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 multi-center study of kidney transplant recipients (KTR) with biopsy proven AR (BPAR) monitored dd-cfDNA for eight 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. Of 488 KTR, 66 with BPAR were analyzed (TCMR: n=37; ABMR: n=24; Mixed: n=5). 76% experienced negative outcomes, 24% positive outcomes. Four distinct dd-cfDNA trends were identified: two with favorable prognosis (n=25), two with unfavorable prognosis (n=41). Among patients with favorable prognosis, the odds of experiencing positive outcomes were 60x higher (p=3.18x10-7), and of experiencing resolving kidney dysfunction at one year were 13x higher (p=2.15x10-5). Among KTR with BPAR, post-rejection dd-cfDNA trends were statistically associated with outcomes, suggesting dd-cfDNA may help physicians manage patients post-BPAR.