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Sample records for acute cardiac rejection

  1. Acute antibody-mediated rejection of cardiac transplants.

    PubMed

    Reed, Elaine F; Demetris, Anthony J; Hammond, Elizabeth; Itescu, Silviu; Kobashigawa, Jon A; Reinsmoen, Nancy L; Rodriguez, E Rene; Rose, Marlene; Stewart, Susan; Suciu-Foca, Nicole; Zeevi, Adriana; Fishbein, Michael C

    2006-02-01

    Under the direction of the International Society for Heart and Lung Transplantation, a multidisciplinary review of the cardiac biopsy grading system was undertaken in 2004, with task forces examining the areas of histopathology of rejection, clinical issues, and research. An important new area addressed by the Immunopathology Task Force sub-committee was the clinical and diagnostic criteria for antibody-mediated rejection. This article is a companion paper to the revised working formulation for the standardization of nomenclature in the diagnosis of heart rejection and reviews the published literature documenting the serologic and morphologic evidence that antibody-mediated rejection is clinically significant and associated with graft loss, accelerated transplant-associated coronary artery disease, and death. This article also provides a more in-depth analysis of antibody-mediated rejection developed by the Immunopathology Task Force for revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection.

  2. [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.

  3. B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection.

    PubMed

    Noorchashm, Hooman; Reed, Amy J; Rostami, Susan Y; Mozaffari, Raha; Zekavat, Ghazal; Koeberlein, Brigitte; Caton, Andrew J; Naji, Ali

    2006-12-01

    Acute allograft rejection requires the activation of alloreactive CD4 T cells. Despite the capacity of B cells to act as potent APCs capable of activating CD4 T cells in vivo, their role in the progression of acute allograft rejection was unclear. To determine the contribution of B cell APC function in alloimmunity, we engineered mice with a targeted deficiency of MHC class II-mediated Ag presentation confined to the B cell compartment. Cardiac allograft survival was markedly prolonged in these mice as compared to control counterparts (median survival time, >70 vs 9.5 days). Mechanistically, deficient B cell-mediated Ag presentation disrupted both alloantibody production and the progression of CD4 T cell activation following heart transplantation. These findings demonstrate that indirect alloantigen presentation by recipients' B cells plays an important role in the efficient progression of acute vascularized allograft rejection.

  4. MRI Investigation of Macrophages in Acute Cardiac Allograft Rejection after Heart Transplantation

    PubMed Central

    Wu, Yijen L.; Ye, Qing; Eytan, Danielle F.; Liu, Li; Rosario, Bedda L.; Hitchens, T. Kevin; Yeh, Fang-Cheng; van Rooijen, Nico; Ho, Chien

    2013-01-01

    Background Current immunosuppressive therapy after heart transplantation either generally suppresses the recipient’s entire immune system or is mainly targeting T-lymphocytes. Monocytes/macrophages are recognized as a hallmark of acute allograft rejection, but the roles that they play are not well characterized in vivo, because the tools for accessing in-situ macrophage infiltration are lacking. In this study, we utilize MRI to investigate the role of macrophages in acute heart allograft rejection by cellular and functional MRI with selectively depleted systemic macrophages without affecting other leukocyte population and to explore the possibility that macrophages could be an alternative therapeutic target. Methods and Results A rodent heterotopic working heart-lung transplantation model was employed for studying acute allograft rejection. Systemic macrophages were selectively depleted by treating recipient animals with clodronate-liposomes. Macrophage infiltration in the graft hearts was monitored by cellular MRI with in-vivo ultra-small iron-oxide particles (USPIO) labeling. Graft heart function was evaluated by tagging MRI, followed by strain analysis. Clodronate-liposome-treatment depletes circulating monocytes/macrophages in transplant recipients, and both cellular MRI and pathological examinations indicate a significant reduction in macrophage accumulation in the rejecting allograft hearts. In clodronate-liposome-treated group, allograft hearts exhibit preserved tissue integrity, partially reverse functional deterioration, and prolong graft survival, compared to untreated controls. Conclusions Cardiac cellular and functional MRI is a powerful tool to explore the roles of targeted immune cells in vivo. Our results indicate that macrophages are essential in acute cardiac allograft rejection, and selective depletion of macrophages with clodronate-liposomes protects hearts against allograft rejection, suggesting a potential therapeutic avenue. Our findings

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

    PubMed

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

    2017-01-01

    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. 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 4(th) 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. Forty grafted hearts were successfully harvested and used in experiments. Histologic examination showed mild rejection at the 2(nd) day and moderate rejection at the 4(th) 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 2(nd) 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 4(th) day, P=0.0064). The current density of Ito was significantly decreased at the 4(th) day after cardiac transplantation. The APD of

  6. 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

  7. 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.

  8. Non-invasive approaches for the diagnosis of acute cardiac allograft rejection.

    PubMed

    Miller, Christopher A; Fildes, James E; Ray, Simon G; Doran, Helen; Yonan, Nizar; Williams, Simon G; Schmitt, Matthias

    2013-04-01

    Despite modern immunosuppressive regimes, acute rejection remains a leading cause of morbidity and mortality in heart transplant recipients. Clinical features are unreliable, and therefore, screening is performed in order to detect rejection, and hence, augment immunosuppressive therapy, at an early stage, with the aim of reducing short- and long-term sequelae. Histological analysis of right ventricular myocardial tissue obtained at endomyocardial biopsy remains the 'gold standard' surveillance technique; however 'biopsy-negative' rejection occurs in up to 20% of patients, the procedure is associated with uncommon but potentially serious complications and it is expensive. Non-invasive screening would, conceivably, be safer, more tolerable and cheaper, and could potentially allow more comprehensive monitoring. The evidence for non-invasive methods of diagnosing acute rejection, including assessment of myocardial deformation, myocardial tissue characterisation, electrophysiological monitoring, visualisation of cellular and molecular components of rejection and peripheral monitoring of immune activation, is reviewed.

  9. Post-translational modification of manganese superoxide dismutase in acutely rejecting cardiac transplants: role of inducible nitric oxide synthase.

    PubMed

    Nilakantan, Vani; Halligan, Nadine L N; Nguyen, Thanh K; Hilton, Gail; Khanna, Ashwani K; Roza, Allan M; Johnson, Christopher P; Adams, Mark B; Griffith, Owen W; Pieper, Galen M

    2005-10-01

    Nitration of a critical tyrosine residue in the active site of manganese superoxide dismutase (MnSOD) can lead to enzyme inactivation. In this study, we examined the effect of inducible nitric oxide synthase (iNOS) on MnSOD expression, activity and nitration in acutely rejecting cardiac transplants. Lewis (isograft) or Wistar-Furth (allograft) donor hearts were transplanted into Lewis recipient rats. Some rats received L-N6-(1-iminoethyl) lysine (l-NIL), a specific iNOS inhibitor. Protein nitration was determined by immunohistochemical, Western blot and slot-blot analyses. MnSOD enzyme activity and gene expression were determined using Western, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoprecipitation techniques. MnSOD protein levels were decreased 50% by post-operative day 6 (POD 6), which was prevented by L-NIL. RT-PCR analysis indicated that this decrease could not be explained by any changes in MnSOD mRNA. MnSOD enzyme activity but not protein was decreased at POD 5 in untreated allografts. The loss of MnSOD activity at POD 5 was also prevented by L-NIL. Immunoreactive nitrotyrosine was apparent in untreated allografts at POD 6. Slot-blot analysis indicated that nitrotyrosine formation in allografts could be blocked by L-NIL. Nitration of MnSOD was evident upon immunoprecipitation of MnSOD followed by Western blotting for nitrotyrosine. These results suggest that the decreased MnSOD enzyme activity in acutely rejecting cardiac allografts can be attributed to a post-translational modification related to nitration arising via an iNOS-dependent pathway. This could be a potential major source of amplified oxidative stress in acute graft rejection.

  10. 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.

  11. Triptolide inhibits CD4(+) memory T cell-mediated acute rejection and prolongs cardiac allograft survival in mice.

    PubMed

    Qiu, Shuiwei; Lv, Dingliang

    2017-10-01

    There have been numerous investigations into the immunosuppressive effects of triptolide; however, its inhibitory effects on memory T cells remain to be elucidated. Using a cluster of differentiation (CD)4(+) memory T-cell transfer model, the aim of the present study was to determine the inhibitory effects of triptolide on CD4(+) memory T cell-mediated acute rejection and to determine the potential underlying mechanisms. At 4 weeks after skin transplantation, mouse cervical heart transplantation was performed following the transfer of CD4(+) memory T cells. Mice were divided into two groups: A Control [normal saline, 30 ml/kg/day; intraperitoneal injection (ip)] and a triptolide group (triptolide, 3 mg/kg/day; ip). Graft survival, pathological examination and the corresponding International Society for Heart & Lung Transplantation (ISHLT) scores were assessed 5 days following heart transplantation, and levels of interleukin (IL)-2, interferon-γ (IFN-γ), IL-10 and transforming growth factor β1 (TGF-β1) in cardiac grafts and peripheral blood were assessed using reverse transcription-quantitative polymerase chain reaction and ELISA. The duration of cardiac graft survival in the triptolide group was significantly increased compared with the control group (14.3±0.4 vs. 5.3±0.2 days; P<0.001). Further pathological examinations revealed that the infiltration of inflammatory cells and myocardial damage in the cardiac grafts was notably reduced by triptolide, and the corresponding ISHLT scores in the triptolide group were significantly lower than those of the control group (grade 2.08±0.15 vs. 3.67±0.17; P<0.001). In addition, triptolide was able to significantly reduce IL-2 and IFN-γ secretion (P<0.01), significantly increase TGF-β1 secretion in the cardiac grafts and peripheral blood (P<0.01) and increase IL-10 secretion in the cardiac grafts. Therefore, the present study suggests that triptolide inhibits CD4(+) memory T cell-mediated acute rejection and

  12. 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

  13. 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.

  14. 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

  15. Hierarchical change in antioxidant enzyme gene expression and activity in acute cardiac rejection: role of inducible nitric oxide synthase.

    PubMed

    Nilakantan, Vani; Zhou, Xianghua; Hilton, Gail; Roza, Allan M; Adams, Mark B; Johnson, Christopher P; Pieper, Galen M

    2005-02-01

    Reactive oxygen and nitrogen may mediate inflammation injury, but the status of the antioxidant defense system that might influence this process is unknown. In the present study, we examined the expression profile of the antioxidant enzymes, manganese superoxide dismutase (MnSOD), catalase and glutathione peroxidase (GPX) in acutely rejecting cardiac allografts and the potential role of inducible nitric oxide synthase (iNOS) in modulating antioxidant gene expression and activity. Donor hearts from Lewis (isograft) or Wistar-Furth (allograft) rats were transplanted into Lewis recipient rats. A subset of the allografts received L-N6-(1-imino-ethyl) lysine (L-NIL), a specific iNOS inhibitor, beginning the day of surgery until the day of harvesting. Catalase and glutathione peroxidase (GPX) protein levels were significantly decreased by postoperative day 4 (POD4) and postoperative day 5 (POD5), respectively, in allografts compared to isografts. While CuZn superoxide dismutase (CuZn SOD) levels were unchanged, there was a 50% decrease in MnSOD protein in allografts at postoperative day 6 (POD6). The sequential loss in antioxidant protein levels was not due to transcriptional regulation since there was no change in RNA levels for any of the genes tested. L-NIL did not alter catalase protein; however, the loss of MnSOD protein at POD6 was prevented by L-NIL. Consistent with a decrease in antioxidant protein levels, there was a sequential loss in enzyme activity for MnSOD, catalase and GPX. L-NIL however, restored MnSOD and GPX activities but not catalase activity. Treatment with CsA restored both protein and enzyme activities of GPX and MnSOD but not catalase. These results indicate that the loss in MnSOD and GPX protein and activity in allografts occurs via an iNOS-dependent mechanism whereas the decrease in catalase appears to be iNOS-independent. This suggests a differential role for iNOS in regulating post-translational modification of individual antioxidant enzymes

  16. Influence of delayed graft function and acute rejection on outcomes after kidney transplantation from donors after cardiac death.

    PubMed

    Nagaraja, Pramod; Roberts, Gareth W; Stephens, Michael; Horvath, Szabolcs; Fialova, Jana; Chavez, Rafael; Asderakis, Argiris; Kaposztas, Zsolt

    2012-12-27

    Delayed graft function (DGF) and acute rejection (AR) exert an adverse impact on graft outcomes after kidney transplantation using organs from donation after brain-stem death (DBD) donors. Here, we examine the impact of DGF and AR on graft survival in kidney transplants using organs from donation after cardiac death (DCD) donors. We conducted a single-center retrospective study of DCD and DBD donor kidney transplants. We compared 1- and 4-year graft and patient survival rates, as well as death-censored graft survival (DCGS) rates, between the two groups using univariate analysis, and the impact of DGF and AR on graft function was compared using multivariate analysis. Eighty DCD and 206 DBD donor transplants were analyzed. Median follow-up was 4.5 years. The incidence of DGF was higher among DCD recipients (73% vs. 27%, P<0.001), and AR was higher among DBD recipients (23% vs. 9%, P<0.001). One-year and 4-year graft survival rates were similar (DCD 94% and 79% vs. DBD 90% and 82%). Among recipients with DGF, the 4-year DCGS rate was better for DCD recipients compared with DBD recipients (100% vs. 92%, P=0.04). Neither DGF nor AR affected the 1-year graft survival rate in DCD recipients, whereas in DBD recipients, the 1-year graft survival rate was worse in the presence of DGF (88% vs. 96%, P=0.04) and the 4-year DCGS rate was worse in the presence of AR (88% vs. 96%, P=0.04). Despite the high incidence of DGF, medium-term outcomes of DCD kidney transplants are comparable to those from DBD transplants. Short-term graft survival from DCD transplants is not adversely influenced by DGF and AR, unlike in DBD transplants.

  17. 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

  18. [Effect of Yunnan-cobra venom factor in overcoming acute humoral rejection after allograft cardiac transplantation in presensitized recipients: experiment with rats].

    PubMed

    Li, Rong; Chen, Gang; Guo, Hui; Wang, Da-wei; Xie, Lin; Wang, Shu-sen; Wang, Wan-yu; Xiong, Yu-liang; Chen, Shi

    2006-06-06

    To investigate the effect of Yunnan-cobra venom factor (Y-CVF) in overcoming acute humoral rejection after allograft cardiac transplantation in presensitized recipients. Fifteen Lewis rats received the transplantation of full-thickness skin graft of BN rats three times so as to be presensitized. Fifteen pairs of Lewis rat, as recipients of heart, and BN rat, as heart donors, were randomly divided into 2 groups: experimental group (n = 8), and control group (n = 7). The Lewis rats in the experimental group received heart transplantation of the heart of the BN rat 7 approximately 10 days after the third skin transplantation, and were injected with Y-CVF 80 microg/kg 24 hours before the heart transplantation. The Lewis rat in the control group received only the heart transplantation without Y-CVF injection. Blood samples were collected from all rats before pre-sensitization and 7 days after the third skin transplantation so as to determine the titer of anti-BN rat lymphocyte antibody. 0 and 24 hours, and 6 and 8 days after Y-CVF injection blood samples were collected from the Lewis rats to determine the total complement activity with the complement activity before Y-CVF injection defined as 100%. The survival time of the transplanted heart was observed. After the transplanted hearts stopped to beat, they were resected and underwent HE staining and microscopy. Immunohistochemistry was used to examine the deposition of IgG and complement 3 (C3). The titer of anti-BN rat lymphocyte antibody was 0 before the pre-sensitization, and increased to 1:1028 - 1:2056 7 days after the third skin pre-sensitization. The serum total complement activity of the Lewis rats decreased to 0 twenty-four hours after the Y-CVF injection, recovered to 2.01% - 15.41% 6 days after, and returned to the normal level (89.61% - 109.46%) 8 days after. The mean survival time of the transplanted hearts of the control group was 12.71 +/- 13.94 hours (with a range of 1.5 - 15 hours), significantly

  19. 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.

  20. Renal graft irradiation in acute rejection

    SciTech Connect

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

    1983-03-01

    To evaluate the effect of graft irradiation in the treatment of acute rejection of renal transplants, a randomized study was conducted from 1978 to 1981. Patients with acute rejection were given standard medical management in the form of intravenous methylprednisolone, and were chosen randomly to receive either graft irradiation (175 rads every other day, to a total of 525 rads) or simulated (sham) irradiation. Eighty-three rejections occurring in 64 grafts were randomized to the protocol. Rejection reversal was recorded in 84.5% of control grafts and 75% of the irradiated grafts. Recurrent rejections were more frequent and graft survival was significantly lower in the irradiated group (22%) than in the control group (54%). Graft irradiation does not appear to be beneficial in the treatment of acute rejection of renal transplants when used in conjunction with high-dose steroids.

  1. Multiparametric cardiovascular magnetic resonance surveillance of acute cardiac allograft rejection and characterisation of transplantation-associated myocardial injury: a pilot study.

    PubMed

    Miller, Christopher A; Naish, Josephine H; Shaw, Steven M; Yonan, Nizar; Williams, Simon G; Clark, David; Bishop, Paul W; Ainslie, Mark P; Borg, Alex; Coutts, Glyn; Parker, Geoffrey J M; Ray, Simon G; Schmitt, Matthias

    2014-07-20

    Serial surveillance endomyocardial biopsies are performed in patients who have recently undergone heart transplantation in order to detect acute cardiac allograft rejection (ACAR) before symptoms occur, however the biopsy process is associated with a number of limitations. This study aimed to prospectively and longitudinally evaluate the performance of multiparametric cardiovascular magnetic resonance (CMR) for detecting and monitoring ACAR in the early phase post-transplant, and characterize graft recovery following transplantation. All patients receiving a heart transplant at a single UK centre over a period of 25 months were approached within one month of transplantation. Multiparametric CMR was prospectively performed on the same day as biopsy on four separate occasions (6 weeks, 10 weeks, 15 weeks and 20 weeks post-transplant). CMR included assessment of global and regional ventricular function, myocardial tissue characterization (T1 mapping, T2 mapping, extracellular volume, LGE) and pixel-wise absolute myocardial blood flow quantification. CMR parameters were compared with biopsy findings. As is standard, grade 2R or higher ACAR was considered significant. 88 CMR-matched biopsies were performed in 22 patients. Eight (9%) biopsies in 5 patients demonstrated significant ACAR. Significant ACAR was associated with a reduction in circumferential strain (-12.7±2.5% vs. -13.7±3.6%, p=0.047) but there was considerable overlap between groups. Whilst trends were observed between ACAR and proposed CMR markers of oedema, particularly after adjusting for primary graft dysfunction, differences were not significant. Significant improvements were seen in markers of graft structure and contractility, oedema and microvascular function over the period studied, although few parameters normalised. This study provides novel insight into the myocardial injury associated with transplantation, and its recovery, however multiparametric CMR was not able to accurately detect ACAR

  2. AS2553627, a novel JAK inhibitor, prevents chronic rejection in rat cardiac allografts.

    PubMed

    Nakamura, Koji; Inami, Masamichi; Morio, Hiroki; Okuma, Kenji; Ito, Misato; Noto, Takahisa; Shirakami, Shohei; Hirose, Jun; Morokata, Tatsuaki

    2017-02-05

    Janus family kinases (JAKs) are essential molecules for cytokine responses and attractive targets for the treatment of transplant rejection and autoimmune diseases. Several JAK inhibitors have shown demonstrable effects on acute rejection in experimental cardiac transplant models. However, little is known about the potential benefits of JAK inhibitors on chronic rejection outcomes such as vasculopathy and fibrosis. Here, we examined the pharmacological profile of a novel JAK inhibitor, AS2553627, and explored its therapeutic potential in chronic rejection as well as acute rejection in a rat cardiac transplant model. AS2553627 potently inhibited JAK kinases but showed no inhibition of other kinases, including TCR-associated molecules. The compound also suppressed proliferation of IL-2 stimulated human and rat T cells. In a rat cardiac transplant model, oral administration of AS2553627 alone or co-administration with a sub-therapeutic dose of tacrolimus effectively prolonged cardiac allograft survival, suggesting the efficacy in treating acute rejection. To evaluate the effect on chronic rejection, recipient rats were administered a therapeutic dose of tacrolimus for 90 days. In combination with tacrolimus, AS2553627 significantly reduced cardiac allograft vasculopathy and fibrosis that tacrolimus alone did not inhibit. AS2553627 at the effective dose in rat transplantation models did not significantly reduce reticulocyte counts in peripheral whole blood after in vivo erythropoietin administration, indicating a low risk for anemia. These results suggest that AS2553627 may be a therapeutic candidate for the prevention of not only acute but also chronic rejection in cardiac transplantation. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Total lymphoid irradiation for treatment of intractable cardiac allograft rejection

    SciTech Connect

    Hunt, S.A.; Strober, S.; Hoppe, R.T.; Stinson, E.B. )

    1991-03-01

    The ability of postoperative total lymphoid irradiation to reverse otherwise intractable cardiac allograft rejection was examined in a group of 10 patients in whom conventional rejection therapy (including pulsed steroids and monoclonal or polyclonal anti-T-cell antibody therapy) had failed to provide sustained freedom from rejection. Follow-up periods range from 73 to 1119 days since the start of total lymphoid irradiation. No patient died or sustained serious morbidity because of the irradiation. Three patients have had no further rejection (follow-up periods, 105 to 365 days). Two patients died--one in cardiogenic shock during the course of total lymphoid irradiation, the other with recurrent rejection caused by noncompliance with his medical regimen. Total lymphoid irradiation appears to be a safe and a moderately effective immunosuppressive modality for 'salvage' therapy of cardiac allograft rejection unresponsive to conventional therapy.

  4. High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance Spectroscopy for the Metabolic Assessment of Acute Rejection After Cardiac Transplantation in Rats.

    PubMed

    Lee, C W; Lee, J S; Woo, C W; Kim, S

    2017-10-01

    To evaluate the potential of high-resolution magic angle spinning (HR-MAS) (1)H nuclear magnetic resonance (NMR) spectroscopy for metabolite characterization and the differentiation of acute rejection after heart transplantation in rat models. We transplanted syngeneic heart grafts from Lewis rats (n = 4) and allogeneic heart grafts from F344 rats (n = 4) heterotopically into Lewis recipients. On day 7 postoperatively, the transplanted hearts were harvested for ex vivo (1)H NMR spectroscopy and HR-MAS (1)H NMR spectroscopy. (1)H NMR spectroscopy and HR-MAS (1)H NMR spectroscopy were performed at 4.7 T and 11.7 T, respectively. Metabolomic profiles contributing to the differentiation of allogeneic and syngeneic graft groups were statistically assessed by orthogonal partial least squares discriminant analysis (OPLS/O2PLS-DA). Metabolite concentrations were normalized by total spectral intensities and were compared using Mann-Whitney U tests. One allogeneic graft that showed extensive necrotic change suggesting graft failure was excluded from the statistical analysis of the NMR spectroscopy. In the 4.7-T (1)H NMR spectroscopy, the creatine peak was decreased in the allogeneic group. The PLS-DA and OPLS/O2PLS-DA score plot demonstrated good discrimination of the allogeneic graft group from syngeneic graft group. The concentrations of creatine, myo-inositol, glucose, niacinamide, hypoxanthine, inosine, and glutamine were significantly decreased in the allogeneic graft group, whereas the concentrations of glycine, phosphoethanolamine, xanthine, sn-glycero-3-phosphocholine, leucine, valine, and tyrosine were significantly increased (P < .05). HR-MAS (1)H NMR spectroscopy can metabolically characterize the acute rejection of heart transplantation. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 19F MRI Detection of Acute Allograft Rejection with In Vivo Perfluorocarbon Labeling of Immune Cells

    PubMed Central

    Hitchens, T. Kevin; Ye, Qing; Eytan, Danielle F.; Janjic, Jelena M.; Ahrens, Eric T.; Ho, Chien

    2010-01-01

    Current diagnosis of organ rejection following transplantation relies on tissue biopsy, which is not ideal due to sampling limitations and risks associated with the invasive procedure. We have previously shown that cellular MRI of iron-oxide labeled immune-cell infiltration can provide a non-invasive measure of rejection status by detecting areas of hypointensity on T2*-weighted images. In the current study, we tested the feasibility of using a fluorine-based cellular tracer agent to detect macrophage accumulation in rodent models of acute allograft rejection by fluorine-19 (19F) MRI and MRS. This study used two rat models of acute rejection, including abdominal heterotopic cardiac transplant and orthotopic kidney transplant models. Following in vivo labeling of monocytes and macrophages with a commercially available agent containing perfluoro-15-crown-5-ether, we observed 19F-signal intensity in the organs experiencing rejection by 19F MRI, and conventional 1H MRI was used for anatomical context. Immunofluorescense and histology confirmed macrophage labeling. These results are consistent with our previous studies and show the complementary nature of the two cellular imaging techniques. With no background signal, 19F MRI/MRS can provide unambiguous detection of fluorine labeled cells, and may be a useful technique for detecting and quantifying rejection grade in patients. PMID:21305593

  13. 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

  14. Noninvasive rejection monitoring of cardiac transplants using high resolution intramyocardial electrograms: initial US multicenter experience.

    PubMed

    Bourge, R; Eisen, H; Hershberger, R; Keller, A; Radovancevic, B; Schreier, G; Kastner, P; Hutten, H; Wery, S; Mehta, N

    1998-11-01

    Endomyocardial biopsy (EMB) remains the mainstay for the diagnosis of acute cellular rejection in cardiac transplant patients. A noninvasive alternative that would supplant or reduce the number of EMBs would be a highly desirable and cost-effective tool. To evaluate one potential alternative, a pacemaker with high resolution telemetry capabilities and two fractally coated epimyocardial leads were implanted in 30 patients at five transplant centers during the heart transplant procedure. Ventricular electrograms were recorded during intrinsic and paced activity and digitized to a laptop-based data acquisition device. Electrograms were recorded at frequent intervals and systematically on days when EMBs were performed. The electrogram data were then transferred via the Internet to a central data processing site. Clinical patient management was blinded to the electrogram results and varied considerably among the five centers. Using EMB together with clinical assessment of the transplant revealed 18 cases of clinically significant rejection beyond postoperative day 27 that required antirejection therapy. The normalized parameter values extracted from the electrogram recordings during pacing (the ventricular evoked response) that were associated with significant rejection were statistically lower (86% +/- 16% versus 96% +/- 22%, P < 0.005). The application of a single-threshold diagnosis model to the parameter values allowed detection of significant rejection with a negative predictive value of 98%. This analysis also showed that as many as 55% of the routine surveillance EMBs could have been eliminated had the pacemaker monitoring technique been used as a screening tool prior to EMB. A prospective study should further define the role of this technique in the detection and management of cardiac transplant patients.

  15. 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.

  16. Failure to diagnose cardiac treatment rejection with Tc99m-PYP images

    SciTech Connect

    McKillop, J.H.; McDougall, I.R.; Goris, M.L.; Mason, J.W.; Reitz, B.A.

    1981-08-01

    The possibility of diagnosing transplant rejection using Tc-99m-PYP imaging was examined in 12 cardiac transplant recipients. Two patients were studied on two occasions. The presence or absence of active rejection was established by endomyocardial biopsy. The intensity and pattern of myocardial uptake of the tracer did not differ significantly in the two patients studied at the time of rejection compared to the remainder. It is concluded that a single Tc-99m-PYP study cannot be used to diagnose cardiac transplant rejection.

  17. Patterns of De Novo Allo B Cells and Antibody Formation in Chronic Cardiac Allograft Rejection After Alemtuzumab Treatment

    PubMed Central

    Kwun, J.; Oh, B. C.; Gibby, A. C.; Ruhil, R.; Lu, V. T.; Kim, D. W.; Page, E. K.; Bulut, O. P.; Song, M. Q.; Farris, A. B.; Kirk, A. D.; Knechtle, S. J.; Iwakoshi, N. N.

    2017-01-01

    Even though the etiology of chronic rejection (CR) is multifactorial, donor specific antibody (DSA) is considered to have a causal effect on CR development. Currently the antibody-mediated mechanisms during CR are poorly understood due to lack of proper animal models and tools. In a clinical setting, we previously demonstrated that induction therapy by lymphocyte depletion, using alemtuzumab (anti-human CD52), is associated with an increased incidence of serum alloantibody, C4d deposition and antibody-mediated rejection in human patients. In this study, the effects of T cell depletion in the development of antibody-mediated rejection were examined using human CD52 transgenic (CD52Tg) mice treated with alemtuzumab. Fully mismatched cardiac allografts were transplanted into alemtuzumab treated CD52Tg mice and showed no acute rejection while untreated recipients acutely rejected their grafts. However, approximately half of long-term recipients showed increased degree of vasculopathy, fibrosis and perivascular C3d depositions at posttransplant day 100. The development of CR correlated with DSA and C3d deposition in the graft. Using novel tracking tools to monitor donor-specific B cells, alloreactive B cells were shown to increase in accordance with DSA detection. The current animal model could provide a means of testing strategies to understand mechanisms and developing therapeutic approaches to prevent chronic rejection. PMID:22759336

  18. 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.

  19. Blocking MHC class II on human endothelium mitigates acute rejection

    PubMed Central

    Abrahimi, Parwiz; Qin, Lingfeng; Chang, William G.; Bothwell, Alfred L.M.; Tellides, George; Saltzman, W. Mark; Pober, Jordan S.

    2016-01-01

    Acute allograft rejection is mediated by host CD8+ cytotoxic T lymphocytes (CTL) targeting graft class I major histocompatibility complex (MHC) molecules. In experimental rodent models, rejection requires differentiation of naive CD8+ T cells into alloreactive CTL within secondary lymphoid organs, whereas in humans, CTL may alternatively develop within the graft from circulating CD8+ effector memory T cells (TEM) that recognize class I MHC molecules on graft endothelial cells (EC). This latter pathway is poorly understood. Here, we show that host CD4+ TEM, activated by EC class II MHC molecules, provide critical help for this process. First, blocking HLA-DR on EC lining human artery grafts in immunodeficient mice reduces CD8+ CTL development within and acute rejection of the artery by adoptively transferred allogeneic human lymphocytes. Second, siRNA knockdown or CRISPR/Cas9 ablation of class II MHC molecules on EC prevents CD4+ TEM from helping CD8+ TEM to develop into CTL in vitro. Finally, implanted synthetic microvessels, formed from CRISPR/Cas9-modified EC lacking class II MHC molecules, are significantly protected from CD8+ T cell–mediated destruction in vivo. We conclude that human CD8+ TEM–mediated rejection targeting graft EC class I MHC molecules requires help from CD4+ TEM cells activated by recognition of class II MHC molecules. PMID:26900601

  20. 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

  1. 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

  2. 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.

  3. Diagnostic performance of late gadolinium enhancement in the assessment of acute cellular rejection after heart transplantation

    PubMed Central

    Şimşek, Evrim; Nalbantgil, Sanem; Ceylan, Naim; Zoghi, Mehdi; Kemal, Hatice Soner; Engin, Çağatay; Yağdı, Tahir; Özbaran, Mustafa

    2016-01-01

    Objective: Allograft rejection is still an important cause of morbidity and mortality after heart transplantation (HTx). Many techniques in cardiac magnetic resonance imaging (CMR) were investigated to diagnose acute cellular rejection (ACR). However, there is not enough information about late gadolinium enhancement (LGE) in the myocardium and ACR. Methods: We prospectively analyzed our consecutive 41 heart transplant recipients who were admitted for routine endomyocardial biopsies. CMR was performed maximum 6 h before the scheduled endomyocardial biopsy. Correlation between LGE in the myocardium and ACR was investigated. Results: Twenty-seven patients showed no rejection, and nine of them had LGE in the myocardium. Fourteen patients had LGE in the left ventricle (LV), and two patients had LGE also in the right ventricle (RV). There was no correlation between LGE and ACR (p=0.879). There was no difference in the left ventricular ejection fraction (LVEF), right ventricular fractional area change (RVFAC), and cardiac ischemic time between the groups (p=0.825, p=0.370, and p=0.419, respectively). LGE in the myocardium could be due to previous rejection episodes; therefore, all patients were retrospectively searched for previous rejection grades and number of episodes. Thirty-eight of the 41 patients had a history of one ACR episode, but none of them had a statistically significant correlation with LGE (for grade 1R, p=0.964 and grade 3R, p=1) There was also no correlation between number of rejection episodes history and LGE. Conclusion: LGE is not suitable to detect ACR in heart transplant patients. LGE and the history of ACR have no correlation. PMID:26467370

  4. Sensitivity of scintigraphy with /sup 111/In-lymphocytes for detection of cardiac allograft rejection

    SciTech Connect

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

    1988-12-01

    We recently demonstrated the feasibility of noninvasive detection of cardiac allograft rejection after administration of indium-111-labeled lymphocytes. To determine the sensitivity and specificity of the technique, as well as its value for delineating the severity of rejection, we studied 16 dogs with heterotopic thoracic cardiac allografts. Five animals were evaluated while exposed to immunosuppressive agents. Animals were scanned sequentially after administration of 100-400 microCi of indium-111-labeled autologous lymphocytes. Myocardial lymphocyte infiltration was expressed as the indium excess (IE), defined as the ratio of indium activity of the transplant or native heart compared with that in blood. Scintigraphic results were compared with characteristics of simultaneously obtained endomyocardial biopsies. Among 17 biopsy documented episodes of rejection, 16 were detected scintigraphically. Among 18 biopsies with no evidence of rejection, scintigraphy was uniformly negative. Thus, the sensitivity and specificity of scintigraphy were 94 and 100%, respectively. Biopsies graded as showing no rejection were associated with an IE of 0.3 +/- 0.5 (+/- SD); those graded as mild, 2.8 +/- 1.7; those as moderate, 10.7 +/- 7.2; and those graded as indicative of severe rejection, 14.2 +/- 4.5. Thus, scintigraphy with indium-111-labeled lymphocytes sensitively and specifically detects cardiac allograft rejection and delineates the intensity of the rejection process. It should be useful clinically for assessing potential allograft rejection noninvasively.

  5. Acute cardiac injury after subarachnoid haemorrhage: two case reports.

    PubMed

    Marcì, Marcello; Savatteri, Paolino; Pizzuto, Antonino; Giammona, Giuseppe; Renda, Baldassare; Lojacono, Francesca; Sanfilippo, Nicola

    2009-12-09

    It is well known that cardiopulmonary complications are often associated to subarachnoid haemorrhage. For appropriate therapeutic managing it is very important to distinguish acute coronary syndrome from neurogenic myocardial injury, which is a reversible condition. Furthermore, because the hearts of brain dead patients may be utilized for therapeutic purpose, it has became of importance to rule out erroneous diagnosis of cardiac ischemia in order to avoid rejection of hearts potential suitable for transplantation.We present a report of two female patients affected by cardiac complications caused by aneurismal subarachnoid haemorrhage admitted to our neurosurgical intensive care department.

  6. Acute kidney injury after pediatric cardiac surgery

    PubMed Central

    Singh, Sarvesh Pal

    2016-01-01

    Acute kidney injury is a common complication after pediatric cardiac surgery. The definition, staging, risk factors, biomarkers and management of acute kidney injury in children is detailed in the following review article. PMID:27052074

  7. Cardiac Rehabilitation After Acute Myocardial Infarction Resuscitated From Cardiac Arrest

    PubMed Central

    Kim, Chul; Choi, Hee Eun; Kang, Seong Hoon

    2014-01-01

    Objective To examine the safety and effectiveness of cardiac rehabilitation on patients resuscitated from cardiac arrest due to acute myocardial infarction. Methods The study included 23 subjects, including 8 with history of cardiac arrest and 15 without history of cardiac arrest. Both groups underwent initial graded exercise test (GXT) and subsequent cardiac rehabilitation for 6 weeks. After 6 weeks, both groups received follow-up GXT. Results Statistically significant (p<0.05) increase of VO2peak and maximal MVO2 but significant (p<0.05) decrease of submaximal MVO2 and resting heart rate were observed in both groups after 6 weeks of cardiac rehabilitation. An increasing trend of maximal heart rates was observed in both groups. However, the increase was not statistically significant (p>0.05). There was no statistically significant change of resting heart rate, maximal heart rate, maximal MVO2, or submaximal MVO2 in both groups after cardiac rehabilitation. Fatal cardiac complications, such as abnormal ECG, cardiac arrest, death or myocardial infarction, were not observed. All subjects finished the cardiac rehabilitation program. Conclusion Improvement was observed in the exercise capacity of patients after aerobic exercise throughout the cardiac rehabilitation program. Therefore, cardiac rehabilitation can be safely administered for high-risk patients with history of cardiac arrest. Similar improvement in exercise capacity can be expected in patients without cardiac arrest experience. PMID:25566479

  8. Detection of rejection of canine orthotopic cardiac allografts with indium-111 lymphocytes and gamma scintigraphy

    SciTech Connect

    Eisen, H.J.; Rosenbloom, M.; Laschinger, J.C.; Saffitz, J.E.; Cox, J.L.; Sobel, B.E.; Bolman, R.M. III; Bergmann, S.R.

    1988-07-01

    Previous studies have demonstrated the feasibility of detecting canine heterotopic cardiac allograft rejection scintigraphically after administration of 111In lymphocytes. To determine whether the approach is capable of detecting rejection in orthotopic cardiac transplants in which labeled lymphocytes circulating in the blood pool may reduce sensitivity, the present study was performed in which canine orthotopic cardiac transplants were evaluated in vivo. Immunosuppression was maintained with cyclosporine A (10-20 mg/kg/day) and prednisone (1 mg/kg/day) for 2 wk after transplantation. Subsequently, therapy was tapered. Five successful allografts were evaluated scintigraphically every 3 days after administration of 100-350 microCi 111In autologous lymphocytes. Correction for labeled lymphocytes circulating in the blood pool, but not actively sequestered in the allografts was accomplished by administering 3-6 mCi 99mTc autologous erythrocytes and employing a previously validated blood-pool activity correction technique. Cardiac infiltration of labeled lymphocytes was quantified as percent indium excess (%IE), scintigraphically detectable 111In in the transplant compared with that in blood, and results were compared with those of concomitantly performed endomyocardial biopsy. Scintigraphic %IE for hearts not undergoing rejection manifest histologically was 0.7 +/- 0.4. Percent IE for rejecting hearts was 6.8 +/- 4.0 (p less than 0.05). Scintigraphy detected each episode of rejection detected by biopsy. Scintigraphic criteria for rejection (%IE greater than 2 s.d. above normal) were not manifest in any study in which biopsies did not show rejection. Since scintigraphic results with 111In-labeled lymphocytes were concordant with biopsy results in orthotopic cardiac transplants, noninvasive detection of graft rejection in patients should be attainable with the approach developed.

  9. Autoantibodies to Vimentin Cause Accelerated Rejection of Cardiac Allografts

    PubMed Central

    Mahesh, Balakrishnan; Leong, Hon-Sing; McCormack, Ann; Sarathchandra, Padmini; Holder, Angela; Rose, Marlene L.

    2007-01-01

    Autoimmune responses to vimentin occur after solid organ transplantation, but their pathogenic effects are unclear. The aim of these studies was to investigate the effects of vimentin preimmunization on allogeneic and isografted hearts in a murine transplant model. Immunization of C57BL/6 mice with murine vimentin in complete Freund’s adjuvant resulted in anti-vimentin antibodies and vimentin-reactive Th-1 cells. Transplantation of 129/sv hearts into vimentin-immunized C57BL/6 recipients resulted in accelerated rejection (8.4 ± 1.5 days; n = 18), compared with hen egg lysozyme-immunized C57BL/6 (13.3 ± 2.2 days; n = 10; P < 0.0001, log-rank test). In contrast, isografts continued to beat beyond 90 days. Immunohistochemical analysis of allografts from vimentin/complete Freund’s adjuvant mice demonstrated increased numbers of T cells and enhanced microvascular deposition of C3d, CD41, and P-selectin compared with controls. Antibodies were necessary for accelerated rejection, shown by the fact that vimentin-immunized B-cell-deficient IgH6 mice did not show accelerated rejection of 129/sv allografts, but rejection was restored by adoptive transfer of serum containing anti-vimentin antibodies. Eluates from donor hearts placed in vimentin/complete Freund’s adjuvant recipients contained anti-vimentin antibodies, shown by Western blotting. Confocal imaging of rejected hearts demonstrated presence of vimentin and C3d on apoptosed leukocytes, endothelial cells, and platelet/leukocyte conjugates. These results demonstrate that autoantibodies to vimentin, in conjunction with the alloimmune response, have a pathogenic role in allograft rejection. PMID:17392180

  10. Peer Rejection Cues Induce Cardiac Slowing after Transition into Adolescence

    ERIC Educational Resources Information Center

    Gunther Moor, Bregtje; Bos, Marieke G. N.; Crone, Eveline A.; van der Molen, Maurits W.

    2014-01-01

    The present study examined developmental and gender differences in sensitivity to peer rejection across the transition into adolescence by examining beat-by-beat heart rate responses. Children between the ages of 8 and 14 years were presented with unfamiliar faces of age-matched peers and were asked to predict whether they would be liked by the…

  11. Peer Rejection Cues Induce Cardiac Slowing after Transition into Adolescence

    ERIC Educational Resources Information Center

    Gunther Moor, Bregtje; Bos, Marieke G. N.; Crone, Eveline A.; van der Molen, Maurits W.

    2014-01-01

    The present study examined developmental and gender differences in sensitivity to peer rejection across the transition into adolescence by examining beat-by-beat heart rate responses. Children between the ages of 8 and 14 years were presented with unfamiliar faces of age-matched peers and were asked to predict whether they would be liked by the…

  12. [Incidence of acute rejection in patients with renal graft dysfunction].

    PubMed

    Alberú-Gómez, Josefina; Hernández-Méndez, Erick Alejandro; Oropeza-Barrera, Ingrid; Dávila-Castro, José Juan; Sánchez-Cedillo, Aczel; Navarro-Vargas, Luis; Noriega-Salas, Lorena; Vilatobá-Chapa, Mario; Gabilondo-Pliego, Bernardo; Contreras-Saldívar, Alan; Uribe-Uribe, Norma; Morales-Buenrostro, Luis Eduardo

    2013-01-01

    Acute rejection has been identified as the main cause of renal graft dysfunction during the first year after transplantation; it is associated with chronic structural and functional damage, which causes loss of graft and decrease in patient survival. We performed a retrospective and descriptive research consisting in a review of the final reports of biopsies performed due to renal graft dysfunction during the postransplant period. Patients included were transplanted at the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) from January 2007 to December 2011. A total number of 223 patients underwent renal transplantation during the period considered for this study purpose, 222 biopsies were performed due to renal graft dysfunction in 118 patients (52.9%). 74.5% of patients developed graft dysfunction in the first year after transplantation. The main histopathological findings reported were immunologic events in both living donor (LDRTR) and deceased donor renal transplant recipients (DDRTR), borderline changes were the most common diagnosis. The median time to detect immune events as cause of dysfunction was shorter for DDRTR and they tend to occur in the first 4 months after transplantation. We observed an incidence of 11.8% for acute rejection in the first year after transplantation for LDRTR and 17.4% for DDRTR. Further studies are needed to determine the causes of immunological events and their implications in the evolution of renal graft and patient's survival.

  13. Ocular and cardiac artifact rejection for real-time analysis in MEG.

    PubMed

    Breuer, Lukas; Dammers, Jürgen; Roberts, Timothy P L; Shah, N Jon

    2014-08-15

    Recently, magnetoencephalography (MEG) based real-time brain computing interfaces (BCI) have been developed to enable novel and promising methods for neuroscience research. It is well known that artifact rejection prior to source localization largely enhances the localization accuracy. However, many BCI approaches neglect real-time artifact removal due to its time consuming process. The method (referred to as ocular and cardiac artifact rejection for real-time analysis, OCARTA) is based on constrained independent component analysis (cICA), where a priori information of the underlying source signals is used to optimize and accelerate signal decomposition. Thereby, prior information is incorporated by using the subject's individual cardiac and ocular activity. The algorithm automatically uses different separation strategies depending on the underlying source activity. OCARTA was tested and applied to data from three different but most commonly used MEG systems (4D-Neuroimaging, VSM MedTech Inc. and Elekta Neuromag). Ocular and cardiac artifacts were effectively reduced within one iteration at a time delay of 1ms performed on a standard PC (Intel Core i5-2410M). The artifact rejection results achieved with OCARTA are in line with the results reported for offline ICA-based artifact rejection methods. Due to the fast and subject-specific signal decomposition the new approach introduced here is capable of real-time ocular and cardiac artifact rejection. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Antimyosin monoclonal antibodies for early detection of cardiac allograft rejection

    SciTech Connect

    Schuetz, A.; Fritsch, S.; Kemkes, B.M.; Kugler, C.; Angermann, C.; Spes, C.; Anthuber, M.; Weiler, A.; Wenke, K.; Gokel, J.M. )

    1990-11-01

    Sixty-eight indium 111-labeled antimyosin Fab-DTPA imaging studies (0.5 mg intravenously with a radioactivity of 65 to 75 MBq) were executed on 37 of 116 patients undergoing heart transplantation to assess diagnostic accuracy and clinical utility. As controls, 21 patients with cardiomyopathy (n = 8), unstable angina (n = 9), and myocardial infarction (n = 4) were selected. After 48 hours, single photon emission computed tomographic images were evaluated visually, and heart/lung ratios were measured, using the region of interest technique. They were compared with echocardiographic and endomyocardial biopsy results. In 40 studies a heart/lung ratio less than or equal to 1.6 corresponded to a negative biopsy result in 98% (40/41). Echocardiography enabled correct identification of 95% of the patients with normal biopsy findings. In 91% (22/24) a positive biopsy finding correlated with a heart/lung ratio greater than 1.6 including 20 mild rejections, but in only 64%, with an increase in wall thickness and/or decrease of fractional diameter shortening seen on echocardiogram. In addition, the various stages of rejection episodes determined the amount of the heart-lung ratio. There was a significant relationship between the histologic findings and the antimyosin uptake. In 13 patients a second investigation was performed after rejection therapy. All patients had a negative biopsy result, and the heart/lung ratio decreased to normal ranges (less than or equal to 1.6). Five antimyosin antibody studies were excluded, as in these cases, negative uptake results were found during rejection therapy with high-dose steroids. The overall sensitivity was calculated at 93% and the specificity at 98%.

  15. 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

  16. Noninvasive assessment of treatment of cardiac allograft rejection with indium-111-labeled lymphocytes

    SciTech Connect

    Rosenbloom, M.; Eisen, H.J.; Laschinger, J.; Saffitz, J.E.; Sobel, B.E.; Bergmann, S.R.; Bolman, R.M. III

    1988-09-01

    We have shown previously that cardiac allograft rejection can be detected noninvasively with gamma scintigraphy after administration of indium-111 (111In)-labeled lymphocytes. To determine whether this technique could be used to monitor salvage immunosuppressive therapy in reversing rejection, 5 dogs were studied after thoracic heterotopic cardiac transplantation. Initial postoperative immunosuppression was maintained with cyclosporine (10-20 mg/kg/day) and prednisone (1 mg/kg/day) for 7 days after transplantation and then discontinued. Scintigraphy after administration of labeled lymphocytes was performed during initial immunosuppression and every 3 days after its termination. Endomyocardial biopsies were obtained on each day scintigraphy was performed. Once scintigraphic criteria for rejection were met (111In-lymphocyte uptake greater than mean +/- 2SD of normal myocardium), animals were treated with high dose methylprednisolone and cyclosporine. Myocardial 111In-lymphocyte activity compared with that in blood was 0.7 +/- 0.8 during initial immunosuppression, increased to 5.7 +/- 3.5 after termination of therapy (P less than 0.01), and diminished with salvage immunosuppressive therapy to 0.5 +/- 0.8 (P = NS compared with native hearts or allografts during initial immunosuppression). Scintigraphy accurately predicted all but one episode of biopsy-documented rejection and accurately detected reversal of rejection during salvage. Thus, scintigraphy with 111In-labeled lymphocytes should facilitate noninvasive monitoring of antirejection therapy in patients.

  17. Confocal Scanning Microscopy in Assessment of Cardiac Allograft Rejection--A Pilot Study.

    PubMed

    White, R; Crossman, D J; Isaacson, M; Gibbs, H; Ruygrok, P N

    2015-10-01

    Cardiac allograft rejection is typically diagnosed on the basis of hematoxylin and eosin (H&E) histology of endomyocardial biopsies. This diagnosis is made based on the degree of immune cell infiltrate and associated myocyte damage. However, considerable variability in rejection grading between pathologists can occur. Confocal microscopy provides high contrast and high resolution imaging that has the potential to provide detailed views of pathological features of allograft rejection. In this pilot study we sought to determine if confocal microscopy could be used to detect features of cardiac rejection. This was achieved by collection of additional sample at 30 biopsy procedures from 15 heart transplant patients. Routine pathological grading of H&E histology identified 5 gradings of 0R, 21 gradings of 1R, and 3 gradings of 2R. From these gradings, 3 samples for 0R, 9 samples for 1R, and 3 samples for 2R were imaged by confocal microscopy. This was achieved by fluorescently labeling sections with DAPI, wheat germ agglutinin, and phalloidin, to visualize the cell nuclei, cell border and extracellular matrix, and muscle cell actin, respectively. Labeling with these fluorescent markers was of high contrast. However, we did note variability in DAPI and phalloidin labeling of tissue sections. Confocal imaging of these labels revealed the following features at high resolution: perivascular and/or interstitial infiltrate, myocyte damage, and Quilty lesions. In particular increased detail of damaged myocytes reveals distortion in myofilament organization that could be exploited to distinguish between 1R and 2R grades. In conclusion, confocal microscopy provided high contrast and resolution imaging of cardiac biopsies that could be explored further to aid assessment of cardiac allograft rejection. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. 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

  19. Histopathologic insights into the mechanism of anti-non-Gal antibody-mediated pig cardiac xenograft rejection

    PubMed Central

    Byrne, Guerard W; Azimzadeh, Agnes M; Ezzelarab, Mohamed; Tazelaar, Henry D; Ekser, Burcin; Pierson, Richard N; Robson, Simon C; Cooper, David K C; McGregor, Christopher G A

    2013-01-01

    The histopathology of cardiac xenograft rejection has evolved over the last 20 yr with the development of new modalities for limiting antibody-mediated injury, advancing regimens for immune suppression, and an ever-widening variety of new donor genetics. These new technologies have helped us progress from what was once an overwhelming anti-Gal-mediated hyperacute rejection to a more protracted anti-Gal-mediated vascular rejection to what is now a more complex manifestation of non-Gal humoral rejection and coagulation dysregulation. This review summarizes the changing histopathology of Gal- and non-Gal-mediated cardiac xenograft rejection and discusses the contributions of immune-mediated injury, species-specific immune-independent factors, transplant and therapeutic procedures, and donor genetics to the overall mechanism(s) of cardiac xenograft rejection. PMID:25098626

  20. Gene expression profiling and cardiac allograft rejection monitoring: is IMAGE just a mirage?

    PubMed

    Mehra, Mandeep R; Parameshwar, Jayan

    2010-06-01

    The search for an effective non-invasive monitoring technique for cardiac allograft rejection eluded us until the discovery and validation of a commercially available gene-based peripheral blood bio-signature signal. The Invasive Monitoring Attenuation through Gene Expression (IMAGE) trial tested the hypothesis of cardiac biopsy minimization using this gene-based panel in stable, low-risk survivors, late after cardiac transplantation and demonstrated non-inferiority of this strategy. We present a clinician's critical perspective on this important effort and outline the key caveats and highlights for the potential way forward in using these results. Furthermore, we contend that it may not be necessary to replace an invasive cardiac biopsy strategy with anything other than better standardized clinical and functional allograft vigilance in low-risk survivors. Copyright 2010 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  1. De novo expression of fetal ED-A(+) fibronectin and B (+) tenascin-C splicing variants in human cardiac allografts: potential impact for targeted therapy of rejection.

    PubMed

    Franz, Marcus; Matusiak-Brückner, Monika; Richter, Petra; Grün, Katja; Ziffels, Barbara; Neri, Dario; Maschek, Hansjörg; Schulz, Uwe; Pfeil, Alexander; Jung, Christian; Figulla, Hans R; Gummert, Jan; Berndt, Alexander; Renner, André

    2014-10-01

    Management of acute and especially chronic rejection after human cardiac transplantation is still challenging. Chronic rejection, represented by allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) is known to cause severe long-term complications. Rejection associated tissue-remodelling entails the reoccurrence of fetal variants of Fibronectin (Fn) and Tenascin-C (Tn-C), which are virtually absent in adult human organs. In a rat model, an extensive re-expression could be demonstrated for ED-A(+) Fn with spatial association to CAV and CIF. Thus, it is of great interest to investigate the cardiac tissue expression and distribution in human samples. From 48 heart transplanted patients, 64 tissue specimens derived from right ventricular biopsies were available. Histopathological analysis was performed according to the International Society for Heart and Lung Transplantation (ISHLT) guidelines for the detection of acute rejection. By immunohistochemistry, protein expression of ED-A(+) Fn, B(+) Tn-C, alpha-smooth muscle actin, CD31 and CD45 was assessed and analysed semiquantitatively. Co-localisation studies were performed by means of immunofluorescence double labelling. Histopathological analysis of the 64 samples revealed different ISHLT grades (0R in 36 cases, 1R in 20 cases and 2R in 8 cases). There was a distinct and quantitatively relevant re-occurrence of ED-A(+) Fn and B(+) Tn-C in most samples. Semi-quantitative evaluation did not show any correlation to the acute rejection grade for all markers. Interestingly, significant correlations to the extent of inflammation could be shown for ED-A(+) Fn (r = 0.442, p = 0.000) and B(+) Tn-C (r = 0.408, p = 0.001) as well as between both proteins (r = 0.663, p = 0.000). A spatial association of ED-A(+) Fn and B(+) Tn-C to CAV and CIF could be demonstrated. A relevant re-occurrence of ED-A(+) Fn and B(+) Tn-C following human heart transplantation could be demonstrated with spatial association to

  2. Delayed xenograft rejection of pig-to-baboon cardiac transplants after cobra venom factor therapy.

    PubMed

    Kobayashi, T; Taniguchi, S; Neethling, F A; Rose, A G; Hancock, W W; Ye, Y; Niekrasz, M; Kosanke, S; Wright, L J; White, D J; Cooper, D K

    1997-11-15

    This study sought to (i) investigate the efficacy of cobra venom factor (CVF) in preventing hyperacute rejection (HAR) after pig-to-baboon heart transplantation, (ii) examine the effect of additional splenectomy (Spx) and pharmacologic immunosuppression (IS), and (iii) study delayed graft rejection when HAR is avoided by complement depletion. Eleven recipient baboons received heterotopic pig heart transplants. Three received either no therapy or IS (cyclosporine + methylprednisolone +/- cyclophosphamide +/- methotrexate) at clinically well-tolerated doses, with graft survival for only 40, 32, and 15 min, respectively. Two received CVF+/-Spx, which extended survival to 5 and 6 days, respectively. Six underwent Spx + CVF therapy + IS; graft survival was 3 hr (technical complication), 6 days (death from sepsis), 10, 12, and 22 days (vascular rejection), and <25 days (euthanized for viral pneumonia with a functioning graft that showed histopathologic features of vascular rejection). Dense deposition of IgM and, to a lesser extent, IgG and IgA were seen on the endothelial cells within 1 hr of transplantation, but only trace levels of complement deposition were present in CVF-treated recipients. Within approximately 5-12 days, cardiac xenografts showed progressive infiltration by mononuclear cells, consisting primarily of activated macrophages producing tumor necrosis factor-alpha and small numbers of natural killer cells; T and B cells were absent. We conclude that (i) CVF prevents HAR, (ii) the addition of Spx + IS delays rejection, but (iii) the early deposition of antibody leads to progressive graft injury, resulting in (iv) delayed vascular rejection. Our findings indicate that the features of delayed xenograft rejection described in small animal models also occur in the pig-to-baboon model, and that rejection may occur in a complement-independent manner from the effects of antibody and/or host macrophages.

  3. Human CD55 Expression Blocks Hyperacute Rejection and Restricts Complement Activation in Gal Knockout Cardiac Xenografts

    PubMed Central

    McGregor, Christopher G.A.; Ricci, Davide; Miyagi, Naoto; Stalboerger, Paul G.; Du, Zeji; Oehler, Elise A.; Tazelaar, Henry D.; Byrne, Guerard W.

    2012-01-01

    Background Transgenic expression of human complement regulatory proteins (hCRPs) reduces the frequency of hyperacute rejection (HAR) in Gal-positive cardiac xenotransplantation. In this study we examine the impact of human CD55 (hCD55) expression on a Gal knock-out (GTKO) background using pig-to-primate heterotopic cardiac xenotransplantation. Methods Cardiac xenotransplantation was performed with GTKO (Group 1; n=6) and GTKO.hCD55 (Group 2; n=5) donor pigs using similar immunosuppression. Cardiac biopsies were obtained 30 minutes after organ reperfusion. Rejection was characterized by histology and immunohistology. Intragraft gene expression, serum non-Gal antibody and antibody recovered from rejected hearts were analyzed. Results HAR of a GTKO heart was observed. Remaining grafts developed delayed xenograft rejection. Median survival was 21 and 28 days for Groups 1 and 2 respectively. Vascular antibody deposition was uniformly detected 30 minutes after organ reperfusion and at explant. A higher frequency of vascular C5b deposition was seen in GTKO organs at explant. Serum non-Gal antibody, antibody recovered from the graft and intragraft gene expression were similar between the groups. Conclusion HAR of GTKO hearts without hCD55 may occur. Expression of hCD55 appeared to restrict local complement activation, but did not improve graft survival. Chronic vascular antibody deposition with evidence of protracted endothelial cell activation was seen. These observations suggest that non-Gal antibody-induced chronic endothelial cell activation coupled to possible haemostatic incompatibilities may be the primary stimulus for DXR of GTKO hearts. To avoid possible HAR, future clinical studies should employ donors expressing hCRPs in the GTKO background. PMID:22391577

  4. Gene-based bio-signature patterns and cardiac allograft rejection.

    PubMed

    Mehra, Mandeep R; Uber, Patricia A; Benitez, Roberto M

    2010-01-01

    Clinicians have long awaited an alternative to invasive endomyocardial biopsy for surveillance of cardiac transplant rejection. Transcriptional signals in peripheral blood mononuclear cells allow for the development of multigene-based panels that can inform on the presence or absence of immunologic quiescence. The informative genes represent several biologic pathways, including T-cell activation (PDCD1), T-cell migration (ITGA4), and mobilization of hematopoietic precursors (WDR40A and microRNA gene family cMIR), and steroid-responsive genes such as IL1R2, the decoy receptor for interleukin 2. The greatest value may include the ability to inform on the potential of future proclivity for rejection, allowing patients to be stratified into low, intermediate, or high risk subsets for future rejection. In these individuals, this knowledge may allow clinicians to use tailored approaches to immunosuppression, thereby avoiding adverse pharmacologic effects in low-risk patients while improving rejection outcomes in those at high risk for future allograft compromise. Despite these advances, clinical entrenchment of gene-based pharmacotherapy in cardiac transplantation will require independent replication and validation of investigational findings.

  5. Late antibody-mediated rejection after heart transplantation: Mortality, graft function, and fulminant cardiac allograft vasculopathy.

    PubMed

    Coutance, Guillaume; Ouldamar, Salima; Rouvier, Philippe; Saheb, Samir; Suberbielle, Caroline; Bréchot, Nicolas; Hariri, Sarah; Lebreton, Guillaume; Leprince, Pascal; Varnous, Shaida

    2015-08-01

    Late antibody-mediated rejection (AMR) after heart transplantation is suspected to be associated with a poor short-term prognosis. A retrospective single-center observational study was performed. Late AMR was defined as AMR occurring at least 1 year after heart transplantation. The study included all consecutive patients with proven and treated late acute AMR at the authors' institution between November 2006 and February 2013. The aim was to analyze the prognosis after late AMR, including mortality, recurrence of AMR, left ventricular ejection fraction, and cardiac allograft vasculopathy (CAV). Selected endomyocardial biopsy specimens obtained before AMR were also blindly reviewed to identify early histologic signs of AMR. The study included 20 patients treated for late AMR. Despite aggressive immunosuppressive therapies (100% of patients received intravenous methylprednisolone, 90% received intravenous immunoglobulin [IVIg],85% received plasmapheresis, 45% received rituximab), the prognosis remained poor. Survival after late AMR was 80% at 1 month, 60% at 3 months, and 50% at 1 year. All early deaths (<3 months, n = 8) were directly attributable to graft dysfunction or to complication of the intense immunosuppressive regimen. Among survivors at 3 months (n = 12), histologic persistence or recurrence of AMR, persistent left ventricular dysfunction, and fulminant CAV were common (33%, 33%, and 17% of patients). Microvascular inflammation was detected in at least 1 biopsy specimen obtained before AMR in 13 patients (65%). Prognosis after late AMR is poor despite aggressive immunosuppressive therapies. Fulminant CAV is a common condition in these patients. Microvascular inflammation is frequent in endomyocardial biopsy specimens before manifestation of symptomatic AMR. Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  6. Indium-111 antimyosin scintigraphy to assess myocardial damage in patients with suspected myocarditis and cardiac rejection

    SciTech Connect

    Carrio, I.; Berna, L.; Ballester, M.; Estorch, M.; Obrador, D.; Cladellas, M.; Abadal, L.; Ginjaume, M.

    1988-12-01

    Indium-111 antimyosin scans were used to assess myocardial damage in patients with suspected myocarditis and cardiac transplant rejection. The calculation of a myocardium to lung ratio (AM index) to quantify antimyosin uptake was performed. AM index in normal subjects (n = 8) at 48 hr postinjection was 1.46 +/- 0.04. In patients with suspected myocarditis (16 studies in 13 patients), AM index was 2.0 +/- 0.5 (p less than 0.001); suggesting a considerable incidence of ongoing cell damage in this group, despite the small proportion of positive right ventricular endomyocardial biopsy (RVbx) (4/13). In patients studied after cardiac transplantation (37 studies in 17 patients), AM indexes correlated with RVbx. In patients with RVbx proven rejection (n = 14), AM index was 1.87 +/- 0.19 (p less than 0.001). In patients with RVbx showing infiltrates but not myocyte damage (n = 13), AM index was 1.80 +/- 0.27 (p = 0.02). In patients with normal RVbx (n = 10), AM index was 1.56 +/- 0.17 (p = NS versus controls; p = 0.001 versus those with positive RVbx). Calculated AM indexes correlated with graded visual analysis of the scans (r = 0.823; p = 0.001). Antimyosin scans are an appropriate method to assess myocardial damage in patients with suspected myocarditis and cardiac rejection.

  7. Computational Chemical Imaging for Cardiovascular Pathology: Chemical Microscopic Imaging Accurately Determines Cardiac Transplant Rejection

    PubMed Central

    Tiwari, Saumya; Reddy, Vijaya B.; Bhargava, Rohit; Raman, Jaishankar

    2015-01-01

    Rejection is a common problem after cardiac transplants leading to significant number of adverse events and deaths, particularly in the first year of transplantation. The gold standard to identify rejection is endomyocardial biopsy. This technique is complex, cumbersome and requires a lot of expertise in the correct interpretation of stained biopsy sections. Traditional histopathology cannot be used actively or quickly during cardiac interventions or surgery. Our objective was to develop a stain-less approach using an emerging technology, Fourier transform infrared (FT-IR) spectroscopic imaging to identify different components of cardiac tissue by their chemical and molecular basis aided by computer recognition, rather than by visual examination using optical microscopy. We studied this technique in assessment of cardiac transplant rejection to evaluate efficacy in an example of complex cardiovascular pathology. We recorded data from human cardiac transplant patients’ biopsies, used a Bayesian classification protocol and developed a visualization scheme to observe chemical differences without the need of stains or human supervision. Using receiver operating characteristic curves, we observed probabilities of detection greater than 95% for four out of five histological classes at 10% probability of false alarm at the cellular level while correctly identifying samples with the hallmarks of the immune response in all cases. The efficacy of manual examination can be significantly increased by observing the inherent biochemical changes in tissues, which enables us to achieve greater diagnostic confidence in an automated, label-free manner. We developed a computational pathology system that gives high contrast images and seems superior to traditional staining procedures. This study is a prelude to the development of real time in situ imaging systems, which can assist interventionists and surgeons actively during procedures. PMID:25932912

  8. Metabonomic analysis of rats with acute heart rejection.

    PubMed

    Tao, M; Xiu, D R

    2013-03-01

    Organs transplantation is an effective treatment for end-stage organ failure. Despite the use of modern immunosuppressants to decrease its incidence, acute rejection episodes (ARE), still present a problem for diagnosis, resolution, and prediction of long-term outcomes due to the absence of sufficiently robust biomarkers. Using an heterotopic heart transplantation model using Dark Agouti to Lewis rats, and sirolimus (rapamycin, Rapa) treatment by gavage, we divided recipients into four groups: controls, ARE, Rapa-14, and Rapa-7. We evaluated recipients by hematoxylin and eosin staining of grafts and reverse transcription polymerase chain reactions. Levels of plasma metabolites were quantified using gas chromatography/time-of-flight mass spectrometry. Data were evaluated employing partial least-squares discriminant analysis (PLS-DA), the area under the receiver operating characteristic curves with negative predictive values (NPV) and positive predictive values (PPV). The graft survival was prolonged by Rapa. Plasma levels of 10 metabolites differed significantly between the ARE and the Rapa-14 groups as illustrated by the total ion current. According to PLS-DA, proline, glycine, serine, phenylalanine, and isocitrate showed the greatest effects with areas under the curve of 0.944, 0.917, 1.0, 0.861, and 0.944 respectively. The NPV values were 85.7%, 85.7%, 100%, 83.3%, and 85.7% and PPV values, 100%, 100%, 100%, 83.3%, and 100% respectively. Therefore, these metabolites may be used to predict the occurrence and progression of ARE. The trend of changes suggested that plasma metabolites correlated with the immune state of recipients. Therefore, metabonomics may provide new biomarkers for graft injury in the early phases of ARE. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

  9. Nerve Regeneration in Rat Limb Allografts: Evaluation of Acute Rejection Rescue

    PubMed Central

    Yan, Ying; MacEwan, Matthew R.; Hunter, Daniel A.; Farber, Scott; Newton, Piyaraj; Tung, Thomas H.; Mackinnon, Susan E.; Johnson, Philip J.

    2013-01-01

    Background Successful nerve regeneration is critical to the functional success of composite tissue allografts (CTA). The present study was designed to characterize the effect of acute rejection on nerve regeneration and functional recovery in the setting of orthotopic limb transplantation. Methods A rat orthotopic limb transplantation model was used to evaluate the effects of acute rejection on nerve regeneration and motor recovery. Continuous administration of FK506 (Full suppression), administration of FK506 for the first 8 of 12 weeks (Late rejection), or delayed administration of FK506 / dexamethasone following noticeable rejection (Early rejection) was used to preclude or induce rejection following limb transplantation. Twelve weeks postoperatively, nerve regeneration was assessed via histomorphometric analysis of explanted sciatic nerve, and motor recovery was assessed via evoked muscle force measurement in extensor digitorum longus (EDL) muscle. Results A single episode of acute rejection that occurs immediately or late after reconstruction does not significantly alter the number of regenerating axonal fibers. Acute rejection occurring late after reconstruction adversely affects EDL muscle function in CTA. Conclusion Collected data reinforces that adequate immunosuppressant administration in cases of allogeneic limb transplantation ensures levels of nerve regeneration and motor functional recovery equivalent to that of syngeneic transplants. Prompt rescue following acute rejection was further demonstrated not to significantly affect nerve regeneration and functional recovery post-operatively. However, instances of acute rejection that occur late after reconstruction affect graft function. In total, the present study begins to characterize the effect of immunosuppression regimens on nerve regeneration and motor recovery in the setting of CTA. PMID:23542267

  10. Acute rejection, T-cell-depleting antibodies, and cancer after transplantation.

    PubMed

    Lim, Wai H; Turner, Robin M; Chapman, Jeremy R; Ma, Maggie K M; Webster, Angela C; Craig, Jonathan C; Wong, Germaine

    2014-04-27

    Systemic inflammatory response has been shown to play a vital role in carcinogenesis and tumor progression. Acute rejection is a systemic inflammatory state and may share a common casual pathway for cancer development after transplantation. The increased burden of immunosuppression used in the treatment of acute rejection, particularly the use of T-cell-depleting antibody may further heighten the risk of cancer development. We aimed to determine the association between acute rejection, T-cell-depleting antibody use and cancer risk after kidney transplantation. Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the risk of incident cancer among those who had experienced rejection stratified by the use of T-cell-depleting antibody using adjusted Cox proportional hazard and competing risk models. A total of 7153 kidney transplant recipients between 1997 and 2009 were included. A total of 467 (6.5%) recipients developed cancers. Recipients who experienced acute rejection and treated with T-cell-depleting antibody were at a 1.4-fold increased risk of cancer (adjusted hazard ratio [HR] 1.42, 95% CI 1.02-1.99, P=0.039) compared with those who did not experience acute rejection. There was an excess risk of genitourinary tract cancers among recipients who had experienced rejection requiring T-cell-depleting antibody compared with recipients who did not experience acute rejection (HR 2.20, 95% CI 1.33-3.66, P=0.007). Acute rejection requiring T-cell-depleting antibody is a significant risk factor for cancer development in kidney transplant recipients independent of competing events such as age and cardiovascular deaths.

  11. 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.

  12. Pretransplant thymic function predicts acute rejection in antithymocyte globulin-treated renal transplant recipients.

    PubMed

    Bamoulid, Jamal; Courivaud, Cécile; Crepin, Thomas; Carron, Clémence; Gaiffe, Emilie; Roubiou, Caroline; Laheurte, Caroline; Moulin, Bruno; Frimat, Luc; Rieu, Philippe; Mousson, Christiane; Durrbach, Antoine; Heng, Anne-Elisabeth; Rebibou, Jean-Michel; Saas, Philippe; Ducloux, Didier

    2016-05-01

    Lack of clear identification of patients at high risk of acute rejection hampers the ability to individualize immunosuppressive therapy. Here we studied whether thymic function may predict acute rejection in antithymocyte globulin (ATG)-treated renal transplant recipients in 482 patients prospectively studied during the first year post-transplant of which 86 patients experienced acute rejection. Only CD45RA(+)CD31(+)CD4(+) T cell (recent thymic emigrant [RTE]) frequency (RTE%) was marginally associated with acute rejection in the whole population. This T-cell subset accounts for 26% of CD4(+) T cells. Pretransplant RTE% was significantly associated with acute rejection in ATG-treated patients (hazard ratio, 1.04; 95% confidence interval, 1.01-1.08) for each increased percent in RTE/CD4(+) T cells), but not in anti-CD25 monoclonal (αCD25 mAb)-treated patients. Acute rejection was significantly more frequent in ATG-treated patients with high pretransplant RTE% (31.2% vs. 16.4%) or absolute number of RTE/mm(3) (31.7 vs. 16.1). This difference was not found in αCD25 monclonal antibody-treated patients. Highest values of both RTE% (>31%, hazard ratio, 2.50; 95% confidence interval, 1.09-5.74) and RTE/mm(3) (>200/mm(3), hazard ratio, 3.71; 95% confidence interval, 1.59-8.70) were predictive of acute rejection in ATG-treated patients but not in patients having received αCD25 monoclonal antibody). Results were confirmed in a retrospective cohort using T-cell receptor excision circle levels as a marker of thymic function. Thus, pretransplant thymic function predicts acute rejection in ATG-treated patients. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  13. Acute respiratory distress syndrome after cardiac surgery

    PubMed Central

    Rong, Lisa Q.; Di Franco, Antonino

    2016-01-01

    Acute respiratory distress syndrome (ARDS) is a leading cause of postoperative respiratory failure, with a mortality rate approaching 40% in the general population and 80% in the subset of patients undergoing cardiac surgery. The increased risk of ARDS in these patients has traditionally been associated with the use of cardiopulmonary bypass (CPB), the need for blood product transfusions, large volume shifts, mechanical ventilation and direct surgical insult. Indeed, the impact of ARDS in the cardiac population is substantial, affecting not only survival but also in-hospital length of stay and long-term physical and psychological morbidity. No patient undergoing cardiac surgery can be considered ARDS risk-free. Early identification of those at higher risk is crucial to warrant the adoption of both surgical and non-surgical specific preventative strategies. The present review focuses on epidemiology, risk assessment, pathophysiology, prevention and management of ARDS in the specific setting of patients undergoing cardiac surgery. PMID:27867583

  14. 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.

  15. 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

  16. Identification of barriers that impede the implementation of nicotine replacement therapy in the acute cardiac care setting.

    PubMed

    May, Fiona C; Stocks, Nigel; Barton, Christopher

    2008-12-01

    Nicotine replacement therapy (NRT) has been shown to increase 12-month abstinence rates by as much as 50% when compared with placebo; however, NRT seems to be underutilized in the acute cardiac setting. This study explores the attitudes and beliefs of healthcare professionals regarding the use of NRT in acute cardiac inpatients, in an effort to identify and expose barriers that may impede the use of this drug in the acute cardiac care environment. Framework analysis formed the methodological foundation of the study and provided the structure for analysis of data generated via qualitative, semistructured one-on-one interviews. A purposive sample of healthcare professionals practicing in the acute cardiac care setting informed the study. Although health care professionals expressed strong views regarding the benefits of implementing NRT as a smoking cessation intervention, barriers were identified that hinder its use. Financial implications, lack of knowledge and safety issues all contributed to the institutional justification for rejecting hospital-based NRT as a secondary prevention intervention in the acute cardiac setting. To proactively reduce the incidence of secondary cardiac events, education of healthcare professionals concerning tobacco addiction and available cessation treatments in the acute cardiac patient is paramount. Nicotine replacement products require further investigation to ascertain their safety and financial viability in the acute cardiac setting. Findings may support the implementation of NRT in the inpatient cardiac setting, and ultimately help curb the incidence of smoking-related mortality owing to secondary cardiac events.

  17. 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

  18. Acute emotional stress and cardiac arrhythmias.

    PubMed

    Ziegelstein, Roy C

    2007-07-18

    Episodes of acute emotional stress can have significant adverse effects on the heart. Acute emotional stress can produce left ventricular contractile dysfunction, myocardial ischemia, or disturbances of cardiac rhythm. Although these abnormalities are often only transient, their consequences can be gravely damaging and sometimes fatal. Despite the many descriptions of catastrophic cardiovascular events in the setting of acute emotional stress, the anatomical substrate and physiological pathways by which emotional stress triggers cardiovascular events are only now being characterized, aided by the advent of functional neuroimaging. Recent evidence indicates that asymmetric brain activity is particularly important in making the heart more susceptible to ventricular arrhythmias. Lateralization of cerebral activity during emotional stress may stimulate the heart asymmetrically and produce areas of inhomogeneous repolarization that create electrical instability and facilitate the development of cardiac arrhythmias. Patients with ischemic heart disease who survive an episode of sudden cardiac death in the setting of acute emotional stress should receive a beta-blocker. Nonpharmacological approaches to manage emotional stress in patients with and without coronary artery disease, including social support, relaxation therapy, yoga, meditation, controlled slow breathing, and biofeedback, are also appropriate to consider and merit additional investigation in randomized trials.

  19. Comparison of Acute Rejection in Sensitized (“Domino”) and Unsensitized Donor Hearts following Heterotopic Transplantation

    PubMed Central

    Schuetz, Albert; Breuer, Martin; Engelhardt, Michael; Brandl, Ulrike; Hammer, Claus; Kemkes, Bernhard M.

    1991-01-01

    Right cervical heart transplantation was performed in 18 mongrel dogs. Three experimental groups (6 dogs in each) were set up. Group I and II dogs received unsensitized donor hearts, while Group III dogs received the potentially sensitized native hearts of Group I and II dogs, following final rejection episodes in those animals. We call the transplantation of a native heart out of a previous recipient “domino” transplantation. Immunosuppression consisted of standard triple-drug therapy in all dogs. Groups II and III received, additionally, high-dose steroids during acute rejection episodes. The donor hearts were assessed daily via transmural biventricular biopsy (graded according to Billingham's criteria), and these results were compared with results of daily cytoimmunologic monitoring (n=259 for activation-index), used as a noninvasive method. Supplementally, antimyosin scintigraphy (n=25, heart-to-lung ratio) was employed for rejection diagnosis. The rejection type was determined by calculating T-cell/B-cell ratios with the aid of fluorescein-conjugated monoclonal antibodies. The invasive data consisted of 587 transmyocardial biopsy results, which were used to establish the rejection kinetics. In the domino grafts of Group III, acute rejection had an earlier onset (an average of 3.2 days) and was permanent, despite repeated cortisonepulse therapy. In contrast, acute rejection followed a biphasic course in Group II (average rejection-free interval, 6.8 days) and was non-uniform in Group I (onset after an average of 5.7 days). Cytoimmunologic monitoring corresponded significantly (p < 0.001) with daily histologic findings in Groups I and II, but not with those in Group III (domino grafts). The T-cell/B-cell ratio increased in Groups I and II (to an average of 3.9), as would be expected during acute cellular rejection. In contrast, the T-cell/B-cell ratio decreased in Group III (to an average of 1.1). The heart-to-lung ratio, as determined by antimyosin

  20. Aminoaciduria as a marker of acute renal transplant rejection--a patient study.

    PubMed

    Macpherson, N A; Moscarello, M A; Goldberg, D M; Ish-Shalom, N; Arbus, G S

    1991-04-01

    Over 12 months, urine samples were systematically collected from 40 children who underwent renal transplantation for the treatment of end-stage renal disease. Sequential determinations of the excretion of individual amino acids relative to that of creatinine were carried out on 15 subjects. Nine of these (including three who sustained episodes of acute rejection) retained a native kidney in-situ, while in six patients (including three who underwent an episode of acute rejection) both native kidneys had been removed. In both subgroups, the amino acid/creatinine ratios of early morning urine samples were higher shortly before clinical manifestations of acute rejection became evident than in patients who, following renal transplantation, had stable kidney function, chronic graft rejection, or acute tubular necrosis, with one exception: a patient with one native kidney in-situ in whom acute tubular necrosis developed immediately after transplantation. The amino acids showing the greatest increase included Thr, Ser, Gly, and Ala. These values fell dramatically immediately prior to the clinical episode of acute rejection, with Thr, Ala, and Phe showing the most consistent changes. These alterations in urinary amino acid excretion occurred several days before changes in urinary protein excretion or the serum concentrations of urea and creatinine, and may have a role to play in the monitoring of renal transplant recipients.

  1. Molecular Assessment of Microcirculation Injury in Formalin-Fixed Human Cardiac Allograft Biopsies With Antibody-Mediated Rejection.

    PubMed

    Afzali, B; Chapman, E; Racapé, M; Adam, B; Bruneval, P; Gil, F; Kim, D; Hidalgo, L; Campbell, P; Sis, B; Duong Van Huyen, J P; Mengel, M

    2017-02-01

    Precise diagnosis of antibody-mediated rejection (AMR) in cardiac allograft endomyocardial biopsies (EMBs) remains challenging. This study assessed molecular diagnostics in human EMBs with AMR. A set of 34 endothelial, natural killer cell and inflammatory genes was quantified in 106 formalin-fixed, paraffin-embedded EMBs classified according to 2013 International Society for Heart and Lung Transplantation (ISHLT) criteria. The gene set expression was compared between ISHLT diagnoses and correlated with donor-specific antibody (DSA), endothelial injury by electron microscopy (EM) and prognosis. Findings were validated in an independent set of 57 EMBs. In the training set (n = 106), AMR cases (n = 70) showed higher gene set expression than acute cellular rejection (ACR; n = 21, p < 0.001) and controls (n = 15, p < 0.0001). Anti-HLA DSA positivity was associated with higher gene set expression (p = 0.01). Endothelial injury by electron microscopy strongly correlated with gene set expression, specifically in AMR cases (r = 0.62, p = 0.002). Receiver operating characteristic curve analysis for diagnosing AMR showed greater accuracy with gene set expression (area under the curve [AUC] = 79.88) than with DSA (AUC = 70.47) and C4d (AUC = 70.71). In AMR patients (n = 17) with sequential biopsies, increasing gene set expression was associated with inferior prognosis (p = 0.034). These findings were confirmed in the validation set. In conclusion, biopsy-based molecular assessment of antibody-mediated microcirculation injury has the potential to improve diagnosis of AMR in human cardiac transplants.

  2. 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.

  3. Chronic cardiac allograft rejection: critical role of ED-A(+) fibronectin and implications for targeted therapy strategies.

    PubMed

    Franz, Marcus; Neri, Dario; Berndt, Alexander

    2012-03-01

    Chronic cardiac allograft rejection is characterized by cardiac allograft vasculopathy (CAV) and cardiac interstitial fibrosis (CIF) causing severe long-term complications after heart transplantation and determining allograft function and patients' prognosis. Until now, there have been no sufficient preventive or therapeutic strategies. CAV and CIF are accompanied by changes in the extracellular matrix, including re-expression of the fetal fibronectin splice variant known as ED-A(+) fibronectin. This molecule has been shown to be crucial for the development of myofibroblasts (MyoFbs) as the main cell type in CIF and for the activation of vascular smooth muscle cells (VSMCs) as the main cell type in CAV. Relevant re-expression and protein deposition of ED-A(+) fibronectin has been demonstrated in animal models of chronic rejection, with spatial association to CAV and CIF, and a quantitative correlation to the rejection grade. The paper by Booth et al published in this issue of The Journal of Pathology could prove for the first time the functional importance of ED-A(+) fibronectin for the development of CIF as a main component of chronic cardiac rejection. Thus, promising conclusions for the development of new diagnostic, preventive, and therapeutic strategies for chronic cardiac rejection focusing on ED-A(+) fibronectin can be suggested.

  4. Immunosuppression in cardiac graft rejection: A human in vitro model to study the potential use of new immunomodulatory drugs

    SciTech Connect

    Crescioli, Clara Squecco, Roberta; Cosmi, Lorenzo; Sottili, Mariangela; Gelmini, Stefania; Borgogni, Elisa; Sarchielli, Erica; Scolletta, Sabino; Francini, Fabio; Annunziato, Francesco; Vannelli, Gabriella Barbara; Serio, Mario

    2008-04-01

    CXCL10-CXCR3 axis plays a pivotal role in cardiac allograft rejection, so that targeting CXCL10 without inducing generalized immunosuppression may be of therapeutic significance in allotransplantation. Since the role of resident cells in cardiac rejection is still unclear, we aimed to establish reliable human cardiomyocyte cultures to investigate Th1 cytokine-mediated response in allograft rejection. We used human fetal cardiomyocytes (Hfcm) isolated from fetal hearts, obtained after legal abortions. Hfcm expressed specific cardiac lineage markers, specific cardiac structural proteins, typical cardiac currents and generated ventricular action potentials. Thus, Hfcm represent a reliable in vitro tool for allograft rejection research, since they resemble the features of mature cells. Hfcm secreted CXCL10 in response to IFN{gamma} and TNF{alpha}{alpha}; this effect was magnified by cytokine combination. Cytokine synergy was associated to a significant TNF{alpha}-induced up-regulation of IFN{gamma}R. The response of Hfcm to some currently used immunosuppressive drugs compared to rosiglitazone, a peroxisome proliferator-activated receptor {gamma} agonist and Th1-mediated response inhibitor, was also evaluated. Only micophenolic acid and rosiglitazone halved CXCL10 secretion by Hfcm. Given the pivotal role of IFN{gamma}-induced chemokines in Th1-mediated allograft rejection, these preliminary results suggest that the combined effects of immunosuppressive agents and rosiglitazone could be potentially beneficial to patients receiving heart transplants.

  5. Profiling immunologic risk for acute rejection in liver transplantation: Recipient age is an important risk factor.

    PubMed

    Kueht, Michael L; Cotton, Ronald T; Galvan, N Thao N; O'Mahony, Christine A; Goss, John A; Rana, Abbas

    2016-09-01

    Careful management of induction and maintenance of immunosuppression is paramount to prevent acute rejection in liver transplantation. A methodical analysis of risk factors for acute cellular rejection may provide a more comprehensive method to profile the immunologic risk of candidates. Using registry data from the Organ Procurement and Transplantation Network (OPTN), we identified 42,508 adult recipients who underwent orthotopic liver transplant (OLT) between 2002 and 2013. We excluded recipients with a blank entry for treated rejection. We analyzed this all inclusive cohort in addition to a subset of 27,493 patients with just tacrolimus immunosuppression. Multivariate logistic regression was used on both cohorts and identified independent risk factors for treated acute rejection at one year. Recipient age (reference group was 40 to 60years) was a dominant risk factor for rejection in both cohorts and had a dose response relationship. The strongest risk factors in the inclusive cohort were: age 18-25 (OR 2.20), age 26-29 (OR 2.03), and primary biliary cholangitis (OR 1.55). The most protective factors were age 70 and older (OR 0.68), and age 65-69 (OR 0.70). The rates of rejection had a similar pattern. Although prior studies have suggested age as a risk factor for rejection in liver transplantation, this is the first study of national-level data to demonstrate a robust dose dependent relationship between age and risk for rejection at one year. Clinicians should place significant weight on recipient age when they assess their recipients for the immunologic risk of rejection. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Intragraft Toll-like receptor profiling in acute renal allograft rejection.

    PubMed

    Dessing, Mark C; Bemelman, Frederike J; Claessen, Nike; Ten Berge, Ineke J M; Florquin, Sandrine; Leemans, Jaklien C

    2010-12-01

    Experimental studies have shown potential for Toll-like receptor (TLR) profiling in renal allograft in predicting renal outcome after transplantation. Our goal was to determine if profiling of TLR1-10 and TLR-related genes could be used as a prognostic value for renal function and late clinical outcome after transplantation. TLR1-10, CD14, MD-2 and negative regulators Toll-interacting protein (TOLLIP) and single immunoglobulin domain IL-1R-related receptor were analysed in 36 biopsies from renal transplant recipients with acute rejection (AR) and in 14 biopsies from renal transplant recipients without rejection (NR). Analysis was performed by multiplex ligation-dependent probe amplification. TLR (-related) genes were correlated to Banff'07 classification, cellular influx, response to conventional anti-rejection therapy, renal function 12 and 24 months after rejection and graft loss. mRNA levels of most TLRs were significantly higher in acute rejection while TOLLIP mRNA level was decreased. mRNA levels of TLR1/2/4/7/8 were highly accurate in distinguishing AR from NR. TLR mRNA levels correlated to inflammatory parameters according to the Banff'07 classification and to cellular influx. Elevated mRNA level of TLR3 in acute rejection was independent from infiltrating leukocytes. TLR (-related) genes were not correlated with response to conventional anti-rejection therapy. Splice variant TLR4r3 was associated with poor renal function 24 months after transplantation, and TLR1 appeared to be associated with graft loss. The elevated mRNA levels of several TLRs in association with reduced mRNA levels of TOLLIP in renal transplant biopsies of patients with acute rejection indicate a pro-inflammatory state, which may contribute to uncontrolled inflammation.

  7. 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

  8. 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

  9. Laughter as a social rejection cue: gelotophobia and transient cardiac responses to other persons' laughter and insult.

    PubMed

    Papousek, Ilona; Aydin, Nilüfer; Lackner, Helmut K; Weiss, Elisabeth M; Bühner, Markus; Schulter, Günter; Charlesworth, Canice; Freudenthaler, H Harald

    2014-11-01

    Other persons' laughter, normally perceived as a signal that persons are friendly and inviting others to approach, can also be perceived as a cue of social rejection. In this study, prerecorded laughter was placed in a realistic and personally relevant context, and participants' responses were related to gelotophobia, a trait predisposing to perceiving laughter as a cue of social rejection. Individuals with gelotophobia showed marked heart rate deceleration in response to the laughter stimulus, possibly indicating a "freezing-like" response. Moreover, cardiac responses to anger provocation by overtly insulting statements indicated heightened aggressive anger in response to cumulated social threat. The study adds to recent research showing specific cardiac responses to social rejection and to the literature on social rejection sensitivity by demonstrating the value of using well interpretable physiological measures in this research context.

  10. Fetal cardiac cine imaging using highly accelerated dynamic MRI with retrospective motion correction and outlier rejection.

    PubMed

    van Amerom, Joshua F P; Lloyd, David F A; Price, Anthony N; Kuklisova Murgasova, Maria; Aljabar, Paul; Malik, Shaihan J; Lohezic, Maelene; Rutherford, Mary A; Pushparajah, Kuberan; Razavi, Reza; Hajnal, Joseph V

    2017-04-03

    Development of a MRI acquisition and reconstruction strategy to depict fetal cardiac anatomy in the presence of maternal and fetal motion. The proposed strategy involves i) acquisition and reconstruction of highly accelerated dynamic MRI, followed by image-based ii) cardiac synchronization, iii) motion correction, iv) outlier rejection, and finally v) cardiac cine reconstruction. Postprocessing entirely was automated, aside from a user-defined region of interest delineating the fetal heart. The method was evaluated in 30 mid- to late gestational age singleton pregnancies scanned without maternal breath-hold. The combination of complementary acquisition/reconstruction and correction/rejection steps in the pipeline served to improve the quality of the reconstructed 2D cine images, resulting in increased visibility of small, dynamic anatomical features. Artifact-free cine images successfully were produced in 36 of 39 acquired data sets; prolonged general fetal movements precluded processing of the remaining three data sets. The proposed method shows promise as a motion-tolerant framework to enable further detail in MRI studies of the fetal heart and great vessels. Processing data in image-space allowed for spatial and temporal operations to be applied to the fetal heart in isolation, separate from extraneous changes elsewhere in the field of view. Magn Reson Med, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.

  11. 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

  12. Inflammatory triggers of acute rejection of organ allografts.

    PubMed

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

    2014-03-01

    Solid organ transplantation is a vital therapy for end stage diseases. Decades of research have established that 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. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. 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

  14. Delta Neutrophil Index as a Marker for Differential Diagnosis between Acute Graft Pyelonephritis and Acute Graft Rejection

    PubMed Central

    Shin, Dong Ho; Kim, Eun Jung; Kim, Soo Jin; Park, Ji-Young; Oh, Jieun

    2015-01-01

    Introduction The delta neutrophil index (DNI) is the fraction of circulating immature granulocytes, which reflect infectious and/or septic condition. Acute graft pyelonephritis (AGPN) versus acute graft rejection is a frequently encountered diagnostic and therapeutic dilemma in kidney transplant recipients, but little is known about the clinical usefulness of DNI value in the differentiation of the two conditions. Material & Methods A total of 90 episodes of AGPN or acute graft rejection were evaluated at the Kangdong Sacred Heart Hospital between 2008 and 2014. We performed retrospective analysis of demographic, clinical, and laboratory parameters data. Receiver operating curves (ROC) and multivariate logistic regression were conducted to ascertain the utility of DNI in discriminating between AGPN and acute graft rejection. Results AGPN group had significantly higher DNI values than acute graft rejection group (2.9% vs. 1.9%, P < 0.001). The area under the ROC curve for DNI value to discriminate between AGPN and acute graft rejection was 0.85 (95% confidence interval [CI]; 0.76–0.92, P < 0.001). A DNI value of 2.7% was selected as the cut-off value for AGPN, and kidney transplant recipients with a DNI value ≥ 2.7% were found to be at a higher risk of infection than those with a DNI < 2.7% (odd ratio [OR] 40.50; 95% CI 8.68–189.08; P < 0.001). In a multivariate logistic regression analysis, DNI was a significant independent factor for predicting AGPN after adjusting age, sex, log WBC count, log neutorphil count, log lymphocyte count, CRP concentration, and procalcitonin concentration (OR 4.32; 95% CI 1.81–10.34, P < 0.001). Conclusions This study showed that DNI was an effective marker to differentiate between AGPN and acute graft rejection. Thus, these finding suggest that DNI may be a useful marker in the management of these patients. PMID:26275220

  15. Prolonged ischemia elicits acute allograft rejection involved in CXCR3 activation in rat kidney transplants.

    PubMed

    Zou, Xun-feng; Song, Bin; Duan, Ji-hui; Hu, Zhan-dong; Cui, Zi-lin; Gu, Chuan

    2015-10-01

    Acute rejection is a major obstacle in patients with prolonged ischemia in deceased-donor renal transplantation. Chemokines and their receptors play a critical role in leukocyte trafficking, resulting in allograft rejection; therefore, the role of chemokine receptor CXCR3 in acute rejection induced by prolonged ischemia in rat kidney transplantation models was evaluated. Syngeneic and allogeneic renal transplantations were performed. For cold ischemia, grafts were stored in 4.0°C University of Wisconsin solution for 12 or 16 h. Serum and renal tissues were harvested 7.0 d after surgery and serum TNF-α, IL-6, and renal function were measured. Graft histology was stained with periodic acid-Schiff and immunohistochemical staining and further evaluated for signs of acute rejection. CXCR3 proteins were quantified by Western blot. The transplanted rats were divided into 4 groups as follows: iso-12-h = isogeneic transplant with 12-h CIT graft; iso-16-h = isogeneic kidney transplant with 16-h CIT graft; allo-12-h = allogeneic renal transplant with 12-h CIT graft; allo-16 h = allogeneic renal transplant with 16-h CIT graft; and 16 h+T = allogeneic 16-h CIT graft received tacrolimus. Prolonged cold ischemia time (CIT; 16 h) enhanced acute glomerular damage, interstitial inflammation, and tubulointerstitial cellular infiltration in allografts with and without immunosuppressant tacrolimus; but it was not apparent in the isografts. The expression of CXCR3 protein and the proportion of CXCR3-positive cells were significantly higher in the allo-16 h and 16 h +T groups than that in the allo-12 h group 7d post-surgery. CIT triggered acute rejection in allogeneic, but not in isogeneic, kidney transplants, accompanied by an elevation of leukocyte recruitment and damaged graft function. The upregulated expression of chemokine receptor CXCR3 promoted inflammatory infiltration and acute allograft rejection. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Cardiac Surgery-Associated Acute Kidney Injury

    PubMed Central

    Mao, Huijuan; Katz, Nevin; Ariyanon, Wassawon; Blanca-Martos, Lourdes; Adýbelli, Zelal; Giuliani, Anna; Danesi, Tommaso Hinna; Kim, Jeong Chul; Nayak, Akash; Neri, Mauro; Virzi, Grazia Maria; Brocca, Alessandra; Scalzotto, Elisa; Salvador, Loris; Ronco, Claudio

    2013-01-01

    Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious postoperative complication of cardiac surgery requiring cardiopulmonary bypass (CPB), and it is the second most common cause of AKI in the intensive care unit. Although the complication has been associated with the use of CPB, the etiology is likely multifactorial and related to intraoperative and early postoperative management including pharmacologic therapy. To date, very little evidence from randomized trials supporting specific interventions to protect from or prevent AKI in broad cardiac surgery populations has been found. The definition of AKI employed by investigators influences not only the incidence of CSA-AKI, but also the identification of risk variables. The advent of novel biomarkers of kidney injury has the potential to facilitate the subclinical diagnosis of CSA-AKI, the assessment of its severity and prognosis, and the early institution of interventions to prevent or reduce kidney damage. Further studies are needed to determine how to optimize cardiac surgical procedures, CPB parameters, and intraoperative and early postoperative blood pressure and renal blood flow to reduce the risk of CSA-AKI. No pharmacologic strategy has demonstrated clear efficacy in the prevention of CSA-AKI; however, some agents, such as the natriuretic peptide nesiritide and the dopamine agonist fenoldopam, have shown promising results in renoprotection. It remains unclear whether CSA-AKI patients can benefit from the early institution of such pharmacologic agents or the early initiation of renal replacement therapy. PMID:24454314

  17. Three-Dimensional Speckle-Tracking Echocardiographic Monitoring of Acute Rejection in Heart Transplant Recipients.

    PubMed

    Du, Guo-Qing; Hsiung, Ming-Chon; Wu, Yan; Qu, Shao-Hui; Wei, Jeng; Yin, Wei-Hsian; Tian, Jia-Wei

    2016-06-01

    This study assessed the use of 3-dimensional (3D) speckle-tracking echocardiography for noninvasive monitoring and diagnosis of acute rejection in heart transplant recipients. Fifteen heart transplant recipients underwent 32 endomyocardial biopsies; echocardiography was performed within 3 hours before biopsy. Twenty-four biopsies (acute rejection-negative group) showed grade 0 or 1A rejection, and 8 biopsies (acute rejection-positive group) showed grade 1B or higher rejection (based on the International Society for Heart and Lung Transplantation criteria). Two-dimensional, M-mode, pulsed Doppler, and tissue Doppler echocardiography were performed to assess conventional heart structure and function, and 3D full-volume echocardiography was recorded and analyzed. Global peak longitudinal strain was significantly lower in the acute rejection-negative group compared to the positive group (mean ± SD, -7.38% ± 1.34% versus -10.88% ± 3.81%; P = .017). Differences in left ventricular global peak radial strain (28.79% ± 10.79% versus 24.32% ± 5.24%; P= .272), global peak circumferential strain (-12.16% ± 4.87% versus -12.61% ± 2.38%; P = .806), and ejection fraction (49.42% ± 12.17% versus 50.68% ± 7.26%; P = .824) between the negative and positive groups were not significant. Significant correlations were observed between the left ventricular ejection fraction and global peak longitudinal, global peak radial, and global peak circumferential (r = -0.72; P < .001; r = 0.60; P < 0.001; and r = -0.69; P < 0.001, respectively). Receiver operating characteristic curve analysis showed that a global peak longitudinal strain cutoff value of less than -9.55% could predict grade 1B or higher rejection with sensitivity of 87.50% and specificity of 54.17%. Three-dimensional speckle-tracking echocardiography-derived global peak longitudinal strain is a useful parameter for detecting acute rejection; thus, 3D speckle-tracking echocardiography can monitor dynamic and acute

  18. 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.

  19. 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

  20. Morphologic and immunohistochemical findings in antibody-mediated rejection of the cardiac allograft.

    PubMed

    Fishbein, Gregory A; Fishbein, Michael C

    2012-12-01

    The recognition and acceptance of the entity of antibody-mediated rejection (AMR) of solid organs has been slow to develop. Greatest acceptance and most information relates to cardiac transplantation. AMR is thought to represent antibody/complement mediated injury to the microvasculature of the graft that can result in allograft dysfunction, allograft loss, accelerated graft vasculopathy, and increased mortality. The morphologic hallmark is microvascular injury with immunoglobulin and complement deposition in capillaries, accumulation of intravascular macrophages, and in more severe cases, microvascular hemorrhage and thrombosis, with inflammation and edema of the affected organ. Understanding of the pathogenesis of AMR, criteria and methods for diagnosis, and treatment strategies are still in evolution, and will be addressed in this review.

  1. Profiling risk for acute rejection in kidney transplantation: recipient age is a robust risk factor.

    PubMed

    Rana, Abbas; Murthy, Bhamidipati; Pallister, Zachery; Kueht, Michael; Cotton, Ronald; Galvan, N Thao N; Etheridge, Whiston; Liu, Hau; Goss, John; O'Mahony, Christine

    2016-09-29

    Careful management of immunosuppression is paramount to prevent acute rejection in kidney transplantation. We studied a cohort of 139,875 kidney transplant recipients from the Organ Procurement and Transplantation Network (OPTN) database between 2002 and 2013. We confirmed the analysis with a cohort of 35,277 who received thymoglobulin induction with tacrolimus maintenance, and a third cohort of 12,161 recipients who received basiliximab induction with tacrolimus maintenance. We performed multivariate logistic regression analyses on data from all three cohorts and identified independent risk factors for treated acute rejection at 1 year. Recipient age was a robust risk factor for rejection in all three cohorts in a dose response pattern. Young age (18-25 years) was among the strongest risk factors for rejection in all three cohorts; thymoglobulin cohort: OR 1.87 (1.59-2.19); basiliximab cohort: OR 2.41 (1.89-3.05); and inclusive cohort: OR 1.97 (1.83-2.12). The opposite was true for old age (65-69 years); thymoglobulin cohort: OR 0.69 (0.59-0.81); basiliximab cohort: OR 0.77 (0.62-0.96); and inclusive cohort: OR 0.75 (0.70-0.80). This study is unique because it is the largest and most comprehensive multivariate analysis that demonstrates recipient age is a robust risk factor for acute rejection in an inverse dose response pattern.

  2. A high isoflavone soy protein diet and intravenous genistein delay rejection of rat cardiac allografts.

    PubMed

    O'Connor, Timothy P; Liesen, Daniel A; Mann, Paul C; Rolando, Lori; Banz, William J

    2002-08-01

    Genistein, a soy isoflavone, has in vitro immunosuppressive properties. We investigated whether genistein or dietary soy protein containing isoflavones could influence the outcome of rat cardiac allografts. Lewis rats were fed a diet with protein from high isoflavone soy protein fraction (HIS), casein (CAS) or casein with isoflavones added (CI) starting 1 wk before heart transplants from Wistar Furth donors, and continuing throughout the study. HIS-fed rats had significantly prolonged time to rejection compared with CAS- and CI-fed recipients (10.8 +/- 2.62 vs. 7.18 +/- 0.75 and 7.22 +/- 0.44 d, P < 0.001). Intravenous genistein [20mg/(kg. d) for 14 d] significantly prolonged heart survival compared with controls and dissolvent-treated recipients (23.2 +/- 7.4 vs. 8.4 +/- 1.3 and 11.4+/3.6 d, P < 0.0005), and had an additive effect when given to heart recipients also receiving low dose cyclosporine for 7 d (30.8 +/- 2.3 vs. 23.4 +/- 2.4 d, P < 0.005). Concanavalin A-stimulated lymphocytes, isolated from Lewis rats given intraperitoneal genistein for 7 d, had decreased production of interferon gamma compared with controls or dimethyl sulfoxide-treated groups (22.6 +/- 9.9 vs 149 +/- 105 and 154 +/- 103 micro g/L, P < 0.05). In conclusion, a high isoflavone soy diet and intravenous genistein, but not isoflavone extract alone, delay rejection of rat cardiac allografts, with an additive effect in cyclosporine-treated rats. In addition, intraperitoneal genistein has immunosuppressive properties in vivo.

  3. Anti-rejection effect of ethanol extract of Poria cocos wolf in rats after cardiac allograft implantation.

    PubMed

    Zhang, Guo-wei; Liu, Hong-yu; Xia, Qiu-ming; Li, Jun-quan; Lü, Hang; Zhang, Qing-hua; Yao, Zhi-fa

    2004-06-01

    A living fetus within the maternal uterus provides an example of allogene tolerance in mammals. Poria cocos Wolf is the main component of many Chinese medicinal combination drugs that have therapeutic effects on recurrent spontaneous abortion and that can maintain pregnancy until delivery. It was hypothesized that this herbal medicine can also prolong allograft survival after organ transplantation. Here, in an in vivo study, we report the anti-rejection effect of the ethanol extract of Poria cocos Wolf (EEPCW) in rats after cardiac allograft implantation. Ten normal rats were healthy controls. Eighty rats receiving homologous heart transplants were divided into 4 groups of 20 rats each based on type of treatment: olive oil 8 ml.kg(-1).d(-1), EEPCW 25 mg.kg(-1).d(-1), EEPCW 50 mg.kg(-1).d(-1) or cyclosporin A 5 mg.kg(-1).d(-1). Allograft survival was observed in 10 rats from each group. On the seventh day post transplantation, pathological lesions and percentages of CD3+, CD4+, and CD8+ lymphocytes and the CD4+/CD8+ ratio in peripheral blood were assessed in another 10 rats from each group and in 10 normal rats. The survival time of donor hearts in the two EEPCW groups was significantly prolonged, to (15.9 +/- 2.4) days and (30.0 +/- 0.0) days, respectively, compared with (6.7 +/- 0.8) days in the control group. Pathological lesions in the two EEPCW groups were also less severe, and the percentages of CD3+, CD4+, and CD8+ lymphocytes and CD4+/CD8+ ratio were significantly lower in the EEPCW groups. Acute rejection of heart transplants and cellular immune reaction can be effectively suppressed using the EEPCW. Taking advantage of novel immunosuppressants derived from Chinese medicinal herbs used to treat abnormal pregnancy provides a hopeful road for future research and treatment in organ transplantation.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. Acute Kidney Injury Subsequent to Cardiac Surgery

    PubMed Central

    Kramer, Robert S.; Herron, Crystal R.; Groom, Robert C.; Brown, Jeremiah R.

    2015-01-01

    Abstract: Acute kidney injury (AKI) after cardiac surgery is a common and underappreciated syndrome that is associated with poor short- and long-term outcomes. AKI after cardiac surgery may be epiphenomenon, a signal for adverse outcomes by virtue of other affected organ systems, and a consequence of multiple factors. Subtle increases in serum creatinine (SCr) postoperatively, once considered inconsequential, have been shown to reflect a kidney injury that likely occurred in the operating room during cardiopulmonary bypass (CPB) and more often in susceptible individuals. The postoperative elevation in SCr is a delayed signal reflecting the intraoperative injury. Preoperative checklists and the conduct of CPB represent opportunities for prevention of AKI. Newer definitions of AKI provide us with an opportunity to scrutinize perioperative processes of care and determine strategies to decrease the incidence of AKI subsequent to cardiac surgery. Recognizing and mitigating risk factors preoperatively and optimizing intraoperative practices may, in the aggregate, decrease the incidence of AKI. This review explores the pathophysiology of AKI and addresses the features of patients who are the most vulnerable to AKI. Preoperative strategies are discussed with particular attention to a readiness for surgery checklist. Intraoperative strategies include minimizing hemodilution and maximizing oxygen delivery with specific suggestions regarding fluid management and plasma preservation. PMID:26390675

  9. Cardiac Arrhythmias and Abnormal Electrocardiograms After Acute Stroke.

    PubMed

    Ruthirago, Doungporn; Julayanont, Parunyou; Tantrachoti, Pakpoom; Kim, Jongyeol; Nugent, Kenneth

    2016-01-01

    Cardiac arrhythmias and electrocardiogram (ECG) abnormalities occur frequently but are often underrecognized after strokes. Acute ischemic and hemorrhagic strokes in some particular area of brain can disrupt central autonomic control of the heart, precipitating cardiac arrhythmias, ECG abnormalities, myocardial injury and sometimes sudden death. Identification of high-risk patients after acute stroke is important to arrange appropriate cardiac monitoring and effective management of arrhythmias, and to prevent cardiac morbidity and mortality. More studies are needed to better clarify pathogenesis, localization of areas associated with arrhythmias and practical management of arrhythmias and abnormal ECGs after acute stroke.

  10. Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection.

    PubMed Central

    Zhao, X M; Frist, W H; Yeoh, T K; Miller, G G

    1994-01-01

    Accelerated coronary atherosclerosis in cardiac transplants (cardiac allograft vasculopathy, CAV) is characterized by coronary intimal hyperplasia. Acidic fibroblast growth factor (aFGF) is a potent mitogen for vascular smooth muscle cells and endothelial cells, and its expression is increased in cardiac allografts, suggesting it may play a role in the pathogenesis of CAV. The activity of aFGF is dependent on binding to transmembrane receptors. To investigate whether receptors for aFGF are also induced after transplantation, polymerase chain reaction, in situ hybridization, and immunohistochemistry were used to analyze expression of four receptors for aFGF (FGFR1-FGFR4). Expression of mRNA encoding extracellular immunoglobulin-like domains of FGFR1 was increased 35-fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures. Alternatively spliced mRNA that encodes transmembrane forms of FGFR1, which contain the signal-transducing tyrosine kinase domains, was induced in allografts during rejection, in infiltrating cells, vascular structures, and myocytes. In vitro experiments showed that differential expression of FGF receptor isoforms was induced by aFGF, and also by IL-6 and TGF-beta, which are expressed in cardiac allografts during rejection. The results show that expression of both aFGF and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of CAV. Images PMID:7521891

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. Haptoglobin activates innate immunity to enhance acute transplant rejection in mice

    PubMed Central

    Shen, Hua; Song, Yang; Colangelo, Christopher M.; Wu, Terence; Bruce, Can; Scabia, Gaia; Galan, Anjela; Maffei, Margherita; Goldstein, Daniel R.

    2011-01-01

    Immune tolerance to transplanted organs is impaired when the innate immune system is activated in response to the tissue necrosis that occurs during harvesting and implantation procedures. A key molecule in this immune pathway is the intracellular TLR signal adaptor known as myeloid differentiation primary response gene 88 (MyD88). After transplantation, MyD88 induces DC maturation as well as the production of inflammatory mediators, such as IL-6 and TNF-α. However, upstream activators of MyD88 function in response to transplantation have not been identified. Here, we show that haptoglobin, an acute phase protein, is an initiator of this MyD88-dependent inflammatory process in a mouse model of skin transplantation. Necrotic lysates from transplanted skin elicited higher inflammatory responses in DCs than did nontransplanted lysates, suggesting DC-mediated responses are triggered by factors released during transplantation. Analysis of transplanted lysates identified haptoglobin as one of the proteins upregulated during transplantation. Expression of donor haptoglobin enhanced the onset of acute skin transplant rejection, whereas haptoglobin-deficient skin grafts showed delayed acute rejection and antidonor T cell priming in a MyD88-dependent graft rejection model. Thus, our results show that haptoglobin release following skin necrosis contributes to accelerated transplant rejection, with potential implications for the development of localized immunosuppressive therapies. PMID:22156194

  17. Role of major histocompatibility complex and ethnicity in acute renal graft rejection.

    PubMed

    Torres-Machorro, A; Camorlinga-Tagle, N; Rodríguez-Ortiz, C; Palafox, D; González, N; López, M; Castelán, N; de Leo, C; Vilatobá, M; Gabilondo, B; Alberú Gómez, J; Morales-Buenrostro, L; Granados, J

    2010-01-01

    The major histocompatibility complex (MHC) plays a main role in antigen presentation. Class I, II, and III genes form defined "blocks" of conserved DNA sequences (conserved extended haplotypes) that are useful to follow the ancestry of a population. Each variant encodes a specific peptide that determines a particular individual's immune response. In addition, differential expression of HLA antigens in certain physiological and pathological conditions may participate in the pathogenesis of allograft rejection versus tolerance. The aim of this study was to determine whether the specific HLA ancestry was associated with acute renal graft rejection among the Mexican mestizo population. We studied 544 Mexican mestizo renal donors and their respective recipients for their serologically determined HLA and based on antigens haplotype assignments. The acute rejection group was compared with the nonrejection group among donors and recipients, correspondingly. Frequent Mexican alleles were observed in this study. Moreover, HLA-B*61/-DR*04, HLA-A*35/-DR*06 (Amerindian ancestry), HLA-A*68/-DR*01, HLA-A*28/-B*65/-DR*01 (African ancestry), and HLA-A*33/-B*65 (Caucasian ancestry) in donors were associated with acute renal graft rejection episodes. Knowing the ancestry of a donor's HLA molecules may help to individualize immunosuppressive therapy for posttransplant surveillance, because they may be more membrane-exposed in parenchymal cells, making them more susceptible of being recognized by the recipient's immune system. Copyright 2010 Elsevier Inc. All rights reserved.

  18. 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

  19. Cardiac surgery-associated acute kidney injury

    PubMed Central

    Ortega-Loubon, Christian; Fernández-Molina, Manuel; Carrascal-Hinojal, Yolanda; Fulquet-Carreras, Enrique

    2016-01-01

    Cardiac surgery-associated acute kidney injury (CSA-AKI) is a well-recognized complication resulting with the higher morbid-mortality after cardiac surgery. In its most severe form, it increases the odds ratio of operative mortality 3–8-fold, length of stay in the Intensive Care Unit and hospital, and costs of care. Early diagnosis is critical for an optimal treatment of this complication. Just as the identification and correction of preoperative risk factors, the use of prophylactic measures during and after surgery to optimize renal function is essential to improve postoperative morbidity and mortality of these patients. Cardiopulmonary bypass produces an increased in tubular damage markers. Their measurement may be the most sensitive means of early detection of AKI because serum creatinine changes occur 48 h to 7 days after the original insult. Tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 are most promising as an early diagnostic tool. However, the ideal noninvasive, specific, sensitive, reproducible biomarker for the detection of AKI within 24 h is still not found. This article provides a review of the different perspectives of the CSA-AKI, including pathogenesis, risk factors, diagnosis, biomarkers, classification, postoperative management, and treatment. We searched the electronic databases, MEDLINE, PubMed, EMBASE using search terms relevant including pathogenesis, risk factors, diagnosis, biomarkers, classification, postoperative management, and treatment, in order to provide an exhaustive review of the different perspectives of the CSA-AKI. PMID:27716701

  20. 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

  1. Acute methamphetamine exposure inhibits cardiac contractile function.

    PubMed

    Turdi, Subat; Schamber, Robbie M; Roe, Nathan D; Chew, Herbert G; Culver, Bruce; Ren, Jun

    2009-09-10

    Methamphetamine, a commonly seen substance of abuse, has been reported to exert detrimental effect on bodily function including the cardiovascular system although its mechanism of action is poorly understood. This study was designed to examine the direct impact of methamphetamine on isolated whole heart and single cardiomyocyte contractile function. Murine hearts and isolated cardiomyocytes from adult FVB mice were exposed to various concentrations of methamphetamine for 30min prior to the assessment of mechanical function using a Langendroff apparatus and an IonOptix Myocam system, respectively. Cardiac contractile properties analyzed included maximal velocity of left ventricular pressure development and decline (+/-dP/dt), peak shortening amplitude (PS), maximal velocity of shortening/relengthening (+/-dLdt), time-to-PS (TPS), time-to-90% relengthening (TR(90)), resting and electrically stimulated increase of intracellular Ca(2+) as well as intracellular Ca(2+) decay. Our results revealed that acute methamphetamine exposure depressed +/-dP/dt, PS and rise of intracellular Ca(2+) without affecting +/-dLdt, TPS, TR(90), resting intracellular Ca(2+) and intracellular Ca(2+) decay. Furthermore, methamphetamine nullified the adrenergic agonist norepinephrine-elicited positive cardiomyocyte contractile response, including elevated PS, +/-dLdt and shortened TR(90) without affecting TPS. Western blot analysis showed unchanged expression of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban, associated with upregulated Na(+)-Ca(2+) exchanger levels following acute methamphetamine exposure. In addition, methamphetamine promoted overt cardiomyocyte protein damage evaluated by carbonyl formation. Taken together, these results demonstrate direct cardiac depressant effect of methamphetamine in myocardium and isolated cardiomyocytes, possibly associated with protein damage and dampened adrenergic response.

  2. Acute Methamphetamine Exposure Inhibits Cardiac Contractile Function

    PubMed Central

    Turdi, Subat; Schamber, Robbie M.; Roe, Nathan D.; Chew, Herbert G.; Culver, Bruce; Ren, Jun

    2009-01-01

    Methamphetamine, a commonly seen substance of abuse, has been reported to exert detrimental effect on bodily function including the cardiovascular system although its mechanism of action is poorly understood. This study was designed to examine the direct impact of methamphetamine on isolated whole heart and single cardiomyocyte contractile function. Murine hearts and isolated cardiomyocytes from adult FVB mice were exposed to various concentrations of methamphetamine for 30 min prior to the assessment of mechanical function using a Langendroff apparatus and an IonOptix Myocam® system, respectively. Cardiac contractile properties analyzed included maximal velocity of left ventricular pressure development and decline (± dP/dt), peak shortening amplitude (PS), maximal velocity of shortening/relengthening (± dLdt), time-to-PS (TPS), time-to-90% relengthening (TR90), resting and electrically-stimulated increase of intracellular Ca2+ as well as intracellular Ca2+ decay. Our results revealed that acute methamphetamine exposure depressed ± dP/dt, PS and rise of intracellular Ca2+ without affecting ± dLdt, TPS, TR90, resting intracellular Ca2+ and intracellular Ca2+ decay. Furthermore, methamphetamine nullified the adrenergic agonist norepinephrine-elicited positive cardiomyocyte contractile response, including elevated PS, ± dLdt and shortened TR90 without affecting TPS. Western blot analysis showed unchanged expression of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) and phospholamban, associated with upregulated Na+-Ca2+ exchanger levels following acute methamphetamine exposure. In addition, methamphetamine promoted overt cardiomyocyte protein damage evaluated by carbonyl formation. Taken together, these results demonstrate direct cardiac depressant effect of methamphetamine in myocardium and isolated cardiomyocytes, possibly associated with protein damage and dampened adrenergic response. PMID:19481142

  3. 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.

  4. Pretransplant Numbers of CD16(+) Monocytes as a Novel Biomarker to Predict Acute Rejection After Kidney Transplantation: A Pilot Study.

    PubMed

    van den Bosch, T P P; Hilbrands, L B; Kraaijeveld, R; Litjens, N H R; Rezaee, F; Nieboer, D; Steyerberg, E W; van Gestel, J A; Roelen, D L; Clahsen-van Groningen, M C; Baan, C C; Rowshani, A T

    2017-10-01

    Acute rejection is one of the major immunological determinants of kidney graft function and survival. Early biomarkers to predict rejection are lacking. Emerging evidence reveals a crucial role for the monocyte/macrophage lineage cells in the pathogenesis of rejection. We hypothesized that higher pretransplant numbers of proinflammatory CD16+ monocytes can predict rejection. The study cohort consisted of 104 kidney transplant recipients (58 with no rejection and 46 with biopsy-proven rejection) and 33 healthy persons. Posttransplant median follow-up time was 14.7 mo (interquartile range 0.3-34 mo). Pretransplantation blood samples were analyzed by flow cytometry for monocyte immunophenotypes. Groups were compared by Cox regression models for the occurrence of acute rejection. We documented a significantly increased absolute number of pretransplant CD16+ monocytes in patients who developed biopsy-proven rejection after transplantation compared with those with no rejection (hazard ratio [HR] 1.60, 95% CI 1.28-2.00, p < 0.001) and healthy persons (HR 1.47, 95% CI 1.18-1.82, p < 0.001). In parallel, significantly fewer absolute numbers of CD16- monocytes were observed at pretransplant time points in rejectors versus nonrejectors (HR 0.74, 95% CI 0.58-0.94, p < 0,014). A higher pretransplant number of CD16+ monocytes is significantly associated with a higher risk of acute rejection after kidney transplantation. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

  5. 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.

  6. CD11c+ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A.

    PubMed

    Oberhuber, Rupert; Heinbokel, Timm; Cetina Biefer, Hector Rodriguez; Boenisch, Olaf; Hock, Karin; Bronson, Roderick T; Wilhelm, Markus J; Iwakura, Yoichiro; Edtinger, Karoline; Uehara, Hirofumi; Quante, Markus; Voskuil, Floris; Krenzien, Felix; Slegtenhorst, Bendix; Abdi, Reza; Pratschke, Johann; Elkhal, Abdallah; Tullius, Stefan G

    2015-07-14

    Organ transplantation has seen an increased use of organs from older donors over the past decades in an attempt to meet the globally growing shortage of donor organs. However, inferior transplantation outcomes when older donor organs are used represent a growing challenge. Here, we characterize the impact of donor age on solid-organ transplantation using a murine cardiac transplantation model. We found a compromised graft survival when older hearts were used. Shorter graft survival of older hearts was independent of organ age per se, because chimeric young or old organs repopulated with young passenger leukocytes showed comparable survival times. Transplantation of older organs triggered more potent alloimmune responses via intragraft CD11c+ dendritic cells augmenting CD4+ and CD8+ T-cell proliferation and proinflammatory cytokine production, particularly that of interleukin-17A. Of note, depletion of donor CD11c+ dendritic cells before engraftment, neutralization of interleukin-17A, or transplantation of older hearts into IL-17A(-/-) mice delayed rejection and reduced alloimmune responses to levels observed when young hearts were transplanted. These results demonstrate a critical role of old donor CD11c+ dendritic cells in mounting age-dependent alloimmune responses with an augmented interleukin-17A response in recipient animals. Targeting interleukin-17A may serve as a novel therapeutic approach when older organs are transplanted. © 2015 American Heart Association, Inc.

  7. 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

  8. 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

  9. Role of C1q complement fixing antibody assay in therapeutic plasma exchange management of pediatric cardiac antibody mediated rejection.

    PubMed

    Onwuemene, Oluwatoyosi A; Heath, Deneen M; Hartman, Carol; Wong, Edward C C

    2017-08-01

    Pediatric cardiac transplant patients with antibody-mediated rejection (AMR) often undergo therapeutic plasma exchange (TPE) to remove pathologic donor specific antibodies (DSA). In cases where DSA persist, it is unclear how long TPE should be continued. We report a case of a 17-year-old cardiac transplant patient with AMR where use of a C1q complement fixing antibody assay helped guide TPE cessation. This report adds to the existing literature that highlights the potential clinical significance of C1q antibodies in AMR management. © 2016 Wiley Periodicals, Inc.

  10. Nitrosative stress and corneal transplant endothelial cell death during acute graft rejection.

    PubMed

    Bourges, Jean-Louis; Torriglia, Alicia; Valamanesh, Fatemeh; Benezra, David; Renard, Gilles; Behar-Cohen, Francine F

    2007-08-15

    Nitrosative stress takes place in endothelial cells (EC) during corneal acute graft rejection. The purpose of this study was to evaluate the potential role of peroxynitrite on corneal EC death. The effect of peroxynitrite was evaluated in vivo. Fifty, 250, and 500 microM in 1.5 microL of the natural or denatured peroxynitrite in 50 microM NaOH, 50 microM NaOH alone, or balanced salt solution were injected into the anterior chamber of rat eyes (n=3/group). Corneal toxic signs after injection were assessed by slit-lamp, in vivo confocal imaging, pachymetry, and EC count. The effect of peroxynitrite was also evaluated on nitrotyrosine and leucocyte elastase inhibitor/LDNase II immunohistochemistry. Human corneas were incubated with peroxynitrite and the effect on EC viability was evaluated. A specific inducible nitric oxide synthase inhibitor (iNOS) was administered systemically in rats undergoing allogeneic corneal graft rejection and the effect on EC was evaluated by EC count. Rat eyes receiving as little as 50 microM peroxynitrite showed a specific dose-dependent toxicity on EC. We observed an intense nitrotyrosine staining of human and rat EC exposed to peroxynitrite associated with leucocyte elastase inhibitor nuclear translocation, a noncaspase dependent apoptosis reaction. Specific inhibition of iNOS generation prevented EC death and enhanced EC survival of the grafted corneas. However, inhibition of iNOS did not have a significant influence on the incidence of graft rejection. Nitrosative stress during acute corneal graft rejection in rat eyes induces a noncaspase dependent apoptotic death in EC. Inhibition of nitric oxide production during the corneal graft rejection has protective effects on the corneal EC survival.

  11. 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.

  12. 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.

  13. 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

  14. 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.

  15. 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

  16. B- and T-lymphocyte attenuator/herpes virus entry mediator as early indicators for acute rejection following kidney transplantation.

    PubMed

    Tian, Ch; Liu, Y-G; Yan, J-K; Liu, S-D; Zhao, S-T; Wang, H-W

    2013-01-01

    The objective of this study was to investigate the roles of B- and T-lymphocyte attenuator (BTLA) and herpes virus entry mediator (HVEM) in acute and chronic transplant rejection and immune tolerance. The expression patterns of BTLA/HVEM, interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-γ were analyzed among patients presenting with acute rejection episodes versus those maintaining stable renal function during therapy with mycophenolate mofetil (MMF), cyclosporine, or tacrolimus (FK506) plus prednisolone. The expressions of BTLA/HVEM in the rejection group were obviously increased compared with the stable group (P < .05), followed by the elevation of serum levels of IL-2 and IFN-γ. The expression levels of BTLA/HVEM can be considered to be early indicators of an acute rejection episode following kidney transplantation. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Molecular Classifiers for Acute Kidney Transplant Rejection in Peripheral Blood by Whole Genome Gene Expression Profiling

    PubMed Central

    Kurian, S. M.; Williams, A. N.; Gelbart, T.; Campbell, D.; Mondala, T. S.; Head, S. R.; Horvath, S.; Gaber, L.; Thompson, R.; Whisenant, T.; Lin, W.; Langfelder, P.; Robison, E. H.; Schaffer, R. L.; Fisher, J. S.; Friedewald, J.; Flechner, S. M.; Chan, L. K.; Wiseman, A. C.; Shidban, H.; Mendez, R.; Heilman, R.; Abecassis, M. M.; Marsh, C. L.; Salomon, D. R.

    2015-01-01

    There are no minimally invasive diagnostic metrics for acute kidney transplant rejection (AR), especially in the setting of the common confounding diagnosis, acute dysfunction with no rejection (ADNR). Thus, though kidney transplant biopsies remain the gold standard, they are invasive, have substantial risks, sampling error issues and significant costs and are not suitable for serial monitoring. Global gene expression profiles of 148 peripheral blood samples from transplant patients with excellent function and normal histology (TX; n = 46), AR (n = 63) and ADNR (n = 39), from two independent cohorts were analyzed with DNA microarrays. We applied a new normalization tool, frozen robust multi-array analysis, particularly suitable for clinical diagnostics, multiple prediction tools to discover, refine and validate robust molecular classifiers and we tested a novel one-by-one analysis strategy to model the real clinical application of this test. Multiple three-way classifier tools identified 200 highest value probesets with sensitivity, specificity, positive predictive value, negative predictive value and area under the curve for the validation cohort ranging from 82% to 100%, 76% to 95%, 76% to 95%, 79% to 100%, 84% to 100% and 0.817 to 0.968, respectively. We conclude that peripheral blood gene expression profiling can be used as a minimally invasive tool to accurately reveal TX, AR and ADNR in the setting of acute kidney transplant dysfunction. PMID:24725967

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

    PubMed

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

    2016-11-07

    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.

  19. 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

  20. Cardiac Function Remains Impaired Despite Reversible Cardiac Remodeling after Acute Experimental Viral Myocarditis

    PubMed Central

    Gotzhein, Frauke; Escher, Felicitas; Blankenberg, Stefan; Westermann, Dirk

    2017-01-01

    Background. Infection with Coxsackievirus B3 induces myocarditis. We aimed to compare the acute and chronic phases of viral myocarditis to identify the immediate effects of cardiac inflammation as well as the long-term effects after resolved inflammation on cardiac fibrosis and consequently on cardiac function. Material and Methods. We infected C57BL/6J mice with Coxsackievirus B3 and determined the hemodynamic function 7 as well as 28 days after infection. Subsequently, we analyzed viral burden and viral replication in the cardiac tissue as well as the expression of cytokines and matrix proteins. Furthermore, cardiac fibroblasts were infected with virus to investigate if viral infection alone induces profibrotic signaling. Results. Severe cardiac inflammation was determined and cardiac fibrosis was consistently colocalized with inflammation during the acute phase of myocarditis. Declined cardiac inflammation but no significantly improved hemodynamic function was observed 28 days after infection. Interestingly, cardiac fibrosis declined to basal levels as well. Both cardiac inflammation and fibrosis were reversible, whereas the hemodynamic function remains impaired after healed viral myocarditis in C57BL/6J mice. PMID:28352641

  1. Immunosuppressive therapies after intestinal transplant modulate the expression of Th1 signature genes during acute cellular rejection. Implications in the search for rejection biomarkers.

    PubMed

    Zambernardi, Agustina; Chiodetti, Ana; Meier, Dominik; Cabanne, Ana; Nachman, Fabio; Solar, Héctor; Rumbo, Carolina; Gondolesi, Gabriel E; Rumbo, Martin

    2014-12-01

    Acute cellular rejection (ACR) and infections are leading causes of graft loss and death in intestinal transplant patients. Our aim was to evaluate the impact of maintenance immunosuppressive therapies on the expression of pro-inflammatory mediators in small bowel at ACR diagnosis. We analyzed expression levels of Th1-associated genes, IFNG, CXCL10, and CXCL11 by qPCR in 46 selected graft biopsies unequivocally assigned to mild ACR (n = 14) or normal histopathology and clinical condition (n = 32) from 15 patients receiving two different immunosuppressive (IS) schemes. Double treatment: corticosteroids and tacrolimus (n = 17) and triple treatment: sirolimus or mycophenolate mofetil in addition to the basal therapy (n = 29). IFNG, CXCL10, and CXCL11 were induced during rejection (p < 0.05; p < 0.005, and p < 0.05, respectively). However, when rejection and control groups were classified according to immunosuppressive treatment, in the rejection group, significant differences of IFNG, CXCL10, and CXCL11 expression (p < 0.001; p < 0.005, and 0.01, respectively) were detected, whereas no differences were observed in the control group. Gene expression of Th1 response mediators is higher during ACR. Triple IS group showed significantly lower expression of pro-inflammatory Th1 mediators during mild ACR indicating that use of these markers to monitor rejection can be affected by the IS treatment used. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. 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.

  3. Comparative Analyses of Signature Genes in Acute Rejection and Operational Tolerance.

    PubMed

    Choi, Jeong-Woo; Kim, Yong-Hee; Oh, Ji Won

    2017-08-01

    Using biomarkers as prediction tools or therapeutic targets can be a valuable strategy in transplantation. Recent studies identified biomarkers of acute rejection (AR) and operational tolerance (TOL) through the application of meta-analysis. In this study, we comparatively analyzed the signature genes in acute rejection and operational tolerance seen in human allogeneic transplantations using massive bioinformatical meta-analysis. To identify the signature genes in opposite immunological conditions, AR and TOL, we first collected the 1,252 gene expression data specifically intended for those circumstances. Then we excluded based on biological cut-values, Principal Component Analysis (PCA) as well as Multi-Dimensional Scaling (MDS). Using differentially expressed genes (DEGs) from meta-analysis, we then applied a ranked scoring system to identify the signature genes of AR and TOL. We identified 53 up-regulated and 32 down-regulated signature genes in acute rejection condition. Among them, ISG20, CXCL9, CXCL10, CCL19, FCER1G, PMSE1, UBD are highly expressed in AR condition. In operational tolerance, we identified 110 up-regulated and 48 down-regulated signature genes. TCL1A, BLNK, MS4A1, EBF1, IGHM are up-regulated in TOL condition. These genes are highly representative of AR or TOL across the different organs such as liver, kidney and heart. Since immune response is the sum of complex biological and molecular dynamics, these signature genes as well as pathway analysis using a systems biology approach could be used to catch the insights of the certain pathways that would be overlooked with the conventional gene-level comparative analysis.

  4. 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.

  5. Lactate and lactate clearance in acute cardiac care patients

    PubMed Central

    Lazzeri, Chiara; Picariello, Claudio; Dini, Carlotta Sorini; Gensini, Gian Franco; Valente, Serafina

    2012-01-01

    Hyperlactataemia is commonly used as a diagnostic and prognostic tool in intensive care settings. Recent studies documented that serial lactate measurements over time (or lactate clearance), may be clinically more reliable than lactate absolute value for risk stratification in different pathological conditions. While the negative prognostic role of hyperlactataemia in several critical ill diseases (such as sepsis and trauma) is well established, data in patients with acute cardiac conditions (i.e. acute coronary syndromes) are scarce and controversial. The present paper provides an overview of the current available evidence on the clinical role of lactic acid levels and lactate clearance in acute cardiac settings (acute coronary syndromes, cardiogenic shock, cardiac surgery), focusing on its prognostic role. PMID:24062898

  6. 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.

  7. New law of renal transplantation in Portugal associated with more acute rejection episodes and higher costs.

    PubMed

    Gonçalves, J A; Jorge, C; Atalaia, A; Matias, P; Bruges, M; Birne, R; Dickson, J; Weigert, A; Machado, D

    2012-10-01

    The new law implemented in August 2007 changed the criteria to select renal transplantation (RT) candidates in Portugal, favoring hyperimmunized subjects and those on the waiting list for a longer time, making human leukocyte antigen (HLA) compatibilities less important. The authors compared patients who received a deceased donor kidney between 2005 and 2010. Patients were divided in group A who underwent transplantation before August 2007 (n = 132) and group B (n = 125) after that date. We considered a value of P < .05. Overall mean age at RT was 46.6 ± 13.9 years with 58.8% men, 88% on hemodialysis (HD), with a mean dialysis time of 82.8 ± 119 months. Also, 10.5% of patients underwent a previous transplantation. The mean follow-up was 35 ± 17.1 months. Group B showed significant adverse differences, including dialysis time (50.9 vs. 117 months), length of hospitalization (14.4 vs. 23.2 days), need for HD (1 vs. 3.4 days), HLA match (3.3 vs. 1.4 compatibilities), previous sensitization (4.4% vs. 21.7%), acute rejection episodes in the 1st year (23% vs. 37%), greater use of immunosuppressive drugs, higher costs of induction therapy (2790 vs 4360ϵ), and greater costs of drugs during first hospitalization (3456 vs. 7144ϵ). Among the 16 subjects who lost their grafts, 7 were in group A (3 in the first year) and 9 in group B all in the first year. There was a 5.1% decrease in graft survival at 12 months (P = .07). Univariate analysis showed an association of acute rejection episodes with HLA mismatches, hyperimmunized patients, absence of immediate graft function, hospitalization time, longer HD need, and higher creatinine level at months 1, 2, 3, and 6. Multivariate analysis revealed acute rejection episodes to be associated with a lower number of HLA compatibilities (odds ratio = 0.65; 95% confidence interval, [0.46-0.9]). Application of the law has led to a greater number of acute rejection episodes in the first year and increased costs. Copyright © 2012

  8. 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.

  9. 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

  10. Acute cellular rejection with isolated v-lesions is not associated with more favorable outcomes than vascular rejection with more tubulointerstitial inflammations.

    PubMed

    Wu, K Y; Budde, K; Schmidt, D; Neumayer, H H; Rudolph, B

    2014-04-01

    The impact of isolated v-lesions on clinical outcome in biopsies with acute cellular rejection (ACR) is unclear. Two hundred and sixty-five biopsies showing the highest ACR severity for each patient were recruited and classified into four groups: (i) acute interstitial rejection (AIR) I with minimal tubulointerstitial inflammation (TI), (ii) AIR II with intensive TI, (iii) acute vascular rejection (AVR) I with minimal TI, and (iv) AVR II with intensive TI. The complete reversal rates of AIR I and AIR II groups were marginally higher than AVR I and AVR II groups (p = 0.16). At eight yr of transplantation, the death-censored graft survival (DCGS) rate of AIR I group (93.3%) was significantly higher compared with the AVR I (72.7%) or AVR II (72.9%) group. AVR I group had a similar DCGS rate with AVR II group (72.7% vs. 74.1%), whereas AVR with v1-lesion showed significantly higher graft survival (GS) rate than those with v2-lesion (70.2% vs. 45.5%). The t-lesion of AIR and v-lesion of AVR group were associated with graft loss. The extent of TI is non-specifically associated with graft loss in biopsies with AVR; the higher grade v-lesion predicts the lower complete reversal rate and poorer long-term graft survival. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Neuroanatomical correlates of severe cardiac arrhythmias in acute ischemic stroke.

    PubMed

    Seifert, Frank; Kallmünzer, Bernd; Gutjahr, Isabell; Breuer, Lorenz; Winder, Klemens; Kaschka, Iris; Kloska, Stephan; Doerfler, Arnd; Hilz, Max-Josef; Schwab, Stefan; Köhrmann, Martin

    2015-05-01

    Neurocardiological interactions can cause severe cardiac arrhythmias in patients with acute ischemic stroke. The relationship between the lesion location in the brain and the occurrence of cardiac arrhythmias is still discussed controversially. The aim of the present study was to correlate the lesion location with the occurrence of cardiac arrhythmias in patients with acute ischemic stroke. Cardiac arrhythmias were systematically assessed in patients with acute ischemic stroke during the first 72 h after admission to a monitored stroke unit. Voxel-based lesion-symptom mapping (VLSM) was used to correlate the lesion location with the occurrence of clinically relevant severe arrhythmias. Overall 150 patients, 56 with right-hemispheric and 94 patients with a left-hemispheric lesion, were eligible to be included in the VLSM study. Severe cardiac arrhythmias were present in 49 of these 150 patients (32.7%). We found a significant association (FDR correction, q < 0.05) between lesions in the right insular, right frontal and right parietal cortex as well as the right amygdala, basal ganglia and thalamus and the occurrence of cardiac arrhythmias. Because left- and right-hemispheric lesions were analyzed separately, the significant findings rely on the 56 patients with right-hemispheric lesions. The data indicate that these areas are involved in central autonomic processing and that right-hemispheric lesions located to these areas are associated with an elevated risk for severe cardiac arrhythmias.

  12. 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.

  13. PPAR-γ signaling and IL-5 inhibition together prevent chronic rejection of MHC Class II-mismatched cardiac grafts.

    PubMed

    Chen, Yan; Li, Daxu; Tsang, Julia Yuen Shan; Niu, Na; Peng, Jiao; Zhu, Jiang; Hui, Kenneth; Xu, Aimin; Lui, Vincent Chi Hang; Lamb, Jonathan Robert; Tam, Paul Kwong Hang

    2011-06-01

    Chronic rejection can prevent long-term survival of organ transplants. Although the beneficial effects of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in reducing graft rejection have been reported, the details of the underlying mechanisms remain unclear, especially in the context of modulating cellular infiltration and preventing vasculopathy and interstitial fibrosis. The therapeutic effects of the PPAR-γ agonist, rosiglitazone, combined with anti-interleukin-5 are explored in a mouse model of MHC Class II-histoincompatible cardiac transplantation. Rosiglitazone treatment alone marginally increased long-term survival and reduced CD8 T-cell infiltration and vasculopathy in the grafts. However, there was no reduction in collagen deposition and interleukin (IL)-4, IL-5 and eosinophil infiltration were increased. Anti-IL-5 antibody treatment alone reduced eosinophil infiltration and collagen deposition, but had no effect on CD8 T-cell infiltration or vasculopathy. Combined treatment with anti-IL-5 antibody and rosiglitazone prevented graft rejection. Furthermore, rosiglitazone treatment increased adiponectin receptor II expression in grafts and on dendritic cells and T cells in vitro. Graft survival correlated with increased expression in grafts of the inhibitory molecule PD-L1. The findings obtained increase the knowledge on the mode of action of rosiglitazone in promoting the survival of MHC Class II-mismatched cardiac transplants in which the CD8 T cells and eosinophils play key roles. PPAR-γ signaling combined with IL-5 blockade prevents graft rejection. Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  14. Management of acute severe perioperative failure of cardiac allografts: a single-centre experience with a review of the literature.

    PubMed

    Ibrahim, Moheb; Hendry, Paul; Masters, Roy; Rubens, Fraser; Lam, B-Khanh; Ruel, Marc; Davies, Ross; Haddad, Haissam; Veinot, John P; Mesana, Thierry

    2007-04-01

    Early graft failure is associated with high mortality and is the main cause of death within the first 30 days after transplantation. The purpose of the present study was to examine the investigators' experience of severe perioperative acute graft failure and to review the literature. Nine of 385 cardiac transplants (2.3%) performed from 1984 through 2005 developed severe perioperative acute graft failure either in the operating room or within 24 h after cardiac transplantation. Four patients had primary graft failure, two had right heart failure secondary to pulmonary hypertension, one had hyperacute rejection, one had accelerated acute rejection and one possibly sustained a particulate coronary embolus intraoperatively. All except the two patients who had right heart failure secondary to pulmonary hypertension received mechanical circulatory support. Three patients were supported with total artificial hearts, two patients received a left ventricular assist device, one patient was supported with extracorporeal life support followed by a right ventricular assist device when the left ventricle recovered, and one patient was supported for several hours with cardiopulmonary bypass. Three patients were retransplanted after mechanical circulatory support, but only one survived. Only one of the nine patients (11%) survived; this patient was supported with a total artificial heart followed by retransplantation. The outcome of severe perioperative acute graft failure is very poor. Mechanical circulatory support and retransplantation are not as successful as in other situations. Due to the shortage of donors and poor outcomes, retransplantation for hyperacute rejection is not advisable.

  15. Management of acute severe perioperative failure of cardiac allografts: A single-centre experience with a review of the literature

    PubMed Central

    Ibrahim, Moheb; Hendry, Paul; Masters, Roy; Rubens, Fraser; Lam, B-Khanh; Ruel, Marc; Davies, Ross; Haddad, Haissam; Veinot, John P; Mesana, Thierry

    2007-01-01

    BACKGROUND: Early graft failure is associated with high mortality and is the main cause of death within the first 30 days after transplantation. The purpose of the present study was to examine the investigators’ experience of severe perioperative acute graft failure and to review the literature. METHODS: Nine of 385 cardiac transplants (2.3%) performed from 1984 through 2005 developed severe perioperative acute graft failure either in the operating room or within 24 h after cardiac transplantation. Four patients had primary graft failure, two had right heart failure secondary to pulmonary hypertension, one had hyperacute rejection, one had accelerated acute rejection and one possibly sustained a particulate coronary embolus intraoperatively. RESULTS: All except the two patients who had right heart failure secondary to pulmonary hypertension received mechanical circulatory support. Three patients were supported with total artificial hearts, two patients received a left ventricular assist device, one patient was supported with extracorporeal life support followed by a right ventricular assist device when the left ventricle recovered, and one patient was supported for several hours with cardiopulmonary bypass. Three patients were retransplanted after mechanical circulatory support, but only one survived. Only one of the nine patients (11%) survived; this patient was supported with a total artificial heart followed by retransplantation. CONCLUSION: The outcome of severe perioperative acute graft failure is very poor. Mechanical circulatory support and retransplantation are not as successful as in other situations. Due to the shortage of donors and poor outcomes, retransplantation for hyperacute rejection is not advisable. PMID:17440641

  16. Histopathological analysis of infiltrating T cell subsets in acute T cell-mediated rejection in the kidney transplant.

    PubMed

    Salcido-Ochoa, Francisco; Hue, Susan Swee-Shan; Peng, Siyu; Fan, Zhaoxiang; Li, Reiko Lixiang; Iqbal, Jabed; Allen, John Carson; Loh, Alwin Hwai Liang

    2017-08-24

    To compare the differential immune T cell subset composition in patients with acute T cell-mediated rejection in the kidney transplant with subset composition in the absence of rejection, and to explore the association of their respective immune profiles with kidney transplant outcomes. A pilot cross-sectional histopathological analysis of the immune infiltrate was performed using immunohistochemistry in a cohort of 14 patients with acute T cell-mediated rejection in the kidney transplant and 7 kidney transplant patients with no rejection subjected to biopsy to investigate acute kidney transplant dysfunction. All patients were recruited consecutively from 2012 to 2014 at the Singapore General Hospital. Association of the immune infiltrates with kidney transplant outcomes at up to 54 mo of follow up was also explored prospectively. In comparison to the absence of rejection, acute T cell-mediated rejection in the kidney transplant was characterised by numerical dominance of cytotoxic T lymphocytes over Foxp3(+) regulatory T cells, but did not reach statistical significance owing to the small sample size in our pilot study. There was no obvious difference in absolute numbers of infiltrating cytotoxic T lymphocytes, Foxp3(+) regulatory T cells and Th17 cells between the two patient groups when quantified separately. Our exploratory analysis on associations of T cell subset quantifications with kidney transplant outcomes revealed that the degree of Th17 cell infiltration was significantly associated with shorter time to doubling of creatinine and shorter time to transplant loss. Although this was a small pilot study, results support our suspicion that in kidney transplant patients the immune balance in acute T cell-mediated rejection is tilted towards the pro-rejection forces and prompt larger and more sophisticated studies.

  17. The severity of acute cellular rejection defined by Banff classification is associated with kidney allograft outcomes.

    PubMed

    Wu, Kaiyin; Budde, Klemens; Lu, Huber; Schmidt, Danilo; Liefeldt, Lutz; Glander, Petra; Neumayer, Hans Helmut; Rudolph, Birgit

    2014-06-15

    It is unclear if the severity or the timing of acute cellular rejection (ACR) defined by Banff classification 2009 is associated with graft survival. Borderline changes, TCMR I (interstitial rejection), and TCMR II/III (vascular rejection) were defined as low, moderate, and high ACR severity, respectively. Approximately 270 patients who had at least one episode of ACR were enrolled, 270 biopsies were chosen which showed the highest ACR severity of each patient and were negative for donor-specific antibodies (DSA), C4d, and microcirculation changes (MC). Six months were used as the cutoff to define early and late ACR; 370 patients without biopsy posttransplantation were recruited in the control group. Up to 8-year posttransplantation, death-censored graft survival (DCGS) rates of control, borderline, TCMR I, and TCMR II/III groups were 97.6%, 93.3%, 79.6%, and 73.6% (log rank test, P<0.001); the control group had significantly higher DCGS rate than the three ACR groups (each pairwise comparison yields P<0.05). The DCGS rate of late ACR was significantly lower compared with early ACR (63.6% vs. 87.4%, P<0.001). Intimal arteritis (Banff v-lesion) was an independent histologic risk factor correlated with long-term graft loss regardless of the timing of ACR. The v-lesions with minimal or high-grade tubulitis displayed similar graft survival (72.7% vs. 72.9%, P=0.96). All types of ACR affect long-term graft survival. Vascular or late ACR predict poorer graft survival; the extent of tubulointerstitial inflammation (TI) is of no prognostic significance for vascular rejection.

  18. Myocardial strain and strain rate from speckle-tracking echocardiography are unable to differentiate asymptomatic biopsy-proven cellular rejection in the first year after cardiac transplantation.

    PubMed

    Ambardekar, Amrut V; Alluri, Nitya; Patel, Amit C; Lindenfeld, JoAnn; Dorosz, Jennifer L

    2015-04-01

    Cellular rejection after cardiac transplantation is treatable with timely diagnosis. Because noninvasive methods for diagnosis are limited, surveillance endomyocardial biopsies are routinely performed in the first year after transplantation. The aim of this study was to test whether myocardial strain and strain rate as assessed by speckle-tracking echocardiography would be a sensitive noninvasive method for the detection of asymptomatic rejection. Surveillance biopsies and echocardiograms obtained in the first year after transplantation were retrospectively reviewed, and patients with asymptomatic biopsy-proven cellular rejection were identified, as well as control transplantation patients without rejection or cardiac complications. Circumferential and longitudinal strain and strain rate were measured using Velocity Vector Imaging software from echocardiograms performed at three time points for patients with rejection-baseline (no rejection), rejection, and resolution (of rejection)-and three time points for control patients-baseline (within the first month after transplantation), 6 months, and 12 months after transplantation. Speckle-tracking strain and strain rate measurements were obtained from 30 patients with asymptomatic biopsy-proven rejection and 14 control transplantation patients. There were no significant differences in circumferential and longitudinal strain or strain rate between the baseline, rejection, and resolution studies. Furthermore, there were no significant differences in strain and strain rate in control transplantation patients during the first year after transplantation or compared with patients with rejection. Speckle-tracking analysis was unable to detect changes on serial studies from patients with asymptomatic rejection and thus cannot replace biopsy. Other noninvasive methods for the diagnosis of cellular-mediated rejection are needed. Copyright © 2015 American Society of Echocardiography. Published by Elsevier Inc. All rights

  19. 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

  20. Clinicopathological study of expression of lymphatic vessels in renal allograft biopsy after treatment for acute rejection.

    PubMed

    Oka, K; Namba, Y; Ichimaru, N; Moriyama, T; Kyo, M; Kokado, Y; Imai, E; Takahara, S

    2009-12-01

    Lymph vessel expression is related to inflammatory cell infiltration, around renal tubules in acute rejection episodes (ARE) of transplanted kidneys. However, there is little information on the lymph vessels after treatment of an ARE, particularly in relation to renal function and histological findings. We investigated 13 cases of ARE diagnosed by kidney transplant biopsy performed from 1997 to 2005 within 3 years of transplantation. Treatment of the ARE lead to an improved serum creatinine level in all cases. There was neither an ABO-incompatible nor an acute humoral rejection case. Lymphatic vessels in re-biopsies were examined using immunohistochemical staining with D2-40 antibody that detected lymphatic endothelium. Re-biopsy cases in which the baseline creatinine had increased by more than 20% despite treatment were considered the severe group; the others, as the stable group. The relation between lymphatic vessel density (LVD) and renal function was examined using Banff scores. LVD was significantly higher in the severe than the stable group. The expression of lymph vessels versus the Banff score showed a direct relation: greater Banff scores showed higher expressions of lymph vessels. The expression of lymph vessels in renal allograft specimens after treatment of an ARE was related to deterioration of renal function and inflammatory cell invasion. We plan a further examination of the relationship between the expression of lymph vessels and long-term prognosis.

  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. 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.

  3. A web-based pilot study of inter-pathologist reproducibility using the ISHLT 2004 working formulation for biopsy diagnosis of cardiac allograft rejection: the European experience.

    PubMed

    Angelini, Annalisa; Andersen, Claus Boegelund; Bartoloni, Giovanni; Black, Fiona; Bishop, Paul; Doran, Helen; Fedrigo, Marny; Fries, Jochen W U; Goddard, Martin; Goebel, Heike; Neil, Desley; Leone, Ornella; Marzullo, Andrea; Ortmann, Monika; Paraf, Francois; Rotman, Samuel; Turhan, Nesrin; Bruneval, Patrick; Frigo, Anna Chiara; Grigoletto, Francesco; Gasparetto, Alessio; Mencarelli, Roberto; Thiene, Gaetano; Burke, Margaret

    2011-11-01

    The aim of this study was to assess, at the European level and using digital technology, the inter-pathologist reproducibility of the ISHLT 2004 system and to compare it with the 1990 system We also assessed the reproducibility of the morphologic criteria for diagnosis of antibody-mediated rejection detailed in the 2004 grading system. The hematoxylin-eosin-stained sections of 20 sets of endomyocardial biopsies were pre-selected and graded by two pathologists (A.A. and M.B.) and digitized using a telepathology digital pathology system (Aperio ImageScope System; for details refer to http://aperio.com/). Their diagnoses were considered the index diagnoses, which covered all grades of acute cellular rejection (ACR), early ischemic lesions, Quilty lesions, late ischemic lesions and (in the 2005 system) antibody-mediated rejection (AMR). Eighteen pathologists from 16 heart transplant centers in 7 European countries participated in the study. Inter-observer reproducibility was assessed using Fleiss's kappa and Krippendorff's alpha statistics. The combined kappa value of all grades diagnosed by all 18 pathologists was 0.31 for the 1990 grading system and 0.39 for the 2005 grading system, with alpha statistics at 0.57 and 0.55, respectively. Kappa values by grade for 1990/2005, respectively, were: 0 = 0.52/0.51; 1A/1R = 0.24/0.36; 1B = 0.15; 2 = 0.13; 3A/2R = 0.29/0.29; 3B/3R = 0.13/0.23; and 4 = 0.18. For the 2 cases of AMR, 6 of 18 pathologists correctly suspected AMR on the hematoxylin-eosin slides, whereas, in each of 17 of the 18 AMR-negative cases a small percentage of pathologists (range 5% to 33%) overinterpreted the findings as suggestive for AMR. Reproducibility studies of cardiac biopsies by pathologists in different centers at the international level were feasible using digitized slides rather than conventional histology glass slides. There was a small improvement in interobserver agreement between pathologists of different European centers when moving from the

  4. Teratocarcinomas Arising from Allogeneic Induced Pluripotent Stem Cell-Derived Cardiac Tissue Constructs Provoked Host Immune Rejection in Mice

    PubMed Central

    Kawamura, Ai; Miyagawa, Shigeru; Fukushima, Satsuki; Kawamura, Takuji; Kashiyama, Noriyuki; Ito, Emiko; Watabe, Tadashi; Masuda, Shigeo; Toda, Koichi; Hatazawa, Jun; Morii, Eiichi; Sawa, Yoshiki

    2016-01-01

    Transplantation of induced pluripotent stem cell-derived cardiac tissue constructs is a promising regenerative treatment for cardiac failure: however, its tumourigenic potential is concerning. We hypothesised that the tumourigenic potential may be eliminated by the host immune response after allogeneic cell transplantation. Scaffold-free iPSC-derived cardaic tissue sheets of C57BL/6 mouse origin were transplanted into the cardiac surface of syngeneic C57BL/6 mice and allogeneic BALB/c mice with or without tacrolimus injection. Syngeneic mice and tacrolimus-injected immunosuppressed allogeneic mice formed teratocarcinomas with identical phenotypes, characteristic, and time courses, as assessed by imaging tools including 18F-fluorodeoxyglucose-positron emission tomography. In contrast, temporarily immunosuppressed allogeneic mice, following cessation of tacrolimus injection displayed diminished progression of the teratocarcinoma, accompanied by an accumulation of CD4/CD8-positive T cells, and finally achieved complete elimination of the teratocarcinoma. Our results indicated that malignant teratocarcinomas arising from induced pluripotent stem cell-derived cardiac tissue constructs provoked T cell-related host immune rejection to arrest tumour growth in murine allogeneic transplantation models. PMID:26763872

  5. Late Failing Heart Allografts: Pathology of Cardiac Allograft Vasculopathy and Association With Antibody-Mediated Rejection.

    PubMed

    Loupy, A; Toquet, C; Rouvier, P; Beuscart, T; Bories, M C; Varnous, S; Guillemain, R; Pattier, S; Suberbielle, C; Leprince, P; Lefaucheur, C; Jouven, X; Bruneval, P; Duong Van Huyen, J P

    2016-01-01

    In heart transplantation, there is a lack of robust evidence of the specific causes of late allograft failure. We hypothesized that a substantial fraction of failing heart allografts may be associated with antibody-mediated injury and immune-mediated coronary arteriosclerosis. We included all patients undergoing a retransplantation for late terminal heart allograft failure in three referral centers. We performed an integrative strategy of heart allograft phenotyping by assessing the heart vascular tree including histopathology and immunohistochemistry together with circulating donor-specific antibodies. The main analysis included 40 explanted heart allografts patients and 402 endomyocardial biopsies performed before allograft loss. Overall, antibody-mediated rejection was observed in 19 (47.5%) failing heart allografts including 16 patients (40%) in whom unrecognized previous episodes of subclinical antibody-mediated rejection occurred 4.5 ± 3.5 years before allograft loss. Explanted allografts with evidence of antibody-mediated rejection demonstrated higher endothelitis and microvascular inflammation scores (0.89 ± 0.26 and 2.25 ± 0.28, respectively) compared with explanted allografts without antibody-mediated rejection (0.42 ± 0.11 and 0.36 ± 0.09, p = 0.046 and p < 0.0001, respectively). Antibody-mediated injury was observed in 62.1% of failing allografts with pure coronary arteriosclerosis and mixed (arteriosclerosis and atherosclerosis) pattern, while it was not observed in patients with pure coronary atherosclerosis (p = 0.0076). We demonstrate that antibody-mediated rejection is operating in a substantial fraction of failing heart allografts and is associated with severe coronary arteriosclerosis. Unrecognized subclinical antibody-mediated rejection episodes may be observed years before allograft failure.

  6. 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

  7. 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

  8. The value of serum neopterin, interferon-gamma levels and interleukin-12B polymorphisms in predicting acute renal allograft rejection

    PubMed Central

    Chin, G K; Adams, C L; Carey, B S; Shaw, S; Tse, W-Y; Kaminski, E R

    2008-01-01

    Acute rejection remains a poor predictor of graft outcome. In this study, we measured serum levels of interferon (IFN)-γ and neopterin by enzyme-linked immunosorbent assay and a single nucleotide polymorphism (SNP) within the 3′ untranslated region of the interleukin (IL)-12 B gene (1188 A/C) to determine whether either of these factors could predict acute rejection in renal transplantation. Significantly higher early post-transplant neopterin levels (days 5–7; 35·7 versus 19·9 nmol/l) were observed in recipients who subsequently rejected their grafts. Post-transplant neopterin levels showed a strong positive correlation with 1-month creatinine levels (Spearman's correlation 0·62, P < 0·001), suggesting macrophage activation early after transplantation. Pretransplant neopterin and IFN-γ levels and the IL-12B gene SNP did not predict acute rejection in this small retrospective study. The ability to predict acute rejection non-invasively early after transplantation could lead to individual tailoring of immunosuppressive regimens and perhaps lead eventually to longer graft survival. PMID:18341612

  9. 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.

  10. Efficacy of rabbit anti-thymocyte globulin for steroid-resistant acute rejection after liver transplantation

    PubMed Central

    Lee, Jae Geun; Lee, Juhan; Lee, Jung Jun; Song, Seung Hwan; Ju, Man Ki; Choi, Gi Hong; Kim, Myoung Soo; Choi, Jin Sub; Kim, Soon Il; Joo, Dong Jin

    2016-01-01

    Abstract Acute cellular rejection after liver transplantation (LT) can be treated with steroid pulse therapy, but there is no ideal treatment for steroid-resistant acute rejection (SRAR). We aimed to determine the feasibility and potential complications of rabbit anti-thymocyte globulin (rATG) application to treat SRAR in liver transplant recipients. We retrospectively reviewed medical records of 429 recipients who underwent LT at Severance Hospital between January 2010 and March 2015. We compared clinical features and graft survival between patients with steroid-sensitive acute rejection (SSAR; n = 23) and SRAR (n = 11). We also analyzed complications and changes in laboratory findings after 2.5 mg/kg rATG treatment in patients with SRAR for 6 to 10 days. There were no significant differences in gender, age, model for end-stage liver disease score, Child–Turcotte–Pugh score, or original liver diseases between patients with SSAR and SRAR, although deceased donors were more frequently associated with the SRAR group (P = 0.004). All SRAR patients responded positively to rATG treatment; after treatment, the patients’ median AST levels decreased from 138 to 63 IU/L, and their median ALT levels dropped from 327 to 70 IU/L 1 day after rATG treatment (P = 0.022 and 0.017, respectively). Median aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin levels significantly decreased 1 month post-treatment (P = 0.038, 0.004, and 0.041, respectively). Median survival after LT was 23 months, and median survival after rATG was 22 months in patients with SRAR. Adverse effects included hepatitis C virus (HCV) reactivation, fungemia, and cytomegalovirus (CMV) infection. Nine SRAR patients survived with healthy liver function, 1 died from a traffic accident during follow-up, and 1 died from graft-versus-host disease and fungemia. Administration of rATG is an effective therapeutic option for SRAR with acceptable complications in liver

  11. Endogenous Memory CD8 T Cells Directly Mediate Cardiac Allograft Rejection

    PubMed Central

    Su, C. A.; Iida, S.; Abe, T.; Fairchild, R. L.

    2014-01-01

    Differences in levels of environmentally induced memory T cells that cross-react with donor MHC molecules are postulated to account for the efficacy of allograft tolerance inducing strategies in rodents versus their failure in nonhuman primates and human transplant patients. Strategies to study the impact of donor-reactive memory T cells on allografts in rodents have relied on the pre-transplant induction of memory T cells cross-reactive with donor allogeneic MHC molecules through recipient viral infection, priming directly with donor antigen, or adoptive transfer of donor-antigen primed memory T cells. Each approach accelerates allograft rejection and confers resistance to tolerance induction, but also biases the T cell repertoire to strong donor-reactivity. The ability of endogenous memory T cells within unprimed mice to directly reject an allograft is unknown. Here we show a direct association between increased duration of cold ischemic allograft storage and numbers and enhanced functions of early graft infiltrating endogenous CD8 memory T cells. These T cells directly mediate rejection of allografts subjected to prolonged ischemia and this rejection is resistant to costimulatory blockade. These findings recapitulate the clinically significant impact of endogenous memory T cells with donor reactivity in a mouse transplant model in the absence of prior recipient priming. PMID:24502272

  12. [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.

  13. Expression of cytokine genes in human cardiac allografts: correlation of IL-6 and transforming growth factor-beta (TGF-beta) with histological rejection.

    PubMed Central

    Zhao, X M; Frist, W H; Yeoh, T K; Miller, G G

    1993-01-01

    Cytokines may play critical roles in allograft rejection. Currently, a clear pattern of cytokine production that correlates with rejection has not emerged. Our preliminary studies suggested a trend toward increased IL-6 and TGF-beta gene expression in cardiac allografts during rejection. We have extended these studies using reverse transcriptase/polymerase chain reaction (RT/PCR) to detect the expression of IL-6, TGF-beta, and T cell receptor beta chain constant region (TCR-beta) genes in 21 additional consecutive myocardial biopsies obtained from six heart transplant patients and from five pre-transplant donor hearts. Cytokine gene expression was compared with histological diagnosis of rejection. There was strong correlation between IL-6 as well as TGF-beta gene expression, and histological rejection (6/8 biopsies with versus 0/7 without rejection (P = 0.006) and 7/9 biopsies with versus 0/7 without rejection (P = 0.003) respectively). Neither IL-6 nor TGF-beta transcripts were detected in any pre-transplant donor heart. TCR-beta chain mRNA was found in all allograft biopsies regardless of the presence of rejection, but was absent in pre-transplant donor hearts. Our results indicate that expression of IL-6 and TGF-beta is highly correlated with allograft rejection and thus may play an important role in regulation of cardiac allograft rejection. T cell infiltration of allografted myocardium is invariably detected by PCR regardless of histological rejection. The long-term functional significance of these cells in transplanted hearts needs further investigation. Images Fig. 1 PMID:8370174

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

    PubMed

    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

    The optimal immunosuppressive regimen in simultaneous pancreas-kidney transplant (SPKT) recipients that prevents acute rejection episodes (AREs) and allows optimal outcome remains elusive. 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. 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. 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.

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. Severe Pneumococcal Pneumonia Causes Acute Cardiac Toxicity and Subsequent Cardiac Remodeling.

    PubMed

    Reyes, Luis F; Restrepo, Marcos I; Hinojosa, Cecilia A; Soni, Nilam J; Anzueto, Antonio; Babu, Bettina L; Gonzalez-Juarbe, Norberto; Rodriguez, Alejandro H; Jimenez, Alejandro; Chalmers, James D; Aliberti, Stefano; Sibila, Oriol; Winter, Vicki T; Coalson, Jacqueline J; Giavedoni, Luis D; Dela Cruz, Charles S; Waterer, Grant W; Witzenrath, Martin; Suttorp, Norbert; Dube, Peter H; Orihuela, Carlos J

    2017-09-01

    Up to one-third of patients hospitalized with pneumococcal pneumonia experience major adverse cardiac events (MACE) during or after pneumonia. In mice, Streptococcus pneumoniae can invade the myocardium, induce cardiomyocyte death, and disrupt cardiac function following bacteremia, but it is unknown whether the same occurs in humans with severe pneumonia. We sought to determine whether S. pneumoniae can (1) translocate the heart, (2) induce cardiomyocyte death, (3) cause MACE, and (4) induce cardiac scar formation after antibiotic treatment during severe pneumonia using a nonhuman primate (NHP) model. We examined cardiac tissue from six adult NHPs with severe pneumococcal pneumonia and three uninfected control animals. Three animals were rescued with antibiotics (convalescent animals). Electrocardiographic, echocardiographic, and serum biomarkers of cardiac damage were measured (troponin T, N-terminal pro-brain natriuretic peptide, and heart-type fatty acid binding protein). Histological examination included hematoxylin and eosin staining, immunofluorescence, immunohistochemistry, picrosirius red staining, and transmission electron microscopy. Immunoblots were used to assess the underlying mechanisms. Nonspecific ischemic alterations were detected by electrocardiography and echocardiography. Serum levels of troponin T and heart-type fatty acid binding protein were increased (P < 0.05) after pneumococcal infection in both acutely ill and convalescent NHPs. S. pneumoniae was detected in the myocardium of all NHPs with acute severe pneumonia. Necroptosis and apoptosis were detected in the myocardium of both acutely ill and convalescent NHPs. Evidence of cardiac scar formation was observed only in convalescent animals by transmission electron microscopy and picrosirius red staining. S. pneumoniae invades the myocardium and induces cardiac injury with necroptosis and apoptosis, followed by cardiac scarring after antibiotic therapy, in an NHP model of severe

  4. [Cardiac insufficiency: acute right heart failure].

    PubMed

    Wetsch, Wolfgang A; Lahm, Tim; Hinkelbein, Jochen; Happel, Christoph M; Padosch, Stephan A

    2011-11-01

    Acute right heart failure (RHF) is a frequent and severe complication during perioperative and intensive care treatment in intensive care units (ICUs). The most common causes are pulmonary hypertension, left heart failure, pulmonary embolism, sepsis, acute lung injury (ALI) and thoracosurgical procedures. Acute RHF is not only a major contributor to morbidity and mortality; it also influences efficacy and outcome of routinely performed procedures, such as vasopressors, in critically ill patients. In contrast to the left ventricle, the right ventricle's physiology and pathophysiology are understudied, and the diagnosis of acute RHF is frequently challenging. Although many drugs are available for the treatment of RHF, randomized trials for this setting are still missing. This article gives an overview of aetiology and pathogenesis of RHF and reviews the diagnostic and therapeutic interventions currently available for providers in anaesthesiology and critical care. © Georg Thieme Verlag Stuttgart · New York.

  5. 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.

  6. Late acute liver allograft rejection; a study of its natural history and graft survival in the current era.

    PubMed

    Thurairajah, Prem H; Carbone, Marco; Bridgestock, Hannah; Thomas, Philip; Hebbar, Srisha; Gunson, Bridget K; Shah, Tahir; Neuberger, James

    2013-04-15

    Late acute rejection (LAR) after liver transplantation is often associated with poor clinical outcomes. We reviewed our experience of managing LAR in the current era to determine its natural history. A database of 970 consecutive adult liver transplants was reviewed retrospectively. LAR was defined as histologically proven acute cellular rejection occurring more than 90 days after transplantation. The incidence of LAR was 11%, with a mean time of 565 days (median, 311 days; range, 90-2922 days) after transplantation. The highest rates for LAR were in seronegative hepatitis (17%), primary biliary cirrhosis (16%), and primary sclerosing cholangitis (13%) with an odds ratio of 2.3, 2.1, and 1.8, respectively. Logistic regression showed that younger recipients, primary biliary cirrhosis, and previous graft loss were independent predictors of LAR (P<0.001). Mean trough whole blood tacrolimus levels were at their lowest levels 1 week before the diagnosis of rejection (5.5 ng/mL; SD, 2.6) compared with levels of 7.7 ng/mL 4 weeks before rejection, showing a clear temporal relation. Graft survival was worse in those with LAR (P<0.01), whereas the best graft survival was among early acute rejection cases (85% 10-year survival; P<0.01). Poor response to treatment correlated with the development of ductopenic rejection (r=0.3; P<0.01). Approximately half with early ductopenic rejection eventually died (n=15). LAR continues to provide a risk to patient and graft survival: understanding risk factors may allow an improvement in monitoring and early intervention and so prevent early graft loss.

  7. Pre-transplant immune state defined by serum markers and alloreactivity predicts acute rejection after living donor kidney transplantation.

    PubMed

    Vondran, Florian W R; Timrott, Kai; Kollrich, Sonja; Steinhoff, Ann-Kristin; Kaltenborn, Alexander; Schrem, Harald; Klempnauer, Juergen; Lehner, Frank; Schwinzer, Reinhard

    2014-09-01

    Acute rejection (AR) remains a major cause for long-term kidney allograft failure. Reliable immunological parameters suitable to define the pre-transplant immune state and hence the individual risk of graft rejection are highly desired to preferably adapt the immunosuppressive regimen in advance. Donor and third party alloreactivities were determined by mixed lymphocyte cultures. Soluble forms of CD25, CD30, and CD44 were detected in patients' serum by ELISA. Various lymphocyte subpopulations were measured using flow cytometry. All patients received triple immunosuppression (tacrolimus/mycophenolate mofetil/steroids) and were grouped according to biopsy results within the first year: rejection-free (RF, n = 13), borderline (BL, n = 5), or acute rejection (AR, n = 7). Patients with AR showed the highest pre-transplant alloreactivities and serum levels (sCD25/sCD30/sCD44) according to the pattern RF < BL < AR. Relying on serum analysis only, multivariate logistic regression (logit link function) yielded a prognostic score for prediction of rejection with 75.0% sensitivity and 69.2% specificity. Patients with rejection showed markedly higher pre-transplant frequencies of CD4(+) /CD8(+) T cells lacking CD28, but lower numbers of CD8(+) CD161(bright) T cells and NK cells than RF individuals. Pre-transplant immune state defined by alloreactivity, serum markers, and particular lymphocyte subsets seems to correlate with occurrence of graft rejection after kidney transplantation. A prognostic score based on pre-transplant serum levels has shown great potential for prediction of rejection episodes and should be further evaluated. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. 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.

  9. Plasma C4d+ Endothelial Microvesicles Increase in Acute Antibody-Mediated Rejection.

    PubMed

    Tower, Cindy M; Reyes, Morayma; Nelson, Karen; Leca, Nicolae; Kieran, Niamh; Muczynski, Kimberly; Jefferson, Jonathan A; Blosser, Christopher; Kukla, Aleksandra; Maurer, David; Chandler, Wayne; Najafian, Behzad

    2017-09-01

    Antibody-mediated rejection (AMR) is a major cause of kidney allograft loss. Currently, AMR diagnosis relies on biopsy which is an invasive procedure. A noninvasive biomarker of acute AMR could lead to early diagnosis and treatment of this condition and improve allograft outcome. Microvesicles are membrane-bound vesicles released from the cell surface after injury. We hypothesized that because AMR is associated with allograft endothelial injury and C4d deposition, plasma microvesicles positive for endothelial (CD144) marker and C4d are increased in this condition. We studied microvesicle concentration in the plasma of 95 kidney transplant patients with allograft dysfunction and compared with 23 healthy volunteers. Biopsy diagnosis and scoring was performed using Banff classification. In the 28 subjects with AMR, the density of C4d+/CD144+ microvesicles was on average 11-fold (P = 0.002) higher than transplant recipients with no AMR and 24-fold (P = 0.008) than healthy volunteers. Densities of C4d+ and C4d+/annexin V+ (C4d+/AVB+) microvesicles were also increased in AMR patients compared with no AMR and healthy subjects. C4d+/AVB+ microvesicles correlated with AMR biopsy severity. Nine patients with acute AMR that received treatment showed a mean 72% decrease (P = 0.01) in C4d+/CD144+ microvesicle concentration compared with pretreatment values. Quantification of plasma C4d+ microvesicles provides information about presence of AMR, its severity and response to treatment in transplant patients.

  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. Perspectives on the value of biomarkers in acute cardiac care and implications for strategic management.

    PubMed

    Kossaify, Antoine; Garcia, Annie; Succar, Sami; Ibrahim, Antoine; Moussallem, Nicolas; Kossaify, Mikhael; Grollier, Gilles

    2013-01-01

    Biomarkers in acute cardiac care are gaining increasing interest given their clinical benefits. This study is a review of the major conditions in acute cardiac care, with a focus on biomarkers for diagnostic and prognostic assessment. Through a PubMed search, 110 relevant articles were selected. The most commonly used cardiac biomarkers (cardiac troponin, natriuretic peptides, and C-reactive protein) are presented first, followed by a description of variable acute cardiac conditions with their relevant biomarkers. In addition to the conventional use of natriuretic peptides, cardiac troponin, and C-reactive protein, other biomarkers are outlined in variable critical conditions that may be related to acute cardiac illness. These include ST2 and chromogranin A in acute dyspnea and acute heart failure, matrix metalloproteinase in acute chest pain, heart-type fatty acid binding protein in acute coronary syndrome, CD40 ligand and interleukin-6 in acute myocardial infarction, blood ammonia and lactate in cardiac arrest, as well as tumor necrosis factor-alpha in atrial fibrillation. Endothelial dysfunction, oxidative stress and inflammation are involved in the physiopathology of most cardiac diseases, whether acute or chronic. In summary, natriuretic peptides, cardiac troponin, C-reactive protein are currently the most relevant biomarkers in acute cardiac care. Point-of-care testing and multi-markers use are essential for prompt diagnostic approach and tailored strategic management.

  12. Perspectives on the Value of Biomarkers in Acute Cardiac Care and Implications for Strategic Management

    PubMed Central

    Kossaify, Antoine; Garcia, Annie; Succar, Sami; Ibrahim, Antoine; Moussallem, Nicolas; Kossaify, Mikhael; Grollier, Gilles

    2013-01-01

    Biomarkers in acute cardiac care are gaining increasing interest given their clinical benefits. This study is a review of the major conditions in acute cardiac care, with a focus on biomarkers for diagnostic and prognostic assessment. Through a PubMed search, 110 relevant articles were selected. The most commonly used cardiac biomarkers (cardiac troponin, natriuretic peptides, and C-reactive protein) are presented first, followed by a description of variable acute cardiac conditions with their relevant biomarkers. In addition to the conventional use of natriuretic peptides, cardiac troponin, and C-reactive protein, other biomarkers are outlined in variable critical conditions that may be related to acute cardiac illness. These include ST2 and chromogranin A in acute dyspnea and acute heart failure, matrix metalloproteinase in acute chest pain, heart-type fatty acid binding protein in acute coronary syndrome, CD40 ligand and interleukin-6 in acute myocardial infarction, blood ammonia and lactate in cardiac arrest, as well as tumor necrosis factor-alpha in atrial fibrillation. Endothelial dysfunction, oxidative stress and inflammation are involved in the physiopathology of most cardiac diseases, whether acute or chronic. In summary, natriuretic peptides, cardiac troponin, C-reactive protein are currently the most relevant biomarkers in acute cardiac care. Point-of-care testing and multi-markers use are essential for prompt diagnostic approach and tailored strategic management. PMID:24046510

  13. Use of indium-111-labeled cells in measurement of cellular dynamics of experimental cardiac allograft rejection

    SciTech Connect

    Oluwole, S.; Wang, T.; Fawwaz, R.; Satake, K.; Nowygrod, R.; Reemtsma, K.; Hardy, M.A.

    1981-01-01

    This study evaluates the kinetics and utility of infused indium-111-labeled cells in detecting rejection in ACI to Lewis rat heart allografts. Syngeneic leukocytes, lymph node lymphocytes, and platelets were isolated and labeled with indium-111 (/sup 111/In) oxine, respectively, and were infused i.v. into Lewis rats carrying beating ACI or syngeneic hearts from post-transplant days 0 to 6. Recipients were imaged serially at 24 hr after infusion of labeled cells followed by excision of both native and transplanted hearts for direct isotope count. Labeled leukocytes accumulative progressively in the allograft with the scan becoming positive by post-transplant day 4. The ratio of allograft to native heart isotope counts rose from 1.25 on day 1 to 10.07 (P less than 0.0001) on day 7. The Lewis recipients infused with labeled lymphocytes showed a positive scan on days 6 and 7 whereas the allograft to native heart isotope count ratio rose from 0.97 on day 1 to 5.33 (P less than 0.001) on day 7. Recipients infused with /sup 111/In-labeled platelets showed a positive scan on days 5 to 7 and the allograft to native heart isotope count ratio rose sharply from 2.56 on day 4 to 16.98 (P less than 0.005) on day 7. Syngeneic heart grafts failed to demonstrate significant accumulation of any of the labeled cell population. These studies confirm the importance of nonlymphocytic cells in cellular rejection, evaluate the kinetics of graft invasion by the various cell types, and suggest that the techniques used afford a method for a safe and an early detection of allograft rejection.

  14. Acute gastrointestinal complications after cardiac surgery.

    PubMed

    Halm, M A

    1996-03-01

    Gastrointestinal problems, with an incidence of about 1%, may complicate the postoperative period after cardiovascular surgery, increasing morbidity, length of stay, and mortality. Several risk factors for the development of these complications, including preexisting conditions; advancing age; surgical procedure, especially valve, combined bypass/valve, emergency, reoperative, and aortic dissection repair; iatrogenic conditions; stress; ischemia; and postpump complications, have been identified in multiple research studies. Ischemia is the most significant of these risk factors after cardiovascular surgery. Mechanisms that have been implicated include longer cardiopulmonary bypass and aortic cross-clamp times and hypoperfusion states, especially if inotropic or intra-aortic balloon pump support is required. These risk factors have been linked to upper and lower gastrointestinal bleeding, paralytic ileus, intestinal ischemia, acute diverticulitis, acute cholecystitis, hepatic dysfunction, hyperamylasemia, and acute pancreatitis. Gastrointestinal bleeding accounts for almost half of all complications, followed by hepatic dysfunction, intestinal ischemia, and acute cholecystitis. Identification of these gastrointestinal complications may be difficult because manifestations may be masked by postoperative analgesia or not reported by patients because they are sedated or require prolonged mechanical ventilation. Furthermore, clinical manifestations may be nonspecific and not follow the "classic" clinical picture. Therefore, astute assessment skills are needed to recognize these problems in high-risk patients early in their clinical course. Such early recognition will prompt aggressive medical and/or surgical management and therefore improve patient outcomes for the cardiovascular surgical population.

  15. 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.

  16. Acute Liver Failure Due to Budd-Chiari Syndrome in the Setting of Cardiac Synovial Sarcoma.

    PubMed

    Stine, Jonathan G; Newton, Kelly; Vinayak, Ajeet G

    2015-04-01

    Primary malignant tumors of the heart, specifically cardiac sarcomas, are rare and mainly diagnosed at autopsy. Acute Budd-Chiari syndrome is a recognized cause of acute liver failure and has been associated with several rare cardiac tumors: atrial myxoma, caval rhabdomyosarcoma, and primary cardiac adenocarcinoma. We present the first case of a fatal, highly differentiated cardiac synovial sarcoma that presented as acute liver failure from Budd-Chiari syndrome.

  17. Average Tacrolimus Trough Level in the First Month After Transplantation May Predict Acute Rejection.

    PubMed

    Aktürk, S; Erdoğmuş, Ş; Kumru, G; Elhan, A H; Şengül, Ş; Tüzüner, A; Keven, K

    2017-04-01

    Although tacrolimus is one of the essential drugs used for the prevention of rejection in kidney recipients, target trough levels are not well established. In this study, we aimed to investigate the association between average tacrolimus trough levels (TTLs) of the first month after transplantation and biopsy-proven acute rejection (BPAR) during the first 12 months after transplant. A total of 274 patients who underwent kidney-alone transplantation between 2002 and 2014 were enrolled in the study. Average TTLs of the first month were assessed by means of receiver operating characteristic (ROC) curve analysis to discriminate patients with and those without BPAR. Univariate and multivariate Cox proportional hazards models were used to determine the effect of average TTLs of the first month on BPAR. According to ROC curve analysis, the highest area under the curve (AUC) was obtained from 8 ng/mL (AUC = 0.73 ± 0.11; 95% confidence interval [CI], 0.62-0.84). Forty-two (31.8%) of the 132 patients with average TTLs <8 ng/mL and 13 (9.1%) of 142 patients with ≥8 ng/mL had BPAR during the first 12 months after transplant (P < .001). In univariable analysis, average TTLs of the first month <8 ng/mL were associated with higher risk of BPAR (P < .001), and the significance remained in Cox multivariable analysis (hazard ratio, 2.79; 95% CI, 1.76-3.82; P = .001). No significant differences were observed in the glomerular filtration rate, cytomegalovirus, BK viremia, or BK nephropathy between groups at post-transplant month 12. Keeping the average TTLs of the first month after transplantation at ≥8 ng/mL not only prevents BPAR occurrence but also minimizes the toxic effects of the use of a single-trough level. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. 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

  19. Molecular dysfunctions in acute rejection after renal transplantation revealed by integrated analysis of transcription factor, microRNA and long noncoding RNA.

    PubMed

    Sui, Weiguo; Lin, Hua; Peng, Wujian; Huang, Yuanshuai; Chen, Jiejing; Zhang, Yue; Dai, Yong

    2013-10-01

    Acute rejection remains a problem in renal transplantation. To further illustrate the mechanism of rejection, we integrated protein array-based proteomics and RNA microarray-based genomics to investigate the transcription factor, microRNA and long noncoding RNA of biopsies of three patients with acute rejections and a control group. 99 transcription factors were identified in acute rejection biopsies compared to normal renal tissue. We correlated transcription factor data with microRNA and long noncoding RNA data sets and reported the expression of 5 transcription factors (AP-1, AP-4, STATx, c-Myc and p53), 12 miRNAs and 32 lncRNAs in acute rejection biopsies. Pathway analysis demonstrated that over-presentation of transcription factor pathway plays a critical role in acute rejection. This is the first study to comprehensively report the acute rejection transcription factor pathway. Integrative analysis of the transcription factor, microRNA and long noncoding RNA provided an expansive view of molecular signaling pathways in acute rejection after renal transplantation. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Prevention of Allogeneic Cardiac Graft Rejection by Transfer of Ex Vivo Expanded Antigen-Specific Regulatory T-Cells

    PubMed Central

    Takasato, Fumika; Morita, Rimpei; Schichita, Takashi; Sekiya, Takashi; Morikawa, Yasuhide; Kuroda, Tatsuo; Niimi, Masanori; Yoshimura, Akihiko

    2014-01-01

    The rate of graft survival has dramatically increased using calcineurin inhibitors, however chronic graft rejection and risk of infection are difficult to manage. Induction of allograft-specific regulatory T-cells (Tregs) is considered an ideal way to achieve long-term tolerance for allografts. However, efficient in vitro methods for developing allograft-specific Tregs which is applicable to MHC full-mismatched cardiac transplant models have not been established. We compared antigen-nonspecific polyclonal-induced Tregs (iTregs) as well as antigen-specific iTregs and thymus-derived Tregs (nTregs) that were expanded via direct and indirect pathways. We found that iTregs induced via the indirect pathway had the greatest ability to prolong graft survival and suppress angiitis. Antigen-specific iTregs generated ex vivo via both direct and indirect pathways using dendritic cells from F1 mice also induced long-term engraftment without using MHC peptides. In antigen-specific Treg transferred models, activation of dendritic cells and allograft-specific CTL generation were suppressed. The present study demonstrated the potential of ex vivo antigen-specific Treg expansion for clinical cell-based therapeutic approaches to induce lifelong immunological tolerance for allogeneic cardiac transplants. PMID:24498362

  1. Acute myocarditis secondary to cardiac tuberculosis: a case report.

    PubMed

    Cowley, Alice; Dobson, Laura; Kurian, John; Saunderson, Christopher

    2017-09-01

    Isolated myocardial involvement in tuberculosis is exceedingly rare but there are reports it can present with sudden cardiac death, atrioventricular block, ventricular arrhythmias or congestive cardiac failure. We report the case of a 33-year-old male, of South Asian descent, who presented with chest pain, shortness of breath and an abnormal ECG. The patient had no significant past medical history and coronary angiogram showed no evidence of coronary artery disease. Of note, the patient had recently been discharged from a local district hospital with an episode of myocarditis. The patient was found to be severely hypoxic with evidence of severe biventricular failure on echocardiography. Computed tomography of the chest demonstrated hilar lymphadenopathy, and the differential diagnosis was thought to be tuberculosis or sarcoidosis. A TB Quantiferon gold test performed at the district hospital was positive; however, fine needle aspiration was negative for acid-fast bacilli. Despite aggressive diuresis, the patient became increasingly hypoxic and suffered a cardiac arrest. Post-mortem confirmed a diagnosis of myocardial tuberculosis - a rare case of acute decompensated heart failure. Tuberculosis myocarditis is a rare diagnosis but should be considered in at risk individuals presenting with acute fulminant myocarditis.Cardiac failure can occur even in the absence of disseminated tubercular disease.TB myocarditis is not just a disease of the immunocompromised.Definitive diagnosis of cardiac tuberculosis during life requires a myocardial biopsy.Echocardiography is a vital tool for the assessment of cardiac function, filling pressures and fluid status in the critically unwell patient. © 2017 The authors.

  2. Treatment of Acute Antibody-Mediated Renal Allograft Rejection With Cyclophosphamide.

    PubMed

    Waiser, Johannes; Duerr, Michael; Budde, Klemens; Rudolph, Birgit; Wu, Kaiyin; Bachmann, Friederike; Halleck, Fabian; Schönemann, Constanze; Lachmann, Nils

    2017-10-01

    Antibody-mediated rejection (AMR) is a major risk for renal allograft survival. Throughout decades, cyclophosphamide treatment has been proven to be effective in patients with antibody-associated autoimmune diseases. We investigated whether cyclophosphamide combined with plasmapheresis and intravenous immunoglobulins is an option for patients with AMR. Between March 2013 and November 2015, we initiated treatment of 13 consecutive patients with biopsy-proven acute AMR with intravenous cyclophosphamide pulses (15 mg/kg adapted to age and renal function) at 3-week intervals, PPH (6×), and high-dose intravenous immunoglobulin (1.5 g/kg). Treatment was completed after 6 cyclophosphamide pulses or in case of return to baseline serum creatinine together with reduction of donor-specific HLA antibodies (DSA) below 500 mean fluorescence intensity. Eleven of 13 patients completed treatment. Median follow-up was 18 (12-44) months. At the end of follow-up, graft survival was 77% (10/13). The 3 graft losses were caused at least in part by nonadherence and premature termination of treatment. Serum creatinine increased from 1.7±0.4 mg/dL at 3 months before diagnosis to 3.7±2.4 mg/dL at diagnosis (P = 0.01), and decreased to 2.1 ± 0.7 mg/dL at 3 months after diagnosis (P = 0.01). In 7 (64%) of 11 patients, who completed treatment, DSA decreased, in 4 (36%) of 11 DSA were below 500 mean fluorescence intensity after treatment. Dose reductions had to be performed in 3 of 13 patients for leukopenia. We observed 14 hospitalizations in 9 of 13 patients. To our knowledge, this is the first systematic report on cyclophosphamide-based treatment of acute AMR based on modern diagnostics. Treatment was effective and relatively safe. Future studies will show, whether cyclophosphamide proves to be a valuable alternative for the treatment of AMR.

  3. 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.

  4. 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

  5. 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

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

    PubMed

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

    2014-01-01

    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. 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. 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. 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 be related to acute renal allograft

  7. Acute kidney injury prediction following elective cardiac surgery: AKICS Score.

    PubMed

    Palomba, H; de Castro, I; Neto, A L C; Lage, S; Yu, L

    2007-09-01

    Acute kidney injury (AKI) following cardiac surgery (AKICS) is associated with increased postoperative (post-op) morbidity and mortality. A prognostic score system for AKI would help anticipate patient (pt) treatment. To develop a predictive score (AKICS) for AKI following cardiac surgery, we used a broad definition of AKI, which included perioperative variables. Six hundred three pts undergoing cardiac surgery were prospectively evaluated for AKI defined as serum creatinine above 2.0 mg/dl or an increase of 50% above baseline value. Univariate and multivariate analyses were used to evaluate pre-, intra-, and post-op parameters associated with AKI. The AKICS scoring system was prospectively validated in a new data set of 215 pts with an incidence of AKI of 14%. Variables included in the AKICS score were age greater than 65, pre-op creatinine above 1.2 mg/dl, pre-op capillary glucose above 140 mg/dl, heart failure, combined surgeries, cardiopulmonary bypass time above 2 h, low cardiac output, and low central venous pressure. The AKICS score presented good calibration and discrimination in both the study group and validation data set. The AKICS system that we developed, which incorporates five risk categories, accurately predicts AKI following cardiac surgery.

  8. 3D cardiac wall thickening assessment for acute myocardial infarction

    NASA Astrophysics Data System (ADS)

    Khalid, A.; Chan, B. T.; Lim, E.; Liew, Y. M.

    2017-06-01

    Acute myocardial infarction (AMI) is the most severe form of coronary artery disease leading to localized myocardial injury and therefore irregularities in the cardiac wall contractility. Studies have found very limited differences in global indices (such as ejection fraction, myocardial mass and volume) between healthy subjects and AMI patients, and therefore suggested regional assessment. Regional index, specifically cardiac wall thickness (WT) and thickening is closely related to cardiac function and could reveal regional abnormality due to AMI. In this study, we developed a 3D wall thickening assessment method to identify regional wall contractility dysfunction due to localized myocardial injury from infarction. Wall thickness and thickening were assessed from 3D personalized cardiac models reconstructed from cine MRI images by fitting inscribed sphere between endocardial and epicardial wall. The thickening analysis was performed in 5 patients and 3 healthy subjects and the results were compared against the gold standard 2D late-gadolinium-enhanced (LGE) images for infarct localization. The notable finding of this study is the highly accurate estimation and visual representation of the infarct size and location in 3D. This study provides clinicians with an intuitive way to visually and qualitatively assess regional cardiac wall dysfunction due to infarction in AMI patients.

  9. Increased monocyte expression of sialoadhesin during acute cellular rejection and other enteritides after intestine transplantation in children.

    PubMed

    Ashokkumar, Chethan; Gabriellan, Anna; Ningappa, Mylarappa; Mazariegos, George; Sun, Qing; Sindhi, Rakesh

    2012-03-15

    Sialoadhesin (CD169) facilitates T-cell priming when overexpressed on inflammatory monocytes. Monocyte-derived macrophages prime acute cellular rejection after intestine transplantation (ITx).The purpose of this study was to evaluate whether CD169-expressing activated monocytes associate with or predict ITx rejection. After informed consent (ClinicalTrials.gov NCT No. 01163578), activated CD169+CD14+monocytes were measured by flow cytometry in five normal healthy adult volunteers (group A), and 56 children with ITx sampled cross-sectionally (group B, 26), longitudinally (group C, 18), or during infection/inflammation without rejection (group D: acute enteritis, 9; Helicobacter pylori, 1; Streptococcal pharyngitis 1; and posttransplant lymphoma, 1). Activated monocytes were tested for correlations with donor-specific alloreactivity in simultaneous mixed lymphocyte co-cultures. Median age was 3 years (range 0.5-21 yr), and distribution of ITx-alone:combined liver-ITx was 25:31. Higher frequencies (%) of activated monocytes were seen during rejection in group B and infection/inflammation without rejection in group D (58 ± 28 and 73 ± 26), compared with nonrejectors or normal controls (10.6 ± 7.9 or 10.7 ± 6.5, P=0.001). In longitudinal monitoring, rejectors also showed higher activated monocyte frequencies (%) before ITx (64 ± 26 vs. 13.4 ± 8.6, P=0.0007) and during acute cellular rejection (55 ± 28 vs. 22.4 ± 15, P=0.006) when compared with nonrejectors. Activated monocytes correlated significantly with allospecific CD154+T-cytotoxic memory cells (Spearman r=0.688, P=7.1E-05) and CD154+B cells (r=0.518, P=0.005) in ITx recipients without inflammation/infection but not in group D. Monocytes overexpress sialoadhesin nonspecifically during ITx rejection and systemic or enteritic inflammatory states. When combined with allospecific T and B cells, this information may differentiate between rejection and other enteritides.

  10. Endothelial RAGE exacerbates acute postischaemic cardiac inflammation.

    PubMed

    Ziegler, Tilman; Horstkotte, Melanie; Lange, Philipp; Ng, Judy; Bongiovanni, Dario; Hinkel, Rabea; Laugwitz, Karl-Ludwig; Sperandio, Markus; Horstkotte, Jan; Kupatt, Christian

    2016-08-01

    Advanced glycation end-products (AGEs) interact with their receptor RAGE, leading to an inflammatory state. We investigated the role of RAGE in postischaemic leukocyte adhesion after myocardial infarction and its effect on postischaemic myocardial function. Wildtype (WT), ICAM-1-/-, RAGE-/- or ICAM-1/RAGE-/- mice underwent 20 minutes (min) of LAD-occlusion followed by 15 min of reperfusion. We applied in vivo fluorescence microscopy visualising Rhodamine-6G labelled leukocytes. To differentiate between endothelial and leukocyte RAGE, we generated bone marrow chimeric mice. Invasive hemodynamic measurements were performed in mice undergoing 45 min of myocardial ischaemia (via LAD-occlusion) followed by 24 hours of reperfusion. Left-ventricular developed pressure (LVDP) was assessed by insertion of a millar-tip catheter into the left ventricle. In the acute model of myocardial ischaemia, leukocyte retention (WT 68 ± 4 cells/hpf) was significantly reduced in ICAM-1-/- (40 ± 3 cells/hpf) and RAGE-/- mice (38 ± 4 cells/hpf). ICAM-1/RAGE-/- mice displayed an additive reduction of leukocyte retention (ICAM-1/RAGE-/- 15 ± 3 cells/hpf). Ly-6G+ neutrophil were predominantly reduced in ICAM-1/RAGE-/- hearts (28 %), whereas Ly-6C+ proinflammatory monocytes decreased to a lesser extent (55 %). Interestingly, PMN recruitment was not affected in chimeric mice with RAGE deficiency in BM cells (WT mice reconstituted with ICAM-1/RAGE-/- BM: 55 ± 4 cells/hpf) while in mice with global RAGE deficiency (ICAM-1/RAGE-/- mice reconstituted with ICAM-1/RAGE-/- BM) leucocyte retention was significantly reduced (13 ± 1 cells/hpf), similar to non-transplanted ICAM/RAGE-/- mice. Furthermore, postischaemic LVDP increased in ICAM-1/RAGE-/- animals (98 ± 4 mmHg vs 86 ± 4 mmHg in WT mice). In conclusion, combined deficiency of ICAM-1 and RAGE reduces leukocyte influx into infarcted myocardium and improves LV function during the acute phase after myocardial ischaemia and reperfusion

  11. Emergency room thoracotomy for acute traumatic cardiac tamponade caused by a blunt cardiac injury: A case report.

    PubMed

    Ishida, Kenichiro; Kinoshita, Yoshihiro; Iwasa, Nobutaka; Nakae, Masaro; Sakaki, Masayuki; Ieki, Yohei; Takahashi, Kyosuke; Shimahara, Yumiko; Sogabe, Taku; Shimono, Keiichiro; Noborio, Mitsuhiro; Sadamitsu, Daikai

    2017-01-01

    Traumatic blunt cardiac injuries have a high mortality rate, and prompt diagnosis and treatment can be lifesaving in cardiac tamponade. A 62-year-old man was transferred to the emergency department after a motor vehicle accident. He was hemodynamically unstable. A focused assessment with sonography in trauma (FAST) showed pericardial fluid with right ventricular collapse consistent with cardiac tamponade in the subxiphoid view. He collapsed despite a subxiphoid pericardiotomy. Owing to the ongoing hemodynamic instability, we performed a left anterolateral thoracotomy. Direct incision of the pericardium showed blood and clots within the pericardial space, indicating hemopericardium. The heart stroke and hemodynamic status recovered on removing the clot. Although the physical findings of cardiac tamponade are not always apparent in life-threatening acute cardiac tamponade after blunt trauma, FAST is a reliable tool for diagnosing and following cardiac tamponade. A median sternotomy is a standard approach for evaluating cardiac injury in hemodynamically stable patients with or without cardiopulmonary bypass. However, a left anterior thoracotomy was the fastest, simplest life-saving procedure considering the need for open-chest cardiac massage given our patient's life-threatening condition. A prompt diagnosis using FAST and treatment can be lifesaving in traumatic acute cardiac tamponade. A pericardiotomy via a thoracotomy is mandatory for lifesaving cardiac decompression in acute traumatic cardiac tamponade in cases of ineffective drainage due to clot formation within the pericardial space. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  12. Cardiac CT: atherosclerosis to acute coronary syndrome

    PubMed Central

    Munnur, Ravi Kiran; Cameron, James D.; Ko, Brian S.; Meredith, Ian T.

    2014-01-01

    Coronary computed tomographic angiography (CCTA) is a robust non-invasive method to assess coronary artery disease (CAD). Qualitative and quantitative assessment of atherosclerotic coronary stenosis with CCTA has been favourably compared with invasive coronary angiography (ICA) and intravascular ultrasound (IVUS). Importantly, it allows the study of preclinical stages of atherosclerotic disease, may help improve risk stratification and monitor the progressive course of the disease. The diagnostic accuracy of CCTA in the assessment of coronary artery bypass grafts (CABG) is excellent and the constantly improving technology is making the evaluation of stents feasible. Novel techniques are being developed to assess the functional significance of coronary stenosis. The excellent negative predictive value of CCTA in ruling out disease enables early and safe discharge of patients with suspected acute coronary syndromes (ACS) in the Emergency Department (ED). In addition, CCTA is useful in predicting clinical outcomes based on the extent of coronary atherosclerosis and also based on individual plaque characteristics such as low attenuation plaque (LAP), positive remodelling and spotty calcification. In this article, we review the role of CCTA in the detection of coronary atherosclerosis in native vessels, stented vessels, calcified arteries and grafts; the assessment of plaque progression, evaluation of chest pain in the ED, assessment of functional significance of stenosis and the prognostic significance of CCTA. PMID:25610801

  13. Comparison of cardiac rehabilitation and acute care nurses perceptions of providing sexual counseling for cardiac patients.

    PubMed

    Barnason, Susan; Steinke, Elaine; Mosack, Victoria; Wright, David W

    2011-01-01

    : The purpose of this study was to examine the differences between outpatient cardiac rehabilitation (CR) and acute care nurses perceived barriers and clinical practices of providing sexual counseling for myocardial infarction patients. : A nonexperimental descriptive, comparative research design with convenience sampling was used to survey CR and acute care nurses using the Survey of Sexuality Related Nursing Practice-Myocardial Infarction questionnaire. : A total of 320 nurses (81 CR nurses, 239 acute care nurses), in midwestern states completed the survey. Using ANCOVA analyses with age, work status, and education level as covariates, findings demonstrated CR nurses had significantly higher levels of role responsibility (F[4, 315] = 5.4, P < .05) and implementation of sexual counseling in clinical practice (F[4, 315] = 9.1, P < .0001). : Findings from this study further elucidate the influence of practice settings on the actual implementation of patient education and counseling of cardiac patients regarding sexual functioning. Outpatient CR nurses reported fewer barriers and reported higher rates of implementing sexual counseling into their practice. These findings support the importance of CR referral to provide both physical and psychosocial rehabilitation after a cardiac event. Findings bring to light the need to address the gap in practice to meet the perceived unmet needs of patients regarding their concerns of sexual functioning while hospitalized and for those patients who may not enroll in CR after hospital discharge.

  14. NFATC1 genotypes affect acute rejection and long-term graft function in cyclosporine-treated renal transplant recipients.

    PubMed

    Xu, Qinxia; Qiu, Xiaoyan; Jiao, Zheng; Zhang, Ming; Chen, Jianping; Zhong, Mingkang

    2017-03-01

    To investigate the effects of SNPs in the cyclophilin A/calcineurin/nuclear factor of activated T-cells (NFATs) pathway genes (PPIA, PPP3CB, PPP3R1, NFATC1 and NFATC2) on cyclosporine (CsA) efficacy in renal transplant recipients. Seventy-six tag SNPs were detected in 155 CsA-treated renal recipients with at least a 5-year follow-up. The associations of SNPs with acute rejection, nephrotoxicity, pneumonia and estimated glomerular filtration rate post transplant were explored. NFATC1 rs3894049 GC was a risk factor for acute rejection compared with CC carriers (p = 0.0005). NFATC1 rs2280055 TT carriers had a more stable estimated glomerular filtration rate level than CC (p = 0.0004). Detecting NFATC1 polymorphisms could help predict CsA efficacy in renal transplant patients.

  15. [Pseudotumorous cardiac infiltration in a patient with acute monoblastic leukemia].

    PubMed

    Orts, M; Ribera, J M; Calatrava, A; Larrouse, E; Catalán, R; Navarro, J T; Millá, F; Feliu, E

    1996-04-13

    Although cardiac infiltration is common in advanced stage of acute leukaemia, it is not usually diagnosed at life and it is extremely rare for it to become pseudotumoral. A 25-years-old patient with an acute monoblastic leukaemia who had a leukaemic infiltration which affected the main part of the left ventricle at the time of diagnosis, is referred. The heart infiltration was detected by a two dimension echocardiography. In spite of a massive infiltration, heart failure was not present and the left ventricle's ejection fraction was 50%. Even though chemotherapy was administered, the patient died four days after diagnosis due to septic shock of respiratory origin. The most relevant autopsy finding was a widespread pseudotumoral infiltration of the left ventricle, the back side of the right ventricle and the interventricular wall. The pseudotumoral infiltration of the heart by acute leukaemia is uncommon and must be differentiated from granulocytic sarcoma. The usefulness of the different diagnostic procedures is discussed.

  16. Polymorphisms in genes related to the complement system and antibody-mediated cardiac allograft rejection.

    PubMed

    Marrón-Liñares, Grecia M; Núñez, Lucía; Crespo-Leiro, María G; Barge-Caballero, Eduardo; Pombo, Jorge; Paniagua-Martin, María Jesús; Suarez-Fuentetaja, Natalia; Cid, Javier; Grille-Cancela, Zulaika; Muñiz-Garcia, Javier; Tan, Carmela D; Rodríguez, E Rene; Vázquez-Rodríguez, José Manuel; Hermida-Prieto, Manuel

    2017-07-15

    Heart transplantation (HT) is a life-saving treatment for patients with end-stage heart failure. One of the main problems after HT is the humoral response termed antibody-mediated rejection (AMR). Complement activation plays a key role in AMR contributing to graft damage. The aim of this study was to analyze genetic variants in genes related to the complement pathways that could be associated with the development of AMR. Analysis of 51 genes related to the complement pathway was performed by next-generation sequencing in 46 HT recipients, 23 with and 23 without AMR. Statistical analysis was performed with SNPstats and R. We identified 2 single nucleotide polymorphisms, 1 in the mannose-binding lectin 2 gene (p.Gly54Asp-MBL2) and 1 in the complement factor properdin gene (p.Asn428(p=)-CFP), that showed significant association with the absence and development of AMR, respectively. Moreover, the presence of the rare allele in p.Gly54Asp-MBL2 control patients correlated with an immunodeficiency of mannose-binding lectin (6.24 ng/ml vs 207.50 ng/ml, p < 0.01), whereas the presence of the rare allele p.Asn428(p=)-CFP in patients with AMR correlated with higher levels of properdin protein (14.65 μg/ml vs 10.77 μg/ml, p < 0.05). AMR is a complex phenotype affected by many recipient factors. Variants in p.Gly54Asp-MBL2 and p.Asn428(p=)-CFP genes, encoding mannose-binding lectin 2 and properdin, may influence the risk of AMR. Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  17. Early detection of acute kidney injury after pediatric cardiac surgery

    PubMed Central

    Jefferies, John Lynn; Devarajan, Prasad

    2016-01-01

    Acute kidney injury (AKI) is increasingly recognized as a common problem in children undergoing cardiac surgery, with well documented increases in morbidity and mortality in both the short and the long term. Traditional approaches to the identification of AKI such as changes in serum creatinine have revealed a large incidence in this population with significant negative impact on clinical outcomes. However, the traditional diagnostic approaches to AKI diagnosis have inherent limitations that may lead to under-diagnosis of this pathologic process. There is a dearth of randomized controlled trials for the prevention and treatment of AKI associated with cardiac surgery, at least in part due to the paucity of early predictive biomarkers. Novel non-invasive biomarkers have ushered in a new era that allows for earlier detection of AKI. With these new diagnostic tools, a more consistent approach can be employed across centers that may facilitate a more accurate representation of the actual prevalence of AKI and more importantly, clinical investigation that may minimize the occurrence of AKI following pediatric cardiac surgery. A thoughtful management approach is necessary to mitigate the effects of AKI after cardiac surgery, which is best accomplished in close collaboration with pediatric nephrologists. Long-term surveillance for improvement in kidney function and potential development of chronic kidney disease should also be a part of the comprehensive management strategy. PMID:27429538

  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. 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.

  20. Thrombolytic therapy in acute cerebral infarction complicating diagnostic cardiac catheterization.

    PubMed

    Chen, Yu-Wei; Sim, Ming-Ming; Smith, Eric E

    2006-10-01

    Diagnostic and interventional percutaneous coronary catheterization is associated with stroke. Many of such strokes are asymptomatic, but some are devastating. Once the diagnosis of acute cerebral infarction is confirmed, thrombolytic therapy should be administrated within the time window of 3 hours. We report a 61-year-old woman who suffered from an acute cerebral infarction during diagnostic cardiac catheterization for unstable angina, which manifested as sudden onset of global aphasia, right hemiplegia and gaze preponderance to the left side. Computed tomography of the head performed immediately after recognition of the symptoms showed a hyperdense middle cerebral artery (MCA) sign. Following prompt recognition and diagnosis, intravenous thrombolytic therapy was administered 2 hours after symptom onset. The patient had a favorable outcome. Initially, National Institutes of Health Stroke Scale score was 21, and 24 hours later it improved to 9. The hyperdense MCA lesion had resolved on the 24-hour follow-up scan. This case illustrates the clinical benefit of thrombolytic therapy in the setting of acute stroke associated with cardiac catheterization.

  1. 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.

  2. Electrocardiographic findings and cardiac manifestations in acute aluminum phosphide poisoning.

    PubMed

    Soltaninejad, Kambiz; Beyranvand, Mohammad-Reza; Momenzadeh, Seyed-Akbar; Shadnia, Shahin

    2012-07-01

    Aluminium phosphide (AlP) poisoning has a high mortality due to cardiovascular involvement. In this study, we evaluated the frequency of cardiac manifestations and electrocardiographic (ECG) findings in 20 patients with acute AlP poisoning, who were admitted to the intensive care unit (ICU) in Tehran, Iran, over a period of 6 months (between October 2008 and April 2009). The sex, age, cause and manner of ingestion, number of ingested AlP tablets, cardiac and ECG manifestations, creatine phosphokinase (CPK), CPK-myocardial band (CPK-mb) and troponin-T (TnT) were extracted from the patients' files. All data were analysed with Statistical Package for the Social Sciences (SPSS) software. The majority (60%) of patients were male. The mean age was 27 ± 8.7 years. The mortality rate was 40%. In all of the patients, the cause of poisoning was intentional suicide and ingestion was the route of exposure. The mean number of ingested AlP tablets per patient was 2.2 ± 1.1. The average time interval between admission and cardiovascular manifestations or ECG findings was 168.8 ± 116.2 min. The range of systolic (SBP) and diastolic blood pressure was 60-130 mmHg and 40-70 mmHg, respectively. Dysrhythmia was observed in nine (45%) cases. Elevation of the ST segment was seen in nine cases (45%). Seven patients (35%) had prolonged QTc intervals. Bundle branch block (BBB) was observed in four (20%) patients. In nine (45%) patients, the serum cardiac TnT qualitative assay was positive. There were no significant differences between normal and abnormal ECG groups according to sex, age, number and manner of ingested AlP tablets and SBP. There was a significant correlation between cardiac manifestations and ECG findings and TnT-positive results with mortality in acute AlP poisoning.

  3. 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

  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. 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. Acute kidney injury in patients undergoing cardiac surgery.

    PubMed

    Coppolino, Giuseppe; Presta, Piera; Saturno, Laura; Fuiano, Giorgio

    2013-01-01

    The incidence of postoperative acute kidney injury (AKI) in patients undergoing cardiac surgery ranges from 7.7% to 28.1% in different studies, probably in relation to the criteria adopted to define AKI. AKI markedly increases mortality risk. However, despite the development of less invasive techniques, cardiac surgery remains the first option in many conditions such as severe coronary artery disease, valve diseases and complex interventions. The risk of postsurgery AKI can be reduced by adopting less invasive approaches, such as off-pump coronary artery bypass grafting or transcatheter aortic valve implantation, but these options cannot be employed in all cases. Thus, since traditional cardiac surgery remains the only option in many cases, it is important to adopt strategies helping the clinician to prevent AKI or diagnose it early. Old age, preprocedural chronic kidney disease, obesity, some comorbidities, wide pulse pressure and some pharmacological regimens represent risk factors for postsurgery AKI and mortality. Important intraoperative factor are use and duration of cardiopulmonary bypass. Postoperative efforts should be aimed toward maximizing cardiac output, avoiding drugs vasoconstricting the renal artery, providing adequate crystalloid infusion and alkalinizing urine. Fluid management should not be based on the measurements for cardiac filling pressures, which are mostly unreliable in these patients. Novel biomarkers such as cystatin C, kidney injury molecule-1 and human neutrophil gelatinase-associated lipocalin have been found to change earlier than creatinine, particularly when measured in combination, so their use in clinical practice can facilitate early diagnosis and treatment of AKI. The occurrence of oliguria despite adequate cardiovascular therapy can be managed with furosemide, possibly using continuous infusion, or renal replacement therapy.

  7. Association of Soluble HLA-G with Acute Rejection Episodes and Early Development of Bronchiolitis Obliterans in Lung Transplantation

    PubMed Central

    White, Steven R.; Floreth, Timothy; Liao, Chuanhong; Bhorade, Sangeeta M.

    2014-01-01

    Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of bronchiolitis obliterans syndrome (BOS). Soluble HLA-G, a mediator of adaptive immunity that modulates regulatory T cells and certain classes of effector T cells, may be a useful marker of survival free of BOS. We conducted a retrospective, single-center, pilot review of 38 lung transplant recipients who underwent collection of serum and bronchoalveolar lavage fluid 3, 6 and 12 months after transplantation, and compared soluble HLA-G concentrations in each to the presence of type A rejection and lymphocytic bronchiolitis in the first 12 months and to the presence of BOS at 24 months after transplantation. Lung soluble HLA-G concentrations were directly related to the presence of type A rejection but not to lymphocytic bronchiolitis. Our data demonstrate that soluble HLA-G concentrations in bronchoalveolar lavage but not in serum correlates with the number of acute rejection episodes in the first 12 months after lung transplantation, and thus may be a reactive marker of rejection. PMID:25068264

  8. Cardiac tamponade, an unusual complication of acute pancreatitis.

    PubMed

    Veron Esquivel, Daniel; Aello, Gerardo; Batiz, Fernando; Fernandez Barrera, Alejandro

    2016-03-11

    A 41-year-old Hispanic man was admitted to our hospital with the diagnosis of acute pancreatitis due to hypertriglyceridemia. During his stay, he developed sudden haemodynamic instability and clinical presentation suggestive of cardiac tamponade. A transthoracic echocardiogram confirmed the diagnosis. Echocardiography-guided pericardiocentesis was performed with immediate haemodynamic improvement. The patient's condition underwent favourable evolution. The pancreatitis was resolved and a control transthoracic echocardiography was performed showing no pericardial effusion. The pathophysiology of this rare entity is unknown. Early diagnosis and treatment are crucial. Although pericardiocentesis is the treatment of choice, there have been a few reports of medical treatment with encouraging results. Although the association of acute pancreatitis and tamponade are anecdotal in literature, medics should be aware of this association in order to perform prompt diagnosis.

  9. 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.

  10. 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.

  11. Acute physical activity effects on cardiac gene expression.

    PubMed

    Simonsen, Michelle L; Alessio, Helaine M; White, Peter; Newsom, David L; Hagerman, Ann E

    2010-11-01

    Regular bouts of physical activity may cause changes in gene expression that accumulate over time and ultimately affect phenotypes, such as body weight, blood lipid profile and tumour development. Furthermore, acute activity may affect gene expression and phenotypes differently depending on whether the individual is regularly inactive or active. One-month-old male Sprague-Dawley rats (n = 72) were equally divided into SED (standard laboratory cage, n = 24), PA (large activity box, n = 24) and EX groups (exercise wheel inside standard cage, n = 24). At 3 months of age, half the animals from each group were killed at rest and the other half following 30 min of physical activity. The RNA was extracted from cardiac tissue, and microarray analysis was performed on 27,000 genes. Select gene results were validated using quantitative PCR. No gene expression differences occurred when comparing all 3-month-old groups at rest. A relatively small percentage of genes (1.9%) were differentially expressed (P < 0.05) following acute swimming activity in all groups, but only 37 unique and identifiable genes reached or exceeded twofold differences in expression. The genes Atf3, Fos, Apold1 and Pxdn were expressed differently among SED, PA and EX following acute activity, with a clear separation of the magnitude in gene expression with SED > PA > EX. Differences in gene expression levels in young physically inactive and active animals following acute activity have different regulatory roles in gene networks that affect health-related phenotypes.

  12. Management of acute cardiac tamponade by subxiphoid pericardiotomy.

    PubMed

    Alcan, K E; Zabetakis, P M; Marino, N D; Franzone, A J; Michelis, M F; Bruno, M S

    1982-02-26

    Eighteen patients with cardiac tamponade were treated by subxiphoid pericardiotomy performed with the patients under local anesthesia. This group included 9 cases of uremic pericarditis (50%), 5 cases of metastatic cancer (28%), 2 cases of trauma (11%), 1 case of tuberculosis (5.5%), and 1 case of unknown cause. Immediate relief from acute cardiac tamponade was obtained in all 18 cases with only minor and self-limiting postoperative complications, including transient supraventricular arrhythmias (five cases) and fever (five cases). There were no deaths related to either the operative procedure or reaccumulation of the pericardial effusion. The drainage period averaged 9.6 days (range, three to 28 days). Pericardial biopsy was performed in 15 of 18 cases. We conclude that subxiphoid pericardiotomy is a safe and effective method for the management of pericardial effusion of diverse causes. The ability to perform this technique safely using local anesthesia and the capacity to obtain a biopsy specimen under direct visualization make this technique superior to both needle pericardiocentesis and pericardiectomy in the acutely ill patient.

  13. 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

  14. Acute effects of carbon monoxide on cardiac electrical stability

    SciTech Connect

    Verrier, R.L.; Mills, A.K.; Skornik, W.A. )

    1990-10-01

    The objective of this project was to determine the effects of acute carbon monoxide exposure on cardiac electrical stability. To obtain a comprehensive assessment, diverse biological models were employed. These involved cardiac electrical testing in the normal and ischemic heart in anesthetized and conscious dogs. The experimental plan was designed both to examine the direct effects of carbon monoxide exposure on the myocardium and to evaluate possible indirect influences through alterations in platelet aggregability or changes in central nervous system activity in the conscious animal. Our results indicate that exposure to relatively high levels of carbon monoxide, leading to carboxyhemoglobin concentrations of up to 20 percent, is without significant effect on ventricular electrical stability. This appears to be the case in the acutely ischemic heart as well as in the normal heart. It is important to note that the total exposure period was in the range of 90 to 124 minutes. The possibility that longer periods of exposure or exacerbation from nicotine in cigarette smoke could have a deleterious effect cannot be excluded. We also examined whether or not alterations in platelet aggregability due to carbon monoxide exposure could be a predisposing factor for cardiac arrhythmias. A model involving partial coronary artery stenosis was used to simulate the conditions under which platelet plugs could lead to myocardial ischemia and life-threatening arrhythmias. We found no changes either in the cycle frequency of coronary blood flow oscillations or in platelet aggregability during carbon monoxide exposure. Thus, carbon monoxide exposure does not appear to alter platelet aggregability or its effect on coronary blood flow during stenosis. In the final series of experiments, we examined the effects of carbon monoxide exposure in the conscious state.

  15. Treatment of steroid-resistant acute renal allograft rejection with alemtuzumab.

    PubMed

    van den Hoogen, M W F; Hesselink, D A; van Son, W J; Weimar, W; Hilbrands, L B

    2013-01-01

    Steroid-resistant renal allograft rejections are commonly treated with rabbit antithymocyte globulin (RATG), but alemtuzumab could be an effective, safe and more convenient alternative. Adult patients with steroid-resistant renal allograft rejection treated with alemtuzumab (15-30 mg s.c. on 2 subsequent days) from 2008 to 2012 (n = 11) were compared to patients treated with RATG (2.5-4.0 mg/kg bodyweight i.v. for 10-14 days; n = 20). We assessed treatment-failure (graft loss, lack of improvement of graft function or need for additional anti-rejection treatment), infections during the first 3 months after treatment and infusion-related side effects. In both groups, the median time-interval between rejection and transplantation was 2 weeks, and approximately 75% of rejections were classified as Banff-IIA or higher. Three alemtuzumab-treated patients (27%) experienced treatment failure, compared to eight RATG treated patients (40%, p = 0.70). There was no difference in the incidence of infections. There were mild infusion-related side-effects in three alemtuzumab-treated patients (27%), and more severe infusion-related side effects in 17 RATG-treated patients (85%, p = 0.013). Drug related costs of alemtuzumab-treatment were lower than of RATG-treatment (€1050 vs. €2024; p < 0.01). Alemtuzumab might be an effective therapy for steroid-resistant renal allograft rejections. In contrast to RATG, alemtuzumab is nearly devoid of infusion-related side-effects. These data warrant a prospective trial. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

  16. Left ventricular longitudinal strain by speckle-tracking echocardiography is associated with treatment-requiring cardiac allograft rejection.

    PubMed

    Sera, Fusako; Kato, Tomoko S; Farr, Maryjane; Russo, Cesare; Jin, Zhezhen; Marboe, Charles C; Di Tullio, Marco R; Mancini, Donna; Homma, Shunichi

    2014-05-01

    Noninvasive detection of rejection is a major objective in the management of heart transplant recipients. To investigate the utility of 2-dimensional speckle-tracking echocardiography (2D-STE), we retrospectively evaluated 160 sets of endomyocardial biopsies and echocardiograms from 59 asymptomatic heart transplant recipients. Conventional International Society for Heart and Lung Transplantation grade 1B or higher rejection was considered as treatment-requiring rejection (group R), whereas International Society for Heart and Lung Transplantation grade 0 or 1A was classified as group Non-R. Left ventricular global longitudinal strain (GLS), global circumferential strain, and global radial strain were assessed by 2D-STE. Twenty-five specimens were classified into group R. GLS was significantly associated with treatment-requiring rejection, whereas neither global radial strain nor global circumferential strain were. Lower GLS remained significantly associated with an increased risk of treatment-requiring rejection (odds ratio, 1.15 [95% CI, 1.01-1.30]; P=0.03) even in multivariate analysis. GLS with the absolute value of less than 14.8% showed sensitivity and specificity of 64% and 63%, respectively, for detection of treatment-requiring rejection. The 2D-STE-derived left ventricular GLS was associated with treatment-requiring rejection. Two-dimensional STE might be useful as a noninvasive supplemental tool for monitoring heart transplant recipients for possible treatment-requiring rejection. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. 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.

  18. Increased BK viremia and progression to BK-virus nephropathy following high-dose intravenous immunoglobulin for acute cellular rejection.

    PubMed

    Boonyapredee, Maytee; Knight, Kendral; Little, Dustin

    2014-06-01

    BK virus nephropathy and cellular rejection are common causes of allograft dysfunction in renal transplant recipients. The two can be difficult to distinguish on allograft biopsy and can be present simultaneously. Management of the patient with coexistent BK infection and rejection is complicated by the conflicting ideals of decreasing immunosuppression to treat the former and increasing immunosuppression to treat the latter. The authors present the case of a 57-year-old renal transplant recipient who underwent allograft biopsy 8 weeks post-transplant for evaluation of increased serum creatinine in the setting of BK viremia (BKV). Biopsy revealed Banff classification 1b acute cellular rejection, with insufficient evidence to diagnose BK virus-associated nephropathy. The patient was administered intravenous immune globulin (IVIG), with no other changes in immunosuppressive therapy. Plasma and urine BK increased exponentially following IVIG administration, and allograft function further deteriorated. Repeat biopsy showed overt BK viral nephropathy, and BKV and creatinine decreased only after reduction in immunosuppression and initiation of leflunomide. Although case series have suggested a potential role for IVIG in the setting of BK infection, further study is needed to define the safety and efficacy of this approach. Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.

  19. Targeted delivery of interleukin-10 to chronic cardiac allograft rejection using a human antibody specific to the extra domain A of fibronectin.

    PubMed

    Franz, Marcus; Doll, Fabia; Grün, Katja; Richter, Petra; Köse, Nilay; Ziffels, Barbara; Schubert, Harald; Figulla, Hans R; Jung, Christian; Gummert, Jan; Renner, André; Neri, Dario; Berndt, Alexander

    2015-09-15

    Management of chronic rejection is challenging since there are not sufficient preventive or therapeutic strategies. The rejection process leads to overexpression of ED-A(+) fibronectin (ED-A(+) Fn). The human antibody F8, specific to ED-A(+) Fn, may serve as a vehicle for targeted delivery of bioactive payloads, e.g. interleukin 10 (IL-10). The aim of this study was to investigate the therapeutic effects of the fusion protein F8-interleukin-10 (F8-IL10) in the process of chronic rejection development. A heterotopic rat heart transplantation model was used to induce chronic rejection. For therapeutic interventions, the immunocytokines F8-humanIL10 (DEKAVIL), F8-ratIL10 as well as KSF-humanIL10 (irrelevant antigen-specificity) were used. Treatment was performed weekly for 10 weeks starting at day 7 after transplantation (1mg/animal). In the cardiac allografts, treatment with F8-huIL10 or F8-ratIL10 was associated with increased heart weights, a higher grade of chronic rejection, increased CIF, higher protein expression levels of alpha-smooth muscle actin (α-SMA), an augmented infiltration with inflammatory cells (CD4+, CD8+ and CD68+ cells) and higher serum levels of brain natriuretic peptide (BNP) compared to the control groups. All observed treatment effects are transplantation-specific since the F8 antibody is specific to ED-A(+) Fn that is not expressed in healthy hearts. A clear targeting effect of F8-huIL10 as well as F8-ratIL10 could be proven. Against that background, a further study is needed to address the question, if F8-IL10 treatment is capable to reduce CAV and CIF starting at a time point when chronic rejection has fully developed (therapeutic approach). Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. TLR Signals Promote IL-6/IL-17-Dependent Transplant Rejection1

    PubMed Central

    Chen, Luqiu; Ahmed, Emily; Wang, Tongmin; Wang, Ying; Ochando, Jordi; Chong, Anita S.; Alegre, Maria-Luisa

    2010-01-01

    Acute allograft rejection has often been correlated with Th1 differentiation, whereas transplantation tolerance is frequently associated with induction of regulation. The discovery of the Th17 phenotype has prompted its scrutiny in transplant rejection. Although IL-17 has recently been observed in settings of acute allograft rejection and drives rejection in T-bet-deficient mice that have impaired type 1 T cell responses, there is little evidence of its requirement during acute rejection in wild-type animals. We and others have previously shown that TLR9 signaling by exogenous CpG at the time of transplantation is sufficient to abrogate anti-CD154-mediated acceptance of fully mismatched cardiac allografts. In this study, we investigated the mechanism by which acute rejection occurs in this inflammatory context. Our results indicate that CpG targets recipient hematopoietic cells and that its pro-rejection effects correlate both with prevention of anti-CD154-mediated conversion of conventional CD4+ T cells into induced regulatory T cells (iTregs) and with the expression of IFN-γ and IL-17 by intra-graft CD4+ T cells. Moreover, the combined elimination of IL-6 and IL-17 signaling abrogated the ability of CpG to promote acute cardiac allograft rejection. Thus, pro-inflammatory signals at the time of transplantation can change the quality of the effector immune response and reveal a pathogenic function for IL-6 and IL-17 in wild-type recipients. PMID:19414775

  5. Bortezomib-containing regimen for primary treatment of early antibody-mediated cardiac allograft rejection: a case report.

    PubMed

    Gazdic, Tomas; Svobodova, Eva; Kubanek, Milos; Kment, Martin; Pagacova, Libuse; Viklicky, Ondrej; Malek, Ivan; Kautzner, Josef

    2015-06-01

    Evidence regarding the use of bortezomib-containing schemes in primary treatment of antibody-mediated rejection in heart transplant recipients is scarce. This case report presents the clinical experience with upstream use of bortezomib in primary treatment of early antibody-mediated rejection in an adult heart transplant recipient. Two cycles of bortezomib together with methylprednisolone, immunoadsorption, rituximab, and supplementary doses of intravenous immunoglobulin G reversed signs of heart failure, production of donor-specific antibodies, and findings of antibody-mediated rejection in biopsy. This treatment regimen was tolerated with only mild hematologic toxicity and proved to be successful during a 12-month follow-up. Primary treatment with a bortezomib-containing regimen appears to be a new therapeutic option for severe antibody-mediated rejection in heart transplant recipients. However, the efficacy and safety of this treatment need to be tested in prospective trials.

  6. Cellular rejection of the conduction system after orthotopic heart transplantation for congenital atrioventricular block.

    PubMed

    Chan, Jessica B; Levi, Daniel S; Lai, Chi K; Alejos, Juan C; Fishbein, Michael C

    2006-11-01

    We report a case of severe acute cellular rejection of the cardiac allograft conduction system in a 15-month-old girl who received orthotopic heart transplantation (OHT) for congestive heart failure from a congenital heart block. Post-operatively, the patient was treated for clinical evidence of rejection, but did not have electrocardiographic findings of heart block. Six weeks after transplantation, the patient developed sudden-onset bradycardia and died. Autopsy showed severe acute cellular rejection involving primarily the conduction system. Cellular rejection of the cardiac conduction system is a potentially lethal complication of OHT. Although diagnostic modalities to predict or detect ongoing cellular rejection in the conduction system are limited, recognizing the early signs, such as post-operative heart block, may prevent devastating consequences.

  7. A ROLE FOR ANTIBODIES TO HLA, COLLAGEN-V AND K-α1-TUBULIN IN ANTIBODY MEDIATED REJECTION AND CARDIAC ALLOGRAFT VASCULOPATHY

    PubMed Central

    Nath, Dilip S.; Tiriveedhi, Venkataswarup; Bash, Haseeb Ilias; Phelan, Donna; Moazami, Nader; Ewald, Gregory A.; Mohanakumar, T.

    2013-01-01

    Background We determined role of donor specific antibodies (DSA) and antibodies (Abs) to self-antigens, collagen-V (Col-V) and K-α1-Tubulin (KAT) in pathogenesis of acute antibody mediated rejection (AMR) and cardiac allograft vasculopathy (CAV) following human heart transplantation (HTx). Methods 137 HTx recipients - 60 early period (≤ 12months) and 77 late period (> 12months) patients were enrolled. Circulating DSA was determined using LUMINEX. Abs against Col-I, II, IV, V and KAT were measured using ELISA. Frequency of CD4+T helper cells (CD4+Th) secreting IFN-γ, IL-5, IL-10 or IL-17 specific to self-antigens were determined using ELISPOT. Results A significant association between AMR and DSA was demonstrated. Development of DSA in AMR patients correlated well with the development of auto-Abs to Col-V(AMR(+): 383±72μg/mL, AMR(−): 172±49μg/mL, p=0.033) and KAT (AMR(+): 252±49μg/mL, AMR(−): 61±21μg/mL, p=0.014). Patients who developed AMR demonstrated increased frequencies of CD4+Th secreting IFN-γ and IL-5 with reduction in IL-10 specific for Col-V/KAT. Patients diagnosed with CAV also developed DSA and auto-Abs to Col-V (CAV(+): 835±142μg/mL, CAV(−): 242±68μg/mL, p=0.025) and KAT (CAV(+): 768±206μg/mL, CAV(−): 196±72μg/mL, p=0.001) with increased frequencies of CD4+Th secreting IL-17 with reduction in IL-10 specific for Col-V/KAT. Conclusions Development of Abs to HLA and self-antigens are associated with increases in CD4+Th secreting IFN-γ and IL-5 in AMR and IL-17 in CAV, with reduction in CD4+Th secreting IL-10 in both AMR and CAV. PMID:21383658

  8. Colchicine Acutely Suppresses Local Cardiac Production of Inflammatory Cytokines in Patients With an Acute Coronary Syndrome.

    PubMed

    Martínez, Gonzalo J; Robertson, Stacy; Barraclough, Jennifer; Xia, Qiong; Mallat, Ziad; Bursill, Christina; Celermajer, David S; Patel, Sanjay

    2015-08-24

    Interleukin (IL)-1β, IL-18, and downstream IL-6 are key inflammatory cytokines in the pathogenesis of coronary artery disease. Colchicine is believed to block the NLRP3 inflammasome, a cytosolic complex responsible for the production of IL-1β and IL-18. In vivo effects of colchicine on cardiac cytokine release have not been previously studied. This study aimed to (1) assess the local cardiac production of inflammatory cytokines in patients with acute coronary syndromes (ACS), stable coronary artery disease and in controls; and (2) determine whether acute administration of colchicine inhibits their production. Forty ACS patients, 33 with stable coronary artery disease, and 10 controls, were included. ACS and stable coronary artery disease patients were randomized to oral colchicine treatment (1 mg followed by 0.5 mg 1 hour later) or no colchicine, 6 to 24 hours prior to cardiac catheterization. Blood samples from the coronary sinus, aortic root (arterial), and lower right atrium (venous) were collected and tested for IL-1β, IL-18, and IL-6 using ELISA. In ACS patients, coronary sinus levels of IL-1β, IL-18, and IL-6 were significantly higher than arterial and venous levels (P=0.017, <0.001 and <0.001, respectively). Transcoronary (coronary sinus-arterial) gradients for IL-1β, IL-18, and IL-6 were highest in ACS patients and lowest in controls (P=0.077, 0.033, and 0.014, respectively). Colchicine administration significantly reduced transcoronary gradients of all 3 cytokines in ACS patients by 40% to 88% (P=0.028, 0.032, and 0.032, for IL-1β, IL-18, and IL-6, respectively). ACS patients exhibit increased local cardiac production of inflammatory cytokines. Short-term colchicine administration rapidly and significantly reduces levels of these cytokines. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  9. 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

  10. THE UTILITY OF RIGHT VENTRICULAR ENDOMYOCARDIAL BIOPSY FOR THE DIAGNOSIS OF XENOGRAFT REJECTION AFTER CD46 PIG-TO-BABOON CARDIAC TRANSPLANTATION

    PubMed Central

    Ricci, Davide; Tazelaar, Henry D; Miyagi, Naoto; Rao, Vinay P; Pedersen, Rachel A; Kremers, Walter K; Byrne, Guerard W; McGregor, Christopher G A

    2007-01-01

    Introduction Endomyocardial biopsy (EmBx) is the standard means of establishing cardiac allograft rejection diagnosis. The efficacy of this procedure in xenotransplantation has not been determined. In this study we compare the histology of right ventricular EmBx specimens with the corresponding full cross sections of explanted right ventricle (RV). We also compare RV with the related left ventricle (LV) cross sections. Methods Heterotopic CD46 pig to baboon cardiac xenotransplants (n=64) were studied. RVEmBxs were taken at cardiac explant, using either a standard bioptome (RVEmBxBT; n=24) or by sharp dissection (RVEmBxSD; n=40). Hematoxylin-eosin stained sections of RV and LV cross section and RVEmBxs were compared in a blinded fashion. Characteristics of delayed xenograft rejection (DXR) and a global assessment of ischemia, were scored from 0 to 4 based on the percentage of myocardium involved (0 = 0%, 1=1−25%, 2 = 26−50%, 3 = 51−75%, 4 = 76−100%). Results Median graft survival was 30 days (range 3–137). Linear regression analysis of histology scores demonstrated that both RVEmBxBT and RVEmBxSD equally represented the histology of RV cross section. Global ischemic injury was strongly correlated between RV and RVEmBx (R2=0.84) and between RV and LV cross sections (R2=0.84). Individual characteristics of DXR showed no significant variation between RV and RVEmBx or between RV and LV (p<0.05). Conclusions These results indicate that DXR is a widespread process involving both right and left ventricles similarly. This study shows that histologic assessment of RVEmBx specimens is an effective method for the monitoring of DXR after cardiac xenotransplantation. PMID:17919623

  11. The Relationship of the Severity and Category of Acute Rejection With Intimal Arteritis Defined in Banff Classification to Clinical Outcomes.

    PubMed

    Wu, Kaiyin; Budde, Klemens; Schmidt, Danilo; Neumayer, Hans-Helmut; Rudolph, Birgit

    2015-08-01

    It is unclear if the category of acute rejection with intimal arteritis (ARV) is relevant to short- and long-term clinical outcomes and if the graft outcomes are affected by the severity of intimal arteritis. One hundred forty-eight ARV episodes were reviewed and categorized according to the 2013 Banff criteria of AMR: T cell-mediated rejection with intimal arteritis (v) lesion (TCMRV; n = 78), total antibody-mediated rejection with v lesion (AMRV), which were further divided into suspicious AMRV (n = 37) and AMRV (n = 33). The Banff scores of intimal arteritis (v1, v2 and v3) represented low, moderate, and high ARV severity. The grafts with TCMRV, suspicious AMRV (sAMRV), and AMRV showed similar responses to antirejection therapy, whereas the grafts with v2- or v3-ARV responded significantly poorer compared to those with v1-ARV. The 8-year death-censored graft survival (DCGS) rate was 56.8% of TCMRV versus 34.1% of total AMRV (Log rank, P = 0.03), but the 1- and 5-year DCGS rates were comparable between the 2 groups; moreover, the 1-, 5-, and 8-year DCGS rates of v1-ARV were evidently higher than v2- and v3-ARV (each pairwise comparison to v1-AVR yields P < 0.01); in contrast, the DCGS rates were similar between sAMRV and AMRV. The existing donor-specific antibodies or moderate microvascular inflammation or C4d-positive staining or intensive tubulointerstitial inflammation played a less significant role on the long-term graft survival. Compared to the category, the ARV severity is more closely associated with the initial response to antirejection therapy and long-term graft failure. The sAMRV and AMRV might represent a spectrum of the same disorder.

  12. Influence of the timing of cardiac catheterization and amount of contrast media on acute renal failure after cardiac surgery.

    PubMed

    Sadeghi, Mohsen Mirmohammad; Gharipour, Mojgan; Nilforoush, Peiman; Shamsolkotabi, Hamid; Sadeghi, Hamid Mirmohammad; Kiani, Amjad; Sadeghi, Pouya Mirmohammad; Farahmand, Niloufar

    2011-04-01

    There is limited data about the influence of timing of cardiac surgery in relation to diagnostic angiography and/or the impact of the amount of contrast media used during angiography on the occurance of acute renal failure (ARF). Therefore, in the present study the effect of the time interval between diagnostic angiography and cardiac surgery and also the amount of contrast media used during the diagnostic procedure on the incidence of ARF after cardiac surgery was investigated. Data of 1177 patients who underwent different types of cardiac surgeries after cardiac catheterization were prospectively examined. The influence of time interval between cardiac catheterization and surgery as well as the amount of contrast agent on postoperative ARF were assessed using multivariable logistic regression. The patients who progressed to ARF were more likely to have received a higher dose of contrast agent compared to the mean dose. However, the time interval between cardiac surgery and last catheterization was not significantly different between the patients with and without ARF (p = 0.05). Overall, postoperative peak creatinine was highest on day 0, then decreased and remained significantly unchanged after this period. Overall prevalence of acute renal failure during follow-up period had a changeable trend and had the highest rates in days 1 (53.57%) and 6 (52.17%) after surgery. Combined coronary bypass and valve surgery were the strongest predictor of postoperative ARF (OR: 4.976, CI = 1.613-15.355 and p = 0.002), followed by intra-aortic balloon pump insertion (OR: 6.890, CI = 1.482-32.032 and p = 0.009) and usage of higher doses of contrast media agent (OR: 1.446, CI = 1.033-2.025 and p = 0.031). Minimizing the amount of contrast agent has a potential role in reducing the incidence of postoperative ARF in patients undergoing cardiac surgery, but delaying cardiac surgery after exposure to these agents might not have this protective effect.

  13. 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

  14. 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.

  15. INHALATION OF OZONE AND DIESEL EXHAUST PARTICLES (DEP) INDUCES ACUTE AND REVERSIBLE CARDIAC GENE EXPRESSION CHANGES

    EPA Science Inventory

    We have recently shown that episodic but not acute exposure to ozone or DEP induces vascular effects that are associated with the loss of cardiac mitochondrial phospholipid fatty acids (DEP 2.0 mg/m3 > ozone, 0.4 ppm). In this study we determined ozone and DEP-induced cardiac gen...

  16. INHALATION OF OZONE AND DIESEL EXHAUST PARTICLES (DEP) INDUCES ACUTE AND REVERSIBLE CARDIAC GENE EXPRESSION CHANGES

    EPA Science Inventory

    We have recently shown that episodic but not acute exposure to ozone or DEP induces vascular effects that are associated with the loss of cardiac mitochondrial phospholipid fatty acids (DEP 2.0 mg/m3 > ozone, 0.4 ppm). In this study we determined ozone and DEP-induced cardiac gen...

  17. Murine model of immune-mediated rejection of the acute lymphoblastic leukemia 70Z/3.

    PubMed

    Labbe, Alain; Tran, Anne H; Paige, Christopher J

    2006-05-01

    70Z/3 is a murine pre-B cell leukemia line derived from BDF(1) mice and has been used in the study of signaling pathways in B cells. 70Z/3 cells were initially found to cause widespread disease upon injections in animals. We have isolated 70Z/3 variants divergent in their capacity to lead to morbidity after injections. One variant, 70Z/3-NL, elicits an immune response protecting the animal from tumor growth. Another variant, 70Z/3-L, does not induce an effective immune response and causes morbidity. We demonstrated that both CD4(+) and CD8(+) T cells are required for the rejection of 70Z/3-NL cells. Interestingly, the immune response generated against 70Z/3-NL cells was found to protect against a challenge with the lethal variant, 70Z/3-L. This indicates that although both lines can be recognized and killed by the immune system, only 70Z/3-NL is capable of inducing a protective response. Further observations, using subclones isolated from 70Z/3-NL, demonstrated that immune recognition of a portion of the cells was sufficient for protection. Depletion of CD4(+) and CD8(+) T cells in animals injected previously with 70Z/3-NL cells showed that T cells, and not Abs, were required for the maintenance of the protection initiated by 70Z/3-NL. We tested the capacity of 70Z/3-NL cells to treat mice challenged with 70Z/3-L. We can delay injections of 70Z/3-NL and still provide protection for the animals. We have a model of immune-mediated rejection which will allow us to dissect the requirements for the initiation of immune responses against an ALL tumor cell line.

  18. 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

  19. MOEMS-based cardiac enzymes detector for acute myocardial infarction

    NASA Astrophysics Data System (ADS)

    Amritsar, Jeetender; Stiharu, Ion G.; Packirisamy, Muthukumaran; Balagopal, Ganesharam; Li, Xing

    2004-10-01

    Biomedical applications of MOEMS are limited only by the mankind imagination. Precision measurements on minute amounts of biological material could be performed by optical means with a remarkable accuracy. Although available in medical laboratories for general purposes, such analyzers are making their way directly to the users in the form of dedicated equipment. Such an example is a test kit to detect the existence of cardiac enzymes in the blood stream. Apart from the direct users, the medical personnel will make use of such tools given the practicality of the kit. In a large proportion of patients admitted to the hospital suspected of Acute Myocardial Infarction (AMI), the symptoms and electrocardiographic changes are inconclusive. This necessitates the use of biochemical markers of myocardial damage for correct exclusion or conformation of AMI. In this study the concept of MOEMS is applied for the detection of enzyme reaction, in which glass spectrums are scanned optically when enzyme molecules adsorb on their surface. This paper presents the optical behavior of glass spectrums under Horseradish Peroxide (HRP) enzyme reaction. The reported experimental results provide valuable information that will be useful in the development of biosensors for enzymatic detection. This paper also reports the dynamic behavior of different glass spectrums.

  20. 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

  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. Mesothelial/monocytic incidental cardiac excrescences (cardiac MICE) associated with acute aortic dissection: a study of two cases

    PubMed Central

    Strecker, Thomas; Bertz, Simone; Wachter, David Lukas; Weyand, Michael; Agaimy, Abbas

    2015-01-01

    Acute aortic dissection is a life-threatening condition mainly caused by hypertension, atherosclerotic disease and other degenerative diseases of the connective tissue of the aortic wall. Mesothelial/monocytic incidental cardiac excrescences (cardiac MICE) is a rare benign reactive tumor-like lesion composed of admixture of histiocytes, mesothelial cells, and inflammatory cells set within a fibrinous meshwork without a vascular network or supporting stroma. Cardiac MICE occurring in association with aortic dissection is exceptionally rare (only one such case reported to date). We herein report on the surgical repair of two Stanford type A aortic dissections caused by idiopathic giant cell aortitis in a 66-year-old-woman and by atherosclerotic disease in a 58-year-old-man, respectively. In both cases, the dissections could be visualized via computed tomography. Histopathology showed cardiac incidental MICE within the external aortic wall near the pericardial surface which was confirmed by immunohistochemistry. PMID:26097568

  3. Cardiac Arrest in Acute Ischemic Stroke: Incidence, Predisposing Factors, and Clinical Outcomes.

    PubMed

    Joundi, Raed A; Rabinstein, Alejandro A; Nikneshan, Davar; Tu, Jack V; Fang, Jiming; Holloway, Robert; Saposnik, Gustavo

    2016-07-01

    Cardiac arrest is a devastating complication of acute ischemic stroke, but little is known about its incidence and characteristics. We studied a large ischemic stroke inpatient population and compared patients with and without cardiac arrest. We studied consecutive patients from the Ontario Stroke Registry who had an ischemic stroke between July 2003 and June 2008 at 11 tertiary care stroke centers in Ontario. Multivariable analyses were used to determine independent predictors of cardiac arrest and associated outcomes. Adjusted survival curves were computed, and hazard ratios for mortality at 30 days and 1 year were determined for cardiac arrest and other major outcomes. Among the 9019 patients with acute ischemic stroke, 352 had cardiac arrest, for an overall incidence of 3.9%. In a sensitivity analysis with palliative patients removed, the incidence of cardiac arrest was 2.5%. Independent predictors of cardiac arrest were as follows: older age, greater stroke severity, preadmission dependence, and a history of diabetes, myocardial infarction, congestive heart failure, and atrial fibrillation. Systemic complications associated with cardiac arrest were as follows: myocardial infarction, pulmonary embolism, sepsis, gastrointestinal hemorrhage, and pneumonia. Patients with cardiac arrest had higher disability at discharge, and a markedly increased 30-day mortality of 82.1% compared with 9.3% without cardiac arrest. Cardiac arrest had a high incidence and was associated with poor outcomes after ischemic stroke, including multiple medical complications and very high mortality. Predictors of cardiac arrest identified in this study could help risk stratify ischemic stroke patients for cardiac investigations and prolonged cardiac monitoring. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  4. Utility of left ventricular systolic torsion derived from 2-dimensional speckle-tracking echocardiography in monitoring acute cellular rejection in heart transplant recipients.

    PubMed

    Sato, Takahiro; Kato, Tomoko S; Komamura, Kazuo; Kamamura, Kazuo; Hashimoto, Shuji; Shishido, Toshiaki; Mano, Akiko; Oda, Noboru; Takahashi, Ayako; Ishibashi-Ueda, Hatsue; Nakatani, Takeshi; Asakura, Masanori; Kanzaki, Hideaki; Hashimura, Kazuhiko; Kitakaze, Masafumi

    2011-05-01

    Reduced left ventricular torsion (LV-tor) has been reported to be associated with acute rejection in heart transplant (HTx) recipients. We investigated the utility of LV-tor analysis derived from 2-dimensional speckle-tracking echocardiography (2D-STE) for detecting allograft rejection. A total of 301 endomyocardial biopsies (EMBs), right heart catheterizations and echocardiograms were performed in 32 HTx recipients. Echocardiography was done within 3 hours from EMB or simultaneously with the procedures. The LV-tor was defined as the difference between apical and basal end-systolic rotations. The LV-tor values with and without cellular rejection were compared. In addition, we investigated whether the change in LV-tor values predicts the change in rejection grade in each patient. The baseline LV-tor value in each patient was defined as a mean value of the first 3 LV-tor measurements obtained when the patient was free from rejection. According to the conventional International Society for Heart and Lung Transplantation criteria, 274 biopsies showed a rejection Grade of 0, 1a or 1b (Group AR(-)), whereas 27 biopsies were Grade 2 or higher (Group AR(+)). LV-tor decreased more in Group AR(+) than in Group AR(-) (9.3 ± 0.7 vs 12.2 ± 0.2 degrees, p < 0.0001). In the LV-tor measurement for each patient, the 25% reduction in LV-tor value from baseline predicted Grade 2 or higher rejection with a predictive accuracy of 92.9%. LV-tor derived from 2D-STE could be of clinical value for non-invasive monitoring of acute rejection in HTx recipients. Copyright © 2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

  5. 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.

  6. Immune biomarker panel monitoring utilizing IDO enzyme activity and CD4 ATP levels: prediction of acute rejection versus viral replication events

    PubMed Central

    Dharnidharka, Vikas R.; Gupta, Sushil; Khasawneh, Eihab Al; Haafiz, Allah; Shuster, Jonathan J.; Theriaque, Douglas W.; Shahlaee, Amir H.; Garrett, Timothy J.

    2011-01-01

    Infections have become as important an event as acute rejection post-transplant for long-term allograft survival. Less invasive biomarkers tested so far predict risk for one event or the other, not both. We prospectively tested blood and urine monthly for twelve months post-transplant from children receiving a kidney transplant. The indoleamine 2,3 dioxygenase (IDO) enzyme pathway was assessed by mass spectrometry assays using the ratio of product L-kynurenine (kyn) to substrate tryptophan (trp). Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with acute rejection or major infection events or stable group (no events) in the next 30 days. The 25 subjects experienced 6 discrete episodes of acute rejection in 5 subjects and 16 discrete events of major infection in 14 subjects (7 BK viruria, 6 cytomegaloviremia, 1 Epstein-Barr and cytomegaloviremia, 2 transplant pyelonephritis). Mean serum kyn/trp ratios were significantly elevated in the group that experienced acute rejection (p = 0.02).Within-subject analyses revealed that over time, urine kyn/trp ratios showed an increase (p = 0.01) and blood CD4-ATP levels showed a decrease (p = 0.007) prior to a major infection event. These pilot results suggest that a panel of biomarkers together can predict over- or under-immunosuppression, but need independent validation. PMID:21492353

  7. iTRAQ-Based Quantitative Proteomic Analysis of Tear Fluid in a Rat Penetrating Keratoplasty Model With Acute Corneal Allograft Rejection.

    PubMed

    Huang, Feifei; Xu, Jianjiang; Jin, Hong; Tan, Jianwen; Zhang, Chaoran

    2015-06-01

    This study aimed to develop a greater understanding of the mechanisms underlying acute corneal allograft rejection by identifying differentially expressed tear proteins at defined stages and discovering potentially important proteins involved in the process. The isobaric tags for relative and absolute quantitation (iTRAQ)-two-dimensional liquid chromatography-tandem mass spectrometry (2DLC-MS/MS) technique was used to identify tear proteins showing significant alterations in a rat penetrating keratoplasty model at different time points. Bioinformatics technology was applied to analyze the significant proteins, and a potential protein was verified by Western blotting. A total of 269 proteins were quantified, and 118 proteins were considered to be significantly altered by at least 2.0- or 0.5-fold. For gene ontology annotations, the top enrichments were neurological disease, free radical scavenging, cell death and survival, and cell movement. For pathway analyses, the top enrichments were LXR/RXR activation, acute phase response signaling, clathrin-mediated endocytosis signaling, and coagulation system. Coronin-1A was verified as a potential protein involved in the early stage of acute corneal allograft rejection. This study first demonstrates that tear proteomics is a powerful tool for better understanding of the mechanisms underlying acute corneal rejection, and that coronin-1A in tears might be closely related to allograft rejection.

  8. The Risk of Acute Rejection Following Kidney Transplant by 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D Status: A Prospective Cohort Study.

    PubMed

    Zimmerman, Deborah; House, Andrew A; Kim, S Joseph; Booth, Ronald A; Zhang, Tinghua; Ramsay, Tim; Knoll, Greg

    2017-01-01

    Prediction of acute kidney transplant rejection remains imperfect despite several known risk factors. There is an increasing appreciation of the potential importance of the vitamin D pathway in immunological disease and transplantation. The purpose of this study was to determine the association of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D with acute rejection. This was a prospective cohort study. Three academic adult kidney transplant programs in Ontario, Canada, were chosen. All consecutive adult patients at the 3 institutions who received a solitary kidney transplant, were able to provide written informed consent, and planned to be followed at the same center post-operatively were included. Serum concentration of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were measured at baseline, 3, and 6 months post-transplantation. Acute rejection was classified using Banff criteria. The co-primary outcome was the association between 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D and time to first occurrence of biopsy-proven acute rejection (BPAR) within the first year after kidney transplantation. Cox proportional hazards models were fitted taking into account the time-varying nature of serum concentrations of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. From 556 screened patients, data on 327 kidney transplant recipients are included. First BPAR occurred in 54 (16.5%) patients. In adjusted Cox proportional hazards models, the serum concentration of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D was not associated with acute renal transplant rejection (hazard ratio 1.00; 95% [confidence interval] CI, 0.87-1.14, per 10 nmol/L increase, and hazard ratio 0.97; 95% CI, 0.84-1.12, per 10 pmol/L increase, respectively). Given the observational design, we cannot rule out the possibility of residual confounding that limited our ability to detect a clinically significant effect of vitamin D metabolites on acute rejection. A low serum concentration of 25-hydroxyvitamin

  9. Identifying Risk for Acute Kidney Injury in Infants and Children Following Cardiac Arrest.

    PubMed

    Neumayr, Tara M; Gill, Jeff; Fitzgerald, Julie C; Gazit, Avihu Z; Pineda, Jose A; Berg, Robert A; Dean, J Michael; Moler, Frank W; Doctor, Allan

    2017-10-01

    Our goal was to identify risk factors for acute kidney injury in children surviving cardiac arrest. Retrospective analysis of a public access dataset. Fifteen children's hospitals associated with the Pediatric Emergency Care Applied Research Network. Two hundred ninety-six subjects between 1 day and 18 years old who experienced in-hospital or out-of-hospital cardiac arrest between July 1, 2003, and December 31, 2004. None. Our primary outcome was development of acute kidney injury as defined by the Acute Kidney Injury Network criteria. An ordinal probit model was developed. We found six critical explanatory variables, including total number of epinephrine doses, postcardiac arrest blood pressure, arrest location, presence of a chronic lung condition, pH, and presence of an abnormal baseline creatinine. Total number of epinephrine doses received as well as rate of epinephrine dosing impacted acute kidney injury risk and severity of acute kidney injury. This study is the first to identify risk factors for acute kidney injury in children after cardiac arrest. Our findings regarding the impact of epinephrine dosing are of particular interest and suggest potential for epinephrine toxicity with regard to acute kidney injury. The ability to identify and potentially modify risk factors for acute kidney injury after cardiac arrest may lead to improved morbidity and mortality in this population.

  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. Longitudinal Tracking of Recipient Macrophages in a Rat Chronic Cardiac Allograft Rejection Model With Noninvasive Magnetic Resonance Imaging Using Micrometer-Sized Paramagnetic Iron Oxide Particles

    PubMed Central

    Ye, Qing; Wu, Yijen L.; Foley, Lesley M.; Hitchens, T. Kevin; Eytan, Danielle F.; Shirwan, Haval; Ho, Chien

    2008-01-01

    Background Long-term survival of heart transplants is hampered by chronic rejection (CR). Studies indicate the involvement of host macrophages in the development of CR; however, the precise role of these cells in CR is unclear. Thus, it is important to develop noninvasive techniques to serially monitor the movement and distribution of recipient macrophages in chronic cardiac allograft rejection in vivo. Methods and Results We have employed a rat heterotopic working-heart CR model for a magnetic resonance imaging experiment. Twenty-one allograft (PVG.1U→PVG.R8) and 9 isograft (PVG.R8→PVG.R8) transplantations were performed. Recipient macrophages are labeled via intravenous injection of micron-sized paramagnetic iron oxide particles (0.9 μm in diameter) at a dose of 4.5 mg Fe per rat 1 day before transplantation. Serial in vivo magnetic resonance images were acquired for up to 16 weeks. The migration of labeled recipient cells in our CR model, in which cardiac CR is evident at 3 weeks and most extensive by 16 weeks after transplantation, can be assessed with the use of in vivo magnetic resonance imaging for >100 days after a single micron-sized paramagnetic iron oxide injection. The location and distribution of labeled recipient cells were confirmed with magnetic resonance microscopy and histology. Conclusions This approach may improve our understanding of the immune cells involved in CR and the management of heart transplantation. Moreover, this study demonstrates the feasibility of noninvasively observing individual targeted cells over long time periods by serial in vivo magnetic resonance imaging. PMID:18591438

  12. Application of Cardiac Troponin in Cardiovascular Diseases Other Than Acute Coronary Syndrome.

    PubMed

    Eggers, Kai M; Lindahl, Bertil

    2017-01-01

    Increased cardiac troponin concentrations in acute coronary syndrome (ACS) identify patients with ongoing cardiomyocyte necrosis who are at increased risk. However, with the use of more precise assays, cardiac troponin increases are commonly noted in other cardiovascular conditions as well. This has generated interest in the use of cardiac troponin for prognostic assessment and clinical management of these patients. In this review, we have summarized the data from studies investigating the implications of cardiac troponin concentrations in various acute and chronic conditions beyond ACS, i.e., heart failure, myocarditis, Takotsubo cardiomyopathy, aortic dissection, supraventricular arrhythmias, valve disease, pulmonary arterial hypertension, stroke, and in the perioperative setting. Cardiac troponin concentrations are often detectable and frankly increased in non-ACS conditions, in particular when measured with high-sensitivity (hs) assays. With the exception of myocarditis and Takotsubo cardiomyopathy, cardiac troponin concentrations carry strong prognostic information, mainly with respect to mortality, or incipient and/or worsening heart failure. Studies investigating the prognostic benefit associated with cardiac troponin-guided treatments however, are almost lacking and the potential role of cardiac troponin in the management of non-ACS conditions is not defined. Increased cardiac troponin indicates increased risk for adverse outcome in patients with various cardiovascular conditions beyond ACS. Routine measurement of cardiac troponin concentrations can however, not be generally recommended unless there is a suspicion of ACS. Nonetheless, any finding of an increased cardiac troponin concentration in a patient without ACS should at least prompt the search for possible underlying conditions and these should be managed meticulously according to current guidelines to improve outcome. © 2016 American Association for Clinical Chemistry.

  13. Incidence and Risk Factors for Postcontrast Acute Kidney Injury in Survivors of Sudden Cardiac Arrest.

    PubMed

    Petek, Bradley J; Bravo, Paco E; Kim, Francis; de Boer, Ian H; Kudenchuk, Peter J; Shuman, William P; Gunn, Martin L; Carlbom, David J; Gill, Edward A; Maynard, Charles; Branch, Kelley R

    2016-04-01

    Survivors of sudden cardiac arrest may be exposed to iodinated contrast from invasive coronary angiography or contrast-enhanced computed tomography, although the effects on incident acute kidney injury are unknown. The study objective was to determine whether contrast administration within the first 24 hours was associated with acute kidney injury in survivors of sudden cardiac arrest. This cohort study, derived from a prospective clinical trial, included patients with sudden cardiac arrest who survived for 48 hours, had no history of end-stage renal disease, and had at least 2 serum creatinine measurements during hospitalization. The contrast group included patients with exposure to iodinated contrast within 24 hours of sudden cardiac arrest. Incident acute kidney injury and first-time dialysis were compared between contrast and no contrast groups and then controlled for known acute kidney injury risk factors. Of the 199 survivors of sudden cardiac arrest, 94 received iodinated contrast. Mean baseline serum creatinine level was 1.3 mg/dL (95% confidence interval [CI] 1.4 to 1.5 mg/dL) for the contrast group and 1.6 mg/dL (95% CI 1.4 to 1.7 mg/dL) for the no contrast group. Incident acute kidney injury was lower in the contrast group (12.8%) than the no contrast group (17.1%; difference 4.4%; 95% CI -9.2% to 17.5%). Contrast administration was not associated with significant increases in incident acute kidney injury within quartiles of baseline serum creatinine level or after controlling for age, sex, race, congestive heart failure, diabetes, and admission serum creatinine level by regression analysis. Older age was independently associated with acute kidney injury. Despite elevated baseline serum creatinine level in most survivors of sudden cardiac arrest, iodinated contrast administration was not associated with incident acute kidney injury even when other acute kidney injury risk factors were controlled for. Thus, although acute kidney injury is not uncommon

  14. Differential diagnosis of acute rejection and chronic cyclosporine nephropathy after rat renal transplantation by detection of endothelial microparticles (EMP).

    PubMed

    Cui, Jiewei; Yang, Jing; Cao, Weike; Sun, Yi

    2010-12-01

    Endothelial microparticles (EMP) are small vesicles smaller than 1.0μm, released from endothelial cells (EC) during their activation and (or) apoptosis. The assay of the level of elevated EMP is a new approach to evaluate the dysfunction of endothelial cell. EMP can be classified into several types according to their membrane molecular, and the levels of various types of EMP may be different. As the most cost-effective immunodepressant, cyclosporine A (CsA) has been used widely in organ transplantation. But its dose is hard to control, under-medication may cause the acute rejection (AR) and overdose may cause chronic cyclosporine nephropathy (CCN). The cyclosporine A (CsA) caused CCN and the AR caused renal injury after renal transplantation are both vascular diseases related with endothelial dysfunction, and up to now, there is still no effective method to distinguish the two kinds of diseases. Owing to distinct pathogenesis of the two kinds of vascular diseases, the level of each type of EMP originated from vascular endothelial cells may be different. We hypothesize that maybe we can distinguish them by detecting the different levels of some types of EMP which is also related with vascular disease, and we propose to prove our hypothesis through animal experiment. If our hypothesis is proved, it will be more helpful for clinicians to adjust the dose of CsA promptly according to the differential diagnosis of the two kinds of diseases. Copyright © 2010 Elsevier Ltd. All rights reserved.

  15. 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.

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

    PubMed Central

    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. PMID:25897756

  17. [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.

  18. 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.

  19. Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach.

    PubMed

    Daher Abdi, Z; Essig, M; Rizopoulos, D; Le Meur, Y; Prémaud, A; Woillard, J B; Rérolle, J P; Marquet, P; Rousseau, A

    2013-06-01

    This study aimed to investigate the association between longitudinal exposure to mycophenolic acid (MPA) and acute rejection (AR) risk in the first year after renal transplantation, and to propose MPA exposure targets conditionally to this association. A joint model, adjusted for monitoring strategy (fixed-dose versus concentration-controlled) and recipient age, was developed; it combined a mixed-effects model to describe the whole pattern of MPA exposure (i.e. area under the concentration-time curve (AUC)) and a survival model. MPA AUC thresholds were determined using time-dependent receiver-operating characteristics (ROC) curves. Data from 490 adult renal-transplant recipients, representative of the general population of adult renal-transplant patients (i.e. including patients considered at low immunological risk-enrolled in the OPERA trial as well as second renal transplant and patients co-treated by either cyclosporine or tacrolimus), were analyzed. A significant association was found between the longitudinal exposure to MPA (MPA AUCs=f(t)) and AR (p=0.0081), and validated by bootstrapping. A significant positive correlation was observed between time post-transplantation and ROC thresholds which increased in average from 35 mg h/L in the first days to 41 mg h/L beyond six months post-transplantation (p<0.001). Using a new modeling approach which recognizes the repeated measures in a same patient, this study supports the association between MPA exposure and AR.

  20. Interleukin-10-1082 G/a polymorphism and acute renal graft rejection: a meta-analysis.

    PubMed

    Hu, Qiongwen; Tian, Hua; Wu, Qing; Li, Jun; Cheng, Xiaocheng; Liao, Pu

    2016-01-01

    The aim of this study was to investigate the association between interleukin (IL)-10-1082 (G/A) promoter polymorphism and acute rejection (AR) in renal transplant recipients. We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register from the inception to March 2015 for relevant studies. Data concerning publication information, population characteristics, and transplant information were extracted. Odds ratios (ORs) was calculated for the association between IL-10-1082 GG genotype (or IL-10-1082 G allele) and AR risk. This meta-analysis included 22 case-control studies including 2779 cases of renal transplant recipients. The pooled estimate showed that the IL-10-1082 GG genotype was not significantly associated with AR risk (ORrandom=1.07, 95% CI 0.80-1.43, p = 0.64). Similarly, the pooled estimate showed that the IL-10-1082 G allele was not significantly associated with AR risk (ORfixed=1.02, 95% CI 0.90-1.16, p = 0.74). None of subgroup analyses yielded significant results in the association between IL-10-1082 GG genotype (or IL-10-1082 G allele) and AR risk. Meta-regression confirmed that there was no significant correlation between the pre-selected trial characteristics and our study results. This meta-analysis suggests that IL-10-1082 G/A polymorphism is not significantly associated with AR risk in renal transplant recipients.

  1. Cardiac Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Sánchez-Quintana, Ana; Quijada-Fumero, Alejandro; Laynez-Carnicero, Ana; Breña-Atienza, Joaquín; Poncela-Mireles, Francisco J.; Llanos-Gómez, Juan M.; Cabello-Rodríguez, Ana I.; Ramos-López, María

    2016-01-01

    Secondary or metastatic cardiac tumors are much more common than primary benign or malignant cardiac tumors. Any tumor can cause myocardial or pericardial metastasis, although isolated or combined tumor invasion of the pericardium is more common. Types of neoplasia with the highest rates of cardiac or pericardial involvement are melanoma, lung cancer, and breast and mediastinal carcinomas. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Initial treatment involves chemotherapy followed by consolidation treatment to reduce the risk of relapse. In high-risk patients, the treatment of choice for consolidation is hematopoietic stem cell transplantation (HSCT). Relapse of AML is the most common cause of HSCT failure. Extramedullary relapse is rare. The organs most frequently affected, called “sanctuaries,” are the testes, ovaries, and central nervous system. We present a case with extramedullary relapse in the form of a solid cardiac mass. PMID:27642531

  2. Giant epicardial cyst presenting as acute cardiac tamponade in a 2-year-old boy.

    PubMed

    Masuoka, Ayumu; Sakurai, Hayato; Shiraishi, Masahisa; Yoshiba, Shigeki; Katogi, Toshiyuki; Suzuki, Takaaki

    2015-09-01

    Cystic structures within the pericardial cavity are rare. They are divided into epicardial and pericardial variants. Pericardial and epicardial cysts rarely cause symptoms. This report describes a case of epicardial cyst with acute cardiac tamponade in a 2-year-old boy with no previous cardiac history who was transferred to our hospital because of hemodynamic instability. Emergency drainage of the pericardial effusion and complete excision of the cyst were performed through a median full sternotomy.

  3. Acute ischemic stroke after cardiac catheterization: the protamine low-dose recombinant tissue plasminogen activator pathway.

    PubMed

    Guevara, Carlos; Quijada, Alonso; Rosas, Carolina; Bulatova, Katya; Lara, Hugo; Nieto, Elena; Morales, Marcelo

    2016-05-20

    Intravenous thrombolysis is the preferred treatment for acute ischemic stroke; however, it remains unestablished in the area of cardiac catheterization. We report three patients with acute ischemic stroke after cardiac catheterization. After reversing the anticoagulant effect of unfractionated heparin with protamine, all of the patients were successfully off-label thrombolyzed with reduced doses of intravenous recombinant tissue plasminogen activator (0.6 mg/kg). This dose was preferred to reduce the risk of symptomatic cerebral or systemic bleeding. The sequential pathway of protamine recombinant tissue plasminogen activator at reduced doses may be safer for reducing intracranial or systemic bleeding events, whereas remaining efficacious for the treatment of acute ischemic stroke after cardiac catheterization.

  4. CD8(+) effector memory T cells induce acute rejection of allogeneic heart retransplants in mice possibly through activating expression of inflammatory cytokines.

    PubMed

    Du, Gang; Yang, Nuo; Gong, Wenlin; Fang, Yuan; He, Jian; Zhou, Nuo; Lu, Xiaoling; Zhao, Yongxiang

    2017-06-01

    To investigate the effects of CD8(+) memory T (Tm) cells and CD8(+) effector memory T (Tem) cells on the results of allogeneic heart retransplantations performed in mice. A skin transplantation model was used to generate sensitized splenic CD8(+) Tem cells for infusion into BALB/c mice. One week after infusion, the BALB/c mice underwent allogeneic heart transplantation in the abdominal cavity. Cyclosporin A was administered via intraperitoneal injection starting one day prior to transplantation to arrest immunological rejection of the transplanted heart. The effects of sensitized CD8(+) Tem cells on allogeneic heart graft rejection were examined by monitoring survival of the transplanted hearts, the infiltration of effector memory CD8(+) T cells into myocardium, and expressions of inflammatory cytokines in blood serum. Adoptive transfer of sensitized CD8(+) Tem cells prior to transplantation induced an acute rejection response which decreased the survival of transplanted hearts. The rejection response was accompanied by an infiltration of CD8(+) Tem cells into the transplanted myocardial tissue. Additionally, infusion of sensitized CD8(+) Tem cells induced markedly increased expressions of IL-2 and IFN-γ, and decreased expression of TGF-β in the transplanted hearts, as well as higher levels of IFN-γ and CXCL-9 in blood serum. The infusion of sensitized CD8(+) Tem cells induced an acute graft rejection response and decreased the survival of grafted hearts by regulating the expressions of inflammatory cytokines including CXCL-9, IL-2, and INF-γ. Cyclosporin A had no therapeutic effect on the graft rejection response induced by sensitized CD8(+) Tem cells. Copyright © 2017. Published by Elsevier Inc.

  5. Decreased percentages of regulatory T cells are necessary to activate Th1-Th17-Th22 responses during acute rejection of the peripheral nerve xenotransplantation in mice.

    PubMed

    Chai, Huihui; Yang, Lujun; Gao, Lei; Guo, Yanwu; Li, Hui; Fan, Xulong; Wu, Bolin; Xue, Shan; Cai, Yingqian; Jiang, Xiaodan; Qin, Bing; Zhang, Shizhong; Ke, Yiquan

    2014-10-15

    T cells have major functions in the initiation and perpetuation of nerve graft rejection. Our study aimed to investigate the function of regulatory T cells (Treg)-Th1-Th17-Th22 cells in the rejection of peripheral nerve xenotransplantation. Adult male C57 BL/6 mice were used as the recipient for nerve xenotransplantation, and Sprague-Dawley rats were used as the donor. These nerve xenotransplanted mice were used as the experimental groups, and those that received autograft transplant were chosen as the control group. All of the animals were pretreated with interferon (IFN)-γ, interleukin (IL)-17, and IL-22 before the experiment was conducted. The percentages of spleen Treg-Th1-Th17-Th22 cells were evaluated by flow cytometry 1, 3, 7, 14, and 28 days after transplantation. Serum levels of IFN-γ, IL-17, and IL-22 were assessed by enzyme-linked immunosorbent assay. Statistical analysis was performed by Wilcoxon rank sum and Spearman correlation test. During acute rejection, the percentages of Th1-Th17-Th22 cells in the spleen and serum IFN-γ, IL-17, and IL-22 levels in the experimental group increased compared with those in the control group. By contrast, CD4CD25Foxp3 T cell level decreased. The rejection of xenograft was significantly prevented after the mice were treated with IL-17-neutralizing, IL-22-neutralizing, and IFN-γ-neutralizing antibodies. Moreover, the percentage of CD4CD25Foxp3 Treg was negatively correlated with the percentages of Th1-Th17-Th22 cells and levels of IL-17, IL-22, and IFN-γ. These results suggested that the Treg-Th1-Th17-Th22 cells involved in xenotransplant rejection and imbalance between Tregs and Th1-Th17-Th22 cells contribute to the acute rejection of peripheral nerve xenotransplant.

  6. Acute Decompensation in Pediatric Cardiac Patients: Outcomes After Rapid Response Events.

    PubMed

    Bavare, Aarti C; Rafie, Kimia S; Bastero, Patricia X; Hagan, Joseph L; Checchia, Paul A

    2017-05-01

    We studied rapid response events after acute clinical instability outside ICU settings in pediatric cardiac patients. Our objective was to describe the characteristics and outcomes after rapid response events in this high-risk cohort and elucidate the cardiac conditions and risk factors associated with worse outcomes. A retrospective single-center study was carried out over a 3-year period from July 2011 to June 2014. Referral high-volume pediatric cardiac center located within a tertiary academic pediatric hospital. All rapid response events that occurred during the study period were reviewed to identify rapid response events in cardiac patients. None. We reviewed 1,906 rapid response events to identify 152 rapid response events that occurred in 127 pediatric cardiac patients. Congenital heart disease was the baseline diagnosis in 74% events (single ventricle, 28%; biventricle physiology, 46%). Seventy-four percent had a cardiac surgery before rapid response, 37% had ICU stay within previous 7 days, and acute kidney injury was noted in 41% post rapid response. Cardiac and/or pulmonary arrest occurred during rapid response in 8.5%. Overall, 81% were transferred to ICU, 22% had critical deterioration (ventilation or vasopressors within 12 hr of transfer), and 56% received such support and/or invasive procedures within 72 hours. Mortality within 30 days post event was 14%. Significant outcome associations included: single ventricle physiology-increased need for invasive procedures and mortality (adjusted odds ratio, 2.58; p = 0.02); multiple rapid response triggers-increased ICU transfer and interventions at 72 hours; critical deterioration-cardiopulmonary arrest and mortality; and acute kidney injury-cardiopulmonary arrest and need for hemodynamic support. Congenital heart disease, previous cardiac surgery, and recent discharge from ICU were common among pediatric cardiac rapid responses. Progression to cardiopulmonary arrest during rapid response, need for ICU

  7. 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

  8. Treatment of Biopsy-Proven Acute Antibody-Mediated Rejection Using Thymoglobulin (ATG) Monotherapy and a Combination of Rituximab, Intravenous Immunoglobulin, and Plasmapheresis: Lesson Learned from Primary Experience.

    PubMed

    Zheng, Jin; Xue, Wujun; Qing, Xin; Jing, Xin; Hou, Jun; Tian, Xiaohui; Guo, Qi; He, Xiaoli; Cai, Junchao

    2014-01-01

    Three strategies have been previously proposed to treat or prevent antibody-mediated rejection (AMR): (1) inhibition/depletion of antibody producing cells; (2) removal/blockage of antibodies; and, (3) inhibition of antibody-mediated tissue injury. Here we test the efficacy of lymphocyte-depleting agent antithymocyte globulin (ATG) and triple therapy of rituximab, intravenous immunoglobulin (IVIG), and plasmapheresis in treating AMR. Five biopsy-proven AMR patients were enrolled in this acute AMR treatment study. All patients received renal transplants from HLA highly mismatched donation after cardiac death (DCD) donors. Four patients received thymoglobulin (ATG) monotherapy at a dose of 75 mg/day for 5-8 days. One patient received a combination of rituximab (375 mg/m2), IVIG (50 g/day x2 days), and double filtration plasmapheresis (4x). Donor specific HLA antibodies (DSA), serum creatinine, and clinical signs and symptoms were used to determine the efficacy of anti-AMR treatment. All 5 patients developed AMR within 2 weeks after transplant. Two patients had class I DSA and 2 patients had class II DSA. One patient had both class I & II DSA. DSA in four patients (#1, 2, 4, 5) were pre-existing and the levels of these DSA surged significantly within a week following transplant. The only patient (#3) without pre-existing DSA developed de novo DSA within 2 weeks post-transplant that rose rapidly regardless of anti-rejection treatment. All patients had positive C4d staining in peritubular capillaries. The proportion of B cells in all patients increased significantly above baseline level when patients experienced AMR. Even though both ATG and rituximab therapies successfully reduced the B cell proportion one week post anti-AMR treatment, their effects on DSA were not ideal. Patient #1 with mild AMR responded well to ATG monotherapy and DSA level steadily decreased from 2 weeks post-ATG treatment and became negative in the last follow-up test. The DSA levels in patient #2

  9. The Acute Impact of Smoking One Cigarette on Cardiac Hemodynamic Parameters

    PubMed Central

    Farha, Khalid Abou; AbouFarha, Ramy; Bolt, Marc

    2011-01-01

    Background The acute impact of tobacco smoking on the cardiac hemodynamic parameters and its pathological implication in the process of arterial atherosclerosis need further exploration. This investigation was purposed to assess the acute impact of tobacco smoke on blood pressure and cardiac hemodynamic parameters. Methods Using an Ultrasonic Cardiac Output Monitor, and DINAMAP Pro 400 Series V2 blood pressure monitor, several cardiac hemodynamic parameters and the blood pressure were assessed in 14 smokers, 11 females and 3 males, at 2 time points, before and after smoking of one cigarette. Data, in terms of ratio of the means and 95% confidence interval were analyzed using ANOVA. Results Single-subject design in which the subject has served as his/her own control has been used. Tobacco smoking led to statistically significant acute increase in the means of all hemodynamic parameters, except for heart rate in female subjects, as compared to the means obtained before smoking. Conclusions Cigarette smoking induces acute non-physiologic alteration in cardiac outflow forces, exposing the aortic valve and arch to mechanical injury that might be implicated in initiating and promoting the process of aortic arch atherosclerosis and associated pathological lesions.

  10. Histological long-term outcomes from acute antibody-mediated rejection following ABO-compatible liver transplantation.

    PubMed

    Del Bello, Arnaud; Danjoux, Marie; Congy-Jolivet, Nicolas; Lavayssière, Laurence; Esposito, Laure; Muscari, Fabrice; Kamar, Nassim

    2017-04-01

    Acute antibody-mediated rejection (aAMR) is an unusual complication after orthotopic ABO-compatible liver transplantation. To date, the clinical and histological long-term outcomes after aAMR are not well known. Herein, we describe nine cases of aAMR that occurred in our liver-transplant center between 2008 and 2016, with an initial and reevaluation liver biopsy available for reexamination. Two patients presented with aAMR at 10.5 (10, 11) days post-transplantation, caused by preformed donor-specific antibodies. Seven other recipients developed de novo donor-specific antibodies and aAMR at 11.2 (3-24) months post-transplantation. Eight of the nine patients received a B-cell targeting agent (rituximab, with or without plasma exchange), associated with polyclonal antibodies (three patients) or intravenous immunoglobulins (three patients). At the last follow up (i.e. 21 [4-90] months post-aAMR), seven patients were alive, including two patients with normal liver tests. Grafts' survival was 66%. A liver biopsy performed at 11.5 (5-48.5) months after the first biopsy showed no significant improvement in aAMR score (from 2 ± 1.3 to 1.6 ± 1.5, P = 0.6), a significant improvement in chronic AMR score (from 37 ± 9 to 25 ± 8, P = 0.003) and an increase in the Metavir score (1.2 ± 0.6 to 2.1 ± 0.9, P = 0.03). In this study, a B-cell-depleting agent seemed to improve the prognosis of aAMR in selected cases, but several patients kept active lesions antibody-mediated rejection. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  11. 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.

  12. Cardiac autonomic denervation and functional response to neurotoxins during acute experimental Chagas' disease in rats.

    PubMed

    Teixeira, A L; Fontoura, B F; Freire-Maia, L; Chiari, E; Machado, C R; Teixeira, M M; Camargos, E R

    2001-06-20

    Severe cardiac autonomic denervation occurs in the acute Chagas' disease in rats. The present study aims at verifying whether this denervation was accompanied by impairment of heart function. Scorpionic (Tityus serrulatus) crude venom was used for neurotransmitter release in isolated hearts (Langendorff's preparation). In control hearts, the venom induced significant bradycardia followed by tachycardia. In infected animals, despite the severe (sympathetic) or moderate (parasympathetic) cardiac denervation, the venom provoked similar bradycardia but the tachycardia was higher. The hearts of infected animals beat at significantly lower rate. Atropine prevented this lower rate. Our results demonstrated sympathetic dysfunction during the acute phase of Trypanosoma cruzi infection in rats, the parasympathetic function being spared.

  13. Fatal cardiac tamponade as the first manifestation of acute myeloid leukemia.

    PubMed

    Leptidis, John; Aloizos, Stavros; Chlorokostas, Panagiotis; Gourgiotis, Stavros

    2014-10-01

    Acute myeloid leukemia is a hemopoietic myeloid stem cell neoplasm. It is the most common acute leukemia affecting adults,and its incidence increases with age. Acute myeloid leukemia is characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. As the leukemic cells keep filling the bone marrow, symptoms of the disease started to appear: fatigue, bleeding, increased frequency of infections, and shortness of breath. Cardiac tamponade or pericardial tamponade is an acute medical condition in which the accumulation of pericardial fluid prevents the function of the heart. Signs and symptoms include Beck triad (hypotension, distended neck veins, and muffled heart sounds), paradoxus pulses, tachycardia, tachypnea, and breathlessness. Pericardial effusion and cardiac tamponade are rare and severe complications of leukemia; they often develop during the radiation therapy, chemotherapy, or infections in the course of leukemia. This study sought to assess the fatal cardiac tamponade as the first manifestation of acute myeloid leukemia (AML). We found no reports in the literature linking these 2 clinical entities. Although the patient had no signs or diagnosis of AML previously, this case was remarkable for the rapidly progressive symptoms and the fatal outcome. The pericardial effusion reaccumulated rapidly after its initial drainage; it is a possible explanation that the leukemic cells interfered with cardiac activity or that they decreased their contractility myocytes secreting a toxic essence.

  14. 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.

  15. Local Tacrolimus (FK506) Delivery for Prevention of Acute Rejection in the Nonhuman Primate Delayed Mixed Chimerism Vascularized Composite Allograft Tolerance Induction Protocol

    DTIC Science & Technology

    2016-10-01

    optimizing a fabrication method, and developing characterization methods to test the pharmacokinetics after drug loading. To this end, the team...planned for testing the PLDS in a small animal model as well as a non-human primate model. 15. SUBJECT TERMS Drug delivery, immunosuppression...delivery of tacrolimus (a potent immunosuppressive drug ) to prevent acute rejection episodes of vascularized composite allografts (VCAs) in non-human

  16. 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

  17. FcγRIIb expression on B cells is associated with treatment efficacy for acute rejection after kidney transplantation.

    PubMed

    Jin, Juan; Gong, Jianguang; Lin, Bo; Li, Yiwen; He, Qiang

    2017-05-01

    Fcγ receptors (FcγR) play a role in the acute rejection (AR) of organ transplants. FcγRIIB is an inhibitory FcγR expressed on B cells. Intravenous IgG (IVIG) and CD28 monoclonal antibody (mAb) have been shown to have immunomodulatory properties against AR. To examine the association between FcγRIIB expression on B cell subpopulations and AR treatment efficacy. Male F344 rats were used as kidney donors and Lewis rats as recipients to establish models of renal transplantation. Rats were divided into five groups: sham, AR-PBS, AR-IVIG, AR-PNGase F-IVIG, and AR-CD28. Serum creatinine (Scr), blood urea nitrogen (BUN), and urine protein content were determined. Inflammatory markers were measured by ELISA, FcγR by western blotting, and spleen B cell activation by flow cytometry. Scr, BUN, urinary protein content, levels of CRP, IL-10, TNF-α, IL-6, IL-8, and IgG were all increased in the AR-PBS group compared with the sham group (all P<0.01); these increases were partly reversed in the AR-IVIG, AR-PNGase F IVIG, and AR-CD28 groups (all P<0.01), with IVIG showing the better efficacy than PNGase F IVIG. Furthermore, blood and spleen FcγRIA and FcγRIIIA were increased by AR, while FcγRIIB expressions in splenic activated B cells and regulatory B cells were decreased; these changes were partly alleviated by all three treatments, with IVIG having the better effect than PNGase F IVIG. We observed an association between B cell FcγRIIB expression and treatment efficacy for AR after kidney transplantation in rats. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. 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

  19. Effects of acute hypoxia at moderate altitude on stroke volume and cardiac output during exercise.

    PubMed

    Fukuda, Taira; Maegawa, Taketeru; Matsumoto, Akihiro; Komatsu, Yutaka; Nakajima, Toshiaki; Nagai, Ryozo; Kawahara, Takashi

    2010-05-01

    It has been unclear how acute hypoxia at moderate altitude affects stroke volume (SV), an index of cardiac function, during exercise. The present study was conducted to reveal whether acute normobaric hypoxia might alter SV during exercise.Nine healthy male subjects performed maximal exercise testing under normobaric normoxic, and normobaric hypoxic conditions (O(2): 14.4%) in a randomized order. A novel thoracic impedance method was used to continuously measure SV and cardiac output (CO) during exercise. Acute hypoxia decreased maximal work rate (hypoxia; 247 + or - 6 [SE] versus normoxia; 267 + or - 8 W, P < 0.005) and VO(2) max (hypoxia; 2761 + or - 99 versus normoxia; 3039 + or - 133 mL/min, P < 0.005). Under hypoxic conditions, SV and CO at maximal exercise decreased (SV: hypoxia; 145 + or - 11 versus normoxia; 163 + or - 11 mL, P < 0.05, CO: hypoxia; 26.7 + or - 2.1 versus normoxia; 30.2 + or - 1.8 L/min, P < 0.05). In acute hypoxia, SV during submaximal exercise at identical work rate decreased. Furthermore, in hypoxia, 4 of 9 subjects attained their highest SV at maximal exercise, while in normoxia, 8 of 9 subjects did.Acute normobaric hypoxia attenuated the increment of SV and CO during exercise, and SV reached a plateau earlier under hypoxia than in normoxia. Cardiac function during exercise at this level of acute normobaric hypoxia might be attenuated.

  20. "CAPS" Cardiac Acute Pain Services-A Nationwide Survey From Canada.

    PubMed

    Cogan, Jennifer; Eipe, Naveen; Vargas-Schaffer, Grisell; Ouimette, Marie-France; Belisle, Sylvain

    2017-08-01

    Acute Pain Services (APS) are well-established worldwide; however, their availability and use in cardiac surgery units are less widespread and, even where present, may be provided less consistently. The authors undertook this survey to assess the current organization of Cardiac Acute Pain Services (CAPS) in Canada. This was a prospectively administered survey. This study included all centers in Canada that conducted adult cardiac surgery. The participants were anesthesiologists. A 20-item questionnaire covered the demographics, functioning and APS structure. The authors achieved a response rate of 100% with completed questionnaires from all 31 centers. Ten centers (32.3%) stated that they had a dedicated CAPS, 9 centers (29%) stated that they did not have an APS, and 12 centers (38.7%) had APS but no CAPS. At the time of the survey for the 10 centers with CAPS, 3 of the CAPS had a physician-run model, 4 had a combined physician and nurse service, and 1 used a combination of protocols, intensivists, and nurse practitioners. Nine centers had an anesthesiologist assigned to daily acute pain rounds. Only in 2 of 10 centers with CAPS were more than 50% of their cardiac surgery patients receiving care. In general, postoperative pain management was a protocol-driven activity. CAPS are varied in both structure and functioning. Further work is required both at the institutional and the national levels to improve the postoperative care and the pain-related outcomes of patients undergoing cardiac surgery. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Acute cardiac effects of 'SCUD' missile attacks on a civilian population.

    PubMed

    Hart, J; Weingarten, M A; Druckman, A; Feldman, Z; Shay, A

    1993-01-01

    The 'SCUD' raids on Israel during the Gulf War afforded a rare opportunity to examine the effect of mass acute fear on the cardiac health of the general population. Press reports suggested an alarming rise in cardiac deaths during the first missile raids. In order to ascertain this statement, we examined the Emergency Room records of a community hospital in the affected area and all the death certificates in the local region. The periods studied were from 1 January to 28 February 1991, and the equivalent weeks in 1990. The Emergency Room records showed that there was an increased rate of cardiac complaints throughout the war, most marked during the first week. However, this was not accompanied by an increased cardiac mortality, either in the hospital or in the region as a whole, except during the first week. A similar increase in cardiac mortality occurred during the same week the previous year. The increased incidence of acute cardiac events during the first week of the war was probably a coincidence, and not a direct consequence of mass fear. Panic, occasioned by press reports, may have led to a lower threshold of referral which persisted throughout the war.

  2. PULMONARY AND CARDIAC GENE EXPRESSION FOLLOWING ACUTE ULTRAFINE CARBON PARTICLE INHALATION IN HYPERTENSIVE RATS

    EPA Science Inventory

    Inhalation of ultrafine carbon particles (ufCP) causes cardiac physiological changes without marked pulmonary injury or inflammation. We hypothesized that acute ufCP exposure of 13 months old Spontaneously Hypertensive (SH) rats will cause differential effects on the lung and hea...

  3. PULMONARY AND CARDIAC GENE EXPRESSION FOLLOWING ACUTE ULTRAFINE CARBON PARTICLE INHALATION IN HYPERTENSIVE RATS

    EPA Science Inventory

    Inhalation of ultrafine carbon particles (ufCP) causes cardiac physiological changes without marked pulmonary injury or inflammation. We hypothesized that acute ufCP exposure of 13 months old Spontaneously Hypertensive (SH) rats will cause differential effects on the lung and hea...

  4. Cardiac myxoma causing acute ischemic stroke in a pediatric patient and a review of literature.

    PubMed

    Fuchs, Jennifer; Leszczyszyn, David; Mathew, Don

    2014-05-01

    Ischemic stroke in the pediatric population is a rare occurrence, and its possible causes span a wide differential that includes atrial myxomas. Myxomas are friable cardiac tumors that produce "showers" of emboli resulting in transient neurological deficits, cutaneous eruptions, and ophthalmologic deficits. We present an 11-year-old boy with a months-long history of an intermittent spotted "rash" who presented with acute ischemic stroke caused by a left atrial myxoma. We also review clinical features in all 16 other cases of cardiac myxoma causing pediatric stroke reported in the literature. Our case, along with the review of the literature, highlights the fact that myxomas often initially present as stroke with acute hemiplegia and transient cutaneous eruptions due to fragmentation of the tumor. Cardiac myxoma should be considered in any child presenting with ischemic stroke, and transient skin findings may provide an important diagnostic clue prior to onset of neurological symptoms. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Case Studies in Cardiac Dysfunction After Acute Aneurysmal Subarachnoid Hemorrhage

    PubMed Central

    Hamilton, Jason C.; Korn-Naveh, Lauren; Crago, Elizabeth A.

    2015-01-01

    Patients with acute aneurysmal subarachnoid hemorrhage (SAH) often present with more than just neurological compromise. A wide spectrum of complicating cardiopulmonary abnormalities have been documented in patients with acute SAH, presenting additional challenges to the healthcare providers who attempt to treat and stabilize these patients. The patients described in this article presented with both acute aneurysmal SAH and cardiopulmonary compromise. Education and further research on this connection is needed to provide optimal care and outcomes for this vulnerable population. Nurses play a key role in balancing the critical and diverse needs of patients presenting with these symptoms. PMID:18856247

  6. Resveratrol Upregulates Cardiac SDF-1 in Mice with Acute Myocardial Infarction through the Deacetylation of Cardiac p53.

    PubMed

    Hong, Wang; Tatsuo, Shimosawa; Shou-Dong, Wang; Qian, Zhang; Jian-Feng, Hou; Jue, Wang; Chen, Jin; Hai-Yan, Qian; Yue-Jin, Yang

    2015-01-01

    We previously demonstrated that resveratrol (RSV) administration causes cardiac stromal cell-derived factor (SDF)-1 upregulation and can enhance the mobilization of stem cells in mice with acute myocardial infarction (AMI). However, the upstream signal transduction involved in SDF-1 regulation in the setting of AMI and RSV administration remains unclear. Because RSV is a sirtuin 1 (SIRT1) activator and SIRT proteins act as deacetylases, we investigated the role of SIRT1 in SDF-1 upregulation and its subsequent effects. In vitro experiments with H9C2 cardiomyocytes under hypoxia and serum-deprivation conditions showed that p53 acted upstream of SDF-1. RSV could not regulate SDF-1 effectively after SIRT1 silencing, indicating that it is dependent on SIRT1. Subsequently, male C57BL/6 mice were divided into four groups: 1) sham, 2) MI, 3) MI+RSV, and 4) MI+RSV plus nicotinamide, an inhibitor of the deacetylase activity of SIRT (MI+RSV+NAM). Compared with the sham mice, AMI caused a slight increase in the cardiac p53 level and resulted in significant SIRT1 downregulation and p53 acetylation or activation. Compared with the MI mice, MI+RSV administration improved the cardiac SDF-1 level and reversed the reduction of SIRT1 and the activation of p53. Furthermore, we observed less cardiac dysfunction in MI+RSV mice and determined that NAM abolished the effects of RSV. RSV enhances cardiac SDF-1 excretion after AMI partially through a SIRT1 normalization/p53 inactivation pathway.

  7. Resveratrol Upregulates Cardiac SDF-1 in Mice with Acute Myocardial Infarction through the Deacetylation of Cardiac p53

    PubMed Central

    Hong, Wang; Tatsuo, Shimosawa; Shou-Dong, Wang; Qian, Zhang; Jian-Feng, Hou; Jue, Wang; Chen, Jin; Hai-Yan, Qian; Yue-Jin, Yang

    2015-01-01

    Aims We previously demonstrated that resveratrol (RSV) administration causes cardiac stromal cell-derived factor (SDF)-1 upregulation and can enhance the mobilization of stem cells in mice with acute myocardial infarction (AMI). However, the upstream signal transduction involved in SDF-1 regulation in the setting of AMI and RSV administration remains unclear. Because RSV is a sirtuin 1 (SIRT1) activator and SIRT proteins act as deacetylases, we investigated the role of SIRT1 in SDF-1 upregulation and its subsequent effects. Methods and Results In vitro experiments with H9C2 cardiomyocytes under hypoxia and serum-deprivation conditions showed that p53 acted upstream of SDF-1. RSV could not regulate SDF-1 effectively after SIRT1 silencing, indicating that it is dependent on SIRT1. Subsequently, male C57BL/6 mice were divided into four groups: 1) sham, 2) MI, 3) MI+RSV, and 4) MI+RSV plus nicotinamide, an inhibitor of the deacetylase activity of SIRT (MI+RSV+NAM). Compared with the sham mice, AMI caused a slight increase in the cardiac p53 level and resulted in significant SIRT1 downregulation and p53 acetylation or activation. Compared with the MI mice, MI+RSV administration improved the cardiac SDF-1 level and reversed the reduction of SIRT1 and the activation of p53. Furthermore, we observed less cardiac dysfunction in MI+RSV mice and determined that NAM abolished the effects of RSV. Conclusions RSV enhances cardiac SDF-1 excretion after AMI partially through a SIRT1 normalization/p53 inactivation pathway. PMID:26053177

  8. Contemporary evaluation of the causes of cardiac tamponade: Acute and long-term outcomes.

    PubMed

    Orbach, Ady; Schliamser, Jorge E; Flugelman, Moshe Y; Zafrir, Barak

    2016-01-01

    Cardiac tamponade is a life-threatening state that complicates various medical conditions. The contemporary interventional era may have led to changes in clinical characteristics, causes and outcomes of cardiac tamponade. We investigated all patients diagnosed with cardiac tamponade, based on clinical and echocardiographic findings, at a single medical center between the years 2000 and 2013. Data on medical history, index hospitalizations, pericardial fluid etiologies, and acute and long-term outcomes were collected. Cardiac tamponade was observed in 83 patients (52% females). Major etiologies included complications of percutaneous cardiac interventions (36%) and malignancies (primarily lung cancer; 23%), infectious/inflammatory causes (15%) and mechanical complications of myocardial infarction (12%). Sixteen (19%) patients died during the index hospitalization. Acute presentation of symptoms and lower quantity of effusion were associated with in-hospital mortality (p = 0.045 and p = 0.007). Tamponade secondary to malignancy was associated with the most substantial increment in post-discharge mortality (from 16% in-hospital to 68% 1-year mortality). During the mean follow-up of 45 months, 39 (45%) patients died. Malignancies, mechanical complications of myocardial infarction and bleeding/coagulation abnormalities were etiologies associated with poor survival (80% mortality during follow-up). Tamponade secondary to complications of percutaneous cardiac interventions or infectious/inflammatory causes were associated with significantly lower mortality (28% and 17%; log rank p < 0.001). In a contemporary cohort, complications of percutaneous cardiac intervention replaced malignant diseases as the leading cause of cardiac tamponade. Nevertheless, these iatrogenic complications were associated with a relatively favorable outcome compared to tamponade induced by complications of myocardial infarction, coagulation abnormalities and malignant diseases.

  9. Identification of Pathogenic Cardiac CD11c+ Macrophages in Nod1-Mediated Acute Coronary Arteritis.

    PubMed

    Motomura, Yoshitomo; Kanno, Shunsuke; Asano, Kenichi; Tanaka, Masato; Hasegawa, Yutaka; Katagiri, Hideki; Saito, Takashi; Hara, Hiromitsu; Nishio, Hisanori; Hara, Toshiro; Yamasaki, Sho

    2015-06-01

    Nod1 is an intracellular pattern recognition receptor for bacterial peptidoglycan fragments. We previously reported that a synthetic Nod1 ligand, FK565, induced acute coronary arteritis in mice similar to that of Kawasaki disease. However, the molecular mechanisms underlying this characteristic inflammation have remained elusive. We found that CD11c(+)MHC class II(+) cells accumulated in the heart of FK565-treated mice before arteritis development. Morphological features and gene expression signatures of the cardiac CD11c(+)MHC class II(+) cells suggested that this population is closely related to macrophages, and thus, we designated them cardiac CD11c(+) macrophages. Nod1 in nonhematopoietic cells, rather than hematopoietic cells, was required for the increase of cardiac CD11c(+) macrophages and arteritis development. Among nonhematopoietic cells, cardiac endothelial cells produced a large amount of chemokines in response to FK565. Endothelial cell-specific blockade of Nod1 signaling suppressed FK565-induced expression of these chemokines, accumulation of cardiac CD11c(+) macrophages, and subsequent coronary arteritis development. We also found that CCR2(+)Ly6C(hi) inflammatory monocytes in peripheral blood supplied precursors of cardiac CD11c(+) macrophages. CCR2-deficient mice or pertussis toxin-treated mice exhibited decreased numbers of cardiac CD11c(+) macrophages and reduced arteritis. These results suggest that Ly6C(hi) monocytes are recruited to FK565-activated endothelial cells to generate cardiac CD11c(+) macrophages, which play a pivotal role in the pathogenesis of acute coronary arteritis. © 2015 American Heart Association, Inc.

  10. Strategies for prevention of acute kidney injury in cardiac surgery: an integrative review

    PubMed Central

    Santana-Santos, Eduesley; Marcusso, Marila Eduara Fátima; Rodrigues, Amanda Oliveira; de Queiroz, Fernanda Gomes; de Oliveira, Larissa Bertacchini; Rodrigues, Adriano Rogério Baldacin; Palomo, Jurema da Silva Herbas

    2014-01-01

    Acute kidney injury is a common complication after cardiac surgery and is associated with increased morbidity and mortality and increased length of stay in the intensive care unit. Considering the high prevalence of acute kidney injury and its association with worsened prognosis, the development of strategies for renal protection in hospitals is essential to reduce the associated high morbidity and mortality, especially for patients at high risk of developing acute kidney injury, such as patients who undergo cardiac surgery. This integrative review sought to assess the evidence available in the literature regarding the most effective interventions for the prevention of acute kidney injury in patients undergoing cardiac surgery. To select the articles, we used the CINAHL and MedLine databases. The sample of this review consisted of 16 articles. After analyzing the articles included in the review, the results of the studies showed that only hydration with saline has noteworthy results in the prevention of acute kidney injury. The other strategies are controversial and require further research to prove their effectiveness. PMID:25028954

  11. 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. PMID:28405605

  12. Clinical and Echocardiographic Characteristics of Acute Cardiac Dysfunction Associated With Acute Brain Hemorrhage - Difference From Takotsubo Cardiomyopathy.

    PubMed

    Lee, Mirae; Oh, Ju Hyeon; Lee, Kyung Been; Kang, Gu Hyun; Park, Yong Hwan; Jang, Woo Jin; Chun, Woo Jung; Lee, Sang Hyuk; Lee, In Chang

    2016-08-25

    Cardiac dysfunction (CD) associated with brain hemorrhage is similar to that with takotsubo cardiomyopathy but still not well understood. We aimed to investigate the clinical and echocardiographic findings of acute CD (ACD) related to brain hemorrhage. Between 2013 and 2014, consecutive patients diagnosed with spontaneous and traumatic brain hemorrhage were prospectively enrolled. Electrocardiography, cardiac enzymes, and echocardiography were performed. Left ventricular (LV) systolic dysfunction on echocardiography was defined as ACD related to brain hemorrhage when all the following conditions were satisfied: abnormal ECG and cardiac troponin level, LV wall motion abnormality or decreased LV systolic function on echocardiography, and no previous history of cardiac disease. Otherwise, LV dysfunction was considered to be other CD unrelated to brain hemorrhage. In a total of 208 patients, 15 (7.2%) showed ACD. Of them, 8 patients were men and 8 showed apex-sparing LV hypokinesia and 9 died in hospital. Other cardiac abnormalities observed in the study patients were NT-proBNP elevation (n=123), QT interval prolongation (n=95), LV hypertrophy (n=89), and troponin I elevation (n=47). There were 36 in-hospital deaths (17.3%). Glasgow coma score and ACD were independently associated with in-hospital death. ACD was observed in patients with various brain hemorrhages. Unlike takotsubo cardiomyopathy, high proportions of male sex, apex-sparing LV dysfunction, and in-hospital death were observed for ACD associated with brain hemorrhage. (Circ J 2016; 80: 2026-2032).

  13. Lunar phases are not related to the occurrence of acute myocardial infarction and sudden cardiac death.

    PubMed

    Eisenburger, Philip; Schreiber, Wolfgang; Vergeiner, Gernot; Sterz, Fritz; Holzer, Michael; Herkner, Harald; Havel, Christof; Laggner, Anton N

    2003-02-01

    Mass media deliver pertinacious rumours that lunar phases influence the progress and long-term results in several medical procedures. Peer reviewed studies support this, e.g. in myocardial infarction, others do not. We looked retrospectively at the dates of cardiac arrests (CA; n=368) of cardiac origin and of acute myocardial infarctions (AMI) with consecutive thrombolytic therapy or acute PTCA (n=872) and at the lunar phases at the corresponding dates. Medical data had been collected prospectively on the patient's admission. The lunar phases were defined as full moon+/-1 day, new moon+/-1 day and the days in between as waning and waxing moon. The incidence of these cardiac events at each phase was calculated as days with a case divided by the total number of days of the specific moon phase in the observation period (1992-1998). Wilcoxon Rank Test was used for statistical analysis. AMI and CA occurred on equal percentages of days within each lunar phase: AMI on 35% of all days with new moon, on 38% of full moon days, on 39% waning, and on 41% of the waxing moon days; CA on 19, 17, 16 and 16% of all days of the respective lunar phase. This difference was not significant. Lunar phases do not appear to correlate with acute coronary events leading to myocardial infarction or sudden cardiac death.

  14. Acute pericarditis with cardiac tamponade induced by pacemaker implantation.

    PubMed

    Shingaki, Masami; Kobayashi, Yutaka; Suzuki, Haruo

    2015-11-01

    An 87-year-old woman was diagnosed with third-degree atrioventricular block and underwent pacemaker implantation. On postoperative day 12, she experienced cardiac tamponade that was suspected on computed tomography to be caused by lead perforation; therefore, we performed open-heart surgery. However, we could not identify a perforation site on the heart, and drained a 400-mL exudative pericardial effusion. Subsequently, we diagnosed the pericardial effusion as due to pericarditis induced by pacemaker implantation. It is sometimes difficult to distinguish pericarditis from pacemaker lead perforation, so both should be included in the differential diagnosis.

  15. Cardiac rehabilitation programme as a non-pharmacological platelet inhibitory tool in acute coronary syndrome survivors.

    PubMed

    Tóth-Zsámboki, Emese; Horváth, Zsófia; Hajtman, László; Leé, Sarolta; Pállinger, Éva; Kuklis, Eszter; Tahy, Ádám; Fekete, György; Kohut, László; Kiss, Róbert G

    2017-07-01

    Background Acute coronary syndrome is associated with platelet hyperactivity, which in its persistent form, promotes recurrent thrombotic events. Complex cardiac rehabilitation after acute coronary syndrome improves clinical outcome; however, its effect on platelet hyperactivity is unknown. Design and methods We enrolled 84 acute coronary syndrome patients on dual antiplatelet therapy, who underwent a new complex cardiac rehabilitation programme (NovaCord physiotherapy, lifestyle counselling, strict diet, stress management and regular coaching) and 51 control acute coronary syndrome patients with traditional cardiac rehabilitation. Platelet functionality was determined at enrolment and at three months follow-up by aggregometry, serum platelet-derived growth factor levels, total- and platelet-derived microvesicle counts (PMV; CD41a+/CD61+, CD62P+). Results Platelet aggregation parameters and platelet-derived growth factor levels were significantly decreased in the complex cardiac rehabilitation group at three months (1 µg/ml collagen, median (interquartile range): 22 (10-45) vs 14 (7.5-25.5)%, p = 0.0015; 2 µg/ml collagen: 36 (22-60) vs 26.5 (16-37)%, p = 0.0019; 1.25 µM adenosine-diphosphate: 4.5 (1-10) vs 1 (0-3)%, p = 0.0006; 5 µM adenosine-diphosphate: 27 (16-38) vs 22 (12-31)%, p = 0.0078; epinephrine: 33 (15-57) vs 27 (12-43)%, p = 0.01; platelet-derived growth factor: 434.6 (256.0-622.7) vs 224.8 (148.5-374.1) pg/ml, p = 0.0001). In contrast, these changes were absent or did not reach statistical significance in the traditional cardiac rehabilitation group. Platelet-derived microvesicle counts were significantly decreased in both groups, while total microvesicle count was significantly reduced only in the complex cardiac rehabilitation group (median (interquartile range): 3945.5 (2138-5661) vs 1739 (780-2303) count/µl; p = 0.0001). Conclusions Platelet hyperactivity three months after acute coronary syndrome

  16. Rapid Changes in Cardiac Myofilament Function following the Acute Activation of Estrogen Receptor-Alpha

    PubMed Central

    Kulpa, Justyna; Chinnappareddy, Nirmala; Pyle, W. Glen

    2012-01-01

    Estrogens have well-recognized and complex cardiovascular effects, including altering myocardial contractility through changes in myofilament function. The presence of multiple estrogen receptor (ER) isoforms in the heart may explain some discrepant findings about the cardiac effects of estrogens. Most studies examining the impact of estrogens on the heart have focused on chronic changes in estrogen levels, and have not investigated rapid, non-genomic pathways. The first objective of this study was to determine how acute activation of ERα impacts cardiac myofilaments. Nongenomic myocardial estrogen signaling is associated with the activation of a variety of signaling pathways. p38 MAPK has been implicated in acute ER signaling in the heart, and is known to affect myofilament function. Thus, the second objective of this study was to determine if acute ERα activation mediates its myofilament effects through p38 MAPK recruitment. Hearts from female C57Bl/6 mice were perfused with the ERα agonist PPT and myofilaments isolated. Activation of ERα depressed actomyosin MgATPase activity and decreased myofilament calcium sensitivity. Inhibition of p38 MAPK attenuated the myofilament effects of ERα activation. ERα stimulation did not affect global myofilament protein phosphorylation, but troponin I phosphorylation at the putative PKA phosphorylation sites was decreased. Changes in myofilament activation did not translate into alterations in whole heart function. The present study provides evidence supporting rapid, non-genomic changes in cardiac myofilament function following acute ERα stimulation mediated by the p38 MAPK pathway. PMID:22859967

  17. Serum neopterin as an indicator of increased risk of renal allograft rejection.

    PubMed

    Carey, B Sean; Jain, Rashmi; Adams, Claire L; Wong, Kam Yim; Shaw, Steve; Tse, Wai Yee; Kaminski, Edward R

    2013-03-01

    Acute rejection remains associated with poor graft outcome. An early predictor of acute renal transplant rejection is the long sought after goal for transplant immunologists. In this study we measured levels of serum neopterin at day 5 post-transplant in a cohort of 216 consecutive renal allograft recipients, and compared this with serum creatinine and acute rejection episodes during the first year post transplant. We compared serum neopterin in recipients from living donors (LD), donors after brain death (DBD) and donors after cardiac death (DCD). In all cases higher neopterin levels were correlated with acute rejection in the first year post transplant, but this was only significant in recipients of DCD kidneys who suffered acute cellular or vascular rejection (p=0.04, odds ratio 1.08, 95% CI 1.003-1.012). The neopterin/creatinine ratio, which takes into account the effect of kidney function on circulating neopterin levels, was significantly higher for all recipients who suffered biopsy proven cellular or vascular rejection in the first year post transplant, compared to all other patients (p=0.001, for an increase of 0.1, odds ratio=1.64, 95% CI 1.21-2.20). The ability to use non-invasive biomarkers in the transplant recipient has the potential to increase transplant survival for these patients. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Investigation of Killer Immunoglobulin-like Receptor (KIR) and HLA Genotypes to Predict the Occurrence of Acute Allograft Rejection after Kidney Transplantation.

    PubMed

    Jafari, Davood; Nafar, Mohsen; Yekaninejad, Mir Saeed; Abdolvahabi, Razieh; Lesan Pezeshki, Mahboob; Razaghi, Efat; Amirzargar, Ali Akbar

    2017-06-01

    After kidney transplantation, natural killer (NK) cells play a pivotal role in triggering the immune response to the allogeneic grafts primarily by their killer-cell immunoglobulin-like receptors (KIR). This process may be one mechanism that contributes to graft rejection. In this study, we have evaluated whether acute rejection after kidney transplantation was associated with predicted NK cell alloreactivity based on KIR gene and ligand along with KIR/HLA compound genotype analysis. After kidney transplantation, natural killer (NK) cells play a pivotal role in triggering the immune response to the allogeneic grafts primarily by their killer-cell immunoglobulin-like receptors (KIR). This process may be one mechanism that contributes to graft rejection. In this study, we have evaluated whether acute rejection after kidney transplantation was associated with predicted NK cell alloreactivity based on KIR gene and ligand along with KIR/HLA compound genotype analysis. DNA from 65 patients with biopsy-proven acute kidney allograft rejection (AKAR), 61 clinically stable graft function (SGF) recipients and 176 healthy subjects were identified for the presence or absence of 10 variable KIR genes (both activating and inhibitory receptors) and their HLA ligands using polymerase chain reaction-sequence specific primers (PCR-SSP) assay. Although no significant difference in the frequency of individual KIR genes, was found the gene content, and the haplotypic distribution between the three categories were detected, the frequency of the KIR3DL1+HLA-Bw4*A allele combination was significantly lower in AKAR patients compared to SGF recipients (p=0.004, OR=0.34, CI=0.16-0.72) and healthy subjects (p=0.019, OR=0.47, CI=0.25-0.89). Kaplan-Meier survival test showed that the KIR3DL1+HLA-Bw4*A allele combination could be considered protective for AKAR (p=0.04 by log-rank). The results of this study suggest that KIR/HLA polymorphism may be a genetic susceptibility factor to alloreactivity

  19. Are There Deleterious Cardiac Effects of Acute and Chronic Endurance Exercise?

    PubMed

    Eijsvogels, Thijs M H; Fernandez, Antonio B; Thompson, Paul D

    2016-01-01

    Multiple epidemiological studies document that habitual physical activity reduces the risk of atherosclerotic cardiovascular disease (ASCVD), and most demonstrate progressively lower rates of ASCVD with progressively more physical activity. Few studies have included individuals performing high-intensity, lifelong endurance exercise, however, and recent reports suggest that prodigious amounts of exercise may increase markers for, and even the incidence of, cardiovascular disease. This review examines the evidence that extremes of endurance exercise may increase cardiovascular disease risk by reviewing the causes and incidence of exercise-related cardiac events, and the acute effects of exercise on cardiovascular function, the effect of exercise on cardiac biomarkers, including "myocardial" creatine kinase, cardiac troponins, and cardiac natriuretic peptides. This review also examines the effect of exercise on coronary atherosclerosis and calcification, the frequency of atrial fibrillation in aging athletes, and the possibility that exercise may be deleterious in individuals genetically predisposed to such cardiac abnormalities as long QT syndrome, right ventricular cardiomyopathy, and hypertrophic cardiomyopathy. This review is to our knowledge unique because it addresses all known potentially adverse cardiovascular effects of endurance exercise. The best evidence remains that physical activity and exercise training benefit the population, but it is possible that prolonged exercise and exercise training can adversely affect cardiac function in some individuals. This hypothesis warrants further examination.

  20. Are There Deleterious Cardiac Effects of Acute and Chronic Endurance Exercise?

    PubMed Central

    Eijsvogels, Thijs M. H.; Fernandez, Antonio B.; Thompson, Paul D.

    2015-01-01

    Multiple epidemiological studies document that habitual physical activity reduces the risk of atherosclerotic cardiovascular disease (ASCVD), and most demonstrate progressively lower rates of ASCVD with progressively more physical activity. Few studies have included individuals performing high-intensity, lifelong endurance exercise, however, and recent reports suggest that prodigious amounts of exercise may increase markers for, and even the incidence of, cardiovascular disease. This review examines the evidence that extremes of endurance exercise may increase cardiovascular disease risk by reviewing the causes and incidence of exercise-related cardiac events, and the acute effects of exercise on cardiovascular function, the effect of exercise on cardiac biomarkers, including “myocardial” creatine kinase, cardiac troponins, and cardiac natriuretic peptides. This review also examines the effect of exercise on coronary atherosclerosis and calcification, the frequency of atrial fibrillation in aging athletes, and the possibility that exercise may be deleterious in individuals genetically predisposed to such cardiac abnormalities as long QT syndrome, right ventricular cardiomyopathy, and hypertrophic cardiomyopathy. This review is to our knowledge unique because it addresses all known potentially adverse cardiovascular effects of endurance exercise. The best evidence remains that physical activity and exercise training benefit the population, but it is possible that prolonged exercise and exercise training can adversely affect cardiac function in some individuals. This hypothesis warrants further examination. PMID:26607287

  1. 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

  2. Flow Cytometry Panel-Reactive Antibody Screening of Anti-HLA Antibodies in the Waiting List Significantly Reduces the Occurrence of Acute Rejection After Kidney Transplantation.

    PubMed

    Dedinská, I; Mäčková, N; Macháleková, K; Miklušica, J; Palkoci, B; Fialová, J; Čellár, M; Galajda, P; Mokáň, M

    2017-10-01

    The presence of preformed HLA-reactive antibodies in recipient serum before transplantation has long been recognized as a prominent risk factor for a generally worse graft outcome. Screening and identification of HLA antibodies can be used to stratify patients into high- and low-risk categories. We determined patients' anti-HLA antibodies using flow cytometry panel-reactive antibody (flowPRA) screening, specifying more than 5% after positive screening. According to the results of the screening test, patients were allocated to the induction immunosuppressive protocol according to the actual immunologic risk. In the group of 78 patients, screening with flowPRA of anti-HLA antibodies was done twice a year. Patients were divided into 2 groups of immunologic risk (low or medium), and we chose the induction immunosuppressive protocol according to the risk. Stratification of the risk was correct, because the only predictor for development of acute rejection in the monitored period of 12 months was delayed graft function (odds ratio 33.2501; 95% confidence interval 10.0095-110.4508; P < .0001). The occurrence of acute rejection upon implementing the screening was reduced in our transplant center from 44% to 19% (P < .0001). No difference was recorded in the 12-month survival of grafts and patients according to the applied induction immunosuppressive protocol. We confirmed significantly reduced occurrence of acute rejection in the follow-up period of 12 months by using individualized induction according to flowPRA screening of anti-HLA antibodies. FlowPRA screening represents a suitable alternative for screening and specification of anti-HLA antibodies in case the Luminex methodology is unavailable. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Phase I and phase II safety and efficacy trial of intercellular adhesion molecule-1 antisense oligodeoxynucleotide (ISIS 2302) for the prevention of acute allograft rejection.

    PubMed

    Kahan, Barry D; Stepkowski, Stanislaw; Kilic, Murat; Katz, Steven M; Van Buren, Charles T; Welsh, Maria S; Tami, Joseph A; Shanahan, William R

    2004-09-27

    ISIS 2302, an antisense oligonucleotide that inhibits the expression of human intercellular adhesion molecule (ICAM)-1, was evaluated in combination with a cyclosporine (CsA)-prednisone (Pred) regimen first in a phase I safety and pharmacokinetic study and then in a phase II assessment of prophylaxis of acute rejection episodes in deceased donor renal allografts. Both phase I and phase II trials were double-blinded and placebo-controlled, including 17 stable and 39 de novo patients, respectively, in time-lagged, ascending-dose regimens. Each study compared the outcomes of 8 alternate-day intravenous infusions of four ISIS 2302 dose levels (0.05, 0.5, 1.0, or 2.0 mg/kg) versus placebo (3:1 ratio). Patients were followed for 34 days (phase I) or 6 months (phase II). All transplant patients were followed for 3 years. ISIS 2302 produced no evident toxicity; a significant, dose-related increase in activated partial thromboplastin time was accompanied by a trend toward a decreased platelet count. ISIS 2302 did not alter the pharmacokinetic behavior of CsA. At 6 months, the rates of acute rejection episodes were 38.1% in the ISIS 2302 group versus 20.0% in the placebo group. Three-year graft survivals were similar. The mean creatinine values at 1, 2, and 3 years for all ISIS dose groups combined versus placebo over 3 years showed no significant differences. ISIS 2302 did not evoke side-effects and produced slightly improved renal function. However, in this pilot study, it did not further reduce the rate of acute rejection episodes or increase graft survival compared to a concentration-controlled CsA-Pred regimen.

  4. ATP-binding cassette subfamily B member 1 polymorphisms do not determine cyclosporin exposure, acute rejection or nephrotoxicity after heart transplantation.

    PubMed

    Taegtmeyer, Anne B; Breen, Jane B; Smith, John; Burke, Margaret; Leaver, Neil; Pantelidis, Panagiotis; Lyster, Haifa; Yacoub, Magdi H; Barton, Paul J R; Banner, Nicholas R

    2010-01-15

    We hypothesized that genetic variation of ATP-binding cassette subfamily B member 1 (ABCB1) that encodes P-glycoprotein (involved in the uptake of cyclosporin A [CsA]) contributes to trough drug concentrations and thereby to CsA's immunosuppressive and toxic effects. Three hundred thirty-seven adult heart transplant recipients were studied retrospectively. White recipients receiving CsA at month 3 and years 1 to 5 after transplantation (n=192, 168, 156, 130, 95, and 74, respectively) were then studied with respect to ABCB1 genotype or haplotype and CsA disposition. Genotyping was performed using a gel-based polymerase chain reaction method. Dose- and weight-adjusted CsA trough concentrations ([microg/L]/[mg/kg]), time to first endomyocardial biopsy-proven acute rejection episode (grade>or=3A), weaning from steroids at 1 year, and renal function at 1 year posttransplant were measured. An association between dose- and weight-adjusted CsA trough concentrations and ABCB1 haplotypes was found, with 12/1236, 21/2677, 26/3435 CC/GG/CC individuals having significantly higher concentrations than TT/TT/TT individuals at years 1 and 5 (68.9+/-26.9 vs. 54.9+/-19.5 and 70.6+/-35 vs. 50.0+/-12.2 [microg/L]/[mg/kg] P<0.05, respectively) There was no difference in the incidence of acute rejection, steroid weaning, or renal impairment between the genotype or haplotype groups. The association of ABCB1 12/1236, 21/2677, and 26/3435 CC/GG/CC haplotype with increased CsA dose- and weight-adjusted CsA trough concentrations in this group of adult white heart transplant recipients was not consistent over time and had no effect on the incidence of acute rejection or on the development of renal impairment.

  5. Effects of acute stress on cardiac endocannabinoids, lipogenesis, and inflammation in rats

    PubMed Central

    Lim, James; Piomelli, Daniele

    2014-01-01

    Objective Trauma exposure can precipitate acute/post-traumatic stress responses (AS/PTSD) and disabling cardiovascular disorders (CVD). Identifying acute stress-related physiologic changes that may increase CVD risk could inform development of early CVD-prevention strategies. The endocannabinoid system (ECS) regulates hypothalamic-pituitary-adrenal (HPA) axis response and stress-related cardiovascular function. We examine stress-related endocannabinoid system (ECS) activity and its association with cardiovascular biochemistry/function following acute stress. Methods Rodents (n=8-16/group) were exposed to predator odor or saline; elevated plus maze (EPM), blood pressure (BP), serum and cardiac tissue ECS markers, and lipid metabolism were assessed at 24h and 2wks post-exposure. Results At 24h the predator odor group demonstrated anxiety-like behavior and had (a) elevated serum markers of cardiac failure/damage (brain natriuretic peptide [BNP]: 275.1 vs. 234.6, p=0.007; troponin-I: 1.50 vs. 0.78, p=0.076), lipogenesis (triacylglycerols [TAG]: 123.5 vs. 85.93, p=0.018), and inflammation (stearoyl delta-9 desaturase activity [SCD-16]: 0.21 vs. 0.07, p<0.001); (b) significant decrease in cardiac endocannabinoid (2-arachidonoyl-sn-glycerol, 2-AG: 29.90 vs. 65.95, p<0.001) and fatty acid ethanolamides (FAE: oleoylethanolamide, OEA: 114.3 vs. 125.4, p=0.047; palmitoylethanolamide, PEA: 72.96 vs. 82.87, p=0.008); and (c) increased cardiac inflammation (IL-1β/IL-6 ratio: 19.79 vs.13.57, p=0.038; TNF-α/IL-6 ratio: 1.73 vs. 1.03, p=0.019) and oxidative stress (thiobarbituric acid reactive substances [TBARS]: 7.81 vs. 7.05, p=0.022), that were associated with cardiac steatosis (higher TAG: 1.09 vs. 0.72, p<0.001). Cardiac lipogenesis persisted, and elevated BP emerged two weeks after exposure. Conclusions Acute psychological stress elicits ECS-related cardiac responses associated with persistent, potentially-pathological changes in rat cardiovascular biochemistry

  6. Acute dissociation and cardiac reactivity to script-driven imagery in trauma-related disorders

    PubMed Central

    Sack, Martin; Cillien, Melanie; Hopper, James W.

    2012-01-01

    Background Potential acute protective functions of dissociation include modulation of stress-induced psychophysiological arousal. This study was designed to explore whether acute dissociative reactions during a stress experiment would override the effects of reexperiencing. Methods Psychophysiological reactions during exposure to script-driven trauma imagery were studied in relation to acute responses of reexperiencing and dissociative symptoms in 61 patients with histories of exposure to a variety of traumas. Acute symptomatic responses were assessed with the Responses to Script-Driven Imagery Scale (RSDI), and participants were divided into four groups by median splits of RSDI reexperiencing and dissociation subscale scores. Results In a comparison of the high RSDI reexperiencing groups with low versus high acute dissociative symptoms, the high dissociators exhibited significantly lower heart rate (HR) during trauma script and a significantly smaller script-induced decrease in parasympathetic cardiac activity. HR reactivity to the trauma script was negatively correlated with acute dissociative symptom severity. Conclusions Acute dissociative reactions are a potential moderator of response to experimental paradigms investigating psychologically traumatized populations. We therefore suggest that future research on psychophysiological stress reactions in traumatized samples should routinely assess for acute dissociative symptoms. PMID:23198029

  7. Acute effects of carbon monoxide on cardiac electrical stability. Research report, Sep 85-Jul 88

    SciTech Connect

    Verrier, R.L.; Mills, A.K.; Skornik, W.A.

    1990-01-01

    The objective of the project was to determine the effects of acute carbon monoxide exposure on cardiac electrical stability in the normal and ischemic heart of anesthetized and conscious dogs. Exposure (90 to 120 minutes) to relatively high levels of carbon monoxide, leading to carboxyhemoglobin concentrations of up to 20 percent, was without significant effect on ventricular electrical stability in laboratory dogs. This appears to be the case in the acutely ischemic heart as well as in the normal heart. Using a model involving partial coronary artery stenosis, no changes were found in either the cycle frequency of coronary blood flow oscillations or in platelet aggregability during carbon monoxide exposure. Also examined were the effects of carbon monoxide exposure in the conscious state in order to take into consideration possible adverse consequences mediated by the central nervous system. The study found no adverse effects on the cardiac-excitable properties in response to either a 2-hour- or 24-hour-exposure paradigm.

  8. Novel biomarkers for early diagnosis of acute kidney injury after cardiac surgery in adults

    PubMed Central

    Kališnik, Jurij Matija

    2016-01-01

    Acute kidney injury after cardiac surgery with cardiopulmonary bypass is a common and serious complication and it is associated with increased morbidity and mortality. Diagnosis of acute kidney injury is based on the serum creatinine levels which rise several hours to days after the initial injury. Thus, novel biomarkers that will enable faster diagnosis are needed in clinical practice. There are numerous urine and serum proteins that indicate kidney injury and are under extensive research. Despite promising basic research results and assembled data, which indicate superiority of some biomarkers to creatinine, we are still awaiting clinical application. PMID:27212976

  9. Biopsy-proven acute cellular rejection as an efficacy endpoint of randomized trials in liver transplantation: a systematic review and critical appraisal.

    PubMed

    Rodríguez-Perálvarez, Manuel; Rico-Juri, Jose M; Tsochatzis, Emmanuel; Burra, Patrizia; De la Mata, Manuel; Lerut, Jan

    2016-09-01

    Biopsy-proven acute cellular rejection (ACR) is the primary efficacy endpoint in most randomized trials evaluating immunosuppression in liver transplantation. However, ACR is not a major cause of graft loss, and a certain grade of immune activation may be even beneficial for long-term graft acceptance. Validated criteria to select candidates for liver biopsy are lacking, and routine clinical practice relies on liver tests, which are inaccurate markers of ACR. Indeed, both the agreement among clinicians to select candidates for liver biopsy and the correlation between the clinical suspicion of ACR and histological findings are poor. In randomized trials evaluating immunosuppression protocols, this concern grows exponentially due to the open-label and multicenter nature of most studies. Therefore, biopsy-proven ACR is a suboptimal efficacy endpoint given its limited impact on prognosis and the heterogeneous diagnosis, which may increase the risk of bias. Chronic rejection and/or graft loss would be more appropriate endpoints, but would certainly require larger studies with prolonged surveillances. An objective method to select candidates for liver biopsy is therefore urgently needed, and only severe episodes of histological ACR should be considered as potentially harmful. Emerging surrogate markers of ACR and antibody-mediated rejection require further investigation to determine their clinical role. © 2015 Steunstichting ESOT.

  10. Nobiletin attenuates adverse cardiac remodeling after acute myocardial infarction in rats via restoring autophagy flux.

    PubMed

    Wu, Xiaoqian; Zheng, Dechong; Qin, Yuyan; Liu, Zumei; Zhang, Guiping; Zhu, Xiaoyan; Zeng, Lihuan; Liang, Zhenye

    2017-10-14

    Our previous study showed that autophagy flux was impaired with sustained heart ischemia, which exacerbated adverse cardiac remodeling after acute myocardial infarction (AMI). Here we investigated whether Nobiletin, a citrus polymethoxylated flavonoids, could restore the autophagy flux and improve cardiac prognosis after AMI. AMI was induced by ligating left anterior descending (LAD) coronary artery in rats. Nobiletin improved the post-infarct cardiac dysfunction significantly and attenuated adverse cardiac remodeling. Meanwhile, Nobiletin protected H9C2 cells against oxygen glucose deprivation (OGD) in vitro. The impaired autophagy flux due to ischemia was ameliorated after Nobiletin treatment by testing the autophagy substrate, LC3BⅡ and P62 protein level both in vivo and in vitro. GFP-mRFP-LC3 adenovirus transfection also supported that Nobiletin restored the impaired autophagy flux. Specifically, the autophagy flux inhibitor, chloroquine, but not 3 MA, alleviated Nobiletin-mediated protection against OGD. Notably, Nobiletin does not affect the activation of classical upstream autophagy signaling pathways. However, Nobiletin increased the lysosome acidation which also supported that Nobiletin accelerated autophagy flux. Taken together, our findings suggested that Nobiletin restored impaired autophagy flux and protected against acute myocardial infarction, suggesting a potential role of autophagy flux in Nobiletin-mediated myocardial protection. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Effect of Acute and Prolonged Alcohol Administration on Mg2+ Homeostasis in Cardiac Cells

    PubMed Central

    Romani, Andrea M.P.

    2015-01-01

    Alcoholic cardiomyopathy represents a major clinical complication in chronic alcoholics. Previous studies from our laboratory indicate that acute and chronic exposure of liver cells to ethanol results in a major loss of cellular Mg2+ as a result of alcohol oxidation. We investigated whether exposure to ethanol induces a similar Mg2+ loss in cardiac cells. The results indicate that chronic exposure to a 6% ethanol-containing diet depleted cardiac myocytes of >25% of their cellular Mg2+ content. Acute ethanol exposure, instead, induced a time- and dose-dependent manner of Mg2+ extrusion from perfused hearts and collagenase-dispersed cardiac ventricular myocytes. Pretreatment with chloromethiazole prevented ethanol-induced Mg2+ loss to a large extent, suggesting a role of ethanol oxidation via cyP4502E1 in the process. Magnesium extrusion across the sarcolemma occurred via the amiloride-inhibited Na+/Mg2+ exchanger. Taken together, our data indicate that Mg2+ extrusion also occurs in cardiac cells exposed to ethanol as a result of alcohol metabolism by cyP4502E1. The extrusion, which is mediated by the Na+/Mg2+ exchanger, only occurs at doses of ethanol ≥ 0.1%, and depends on ethanol-induced decline in cellular ATP. The significance of Mg2+ extrusion for the onset of alcoholic cardiomyopathy remains to be elucidated. PMID:25800156

  12. Effect of acute and prolonged alcohol administration on Mg(2+) homeostasis in cardiac cells.

    PubMed

    Romani, Andrea M P

    2015-05-01

    Alcoholic cardiomyopathy represents a major clinical complication in chronic alcoholics. Previous studies from our laboratory indicate that acute and chronic exposure of liver cells to ethanol results in a major loss of cellular Mg(2+) as a result of alcohol oxidation. We investigated whether exposure to ethanol induces a similar Mg(2+) loss in cardiac cells. The results indicate that chronic exposure to a 6% ethanol-containing diet depleted cardiac myocytes of >25% of their cellular Mg(2+) content. Acute ethanol exposure, instead, induced a time- and dose-dependent manner of Mg(2+) extrusion from perfused hearts and collagenase-dispersed cardiac ventricular myocytes. Pretreatment with chlormethiazole prevented ethanol-induced Mg(2+) loss to a large extent, suggesting a role of ethanol oxidation via cyP4502E1 in the process. Magnesium extrusion across the sarcolemma occurred via the amiloride-inhibited Na(+)/Mg(2+) exchanger. Taken together, our data indicate that Mg(2+) extrusion also occurs in cardiac cells exposed to ethanol as a result of alcohol metabolism by cyP4502E1. The extrusion, which is mediated by the Na(+)/Mg(2+) exchanger, only occurs at doses of ethanol ≥0.1%, and depends on ethanol-induced decline in cellular ATP. The significance of Mg(2+) extrusion for the onset of alcoholic cardiomyopathy remains to be elucidated.

  13. Update on management of cardiac arrhythmias in acute coronary syndromes.

    PubMed

    Willich, T; Goette, A

    2015-04-01

    This review summarizes different types of arrhythmias in patients with acute coronary syndromes and provides an overview of the available therapeutic options for acute care and management of critical arrhythmias. The different therapeutic options are depending on the origin and type of arrhythmia. The main common dominant mechanisms are intramural re-entry in ischemia and triggered activity in reperfusion. The different forms of arrhythmia were explained in detail. Atrial arrhythmias are mainly atrial fibrillation; other forms are rare and usually self-limited. As therapeutic options antiarrhythmic drug therapy with beta-blockers or amiodarone and direct current cardioversion are suitable. Ventricular arrhythmias can be divided in premature ventricular complexes, accelerated idioventricular rhythm, non-sustained ventricular tachycardia, sustained ventricular tachycardia (VT), ventricular fibrillation (VF) and electrical storm. As therapeutic options antiarrhythmic drug therapy, implantable cardioverter defibrillator therapy (ICD), radiofrequency catheter ablation (RFA) and stellate ganglion blockade are available. The treatment with antiarrhythmic drug is rather cautious recommended, with the exception of beta-blockers. An additional drug therapy with ranolazine may be considered. The advantage of ICD therapy for long-term primary or secondary prophylactic therapy has been well documented. ICD therapy is associated with significant reduction in mortality compared with antiarrhythmic drug therapy (mainly amiodarone), with the exception of beta-blockers. RFA and stellate ganglion blockade are rather intended as therapeutically options for incessant VT/VF or electrical storm.

  14. 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

  15. Preventing Rejection

    MedlinePlus

    ... medications work best. These medications work in different phases of the immune response to minimize side effects ... effective immunosuppression. Clinical immunosuppression usually occurs in three phases: induction, maintenance and anti-rejection. Reference and Publication ...

  16. 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.

  17. Cardiac xenotransplantation.

    PubMed

    DiSesa, V J

    1997-12-01

    Heart failure is an important medical and public health problem. Although medical therapy is effective for many people, the only definitive therapy is heart transplantation, which is limited severely by the number of donors. Mechanical devices presently are used as "bridges" to transplantation. Their widespread use may solve the donor shortage problem, but at present, mechanical devices are limited by problems related to blood clotting, power supply, and foreign body infection. Cardiac xenotransplantation using animal donors is a potential biologic solution to the donor organ shortage. The immune response, consisting of hyperacute rejection, acute vascular rejection, and cellular rejection, currently prevents clinical xenotransplantation. Advances in the solution of these problems have been made using conventional immunosuppressive drugs and newer agents whose use is based on an understanding of important steps in xenoimmunity. The most exciting approaches use tools of molecular biology to create genetically engineered donors and to induce states of donor and recipient bone marrow chimerism and tolerance in xenogeneic organ recipients. The successful future strategy may use a combination of a genetically engineered donor and a chimeric recipient with or without nonspecific immunosuppressive drugs.

  18. The role of cardiac magnetic resonance imaging (MRI) in acute myocardial infarction (AMI).

    PubMed

    Ahmed, Nadeem; Carrick, David; Layland, Jamie; Oldroyd, Keith G; Berry, Colin

    2013-04-01

    Acute myocardial infarction (AMI) is a leading cause of mortality and morbidity in the world, despite the rate having significantly declined over the past decade. The aim of this review is to consider the emerging diagnostic and clinical utility of cardiac MRI in patients with recent AMI. Cardiac MRI has high reproducibility and accuracy, allowing detailed functional assessment and characterisation of myocardial tissue. In addition to traditional measures including infarct size (IS), transmural extent of necrosis and microvascular obstruction (MVO), other infarct characteristics can now be identified using innovative MRI techniques. These novel pathologies include myocardial oedema and myocardial haemorrhage which also have functional and prognostic implications for patients. In addition to its diagnostic utility in ordinary clinical practice, cardiac MRI has been increasingly used to provide information on surrogate outcome measures, such as left ventricular ejection fraction (LVEF) and volumes, in clinical trials. MRI is becoming more available in secondary care, however, the potential clinical utility and cost effectiveness of MRI in post-MI patients remains uncertain. Cardiac MRI is most likely to be useful in high risk patients with risk factors for heart failure (HF). This includes individuals with early signs of pump failure and risk factors for adverse remodelling, such as MVO. This review focuses on the role of cardiac MRI in the assessment of patients with AMI.

  19. Cardiac function after acute support with direct mechanical ventricular actuation in chronic heart failure.

    PubMed

    McConnell, Patrick I; Anstadt, Mark P; Del Rio, Carlos L; Preston, Thomas J; Ueyama, Yukie; Youngblood, Brad L

    2014-01-01

    Direct mechanical ventricular actuation (DMVA) exerts direct cardiac compression/decompression and does not require blood contact. The safety and effects of DMVA support in chronically dysfunctional beating hearts in vivo have not been established. This study evaluated hemodynamics and load-independent systolic/diastolic cardiac function before/after acute support (2 hours) using DMVA in small hearts with induced chronic failure. Chronic heart failure was created in seven small dogs (15 ± 2 kg) via either serial coronary microembolizations or right-ventricular overdrive pacing. Dogs were instrumented to measure cardiac output, hemodynamic pressures, left ventricular volumes for pressure-volume analysis via preload reduction. Temporary cardiac support using a DMVA device was instituted for 2 hours. Hemodynamic and mechanical assessments, including dobutamine dose-responses, were compared both before and after support. Hemodynamic indices were preserved with support. Both left-ventricular systolic and diastolic function were improved postsupport, as the slopes of the preload-recruitable stroke work (+29 ± 7%, p < 0.05) and the end-diastolic pressure-volume relationship (EDPVR: -28 ± 9%, p < 0.05) improved post-DMVA support. Diastolic/systolic myocardial reserve, as assessed by responsiveness to dobutamine challenges, was preserved after DMVA support. Short-term DMVA support can safely and effectively sustain hemodynamics, whereas triggering favorable effects on cardiac function in the setting of chronic heart failure. In particular, DMVA support preserved load-independent diastolic function and reserve.

  20. Traditional Chinese Medication Qiliqiangxin attenuates cardiac remodeling after acute myocardial infarction in mice

    PubMed Central

    Tao, Lichan; Shen, Sutong; Fu, Siyi; Fang, Hongyi; Wang, Xiuzhi; Das, Saumya; Sluijter, Joost P. G.; Rosenzweig, Anthony; Zhou, Yonglan; Kong, Xiangqing; Xiao, Junjie; Li, Xinli

    2015-01-01

    In a multicenter randomized double-blind study we demonstrated that Qiliqiangxin (QLQX), a traditional Chinese medicine, had a protective effect in heart failure patients. However, whether and via which mechanism QLQX attenuates cardiac remodeling after acute myocardial infarction (AMI) is still unclear. AMI was created by ligating the left anterior descending coronary artery in mice. Treating the mice in the initial 3 days after AMI with QLQX did not change infarct size. However, QLQX treatment ameliorated adverse cardiac remodeling 3 weeks after AMI including better preservation of cardiac function, decreased apoptosis and reduced fibrosis. Peroxisome proliferator-activated receptor-γ (PPARγ) was down-regulated in control animals after AMI and up-regulated by QLQX administration. Interestingly, expression of AKT, SAPK/JNK, and ERK was not altered by QLQX treatment. Inhibition of PPARγ reduced the beneficial effects of QLQX in AMI remodeling, whereas activation of PPARγ failed to provide additional improvement in the presence of QLQX, suggesting a key role for PPARγ in the effects of QLQX during cardiac remodeling after AMI. This study indicates that QLQX attenuates cardiac remodeling after AMI by increasing PPARγ levels. Taken together, QLQX warrants further investigation as as a therapeutic intervention to mitigate remodeling and heart failure after AMI. PMID:25669146

  1. Orthogonal Comparison of Molecular Signatures of Kidney Transplants With Subclinical and Clinical Acute Rejection: Equivalent Performance Is Agnostic to Both Technology and Platform.

    PubMed

    Kurian, S M; Velazquez, E; Thompson, R; Whisenant, T; Rose, S; Riley, N; Harrison, F; Gelbart, T; Friedewald, J J; Charette, J; Brietigam, S; Peysakhovich, J; First, M R; Abecassis, M M; Salomon, D R

    2017-08-01

    We performed orthogonal technology comparisons of concurrent peripheral blood and biopsy tissue samples from 69 kidney transplant recipients who underwent comprehensive algorithm-driven clinical phenotyping. The sample cohort included patients with normal protocol biopsies and stable transplant (sTx) function (n = 25), subclinical acute rejection (subAR, n = 23), and clinical acute rejection (cAR, n = 21). Comparisons between microarray and RNA sequencing (RNA-seq) signatures were performed and demonstrated a strong correlation between the blood and tissue compartments for both technology platforms. A number of shared differentially expressed genes and pathways between subAR and cAR in both platforms strongly suggest that these two clinical phenotypes form a continuum of alloimmune activation. SubAR is associated with fewer or less expressed genes than cAR in blood, whereas in biopsy tissues, this clinical phenotype demonstrates a more robust molecular signature for both platforms. The discovery work done in this study confirms a clear ability to detect gene expression profiles for sTx, subAR, and cAR in both blood and biopsy tissue, yielding equivalent predictive performance that is agnostic to both technology and platform. Our data also provide strong biological insights into the molecular mechanisms underlying these signatures, underscoring their logistical potential as molecular diagnostics to improve clinical outcomes following kidney transplantation. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

  2. Impact of HLA-G 14-bp polymorphism on acute rejection and cytomegalovirus infection in kidney transplant recipients from northwestern China.

    PubMed

    Jin, Zhan-Kui; Xu, Cui-Xiang; Tian, Pu-Xun; Xue, Wu-Jun; Ding, Xiao-Ming; Zheng, Jin; Ding, Chen-Guang; Ge, Guan-Qun; Mao, Tian-Ci; Lin, Yuan

    2012-10-01

    Human leukocyte antigen (HLA)-G plays an important role in promoting transplant tolerance and helping human cytomegalovirus (CMV) to subvert host defenses. Strong evidence suggests that HLA-G 14-bp insertion/deletion polymorphism influences the stability of HLA-G mRNAs and levels of protein expression. We hypothesized that HLA-G 14-bp polymorphism of recipients has an influence on the risk of acute rejection (AR) and CMV infection. We investigated the impact of HLA-G 14-bp polymorphism on a total of 363 unrelated Chinese Han individuals who included 42 kidney transplant recipients with AR, 43 recipients with CMV infection, 102 recipients with stable allograft function (STA), and 176 healthy controls (HC). No statistically significant difference was found between all kidney transplant patients and HC (P=0.149). But, our data showed an increased frequency of homozygous genotype +14/+14 bp (P(c)=0.004) and allele +14 bp (P(c)=0.002) in patients with AR when compared with STA, with the odds ratio of 3.17 and 2.28, respectively. Moreover, we found that the frequency of the -14/-14 bp genotype (P(c)=0.008) and the -14 bp allele (P(c)=0.016) was increased in patients with CMV infection when compared with STA, with the OR of 2.66 and 1.96, respectively. Multivariate analysis further demonstrated that HLA-G homozygous +14 bp and -14 bp genotypes were an independent risk factor for allograft rejection and CMV infection, respectively. In conclusion, this study identified an important genetic risk factor for acute allograft rejection, and it was the first to show a significant correlation between HLA-G 14-bp polymorphism and CMV infection after kidney transplantation from northwestern China. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

  3. Transforming growth factor-β activated long non-coding RNA ATB plays an important role in acute rejection of renal allografts and may impacts the postoperative pharmaceutical immunosuppression therapy.

    PubMed

    Qiu, Jiang; Chen, Yehui; Huang, Gang; Zhang, Zhi; Chen, Lizhong; Na, Ning

    2017-10-01

    Long noncoding RNAs (lncRNAs) are novel intracellular noncoding ribonucleotides regulating the genome and proteome. The lncRNA activated by transforming growth factor β (TGF-β) (lncRNA-ATB) was discovered as a prognostic factor in hepatocellular carcinoma, gastric cancer, and colorectal cancer. However, little is known about the role of lncRNA-ATB in renal transplantation. This study aimed to assess lncRNA-ATB expression in renal transplant patients with acute kidney injury and explore its role in postoperative pharmaceutical immunosuppression therapy. We detected lncRNA-ATB expression in the kidney biopsies of a cohort of 72 patients with renal allograft rejection and 36 control transplant patients. lncRNA-ATB were overexpressed from lentiviral vectors in renal cells. We found that lncRNA-ATB was remarkably upregulated in patients with acute rejection compared with controls. Meanwhile, lncRNA-ATB could influence the kidney cell phenotypes and impact the nephrotoxicity of immunosuppressive drug. In conclusion, lncRNA-ATB are strongly altered in patients with acute rejection and may serve as a novel biomarker of acute kidney rejection, identifying patients with acute rejection and predicting loss of kidney function. © 2016 Asian Pacific Society of Nephrology.

  4. High sensitivity cardiac troponin T in patients not having an acute coronary syndrome: results from the TRAPID-AMI study.

    PubMed

    Nowak, Richard; Mueller, Christian; Giannitsis, Evangelos; Christ, Michael; Ordonez-Llanos, Jordi; DeFilippi, Christopher; McCord, James; Body, Richard; Panteghini, Mauro; Jernberg, Tomas; Plebani, Mario; Verschuren, Franck; French, John K; Christenson, Robert; Jacobsen, Gordon; Dinkel, Carina; Lindahl, Bertil

    2017-06-14

    To describe the baseline, 1 hr and delta high sensitivity cardiac troponin (hs-cTnT) values in patients with suspected acute myocardial infarction (AMI) but without a final acute coronary syndrome (ACS) diagnosis. hs-cTnT assay for RAPID rule out of acute myocardial infarction (TRAPID-AMI) was a prospective diagnostic trial that enrolled emergency department (ED) patients with suspected AMI. Final patient diagnoses were adjudicated by a clinical events committee and subjects placed in different clinical groups: AMI, unstable angina, non-ACS cardiac, non-cardiac and unknown origin. The baseline, 1 hr and delta hs-cTnT values were analysed in the 902 non-ACS patients. Amongst the 1282 studied the patient groups were 213 (17%) AMI, 167 (13%) unstable angina, 113 (9%) non-ACS cardiac, 288 (22%) non-cardiac and 501 (39%) unknown origin. The hs-cTnT values in the non-cardiac and unknown origin groups were combined. The median hs-cTnT values (ng/L) were higher (p < 0.001) in the non-ACS cardiac compared to the non-cardiac/unknown origin group at baseline (11.8, <5) and 1 hr (12.3, <5). Their negative predictive values were 0.955 (baseline) and 0.954 (1 hr) for predicting non-ACS cardiac versus non-cardiac/unknown origin diagnoses. Hs-cTnT may help predict whether non-ACS ED patients have a final non-ACS cardiac or non-cardiac/unknown origin diagnoses.

  5. Cardiac function in an endothermic fish: cellular mechanisms for overcoming acute thermal challenges during diving

    PubMed Central

    Shiels, H. A.; Galli, G. L. J.; Block, B. A.

    2015-01-01

    Understanding the physiology of vertebrate thermal tolerance is critical for predicting how animals respond to climate change. Pacific bluefin tuna experience a wide range of ambient sea temperatures and occupy the largest geographical niche of all tunas. Their capacity to endure thermal challenge is due in part to enhanced expression and activity of key proteins involved in cardiac excitation–contraction coupling, which improve cardiomyocyte function and whole animal performance during temperature change. To define the cellular mechanisms that enable bluefin tuna hearts to function during acute temperature change, we investigated the performance of freshly isolated ventricular myocytes using confocal microscopy and electrophysiology. We demonstrate that acute cooling and warming (between 8 and 28°C) modulates the excitability of the cardiomyocyte by altering the action potential (AP) duration and the amplitude and kinetics of the cellular Ca2+ transient. We then explored the interactions between temperature, adrenergic stimulation and contraction frequency, and show that when these stressors are combined in a physiologically relevant way, they alter AP characteristics to stabilize excitation–contraction coupling across an acute 20°C temperature range. This allows the tuna heart to maintain consistent contraction and relaxation cycles during acute thermal challenges. We hypothesize that this cardiac capacity plays a key role in the bluefin tunas' niche expansion across a broad thermal and geographical range. PMID:25540278

  6. Cardiac function in an endothermic fish: cellular mechanisms for overcoming acute thermal challenges during diving.

    PubMed

    Shiels, H A; Galli, G L J; Block, B A

    2015-02-07

    Understanding the physiology of vertebrate thermal tolerance is critical for predicting how animals respond to climate change. Pacific bluefin tuna experience a wide range of ambient sea temperatures and occupy the largest geographical niche of all tunas. Their capacity to endure thermal challenge is due in part to enhanced expression and activity of key proteins involved in cardiac excitation-contraction coupling, which improve cardiomyocyte function and whole animal performance during temperature change. To define the cellular mechanisms that enable bluefin tuna hearts to function during acute temperature change, we investigated the performance of freshly isolated ventricular myocytes using confocal microscopy and electrophysiology. We demonstrate that acute cooling and warming (between 8 and 28°C) modulates the excitability of the cardiomyocyte by altering the action potential (AP) duration and the amplitude and kinetics of the cellular Ca(2+) transient. We then explored the interactions between temperature, adrenergic stimulation and contraction frequency, and show that when these stressors are combined in a physiologically relevant way, they alter AP characteristics to stabilize excitation-contraction coupling across an acute 20°C temperature range. This allows the tuna heart to maintain consistent contraction and relaxation cycles during acute thermal challenges. We hypothesize that this cardiac capacity plays a key role in the bluefin tunas' niche expansion across a broad thermal and geographical range. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  7. Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation.

    PubMed

    Agbor-Enoh, Sean; Tunc, Ilker; De Vlaminck, Iwijn; Fideli, Ulgen; Davis, Andrew; Cuttin, Karen; Bhatti, Kenneth; Marishta, Argit; Solomon, Michael A; Jackson, Annette; Graninger, Grace; Harper, Bonnie; Luikart, Helen; Wylie, Jennifer; Wang, Xujing; Berry, Gerald; Marboe, Charles; Khush, Kiran; Zhu, Jun; Valantine, Hannah

    2017-09-01

    Use of new genomic techniques in clinical settings requires that such methods are rigorous and reproducible. Previous studies have shown that quantitation of donor-derived cell-free DNA (%ddcfDNA) by unbiased shotgun sequencing is a sensitive, non-invasive marker of acute rejection after heart transplantation. The primary goal of this study was to assess the reproducibility of %ddcfDNA measurements across technical replicates, manual vs automated platforms, and rejection phenotypes in distinct patient cohorts. After developing and validating the %ddcfDNA assay, we subjected the method to a rigorous test of its reproducibility. We measured %ddcfDNA in technical replicates performed by 2 independent laboratories and verified the reproducibility of %ddcfDNA patterns of 2 rejection phenotypes: acute cellular rejection and antibody-mediated rejection in distinct patient cohorts. We observed strong concordance of technical-replicate %ddcfDNA measurements across 2 independent laboratories (slope = 1.02, R(2) > 0.99, p < 10(-6)), as well as across manual and automated platforms (slope = 0.80, R(2) = 0.92, p < 0.001). The %ddcfDNA measurements in distinct heart transplant cohorts had similar baselines and error rates. The %ddcfDNA temporal patterns associated with rejection phenotypes were similar in both patient cohorts; however, the quantity of ddcfDNA was significantly higher in samples with severe vs mild histologic rejection grade (2.73% vs 0.14%, respectively; p < 0.001). The %ddcfDNA assay is precise and reproducible across laboratories and in samples from 2 distinct types of heart transplant rejection. These findings pave the way for larger studies to assess the clinical utility of %ddcfDNA as a marker of acute rejection after heart transplantation. Copyright © 2017. Published by Elsevier Inc.

  8. Preoperative Low Serum Bicarbonate Levels Predict Acute Kidney Injury After Cardiac Surgery.

    PubMed

    Jung, Su-Young; Park, Jung Tak; Kwon, Young Eun; Kim, Hyung Woo; Ryu, Geun Woo; Lee, Sul A; Park, Seohyun; Jhee, Jong Hyun; Oh, Hyung Jung; Han, Seung Hyeok; Yoo, Tae-Hyun; Kang, Shin-Wook

    2016-03-01

    Acute kidney injury (AKI) after cardiac surgery is a common and serious complication. Although lower than normal serum bicarbonate levels are known to be associated with consecutive renal function deterioration in patients with chronic kidney injury, it is not well-known whether preoperative low serum bicarbonate levels are associated with the development of AKI in patients who undergo cardiac surgery. Therefore, the clinical implication of preoperative serum bicarbonate levels on AKI occurrence after cardiac surgery was investigated. Patients who underwent coronary artery bypass or valve surgery at Yonsei University Health System from January 2013 to December 2014 were enrolled. The patients were divided into 3 groups based on preoperative serum bicarbonate levels, which represented group 1 (below normal levels) <23 mEq/L; group 2 (normal levels) 23 to 24 mEq/L; and group 3 (elevated levels) >24 mEq/L. The primary outcome was the predicated incidence of AKI 48 hours after cardiac surgery. AKI was defined according to Acute Kidney Injury Network criteria. Among 875 patients, 228 (26.1%) developed AKI within 48 hours after cardiac surgery. The incidence of AKI was higher in group 1 (40.9%) than in group 2 (26.5%) and group 3 (19.5%) (P < 0.001). In addition, the duration of postoperative stay in a hospital intensive care unit (ICU) was longer for AKI patients and for those in the low-preoperative-serum-bicarbonate-level groups. A multivariate logistic regression analysis showed that low preoperative serum bicarbonate levels were significantly associated with AKI even after adjustment for age, sex, hypertension, diabetes mellitus, operation type, preoperative hemoglobin, and estimated glomerular filtration rate. In conclusion, low serum bicarbonate levels were associated with higher incidence of AKI and prolonged ICU stay. Further studies are needed to clarify whether strict correction of bicarbonate levels close to normal limits may have a protective

  9. Acute Coronary Syndrome and Cardiac Arrest: Using Simulation to Assess Resident Performance and Program Outcomes

    PubMed Central

    Opar, Susan P.; Short, Matthew W.; Jorgensen, Jennifer E.; Blankenship, Robert B.; Roth, Bernard J.

    2010-01-01

    Background Simulation training has emerged as an effective method of educating residents in cardiac emergencies. Few studies have used emergency simulation scenarios as an outcome measure to identify training deficiencies within residency programs. Purpose The purpose of this study was to evaluate postgraduate year-1 (PGY-1) residents on their ability to manage an acute coronary syndrome and cardiac arrest scenario before and after internship in order to provide outcome data to improve program performance. Methods A total of 58 PGY-1 residents from 10 medical specialties were evaluated using a human patient simulator before and after internship. They were given 12 minutes to manage a patient with acute coronary syndrome and ventricular fibrillation due to hyperkalemia. An objective checklist following basic and advanced cardiac life support guidelines was used to assess performance. Results A total of 58 interns (age, 25 to 44 years [mean, 29.1]; 38 [65.6%] men; 41 [70.7%] allopathic medical school graduates) participated in both the incoming and outgoing examination. Overall chest pain scores increased from a mean of 60.0% to 76.1% (P < .01). Medical knowledge performance improved from 51.1% to 76.1% (P < .01). Systems-based practice performance improved from 40.9% to 71.0% (P < .01). However, patient care performance declined from 93.4% to 80.2% (P < .01). Conclusions A simulated acute coronary syndrome and cardiac arrest scenario can evaluate incoming PGY-1 competency performance and test for interval improvement. This assessment tool can measure resident competency performance and evaluate program effectiveness. PMID:21976090

  10. The factors associated with sexual recovery in male patients with acute myocardial infarction under phase II cardiac rehabilitation.

    PubMed

    Lim, Seung-Kyu; Sim, Doo Sun; Han, Jae-Young

    2016-10-01

    The aim of the study was to assess the prognostic factors of short-term sexual recovery in patients with acute myocardial infarction after phase II cardiac rehabilitation for six weeks. It is often observed that patients who have suffered acute myocardial infarction and have sufficient aerobic capacity for sexual activity do not recover sexual activity. Until now, few studies have investigated factors associated with recovery of sexual activity. Observational study. Among 627 male patients with acute myocardial infarction who were referred for cardiac rehabilitation from October 2010-September 2014, 72 were finally analysed. Subjects who met all the following criteria were included: (1) completed a questionnaire about sexual activity before and after phase II cardiac rehabilitation; (2) showed usual sexual activity before onset of acute myocardial infarction and (3) revealed decreased sexual activity at baseline of cardiac rehabilitation compared to preacute myocardial infarction status despite ≥5 maximal metabolic equivalents. Information on sociodemographic characteristics and cardiopulmonary function obtained before cardiac rehabilitation was used for the analysis. (1) Twenty-five of the 72 subjects (34·7%) had improved sexual activity after six weeks of cardiac rehabilitation, but 47 (65·3%) continued the status of no-recovery sexual activity after cardiac rehabilitation. (2) Age, body mass index and use of statins were significantly different between subjects who recovered and those who did not. (3) No differences in other clinical characteristics and cardiopulmonary functions were detected between the two groups. (4) Age and body mass index were significant factors associated with recovery of sexual activity. Age and body mass index were significant factors associated with recovery of sexual activity in acute myocardial infarction patients. Aerobic capacity at baseline of cardiac rehabilitation was not an independent factor to predict the recovery of

  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. Cardiac magnetic resonance evaluation of edema after ST-elevation acute myocardial infarction.

    PubMed

    Monmeneu, José V; Bodí, Vicente; Sanchis, Juan; López-Lereu, María P; Mainar, Luis; Núñez, Julio; Chaustre, Fabián; Rumiz, Eva; Chorro, Francisco J; Llácer, Angel

    2009-08-01

    The aims of the study were to characterize myocardial edema after ST-elevation acute myocardial infarction using cardiac magnetic resonance imaging and to investigate its impact on ventricular function and its subsequent evolution. In total, 134 patients admitted to hospital for a first ST-elevation myocardial infarction who had a patent infarct-related artery underwent cardiac magnetic resonance imaging. Cine images (at rest and with low-dose dobutamine) and edema, perfusion and viability images were acquired. Imaging was repeated after 6 months. In the first week after infarction, edema was detected in at least one segment in 96.6% of patients (4+/-2.1 segments per patient). Extensive edema (> or = 4 segments) was associated with large ventricular end-diastolic and end-systolic volumes (P< .0001), a small left ventricular ejection fraction at rest (P=.001) and with low-dose dobutamine (P=.006), a large number of segments showing hypoperfusion (P=.001) or microvascular obstruction (P=.009), a more extensive infarct (P=.017) and greater transmural extent of the infarct (P=.003). The association between the presence and extent of edema during the first week and functional, perfusion and viability variables was still observable after 6 months. No patient exhibited edema at 6 months. Cardiac magnetic resonance imaging was useful for characterizing the myocardial edema that occurred after ST-elevation acute myocardial infarction. Extensive edema was associated with poor left ventricular characteristics. Edema was a transitory phenomenon that vanished within 6 months.

  13. Evaluation of the acute cardiac and central nervous system effects of the fluorocarbon trifluoromethane in baboons

    SciTech Connect

    Branch, C.A.; Goldberg, D.A.; Ewing, J.R.; Butt, S.S.; Gayner, J.; Fagan, S.C.

    1994-12-31

    The gaseous fluorocarbon trifluoromethane has recently been investigated for its potential as an in vivo gaseous indicator for nuclear magnetic resonance studies of brain perfusion. Trifluoromethane may also have significant value as a replacement for chlorofluorocarbon fire retardants. Because of possible species-specific cardiotoxic and anesthetic properties, the toxicological evaluation of trifluoromethane in primates (Papio anubis) is necessary prior to its evaluation in humans. We report the acute cardiac and central nervous system effects of trifluoromethane in eight anesthetized baboons. A dose-response effect was established for respiratory rate, electroencephalogram, and cardiac sinus rate, which exhibited a stepwise decrease from 10% trifluoromethane. No spontaneous arrhythmias were noted, and arterial blood pressure remained unchanged at any inspired level. Intravenous epinephrine infusions (1 {mu}g/kg) induced transient cardiac arrhythmia in 1 animal only at 70% FC-23 (v/v) trifluoromethane. Trifluoromethane appears to induce mild dose-related physiological changes at inspired levels of 30% or more, indicative of an anesthetic effect. These data suggest that trifluoromethane may be safe to use in humans, without significant adverse acute effects, at an inspired level of 30%. 23 refs., 3 figs., 3 tabs.

  14. Bone marrow transplantation modulates tissue macrophage phenotype and enhances cardiac recovery after subsequent acute myocardial infarction.

    PubMed

    Protti, Andrea; Mongue-Din, Heloise; Mylonas, Katie J; Sirker, Alexander; Sag, Can Martin; Swim, Megan M; Maier, Lars; Sawyer, Greta; Dong, Xuebin; Botnar, Rene; Salisbury, Jon; Gray, Gillian A; Shah, Ajay M

    2016-01-01

    Bone marrow transplantation (BMT) is commonly used in experimental studies to investigate the contribution of BM-derived circulating cells to different disease processes. During studies investigating the cardiac response to acute myocardial infarction (MI) induced by permanent coronary ligation in mice that had previously undergone BMT, we found that BMT itself affects the remodelling response. Compared to matched naive mice, animals that had previously undergone BMT developed significantly less post-MI adverse remodelling, infarct thinning and contractile dysfunction as assessed by serial magnetic resonance imaging. Cardiac rupture in male mice was prevented. Histological analysis showed that the infarcts of mice that had undergone BMT had a significantly higher number of inflammatory cells, surviving cardiomyocytes and neovessels than control mice, as well as evidence of significant haemosiderin deposition. Flow cytometric and histological analyses demonstrated a higher number of alternatively activated (M2) macrophages in myocardium of the BMT group compared to control animals even before MI, and this increased further in the infarcts of the BMT mice after MI. The process of BMT itself substantially alters tissue macrophage phenotype and the subsequent response to acute MI. An increase in alternatively activated macrophages in this setting appears to enhance cardiac recovery after MI. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Novel biomarkers for cardiac surgery-associated acute kidney injury: a skeptical assessment of their role.

    PubMed

    Sidebotham, David

    2012-12-01

    Cardiac surgery-associated acute kidney injury (AKI) is common and is associated with a high mortality rate. Traditional biomarkers of AKI (creatinine and urea) increase slowly in response to renal injury, are insensitive to mild degrees of AKI, and are influenced by nonrenal factors. There is considerable interest in novel biomarkers of AKI such as neutrophil gelatinase-associated lipocalin that increase rapidly after renal injury, detect mild degrees of AKI, and are less subject to nonrenal factors. It has been postulated that the early diagnosis of cardiac surgery-associated AKI using novel biomarkers will result in improved outcomes. However, there is little evidence that interventions started early in the course of evolving AKI enhance renal recovery. Until effective therapies are developed that significantly improve the outcome from AKI, there is little benefit from early diagnosis using novel biomarkers.

  16. [Immediate Cardiac Life Support (ICLS) course developed by Japanese Association for Acute Medicine].

    PubMed

    Okudera, Hiroshi; Wakasugi, Masahiro

    2011-04-01

    The Immediate Cardiac Life Support (ICLS) course was developed and launched by Japanese Association for Acute Medicine (JAAM) for resident training, in April 2002. The ICLS course is designed as multi-professional one-day (8 hours) resuscitation course and teaches the essential skills and team dynamics required to manage a patient in cardiac arrest for 10 minutes before the arrival of a cardiovascular specialist. The course consists of skill stations and scenario stations. The skill stations provide basic life support (BLS) with automated external defibrillator (AED), basic airway management and in-hospital management with electrocardiographic (ECG) monitoring with manual external defibrillator. In total, 117,246 candidates attended 6,971 ICLS courses until the end of December 2010. Furthermore, we developed additional course of ICLS to manage stroke, Immediate Stroke Life Support (ISLS). We also describe the development and structure of, and rationale for the ICLS course.

  17. 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

  18. AGT*M235T polymorphism in acute ischemic cardiac dysfunction: the gisca project.

    PubMed

    Saud, Claudia Guerra Murad; Reis, Amália Faria Dos; Dias, Arlisa Monteiro de Castro; Cardoso, Rosemery Nunes; Carneiro, Ana Cristina Klem Vargas; Souza, Leandro Pereira de; Fonseca, Ana Beatriz Monteiro; Ribeiro, Georgina Severo; Faria, Carlos Augusto Cardozo de

    2010-08-01

    AGT*M235T polymorphism has been associated with high serum angiotensinogen (AGT) levels, systemic hypertension and cardiac dysfunction (CD). To test the hypothesis of AGT*M235T polymorphism being associated with the risk of developing cardiac dysfunction (heart failure or asymptomatic left ventricular systolic dysfunction) after acute coronary syndrome (ACS) during hospitalization. A total of 363 patients (mean age of 62 ± 12 years), of whom 233 (64%) were men and 130 (36%) were women, all from the same cohort and hospitalized for ACS, were studied. Clinical and genetic data from the 117 (32.2%) patients who developed cardiac dysfunction (case group) were compared to those of the 246 (67.8%) who did not develop this condition (control group). The AGT*M235T polymorphism was determined by sequence analysis and was in Hardy-Weinberg equilibrium. There was a significant difference in the distribution of genotypes among women, with a predominance of the *235MM genotype in the control group (p = 0.001) and of the *235T allele in the case group. In the logistic regression models, the diagnosis of anterior wall myocardial infarction at admission was related to an increased risk of CD in both genders, whereas unstable angina at admission.; absence of the *235T allele; blood glucose <100 mg/dl; use of betablocker; serum creatinine level < 1.5 mg/dl;heart rate range > 60 and < 90 bpm; and current cigarette smoking were related to a lower risk of CD. This study suggests that the absence of the AGT *235T allele contributes to a reduced risk of cardiac dysfunction after acute coronary syndrome.

  19. Evaluation of cardiac autonomic function using heart rate variability in children with acute carbon monoxide poisoning.

    PubMed

    Vural, Cagdas; Dinleyici, Ener Cagri; Kosger, Pelin; Bolluk, Ozge; Kilic, Zubeyir; Ucar, Birsen

    2017-08-01

    Introduction Carbon monoxide poisoning may cause myocardial toxicity and cardiac autonomic dysfunction, which may contribute to the development of life-threatening arrhythmias. We investigated the potential association between acute carbon monoxide exposure and cardiac autonomic function measured by heart rate variability. The present study included 40 children aged 1-17 years who were admitted to the Pediatric Intensive Care Unit with acute carbon monoxide poisoning and 40 healthy age- and sex-matched controls. Carboxyhaemoglobin and cardiac enzymes were measured at admission. Electrocardiography was performed on admission and discharge, and 24-hour Holter electrocardiography was digitally recorded. Heart rate variability was analysed at both time points - 24-hour recordings - and frequency domains - from the first 5 minutes of intensive care unit admission. Time domain and frequency indices such as high-frequency spectral power and low-frequency spectral power were similar between patient and control groups (p>0.05). The ratio of low-frequency spectral power to high-frequency spectral power was significantly lower in the carbon monoxide poisoning group (p<0.001) and was negatively correlated with carboxyhaemoglobin levels (r=-0.351, p<0.05). The mean heart rate, QT dispersion, corrected QT dispersion, and P dispersion values were higher in the carbon monoxide poisoning group (p<0.05) on admission. The QT dispersion and corrected QT dispersion remained longer in the carbon monoxide poisoning group compared with controls on discharge (p<0.05). The frequency domain indices, especially the ratio of low-frequency spectral power to high-frequency spectral power, are useful for the evaluation of the cardiac autonomic function. The decreased low-frequency spectral power-to-high-frequency spectral power ratio reflects a balance of the autonomic nervous system, which shifted to parasympathetic components.

  20. Acute vagal stimulation attenuates cardiac metabolic response to β-adrenergic stress

    PubMed Central

    Vimercati, Claudio; Qanud, Khaled; Ilsar, Itamar; Mitacchione, Gianfranco; Sarnari, Roberto; Mania, Daniella; Faulk, Ryan; Stanley, William C; Sabbah, Hani N; Recchia, Fabio A

    2012-01-01

    The effects of vagal stimulation (VS) on cardiac energy substrate metabolism are unknown. We tested the hypothesis that acute VS alters the balance between free fatty acid (FFA) and carbohydrate oxidation and opposes the metabolic effects of β-adrenergic stimulation. A clinical-type selective stimulator of the vagal efferent fibres was connected to the intact right vagus in chronically instrumented dogs. VS was set to reduce heart rate by 30 beats min−1, and the confounding effects of bradycardia were then eliminated by pacing the heart at 165 beats min−1. [3H]Oleate and [14C]glucose were infused to measure FFA and glucose oxidation. The heart was subjected to β-adrenergic stress by infusing dobutamine at 5, 10 and 15 μg kg−1 min−1 before and during VS. VS did not significantly affect baseline cardiac performance, haemodynamics or myocardial metabolism. However, at peak dobutamine stress, VS attenuated the increase in left ventricular pressure–diameter area from 235.9 ± 72.8 to 167.3 ± 55.8%, and in cardiac oxygen consumption from 173.9 ± 23.3 to 127.89 ± 6.2% (both P < 0.05), and thus mechanical efficiency was not enhanced. The increase in glucose oxidation fell from 289.3 ± 55.5 to 131.1 ± 20.9%(P < 0.05), while FFA oxidation was not increased by β-adrenergic stress and fell below baseline during VS only at the lowest dose of dobutamine. The functional and in part the metabolic changes were reversed by 0.1 mg kg−1 atropine i.v. Our data show that acute right VS does not affect baseline cardiac metabolism, but attenuates myocardial oxygen consumption and glucose oxidation in response to adrenergic stress, thus functioning as a cardio-selective antagonist to β-adrenergic activation. PMID:22966163

  1. Acute vagal stimulation attenuates cardiac metabolic response to β-adrenergic stress.

    PubMed

    Vimercati, Claudio; Qanud, Khaled; Ilsar, Itamar; Mitacchione, Gianfranco; Sarnari, Roberto; Mania, Daniella; Faulk, Ryan; Stanley, William C; Sabbah, Hani N; Recchia, Fabio A

    2012-12-01

    The effects of vagal stimulation (VS) on cardiac energy substrate metabolism are unknown. We tested the hypothesis that acute VS alters the balance between free fatty acid (FFA) and carbohydrate oxidation and opposes the metabolic effects of β-adrenergic stimulation. A clinical-type selective stimulator of the vagal efferent fibres was connected to the intact right vagus in chronically instrumented dogs. VS was set to reduce heart rate by 30 beats min(-1), and the confounding effects of bradycardia were then eliminated by pacing the heart at 165 beats min(-1). [(3)H]Oleate and [(14)C]glucose were infused to measure FFA and glucose oxidation. The heart was subjected to β-adrenergic stress by infusing dobutamine at 5, 10 and 15 μg kg(-1) min(-1) before and during VS. VS did not significantly affect baseline cardiac performance, haemodynamics or myocardial metabolism. However, at peak dobutamine stress, VS attenuated the increase in left ventricular pressure-diameter area from 235.9 ± 72.8 to 167.3 ± 55.8%, and in cardiac oxygen consumption from 173.9 ± 23.3 to 127.89 ± 6.2% (both P < 0.05), and thus mechanical efficiency was not enhanced. The increase in glucose oxidation fell from 289.3 ± 55.5 to 131.1 ± 20.9% (P < 0.05), while FFA oxidation was not increased by β-adrenergic stress and fell below baseline during VS only at the lowest dose of dobutamine. The functional and in part the metabolic changes were reversed by 0.1 mg kg(-1) atropine i.v. Our data show that acute right VS does not affect baseline cardiac metabolism, but attenuates myocardial oxygen consumption and glucose oxidation in response to adrenergic stress, thus functioning as a cardio-selective antagonist to β-adrenergic activation.

  2. Pulse contour cardiac output monitoring in acute heart failure patients : Assessment of hemodynamic measurements.

    PubMed

    Wernly, Bernhard; Lichtenauer, Michael; Franz, Marcus; Fritzenwanger, Michael; Kabisch, Bjoern; Figulla, Hans-Reiner; Jung, Christian

    2016-12-01

    Heart failure is known to be a major public health problem. Fluid redistribution contributes to acute heart failure; therefore, knowledge of hemodynamic parameters could be important for optimizing outcomes. The pulse contour cardiac output monitor PiCCO uses the single thermal indicator technique and pulse contour analysis to calculate hemodynamic parameters of preload, afterload, cardiac output, systemic vascular resistance and extravascular lung water. We primarily aimed to describe values and parameters seen in acute heart failure patients admitted to the intensive care unit (ICU) and secondly to investigate associations between hemodynamic measurements and survival data. In this study 420 consecutive patients admitted to a tertiary medical university hospital ICU between January 2004 and December 2009 were retrospectively investigated. The study sample was divided into two subgroups: patients monitored by PiCCO (n = 47) and those not monitored by thermodilution measurements (n = 373). No predetermined treatment algorithm based on knowledge obtained by the PiCCO monitor was used and measurements were individually interpreted by the treating physician. The PiCCO monitor measurements were carried out according to manufacturer's directions. Patients with PiCCO monitoring were clinically in poorer health with a mean simplified acute physiology score II (SAPS2) of 45 ± 17 vs. 56 ± 20 (p < 0.01). The ICU mortality (22 % vs. 38 %, p = 0.02) and, at least as a tendency, long-term-mortality were increased in patients monitored by PiCCO (RR 1.49, 95 % CI 0.96-2.31, p = 0.08). We provide hemodynamic measurements in acute heart failure patients: cardiac index (2.7 ± 1.2 l/min/m²) was reduced, preload and extravascular lung water index (EVLWI, 11.5 ± 5.1 ml/kg body weight), representing lung edema, were increased. We provide real world values for PiCCO parameters in acutely decompensated heart failure. In our study patients who were clinically in

  3. 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. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  4. 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

  5. Gene Expression in Biopsies of Acute Rejection and Interstitial Fibrosis/Tubular Atrophy Reveals Highly Shared Mechanisms That Correlate With Worse Long-Term Outcomes

    PubMed Central

    Modena, B. D.; Kurian, S. M.; Gaber, L. W.; Waalen, J.; Su, A. I.; Gelbart, T.; Mondala, T. S.; Head, S. R.; Papp, S.; Heilman, R.; Friedewald, J. J.; Flechner, S.M.; Marsh, C. L.; Sung, R. S.; Shidban, H.; Chan, L.; Abecassis, M. M.; Salomon, D. R.

    2017-01-01

    Interstitial fibrosis and tubular atrophy (IFTA) is found in approximately 25% of 1-year biopsies posttransplant. It is known that IFTA correlates with decreased graft survival when histological evidence of inflammation is present. Identifying the mechanistic etiology of IFTA is important to understanding why long-term graft survival has not changed as expected despite improved immunosuppression and dramatically reduced rates of clinical acute rejection (AR) (Services UDoHaH. http://www.ustransplant.org/annual_reports/current/509a_ki.htm). Gene expression profiles of 234 graft biopsy samples were obtained with matching clinical and outcome data. Eighty-one IFTA biopsies were divided into subphenotypes by degree of histological inflammation: IFTA with AR, IFTA with inflammation, and IFTA without inflammation. Samples with AR (n = 54) and normally functioning transplants (TX; n = 99) were used in comparisons. A novel analysis using gene coexpression networks revealed that all IFTA phenotypes were strongly enriched for dysregulated gene pathways and these were shared with the biopsy profiles of AR, including IFTA samples without histological evidence of inflammation. Thus, by molecular profiling we demonstrate that most IFTA samples have ongoing immune-mediated injury or chronic rejection that is more sensitively detected by gene expression profiling. These molecular biopsy profiles correlated with future graft loss in IFTA samples without inflammation. PMID:26990570

  6. Selective Blockade of Periostin Exon 17 Preserves Cardiac Performance in Acute Myocardial Infarction.

    PubMed

    Taniyama, Yoshiaki; Katsuragi, Naruto; Sanada, Fumihiro; Azuma, Junya; Iekushi, Kazuma; Koibuchi, Nobutaka; Okayama, Keita; Ikeda-Iwabu, Yuka; Muratsu, Jun; Otsu, Rei; Rakugi, Hiromi; Morishita, Ryuichi

    2016-02-01

    We previously reported that overexpression of full-length periostin, Pn-1, resulted in ventricular dilation with enhanced interstitial collagen deposition in a rat model. However, other reports have documented that the short-form splice variants Pn-2 (lacking exon 17) and Pn-4 (lacking exons 17 and 21) promoted cardiac repair by angiogenesis and prevented cardiac rupture after acute myocardial infarction. The apparently differing findings from those reports prompted us to use a neutralizing antibody to selectively inhibit Pn-1 by blockade of exon 17 in a rat acute myocardial infarction model. Administration of Pn neutralizing antibody resulted in a significant decrease in the infarcted and fibrotic areas of the myocardium, which prevented ventricular wall thinning and dilatation. The inhibition of fibrosis by Pn neutralizing antibody was associated with a significant decrease in gene expression of fibrotic markers, including collagen I, collagen III, and transforming growth factor-β1. Importantly, the number of α-smooth muscle actin-positive myofibroblasts was significantly reduced in the hearts of animals treated with Pn neutralizing antibody, whereas cardiomyocyte proliferation and angiogenesis were comparable in the IgG and neutralizing antibody groups. Moreover, the level of Pn-1 expression was significantly correlated with the severity of myocardial infarction. In addition, Pn-1, but not Pn-2 or Pn-4, inhibited fibroblast and myocyte attachment, which might account for the cell slippage observed during cardiac remodeling. Collectively, these results indicate that therapeutics that specifically inhibit Pn exon-17, via a neutralizing antibody or drug, without suppressing other periostin variants might offer a new class of medication for the treatment of acute myocardial infarction patients. © 2015 American Heart Association, Inc.

  7. Serum and salivary cardiac analytes in acute myocardial infarction related to oral health status

    NASA Astrophysics Data System (ADS)

    Ebersole, Jeffrey L.; Kryscio, Richard J.; Campbell, Charles; Kinane, Denis F.; McDevitt, John T.; Christodoulides, Nicolaos; Floriano, Pierre N.; Miller, Craig S.

    2014-06-01

    With the advent of an increased emphasis on the potential to utilize biomarkers in saliva for systemic diseases, the issue of existing oral disease is an important consideration that could adversely affect the interpretation of diagnostic results obtained from saliva. We addressed the question does a patient's oral inflammation status confound biomarker levels used in diagnosis of acute myocardial infarction (AMI). The results demonstrated that multiple serum biomarkers and a few salivary biomarkers reflected the cardiac event. Importantly, oral health of the individual had minimal impact on the validity of the serum or salivary biomarker effectiveness.

  8. Quantifying cardiac hemodynamic stress and cardiomyocyte damage in ischemic and nonischemic acute heart failure.

    PubMed

    Drexler, Beatrice; Heinisch, Corinna; Balmelli, Cathrin; Lassus, Johan; Siirilä-Waris, Krista; Arenja, Nisha; Socrates, Thenral; Noveanu, Markus; Potocki, Mihael; Meune, Christophe; Haaf, Philip; Degen, Christian; Breidthardt, Tobias; Reichlin, Tobias; Nieminen, Markku S; Veli-Pekka, Harjola; Osswald, Stefan; Mueller, Christian

    2012-01-01

    The early and noninvasive differentiation of ischemic and nonischemic acute heart failure (AHF) in the emergency department (ED) is an unmet clinical need. We quantified cardiac hemodynamic stress using B-type natriuretic peptide (BNP) and cardiomyocyte damage using 2 different cardiac troponin assays in 718 consecutive patients presenting to the ED with AHF (derivation cohort). The diagnosis of ischemic AHF was adjudicated using all information, including coronary angiography. Findings were validated in a second independent multicenter cohort (326 AHF patients). Among the 718 patients, 400 (56%) were adjudicated to have ischemic AHF. BNP levels were significantly higher in ischemic compared with nonischemic AHF (1097 [604-1525] pg/mL versus 800 [427-1317] pg/mL; P<0.001). Cardiac troponin T (cTnT) and sensitive cardiac troponin I (s-cTnI) were also significantly higher in ischemic compared with nonischemic AHF patients (0.040 [0.010-0.306] μg/L versus 0.018 [0.010-0.060] μg/L [P<0.001]; 0.024 [0.008-0.106] μg/L versus 0.016 [0.004-0.044 ] μg/L [P=0.002]). The diagnostic accuracy of BNP, cTnT, and s-cTnI for the diagnosis of ischemic AHF, as quantified by the area under the receiver-operating characteristic curve, was low (0.58 [95% CI, 0.54-0.63], 0.61 [95% CI, 0.57-0.66], and 0.59 [95% CI,0.54-0.65], respectively). These findings were confirmed in the validation cohort. At presentation to the ED, patients with ischemic AHF exhibit more extensive hemodynamic cardiac stress and cardiomyocyte damage than patients with nonischemic AHF. However, the overlap is substantial, resulting in poor diagnostic accuracy.

  9. Predictors of Acute Renal Failure During Extracorporeal Membrane Oxygenation in Pediatric Patients After Cardiac Surgery.

    PubMed

    Lv, Lin; Long, Cun; Liu, Jinping; Hei, Feilong; Ji, Bingyang; Yu, Kun; Hu, Qiang; Hu, Jinxiao; Yuan, Yuan; Gao, Guodong

    2016-05-01

    Acute renal failure (ARF) is associated with increased mortality in pediatric extracorporeal membrane oxygenation (ECMO). The aim of this study was to identify predictors of ARF during ECMO in pediatric patients after cardiac surgery. A retrospective study analyzed 42 children (≤15 years) after cardiac surgery requiring venous-arterial ECMO between December 2008 and December 2014 at Fuwai Hospital. ARF was defined as ≥300% rise in serum creatinine (SCr) concentration from baseline or application of dialysis. Multivariate logistic regression was performed to identify the predictors of ARF during ECMO. A total of 42 children (age, interquartile range [IQR], 13.0 [7.2-29.8] months; weight, IQR, 8.5 [6.7-11.0] kg) after cardiac surgery requiring ECMO were included in this study. The total survival rate was 52.4%, and the incidence of ARF was 40.5%. As the result of univariate analysis, ECMO duration, cardiopulmonary resuscitation, maximum free hemoglobin (FHB) during ECMO, lactate level, and mean blood pressure before initiation of ECMO were entered in multiple logistic regression analysis. In multiple logistic regression analysis, FHB during ECMO (OR 1.136, 95% CI 1.023-1.261) and lactate level before initiation of ECMO (OR 1.602, 95% CI 1.025-2.502) were risk factors for ARF during ECMO after pediatric cardiac surgery. There was a linear correlation between maximum SCr and maximum FHB (Pearson's r = 0.535, P = 0.001). Maximum SCr during ECMO has also a linear correlation with lactate level before initiation of ECMO (Pearson's r = 0.342, P = 0.044). Increased FHB during ECMO and high lactate level before initiation of ECMO were risk factors for ARF during ECMO in pediatric patients after cardiac surgery.

  10. Determinants of Acute Kidney Injury Duration After Cardiac Surgery: An Externally Validated Tool

    PubMed Central

    Brown, Jeremiah R.; Kramer, Robert S.; MacKenzie, Todd A.; Coca, Steven G.; Sint, Kyaw; Parikh, Chirag R.

    2013-01-01

    Background Acute kidney injury (AKI) duration following cardiac surgery is associated with poor survival in a dose-dependent manner. However, it is not known what peri-operative risk factors contribute to prolonged AKI and delayed recovery. We sought to identify peri-operative risk factors that predict duration of AKI, a complication that effects short and long term survival. Methods We studied 4,987 consecutive cardiac surgery patients from 2002 through 2007. AKI was defined as a ≥0.3 (mg/dL) or ≥50% increase in SCr from baseline. Duration of AKI was defined by the number of days AKI was present. Step-wise multivariable negative binomial regression analysis was conducted using peri-operative risk factors for AKI duration. C-index was estimated by Kendall’s tau. Results AKI developed in 39% of patients with a median duration of AKI at 3 days and ranged from 1 to 108 days. Patients without AKI had duration of zero days. Independent predictors of AKI duration included baseline patient and disease characteristics, operative and post-operative factors. Prediction for mean duration of AKI was developed using coefficients from the regression model and externally validated the model on 1,219 cardiac surgery patients in a separate cardiac surgery cohort (TRIBE-AKI). The C-index was 0.65 (p<0.001) for the derivation cohort and 0.62 (p<0.001) for the validation cohort. Conclusion We identified and externally validated peri-operative predictors of AKI duration. These risk-factors will be useful to evaluate a patient’s risk for the tempo of recovery from AKI after cardiac surgery and subsequent short and long term survival. The level of awareness created by working with these risk factors have implications regarding positive changes in processes of care that have the potential to decrease the incidence and mitigate AKI. PMID:22206952

  11. 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.

  12. Depression of Complement Regulatory Factors in Rat and Human Renal Grafts Is Associated with the Progress of Acute T-Cell Mediated Rejection

    PubMed Central

    Yamanaka, Kazuaki; Kakuta, Yoichi; Miyagawa, Shuji; Nakazawa, Shigeaki; Kato, Taigo; Abe, Toyofumi; Imamura, Ryoichi; Okumi, Masayoshi; Maeda, Akira; Okuyama, Hiroomi; Mizuno, Masashi; Nonomura, Norio

    2016-01-01

    Background The association of complement with the progression of acute T cell mediated rejection (ATCMR) is not well understood. We investigated the production of complement components and the expression of complement regulatory proteins (Cregs) in acute T-cell mediated rejection using rat and human renal allografts. Methods We prepared rat allograft and syngeneic graft models of renal transplantation. The expression of Complement components and Cregs was assessed in the rat grafts using quantitative real-time PCR (qRT-PCR) and immunofluorescent staining. We also administered anti-Crry and anti-CD59 antibodies to the rat allograft model. Further, we assessed the relationship between the expression of membrane cofactor protein (MCP) by immunohistochemical staining in human renal grafts and their clinical course. Results qRT-PCR results showed that the expression of Cregs, CD59 and rodent-specific complement regulator complement receptor 1-related gene/protein-y (Crry), was diminished in the rat allograft model especially on day 5 after transplantation in comparison with the syngeneic model. In contrast, the expression of complement components and receptors: C3, C3a receptor, C5a receptor, Factor B, C9, C1q, was increased, but not the expression of C4 and C5, indicating a possible activation of the alternative pathway. When anti-Crry and anti-CD59 mAbs were administered to the allograft, the survival period for each group was shortened. In the human ATCMR cases, the group with higher MCP expression in the grafts showed improved serum creatinine levels after the ATCMR treatment as well as a better 5-year graft survival rate. Conclusions We conclude that the expression of Cregs in allografts is connected with ATCMR. Our results suggest that controlling complement activation in renal grafts can be a new strategy for the treatment of ATCMR. PMID:26928779

  13. 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

  14. Clinical accuracy of RIFLE and Acute Kidney Injury Network (AKIN) criteria for acute kidney injury in patients undergoing cardiac surgery

    PubMed Central

    2011-01-01

    Introduction The RIFLE (risk, injury, failure, loss of kidney function, and end-stage renal failure) classification for acute kidney injury (AKI) was recently modified by the Acute Kidney Injury Network (AKIN). The two definition systems differ in several aspects, and it is not clearly determined which has the better clinical accuracy. Methods In a retrospective observational study we investigated 4,836 consecutive patients undergoing cardiac surgery with cardiopulmonary bypass from 2005 to 2007 at Mayo Clinic, Rochester, MN, USA. AKI was defined by RIFLE and AKIN criteria. Results Significantly more patients were diagnosed as AKI by AKIN (26.3%) than by RIFLE (18.9%) criteria (P < 0.0001). Both definitions showed excellent association to outcome variables with worse outcome by increased severity of AKI (P < 0.001, all variables). Mortality was increased with an odds ratio (OR) of 4.5 (95% CI 3.6 to 5.6) for one class increase by RIFLE and an OR of 5.3 (95% CI 4.3 to 6.6) for one stage increase by AKIN. The multivariate model showed lower predictive ability of RIFLE for mortality. Patients classified as AKI in one but not in the other definition set were predominantly staged in the lowest AKI severity class (9.6% of patients in AKIN stage 1, 2.3% of patients in RIFLE class R). Potential misclassification of AKI is higher in AKIN, which is related to moving the 48-hour diagnostic window applied in AKIN criteria only. The greatest disagreement between both definition sets could be detected in patients with initial postoperative decrease of serum creatinine. Conclusions Modification of RIFLE by staging of all patients with acute renal replacement therapy (RRT) in the failure class F may improve predictive value. AKIN applied in patients undergoing cardiac surgery without correction of serum creatinine for fluid balance may lead to over-diagnosis of AKI (poor positive predictive value). Balancing limitations of both definition sets of AKI, we suggest application of the

  15. Prognostic implications of cardiac scintigraphic parameters obtained in the early phase of acute myocardial infarction

    SciTech Connect

    Suzuki, A.; Matsushima, H.; Satoh, A.; Hayashi, H.; Sotobata, I.

    1988-06-01

    A cohort of 76 patients with acute myocardial infarction was studied with infarct-avid scan, radionuclide ventriculography, and thallium-201 myocardial perfusion scintigraphy. Infarct area, left ventricular ejection fraction, and defect score were calculated as radionuclide indices of the extent of myocardial infarction. The correlation was studied between these indices and cardiac events (death, congestive heart failure, postinfarction angina, and recurrence of myocardial infarction) in the first postinfarction year. High-risk patients (nonsurvivors and patients who developed heart failure) had a larger infarct area, a lower left ventricular ejection fraction, and a larger defect score than the others. Univariate linear discriminant analysis was done to determine the optimal threshold of these parameters for distinguishing high-risk patients from others. Radionuclide parameters obtained in the early phase of acute myocardial infarction were useful for detecting both patients with grave complications and those with poor late prognosis during a mean follow-up period of 2.6 years.

  16. Cardiac troponins I and T: molecular markers for early diagnosis, prognosis, and accurate triaging of patients with acute myocardial infarction.

    PubMed

    Tiwari, Ram P; Jain, Anubhav; Khan, Zakir; Kohli, Veena; Bharmal, R N; Kartikeyan, S; Bisen, Prakash S

    2012-12-01

    Acute myocardial infarction (AMI) is the leading cause of death worldwide, with early diagnosis still being difficult. Promising new cardiac biomarkers such as troponins and creatine kinase (CK) isoforms are being studied and integrated into clinical practice for early diagnosis of AMI. The cardiac-specific troponins I and T (cTnI and cTnT) have good sensitivity and specificity as indicators of myocardial necrosis and are superior to CK and its MB isoenzyme (CK-MB) in this regard. Besides being potential biologic markers, cardiac troponins also provide significant prognostic information. The introduction of novel high-sensitivity troponin assays has enabled more sensitive and timely diagnosis or exclusion of acute coronary syndromes. This review summarizes the available information on the potential of troponins and other cardiac markers in early diagnosis and prognosis of AMI, and provides perspectives on future diagnostic approaches to AMI.

  17. 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

  18. 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.

  19. Acute Mesenteric Ischemia after Cardiac Surgery: An Analysis of 52 Patients

    PubMed Central

    Gucu, Arif; Toktas, Faruk; Erdolu, Burak; Ozyazıcıoglu, Ahmet

    2013-01-01

    Objective. Acute mesenteric ischemia (AMI) is a rare but serious complication after cardiac surgery. The aim of this retrospective study was to evaluate the incidence, outcome, and perioperative risk factors of AMI in the patients undergoing elective cardiac surgery. Methods. From January 2005 to May 2013, all patients who underwent cardiac surgery were screened for participation, and patients with registered gastrointestinal complications were retrospectively reviewed. Univariate analyses were performed. Results. The study included 6013 patients, of which 52 (0.86%) patients suffered from AMI, 35 (67%) of whom died. The control group (150 patients) was randomly chosen from among cases undergoing cardiopulmonary bypass (CPB). Preoperative parameters including age (P = 0.03), renal insufficiency (P = 0.004), peripheral vascular disease (P = 0.04), preoperative inotropic support (P < 0.001), poor left ventricular ejection fraction (P = 0.002), cardiogenic shock (P = 0.003), and preoperative intra-aortic balloon pump (IABP) support (P = 0.05) revealed significantly higher levels in the AMI group. Among intra- and postoperative parameters, CPB time (P < 0.001), dialysis (P = 0.04), inotropic support (P = 0.007), prolonged ventilator time (P < 0.001), and IABP support (P = 0.007) appeared significantly higher in the AMI group than the control group. Conclusions. Prompt diagnosis and early treatment should be initiated as early as possible in any patient suspected of AMI, leading to dramatic reduction in the mortality rate. PMID:24288499

  20. Characterization of Cardiac Dysfunction by Echocardiography in Early Severe Acute Pancreatitis.

    PubMed

    Thandassery, Ragesh Babu; Choudhary, Nikhil; Bahl, Ajay; Kochhar, Rakesh

    Persistent organ failure is a feature of severe acute pancreatitis (SAP) and the leading cause of death. Although usually defined by hypotension, cardiovascular dysfunction (CD) in early SAP has not been well characterized. We aim to characterize CD in patients with SAP and hypotension and determine its impact on clinical outcome. Patients with SAP and hypotension were studied to define the frequency, nature, and prognostic significance of CD characterized by echocardiography and classified as systolic, diastolic, or combined dysfunction. Of the 72 patients (median age, 41 years, 44 men), 10 (14%) had percutaneous drain placement, 12 (17%) underwent surgery, and 14 (19%) died. Persistent hypotension was present in 58 (81%) and transient hypotension in 14 (19%) patients. Cardiovascular dysfunction was present in 47 (65%) patients: 28 (60%) with diastolic dysfunction, 8 (17%) with systolic dysfunction, and 11 (23%) with combined dysfunction. Left ventricular end diastolic volume, stroke volume index, cardiac index, and diastolic dysfunction correlated with mortality on univariate analysis. Two thirds of patients with early SAP and hypotension had cardiac dysfunction, which was most commonly diastolic dysfunction. A better understanding of the nature of cardiac dysfunction in this setting may allow more accurate diagnosis, prognostication, and management.

  1. Acute hypercalcemia and cardiac autotransplantation in dogs: long-term hemodynamic adaptability.

    PubMed

    Dumont, L; Stanley, P; Chartrand, C

    1986-11-01

    Cardiac autotransplantation (excision and reimplantation) is a unique model that isolates totally the cardiac afferent and efferent neural pathways and results in hemodynamic misadaptability to many provocative tests. Since the cardiovascular response to acute hypercalcemia is modulated by numerous factors among which the autonomic innervation plays a major role, the hemodynamic response to bolus administration of calcium gluconate was compared in normal and cardiac autotransplanted dogs. Twenty-two animals underwent an autotransplantation while a sham procedure was performed in 18 animals. Each dog was equipped with an electromagnetic flow probe positioned around the ascending aorta and with central venous and aortic catheters. Hemodynamic data were collected daily during 1 month, before and during rapid intravenous administration of calcium gluconate (0.90 mEq). Baseline hemodynamic studies indicate that for both groups myocardial failure is evident in the immediate postoperative period; despite progressive recovery, the autotransplants always show lower cardiovascular performance. Calcium administration elicits transient positive inotropism, which is more important in presence of myocardial failure; this is true for both control and autotransplanted dogs. In the early postoperative period, hemodynamic adaptability to this stress is impaired in the autotransplants. However, long-term results indicate that minimal differences subsist over time in response to calcium administration, and when they are observed, they result from interferences in baroreceptor regulation and reflexes.

  2. Case report: cardiac tamponade resembling an acute myocardial infarction as the initial manifestation of metastatic pericardial adenocarcinoma.

    PubMed

    Scheinin, Scott A; Sosa-Herrera, Jose

    2014-01-01

    Pericardial malignancies are uncommon, usually metastatic, linked to terminal oncology patients, and rarely diagnosed premortem. A very small number of patients will develop signs and symptoms of malignant pericardial effusion as initial clinical manifestation of neoplastic disease. Among these patients, a minority will progress to a life-threatening cardiac tamponade. It is exceedingly rare for a cardiac tamponade to be the unveiling clinical manifestation of an unknown malignancy, either primary or metastatic to pericardium. We present the case of a 50-year-old male who was admitted to the emergency department with an acute myocardial infarction diagnosis that turned out to be a cardiac tamponade of unknown etiology. Further studies revealed a metastatic pericardial adenocarcinoma with secondary cardiac tamponade. We encourage considering malignancies metastatic to pericardium as probable etiology for large pericardial effusions and cardiac tamponade of unknown etiology.

  3. Case Report: Cardiac Tamponade Resembling an Acute Myocardial Infarction as the Initial Manifestation of Metastatic Pericardial Adenocarcinoma

    PubMed Central

    2014-01-01

    Pericardial malignancies are uncommon, usually metastatic, linked to terminal oncology patients, and rarely diagnosed premortem. A very small number of patients will develop signs and symptoms of malignant pericardial effusion as initial clinical manifestation of neoplastic disease. Among these patients, a minority will progress to a life-threatening cardiac tamponade. It is exceedingly rare for a cardiac tamponade to be the unveiling clinical manifestation of an unknown malignancy, either primary or metastatic to pericardium. We present the case of a 50-year-old male who was admitted to the emergency department with an acute myocardial infarction diagnosis that turned out to be a cardiac tamponade of unknown etiology. Further studies revealed a metastatic pericardial adenocarcinoma with secondary cardiac tamponade. We encourage considering malignancies metastatic to pericardium as probable etiology for large pericardial effusions and cardiac tamponade of unknown etiology. PMID:25114766

  4. Preoperative Low Serum Bicarbonate Levels Predict Acute Kidney Injury After Cardiac Surgery

    PubMed Central

    Jung, Su-Young; Park, Jung Tak; Kwon, Young Eun; Kim, Hyung Woo; Ryu, Geun Woo; Lee, Sul A.; Park, Seohyun; Jhee, Jong Hyun; Oh, Hyung Jung; Han, Seung Hyeok; Yoo, Tae-Hyun; Kang, Shin-Wook

    2016-01-01

    Abstract Acute kidney injury (AKI) after cardiac surgery is a common and serious complication. Although lower than normal serum bicarbonate levels are known to be associated with consecutive renal function deterioration in patients with chronic kidney injury, it is not well-known whether preoperative low serum bicarbonate levels are associated with the development of AKI in patients who undergo cardiac surgery. Therefore, the clinical implication of preoperative serum bicarbonate levels on AKI occurrence after cardiac surgery was investigated. Patients who underwent coronary artery bypass or valve surgery at Yonsei University Health System from January 2013 to December 2014 were enrolled. The patients were divided into 3 groups based on preoperative serum bicarbonate levels, which represented group 1 (below normal levels) <23 mEq/L; group 2 (normal levels) 23 to 24 mEq/L; and group 3 (elevated levels) >24 mEq/L. The primary outcome was the predicated incidence of AKI 48 hours after cardiac surgery. AKI was defined according to Acute Kidney Injury Network criteria. Among 875 patients, 228 (26.1%) developed AKI within 48 hours after cardiac surgery. The incidence of AKI was higher in group 1 (40.9%) than in group 2 (26.5%) and group 3 (19.5%) (P < 0.001). In addition, the duration of postoperative stay in a hospital intensive care unit (ICU) was longer for AKI patients and for those in the low-preoperative-serum-bicarbonate-level groups. A multivariate logistic regression analysis showed that low preoperative serum bicarbonate levels were significantly associated with AKI even after adjustment for age, sex, hypertension, diabetes mellitus, operation type, preoperative hemoglobin, and estimated glomerular filtration rate. In conclusion, low serum bicarbonate levels were associated with higher incidence of AKI and prolonged ICU stay. Further studies are needed to clarify whether strict correction of bicarbonate levels close to normal limits may have a

  5. Congestive kidney failure in cardiac surgery: the relationship between central venous pressure and acute kidney injury.

    PubMed

    Gambardella, Ivancarmine; Gaudino, Mario; Ronco, Claudio; Lau, Christopher; Ivascu, Natalia; Girardi, Leonard N

    2016-11-01

    Acute kidney injury (AKI) in cardiac surgery has traditionally been linked to reduced arterial perfusion. There is ongoing evidence that central venous pressure (CVP) has a pivotal role in precipitating acute renal dysfunction in cardiac medical and surgical settings. We can regard this AKI driven by systemic venous hypertension as 'kidney congestive failure'. In the cardiac surgery population as a whole, when the CVP value reaches the threshold of 14 mmHg in postoperative period, the risk of AKI increases 2-fold with an odds ratio (OR) of 1.99, 95% confidence interval (95% CI) of 1.16-3.40. In cardiac surgery subsets where venous hypertension is a hallmark feature, the incidence of AKI is higher (tricuspid disease 30%, carcinoid valve disease 22%). Even in the non-chronically congested coronary artery bypass population, CVP measured 6 h postoperatively showed significant association to renal failure: risk-adjusted OR for AKI was 5.5 (95% CI 1.93-15.5; P = 0.001) with every 5 mmHg rise in CVP for patients with CVP <9 mmHg; for CVP increments of 5 mmHg above the threshold of 9 mmHg, the risk-adjusted OR for AKI was 1.3 (95% CI 1.01-1.65; P = 0.045). This and other clinical evidence are discussed along with the underlying pathophysiological mechanisms, involving the supremacy of volume receptors in regulating the autonomic output in hypervolaemia, and the regional effect of venous congestion on the nephron. The effect of CVP on renal function was found to be modulated by ventricular function class, aetiology and acuity of venous congestion. Evidence suggests that acute increases of CVP should be actively treated to avoid a deterioration of the renal function, particularly in patients with poor ventricular fraction. Besides, the practice of treating right heart failure with fluid loading should be avoided in favour of other ways to optimize haemodynamics in this setting, because of the detrimental effects on the kidney function.

  6. Risk factor paradox in the occurrence of cardiac arrest in acute coronary syndrome patients

    PubMed Central

    Rosa, Silvia Aguiar; Timóteo, Ana Teresa; Nogueira, Marta Afonso; Belo, Adriana; Ferreira, Rui Cruz

    2016-01-01

    Objective To compare patients without previously diagnosed cardiovascular risk factors) and patients with one or more risk factors admitted with acute coronary syndrome. Methods This was a retrospective analysis of patients admitted with first episode of acute coronary syndrome without previous heart disease, who were included in a national acute coronary syndrome registry. The patients were divided according to the number of risk factors, as follows: 0 risk factor (G0), 1 or 2 risk factors (G1 - 2) and 3 or more risk factors (G ≥ 3). Comparative analysis was performed between the three groups, and independent predictors of cardiac arrest and death were studied. Results A total of 5,518 patients were studied, of which 72.2% were male and the mean age was 64 ± 14 years. G0 had a greater incidence of ST-segment elevation myocardial infarction, with the left anterior descending artery being the most frequently involved vessel, and a lower prevalence of multivessel disease. Even though G0 had a lower Killip class (96% in Killip I; p < 0.001) and higher ejection fraction (G0 56 ± 10% versus G1 - 2 and G ≥ 3 53 ± 12%; p = 0.024) on admission, there was a significant higher incidence of cardiac arrest. Multivariate analysis identified the absence of risk factors as an independent predictor of cardiac arrest (OR 2.78; p = 0.019). Hospital mortality was slightly higher in G0, although this difference was not significant. By Cox regression analysis, the number of risk factors was found not to be associated with mortality. Predictors of death at 1 year follow up included age (OR 1.05; p < 0.001), ST-segment elevation myocardial infarction (OR 1.94; p = 0.003) and ejection fraction < 50% (OR 2.34; p < 0.001). Conclusion Even though the group without risk factors was composed of younger patients with fewer comorbidities, better left ventricular function and less extensive coronary disease, the absence of risk factors was an independent predictor of cardiac arrest. PMID

  7. Cardiac Autonomic Effects of Acute Exposures to Airborne Particulates in Men and Women

    NASA Technical Reports Server (NTRS)

    Howarth, M. S.; Schlegel, T. T.; Knapp, C. F.; Patwardhan, A. R.; Jenkins, R. A.; Ilgner, R. H.; Evans, J. M.

    2007-01-01

    The aim of this research was to investigate cardiac autonomic changes associated with acute exposures to airborne particulates. Methods: High fidelity 12-lead ECG (CardioSoft, Houston, TX) was acquired from 19 (10 male / 9 female) non-smoking volunteers (age 33.6 +/- 6.6 yrs) during 10 minutes pre-exposure, exposure and post-exposure to environmental tobacco smoke (ETS), cooking oil fumes, wood smoke and sham (water vapor). To control exposure levels, noise, subject activity, and temperature, all studies were conducted inside an environmental chamber. Results: The short-term fractal scaling exponent (Alpha-1) and the ratio of low frequency to high frequency Heart Rate Variability (HRV) powers (LF/HF, a purported sympathetic index) were both higher in males (p<0.017 and p<0.05, respectively) whereas approximate entropy (ApEn) and HF/(LF+HF) (a purported parasympathetic index) were both lower in males (p<0.036, and p<0.044, respectively). Compared to pre-exposure (p<0.0002) and sham exposure (p<0.047), male heart rates were elevated during early ETS post-exposure. Our data suggest that, in addition to tonic HRV gender differences, cardiac responses to some acute airborne particulates are gender related.

  8. Acute effects of intravenous dronedarone on electrocardiograms, hemodynamics and cardiac functions in anesthetized dogs.

    PubMed

    Saengklub, Nakkawee; Limprasutr, Vudhiporn; Sawangkoon, Suwanakiet; Buranakarl, Chollada; Hamlin, Robert L; Kijtawornrat, Anusak

    2016-02-01

    Dronedarone is a class III antiarrhythmic that has been used for management of atrial fibrillation in humans, but limited information was found in dogs. The objective of this study was to determine the acute effects of escalating concentrations of dronedarone on electrocardiograms (ECG), hemodynamics and cardiac mechanics in healthy dogs. A total of 7 beagle dogs were anesthetized with isoflurane and instrumented to obtain lead II ECG, pressures at ascending aorta, right atrium, pulmonary artery and left ventricle, and left ventricular pressure-volume relationship. Five dogs were given vehicle and followed by escalating doses of dronedarone (0.5, 1.0 and 2.5 mg/kg, 15 min for each dose), and two dogs were used as a vehicle-treated control. All parameters were measured at 15 min after the end of each dose. The results showed that all parameters in vehicle-treated dogs were unaltered. Dronedarone at 2.5 mg/kg significantly lengthened PQ interval (P<0.01), reduced cardiac output (P<0.01) and increased systemic vascular resistance (P<0.01). Dronedarone produced negative inotropy assessed by significantly lowered end-systolic pressure-volume relationship, preload recruitable stroke work, contractility index and dP/dtmax. It also impaired diastolic function by significantly increased end-diastolic pressure-volume relationship, tau and dP/dtmin. These results suggested that acute effects of dronedarone produced negative dromotropy, inotropy and lusitropy in anesthetized dogs. Care should be taken when given dronedarone to dogs, especially when the patients have impaired cardiac function.

  9. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury

    SciTech Connect

    Chen, Lijuan; Wang, Yingjie; Pan, Yaohua; Zhang, Lan; Shen, Chengxing; Qin, Gangjian; Ashraf, Muhammad; Weintraub, Neal; Ma, Genshan; Tang, Yaoliang

    2013-02-15

    Highlights: ► Cardiac progenitor-derived (CPC) Exosomes protect H9C2 from apoptosis in vitro. ► CPC-exosomes protect cardiomyoyctes from MI/R induced apoptosis in vivo. ► CPC-exosomes were taken up by H9C2 with high efficiency using PKH26 labeling. ► miR-451, one of GATA4-responsive miRNA cluster, is enriched in CPC-exosomes. -- Abstract: Background: Cardiac progenitors (CPC) mediate cardioprotection via paracrine effects. To date, most of studies focused on secreted paracrine proteins. Here we investigated the CPC-derived-exosomes on protecting myocardium from acute ischemia/reperfusion (MI/R) injury. Methods and results: CPC were isolated from mouse heart using two-step protocol. Exosomes were purified from conditional medium, and confirmed by electron micrograph and Western blot using CD63 as a marker. qRT-PCR shows that CPC-exosomes have high level expression of GATA4-responsive-miR-451. Exosomes were ex vivo labeled with PKH26, We observed exosomes can be uptaken by H9C2 cardiomyoblasts with high efficiency after 12 h incubation. CPC-exosomes protect H9C2 from oxidative stress by inhibiting caspase 3/7 activation invitro. In vivo delivery of CPC-exosomes in an acute mouse myocardial ischemia/reperfusion model inhibited cardiomyocyte apoptosis by about 53% in comparison with PBS control (p < 0.05). Conclusion: Our results suggest, for the first time, the CPC-exosomes can be used as a therapeutic vehicle for cardioprotection, and highlights a new perspective for using non-cell exosomes for cardiac disease.

  10. Early Acute Antibody-Mediated Rejection of a Negative Flow Crossmatch 3rd Kidney Transplant with Exclusive Disparity at HLA-DP

    PubMed Central

    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

    2014-01-01

    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. PMID:24755353

  11. 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.

  12. Vasopressin, renin, and cortisol responses to hemorrhage during acute blockade of cardiac nerves in conscious dogs

    NASA Technical Reports Server (NTRS)

    O'Donnell, C. P.; Keil, L. C.; Thrasher, T. N.

    1993-01-01

    The effect of acute cardiac nerve blockade (CNB) on the increases in plasma renin activity (PRA), arginine vasopressin (AVP), and cortisol in response to a 30 ml/kg hemorrhage was determined in conscious dogs (n = 9). Procaine was infused into the pericardial space to produce acute reversible CNB, or saline was infused in the control hemorrhage. Blood was removed from the inferior vena cava at a rate of 1 ml.kg-1.min-1. In the control hemorrhage, plasma AVP increased from 1.8 +/- 0.3 to 219 +/- 66 pg/ml, PRA increased from 0.63 +/- 0.20 to 3.08 +/- 0.91 ng angiotensin I (ANG I).ml-1.3 h-1, and cortisol increased from 1.4 +/- 0.2 to 4.0 +/- 0.7 micrograms/dl. When the hemorrhage was repeated during acute CNB, plasma AVP increased from 2.8 +/- 1.6 to 185 +/- 59 pg/ml, PRA increased from 0.44 +/- 0.14 to 2.24 +/- 0.27 ng ANG I.ml-1.3 h-1, and cortisol increased from 1.9 +/- 0.3 to 5.4 +/- 0.6 micrograms/dl, and none of the increases differed significantly from the responses during the control hemorrhage. Left atrial pressure fell significantly after removal of 6 ml/kg of blood, but mean arterial pressure was maintained at control levels until blood loss reached 20 ml/kg during pericardial infusion of either saline or procaine. The declines in MAP at the 30 ml/kg level of hemorrhage in both treatments were similar. These results demonstrate that acutely blocking input from cardiac receptors does not reduce the increases in plasma AVP, cortisol, and PRA in response to a 30 ml/kg hemorrhage. The results of this study do not support the hypothesis that input from cardiac receptors is required for a normal AVP response to hemorrhage and suggest that other receptors, presumably arterial baroreceptors, can stimulate AVP and cortisol secretion in the absence of signals from the heart.

  13. Vasopressin, renin, and cortisol responses to hemorrhage during acute blockade of cardiac nerves in conscious dogs

    NASA Technical Reports Server (NTRS)

    O'Donnell, C. P.; Keil, L. C.; Thrasher, T. N.

    1993-01-01

    The effect of acute cardiac nerve blockade (CNB) on the increases in plasma renin activity (PRA), arginine vasopressin (AVP), and cortisol in response to a 30 ml/kg hemorrhage was determined in conscious dogs (n = 9). Procaine was infused into the pericardial space to produce acute reversible CNB, or saline was infused in the control hemorrhage. Blood was removed from the inferior vena cava at a rate of 1 ml.kg-1.min-1. In the control hemorrhage, plasma AVP increased from 1.8 +/- 0.3 to 219 +/- 66 pg/ml, PRA increased from 0.63 +/- 0.20 to 3.08 +/- 0.91 ng angiotensin I (ANG I).ml-1.3 h-1, and cortisol increased from 1.4 +/- 0.2 to 4.0 +/- 0.7 micrograms/dl. When the hemorrhage was repeated during acute CNB, plasma AVP increased from 2.8 +/- 1.6 to 185 +/- 59 pg/ml, PRA increased from 0.44 +/- 0.14 to 2.24 +/- 0.27 ng ANG I.ml-1.3 h-1, and cortisol increased from 1.9 +/- 0.3 to 5.4 +/- 0.6 micrograms/dl, and none of the increases differed significantly from the responses during the control hemorrhage. Left atrial pressure fell significantly after removal of 6 ml/kg of blood, but mean arterial pressure was maintained at control levels until blood loss reached 20 ml/kg during pericardial infusion of either saline or procaine. The declines in MAP at the 30 ml/kg level of hemorrhage in both treatments were similar. These results demonstrate that acutely blocking input from cardiac receptors does not reduce the increases in plasma AVP, cortisol, and PRA in response to a 30 ml/kg hemorrhage. The results of this study do not support the hypothesis that input from cardiac receptors is required for a normal AVP response to hemorrhage and suggest that other receptors, presumably arterial baroreceptors, can stimulate AVP and cortisol secretion in the absence of signals from the heart.

  14. Infarct-Induced Steroidogenic Acute Regulatory Protein: A Survival Role in Cardiac Fibroblasts

    PubMed Central

    Anuka, Eli; Yivgi-Ohana, Natalie; Eimerl, Sarah; Garfinkel, Benjamin; Melamed-Book, Naomi; Chepurkol, Elena; Aravot, Dan; Zinman, Tova; Shainberg, Asher; Hochhauser, Edith

    2013-01-01

    Steroidogenic acute regulatory protein (StAR) is indispensable for steroid hormone synthesis in the adrenal cortex and the gonadal tissues. This study reveals that StAR is also expressed at high levels in nonsteroidogenic cardiac fibroblasts confined to the left ventricle of mouse heart examined 3 days after permanent ligation of the left anterior descending coronary artery. Unlike StAR, CYP11A1 and 3β-hydroxysteroid dehydrogenase proteins were not observed in the postinfarction heart, suggesting an apparent lack of de novo cardiac steroidogenesis. Work with primary cultures of rat heart cells revealed that StAR is induced in fibroblasts responding to proapoptotic treatments with hydrogen peroxide or the kinase inhibitor staurosporine (STS). Such induction of StAR in culture was noted before spontaneous differentiation of the fibroblasts to myofibroblasts. STS induction of StAR in the cardiac fibroblasts conferred a marked resistance to apoptotic cell death. Consistent with that finding, down-regulation of StAR by RNA interference proportionally increased the number of STS-treated apoptotic cells. StAR down-regulation also resulted in a marked increase of BAX activation in the mitochondria, an event known to associate with the onset of apoptosis. Last, STS treatment of HeLa cells showed that apoptotic demise characterized by mitochondrial fission, cytochrome c release, and nuclear fragmentation is arrested in individual HeLa cells overexpressing StAR. Collectively, our in vivo and ex vivo evidence suggests that postinfarction expression of nonsteroidogenic StAR in cardiac fibroblasts has novel antiapoptotic activity, allowing myofibroblast precursor cells to survive the traumatized event, probably to differentiate and function in tissue repair at the infarction site. PMID:23831818

  15. Infarct-induced steroidogenic acute regulatory protein: a survival role in cardiac fibroblasts.

    PubMed

    Anuka, Eli; Yivgi-Ohana, Natalie; Eimerl, Sarah; Garfinkel, Benjamin; Melamed-Book, Naomi; Chepurkol, Elena; Aravot, Dan; Zinman, Tova; Shainberg, Asher; Hochhauser, Edith; Orly, Joseph

    2013-09-01

    Steroidogenic acute regulatory protein (StAR) is indispensable for steroid hormone synthesis in the adrenal cortex and the gonadal tissues. This study reveals that StAR is also expressed at high levels in nonsteroidogenic cardiac fibroblasts confined to the left ventricle of mouse heart examined 3 days after permanent ligation of the left anterior descending coronary artery. Unlike StAR, CYP11A1 and 3β-hydroxysteroid dehydrogenase proteins were not observed in the postinfarction heart, suggesting an apparent lack of de novo cardiac steroidogenesis. Work with primary cultures of rat heart cells revealed that StAR is induced in fibroblasts responding to proapoptotic treatments with hydrogen peroxide or the kinase inhibitor staurosporine (STS). Such induction of StAR in culture was noted before spontaneous differentiation of the fibroblasts to myofibroblasts. STS induction of StAR in the cardiac fibroblasts conferred a marked resistance to apoptotic cell death. Consistent with that finding, down-regulation of StAR by RNA interference proportionally increased the number of STS-treated apoptotic cells. StAR down-regulation also resulted in a marked increase of BAX activation in the mitochondria, an event known to associate with the onset of apoptosis. Last, STS treatment of HeLa cells showed that apoptotic demise characterized by mitochondrial fission, cytochrome c release, and nuclear fragmentation is arrested in individual HeLa cells overexpressing StAR. Collectively, our in vivo and ex vivo evidence suggests that postinfarction expression of nonsteroidogenic StAR in cardiac fibroblasts has novel antiapoptotic activity, allowing myofibroblast precursor cells to survive the traumatized event, probably to differentiate and function in tissue repair at the infarction site.

  16. [Cardiac rupture in acute myocardial infarct. Presentation of 20 postmortem cases].

    PubMed

    Cruz, H; Cruz, J C; Badui, E; Galindo, M E; Solorio, S; Bojorges, R

    1997-01-01

    With the advancement of the Coronary Care Units in the past three decades, there had been an important reduction in mortality secondary to arrhythmias in acute myocardial infarction (AMI): been now days, cardiogenic shock and cardiac rupture the first and second causes of in-hospital death in these patients. The purpose of this report is to know the anatomoclinical characteristics in our hospital of cardiac rupture and to look for risk factors that may be considered to diagnose at the precise time this complication that might cause sudden death secondary to hemodynamic and electromechanical changes. From 300 postmortem cases with AMI proved clinical, and by anatomopathological studies, 20 cases with cardiac rupture were obtained, among which: 11 (55%) were males with an average age of 61.7 years and 9 (45%) females, with an average age of 60 years. The following coronary risk factors were detected: systemic hypertension in 15 (75%) cases; cigarette smoking in 13 (65%) cases and diabetes mellitus in 11 (55%) cases. Long lasting or recurrent history of chest pain previous to death was present in 14 (70%) cases. Conduction disturbances were detected in 13 (65%) cases; among them, 7 (35%) had third degree heart block in whom permanent pacemaker was inserted; 4 (20%) had CRBBB and 2 (10%) ASB. The average heart weight was 478 gr. in males and 434 gr. in females. Evidence of an old MI was present in 7 (35%) cases. All patients had transmural MI. Free cardiac wall rupture was seen in 14 (70%) cases and from the ventricular septum, 6 (30%) cases. Hemopericardium was present in all cases (100%) with an average amount of 425 ml of blood. Pericarditis in 3 (15%). The average time of evolution since the beginning of the AMI until death were 4 days and the main causes of death were cardiogenic shock in 17 (85%) and congestive heart failure in 3 (15%).

  17. Renal ultrasound provides low utility in evaluating cardiac surgery associated acute kidney injury.

    PubMed

    Young, Allen; Crawford, Todd; Pierre, Alejandro Suarez; Trent Magruder, J; Fraser, Charles; Conte, John; Whitman, Glenn; Sciortino, Christopher

    2017-09-02

    Renal ultrasonography is part of the algorithm in assessing acute kidney injury (AKI). The purpose of this study was to assess the clinical utility of renal US in postoperative cardiac patients who develop AKI. We conducted a retrospective study of 90 postoperative cardiac surgery patients at a single institution from 1/19/2010 to 3/19/2016 who underwent renal US for AKI. We reviewed provider documentation to determine whether renal US changed management. We defined change as: administration of crystalloid or colloid, addition of inotropic or vasopressor, or procedural interventions on the renal system. Mean age of study patients was 68 ± 13 years. 48/90 patients (53.3%) had pre-existing chronic kidney disease of varying severity. 48 patients (53.3%) had normal renal US with incidental findings and 31 patients (34.4%) had US evidence of medical kidney disease. 10 patients (11.1%) had limited US results due to poor visualization and 1 patient (1.1%) had mild right-sided hydronephrosis. No patients were found to have obstructive uropathy or renal artery stenosis. Clinical management was altered in only 4/90 patients (4.4%), which included 3 patients that received a fluid bolus and 1 patient that received a fluid bolus and inotropes. No vascular or urologic procedures resulted from US findings. Although renal ultrasound is often utilized in the work-up of AKI, our study shows that renal US provides little benefit in managing postoperative cardiac patients. This diagnostic modality should be scrutinized rather than viewed as a universal measure in the cardiac surgery population.

  18. MicroRNAs as non-invasive biomarkers of heart transplant rejection.

    PubMed

    Duong Van Huyen, Jean-Paul; Tible, Marion; Gay, Arnaud; Guillemain, Romain; Aubert, Olivier; Varnous, Shaida; Iserin, Franck; Rouvier, Philippe; François, Arnaud; Vernerey, Dewi; Loyer, Xavier; Leprince, Pascal; Empana, Jean-Philippe; Bruneval, Patrick; Loupy, Alexandre; Jouven, Xavier

    2014-12-01

    Rejection is one of the major causes of late cardiac allograft failure and at present can only be diagnosed by invasive endomyocardial biopsies. We sought to determine whether microRNA profiling could serve as a non-invasive biomarker of cardiac allograft rejection. We included 113 heart transplant recipients from four referral French institutions (test cohort, n = 60, validation cohort, n = 53). In the test cohort, we compared patients with acute biopsy-proven allograft rejection (n = 30) to matched control patients without rejection (n = 30), by assessing microRNAs expression in the heart allograft tissue and patients concomitant serum using RNA extraction and qPCR analysis. Fourteen miRNAs were selected on the basis of their implication in allograft rejection, endothelial activation, and inflammation and tissue specificity. We identified seven miRNAs that were differentially expressed between normal and rejecting heart allografts: miR-10a, miR-21, miR-31, miR-92a, miR-142-3p miR-155, and miR-451 (P < 0.0001 for all comparisons). Four out of seven miRNAs also showed differential serological expression (miR-10a, miR-31, miR-92a, and miR-155) with strong correlation with their tissular expression. The receiver-operating characteristic analysis showed that these four circulating miRNAs strongly discriminated patients with allograft rejection from patients without rejection: miR-10a (AUC = 0.975), miR-31 (AUC = 0.932), miR-92a (AUC = 0.989), and miR-155 (AUC = 0.998, P < 0.0001 for all comparisons). We confirmed in the external validation set that these four miRNAs highly discriminated patients with rejection from those without. The discrimination capability of the four miRNAs remained significant when stratified by rejection diagnosis (T-cell-mediated rejection or antibody-mediated rejection) and time post-transplant. This study demonstrates that a differential expression of miRNA occurs in rejecting allograft patients, not only at the tissue level but also in the

  19. Urinary metabolomics for noninvasive detection of borderline and acute T cell-mediated rejection in children after kidney transplantation.

    PubMed

    Blydt-Hansen, T D; Sharma, A; Gibson, I W; Mandal, R; Wishart, D S

    2014-10-01

    The goal of this study was to evaluate the utility of urinary metabolomics for noninvasive diagnosis of T cell-mediated rejection (TCMR) in pediatric kidney transplant recipients. Urine samples (n = 277) from 57 patients with surveillance or indication kidney biopsies were assayed for 134 unique metabolites by quantitative mass spectrometry. Samples without TCMR (n = 183) were compared to borderline tubulitis (n = 54) and TCMR (n = 30). Partial least squares discriminant analysis identified distinct classifiers for TCMR (area under receiver operating characteristic curve [AUC] = 0.892; 95% confidence interval [CI] 0.827-0.957) and borderline tubulitis (AUC = 0.836; 95% CI 0.781-0.892), respectively. Application of the TCMR classifier to borderline tubulitis samples yielded a discriminant score (-0.47 ± 0.33) mid-way between TCMR (-0.20 ± 0.34) and No TCMR (-0.80 ± 0.32) (p < 0.001 for all comparisons). Discriminant scoring for combined borderline/TCMR versus No TCMR (AUC = 0.900; 95% CI 0.859-0.940) applied to a validation cohort robustly distinguished between samples with (-0.08 ± 0.52) and without (-0.65 ± 0.54, p < 0.001) borderline/TCMR (p < 0.001). The TCMR discriminant score was driven by histological t-score, ct-score, donor-specific antibody and biopsy indication, and was unaffected by renal function, interstitial or microcirculatory inflammation, interstitial fibrosis or pyuria. These preliminary findings suggest that urinary metabolomics is a sensitive, specific and noninvasive tool for TCMR identification that is superior to serum creatinine, with minimal confounding by other allograft injury processes. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

  20. Cardiac MR enables diagnosis in 90% of patients with acute chest pain, elevated biomarkers and unobstructed coronary arteries

    PubMed Central

    Emrich, K; Abegunewardene, N; Oberholzer, K; Dueber, C; Muenzel, T; Kreitner, K-F

    2015-01-01

    Objective: To assess the diagnostic value of cardiac MRI (CMR) in patients with acute chest pain, elevated cardiac enzymes and a negative coronary angiogram. Methods: This study included a total of 125 patients treated in the chest pain unit during a 39-month period. Each included patient underwent MRI within a median of 3 days after cardiac catheterization. The MRI protocol comprised cine, oedema-sensitive and late gadolinium-enhancement imaging. The standard of reference was a consensus diagnosis based on clinical follow-up and the synopsis of all clinical, laboratory and imaging data. Results: MRI revealed a multitude of diagnoses, including ischaemic cardiomyopathy (CM), dilated CM, myocarditis, Takotsubo CM, hypertensive heart disease, hypertrophic CM, cardiac amyloidosis and non-compaction CM. MRI-based diagnoses were the same as the final reference diagnoses in 113/125 patients (90%), with the two diagnoses differing in only 12/125 patients. In two patients, no final diagnosis could be established. Conclusion: CMR performed early after the onset of symptoms revealed a broad spectrum of diseases. CMR delivered a correct final diagnosis in 90% of patients with acute chest pain, elevated cardiac enzymes and a negative coronary angiogram. Advances in knowledge: Diagnosing patients with acute coronary syndrome but unobstructed coronary arteries remains a challenge for cardiologists. CMR performed early after catheterization reveals a broad spectrum of diseases with only a simple and quick examination protocol, and there is a high concordance between MRI-based diagnoses and final reference diagnoses. PMID:25782462

  1. Cardiac MR enables diagnosis in 90% of patients with acute chest pain, elevated biomarkers and unobstructed coronary arteries.

    PubMed

    Emrich, T; Emrich, K; Abegunewardene, N; Oberholzer, K; Dueber, C; Muenzel, T; Kreitner, K-F

    2015-05-01

    To assess the diagnostic value of cardiac MRI (CMR) in patients with acute chest pain, elevated cardiac enzymes and a negative coronary angiogram. This study included a total of 125 patients treated in the chest pain unit during a 39-month period. Each included patient underwent MRI within a median of 3 days after cardiac catheterization. The MRI protocol comprised cine, oedema-sensitive and late gadolinium-enhancement imaging. The standard of reference was a consensus diagnosis based on clinical follow-up and the synopsis of all clinical, laboratory and imaging data. MRI revealed a multitude of diagnoses, including ischaemic cardiomyopathy (CM), dilated CM, myocarditis, Takotsubo CM, hypertensive heart disease, hypertrophic CM, cardiac amyloidosis and non-compaction CM. MRI-based diagnoses were the same as the final reference diagnoses in 113/125 patients (90%), with the two diagnoses differing in only 12/125 patients. In two patients, no final diagnosis could be established. CMR performed early after the onset of symptoms revealed a broad spectrum of diseases. CMR delivered a correct final diagnosis in 90% of patients with acute chest pain, elevated cardiac enzymes and a negative coronary angiogram. Diagnosing patients with acute coronary syndrome but unobstructed coronary arteries remains a challenge for cardiologists. CMR performed early after catheterization reveals a broad spectrum of diseases with only a simple and quick examination protocol, and there is a high concordance between MRI-based diagnoses and final reference diagnoses.

  2. Neural, hormonal and intrinsic mechanisms of cardiac control during acute coronary occlusion in the intact dog.

    PubMed

    Randall, D C; Evans, J M; Billman, G E; Ordway, G A; Knapp, C F

    1981-02-01

    Three basic mechanisms may be involved in the control of cardiac function during acute coronary occlusion: (1) neural; (2) hormonal (circulating catecholamine); and (3) intrinsic (e.g. Frank--Starling law). The response of intact, sedated (Innovar-Vet, 0.08 cc/kg), chronically instrumented dogs to a 5 min left circumflex coronary occlusion was tested to delineate the relative roles of each of the above mechanisms. First, 6 innervated and 6 cardiac denervated dogs were examined. The major difference between groups was that the occlusion-induced tachycardia was significantly smaller in the denervated dogs than in the normally innervated animals (+10 +/- 7 vs +27 +/- 4/min, respectively, (mean +/- S.D.)). Changes in the first time derivative of left ventricular pressure (d(LVP)/dt) were similar (--898 +/- 556 vs --796 +/- 274 mm Hg/sec, denervated vs innervated). Decreases in stroke volume and mean arterial pressure were also similar in the two groups. The occlusion-induced tachycardia was compared in a second group of denervated dogs (n = 5) before and after administration of propranolol to examine the role of circulating catecholamines, and, by exclusion, to observe the response of the heart per se, independently of extrinsic control factors. The heart rate response was similar in both cases (+8 +/- 4 vs +6 +/- 4/min, unblocked vs blocked). Finally, blood pressure was prevented from falling during coronary occlusion in 3 normally innervated dogs by coupling the femoral artery to a reservoir of saline suspended above the animals. Blunting the input to the baroreceptors in this manner did not significantly change the size of the occlusion-induced tachycardia. We conclude that during acute coronary occlusion in dog: (1) the major role of the cardiac nerves involves modulating changes in the chronotropic state of the heart; (2) changes in d(LVP)/dt result principally from intrinsic phenomena linked to ischemia-induced alterations in myocardial performance; (3) changes

  3. Prolonged cardiac allograft survival in mouse model after complement depletion with Yunnan cobra venom factor.

    PubMed

    Wu, W; Wang, H-D; Zhu, X-X; Lan, G; Yang, K

    2009-12-01

    Activation of the complement system is the leading mechanism that causes antibody-mediated acute rejection and hyperacute rejection after xenotransplantation. The major cause of acute rejection in allogeneic transplantation is the T cell-mediated specific immune response. We studied the effects of complement on acute rejection after cardiac allotransplantation using complement depletion with cobra venom factor (CVF) in the mouse. The Balb/c-C57 mouse model of heterotopic cardiac allograft was used. The mice were divided into 2 groups, a control group and a CVF-treated group. After intravenous injection of CVF, the experimental group was observed for allograft survival time. Twelve mice from the control and experimental groups were sacrificed on days 3, 5, and 7 after the operation. The pathologic grade of acute rejection, deposition of C3 in tissue, extent of infiltration by CD4+ and CD8+ T cells, and expression of MHC-II, B7-1, and B7-2 were compared between the 2 groups. In the CVF-treated group, mean (SD) survival of the cardiac allograft was 26.2 (1.7) days, and in the control group was 8.4 (0.4) days (P < .01). Pathologic examination and immunohistochemistry demonstrated that the grade of acute rejection, deposition of C3 in tissue, extent of infiltration of CD4+ and CD8+ T cells, and expression of MHC-II, B7-1, and B7-2 were significantly decreased in the CVF-treated group. Depletion of complement in the serum with CVF inhibits acute cardiac allograft rejection in the mouse.

  4. Acute hypopituitarism associated with periorbital swelling and cardiac dysfunction in a patient with pituitary tumor apoplexy: a case report.

    PubMed

    Ohara, Nobumasa; Yoneoka, Yuichiro; Seki, Yasuhiro; Akiyama, Katsuhiko; Arita, Masataka; Ohashi, Kazumasa; Suzuki, Kazuo; Takada, Toshinori

    2017-08-24

    Pituitary tumor apoplexy is a rare clinical syndrome caused by acute hemorrhage or infarction in a preexisting pituitary adenoma. It typically manifests as an acute episode of headache, visual disturbance, mental status changes, cranial nerve palsy, and endocrine pituitary dysfunction. However, not all patients present with classical symptoms, so it is pertinent to appreciate the clinical spectrum of pituitary tumor apoplexy presentation. We report an unusual case of a patient with pituitary tumor apoplexy who presented with periorbital edema associated with hypopituitarism. An 83-year-old Japanese man developed acute anterior hypopituitarism; he showed anorexia, fatigue, lethargy, severe bilateral periorbital edema, and mild cardiac dysfunction in the absence of headache, visual disturbance, altered mental status, and cranial nerve palsy. Magnetic resonance imaging showed a 2.5-cm pituitary tumor containing a mixed pattern of solid and liquid components indicating pituitary tumor apoplexy due to hemorrhage in a preexisting pituitary adenoma. Replacement therapy with oral hydrocortisone and levothyroxine relieved his symptoms of central adrenal insufficiency, central hypothyroidism, periorbital edema, and cardiac dysfunction. Common causes of periorbital edema include infections, inflammation, trauma, allergy, kidney or cardiac dysfunction, and endocrine disorders such as primary hypothyroidism. In the present case, the patient's acute central hypothyroidism was probably involved in the development of both periorbital edema and cardiac dysfunction. The present case highlights the need for physicians to consider periorbital edema as an unusual predominant manifestation of pituitary tumor apoplexy.

  5. Sex, socioeconomic status, access to cardiac catheterization, and outcomes for acute coronary syndromes in the context of universal healthcare coverage.

    PubMed

    Fabreau, Gabriel E; Leung, Alexander A; Southern, Danielle A; Knudtson, Merrill L; McWilliams, J Michael; Ayanian, John Z; Ghali, William A

    2014-07-01

    Sex and neighborhood socioeconomic status (nSES) may independently affect the care and outcomes of acute coronary syndrome, partly through barriers in timely access to cardiac catheterization. We sought to determine whether sex modifies the association between nSES and the receipt of cardiac catheterization and mortality after an acute coronary syndrome in a universal healthcare system. We studied 14 012 patients with acute coronary syndrome admitted to cardiology services between April 18, 2004, and December 31, 2011, in Southern Alberta, Canada. We used multivariable logistic regression to compare the odds of cardiac catheterization within 2 and 30 days of admission and the odds of 30-day and 1-year mortality for men and women by quintile of neighborhood median household income. Significant relationships between nSES and the receipt of cardiac catheterization and mortality after acute coronary syndrome were detected for women but not men. When examined by nSES, each incremental decrease in neighborhood income quintile for women was associated with a 6% lower odds of receiving cardiac catheterization within 30 days (P=0.01) and a 14% higher odds of 30-day mortality (P=0.03). For men, each decrease in neighborhood income quintile was associated with a 2% lower odds of receiving catheterization within 30 days (P=0.10) and a 5% higher odds of 30-day mortality (P=0.36). Associations between nSES and receipt of cardiac catheterization and 30-day mortality were noted for women but not men in a universal healthcare system. Care protocols designed to improve equity of access to care and outcomes are required, especially for low-income women. © 2014 American Heart Association, Inc.

  6. Intermittent cardiac overload results in adaptive hypertrophy and provides protection against left ventricular acute pressure overload insult.

    PubMed

    Moreira-Gonçalves, Daniel; Henriques-Coelho, Tiago; Fonseca, Hélder; Ferreira, Rita; Padrão, Ana Isabel; Santa, Cátia; Vieira, Sara; Silva, Ana Filipa; Amado, Francisco; Leite-Moreira, Adelino; Duarte, José Alberto

    2015-09-01

    The present study aimed to test whether a chronic intermittent workload could induce an adaptive cardiac phenotype Chronic intermittent workload induced features of adaptive hypertrophy This was paralleled by protection against acute pressure overload insult The heart may adapt favourably to balanced demands, regardless of the nature of the stimuli. The present study aimed to test whether submitting the healthy heart to intermittent and tolerable amounts of workload, independently of its nature, could result in an adaptive cardiac phenotype. Male Wistar rats were subjected to treadmill running (Ex) (n = 20), intermittent cardiac overload with dobutamine (ITO) (2 mg kg(-1) , s.c.; n = 20) or placebo administration (Cont) (n = 20) for 5 days week(-1) for 8 weeks. Animals were then killed for histological and biochemical analysis or subjected to left ventricular haemodynamic evaluation under baseline conditions, in response to isovolumetric contractions and to sustained LV acute pressure overload (35% increase in peak systolic pressure maintained for 2 h). Baseline cardiac function was enhanced only in Ex, whereas the response to isovolumetric heartbeats was improved in both ITO and Ex. By contrast to the Cont group, in which rats developed diastolic dysfunction with sustained acute pressure overload, ITO and Ex showed increased tolerance to this stress test. Both ITO and Ex developed cardiomyocyte hypertrophy without fibrosis, no overexpression of osteopontin-1 or β-myosin heavy chain, and increased expression of sarcoplasmic reticulum Ca(2+) protein. Regarding hypertrophic pathways, ITO and Ex showed activation of the protein kinase B/mammalian target of rapamycin pathway but not calcineurin. Mitochondrial complex IV and V activities were also increased in ITO and Ex. Chronic submission to controlled intermittent cardiac overload, independently of its nature, results in an adaptive cardiac phenotype. Features of the cardiac overload, such as the duration and

  7. Acute Primary Pneumococcal Purulent Pericarditis With Cardiac Tamponade: A Case Report and Literature Review.

    PubMed

    Patel, Hiren; Patel, Charmi; Soni, Mrugesh; Patel, Amit; Banda, Venkat

    2015-10-01

    Bacterial pericarditis is a rapidly progressive and highly fatal infection, and is often diagnosed postmortem in half of the cases. Even with drainage and antibiotics, the mortality rate is high. Gram-positive cocci, specifically Streptococcus penumoniae, have been the most common cause of bacterial pericarditis with a preceding primary site of infection. Following the introduction of antibiotics in the 1940s and more recently the pneumococcal conjugate vaccine, the incidence has drastically decreased.We describe an extremely rare case of primary streptococcus pneumoniae purulent pericarditis that presented with cardiac tamponade. The patient was successfully treated with broad-spectrum antibiotics and urgent pericardiocentesis.Due to the high mortality rate with purulent pericarditis, a high index of suspicion is needed when acute pericarditis is suspected for early diagnosis to instate appropriate therapy with antibiotics and drainage.

  8. Cardiac CT angiography in the emergency room: Apical hypertrophic cardiomyopathy presenting as acute coronary syndrome.

    PubMed

    Turner, Michael C; Kerut, Edmund K; Mckinnie, James; Davis, Michael; Hinton, Christine

    2017-03-07

    A 59-year-old male presented to the emergency room with symptoms of chest tightness and palpitations. Following conversion of atrial fibrillation to sinus rhythm, he had deep symmetrical T-wave changes on his electrocardiogram. Symptoms resolved almost immediately, and his initial troponin was negative. He underwent cardiac CT angiography utilizing an emergency room triage protocol which resulted in a diagnosis of nonobstructive coronary artery disease and apical hypertrophic cardiomyopathy. Following a hospital stay of less than 24 hours, he was discharged to outpatient follow-up on medical management and has remained asymptomatic over 6 months. This case presentation illustrates an example of the diversity of pathology that presents in emergency rooms with symptoms consistent with acute coronary syndrome.

  9. 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.

  10. Cost-effectiveness analysis of acute kidney injury biomarkers in pediatric cardiac surgery.

    PubMed

    Petrovic, Stanislava; Bogavac-Stanojevic, Natasa; Lakic, Dragana; Peco-Antic, Amira; Vulicevic, Irena; Ivanisevic, Ivana; Kotur-Stevuljevic, Jelena; Jelic-Ivanovic, Zorana

    2015-01-01

    Acute kidney injury (AKI) is significant problem in children with congenital heart disease (CHD) who undergo cardiac surgery. The economic impact of a biomarker-based diagnostic strategy for AKI in pediatric populations undergoing CHD surgery is unknown. The aim of this study was to perform the co