Inflammation in the setting of chronic allograft dysfunction post-kidney transplant: Phenotype and genotype

Background: Chronic allograft dysfunction (CGD) is a common outcome in kidney transplants, but its pathogenesis is unclear. We investigated the CGD phenotype and single-nucleotide polymorphisms (SNPs) associated with CGD. Method: This prospective study enrolled 2336 transplants from seven transplant centers in North America. CGD was defined as a >25% rise in serum creatinine relative to a three-month post-transplant baseline, requiring a kidney biopsy. We genotyped 2724 SNPs in the initial 979 transplants, which form the test cohort. Results: CGD occurred 11.2 times per 100 person-years at a median of 509 ± 387 days from the three-month baseline. CGD was independently associated with death-censored, allograft failure, in an adjusted analysis [HR=20.6 (11.8-35.8, p < 0.001)]. Among 366 transplant recipients with CGD, 91% had inflammation on biopsy scores. 94 (26%) had inflammatory changes consistent with a diagnosis of concomitant acute rejection. SNPs in FM06 and FM03, potential drug metabolism genes, were associated with CGD, after accounting for multiple testing. Conclusion: CGD phenotype with concomitant inflammation is associated with increased risk of allograft failure. SNPs associated with CGD in novel drug metabolism and transport genes, will be validated in subsequent transplants.