Background: Acute rejection remains a major complication following liver transplantation, yet reliable noninvasive biomarkers for its early prediction and diagnosis remain unidentified. This exploratory study characterized bile and serum metabolites associated with acute rejection in living donor liver transplantation using comprehensive metabolomic profiling combined with machine learning. Methods: Non-targeted metabolomics were performed on bile samples collected on post-operative day (POD) 1 (n = 38) and serum on POD 14 (n = 45) from liver transplant recipients. Partial least squares discriminant analysis-based variable selection was followed by logistic regression and least absolute shrinkage and selection operator models, which were evaluated via cross-validation in the discovery cohort to explore potential biomarkers for acute rejection. Results: A three-variable, bile-based model for predicting acute rejection achieved a mean cross-validated AUC of 0.872 (95% confidence interval: 0.814–0.930). Glycohyocholic acid and sulfolithocholylglycine were the main contributors. A nine-variable serum model for the Rejection Activity Index, including the change in γ-glutamyl transferase, showed a mean cross-validated R2 of 0.728 (95% confidence interval: 0.609–0.846), with methionine, creatine, and oxidized fatty acids contributing prominently. Conclusions: These findings suggest that metabolomic profiling combined with machine learning may provide candidate biomarkers for acute rejection after liver transplantation. However, given the exploratory nature of the study and the lack of external validation, the clinical utility of these metabolite signatures remains to be determined. Therefore, external validation in larger, independent cohorts will be required.
Hirata et al. (Fri,) studied this question.