Eplet mismatch analysis in kidney transplantation: from concept to clinical practice

Eplet mismatch analysis offers a refined approach to assessing donor-recipient compatibility in kidney transplantation, surpassing conventional antigen-level human leukocyte antigen (HLA) matching in predicting immunologic outcomes. By identifying polymorphic amino acid residues on HLA molecules recognized by B cell receptors, this method quantifies immunologic risk. Clinical studies demonstrate that high eplet mismatch loads, particularly at HLA-DQ, are strongly associated with de novo donor-specific antibody development, antibody-mediated rejection, and reduced graft survival. Single-molecule mismatch analysis further enables risk stratification when integrated with T cell epitope prediction tools such as PIRCHE-II (Predicted Indirectly Recognizable HLA Epitopes Presented by HLA Class II Molecules). This review outlines the immunologic basis, methodologies, and clinical evidence supporting eplet mismatch analysis. It also addresses current limitations in validation and clinical implementation, and proposes future directions for its use in personalized immunosuppression and organ allocation.