The Janus Effect of Bilirubin After Liver Transplantation: A Retrospective Study of Phase‐Dependent Risk and Protection Against Chronic Kidney Disease

AIM: The temporal relationship between post-operative bilirubin dynamics and chronic kidney disease (CKD) following liver transplantation (LT) remains unclear. Given the potential dual (injurious and protective) biological effects of bilirubin, this study aimed to investigate the phase-dependent impact of bilirubin on CKD development. METHODS: We retrospectively analysed 552 adult LT recipients (2018-2023) with a 2-year follow-up. Mean total bilirubin (tBil) levels were measured at regular post-operative intervals and stratified into two phases: early (0-3 months) and late (3-24 months). Fine-Grey competing risk models with restricted cubic splines (RCS) evaluated nonlinear associations between tBil and CKD risk. CKD incidence was estimated using cumulative incidence functions. Longitudinal bilirubin trajectories were assessed using linear mixed-effects models (LMM). RESULTS: Early post-operative tBil > 51.30 μmol/L was independently associated with increased CKD risk (adjusted SHR 1.666; 95% CI 1.158-2.397; p = 0.006), with a U-shaped RCS curve. CKD incidence was significantly higher in patients with early tBil > 51.30 μmol/L (44.6%) compared to 25.65-51.30 μmol/L (27.4%, p = 0.006). Late post-operative tBil of 25.65-51.30 μmol/L was protective (adjusted SHR 0.321; 95% CI 0.173-0.594; p < 0.001), and RCS showed a gradual risk reduction with increasing tBil. The lowest CKD incidence (12.2%) occurred in patients with moderate tBil during the late phase (p < 0.001). LMM demonstrated higher sustained tBil from 6 months onward in non-CKD patients (p < 0.001). CONCLUSION: Post-LT bilirubin exhibits a Janus-like, phase-specific association with CKD: early elevations increase risk, while late moderate levels appear protective. These findings suggest a role for phase-specific bilirubin monitoring and management.