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Leendert C. Paul - One of the best experts on this subject based on the ideXlab platform.
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Antibody Response Against the Glomerular Basement Membrane Protein Agrin in Patients with Transplant Glomerulopathy
American Journal of Transplantation, 2005Co-Authors: Simone A. Joosten, Yvo W.j. Sijpkens, Leendert A. Trouw, Johan Van Der Vlag, Bert Van Den Heuvel, Cees Van Kooten, Leendert C. PaulAbstract:Chronic allograft nephropathy (CAN) of renal allografts is still the most important cause of graft loss. A subset of these patients have Transplant Glomerulopathy (TGP), characterized by glomerular basement membrane (GBM) duplications, but of unknown etiology. Recently, a role for the immune system in the pathogenesis of TGP has been suggested. In 11 of 16 patients with TGP and in 3 of 16 controls with CAN in the absence of TGP we demonstrate circulating antibodies reactive with GBM isolates. The presence of anti-GBM antibodies was associated with the number of rejection episodes prior to diagnosis of TGP. Sera from the TGP patients also reacted with highly purified GBM heparan sulphate proteoglycans (HSPG). Indirect immunofluorescence with patient IgG showed a GBM-like staining pattern and colocalization with the HSPGs perlecan and especially agrin. Using patient IgG, we affinity purified the antigen and identified it as agrin. Reactivity with agrin was found in 7 of 16 (44%) of patients with TGP and in 7 of 11 (64%) patients with anti-GBM reactivity. In conclusion, we have identified a humoral response against the GBM-HSPG agrin in patients with TGP, which may play a role in the pathogenesis of TGP.
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Immunologic risk factors and glomerular C4d deposits in chronic Transplant Glomerulopathy
Kidney international, 2004Co-Authors: Yvo W.j. Sijpkens, Simone A. Joosten, Man-chi Wong, Friedo W. Dekker, Hallgrimur Benediktsson, Ingeborg M. Bajema, Jan A. Bruijn, Leendert C. PaulAbstract:Immunologic risk factors and glomerular C4d deposits in chronic Transplant Glomerulopathy. Background Chronic Transplant Glomerulopathy is an uncommon cause of chronic Transplant dysfunction of unknown pathogenesis. We evaluated the epidemiologic, clinical, and histologic features of chronic Transplant Glomerulopathy. To determine the possible contribution of humoral immune responses, we assessed glomerular deposition of C4d. Methods From a cohort of 1111 kidney Transplants (1983 to 2001) with at least 6months of graft function, we identified 18 cases with chronic Transplant Glomerulopathy (1.6%) showing double contours of the glomerular basement membrane (GBM) on light microscopy. To assess the risk factors, this group was compared with 739 patients with stable function using multivariate Cox regression analysis. Paraffin sections of 11/18 biopsies were stained with polyclonal C4d antibodies. Sera of 13/18 patients could be tested for antidonor human leukocyte antigen (HLA) antibodies by enzyme-linked immunosorbent assay (ELISA). Patients with chronic allograft nephropathy without chronic Transplant Glomerulopathy or predominant cyclosporine nephrotoxicity were used as controls. Results Chronic Transplant Glomerulopathy was diagnosed at a median of 8.3 (range 2.6–12.5) years postTransplantation. Panel reactive antibodies at time of Transplantation, RR 1.23 (1.05–1.45) per 10% increase, and late acute rejection episodes, RR 7.6 (1.8–31.7), were independently associated with chronic Transplant Glomerulopathy. We found glomerular C4d deposits in 10/11 biopsies showing chronic Transplant Glomerulopathy and in only 2/13 controls. Peritubular capillary C4d deposits and donor-specific anti-HLA antibodies were demonstrated in 4 and 3 of the 10 patients with glomerular C4d deposits, respectively. Conclusion Presensitization and late acute rejection episodes were the risk factors identified. Glomerular C4d deposits suggest that chronic Transplant Glomerulopathy emerges from in situ humoral rejection. Chronic Transplant Glomerulopathy should be considered as a manifestation of immune-mediated injury.
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antibody response against perlecan and collagen types iv and vi in chronic renal allograft rejection in the rat
American Journal of Pathology, 2002Co-Authors: Simone A. Joosten, Hallgrimur Benediktsson, Mieneke G A Van Dixhoorn, Maria C Borrias, Peter A Van Veelen, Cees Van Kooten, Leendert C. PaulAbstract:Chronic rejection is the leading cause of late renal Transplant failure. Various structural lesions are observed in grafts undergoing chronic rejection including glomerular basement membrane (GBM) duplications. The well-established Fisher (F344) to Lewis (LEW) rat renal Transplant model for chronic rejection was used to assess the presence and role of the humoral immune response against graft antigens during chronic rejection. LEW recipients of F344 allografts develop Transplant Glomerulopathy and produce IgG1 antibodies directed against F344 GBM preparations that are detectable 3 weeks after Transplantation. Glomerular IgG1 deposition was observed that in vitro co-localized with a rabbit anti-rat GBM antiserum in rejecting F344 grafts; elution experiments of isolated glomeruli yielded IgG1 antibodies reactive in vitro with F344 GBM, but not LEW GBM. Prevention of acute rejection by transient treatment of the recipients with cyclosporin A completely abrogated the production of anti-GBM antibodies. Using proteomic techniques we identified the antigens recognized by the LEW postTransplant sera as being the heparan sulfate proteoglycan perlecan and the α1 chain of collagen type VI in association with the α5 chain of collagen type IV. In conclusion, LEW recipients of F344 kidney grafts produce IgG1 antibodies against donor type perlecan and α1(VI)/α5(IV) collagen and develop Transplant Glomerulopathy. These data implicate an important role for the humoral immune response in the development of Glomerulopathy during chronic rejection.
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chronic allograft nephropathy an update
Kidney International, 1999Co-Authors: Leendert C. PaulAbstract:Chronic allograft nephropathy is the most prevalent cause of renal Transplant failure in the first post-Transplant decade, but its pathogenesis has remained elusive. Clinically, it is characterized by a slow but variable loss of function, often in combination with proteinuria and hypertension. The histopathology is also not specific, but Transplant Glomerulopathy and multilayering of the peritubular capillaries are highly characteristic. Several risk factors have been identified, such as advanced donor age, delayed graft function, repeated acute rejection episodes, vascular rejection episodes, and rejections that occur late after Transplantation. A common feature of chronic allograft nephropathy is that it develops in grafts that have undergone previous damage, although the mechanism(s) responsible for the progressive fibrosis and tissue remodeling has not yet been defined. Hypotheses to explain chronic allograft nephropathy include the immunolymphatic theory, the cytokine excess theory, the loss of supporting architecture theory, and the premature senescence theory. The most effective option to prevent chronic allograft nephropathy is to avoid graft injury from both immune and nonimmune mechanisms.
Fernando G Cosio - One of the best experts on this subject based on the ideXlab platform.
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kidney allograft survival after acute rejection the value of follow up biopsies
American Journal of Transplantation, 2013Co-Authors: El M Ters, Patrick G Dean, Mark D Stegall, Joseph P Grande, Mira T Keddis, E Rodrigo, B Chopra, Fernando G CosioAbstract:Kidney allografts are frequently lost due to alloimmunity. Still, the impact of early acute rejection (AR) on long-term graft survival is debated. We examined this relationship focusing on graft histology post-AR and assessing specific causes of graft loss. Included are 797 recipients without anti-donor antibodies (DSA) at Transplant who had 1 year protocol biopsies. 15.2% of recipients had AR diagnosed by protocol or clinical biopsies. Compared to no-AR, all histologic types of AR led to abnormal histology in 1 and 2 years protocol biopsies, including more fibrosis + inflammation (6.3% vs. 21.9%), moderate/severe fibrosis (7.7% vs. 13.5%) and Transplant Glomerulopathy (1.4% vs. 8.3%, all p < 0.0001). AR were associated with reduced graft survival (HR = 3.07 (1.92–4.94), p < 0.0001). However, only those AR episodes followed by abnormal histology led to reduced graft survival. Early AR related to more late alloimmune-mediated graft losses, particularly Transplant Glomerulopathy (31% of losses). Related to this outcome, recipients with AR were more likely to have new DSA class II 1 year postTransplant (no-AR, 11.1%; AR, 21.2%, p = 0.039). In DSA negative recipients, early AR often leads to persistent graft inflammation and increases the risk of new DSA II production. Both of these post-AR events are associated with increased risk of graft loss.
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terminal complement inhibition decreases antibody mediated rejection in sensitized renal Transplant recipients
American Journal of Transplantation, 2011Co-Authors: Mark D Stegall, Lynn D Cornell, Fernando G Cosio, Patrick G Dean, Tayyab S Diwan, Suresh Raghavaiah, Justin M Burns, Manish J Gandhi, Walter K KremersAbstract:Sensitized renal Transplant recipients with high levels of donor-specific alloantibody (DSA) commonly develop antibody-mediated rejection (AMR), which may cause acute graft loss or shorten allograft survival. We examined the efficacy of terminal complement inhibition with the humanized anti-C5 antibody, eculizumab, in the prevention AMR in renal Transplant recipients with a positive crossmatch against their living donor. The incidence of biopsy-proven AMR in the first 3 months postTransplant in 26 highly sensitized recipients of living donor renal Transplants who received eculizumab postTransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange (PE)-based protocol without eculizumab. The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group (p = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after Transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with PE reducing the need for splenectomy. On 1-year protocol biopsy, Transplant Glomerulopathy was found to be present in 6.7% (1/15) eculizumab-treated recipients and in 35.7% (15/42) of control patients (p = 0.044). Inhibition of terminal complement activation with eculizumab decreases the incidence of early AMR in sensitized renal Transplant recipients (ClincalTrials.gov number NCT006707).
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baseline donor specific antibody levels and outcomes in positive crossmatch kidney Transplantation
American Journal of Transplantation, 2010Co-Authors: James M Gloor, Lynn D Cornell, Fernando G Cosio, Manish J Gandhi, Walter K Kremers, Jeffrey L Winters, Lynette Fix, Steven R Degoey, R M Knauer, Mark D StegallAbstract:Renal Transplant candidates with donor-specific alloantibody (DSA) have increased risk of antibody-mediated allograft injury. The goal of this study was to correlate the risk of antibody-mediated rejection (AMR), Transplant Glomerulopathy (TG) and graft survival with the baseline DSA level (prior to initiation of preTransplant conditioning). These analyses include 119 positive crossmatch (+XM) compared to 70 negative crossmatch (-XM) Transplants performed between April 2000 and July 2007. Using a combination of cell-based crossmatch tests, DSA level was stratified into very high +XM, high +XM, low +XM and -XM groups. In +XM Transplants, increasing DSA level was associated with increased risk for AMR (HR = 1.76 [1.51, 2.07], p = 0.0001) but not TG (p = 0.18). We found an increased risk for both early and late allograft loss associated with very high DSA (HR = 7.71 [2.95, 20.1], p = 0.0001). Although lower DSA recipients commonly developed AMR and TG, allograft survival was similar to that of -XM patients (p = 0.31). We conclude that the baseline DSA level correlates with risk of early and late alloantibody-mediated allograft injury. With current protocols, very high baseline DSA patients have high rates of AMR and poor long-term allograft survival highlighting the need for improved therapy for these candidates.
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identifying specific causes of kidney allograft loss
American Journal of Transplantation, 2009Co-Authors: Ziad M Elzoghby, James M Gloor, Mark D Stegall, Walter K Kremers, Donna J Lager, Hatem Amer, Fernando G CosioAbstract:The causes of kidney allograft loss remain unclear. Herein we investigated these causes in 1317 conventional kidney recipients. The cause of graft loss was determined by reviewing clinical and histologic information the latter available in 98% of cases. During 50.3 ± 32.6 months of follow-up, 330 grafts were lost (25.0%), 138 (10.4%) due to death with function, 39 (2.9%) due to primary nonfunction and 153 (11.6%) due to graft failure censored for death. The latter group was subdivided by cause into: glomerular diseases (n = 56, 36.6%); fibrosis/atrophy (n = 47, 30.7%); medical/surgical conditions (n = 25, 16.3%); acute rejection (n = 18, 11.8%); and unclassifiable (n = 7, 4.6%). Glomerular pathologies leading to failure included recurrent disease (n = 23), Transplant Glomerulopathy (n = 23) and presumed nonrecurrent disease (n = 10). In cases with fibrosis/atrophy a specific cause(s) was identified in 81% and it was rarely attributable to calcineurin inhibitor (CNI) toxicity alone (n = 1, 0.7%). Contrary to current concepts, most cases of kidney graft loss have an identifiable cause that is not idiopathic fibrosis/atrophy or CNI toxicity. Glomerular pathologies cause the largest proportion of graft loss and alloinmunity remains the most common mechanism leading to failure. This study identifies targets for investigation and intervention that may result in improved kidney Transplantation outcomes.
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Transplant Glomerulopathy risk and prognosis related to anti human leukocyte antigen class ii antibody levels
Transplantation, 2008Co-Authors: Naim Issa, Fernando G Cosio, James M Gloor, Sanjeev Sethi, Patrick G Dean, Breanndan S Moore, Steve Degoey, Mark D StegallAbstract:Background. Transplant Glomerulopathy (TG) is a histopathologic entity of kidney allografts related to anti-human leukocyte antigen (HLA) antibodies. The goal of this study was to determine the relationships among antibody characteristics (level and specificity), risk for TG, and graft survival. Methods. The presence and characteristics of anti-HLA antibody were assessed by single antigen beads assays in stored preTransplant sera from 598 kidney recipients with negative T-cell crossmatch. Transplant Glomerulopathy was diagnosed by surveillance and clinical biopsies. Results. Thirty-nine percent of patients presented with anti-HLA antibodies preTransplant. Transplant Glomerulopathy was diagnosed in 73 patients (12%) during 54±19 months of follow-up. The risk of TG increased with higher anti-HLA-II antibody levels (HR= 1.890, 95% CI 1.42-2.52; P<0.0001), donor specificity of the antibodies (3.524 [1.67-7.44]; P=0.001), and in patients with history of antibody-mediated rejection (4.985 [2.77-8.97]; P<0.0001, multivariate Cox). Graft survival during the follow-up period was 95% without TG and 62% with TG (P<0.0001). The presence of C4d in peritubular capillaries was an independent risk factor for graft failure after TG diagnosis. Thus, 25% of TG/C4d - and 80% of TG/C4d + grafts failed (P<0.0001). Of interest, higher anti-HLA-II levels were related to the presence of C4d (3.216 [1.376-7.517]; P=0.007). Conclusions. In T-cell negative crossmatch patients, higher anti-HLA-II antibody levels are related to the increase in the risk of developing TG. Higher antibody levels are also related to the presence of C4d in peritubular capillaries in TG biopsies. Furthermore, the presence of C4d in TG is related to the reduced graft survival.
Mark D Stegall - One of the best experts on this subject based on the ideXlab platform.
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kidney allograft survival after acute rejection the value of follow up biopsies
American Journal of Transplantation, 2013Co-Authors: El M Ters, Patrick G Dean, Mark D Stegall, Joseph P Grande, Mira T Keddis, E Rodrigo, B Chopra, Fernando G CosioAbstract:Kidney allografts are frequently lost due to alloimmunity. Still, the impact of early acute rejection (AR) on long-term graft survival is debated. We examined this relationship focusing on graft histology post-AR and assessing specific causes of graft loss. Included are 797 recipients without anti-donor antibodies (DSA) at Transplant who had 1 year protocol biopsies. 15.2% of recipients had AR diagnosed by protocol or clinical biopsies. Compared to no-AR, all histologic types of AR led to abnormal histology in 1 and 2 years protocol biopsies, including more fibrosis + inflammation (6.3% vs. 21.9%), moderate/severe fibrosis (7.7% vs. 13.5%) and Transplant Glomerulopathy (1.4% vs. 8.3%, all p < 0.0001). AR were associated with reduced graft survival (HR = 3.07 (1.92–4.94), p < 0.0001). However, only those AR episodes followed by abnormal histology led to reduced graft survival. Early AR related to more late alloimmune-mediated graft losses, particularly Transplant Glomerulopathy (31% of losses). Related to this outcome, recipients with AR were more likely to have new DSA class II 1 year postTransplant (no-AR, 11.1%; AR, 21.2%, p = 0.039). In DSA negative recipients, early AR often leads to persistent graft inflammation and increases the risk of new DSA II production. Both of these post-AR events are associated with increased risk of graft loss.
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terminal complement inhibition decreases antibody mediated rejection in sensitized renal Transplant recipients
American Journal of Transplantation, 2011Co-Authors: Mark D Stegall, Lynn D Cornell, Fernando G Cosio, Patrick G Dean, Tayyab S Diwan, Suresh Raghavaiah, Justin M Burns, Manish J Gandhi, Walter K KremersAbstract:Sensitized renal Transplant recipients with high levels of donor-specific alloantibody (DSA) commonly develop antibody-mediated rejection (AMR), which may cause acute graft loss or shorten allograft survival. We examined the efficacy of terminal complement inhibition with the humanized anti-C5 antibody, eculizumab, in the prevention AMR in renal Transplant recipients with a positive crossmatch against their living donor. The incidence of biopsy-proven AMR in the first 3 months postTransplant in 26 highly sensitized recipients of living donor renal Transplants who received eculizumab postTransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange (PE)-based protocol without eculizumab. The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group (p = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after Transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with PE reducing the need for splenectomy. On 1-year protocol biopsy, Transplant Glomerulopathy was found to be present in 6.7% (1/15) eculizumab-treated recipients and in 35.7% (15/42) of control patients (p = 0.044). Inhibition of terminal complement activation with eculizumab decreases the incidence of early AMR in sensitized renal Transplant recipients (ClincalTrials.gov number NCT006707).
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baseline donor specific antibody levels and outcomes in positive crossmatch kidney Transplantation
American Journal of Transplantation, 2010Co-Authors: James M Gloor, Lynn D Cornell, Fernando G Cosio, Manish J Gandhi, Walter K Kremers, Jeffrey L Winters, Lynette Fix, Steven R Degoey, R M Knauer, Mark D StegallAbstract:Renal Transplant candidates with donor-specific alloantibody (DSA) have increased risk of antibody-mediated allograft injury. The goal of this study was to correlate the risk of antibody-mediated rejection (AMR), Transplant Glomerulopathy (TG) and graft survival with the baseline DSA level (prior to initiation of preTransplant conditioning). These analyses include 119 positive crossmatch (+XM) compared to 70 negative crossmatch (-XM) Transplants performed between April 2000 and July 2007. Using a combination of cell-based crossmatch tests, DSA level was stratified into very high +XM, high +XM, low +XM and -XM groups. In +XM Transplants, increasing DSA level was associated with increased risk for AMR (HR = 1.76 [1.51, 2.07], p = 0.0001) but not TG (p = 0.18). We found an increased risk for both early and late allograft loss associated with very high DSA (HR = 7.71 [2.95, 20.1], p = 0.0001). Although lower DSA recipients commonly developed AMR and TG, allograft survival was similar to that of -XM patients (p = 0.31). We conclude that the baseline DSA level correlates with risk of early and late alloantibody-mediated allograft injury. With current protocols, very high baseline DSA patients have high rates of AMR and poor long-term allograft survival highlighting the need for improved therapy for these candidates.
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identifying specific causes of kidney allograft loss
American Journal of Transplantation, 2009Co-Authors: Ziad M Elzoghby, James M Gloor, Mark D Stegall, Walter K Kremers, Donna J Lager, Hatem Amer, Fernando G CosioAbstract:The causes of kidney allograft loss remain unclear. Herein we investigated these causes in 1317 conventional kidney recipients. The cause of graft loss was determined by reviewing clinical and histologic information the latter available in 98% of cases. During 50.3 ± 32.6 months of follow-up, 330 grafts were lost (25.0%), 138 (10.4%) due to death with function, 39 (2.9%) due to primary nonfunction and 153 (11.6%) due to graft failure censored for death. The latter group was subdivided by cause into: glomerular diseases (n = 56, 36.6%); fibrosis/atrophy (n = 47, 30.7%); medical/surgical conditions (n = 25, 16.3%); acute rejection (n = 18, 11.8%); and unclassifiable (n = 7, 4.6%). Glomerular pathologies leading to failure included recurrent disease (n = 23), Transplant Glomerulopathy (n = 23) and presumed nonrecurrent disease (n = 10). In cases with fibrosis/atrophy a specific cause(s) was identified in 81% and it was rarely attributable to calcineurin inhibitor (CNI) toxicity alone (n = 1, 0.7%). Contrary to current concepts, most cases of kidney graft loss have an identifiable cause that is not idiopathic fibrosis/atrophy or CNI toxicity. Glomerular pathologies cause the largest proportion of graft loss and alloinmunity remains the most common mechanism leading to failure. This study identifies targets for investigation and intervention that may result in improved kidney Transplantation outcomes.
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Transplant Glomerulopathy risk and prognosis related to anti human leukocyte antigen class ii antibody levels
Transplantation, 2008Co-Authors: Naim Issa, Fernando G Cosio, James M Gloor, Sanjeev Sethi, Patrick G Dean, Breanndan S Moore, Steve Degoey, Mark D StegallAbstract:Background. Transplant Glomerulopathy (TG) is a histopathologic entity of kidney allografts related to anti-human leukocyte antigen (HLA) antibodies. The goal of this study was to determine the relationships among antibody characteristics (level and specificity), risk for TG, and graft survival. Methods. The presence and characteristics of anti-HLA antibody were assessed by single antigen beads assays in stored preTransplant sera from 598 kidney recipients with negative T-cell crossmatch. Transplant Glomerulopathy was diagnosed by surveillance and clinical biopsies. Results. Thirty-nine percent of patients presented with anti-HLA antibodies preTransplant. Transplant Glomerulopathy was diagnosed in 73 patients (12%) during 54±19 months of follow-up. The risk of TG increased with higher anti-HLA-II antibody levels (HR= 1.890, 95% CI 1.42-2.52; P<0.0001), donor specificity of the antibodies (3.524 [1.67-7.44]; P=0.001), and in patients with history of antibody-mediated rejection (4.985 [2.77-8.97]; P<0.0001, multivariate Cox). Graft survival during the follow-up period was 95% without TG and 62% with TG (P<0.0001). The presence of C4d in peritubular capillaries was an independent risk factor for graft failure after TG diagnosis. Thus, 25% of TG/C4d - and 80% of TG/C4d + grafts failed (P<0.0001). Of interest, higher anti-HLA-II levels were related to the presence of C4d (3.216 [1.376-7.517]; P=0.007). Conclusions. In T-cell negative crossmatch patients, higher anti-HLA-II antibody levels are related to the increase in the risk of developing TG. Higher antibody levels are also related to the presence of C4d in peritubular capillaries in TG biopsies. Furthermore, the presence of C4d in TG is related to the reduced graft survival.
Béla Iványi - One of the best experts on this subject based on the ideXlab platform.
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peritubular capillary basement membrane multilayering in early and advanced Transplant Glomerulopathy quantitative parameters and diagnostic aspects
Virchows Archiv, 2016Co-Authors: Dejan Dobi, Edit Szederkenyi, Pal Szenohradszky, Zsolt Bodo, Laszlo Bidiga, Zoltan Hodi, Aniko Szilvasi, E. Kemény, Béla IványiAbstract:The ultrastructural quantitative aspects of peritubular capillary basement membrane multilayering (PTCBML) were examined in 57 kidney Transplant biopsies with Transplant Glomerulopathy (TG). The measurements included three cutoffs [permissive: 1 PTC with 5 basement membrane (BM) layers, intermediate: 3 PTCs with 5 layers or 1 PTC with 7 layers, strict: 1 PTC with 7 layers and 2 PTCs with 5 layers] and the mean number of BM layers (PTCcirc). Two groups were assigned, namely patients with mild TG (Banff cg1a and cg1b) and those with moderate-to-severe TG (cg2 and cg3). Their respective clinical, serological, and morphological characteristics were then compared. The clinical data revealed that mild TG corresponded to early chronic antibody-mediated rejection (cABMR), while moderate-to-severe TG corresponded to the advanced stage of the disease. The permissive threshold displayed the lowest specificity (73 %) and the highest sensitivity (83 %) for moderate-to-severe TG, and its corresponding PTCcirc value was 3 layers. In contrast, the strict threshold—adopted by the Banff 2013 classification—displayed a specificity and sensitivity of 93 and 52 %, respectively, and the corresponding PTCcirc was 4 layers. In mild TG, 26 % of the cases met the permissive cutoff and 6 % the strict cutoff. Mild TG was associated with a lower PTCcirc (2.6 layers vs 4.5 layers in moderate-to-severe TG; p < 0.0001). Amongst the various criteria, the permissive criterion was associated most frequently with mild TG, and had prognostic relevance. Because of this, we propose its usage as a marker of early cABMR-induced PTCBML if non-alloimmune causes of PTCBML can be ruled out.
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better understanding of Transplant Glomerulopathy secondary to chronic antibody mediated rejection
Nephrology Dialysis Transplantation, 2015Co-Authors: Adam Remport, Béla Iványi, Kathryn Tinckam, Zoltan Mathe, Istvan Mucsi, Miklos Z. MolnarAbstract:Abstract Transplant Glomerulopathy (TG) is generally accepted to result from repeated episodes of endothelial activation, injury and repair, leading to pathological abnormalities of double contouring or multi-layering of the glomerular basement membrane. TG is a major sequel of chronic active antibody-mediated rejection (cABMR), from pre-existing or de novo anti-HLA antibodies. Hepatitis C infection, thrombotic microangiopathy or other factors may also contribute to TG development. TG prevalence is 5-20% in most series, reaching 55%, in some high-risk cohorts, and is associated with worse allograft outcomes. Despite its prevalence and clinical significance, few well-studied treatment options have been proposed. Similar to desensitization protocols, plasmapheresis with or without immunoabsorption, high-dose intravenous immunoglobulin, rituximab, bortezomib and eculizumab have been proposed in the treatment of TG due to cABMR individually or in various combinations. Robust clinical trials are urgently needed to address this major cause of allograft loss. This review summarizes the current knowledge of the epidemiology, etiology, pathology, and the preventive and treatment options for TG secondary to cABMR.
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peritubular capillary damage in acute humoral rejection an ultrastructural study on human renal allografts
American Journal of Transplantation, 2005Co-Authors: Peter Liptak, Edit Szederkenyi, Pal Szenohradszky, F Marofka, E. Kemény, Zita Morvay, József Toldi, Markus Exner, Béla IványiAbstract:The ultrastructural features of peritubular capillary (PC) damage was studied in 12 kidney allografts with acute humoral rejection (AHR). AHR manifested in diffuse linear PC staining for C4d, and histology consistent with Banff grade III in 7 recipients and Banff grade II in 5. Allografts with acute tubular necrosis served as controls. First biopsies (post-Transplantation day 16.2 ± 2.2): The intra-capillary exudate comprised monocytes (59%), polymorphonuclears (14%), lymphocytes (12%) and not otherwise specified mononuclears (15%). Three patterns of focal PC endothelial injury were observed: lysis, an increased rate of apoptosis and fragmentation. No correlation was found between the respective damage types and the inflammatory cell types or the Banff grades. Controls revealed endothelial swelling, detachment from basement membrane and fragmentation. Follow-up biopsies: Monocytes transformed into macrophages intra-luminally. The reparative changes comprised endothelial cytoplasmic protrusions, binucleated endothelial cells and capillary sprouts. Early Transplant capillaropathy and Transplant Glomerulopathy were noted in 2 recipients. Literature data indicate that lysis is mediated by anti-HLA alloantibodies; apoptosis, demonstrated first in the present study, may be induced by non-HLA-type anti-endothelial antibodies. Fragmentation is caused by ischemia. Ongoing endothelial injury leads to Transplant capillaropathy and Transplant Glomerulopathy, the characteristic lesions of chronic rejection.
Robert B Colvin - One of the best experts on this subject based on the ideXlab platform.
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overlapping pathways to Transplant Glomerulopathy chronic humoral rejection hepatitis c infection and thrombotic microangiopathy
Kidney International, 2011Co-Authors: Seema Baidagrawal, Shamila Mauiyyedi, Bernard A Collins, Manuel Pascual, Nina Tolkoffrubin, Alton B Farris, Mary Lin Farrell, Ulrich Frei, Robert B ColvinAbstract: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.
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four stages and lack of stable accommodation in chronic alloantibody mediated renal allograft rejection in cynomolgus monkeys
American Journal of Transplantation, 2008Co-Authors: R N Smith, Tatsuo Kawai, S Boskovic, O Nadazdin, David H Sachs, A B Cosimi, Robert B ColvinAbstract:The etiology of immunologically mediated chronic renal allograft failure is unclear. One cause is thought to be alloantibodies. Previously in Cynomolgus monkeys, we observed a relationship among donor-specific alloantibodies (DSA), C4d staining, allograft Glomerulopathy, allograft arteriopathy and progressive renal failure. To define the natural history of chronic antibody-mediated rejection and its effect on renal allograft survival, we now extend this report to include 417 specimens from 143 Cynomolgus monkeys with renal allografts. A subset of animals with long-term renal allografts made DSA (48%), were C4d positive (29%), developed Transplant Glomerulopathy (TG) (22%) and chronic allograft arteriopathy (CAA) (19%). These four features were highly correlated and associated with statistically significant shortened allograft survival. Acute cellular rejection, either Banff type 1 or 2, did not correlate with alloantibodies, C4d deposition or TG. However, endarteritis (Banff type 2) correlated with later CAA. Sequential analysis identified four progressive stages of chronic antibody-mediated rejection: (1) DSA, (2) deposition of C4d, (3) TG and (4) rising creatinine/renal failure. These new findings provide strong evidence that chronic antibody-mediated rejection develops without enduring stable accommodation, progresses through four defined clinical pathological stages and shortens renal allograft survival.
