Contribution of non-HLA incompatibility between donor and recipient to kidney allograft survival: genome-wide analysis in a prospective cohort.
Reindl-Schwaighofer R1, Heinzel A1, Kainz A1, van Setten J2, Jelencsics K1, Hu K1, Loza BL3, Kammer M4, Heinze G4, Hruba P5, Koňaříková A6, Viklicky O7, Boehmig GA1, Eskandary F1, Fischer G8, Claas F9, Tan JC10, Albert TJ10, Patel J10, Keating B3, Oberbauer R11; iGeneTRAiN consortium.
- Department of Nephrology, Medical University of Vienna, Vienna, Austria.
- Department of Cardiology, University Medical Center Utrecht, University of Utrecht, Utrecht, Netherlands.
- Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.
- Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
- Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
- Transplant Laboratory, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
- Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre, Leiden, Netherlands.
- Roche Madison, Madison, WI, USA.
- Department of Nephrology, Medical University of Vienna, Vienna, Austria. Electronic address: firstname.lastname@example.org.
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.
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.
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.
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.
Austrian Science Fund, WWTF (Vienna Science and Technology Fund), and Ministry of Health of the Czech Republic.
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