Associations between donor-derived cell-free DNA dynamics and clinical outcomes after kidney allograft rejection: A prospective, multicenter study
Suphamai Bunnapradist, Nicolae Leca, Ziad Zaky, Robert J. Stratta, Hasan Khamash, Fuad S. Shihab, Obi Ekwenna, Martin Aldana-Campos, Joseph Kahwaji, Luigi Biancone, Thin Thin Maw, D. Giovanni Biagini, Navchetan Kaur, Adam Prewett, Geethanjali Gude, Paul Van Hummelen, Michelle S. Bloom, Zachary Demko, Matthew Rabinowitz, Steven L. Chapman, Phil Gauthier, Sangeeta Bhorade, Hossein Tabriziani, Yasir Qazi
Abstract
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.