Risk factors, histopathological features, and graft outcome of transplant glomerulopathy in the absence of donor-specific HLA antibodies

Abstract

Transplant glomerulopathy is established as a hallmark of chronic antibody-mediated rejection in kidney transplant patients with donor-specific HLA antibodies (HLA-DSA). The clinical importance of transplant glomerulopathy in the absence of HLA-DSA is not well established. To help define this, 954 patients (encompassing 3744 biopsies) who underwent kidney transplantation 2004-2013 were studied with retrospective high-resolution HLA genotyping of both donors and recipients. The risk factors, histopathological appearance and prognosis of cases with transplant glomerulopathy in the absence of HLA-DSA were compared to those cases with HLA-DSA, and the impact of the PIRCHE-II score and eplet mismatches on development of transplant glomerulopathy evaluated. In this cohort, 10.3% developed transplant glomerulopathy, on average 3.2 years post-transplant. At the time of glomerulopathy, 23.5% had persistent pre-transplant or de novo HLA-DSA, while 76.5% were HLA-DSA negative. Only HLA-DSA was identified as a risk factor for glomerulopathy development as eplet mismatches and the PIRCHE-II score did not associate. HLA-DSA negative biopsies with glomerulopathy had less interstitial inflammation, less glomerulitis, and less C4d deposition in the peritubular capillaries compared to the HLA-DSA positive biopsies with glomerulopathy. While graft function was comparable between the two groups, HLA-DSA positive glomerulopathy was associated with a significantly higher risk of graft failure compared to HLA-DSA negative glomerulopathy (Hazard Ratio 3.84; 95% confidence interval 1.94-7.59). Landmark analysis three-years post-transplant showed that HLA-DSA negative patients with glomerulopathy still had a significant increased risk of graft failure compared to patients negative for glomerulopathy (2.62; 1.46-4.72). Thus, transplant glomerulopathy often occurs in the absence of HLA-DSA, independent of HLA molecular mismatches, and represents a different phenotype with less concomitant inflammation and better graft survival compared to that developed in the presence of HLA-DSA. Transplant glomerulopathy is established as a hallmark of chronic antibody-mediated rejection in kidney transplant patients with donor-specific HLA antibodies (HLA-DSA). The clinical importance of transplant glomerulopathy in the absence of HLA-DSA is not well established. To help define this, 954 patients (encompassing 3744 biopsies) who underwent kidney transplantation 2004-2013 were studied with retrospective high-resolution HLA genotyping of both donors and recipients. The risk factors, histopathological appearance and prognosis of cases with transplant glomerulopathy in the absence of HLA-DSA were compared to those cases with HLA-DSA, and the impact of the PIRCHE-II score and eplet mismatches on development of transplant glomerulopathy evaluated. In this cohort, 10.3% developed transplant glomerulopathy, on average 3.2 years post-transplant. At the time of glomerulopathy, 23.5% had persistent pre-transplant or de novo HLA-DSA, while 76.5% were HLA-DSA negative. Only HLA-DSA was identified as a risk factor for glomerulopathy development as eplet mismatches and the PIRCHE-II score did not associate. HLA-DSA negative biopsies with glomerulopathy had less interstitial inflammation, less glomerulitis, and less C4d deposition in the peritubular capillaries compared to the HLA-DSA positive biopsies with glomerulopathy. While graft function was comparable between the two groups, HLA-DSA positive glomerulopathy was associated with a significantly higher risk of graft failure compared to HLA-DSA negative glomerulopathy (Hazard Ratio 3.84; 95% confidence interval 1.94-7.59). Landmark analysis three-years post-transplant showed that HLA-DSA negative patients with glomerulopathy still had a significant increased risk of graft failure compared to patients negative for glomerulopathy (2.62; 1.46-4.72). Thus, transplant glomerulopathy often occurs in the absence of HLA-DSA, independent of HLA molecular mismatches, and represents a different phenotype with less concomitant inflammation and better graft survival compared to that developed in the presence of HLA-DSA. Transplant glomerulopathy (TG), duplication or multilayering of the glomerular basement membrane, is considered to represent the morphologic reflection of chronic or repetitive injury to the glomerular endothelium of renal allografts.1Van Loon E. Lerut E. Naesens M. The time dependency of renal allograft histology.Transpl Int. 2017; 30: 1081-1091Crossref PubMed Scopus (11) Google Scholar,2Filippone E.J. McCue P.A. Farber J.L. Transplant glomerulopathy.Mod Pathol. 2018; 31: 235-252Crossref PubMed Scopus (19) Google Scholar While its pathogenesis is essentially unclear, and the clinical presentation is heterogeneous, the diagnosis of TG is associated with kidney graft functional deterioration and shortened allograft survival.3Naesens M. Kuypers D.R.J. De Vusser K. et al.Chronic histological damage in early indication biopsies is an independent risk factor for late renal allograft failure.Am J Transplant. 2013; 13: 86-99Crossref PubMed Scopus (46) Google Scholar, 4Baid-Agrawal S. Farris A.B. Pascual M. et al.Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy.Kidney Int. 2011; 80: 879-885Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 5Naesens M. Lerut E. Emonds M. et al.Proteinuria as a noninvasive marker for renal allograft histology and failure: an observational cohort study.J Am Soc Nephrol. 2016; 27: 281-292Crossref PubMed Scopus (42) Google Scholar To date, no effective therapeutic approaches have been able to reverse the poor outcomes of kidney transplants with TG.6Patri P. Seshan S.V. Matignon M. et al.Development and validation of a prognostic index for allograft outcome in kidney recipients with transplant glomerulopathy.Kidney Int. 2016; 89: 450-458Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar Therefore, there is an unmet need to better understand the causes and effector mechanisms of the different phenotypes of TG that can lead to the development of new therapeutics for TG and subsequently to improved kidney graft outcome. Improvements in HLA antibody detection methods have allowed the investigation of the role of donor-specific human leukocyte antigen antibodies (HLA-DSA) in antibody-mediated graft injury in great detail. This led to the well-evidenced paradigm that circulating HLA-DSA play a role in the pathogenesis of TG.7Hanf W. Bonder C.S. Coates P.T.H. Transplant glomerulopathy: the interaction of HLA antibodies and endothelium.J Immunol Res. 2014; 2014: 549315Crossref PubMed Scopus (17) Google Scholar, 8Cosio F.G. Gloor J.M. Sethi S. Stegall M.D. Transplant glomerulopathy.Am J Transplant. 2008; 8: 492-496Crossref PubMed Scopus (188) Google Scholar, 9Willicombe M. Brookes P. Sergeant R. et al.De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy.Transplantation. 2012; 94: 172-177Crossref PubMed Scopus (166) Google Scholar, 10Issa N. Cosio F.G. Gloor J.M. et al.Transplant glomerulopathy: risk and prognosis related to anti-human leukocyte antigen class II antibody levels.Transplantation. 2008; 86: 681-685Crossref PubMed Scopus (156) Google Scholar Now, TG is classified as one of the final pathways of chronic allograft damage driven by HLA-DSA and has been incorporated into the Banff consensus criteria for the diagnosis of chronic active antibody-mediated rejection (caABMR).11Loupy A. Haas M. Roufosse C. et al.The Banff 2019 Kidney Meeting Report (I): updates on and clarification of criteria for T cell– and antibody-mediated rejection.Am J Transplant. 2020; 20: 2318-2331Crossref PubMed Scopus (90) Google Scholar For biopsies showing TG in the absence of evidence of current or recent antibody interaction with the endothelium but with a prior diagnosis of active or or prior evidence of HLA-DSA, the chronic is A. Haas M. Roufosse C. et al.The Banff 2019 Kidney Meeting Report (I): updates on and clarification of criteria for T cell– and antibody-mediated rejection.Am J Transplant. 2020; 20: 2318-2331Crossref PubMed Scopus (90) Google Scholar there in and of and cases with TG in absence of HLA-DSA are comparable to cases with TG and patients TG is not for or and can in the glomerular J.M. Sethi S. Stegall M.D. et al.Transplant glomerulopathy: and with J Transplant. PubMed Scopus Google E. R. S. et al.Transplant glomerulopathy in the absence of donor-specific antibody and C4d J Am Soc Nephrol. PubMed Scopus Google Scholar have of and an TG and hepatitis C infection, and chronic thrombotic S. Farris A.B. Pascual M. et al.Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy.Kidney Int. 2011; 80: 879-885Abstract Full Text Full Text PDF PubMed Scopus (106) Google A. et of transplant glomerulopathy to chronic antibody-mediated Transplant. 30: PubMed Scopus Google M. Transplant glomerulopathy: not chronic Int. 2011; 80: Full Text Full Text PDF PubMed Scopus (17) Google Scholar The risk and clinical of patients with TG In this recent have that the of HLA eplet mismatches is associated with the of development TG and graft in the absence of R. A. et as by eplet mismatches risk of kidney transplant Int. 2020; Full Text Full Text PDF PubMed Scopus Google R. K. K. et and eplet mismatches and transplant glomerulopathy: a J Transplant. PubMed Scopus Google Scholar that HLA in with an increased risk of TG the of is by the of on de novo HLA-DSA and by the of and HLA A. Emonds et importance of high-resolution HLA genotyping for kidney J Transplant. 2020; 20: PubMed Scopus (22) Google Scholar The of HLA molecular mismatches on the development of transplant glomerulopathy, in the absence of HLA-DSA, Therefore, the risk factors, and impact of TG in a high-resolution HLA cohort and HLA antibody with on the of TG in the absence of HLA-DSA, as this represents an clinical kidney the between and were for this were and and with negative clinical were clinical and in This retrospective was by the of the and recipients and donors of this cohort with were the high-resolution for HLA and of the donors were the HLA on the The of the donors and recipients were high-resolution the of HLA and for HLA class and and for HLA class A. M. Lerut E. et and de novo of donor-specific rejection, and graft failure kidney an observational cohort study.J Am Soc Nephrol. 2020; 31: PubMed Scopus Google Scholar the and HLA to HLA molecular M. et on the antibody of and in the HLA 2014; PubMed Scopus Google N. M. P. et on HLA the of de novo donor-specific HLA antibodies renal J Transplant. 2017; PubMed Scopus Google Scholar The high-resolution HLA for were to and this, the eplet mismatches and PIRCHE-II The and post-transplant antibodies were a and or the time of an indication In a of positive HLA antibodies were identified by antibodies in the were for and presence of HLA-DSA was for the final of HLA-DSA, as in A. Emonds et importance of high-resolution HLA genotyping for kidney J Transplant. 2020; 20: PubMed Scopus (22) Google Scholar the of the patients was At the time of an allograft HLA-DSA was by the persistent presence of the HLA-DSA or of de novo HLA-DSA. post-transplant renal allograft biopsies in this cohort kidney transplant biopsies were the time of transplantation and and In patients who transplants were for a and patients between and for a and and patients between and for a of the biopsies was in A. M. Lerut E. et of antibody-mediated rejection donor-specific clinical presentation and for J Transplant. PubMed Scopus Google Scholar The of the chronic allograft glomerulopathy was to the Banff as and on C. N. M. et to the Banff of renal allograft 2018; PubMed Scopus Google Scholar The diagnosis of the phenotypes of rejection and was established to Banff 2019 consensus and on the Banff A. Haas M. Roufosse C. et al.The Banff 2019 Kidney Meeting Report (I): updates on and clarification of criteria for T cell– and antibody-mediated rejection.Am J Transplant. 2020; 20: 2318-2331Crossref PubMed Scopus (90) Google Scholar were not in the inflammation was as the score of and peritubular In this TG was as a Banff score the of chronic thrombotic and or de novo or of or with C4d the biopsies with TG were classified as in the presence of HLA-DSA and as histology of in the absence of HLA-DSA. in the absence of and C4d TG biopsies were classified as in the presence of HLA-DSA and as histology of in the absence of HLA-DSA. The different TG were were to the TG and Kidney S. et analysis in renal transplant recipients with transplant glomerulopathy associated with allograft Am Soc Nephrol. 30: PubMed Scopus Google Scholar groups, was for the for the and the for the of failure was as a to or In of with a graft survival the time of who did not graft failure and who were still in clinical time of were on were the and were compared by and were to the of transplant for TG or kidney allograft TG was as in survival the was considered as the of were and years post-transplant. were considered to and for the The cohort 954 kidney transplant recipients with allograft The time post-transplant of this cohort was years identified cases with with a Banff score on TG was in of 954 patients to the Banff 2019 on average years A. Haas M. Roufosse C. et al.The Banff 2019 Kidney Meeting Report (I): updates on and clarification of criteria for T cell– and antibody-mediated rejection.Am J Transplant. 2020; 20: 2318-2331Crossref PubMed Scopus (90) Google Scholar patients had with chronic thrombotic or and were not as TG in this C. N. M. et to the Banff of renal allograft 2018; PubMed Scopus Google Scholar The patients did not have TG on in of biopsies the The of TG in this cohort of 954 kidney transplant recipients and years transplantation was and In the kidney and HLA-DSA were associated with an increased risk of TG development no significant between HLA antigen mismatches, eplet mismatches, and PIRCHE-II score with the development of In a significant of the HLA-DSA as an independent risk factor for TG 95% confidence interval and of the between and the development of of patients of glomerular kidney index of time antibodies antibodies HLA-DSA antigen antigen HLA eplet mismatches of transplant were this analysis to the of HLA for HLA class eplet class II eplet eplet eplet eplet score of transplant were this analysis to the of HLA for HLA score for HLA class score for HLA class II score for score for score for HLA-DSA kidney of time confidence donor-specific human leukocyte HLA-DSA, donor-specific HLA HLA transplant in this analysis were the of the significant are in of transplant were this analysis to the of HLA for HLA in a new confidence donor-specific human leukocyte HLA-DSA, donor-specific HLA HLA transplant in this analysis were the of the significant are in The of TG years transplantation was significantly higher in the patients with HLA-DSA compared with patients who are of the patients with had HLA-DSA the time of TG class II of and were as the TG phenotype was the in the absence in the presence of HLA-DSA, the of TG in patients who are the time of de novo HLA-DSA In this 95% and 95% associated with the development of TG in the absence of HLA-DSA. 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95% with de novo HLA-DSA 95% and persistent HLA-DSA 95% the TG had significantly graft survival compared with that of the patients who were were no patients who developed de novo HLA-DSA that were the time of the TG patients who HLA-DSA and the time of diagnosis of TG had graft survival and risk of graft failure 95% as the patients with TG who had HLA-DSA and for graft failure for the with of patients of eplet mismatches HLA class eplet HLA class II eplet eplet eplet II score II score for class II II score for II score for II score for in chronic on TG prior to TG prior to or on TG or prior to or on TG score on indication TG TG and C4d C4d prior to and on TG C4d prior to or on TG HLA-DSA the time of TG HLA-DSA TG De novo 2019 phenotypes analysis of TG De novo analysis TG analysis chronic TG analysis 2019 chronic 2019 phenotypes analysis TG histology of antibody-mediated rejection of the Banff chronic active antibody-mediated rejection to the Banff histology of chronic active antibody-mediated rejection of the Banff chronic antibody-mediated rejection to the Banff histology of chronic antibody-mediated rejection of the Banff deposition in chronic allograft interstitial confidence glomerular human leukocyte HLA-DSA, donor-specific HLA interstitial and HLA peritubular transplant significant are in The were for the time transplantation the TG of the and in a new histology of antibody-mediated rejection of the Banff chronic active antibody-mediated rejection to the Banff histology of chronic active antibody-mediated rejection of the Banff chronic antibody-mediated rejection to the Banff histology of chronic antibody-mediated rejection of the Banff deposition in chronic allograft interstitial confidence glomerular human leukocyte HLA-DSA, donor-specific HLA interstitial and HLA peritubular transplant significant are in The were for the time transplantation the TG of the and analysis of patients to the HLA-DSA and Banff 2019 phenotypes of that the HLA-DSA the time of TG graft survival cases had graft survival as 95% and 95% while patients HLA-DSA but with the Banff criteria for had graft outcome as the biopsies with TG in the absence of active 95% the patients with TG were to TG S. et analysis in renal transplant recipients with transplant glomerulopathy associated with allograft Am Soc Nephrol. 30: PubMed Scopus Google Scholar increased risk of graft failure was for and compared with with graft failure TG diagnosis were for interstitial inflammation, interstitial chronic indication glomerular the time the TG HLA-DSA, and TG mismatches 95% or PIRCHE-II 95% did not with graft failure TG compared with patients of rejection, patients who had with did not have an increased risk of graft failure 95% In the for the time transplantation the TG of the and with and significant the analysis In 95% 95% and HLA-DSA the TG 95% were associated with kidney graft In the with the different of HLA-DSA, the for graft failure was for de novo HLA-DSA 95% by the risk associated with persistent HLA-DSA 95% with HLA-DSA that transplantation had a risk of graft failure patients who were did 95% In an independent for graft failure was the presence of interstitial 95% In the with the independent of graft failure were the 95% and chronic 95% the Banff 2019 phenotypes into associated with graft failure 95% In with the of TG the 95% was associated with graft failure the TG the to the patients with TG HLA-DSA and the of graft failure In the the chronic score 95% 95% and 95% were associated with graft failure TG is in the absence of HLA-DSA. the between TG and graft in to patients TG and to HLA-DSA in a survival analysis years who graft failure the years transplantation or who were to years post-transplant were this with the patients TG developed the years transplantation graft survival was the post-transplant not in the presence 95% but in the absence of HLA-DSA 95% In this cohort with high-resolution HLA genotyping and antibody that TG in the absence of HLA-DSA is and represents a phenotype with better outcome TG developed in the presence of HLA-DSA. TG with less inflammation, there was still an with increased risk of graft failure compared with patients not that HLA molecular mismatches, as eplet mismatches or PIRCHE-II are associated with the risk of the not lead to HLA-DSA, was the independent of TG to that was the risk factor that was associated with TG in the absence of HLA-DSA. outcome TG diagnosis was driven by the of concomitant inflammation, of the HLA-DSA, and graft The of this is the of high-resolution HLA genotyping and of the antibodies by for the cohort, allowed to the presence of HLA-DSA time of this the between HLA-DSA and an increased risk of the of patients who were to the of TG in the absence in the presence of HLA-DSA The of TG cases in HLA-DSA have not been identified is in the but has not been to et al.Transplant glomerulopathy, late antibody-mediated rejection and the in kidney allograft biopsies for J Transplant. PubMed Scopus Google S. et analysis in renal transplant recipients with transplant glomerulopathy associated with allograft Am Soc Nephrol. 30: PubMed Scopus Google Scholar This development of TG in the and of with HLA molecular mismatches that mechanisms of chronic glomerular damage transplantation the cases of hepatitis C infection, and chronic thrombotic The with is in this this that this of glomerular damage in absence of HLA-DSA is the of an In an to the of that an between HLA molecular mismatches and the risk of R. A. et as by eplet mismatches risk of kidney transplant Int. 2020; Full Text Full Text PDF PubMed Scopus Google R. K. K. et and eplet mismatches and transplant glomerulopathy: a J Transplant. PubMed Scopus Google Scholar not between eplet mismatches or PIRCHE-II with the risk of TG development and graft high-resolution HLA genotyping by the absence of de novo HLA-DSA in the and of high-resolution HLA with and to represents a risk of HLA-DSA and risk of for At the time of of cases had less rejection and of glomerulitis, peritubular and interstitial inflammation cases This less and of glomerular injury in the absence of HLA-DSA. that TG is associated with better outcome in the absence compared with in the presence of HLA-DSA the that need to both This is in to a retrospective on indication biopsies that a outcome in both et antibody-mediated rejection with or donor-specific antibodies has and clinical retrospective Int. 2018; 31: PubMed Scopus (17) Google Scholar This by the of biopsies in cohort, and detection of TG cases and of high-resolution HLA genotyping the risk of HLA-DSA in cohort, an for the A. Emonds et importance of high-resolution HLA genotyping for kidney J Transplant. 2020; 20: PubMed Scopus (22) Google Scholar has been that the of TG is higher in recipients with HLA-DSA, HLA class N. Cosio F.G. Gloor J.M. et al.Transplant glomerulopathy: risk and prognosis related to anti-human leukocyte antigen class II antibody levels.Transplantation. 2008; 86: 681-685Crossref PubMed Scopus (156) Google Scholar In current and Only HLA-DSA was there a increased risk of TG and graft In patients with TG and de novo HLA-DSA were the risk of graft The with outcomes in patients who were with TG the Banff criteria of the phenotype is for the of graft survival with the HLA-DSA to to the of the injury or the presence of that not the Banff for M. Transplant glomerulopathy: the the of the basement Am Soc Nephrol. PubMed Scopus Google Scholar Therefore, in the absence of the phenotype on the current the of HLA-DSA with outcome in patients with TG that patients still HLA-DSA that can the injury by HLA-DSA. the in the patients with TG in the absence of HLA-DSA, of or was not associated with graft This that in in patients with TG but HLA-DSA, who have prognosis did not an independent with the outcome of the different TG in S. et analysis in renal transplant recipients with transplant glomerulopathy associated with allograft Am Soc Nephrol. 30: PubMed Scopus Google Scholar In this et S. et analysis in renal transplant recipients with transplant glomerulopathy associated with allograft Am Soc Nephrol. 30: PubMed Scopus Google Scholar an analysis to risk and the the patients with on and outcome identified of patients with in HLA-DSA the time of a TG and graft function were for graft outcome the different TG well that with higher of are to have to between the different TG are to this TG diagnosis was on and not have for cases with M.D. M. et al.Transplant glomerulopathy: early in analysis of J Transplant. PubMed Scopus Google Scholar the of patients with TG and the absence of biopsies years transplantation is for TG as a chronic there is no consensus on antibodies are is the absence of on associated with as R. A. A. et of between and to kidney allograft analysis in a Full Text Full Text PDF PubMed Scopus Google R. A. A. et to in transplant Am Soc Nephrol. 2011; PubMed Scopus Google Scholar not the importance of hepatitis C for the development of TG as the of patients was S. Farris A.B. Pascual M. et al.Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy.Kidney Int. 2011; 80: 879-885Abstract Full Text Full Text PDF PubMed Scopus (106) Google J.M. Sethi S. Stegall M.D. et al.Transplant glomerulopathy: and with J Transplant. PubMed Scopus Google Scholar the C4d of and the presence of HLA-DSA of that transplantation the significantly better survival in the patients who were of the with TG in to those in the that phenotypes are the current or C4d in of patients did not independent factor of TG development in the absence of HLA-DSA in of patients Therefore, play a role in the development of The of high-resolution HLA and for antibody detection have the of or circulating HLA-DSA in the of the the time of TG increased risk of graft failure that the cases with outcome were the for this are to the or approaches for TG in the absence of HLA-DSA. that TG in the absence of HLA-DSA represents a clinical with less concomitant inflammation in the presence of HLA-DSA, and this with graft in the absence of HLA-DSA, TG an independent risk factor for graft with persistent HLA-DSA, class and TG considered for HLA-DSA as patients had graft survival in absence of current evidence for are to the of antibodies or in the development of the TG in the absence of HLA-DSA. the no This is by the and the and with a is clinical of the and is by a the and and the and were in the and the and and the and and with

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