Prognostic Significance of Early Donor-derived Cell-free DNA Trajectories After Kidney Transplantation

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.