Early Post-Transplant Recipient-Derived Cell-Free DNA Predicts One-Year Graft Survival in Liver Transplant Recipients

Background: Early identification of liver transplant (LT) recipients at risk for graft failure remains challenging. Cell-free DNA (cfDNA) may capture both allograft injury and recipient tissue injury; however, its prognostic relevance after LT has been underexplored.
Methods: We retrospectively analyzed 172 LT recipients with prospectively collected cfDNA samples, routinely obtained on postoperative day (POD) 7 and 14, and selectively thereafter. Total cfDNA, donor-derived cfDNA (dd-cfDNA), recipient-derived cfDNA (rd-cfDNA), and the percentage of dd-cfDNA (%dd-cfDNA) were quantified using low-depth whole-genome sequencing based on genotyping. Multivariable regression models were used to assess associations between cfDNA metrics and the primary outcome of 1-year graft loss and secondary outcomes.
Results: During 1-year follow-up, 21 recipients experienced graft loss. Among cfDNA-derived metrics, POD14 rd-cfDNA (log10-transformed) demonstrated the strongest association with 1-year graft loss (adjusted hazard ratio [HR] 8.81, 95% confidence interval [CI] 3.57–21.73; P<0.001) and the highest discrimination (adjusted C-index 0.878). Restricted cubic spline analysis confirmed a significant association between POD14 rd-cfDNA (log10) and 1-year graft loss (overall P<0.001). Using a cutoff derived from time-dependent receiver operating characteristic analysis (POD14 rd-cfDNA ≥32,839.25 pg/mL), the high rd-cfDNA group (n=56) had markedly worse 1-year graft survival (adjusted HR 10.68, 95% CI 3.48–32.81; P<0.001; adjusted C-index 0.891). The high rd-cfDNA group also showed higher incidence of post-transplant sepsis and biliary complications than the low rd-cfDNA group (n=116) (P=0.02 and P=0.003, respectively).