Tumor necrosis factor-α gene polymorphism is associated with short- and long-term kidney allograft outcomes

Introduction Kidney transplantation has excellent short-term results with current immunosuppression regimes, but long-term outcomes have barely improved. Hence, there is a need for new therapeutic options to increase long-term survival of kidney grafts. Drug development for transplantation has slowly plateaued, limiting progress while making drug repurposing an attractive alternative. We, therefore, investigated the impact of tumor necrosis factor-alpha (TNF-alpha) gene (TNF) polymorphisms on kidney graft survival. Methods We performed a prospective cohort study to assess the association of TNF polymorphisms (rs1800629 G>A and rs3093662 A>G) with primary non-function (PNF) and death-censored kidney allograft survival in 1,271 kidney transplant pairs from the University Medical Center Groningen in The Netherlands. Results The G-allele of the TNF rs3093662 polymorphism in donor kidneys was associated with a higher risk of PNF (odds ratio: 2.05; 95%-CI: 1.06-3.97; P = 0.032). Furthermore, the G-allele of this TNF rs3093662 polymorphism in the donor was also associated with worse 5-year, 10-year, and 15-year death-censored kidney graft survival (P<0.05). The cumulative incidence of graft loss was 15.9% in the reference AA-genotype group and 25.2% in the AG/GG-genotype group, respectively. In multivariable analysis, the association between the TNF rs3093662 polymorphism in the donor and 15-year death-censored kidney graft survival remained significant (hazard ratio: 1.51; 95%-CI: 1.05-2.19, P = 0.028). Conclusion Kidney allografts possessing a high-producing TNF polymorphism have a greater risk of immediate and late graft loss. Our study adds to a growing body of literature indicating the potential of TNF-alpha blockade in improving kidney transplantation outcomes.