Molecular HLA matching in kidney transplantation: the emerging role of eplet mismatch analysis

INTRODUCTION: Kidney transplantation is the preferred treatment for end-stage kidney disease, but long-term graft survival remains limited by alloimmune injury, particularly donor-specific antibody-mediated rejection. This review evaluates molecular HLA matching as an approach to improve donor-recipient compatibility assessment beyond conventional antigen-level matching. AREAS COVERED: The biological basis of HLA epitopes and eplets is described, with emphasis on HLAMatchmaker, HLA-EMMA, PIRCHE-II, and related computational approaches. Evidence linking molecular mismatch with de novo donor-specific antibodies, antibody-mediated rejection, chronic allograft injury, and graft survival is reviewed. Qualitative eplet immunogenicity, structural accessibility, amino-acid properties, antibody verification, and HLA-DQ-associated risk are also examined. A literature search was conducted using PubMed/MEDLINE and Scopus, focusing on studies published during the preceding 10 years, employing terms related to kidney transplantation, HLA eplet mismatch, molecular HLA matching, donor-specific antibodies, rejection, and graft outcomes. EXPERT OPINION: HLA eplet-based matching may improve immunological risk stratification and individualized surveillance. However, algorithmic variability, incomplete antibody verification, differences in HLA typing resolution, population limitations, and lack of standardized thresholds restrict implementation. Prospective multi-center studies are needed to establish clinical utility, cost-effectiveness, and whether molecularly informed donor selection or monitoring improves patient and graft outcomes.