Impact of Solvent-Accessible HLA Amino Acid Mismatches on Kidney Transplant Outcomes: A Multicenter Longitudinal Study

Current alloimmune risk assessment in kidney transplantation relies on HLA antigen mismatches, lacking precision for individualized care. In contrast, solvent-accessible HLA amino acid (saAA) mismatches, empirically defined across all HLA loci, offer a stable and objective alternative. We conducted a multicenter longitudinal study evaluating saAA mismatches, calculated using HLA-EMMA, in relation to key transplant outcomes. Among 2,473 kidney transplant recipients (median follow-up 6.9 years), 36% reached a hierarchical composite endpoint of death-censored graft failure(DCGF), biopsy-proven acute rejection(BPAR), or de novo donor-specific antibody(dnDSA). Multivariable analyses showed total, class I, class II, and locus-specific saAA mismatch scores were significantly associated with the composite outcome, as well as DCGF, BPAR and dnDSA individually (all P<.001). These findings suggest that saAA mismatch load provides a more granular and reproducible measure of alloimmune risk compared to traditional antigen-level mismatches. Incorporating saAA mismatch analysis could enable personalized immunosuppression strategies and optimized transplant monitoring in clinical practice.