Eplet Mismatch Load and De Novo Occurrence of Donor-Specific Anti-HLA Antibodies, Rejection, and Graft Failure after Kidney Transplantation: An Observational Cohort Study
Aleksandar Senev, Maarten Coemans, Evelyne Lerut, Vicky Van Sandt, Johan Kerkhofs, Liesbeth Daniëls, Marleen Vanden Driessche, Veerle Compernolle, Ben Sprangers, Elisabet Van Loon, Jasper Callemeyn, Frans H.J. Claas, Anat R. Tambur, Geert Verbeke, Dirk Kuypers, Marie‐Paule Emonds, Maarten Naesens
Abstract
Significance Statement HLA matching for three HLA loci (HLA-A, HLA-B, and HLA-DR) at a low-resolution antigen level has been integral to algorithms for allocating donor kidneys for transplant since the 1970s. The authors used high-resolution genotyping of the 11 HLA loci and analysis of mismatches of HLA eplets—small patches of surface-exposed amino acids of the HLA molecule—to evaluate the effect of eplet mismatches on de novo formation of donor-specific HLA antibodies (DSAs) and kidney transplant outcome. They found that eplet mismatches in the HLA-DQ locus are most important for DSA formation, rejection, decline of graft function, and graft failure. Their findings suggest that molecular HLA-DQ matching might be more helpful than antigen matching for HLA-A, HLA-B, and HLA-DR when aiming to minimize formation of DSAs and improve outcomes after transplant. Background In kidney transplantation, evaluating mismatches of HLA eplets—small patches of surface-exposed amino acids of the HLA molecule—instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes. Methods To evaluate the effect of number of eplet mismatches (mismatch load) on de novo formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches. Results De novo DSAs occurred in 43 (4.6%) patients. Multivariable analysis showed a significant independent association between antibody-verified eplet mismatch load and de novo DSA occurrence and graft failure, mainly explained by DQ antibody-verified eplet effects. The association with DQ antibody-verified eplet mismatches was linear, without a safe threshold at which de novo DSA did not occur. Odds for T cell– or antibody-mediated rejection increased by 5% and 12%, respectively, per antibody-verified DQ eplet mismatch. Conclusions Eplet mismatches in HLA-DQ confer substantial risk for de novo DSA formation, graft rejection, and graft failure after kidney transplantation. Mismatches in other loci seem to have less effect. The results suggest that antibody-verified HLA-DQ eplet mismatch load could be used to guide personalized post-transplant immunosuppression. Adoption of molecular matching for DQA 1 and DQB 1 alleles could also help to minimize de novo DSA formation and potentially improve transplant outcomes.