Contribution of non-HLA incompatibility between donor and recipient to kidney allograft survival: genome-wide analysis in a prospective cohort

Summary Background The introduction of HLAmatching of donors and recipients was a breakthrough in kidney transplantation. However, half of all transplanted kidneys still fail within 15 years after transplantation. Epidemiological data suggest a fundamental role of non- HLA alloimmunity. Methods We genotyped 477 pairs of deceased donors and first kidney transplant recipients with stable graft function at three months that were transplanted between Dec 1, 2005, and April 30, 2015. Genome-wide genetic mismatches in non-synonymous single nucleotide polymorphisms (nsSNPs) were calculated to identify incompatibilities in transmembrane and secreted proteins. We estimated the association between nsSNP mismatch and graft loss in a Cox proportional hazard model, adjusting for HLAmismatch and clinical covariates. Customised peptide arrays were generated to screen for antibodies against genotype-derived mismatched epitopes in 25 patients with biopsy-confirmed chronic antibody-mediated rejection. Findings 59 268 nsSNPs affecting a transmembrane or secreted protein were analysed. The median number of nsSNP mismatches in immune-accessible transmembrane and secreted proteins between donors and recipients was 1892 (IQR 1850–1936). The degree of nsSNP mismatch was independently associated with graft loss in a multivariable model adjusted for HLAeplet mismatch ( HLA-A, HLA-B, HLA-C, HLA-DP, HLA-DQ, and HLA-DR ). Each increase by a unit of one IQR had an HR of 1·68 (95% CI 1·17–2·41, p=0·005). 5-year death censored graft survival was 98% in the quartilewith the lowest mismatch, 91% in the second quartile, 89% in the third quartile, and 82% in the highest quartile(p=0·003, log-rank test). Customised peptide arrays verified a donor-specific alloimmuneresponse to genetically predicted mismatched epitopes. Interpretation Genetic mismatch of non- HLAhaplotypes coding for transmembrane or secreted proteins is associated with an increased risk of functional graft loss independently of HLAincompatibility. As in HLA alloimmunity, donor-specific alloantibodies can be identified against genotype derived non- HLAepitopes. FundingAustrian ScienceFund, WWTF (Vienna Science and Technology Fund), and Ministry of Health of the Czech Republic.