Abstract: FR-OR132
Genome-Wide Non-HLA Incompatibility between Donor and Recipient Contributes to Kidney Allograft Attrition
Session Information
- Translational and Transplant Pathology
October 26, 2018 | Location: 6E, San Diego Convention Center
Abstract Time: 04:30 PM - 04:42 PM
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.