The combined impact of HLA and non-HLA mismatch between donors and recipients on kidney transplant survival: a genomic analysis in a prospective cohort

Background: Kidney transplantation outcomes are strongly influenced by immunological compatibility between donor and recipient. While genetic mismatches in the human leukocyte antigen (HLA) region have long been recognised as key determinants of graft survival, increasing evidence, including our own previous work, suggests that non-HLA alloimmunity also plays a critical role. Methods: We sequenced exomes of deceased kidney donor and recipient pairs in the prospective kidney transplant cohort at the Vienna General Hospital, recruited between January 1, 2012, and June 15, 2023. Out of 1209 pairs, 1187 passed quality control for analysis. Non-HLA mismatch was computed by considering non-synonymous single nucleotide polymorphisms specifically encoding trans-cell membrane or secreted proteins in the kidney (nsSNP-tcmsk). Using adjusted Cox proportional hazards models, we replicated results from our earlier work in recipients with primary graft function after 90 days, and extended the analysis to the combination of nsSNP-tcmsk with eplet mismatch to assess their associations with graft loss in the full cohort. Findings: Of 20,421 human proteins, 2371 were considered for the nsSNP-tcmsk score. In our replication analysis we estimated for nsSNP-tcmsk a hazard ratio (HR) of 1.33 (95% CI 1.02–1.74) for graft loss per increase of one interquartile range. The nsSNP-tcmsk and eplet mismatch were uncorrelated (Spearman correlation coefficient 0.02, p = 0.47). A composite score of nsSNP-tcmsk and eplet mismatch was associated with graft loss with a HR of 1.76 (95% CI 1.20–2.57) corresponding to an absolute difference in 7-year restricted mean survival time between the first and fourth quartiles of 0.52 years (95% CI 0.16–0.87 years). Interpretation: The impact of non-HLA donor-recipient mismatch on transplant loss is of the same magnitude as established mismatch scores in the HLA region. Together, these scores may be further validated as guiding markers for the required strength of maintenance immunosuppression. Funding: Vienna Science and Technology Fund, NIH/NIAID.