HLA Amino Acid Polymorphisms and Kidney Allograft Survival.

Background: The association of HLA mismatching with kidney allograft survival has been well established. We examined whether amino acid mismatches at the antigen recognition site of HLA molecules represent independent and incremental risk factors for kidney graft failure (GF) beyond those mismatches assessed at the antigenic (2-digit) specificity. Methods: Data on 240,024 kidney transplants performed between 1987 and 2009 were obtained from the Scientific Registry of Transplant Recipients. We imputed HLA-A, -B, and -DRB1 alleles and corresponding amino acid polymorphisms from antigenic specificity through the application of statistical and population genetics inferences. GF risk was evaluated using Cox proportional-hazards regression models adjusted for covariates including patient and donor risk factors and HLA antigen mismatches. Results: We show that estimated amino acid mismatches at particular positions in the peptide-binding pockets of HLA-DRB1 molecule account for a significant incremental risk that was independent of the well-known association of HLA antigen mismatches with graft survival. A statistically significant linear relationship between the estimated number of amino acid mismatches and risk of GF was observed for HLA-DRB1 in deceased donor and living donor transplants. This relationship was strongest during the first 12 months following transplantation (HR = 1.30 per 15 DRB1 amino acid MM; P

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