Impact of HLA evolutionary divergence and donor-recipient molecular mismatches on antibody-mediated rejection of kidney allografts

Several in-silico methods emerge to assess HLA immunogenicity and stratify immunological risk, including HLA molecular mismatches and HLA evolutionary divergence (HED). However, their added value in risk-stratifying antibody-mediated rejection (AMR) remains uncertain. We include 5159 kidney transplant recipients from four centers. Thirty-three clinical and immunological parameters are assessed, including HLA eplet mismatches, PIRCHE-II scores, and HED. Their associations with AMR are evaluated using Cox models. AMR occurrs in 1024 patients (19.9%). Immunological determinants of AMR include anti-HLA DSA (MFI:500-1400, HR:1.87; MFI > 1400, HR:3.84, p < 0.001) and HLA Class II eplet mismatches (HR:1.02, p < 0.001). HLA-DQB1-derived (HR:1.01, p = 0.005) and HLA-DRB1-derived PIRCHE-II scores (HR:1.01, p = 0.001) are also associated with AMR, while HED is not. These findings remain consistent across centers and subpopulations, including non-sensitized patients (n = 4137). Our findings show that Class II molecular mismatches are independently associated with AMR. HED shows no association, suggesting limited utility for immune-risk stratification at a population level. Clinicaltrials.gov: NCT06436586.