Comparison Between Antigen and Allelic <scp>HLA</scp> Mismatches, and the Risk of Acute Rejection in Kidney Transplant Recipients

Deceased donor kidney allocation relies on HLA compatibility at the antigen level, as optimal matching reduces the risk of acute rejection. Whether HLA allele-level mismatches improve, the prediction of acute rejection after transplantation remains unclear. Using data from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) from 2017 to 2020, HLA antigenic and allelic mismatches between recipients and deceased donors were calculated with imputation of two-field allelic equivalents undertaken where required. The discordance between antigen and allele mismatches was calculated, and oblique random survival forest models were used to predict acute rejection. Predictive performance of antigen (HLA-A, -B, -DRB1 and -DQB1), allele (HLA-A, -B, -DRB1 and -DQB1) and extended allele (HLA-A, -B, -C, -DRB1, -DQA1 and -DQB1) models was examined using concordance index and integrated Brier scores, with variable importance calculated using permutation-based methods. Among 2644 recipients followed for a median of 1.7 years, 521 recipients (20%) experienced acute rejection. Discordant numbers of antigenic and allelic mismatches occurred in 8%, 9%, 24% and 17% of HLA-A, -B, -DRB1 and -DQB1 loci, respectively. Predictive performances were similar across all models, with concordance indices of 0.62-0.63 and integrated Brier scores of 0.09. HLA-DRB1 and -DQB1 mismatches were the strongest predictors of acute rejection across models. In patients matched at the HLA-DRB1 or -DQB1 antigen, those with allelic mismatches had similar incidences of rejection compared to those without. Allelic-level assessment of HLA compatibility did not improve the prediction of acute rejection and may disadvantage certain recipients by reclassifying them into higher mismatch categories in allocation algorithms without providing clear clinical benefit.