Early Elevations in Donor-derived Cell-free DNA are Associated With Increased Risk of Future Rejection and Graft Dysfunction After Kidney Transplant

Background. Donor-derived cell-free DNA (dd-cfDNA) is a marker of the presence and severity of injury in kidney transplant recipients (KTRs). The impact of early elevations in dd-cfDNA on long-term outcomes remains unclear. Methods. We included all KTR from February 2019 to March 2022 with dd-cfDNA (AlloSure) surveillance and without rejection or graft failure in the first 90 d posttransplant. Participants were stratified into groups based on the highest dd-cfDNA in the first 90 d: <0.5%, 0.5% to <1%, or ≥1%. Outcomes included graft dysfunction (estimated glomerular filtration rate <45 mL/min), de novo donor-specific antibodies, biopsy-proven acute rejection, death, and graft failure, over the following 2 y. Results. A total of 255 KTR were analyzed. Sixty (23.5%) had their highest dd-cfDNA result between 0.5% and 1%, and 16 (6.3%) were ≥1.0%. Participants with elevated dd-cfDNA had significantly lower freedom from rejection (<0.5% = 94.0%, 0.5% to <1% = 86.2%, ≥1% = 66.7%; P = 0.001) and trended toward lower freedom from graft dysfunction (<0.5% = 54.9%, 0.5% to <1% = 49.2%, ≥1% = 31.3%; P = 0.122) over the subsequent 2 y. The hazard ratio of a step up between 2 of the 3 groups was 2.12 (95% confidence interval, 1.18-3.81; P = 0.01) for rejection and 1.17 (95% confidence interval, 0.88-1.56; P = 0.29) for graft dysfunction. The groups had similar freedom from de novo donor-specific antibody, graft failure, or death. Conclusions. Our data demonstrate that early elevations in dd-cfDNA are associated with an increased risk of rejection and lower estimated glomerular filtration rate in KTR. As dd-cfDNA is a leading indicator of injury, surveillance may add prognostic value beyond biopsy alone and identify patients at risk who warrant closer monitoring.