Synergistic impact of three complement polymorphisms in the donor, not the recipient, on long-term kidney allograft survival

Author:

Poppelaars FelixORCID,Gaya da Costa MarianaORCID,Faria BernardoORCID,Eskandari Siawosh K.ORCID,Petr VojtechORCID,Holers V. MichaelORCID,Daha Mohamed R.ORCID,Berger Stefan P.ORCID,Damman JeffreyORCID,Seelen Marc A.ORCID,Thurman Joshua M.ORCID

Abstract

AbstractBackgroundGenetic analysis in transplantation offers potential for personalized medicine. Given the crucial role of the complement system in renal allograft injury, we investigated in kidney transplant pairs the impact of complement polymorphisms on long-term outcomes.MethodsIn this observational cohort study, we analyzed polymorphisms in C3 (C3R102G), factor B (CFBR32Q), and factor H (CFHV62I) genes of 1,271 donor-recipient kidney transplant pairs and assessed their association with 15-year death-censored allograft survival.ResultsIndividually, only the presence of theCFB32Qvariant in the donor and the combined presence in donor-recipient pairs were associated with better graft survival (P=0.027 andP=0.045, respectively). In the combined analysis, theC3R102G,CFBR32Q, andCFHV62Ivariants in the donor independently associated with the risk of graft loss (HR 1.32; 95%-CI, 1.08– 1.58;P=0.005). Thus, donor kidneys carrying the genetic variants that promote the highest complement activity exhibited the worst graft survival, whereas those with the genetic variants causing the lowest complement activity showed the best graft survival (15-year death-censored allograft survival: 48.8% vs 87.8%,P=0.001).ConclusionOur study demonstrates that the combination of complement polymorphisms in the donor strongly associates with long-term allograft survival following kidney transplantation. These findings hold significance for therapeutic strategies involving complement inhibition in kidney transplantation.

Publisher

Cold Spring Harbor Laboratory

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