Abstract
Current strategies to improve graft outcome following kidney transplantation consider information at the human leukocyte antigen (HLA) loci. Cell surface antigens, in addition to HLA, may serve as the stimuli as well as the targets for the anti-allograft immune response and influence long-term graft outcomes. We therefore performed exome sequencing of DNA from kidney graft recipients and their living donors and estimated all possible cell surface antigens mismatches for a given donor/recipient pair by computing the number of amino acid mismatches in trans-membrane proteins. We designated this tally as the allogenomics mismatch score (AMS). We examined the association between the AMS and post-transplant estimated glomerular filtration rate (eGFR) using mixed models, considering transplants from three independent cohorts (a total of 53 donor-recipient pairs, 106 exomes, and 239 eGFR measurements). We found that the AMS has a significant effect on eGFR (mixed model, effect size across the entire range of the score: -19.4 [-37.7, -1.1], P = 0.0042, χ2 = 8.1919, d.f. = 1) that is independent of the HLA-A, B, DR matching, donor age, and time post-transplantation. The AMS effect is consistent across the three independent cohorts studied and similar to the strong effect size of donor age. Taken together, these results show that the AMS, a novel tool to quantify amino acid mismatches in trans-membrane proteins in individual donor/recipient pair, is a strong, robust predictor of long-term graft function in kidney transplant recipients.
Highlights
Survival of patients afflicted with End Stage Renal Disease (ESRD) is superior following kidney transplantation compared to dialysis therapy
We found that the allogenomics mismatch score (AMS) has a significant effect on estimated glomerular filtration rate (eGFR) that is independent of the human leukocyte antigen (HLA)-A, B, DR matching, donor age, and time post-transplantation
Prior studies often assumed that only a small number of locations in the genome were most likely to have an impact on graft function, while this study found initial evidence that differences across DNA that code for a large number of proteins can have a combined impact on graft function
Summary
Survival of patients afflicted with End Stage Renal Disease (ESRD) is superior following kidney transplantation compared to dialysis therapy. The short-term outcomes of kidney grafts have steadily improved since the early transplants with refinements in immunosuppressive regimens, use of DNA-based human leukocyte antigen (HLA) typing, and better infection prophylaxis [1,2,3]. Despite these advances, data collected across the USA and Europe show that 40– 50% of kidney allografts fail within ten years of transplantation [4]. Data collected across the USA and Europe show that 40– 50% of kidney allografts fail within ten years of transplantation [4] This observation strongly suggests that as yet uncharacterized factors, including genomic loci, may adversely impact long-term post-transplantation outcomes. It has been reported that the presence of anti-MICA antibodies in the pre-transplant sera is associated with graft failure despite HLA matching of the kidney recipient with the organ donor
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