Graft bile analysis for predicting post-transplant outcomes: A literature review and a protocol for a novel biomarker.

Liver transplantation (LT) remains the definitive treatment for end-stage liver disease, yet early detection of graft dysfunction and rejection is still challenging. Conventional blood-based markers provide systemic information but lack hepatic specificity. Bile, directly secreted by hepatocytes and cholangiocytes, represents an organ-specific biofluid with diagnostic potential for assessing graft viability and early complications. This minireview examined the biochemical, immunological, and molecular features of bile as biomarkers in LT, focusing on pH, bicarbonate, glucose, lactate, bile acids, and proteomic/lipidomic profiles in relation to ischemia-reperfusion injury, early allograft dysfunction, and ischemic-type biliary lesions. The integration of bile-based parameters into ex situ perfusion and post-transplant monitoring, supported by omics technologies and predictive modeling, was also discussed. Building on these insights, we designed a single-center prospective study (ClinicalTrials.gov: NCT03882164) evaluating biliary tacrolimus (TACbile) as a predictor of acute rejection after LT. Paired daily TACbile and plasma tacrolimus levels are measured in recipients with Kehr T-tubes to define a blood-bile ratio of tacrolimus. The primary endpoint was the predictive accuracy of blood-bile ratio of tacrolimus for biopsy-proven rejection; secondary outcomes include associations with early allograft dysfunction. Bile-based biomarkers, particularly TACbile, may revolutionize graft monitoring and personalize immunological surveillance after LT.