Eplet Mismatch Load and De Novo Occurrence of Donor-Specific Anti-HLA Antibodies, Rejection, and Graft Failure after Kidney Transplantation: An Observational Cohort Study
Authors: Senev Aleksandar , Coemans Maarten , Lerut Evelyne , Van Sandt Vicky , Kerkhofs Johan , Daniëls Liesbeth , Driessche Marleen Vanden , Compernolle Veerle , Sprangers Ben , Van Loon Elisabet , Callemeyn Jasper , Claas Frans , Tambur Anat R. , Verbeke Geert , Kuypers Dirk , Emonds Marie-Paule , Naesens Maarten 
Published: August 2020

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 DQA1 and DQB1 alleles could also help to minimize de novo DSA formation and potentially improve transplant outcomes.