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. 2019 Mar 2;393(10174):910-917.
doi: 10.1016/S0140-6736(18)32473-5. Epub 2019 Feb 14.

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

Roman Reindl-Schwaighofer  1 , Andreas Heinzel  1 , Alexander Kainz  1 , Jessica van Setten  2 , Kira Jelencsics  1 , Karin Hu  1 , Bao-Li Loza  3 , Michael Kammer  4 , Georg Heinze  4 , Petra Hruba  5 , Alena Koňaříková  6 , Ondrej Viklicky  7 , Georg A Boehmig  1 , Farsad Eskandary  1 , Gottfried Fischer  8 , Frans Claas  9 , John C Tan  10 , Tom J Albert  10 , Jigar Patel  10 , Brendan Keating  3 , Rainer Oberbauer  11 ; iGeneTRAiN consortium
Affiliations

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

Roman Reindl-Schwaighofer et al. Lancet. .

Abstract

Background: The introduction of HLA matching 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 HLA mismatch 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 HLA eplet 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 quartile with 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 alloimmune response to genetically predicted mismatched epitopes.

Interpretation: Genetic mismatch of non-HLA haplotypes coding for transmembrane or secreted proteins is associated with an increased risk of functional graft loss independently of HLA incompatibility. As in HLA alloimmunity, donor-specific alloantibodies can be identified against genotype derived non-HLA epitopes.

Funding: Austrian Science Fund, WWTF (Vienna Science and Technology Fund), and Ministry of Health of the Czech Republic.

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