Prognostic Significance of Early Donor-derived Cell-free DNA Trajectories After Kidney Transplantation
Kalathil Sureshkumar, Jeffrey A. Klein, Dhiren Kumar, Nadiesda Costa, Renata Glehn-Ponsirenas, Peale Chuang, Ling Shen, James Lu, David Wojciechowski, Pranjal Jain, Yihung Huang, Alexander Wiseman, Edmund Huang, Stuart Knechtle, Suphamai Bunnapradist, Rafael Villicana, Puneet Sood, Anil Paramesh, Rashikh A. Choudhury, James Piper, Jiashu Xue, Yasir Qazi, Divya Jain, Sandesh Parajuli, Nicolae Leca, Didier A. Mandelbrot, Jonathan Bromberg, Thin Thin Maw, Daniel C. Brennan, Tarek Alhamad,Background.
Early post-transplant elevations in donor-derived cell-free DNA are often attributed to ischemia–reperfusion injury, with uncertain prognostic significance. We assessed whether donor-derived cell-free DNA (dd-cfDNA) results during the first 4 mo post-transplantation are associated with long-term graft outcomes.
Methods.
We analyzed 1137 kidney transplant recipients enrolled in the prospective multicenter Kidney Outcomes AlloSure Registry. Recipients were categorized into 4 trajectory groups based on dd-cfDNA measurements obtained within the first 4 mo post-transplant: consistently low, transient-elevation, late-elevation, and persistent-elevation. Associations with donor-specific antibody (DSA) development, rejection, graft dysfunction, and graft loss were evaluated over 3 y using hazard regression, with multivariable models adjusted for calculated Panel Reactive Antibody (cPRA) and retransplant.
Results.
Among the 1137 recipients, 83.7% exhibited consistently low dd-cfDNA, 9.8% transient-elevation, 3.2% late-elevation, and 3.3% persistent-elevation. Late elevation was associated with the highest cumulative incidence of DSA development, whereas persistent-elevation had the highest incidence of rejection, graft dysfunction, and graft loss. Graft loss occurred in 20.0% of recipients with persistent-elevation and 8.8% with late-elevation and was uncommon among consistently low (2.2%) and transient (2.9%) groups. On multivariable analysis, late elevation was independently associated with DSA development, rejection, and graft loss, and persistent-elevation with rejection, graft dysfunction, and graft loss, regardless of prior transplantation or sensitization status.
Conclusions.
Early dd-cfDNA trajectories stratify kidney transplant recipients into clinically meaningful risk phenotypes. Persistent or late-emerging elevation identifies patients at independently increased risk of rejection and graft loss, with persistent-elevation also associated with graft dysfunction, supporting serial dd-cfDNA monitoring as a tool for early post-transplant risk stratification.