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

Abstract

Background: Genetic 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. Methods: In 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. Results: Individually, only the presence of the CFB32Q variant in the donor and the combined presence in donor-recipient pairs were associated with better graft survival (P=0.027 and P=0.045, respectively). In the combined analysis, the C3R102G, CFBR32Q, and CFHV62I variants 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). Conclusion: Our 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.