The Experts below are selected from a list of 3279 Experts worldwide ranked by ideXlab platform

Manuel Pascual - One of the best experts on this subject based on the ideXlab platform.

  • overlapping pathways to transplant glomerulopathy chronic Humoral Rejection hepatitis c infection and thrombotic microangiopathy
    Kidney International, 2011
    Co-Authors: Seema Baidagrawal, Shamila Mauiyyedi, Bernard A Collins, Manuel Pascual, Nina Tolkoffrubin, Alton B Farris, Mary Lin Farrell, Ulrich Frei, Robert B Colvin
    Abstract:

    Transplant glomerulopathy (TG) has received much attention in recent years as a symptom of chronic Humoral Rejection; however, many cases lack C4d deposition and/or circulating donor-specific antibodies (DSAs). To determine the contribution of other causes, we studied 209 consecutive renal allograft indication biopsies for chronic allograft dysfunction, of which 25 met the pathological criteria of TG. Three partially overlapping etiologies accounted for 21 (84%) cases: C4d-positive (48%), hepatitis C-positive (36%), and thrombotic microangiopathy (TMA)-positive (32%) TG. The majority of patients with confirmed TMA were also hepatitis C positive, and the majority of hepatitis C-positive patients had TMA. DSAs were significantly associated with C4d-positive but not with hepatitis C-positive TG. The prevalence of hepatitis C was significantly higher in the TG group than in 29 control patients. Within the TG cohort, those who were hepatitis C-positive developed allograft failure significantly earlier than hepatitis C-negative patients. Thus, TG is not a specific diagnosis but a pattern of pathological injury involving three major overlapping pathways. It is important to distinguish these mechanisms, as they may have different prognostic and therapeutic implications.

  • new treatments for acute Humoral Rejection of kidney allografts
    Expert Opinion on Investigational Drugs, 2007
    Co-Authors: Jeanpierre Venetz, Manuel Pascual
    Abstract:

    Acute antibody-mediated Rejection (acute Humoral Rejection; AHR) of organ allografts usually presents as severe dysfunction with a high risk of allograft loss. Peritubular capillary complement C4d deposition with renal dysfunction, associated with circulating donor-specific anti-human leukocyte antigen alloantibodies, is diagnostic of AHR in kidney allografts. Removal of alloantibodies with suppression of antibody production and Rejection reversal is now possible. Therapeutic strategies that include combinations of plasmapheresis (or immunoadsorption), tacrolimus, mycophenolate mofetil and/or intravenous immunoglobulins, as well as rituximab or splenectomy, have been recently used to successfully treat AHR. However, the optimal protocol to treat AHR still remains to be defined. Anti-CD20+ monoclonal antibody therapy (rituximab) aiming at depleting B cells and suppressing antibody production has been used as rescue therapy in some episodes of steroid- and antilymphocyte-resistant Humoral Rejection. Plasmapheresis and/or intravenous polyclonal immunoglobulin, as well as rituximab, have also been used to successfully desensitize selected high-immunological risk patients in anticipation of a previously cross-match positive (or ABO incompatible) kidney transplantation. In the near future, the possible role of new specific anti-B-cell approaches or, possibly, of new anti-T-cell activation approaches using selective agents such as belatacept should be assessed to further refine the present treatment of Humoral Rejection.

  • Humoral Rejection of organ allografts
    American Journal of Transplantation, 2005
    Co-Authors: Solange Moll, Manuel Pascual
    Abstract:

    In recent years, the deleterious clinical consequences of recipient de novo alloantibody production against HLA antigens from human organ allografts have been extensively investigated. In kidney transplantation, the identification of the complement C4d fragment in peritubular capillaries as a specific marker for Humoral Rejection has helped to define and characterize distinct clinical alloantibody-mediated syndromes. This knowledge is relevant for patient management as new therapeutic strategies to remove and control anti-donor antibody production, particularly in the setting of acute Humoral Rejection, have been reported. For recipients of nonrenal organ allografts such as heart transplant recipients, de novo anti-HLA alloantibody may also be important, although more studies are needed before clear guidelines can be proposed.

  • hepatitis c acute Humoral Rejection and renal allograft survival
    Journal of The American Society of Nephrology, 2004
    Co-Authors: John P Forman, Manuel Pascual, Nina Tolkoffrubin, Julie Lin
    Abstract:

    The effect of recipient hepatitis C virus (HCV) infection on renal allograft loss and acute Rejection in kidney transplantation remains controversial. We studied 354 renal allograft recipients transplanted during 1996 to 2001 who had HCV antibodies (Ab) measured before transplantation. The primary outcome was death-censored allograft loss and the secondary outcome was acute Humoral Rejection (AHR). Compared with HCV Ab-negative patients, those with positive HCV Ab had longer time on dialysis before transplantation, higher percentage of panel-reactive antibodies (PRA), were more likely to receive a cadaveric transplant, and were more likely to develop delayed graft function (DGF). In univariate analyses, predictors of renal allograft loss included HCV, cadaveric graft, PRA >20%, HLA mismatch ≥5, retransplantation, DGF, induction therapy, and AHR. When adjusted for PRA >20%, HLA mismatch ≥5, and multiple transplant status, HCV was not a statistically significant predictor of allograft loss. HCV was also associated with AHR but lost significance when adjusted for PRA >20%. HCV Ab-positive patients were more likely to have longer duration of dialysis before transplantation prior to kidney transplants, higher PRA, and to receive cadaveric transplants. These characteristics likely resulted in more DGF and AHR after transplantation. After adjusting for these confounding factors, the association between HCV Ab positivity and renal allograft loss was notably attenuated and no longer statistically significant.

  • acute Humoral Rejection in hepatitis c infected renal transplant recipients receiving antiviral therapy
    American Journal of Transplantation, 2003
    Co-Authors: Seema Baid, Susan L Saidman, Nina Tolkoffrubin, Winfred W Williams, Francis L Delmonico, Benedict A Cosimi, Robert B Colvin, Raymond T Chung, Hugh Auchincloss, Manuel Pascual
    Abstract:

    The use of interferon-alpha (IFN) in hepatitis C (HCV)-infected renal recipients has been associated with acute Rejection and graft loss. We reviewed our recent experience in HCV (+) renal recipients treated with antiviral therapy for biopsy proven chronic hepatitis C. Twelve HCV (+) recipients who recently received antiviral therapy were analyzed. Post-treatment sera were tested for donor-specific human leukocyte antigen (HLA) antibodies (DSA). Within 6 months of initiating antiviral therapy, two of 12 patients (17%) developed acute Rejection, which was characterized as acute Humoral Rejection (de novo DSA in serum and C4d deposits in peritubular capillaries). Both progressed to graft failure. Nine of the remaining 10 patients tested did not have DSA. The use of IFN was associated with severe acute Humoral Rejection (C4d +, DSA +). The recognition of IFN-associated acute Humoral Rejection in this series may explain the high rate of graft loss reported previously in renal recipients receiving IFN.

Robert B Colvin - One of the best experts on this subject based on the ideXlab platform.

  • overlapping pathways to transplant glomerulopathy chronic Humoral Rejection hepatitis c infection and thrombotic microangiopathy
    Kidney International, 2011
    Co-Authors: Seema Baidagrawal, Shamila Mauiyyedi, Bernard A Collins, Manuel Pascual, Nina Tolkoffrubin, Alton B Farris, Mary Lin Farrell, Ulrich Frei, Robert B Colvin
    Abstract:

    Transplant glomerulopathy (TG) has received much attention in recent years as a symptom of chronic Humoral Rejection; however, many cases lack C4d deposition and/or circulating donor-specific antibodies (DSAs). To determine the contribution of other causes, we studied 209 consecutive renal allograft indication biopsies for chronic allograft dysfunction, of which 25 met the pathological criteria of TG. Three partially overlapping etiologies accounted for 21 (84%) cases: C4d-positive (48%), hepatitis C-positive (36%), and thrombotic microangiopathy (TMA)-positive (32%) TG. The majority of patients with confirmed TMA were also hepatitis C positive, and the majority of hepatitis C-positive patients had TMA. DSAs were significantly associated with C4d-positive but not with hepatitis C-positive TG. The prevalence of hepatitis C was significantly higher in the TG group than in 29 control patients. Within the TG cohort, those who were hepatitis C-positive developed allograft failure significantly earlier than hepatitis C-negative patients. Thus, TG is not a specific diagnosis but a pattern of pathological injury involving three major overlapping pathways. It is important to distinguish these mechanisms, as they may have different prognostic and therapeutic implications.

  • chronic Humoral Rejection of human kidney allografts associates with broad autoantibody responses
    Transplantation, 2010
    Co-Authors: Fabrice Porcheray, Susan L Saidman, Robert B Colvin, Julie Devito, Ian Dargon, Beow Y Yeap, Lijuan Xue, Rosemary Paine, Timothy C Girouard, Waichi Wong
    Abstract:

    Chronic Humoral Rejection (CHR) is currently recognized as one of the most serious complications after kidney transplantation. The reason why some transplant recipients develop CHR and others do not is still unknown. CHR is primarily characterized by the development of de novo donor-specific antibodies (DSA). These alloantibodies have been directly associated with late graft failure (1–4). In 2005, a series of criteria were adopted to define CHR beyond the development of DSA (5). Because this classification was accepted, a growing number of cases have been diagnosed in different institutions, revealing a higher incidence of CHR than initially presumed. Retrospective studies looking at the deposition of the complement molecule C4d and the development of DSA as markers of antibody-mediated Rejection estimated that up to 61% of all chronic Rejection cases involved a Humoral component (3, 6, 7). In addition, Lee et al. (8) demonstrated that virtually all cases of late graft loss were accompanied by some levels of antibody responses to the allografts. Collectively, these findings suggest that CHR is responsible for a majority of late graft loss cases. In addition to DSA, a number of studies have demonstrated the development of de novo autoantibodies after organ transplantation. Anti-endothelial cell antibodies (AECAs) have been observed for a number of years (9, 10). Their detection in the serum or directly in the graft of kidney transplant recipients has been associated with tissue damage and subsequent graft Rejection (11). Although recognized targets of AECAs are often alloantigens, it has been shown that these antibodies can also react to self-proteins (12). Additional studies have reported the development of antibodies to specific self-antigens after transplantation. Autoantigenic targets include angiotensin II type 1 receptor (13), agrin (14), tubulin-α, heat shock protein 60 (15), vimentin (15, 16), cardiac myosin (17), cardiolipin (18), and ribosomal protein L7 (19). The detection of these antibodies was associated with graft Rejection episodes or hypertension. Increased serum reactivity to nonprotein structures such as phospholipids and oxidized low-density lipoprotein have also been observed in kidney transplant recipients (20–23). These antibodies were associated with atherosclerosis, a common feature among late transplant recipients and patients with CHR. Overall, these studies demonstrated the presence of various types of autoantibodies in transplant recipients. We hypothesized that such autoantibodies develop more frequently after organ transplantation than initial studies indicated. We also surmised that this Humoral autoimmunity could reveal an underlying context of immunologic imbalance that may also have facilitated the generation of DSA. The aim of the present study was to investigate the development and specificity of autoantibody responses in patients with biopsy-proven CHR.

  • pathology of chronic Humoral Rejection
    Contributions To Nephrology, 2009
    Co-Authors: Robert B Colvin
    Abstract:

    Since its initial description in 2001, chronic Humoral Rejection (CHR, aka ‘chronic anti-body-mediated Rejection’) has been recognized as a distinct and common cause of late graft dysfunction and loss. The pathology is focused on the microvascular components of the kid-ney, manifested by endothelial ‘activation’, multilamination of glomerular and peritubular capillary basement membranes, interstitial fibrosis and tubular atrophy, and sometimes chronic transplant arteriopathy. Diagnosis requires a biopsy and demonstration of the complement degradation product, C4d in peritubular and/or glomerular capillaries. For definitive diagnosis, detection of donor-specific anti-endothelial antibodies is required (most commonly to class II MHC antigens). Here we review the diagnostic criteria, pathologic manifestations, new molecular markers and related studies in experimental animals.

  • national conference to assess antibody mediated Rejection in solid organ transplantation
    American Journal of Transplantation, 2004
    Co-Authors: Steven K Takemoto, Robert B Colvin, Adriana Zeevi, Robert A Montgomery, Sandy Feng, Stanley C Jordan, J Kobashigawa, Jerzy W Kupiecweglinski, Arthur J Matas, Peter Nickerson
    Abstract:

    The process of Humoral Rejection is multifaceted and has different manifestations in the various types of organ transplants. Because this process is emerging as a leading cause of graft loss, a conference was held in April 2003 to comprehensively address issues regarding Humoral Rejection. Though Humoral Rejection may result from different factors, discussion focused on a paradigm caused by antibodies, typically against donor HLA antigens, leading to the term 'antibody-mediated Rejection' (AMR). Conference deliberations were separated into four workgroups: The Profiling Workgroup evaluated strengths and limitations of different methods for detecting HLA reactive antibody, and created risk assessment guidelines for AMR; The Diagnosis Workgroup reviewed clinical, pathologic, and serologic criteria for assessing AMR in renal, heart and lung transplant recipients; The Treatment Workgroup discussed advantages, limitations and possible mechanisms of action for desensitization protocols that may reverse AMR; and The Basic Science Workgroup presented animal and human immunologic models for Humoral Rejection and proposed potential targets for future intervention. This work represents a comprehensive review with contributions from experts in the fields of Transplantation Surgery, Medicine, Pathology, Histocompatibility, Immunology, and clinical trial design. Immunologic barriers once considered insurmountable are now consistently overcome to enable more patients to undergo organ transplantation.

  • Humoral Rejection of human organ transplants
    Springer Seminars in Immunopathology, 2003
    Co-Authors: Paul J Michaels, Michael C Fishbein, Robert B Colvin
    Abstract:

    Although T-cell mediated Rejection has remained the most common form of acute Rejection, Humoral Rejection now accounts for a substantial fraction in patients with kidney or heart allografts, and probably causes the majority of acute graft losses. The frequency, variously estimated at 20-30%, is attributed to improved methods of detection, including staining for C4d in tissues, which is more sensitive and specific than histological features. Detection of circulating anti-donor reactive antibody (usually to donor HLA antigens) confirms the diagnosis. The clinico-pathological entity of acute Humoral Rejection is well accepted in kidney and increasingly in heart transplantation. Recent evidence points to a new category of chronic Humoral Rejection, which accounts for about 60% of chronic Rejection of kidneys. Importantly, the hallmark of Humoral Rejection, C4d, can be detected in the grafts before development of histological evidence of chronic Rejection. Humoral Rejection is generally not responsive to the usual anti-T cell immunosuppressive agents, but small, non-controlled trials suggest Humoral Rejection can be reversed with plasmapheresis, intravenous immunoglobulin, anti-CD20 and other treatments, all of which deserve formal clinical evaluation. Prophylaxis for chronic Rejection is expected to require donor-specific serological monitoring and protocol biopsies.

Nina Tolkoffrubin - One of the best experts on this subject based on the ideXlab platform.

  • overlapping pathways to transplant glomerulopathy chronic Humoral Rejection hepatitis c infection and thrombotic microangiopathy
    Kidney International, 2011
    Co-Authors: Seema Baidagrawal, Shamila Mauiyyedi, Bernard A Collins, Manuel Pascual, Nina Tolkoffrubin, Alton B Farris, Mary Lin Farrell, Ulrich Frei, Robert B Colvin
    Abstract:

    Transplant glomerulopathy (TG) has received much attention in recent years as a symptom of chronic Humoral Rejection; however, many cases lack C4d deposition and/or circulating donor-specific antibodies (DSAs). To determine the contribution of other causes, we studied 209 consecutive renal allograft indication biopsies for chronic allograft dysfunction, of which 25 met the pathological criteria of TG. Three partially overlapping etiologies accounted for 21 (84%) cases: C4d-positive (48%), hepatitis C-positive (36%), and thrombotic microangiopathy (TMA)-positive (32%) TG. The majority of patients with confirmed TMA were also hepatitis C positive, and the majority of hepatitis C-positive patients had TMA. DSAs were significantly associated with C4d-positive but not with hepatitis C-positive TG. The prevalence of hepatitis C was significantly higher in the TG group than in 29 control patients. Within the TG cohort, those who were hepatitis C-positive developed allograft failure significantly earlier than hepatitis C-negative patients. Thus, TG is not a specific diagnosis but a pattern of pathological injury involving three major overlapping pathways. It is important to distinguish these mechanisms, as they may have different prognostic and therapeutic implications.

  • chronic Humoral Rejection of human kidney allografts is associated with mmp 2 accumulation in podocytes and its release in the urine
    American Journal of Transplantation, 2010
    Co-Authors: Waichi Wong, Nina Tolkoffrubin, Julie Devito, H Nguyen, D Sarracino, Fabrice Porcheray, Ian Dargon, Patricia Della Pelle, A B Collins, R N Smith
    Abstract:

    Chronic Humoral Rejection (CHR) is an important cause of late graft failures following kidney transplantation. Overall, the pathophysiology of CHR is poorly understood. Matrix metalloproteinase-2 (MMP-2), a type IV collagenase, has been implicated in chronic kidney disease and allograft Rejection in previous studies. We examined the presence of MMP-2 in allograft biopsies and in the urine of kidney transplant recipients with CHR. MMP-2 staining was detected by immunohistochemistry in podocytes for all CHR patients but less frequently in patients with other renal complications. Urinary MMP-2 levels were also significantly higher in CHR patients (median 4942 pg/mL, N = 27) compared to non-CHR patients (median 598 pg/mL, N = 65; p < 0.001). Elevated urinary MMP-2 correlated with higher levels of proteinuria in both CHR and non-CHR patients. Longitudinal analysis indicated that increase in urine MMP-2 coincided with initial diagnosis of CHR as documented by the biopsies. Using an enzymatic assay, we demonstrated that MMP-2 was present in its active form in the urine of patients with CHR. Overall, our findings associate MMP-2 with glomerular injury as well as interstitial fibrosis and tubular atrophy observed in patients with CHR.

  • hepatitis c acute Humoral Rejection and renal allograft survival
    Journal of The American Society of Nephrology, 2004
    Co-Authors: John P Forman, Manuel Pascual, Nina Tolkoffrubin, Julie Lin
    Abstract:

    The effect of recipient hepatitis C virus (HCV) infection on renal allograft loss and acute Rejection in kidney transplantation remains controversial. We studied 354 renal allograft recipients transplanted during 1996 to 2001 who had HCV antibodies (Ab) measured before transplantation. The primary outcome was death-censored allograft loss and the secondary outcome was acute Humoral Rejection (AHR). Compared with HCV Ab-negative patients, those with positive HCV Ab had longer time on dialysis before transplantation, higher percentage of panel-reactive antibodies (PRA), were more likely to receive a cadaveric transplant, and were more likely to develop delayed graft function (DGF). In univariate analyses, predictors of renal allograft loss included HCV, cadaveric graft, PRA >20%, HLA mismatch ≥5, retransplantation, DGF, induction therapy, and AHR. When adjusted for PRA >20%, HLA mismatch ≥5, and multiple transplant status, HCV was not a statistically significant predictor of allograft loss. HCV was also associated with AHR but lost significance when adjusted for PRA >20%. HCV Ab-positive patients were more likely to have longer duration of dialysis before transplantation prior to kidney transplants, higher PRA, and to receive cadaveric transplants. These characteristics likely resulted in more DGF and AHR after transplantation. After adjusting for these confounding factors, the association between HCV Ab positivity and renal allograft loss was notably attenuated and no longer statistically significant.

  • acute Humoral Rejection in hepatitis c infected renal transplant recipients receiving antiviral therapy
    American Journal of Transplantation, 2003
    Co-Authors: Seema Baid, Susan L Saidman, Nina Tolkoffrubin, Winfred W Williams, Francis L Delmonico, Benedict A Cosimi, Robert B Colvin, Raymond T Chung, Hugh Auchincloss, Manuel Pascual
    Abstract:

    The use of interferon-alpha (IFN) in hepatitis C (HCV)-infected renal recipients has been associated with acute Rejection and graft loss. We reviewed our recent experience in HCV (+) renal recipients treated with antiviral therapy for biopsy proven chronic hepatitis C. Twelve HCV (+) recipients who recently received antiviral therapy were analyzed. Post-treatment sera were tested for donor-specific human leukocyte antigen (HLA) antibodies (DSA). Within 6 months of initiating antiviral therapy, two of 12 patients (17%) developed acute Rejection, which was characterized as acute Humoral Rejection (de novo DSA in serum and C4d deposits in peritubular capillaries). Both progressed to graft failure. Nine of the remaining 10 patients tested did not have DSA. The use of IFN was associated with severe acute Humoral Rejection (C4d +, DSA +). The recognition of IFN-associated acute Humoral Rejection in this series may explain the high rate of graft loss reported previously in renal recipients receiving IFN.

  • acute Humoral Rejection in kidney transplantation ii morphology immunopathology and pathologic classification
    Journal of The American Society of Nephrology, 2002
    Co-Authors: Shamila Mauiyyedi, Marta Crespo, Bernard A Collins, Eveline E Schneeberger, Manuel Pascual, Susan L Saidman, Nina Tolkoffrubin, Winfred W Williams, Francis L Delmonico, Benedict A Cosimi
    Abstract:

    The incidence of acute Humoral Rejection (AHR) in renal allograft biopsies has been difficult to determine because widely accepted diagnostic criteria have not been established. C4d deposition in peritubular capillaries (PTC) of renal allografts has been proposed as a useful marker for AHR. This study was designed to test the relative value of C4d staining, histology, and serology in the diagnosis of AHR. Of 232 consecutive kidney transplants performed at a single institution from July 1995 to July 1999, all patients (n = 67) who developed acute Rejection within the first 3 mo and had a renal biopsy with available frozen tissue at acute Rejection onset, as well as posttransplant sera within 30 d of the biopsy, were included in this study. Hematoxylin and eosin and periodic acid-Schiff stained sections were scored for glomerular, vascular, and tubulointerstitial pathology. C4d staining of cryostat sections was done by a sensitive three-layer immunofluorescence method. Donor-specific antibodies (DSA) were detected in posttransplant recipient sera using antihuman-globulin-enhanced T cell and B cell cytotoxicity assays and/or flow cytometry. Widespread C4d staining in PTC was present in 30% (20 of 67) of all acute Rejection biopsies. The initial histologic diagnoses of the C4d(+) acute Rejection cases were as follows: AHR only, 30%; acute cellular Rejection (ACR) and AHR, 45%; ACR (CCTT types 1 or 2) alone, 15%; and acute tubular injury (ATI), 10%. The distinguishing morphologic features in C4d(+) versus C4d(-) acute Rejection cases included the following: neutrophils in PTC, 65% versus 9%; neutrophilic glomerulitis, 55% versus 4%; neutrophilic tubulitis, 55% versus 9%; severe ATI, 75% versus 9%; and fibrinoid necrosis in glomeruli, 20% versus 0%, or arteries, 25% versus 0%; all P < 0.01. Mononuclear cell tubulitis was more common in the C4d(-) group (70% versus 100%; P < 0.01). No significant difference between C4d(+) and C4d(-) acute Rejection was noted for endarteritis, 25% versus 32%; interstitial inflammation (mean % cortex), 27.2 +/- 27% versus 38 +/- 21%; interstitial hemorrhage, 25% versus 15%; or infarcts, 5% versus 2%. DSA were present in 90% (18 of 20) of the C4d(+) cases compared with 2% (1 of 47) in the C4d(-) acute Rejection cases (P < 0.001). The pathology of the C4d(+) but DSA(-) cases was not distinguishable from the C4d(+), DSA(+) cases. The C4d(+) DSA(-) cases may be due to non-HLA antibodies or subthreshold levels of DSA. The sensitivity of C4d staining is 95% in the diagnosis of AHR compared with the donor-specific antibody test (90%). Overall, eight grafts were lost to acute Rejection in the first year, of which 75% (6 of 8) had AHR. The 1-yr graft failure rate was 27% (4 of 15) for those AHR cases with only capillary neutrophils versus 40% (2 of 5) for those who also had fibrinoid necrosis of arteries. In comparison, the 1-yr graft failure rates were 3% and 7%, respectively, in ACR 1 (Banff/CCTT type 1) and ACR 2 (Banff/CCTT type 2) C4d(-) groups. A substantial fraction (30%) of biopsy-confirmed acute Rejection episodes have a component of AHR as judged by C4d staining; most (90%), but not all, have detectable DSA. AHR may be overlooked in the presence of ACR or ATI by histology or negative serology, arguing for routine C4d staining of renal allograft biopsies. Because AHR has a distinct therapy and prognosis, we propose that it should be classified separately from ACR, with further sub-classification into AHR 1 (neutrophilic capillary involvement) and AHR 2 (arterial fibrinoid necrosis).

Benedict A Cosimi - One of the best experts on this subject based on the ideXlab platform.

  • acute Humoral Rejection in hepatitis c infected renal transplant recipients receiving antiviral therapy
    American Journal of Transplantation, 2003
    Co-Authors: Seema Baid, Susan L Saidman, Nina Tolkoffrubin, Winfred W Williams, Francis L Delmonico, Benedict A Cosimi, Robert B Colvin, Raymond T Chung, Hugh Auchincloss, Manuel Pascual
    Abstract:

    The use of interferon-alpha (IFN) in hepatitis C (HCV)-infected renal recipients has been associated with acute Rejection and graft loss. We reviewed our recent experience in HCV (+) renal recipients treated with antiviral therapy for biopsy proven chronic hepatitis C. Twelve HCV (+) recipients who recently received antiviral therapy were analyzed. Post-treatment sera were tested for donor-specific human leukocyte antigen (HLA) antibodies (DSA). Within 6 months of initiating antiviral therapy, two of 12 patients (17%) developed acute Rejection, which was characterized as acute Humoral Rejection (de novo DSA in serum and C4d deposits in peritubular capillaries). Both progressed to graft failure. Nine of the remaining 10 patients tested did not have DSA. The use of IFN was associated with severe acute Humoral Rejection (C4d +, DSA +). The recognition of IFN-associated acute Humoral Rejection in this series may explain the high rate of graft loss reported previously in renal recipients receiving IFN.

  • acute Humoral Rejection in kidney transplantation ii morphology immunopathology and pathologic classification
    Journal of The American Society of Nephrology, 2002
    Co-Authors: Shamila Mauiyyedi, Marta Crespo, Bernard A Collins, Eveline E Schneeberger, Manuel Pascual, Susan L Saidman, Nina Tolkoffrubin, Winfred W Williams, Francis L Delmonico, Benedict A Cosimi
    Abstract:

    The incidence of acute Humoral Rejection (AHR) in renal allograft biopsies has been difficult to determine because widely accepted diagnostic criteria have not been established. C4d deposition in peritubular capillaries (PTC) of renal allografts has been proposed as a useful marker for AHR. This study was designed to test the relative value of C4d staining, histology, and serology in the diagnosis of AHR. Of 232 consecutive kidney transplants performed at a single institution from July 1995 to July 1999, all patients (n = 67) who developed acute Rejection within the first 3 mo and had a renal biopsy with available frozen tissue at acute Rejection onset, as well as posttransplant sera within 30 d of the biopsy, were included in this study. Hematoxylin and eosin and periodic acid-Schiff stained sections were scored for glomerular, vascular, and tubulointerstitial pathology. C4d staining of cryostat sections was done by a sensitive three-layer immunofluorescence method. Donor-specific antibodies (DSA) were detected in posttransplant recipient sera using antihuman-globulin-enhanced T cell and B cell cytotoxicity assays and/or flow cytometry. Widespread C4d staining in PTC was present in 30% (20 of 67) of all acute Rejection biopsies. The initial histologic diagnoses of the C4d(+) acute Rejection cases were as follows: AHR only, 30%; acute cellular Rejection (ACR) and AHR, 45%; ACR (CCTT types 1 or 2) alone, 15%; and acute tubular injury (ATI), 10%. The distinguishing morphologic features in C4d(+) versus C4d(-) acute Rejection cases included the following: neutrophils in PTC, 65% versus 9%; neutrophilic glomerulitis, 55% versus 4%; neutrophilic tubulitis, 55% versus 9%; severe ATI, 75% versus 9%; and fibrinoid necrosis in glomeruli, 20% versus 0%, or arteries, 25% versus 0%; all P < 0.01. Mononuclear cell tubulitis was more common in the C4d(-) group (70% versus 100%; P < 0.01). No significant difference between C4d(+) and C4d(-) acute Rejection was noted for endarteritis, 25% versus 32%; interstitial inflammation (mean % cortex), 27.2 +/- 27% versus 38 +/- 21%; interstitial hemorrhage, 25% versus 15%; or infarcts, 5% versus 2%. DSA were present in 90% (18 of 20) of the C4d(+) cases compared with 2% (1 of 47) in the C4d(-) acute Rejection cases (P < 0.001). The pathology of the C4d(+) but DSA(-) cases was not distinguishable from the C4d(+), DSA(+) cases. The C4d(+) DSA(-) cases may be due to non-HLA antibodies or subthreshold levels of DSA. The sensitivity of C4d staining is 95% in the diagnosis of AHR compared with the donor-specific antibody test (90%). Overall, eight grafts were lost to acute Rejection in the first year, of which 75% (6 of 8) had AHR. The 1-yr graft failure rate was 27% (4 of 15) for those AHR cases with only capillary neutrophils versus 40% (2 of 5) for those who also had fibrinoid necrosis of arteries. In comparison, the 1-yr graft failure rates were 3% and 7%, respectively, in ACR 1 (Banff/CCTT type 1) and ACR 2 (Banff/CCTT type 2) C4d(-) groups. A substantial fraction (30%) of biopsy-confirmed acute Rejection episodes have a component of AHR as judged by C4d staining; most (90%), but not all, have detectable DSA. AHR may be overlooked in the presence of ACR or ATI by histology or negative serology, arguing for routine C4d staining of renal allograft biopsies. Because AHR has a distinct therapy and prognosis, we propose that it should be classified separately from ACR, with further sub-classification into AHR 1 (neutrophilic capillary involvement) and AHR 2 (arterial fibrinoid necrosis).

  • control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic Rejection
    Transplantation, 2001
    Co-Authors: Tom P Theruvath, Shamila Mauiyyedi, Bernard A Collins, Susan L Saidman, Nina Tolkoffrubin, Winfred W Williams, Francis L Delmonico, Benedict A Cosimi, Robert B Colvin, Manuel Pascual
    Abstract:

    Background. In renal transplantation, chronic Rejection is a major cause of late allograft loss. Recent studies indicate that a subset of chronic Rejection is associated with anti-HLA donor specific antibodies (DSA) and complement C4d deposition in peritubular capillaries (PTC). Since rescue therapy with tacrolimus and mycophenolate mofetil has been found to limit antidonor B-cell responses in recipients with acute Humoral Rejection, we sought to determine whether a similar immunosuppressive regimen might be effective in patients with chronic Humoral Rejection'. Methods. Four renal allograft recipients with chronic Humoral Rejection' were prospectively identified. The diagnosis was based on: (1) progressive rise in serum creatinine over 12 months; (2) typical pathologic features by light microscopy (transplant arteriopathy and glomerulopathy); (3) widespread C4d deposits in PTC by immunofluorescence; (4) detection of 'de novo' DSA at the time of biopsy. Maintenance immunosuppression was CsA, prednisone and azathioprine (n=3) or prednisone and azathioprine (n=1). Rescue therapy with tacrolimus and mycophenolate mofetil was initiated in all patients, 12 hr after cyclosporine and azathioprine discontinuation. Results. At diagnosis, the mean serum creatinine was 3.9 mg/dl (range: 3.3 to 5.4 mg/dl). DSA was an IgG directed against HLA class II (n=3) or class I (n=2), that is one patient had both anti-HLA class I and class II antibodies. Pretreatment antibody titers varied between 1:8 and 1:128. Rescue therapy was associated with a rapid and sustained decrease in antibody titers. In two patients, DSA became undetectable after 9 months and a repeat biopsy performed after 12 months revealed a decrease in C4d deposition in PTC. Conclusion. These results suggest that a decrease in DSA production can be induced in renal allograft recipients with chronic Humoral Rejection' by using an immunosuppressive regimen that combines tacrolimus and mycophenolate mofetil. Limitation of antidonor antibody synthesis may be important for the treatment or the prevention of chronic Rejection in organ transplantation.

  • acute Humoral Rejection in renal allograft recipients i incidence serology and clinical characteristics
    Transplantation, 2001
    Co-Authors: Marta Crespo, Shamila Mauiyyedi, Bernard A Collins, Manuel Pascual, Nina Tolkoffrubin, Winfred W Williams, Francis L Delmonico, Mary Lin Farrell, Donna M Fitzpatrick, Benedict A Cosimi
    Abstract:

    Background. Acute Rejection (AR) associated with de novo production of donor-specific antibodies (DSA) is a clinicopathological entity that carries a poor prognosis (acute Humoral Rejection, AHR). The aim of this study was to determine the incidence and clinical characteristics of AHR in renal allograft recipients, and to further analyze the antibodies involved. Methods. During a 4-year period, 232 renal transplants (Tx) were performed at our institution. Assays for DSA included T and B cell cytotoxic and/or flow cytometric cross-matches and cytotoxic antibody screens (PRA). C4d complement staining was performed on frozen biopsy tissue. Results. A total of 81 patients (35%) suffered at least one episode of AR within the first 3 months: 51 had steroid-insensitive AR whereas the remaining 30 had steroid-sensitive AR. No DSA were found in patients with steroid-sensitive AR. In contrast, circulating DSA were found in 19/51 patients (37%) with steroid-insensitive AR, and widespread C4d deposits in peritubular capillaries were present in 18 of these 19 (95%). In at least three cases, antibodies were against donor HLA class II antigens. DSA were not found in the remaining 32 patients but C4d staining was positive in 2 of 32. The DSA/C4d positive (n=18) and DSA/C4d negative (n=30) groups differed in pre-Tx PRA levels, percentage of re-Tx patients, refractoriness to antilymphocyte therapy, and outcome. Plasmapheresis and tacrolimus-mycophenolate mofetil rescue reversed Rejection in 9 of 10 recipients with refractory AHR. Conclusion. More than one-third of the patients with steroid-insensitive AR had evidence of AHR, often resistant to antilymphocyte therapy. Most cases (95%) with DSA at the time of Rejection had widespread C4d deposits in peritubular capillaries, suggesting a pathogenic role of the circulating alloantibody. Combined DSA testing and C4d staining provides a useful approach for the early diagnosis of AHR, a condition that often necessitates a more intensive therapeutic rescue regimen.

  • plasma exchange and tacrolimus mycophenolate rescue for acute Humoral Rejection in kidney transplantation
    Transplantation, 1998
    Co-Authors: Manuel Pascual, Shamila Mauiyyedi, Susan L Saidman, Nina Tolkoffrubin, Winfred W Williams, Benedict A Cosimi, Robert B Colvin, Mary Lin Farrell, Ji Ming Duan, Francis L Delmonico
    Abstract:

    Background. Acute renal allograft Rejection associated with the development of donor-specific alloantibody (acute Humoral Rejection, AHR) typically carries a poor prognosis. The best treatment of this condition remains undefined. tk;2Methods. During a 14-month period, 73 renal transplants were performed. During the first postoperative month, five recipients (6.8%) with AHR were identified. The diagnosis was based on: (1) evidence of severe Rejection, resistant to steroid and antilymphocyte therapy; (2) typical pathologic features; and (3) demonstration of donor-specific alloantibody (DSA) in recipient’s serum at the time of Rejection. Pretransplant donor-specific T- and B-cell cross-matches were negative. Results. Plasma exchange (PE, four to seven treatments per patient) significantly decreased circulating DSA to almost pretransplant levels in four of five patients, and improvement in renal function occurred in all patients. One patient had recurrent renal dysfunction in the setting of an increase in circulating DSA. A second series of five PE treatments decreased DSA and reversed the Rejection episode. Rescue therapy with tacrolimus (initial mean dose: 0.1460.32 mg/kg/ day) and mycophenolate mofetil (2 g/day) was used in five of five and four of five patients, respectively. With a mean follow-up of 19.665.6 months, patient and allograft survival are 100%. Renal function remains excellent with a mean current serum creatinine of 1.260.3 mg/dl. (range: 0.9 ‐1.8 mg/dl). Conclusions. Our findings suggest that a therapeutic approach combining PE and tacrolimus-mycophenolate mofetil rescue has the potential to improve the outcome of AHR.

Michael C Fishbein - One of the best experts on this subject based on the ideXlab platform.

  • Humoral Rejection in pediatric orthotopic heart transplantation
    Journal of Heart and Lung Transplantation, 2007
    Co-Authors: Tim W Casarez, Elaine F Reed, Michael C Fishbein, Juan C Alejos, Gregory Perens, Ryan J Williams, Erin Kutay, Daniel S Levi
    Abstract:

    Background Pediatric heart transplant grafts may fail without evidence of cellular Rejection or transplant coronary artery disease. The role of antibody-mediated Humoral Rejection (HR) in graft failure has not yet been described in the pediatric population. Methods We reviewed the medical records of 103 pediatric heart transplantations performed at our institution from July 1997 to June 2004. Biopsy specimens were evaluated for HR histologically and by immunoperoxidase and immunofluorescence staining. Risk factors for HR were determined by statistical analysis. Graft survival curves were constructed and compared for patients testing negative or positive for HR. Results A total of 358 endomyocardial biopsies (EMBs) from 103 pediatric heart transplant patients (age 3 weeks to 20 years; 52% males) were analyzed for HR. Thirty-six grafts (32%) showed evidence of HR. Grafts with a history of HR during the first year after transplant had a 47% failure rate over 3 years, compared with 29% of those hearts with no evidence of HR ( p = 0.06). Although patients with congenital heart disease (CHD) appeared to be at greatest risk for developing HR ( p = 0.01), patients with positive donor-specific crossmatch data showed a trend toward more significant risks for HR ( p = 0.055). Hemodynamic data (including pulmonary capillary wedge pressure [PCWP] and cardiac index [CI]), left ventricular ejection fraction (LVEF), gender matching, recipient age, race of recipient vs donor and pre-transplant panel-reactive antibody (PRA) were not predictive of HR. Conclusions Patients with a pathologic diagnosis of HR have increased graft failure rates and overall mortality. Patients with congenital heart disease and positive cross-match results may be at increased risk for HR.

  • c4d staining of pulmonary allograft biopsies an immunoperoxidase study
    Journal of Heart and Lung Transplantation, 2005
    Co-Authors: Dean W Wallace, Charles Lassman, Elaine F Reed, David J Ross, Michael C Fishbein
    Abstract:

    BACKGROUND: The role of antibody-mediated/Humoral Rejection in lung allografts is not fully elucidated. In other organ systems, deposition of a specific complement product, C4d, is a sensitive and specific marker for Humoral Rejection. C4d can be evaluated in tissue biopsies by immunofluorescence or light microscopic immunohistochemical staining techniques. Using immunohistochemical staining techniques we sought to determine whether there was any specific staining pattern for C4d in lung allograft biopsies with or without the diagnosis of acute or chronic cellular or Humoral Rejection. METHODS: A total of 68 lung transplant biopsies, performed at UCLA Medical Center from January 2002 to August 2004, were collected and the paraffin blocks were re-cut and stained for C4d by an immunoperoxidase technique. The cases were separated by the presence or absence of features of acute and/or chronic Rejection based on the International Society for Heart and Lung Transplantation working formulation for the classification of pulmonary allograft Rejection, revised 1995. The pattern of staining for C4d was then systematically examined. RESULTS: Positive staining in a variable, focal non-specific pattern was observed. There was no consistent staining pattern within the different diagnostic groups. CONCLUSIONS: C4d staining of paraffin-embedded lung allograft biopsies, using currently available techniques, does not identify acute or chronic cellular or Humoral Rejection in lung allograft tissue.

  • biopsy negative cardiac transplant Rejection etiology diagnosis and therapy
    Current Opinion in Cardiology, 2004
    Co-Authors: Michael C Fishbein, J A Kobashigawa
    Abstract:

    Purpose of review As the frequency of cellular Rejection after heart transplantation is decreasing, biopsy-negative episodes of Rejection are being recognized more often. This article reviews the features of Humoral Rejection, which we believe is responsible for most episodes of biopsy-negative Rejection. Hemodynamic compromise, in the absence of acute cellular Rejection, called biopsy-negative Rejection occurs in 10 to 20% of cardiac allograft recipients. These episodes of Rejection are often more severe, and more difficult to treat, than classical acute cellular Rejection. Histologic, immunofluorescence, and immunoperoxidase studies of endomyocardial biopsies from such patients often reveal intravascular macrophages, and immunoglobulin and complement deposition in capillaries, in the absence of lymphoid infiltrates, suggesting an antibody-mediated or Humoral form of Rejection. Recent findings Humoral Rejection is associated with increased graft loss, accelerated transplant coronary artery disease, and increased mortality. Severely ill patients require intense therapy, which includes high-dose corticosteroids, cytolytic agents, intravenous heparin, intravenous gamma globulin, plasmapheresis, and/or antiproliferative agents. Summary Currently, our knowledge of the pathogenesis, diagnostic criteria, and optimal therapy for biopsy-negative Rejection is incomplete, and evolving.

  • Humoral Rejection of human organ transplants
    Springer Seminars in Immunopathology, 2003
    Co-Authors: Paul J Michaels, Michael C Fishbein, Robert B Colvin
    Abstract:

    Although T-cell mediated Rejection has remained the most common form of acute Rejection, Humoral Rejection now accounts for a substantial fraction in patients with kidney or heart allografts, and probably causes the majority of acute graft losses. The frequency, variously estimated at 20-30%, is attributed to improved methods of detection, including staining for C4d in tissues, which is more sensitive and specific than histological features. Detection of circulating anti-donor reactive antibody (usually to donor HLA antigens) confirms the diagnosis. The clinico-pathological entity of acute Humoral Rejection is well accepted in kidney and increasingly in heart transplantation. Recent evidence points to a new category of chronic Humoral Rejection, which accounts for about 60% of chronic Rejection of kidneys. Importantly, the hallmark of Humoral Rejection, C4d, can be detected in the grafts before development of histological evidence of chronic Rejection. Humoral Rejection is generally not responsive to the usual anti-T cell immunosuppressive agents, but small, non-controlled trials suggest Humoral Rejection can be reversed with plasmapheresis, intravenous immunoglobulin, anti-CD20 and other treatments, all of which deserve formal clinical evaluation. Prophylaxis for chronic Rejection is expected to require donor-specific serological monitoring and protocol biopsies.

  • Humoral Rejection in cardiac transplantation risk factors hemodynamic consequences and relationship to transplant coronary artery disease
    Journal of Heart and Lung Transplantation, 2003
    Co-Authors: Paul J Michaels, Elaine F Reed, J A Kobashigawa, Maria L Espejo, Juan C Alejos, C Burch, S Takemoto, Michael C Fishbein
    Abstract:

    Abstract Background Acute cellular Rejection is the mechanism of most immune-related injury in cardiac transplant recipients. However, antibody-mediated Humoral Rejection (HR) has also been implicated as an important clinical entity following orthotopic heart transplantation. Humoral Rejection has been reported to play a role in graft dysfunction in the early post-transplant period, and to be a risk factor for the development of transplant coronary artery disease. Some involved in transplantation pathology doubt the existence of clinically significant Humoral Rejection in cardiac allografts. Those who recognize its existence disagree on its possible role in graft dysfunction or graft coronary artery disease. In this study, we report clinical features of patients with the pathologic diagnosis of HR at our institution since July 1997, when we began systematic surveillance for Humoral Rejection. Methods We reviewed medical records of patients with the pathologic diagnosis of HR without concurrent cellular Rejection between July 1997 and January 2001. Diagnosis was based on routine histology (“swollen cells” distending capillaries, interstitial edema and hemorrhage) and immunofluorescence (capillary deposition of immunoglobulin and complement with HLA-DR positivity), or immunoperoxidase staining of paraffin-embedded tissue (numerous CD68-positive macrophages and fewer swollen endothelial cells distending capillaries). Results A total of 44 patients (4 to 74 years old) showed evidence of HR without concurrent cellular Rejection at autopsy or on one or more biopsies. Although females comprised only 26% of our transplant population, 23 patients (52%) with HR were female. A positive peri-operative flow cytometry T-cell crossmatch was observed in 32% of HR patients compared with 12% of controls ( p = 0.02). Hemodynamic compromise consisting of shock, hypotension, decreased cardiac output/index and/or a rise in capillary wedge or pulmonary artery pressure was observed in 47% of patients at the time of diagnosis of HR. Six patients (5 females) died (14% mortality) with evidence of HR at or just before autopsy, 6 days to 16 months after transplantation. The incidence of transplant coronary artery disease was 10% greater at 1 year, and 36% greater at 5 years, in patients with HR when compared with non-HR patients. Conclusion Humoral Rejection was associated with acute hemodynamic compromise in 47% of patients, and was the direct cause of death in 6 patients (13%). Humoral Rejection is a clinicopathologic entity with a high incidence in women and is associated with acute hemodynamic compromise, accelerated transplant coronary artery disease and death.