HLA-DR and -DQ Eplet Mismatches and Transplant Glomerulopathy: A Nested Case–Control Study

Abstract

We conducted a nested case-control study from a cohort of adult kidney transplant recipients to assess the risk of transplant glomerulopathy (TG) as a function of donor and recipient HLA-DR and -DQ incompatibility at the eplet level. Cases (n ¼ 52) were defined as patients diagnosed with transplant glomerulopathy based on biopsies showing glomerular basement membrane duplication without immune complex deposition. Controls (n ¼ 104) with a similar follow-up from transplantation were randomly selected from the remaining cohort. HLAMatchmaker was used to ascertain the number of DRB1/3/4/5, DQA1 and DQB1 related eplet mismatches (eplet load). Multivariable conditional logistic regression models demonstrated an increase in the odds of TG (odds ratios [OR] of 2.84 [95% confidence interval (CI): 1.03, 7.84] and 4.62 [95% CI: 1.51, 14.14]) in the presence of 27-43 and >43 HLA-DR þ DQ related eplet mismatches versus <27 eplet mismatches, respectively. When the eplet load was modeled as a continuous variable, the OR for TG was 1.25 (95% CI: 1.04, 1.50) for every 10 additional HLA-DR þ DQ eplet mismatches. Our study suggests that minimization of HLA-DR þ DQ eplet mismatches may decrease the incidence of transplant glomerulopathy diagnosed by indication biopsies. The role of eplet immunogenicity/antigenicity as determinants of allograft outcomes requires further study.

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

“…Interestingly, the occurrence of clinical rejection episodes was identified as an independent predictor of dn DSA development (odds ratio, 2.6 per rejection episode, P < 0.001). In a separate study of 1753 kidney transplant recipients followed for 3.97 ± 2.71 years, Sapir-Pichhadze et al 17 showed an association between class II HLA eplet mismatches and the development of transplant glomerulopathy. 17 Compared to less than 27 class II (HLA-DR + DQ) eplet mismatches, 27 to 43 eplet mismatches were associated with a greater than twofold risk of transplant glomerulopathy (odds ratio, 2.84; P = 0.043).…”

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

“…Although HLA-DQ and -DR may be closely related at an antigen level, it has been shown that small differences in one or more epitopes between donors and recipients at either locus are sufficient to generate a humoral and/or T cell-mediated immune response (18,19). In a nested casecontrol study of a cohort of 52 kidney transplant recipients with established transplant glomerulopathy, an increasing number of HLA-DQ and HLA-DR eplet mismatches was associated with an increased risk of developing transplant glomerulopathy, suggesting that epitope mismatches at either HLA-DQ or HLA-DR locus are equally important in predicting graft outcomes (5). Future studies evaluating both broad antigen and epitope HLA-DQ mismatches are crucial in establishing a better understanding of the association between HLA-DQ mismatches and clinical outcomes.…”

“…Although differences in HLA-DQ matching between donors and recipients have been shown to be associated with adverse graft outcomes, matching at the HLA-DQ locus is not explicitly considered in the allocation algorithm for deceased donor kidney transplantation (4,5). There is a general consensus suggesting that HLA-DQ mismatches are unlikely to have a major effect on graft survival, because serologic compatibility for HLA-DR usually ensures a corresponding compatibility for HLA-DQ (6)(7)(8).…”

Re-Examining Risk of Repeated HLA Mismatch in Kidney Transplantation

“…We hypothesized that, in the context of therapeutic and diagnostic advances, the effect of RMM on graft loss would be attenuated compared with historical cohorts. We further hypothesized that the effect of RMM may be greater for class 2 RMM (given increasing evidence of the deleterious effect of class 2 mismatch on transplant outcomes) [9][10][11] and modified by predefined panel-reactive antibody (PRA), immunosuppression, and nephrectomy of the first transplant. Exploratory analyses for interactions between RMM and these covariates were also performed.…”