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Abstract: FR-OR132

Genome-Wide Non-HLA Incompatibility between Donor and Recipient Contributes to Kidney Allograft Attrition

Session Information

Category: Transplantation

  • 1802 Transplantation: Clinical

Authors

  • Oberbauer, Rainer, Medical University of Vienna, Vienna, Austria
  • Reindl-Schwaighofer, Roman, Medical University of Vienna, Vienna, Austria
  • Heinzel, Andreas, Medical University of Vienna, Vienna, Austria
  • Hruba, Petra, Institute for Clinical and Experimental Medicine, Department of Nephrology, Prague, Czechia
  • Viklicky, Ondrej, Institute for Clinical and Experimental Medicine, Department of Nephrology, Prague, Czechia
  • Jelencsics, Kira, Medical University of Vienna, Vienna, Austria
  • Hu, Karin, Medical University of Vienna, Vienna, Austria
  • Kainz, Alexander, Medical University of Vienna, Vienna, Austria
  • Kammer, Michael, Medical University of Vienna, Vienna, Austria
  • Heinze, Georg, Medical University of Vienna, Vienna, Austria
  • Bohmig, Georg, Medical University of Vienna, Vienna, Austria
  • Claas, Frans, University Leiden, Leiden, Netherlands
  • Eskandary, Farsad Alexander, Medical University of Vienna, Vienna, Austria
  • Keating, Brendan, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Background

The introduction of HLA matching of donors and recipients was a breakthrough in kidney transplantation but epidemiological data suggest also a fundamental role of non-HLA alloimmunity.

Methods

477 deceased donor and first kidney transplant recipient pairs from a prospective multi-center transplant cohort study were successfully genotyped and genome-wide genetic mismatches in nsSNPs were calculated to identify incompatibilities in transmembrane and secreted proteins. Association of nsSNP mismatch and graft loss was estimated in a Cox model adjusting for HLA mismatch and clinical covariates. Customized peptide arrays were generated to screen for antibodies against genotype-derived mismatched epitopes.

Results

The median nsSNP mismatch in immune-accessible transmembrane and secreted proteins between donors and recipients was 1,892 with an interquartile range (IQR) of 86. The degree of nsSNP mismatch was independently associated with graft loss in a multivariable model adjusted for HLA eplet mismatch (HLA-A, B, C, DP, DQ, DR). Each increase by a unit of one IQR exhibited a HR of 1.68 (95% CI 1.17-2.41, p=0.005). Five-year death censored graft survival was 98% in the quartile with the lowest mismatch but only 82% in the highest quartile (p=0.003, logrank test).(Figure). Customized peptide arrays verified a donor-specific alloimmune response to genetically predicted mismatched epitopes for selected transmembrane proteins.

Conclusion

Genetic mismatch of non-HLA haplotypes coding for transmembrane or secreted proteins is associated with an increased risk of functional graft. DSAs can be identified against genotype derived non-HLA epitopes.