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.

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.

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.

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.