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

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. ### Competing Interest Statement FP owns or owned stock in Apellis Pharmaceuticals, Chemocentryx, InflaRx, Iveric Bio, as well as Omeros and has been involved as a consultant for Invizius and Alnylam Pharmaceuticals. JMT and VMH are consultants for Q32 Bio, Inc., a company developing complement inhibitors. Both also hold stock and may receive royalty income from Q32 Bio, Inc. The remaining authors of this paper declare that they have no competing interests. ### Funding Statement FP was supported by a Veni grant of the Netherlands Organization for Scientific Research (NWO), project no. 09150162010171. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the medical ethics committee at the UMCG under file number METc 2014/077 and the study was performed in accordance with the principles of the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding authors upon reasonable request. * AMD : Age-related macular degeneration C3 : Complement component 3 gene CFB : Complement Factor B gene CFH : Complement Factor H gene DGF : Delayed graft function HLA : Human leukocyte antigen SNP : Single-nucleotide polymorphism