Associations between donor-derived cell-free DNA dynamics and clinical outcomes after kidney allograft rejection: A prospective, multicenter study

Active rejection (AR) remains a major risk factor for graft dysfunction and loss. Donor-derived cell-free DNA (dd-cfDNA) is a dynamic, noninvasive biomarker for AR. We hypothesized that dd-cfDNA monitoring post-rejection may enable physicians to stratify patients into those with more and less favorable prognoses. This prospective multicenter study of kidney transplant recipients (KTRs) with biopsy-proven AR (BPAR) monitored dd-cfDNA for 8 weeks following diagnosis and recorded clinical outcomes at 12 months. Patients were classified using dd-cfDNA trends; trends were then associated with outcomes. Negative outcomes comprised graft loss, subsequent BPAR, post-biopsy donor-specific antibody, and/or lack of resolution of renal dysfunction. Out of 488 KTRs, 66 with BPAR were analyzed (T cell-mediated rejection, n = 37; antibody-mediated rejection, n = 24; and mixed rejection, n = 5). A total of 76% experienced negative outcomes, and 24% experienced positive outcomes. Four distinct dd-cfDNA trends were identified: 2 with a favorable prognosis (n = 25) and 2 with an unfavorable prognosis (n = 41). Among patients with a favorable prognosis, the odds of experiencing positive outcomes were 60× higher ( P = 3.18 × 10−7) and of experiencing resolving kidney dysfunction at 1 year were 13× higher ( P = 2.15 × 10−5). Among KTRs with BPAR, post-rejection dd-cfDNA trends were statistically associated with outcomes, suggesting that dd-cfDNA may help physicians manage patients post-BPAR.