Elevations in Donor-Derived Cell-Free DNA and Allograft Outcomes in Kidney Transplantation

Key Points We assessed whether an initial donor-derived cell-free DNA elevation during routine surveillance was associated with allograft dysfunction and loss in kidney transplant recipients. Intermediate and high donor-derived cell-free DNA states were independently associated with 3.7-fold and 6.4-fold higher risks of allograft loss, respectively. Persistently low donor-derived cell-free DNA levels were associated with low rates of rejection and allograft loss, identifying a low-risk population. Background Although donor-derived cell-free DNA (dd-cfDNA) correlates with histologic rejection and injury severity, its association with long-term graft outcomes has yet to be well established in kidney transplant recipients. We hypothesize that among patients monitored with dd-cfDNA, an initial elevation may be associated with subsequent allograft dysfunction and loss. Methods The Kidney Allograft Outcomes AlloSure Registry is a prospective, multicenter cohort of 1743 adult kidney transplant recipients from 56 US centers; this analysis included 1258 patients who initiated dd-cfDNA surveillance 15–60 days post-transplant with up to 3-year follow-up. A multistate model was applied to characterize transitions from a low dd-cfDNA state (no elevations) to intermediate (0.5%–1.0% with ≥61% relative change value) or high (≥1.0%) dd-cfDNA states, and their unadjusted and covariate-adjusted associations with allograft loss or all-cause death were quantified using hazard regression models. Results Within 3 years, 36% of patients transitioned to an elevated dd-cfDNA state (intermediate n =216; high n =233). Allograft dysfunction by 36 months occurred significantly more often in patients with dd-cfDNA elevations despite preserved allograft function at the time of elevation (eGFR ≥60 ml/min per 1.73 m 2 in 42% of intermediate and 33% of high), consistent with subclinical injury. Transitions from low to elevated dd-cfDNA states were strongly associated with subsequent allograft loss (adjusted hazard ratios, 3.70 [95% confidence interval [CI], 1.38 to 9.90] for intermediate; 6.36 [95% CI, 2.80 to 14.42] for high) while mortality did not differ by dd-cfDNA state. Conclusions Initial dd-cfDNA elevations exceeding established thresholds were independently associated with higher risks of allograft dysfunction and loss across both elevation categories, whereas patients who remained in the low dd-cfDNA state experienced favorable outcomes.