (68%) and functional bowel problems (15%) are two major indications for intestinal transplantation. The 3 major types of transplants involving the intestine include: isolated intestine transplant (I); simultaneous intestine, liver, and pancreas transplant (I+L+P); and, combined intestine and liver (I+L) transplant. Graft survival has significantly improved in recent years, mainly due to improved first year graft survival. The 1-, 5-, and 10-year graft survivals were: 74%, 42%,and 26%, respectively (I); 70%, 50%, and 40%, respectively (I+L+P); and 61%, 46%, and 40%, respectively (I+L). The longest graft survivals for I, l+L+P, and l+L were 19 years, 16 years, and 23 years, respectively. Steroids, Thymoglobulin, and rituximab are 3 major induction agents used in recent years. Prograf, steroids, and Cellcept are 3 major maintenance agents. Induction recipients (68% of all patients) had a significantly lower acute rejection rate than nonrecipients before discharge (60% versus 75%, p < 0.001). Most of the patients received 2 (53%) or 3 (25%) maintenance immunosuppressants. Acute rejection episodes were usually treated with one (60%) or two agents (27%). Steroids were most commonly used (50-60%). OKT3 has been replaced with antithymocyte globulin (since 1999) and rituximab (since 2006). During 1990-2000, 94% (N = 445) of patients received ABO identical intestinal transplants, while 6% (N = 29) received ABO compatible transplants. ABO identical transplant recipients had a significantly higher 5-year graft survival rate than ABO compatible recipients (39% versus 21%, p < 0.0001). In recent years (2001- 2012), more patients received ABO compatible (N = 188, 11%) than in the early decade (p < 0

  9. Chronic hepatitis E virus infection in a pediatric female liver transplant recipient.

    PubMed

    Passos-Castilho, Ana Maria; Porta, Gilda; Miura, Irene K; Pugliese, Renata P S; Danesi, Vera L B; Porta, Adriana; Guimarães, Teresa; Seda, João; Antunes, Eduardo; Granato, Celso F H

    2014-12-01

    We describe a case of chronic hepatitis E virus (HEV) infection in a 13-year-old female liver transplant recipient with recurrent increased aminotransferase levels and acute cellular rejection. This finding demonstrates that chronic HEV infection can occur and should be further investigated in immunocompromised patients in Latin America.

  10. Reduced-intensity stem-cell transplantation for adult acute lymphoblastic leukemia: a retrospective study of 33 patients.

    PubMed

    Hamaki, T; Kami, M; Kanda, Y; Yuji, K; Inamoto, Y; Kishi, Y; Nakai, K; Nakayama, I; Murashige, N; Abe, Y; Ueda, Y; Hino, M; Inoue, T; Ago, H; Hidaka, M; Hayashi, T; Yamane, T; Uoshima, N; Miyakoshi, S; Taniguchi, S

    2005-03-01

    Efficacy of reduced-intensity stem-cell transplantation (RIST) for acute lymphoblastic leukemia (ALL) was investigated in 33 patients (median age, 55 years). RIST sources comprised 20 HLA-identical related donors, five HLA-mismatched related, and eight unrelated donors. Six patients had undergone previous transplantation. Disease status at RIST was first remission (n=13), second remission (n=6), and induction failure or relapse (n=14). All patients tolerated preparatory regimens and achieved neutrophil engraftment (median, day 12.5). Acute and chronic graft-versus-host disease (GVHD) developed in 45 and 64%, respectively. Six patients received donor lymphocyte infusion (DLI), for prophylaxis (n=1) or treatment of recurrent ALL (n=5). Nine patients died of transplant-related mortality, with six deaths due to GVHD. The median follow-up of surviving patients was 11.6 months (range, 3.5-37.3 months). The 1-year relapse-free and overall survival rates were 29.8 and 39.6%, respectively. Of the 14 patients transplanted in relapse, five remained relapse free for longer than 6 months. Cumulative rates of progression and progression-free mortality at 3 years were 50.9 and 30.4%, respectively. These findings suggest the presence of a graft-versus-leukemia effect for ALL. RIST for ALL is worth considering for further evaluation.

  11. First case of atypical takotsubo cardiomyopathy in a bilateral lung-transplanted patient due to acute respiratory failure.

    PubMed

    Ghadri, Jelena R; Bataisou, Roxana D; Diekmann, Johanna; Lüscher, Thomas F; Templin, Christian

    2015-10-01

    Takotsubo cardiomyopathy which is characterised by a transient left ventricular wall motion abnormality was first described in 1990. The disease is still not well known, and as such it is suggested that an emotional trigger is mandatory in this disease. We present the case of a 51-year old female patient seven years after bilateral lung transplantation, who developed acute respiratory distress syndrome and subsequently suffered from atypical takotsubo cardiomyopathy with transient severe reduction of ejection fraction and haemodynamic instability needing acute intensive care treatment. Acute respiratory failure has emerged as an important physical trigger factor in takotsubo cardiomyopathy. Little is known about the association of hypoxia and takotsubo cardiomyopathy which can elicit a life-threatening condition r