Reduced Histidine Metabolism Is Associated with Early Allograft Dysfunction Following Liver Transplantation

Background/Objectives: Early allograft dysfunction (EAD) is a common complication after liver transplantation and is associated with inferior graft survival. While normothermic machine perfusion (NMP) has reduced EAD incidence, the prediction of early graft performance prior to implantation remains elusive. We aimed to correlate the peri-transplant energetic and metabolic profile of liver grafts with post-transplant outcome in a cohort that included grafts preserved with NMP. Methods: Sequential biopsies were taken from 20 transplanted livers (10 immediate graft function [IGF] and 10 EAD), preserved by either static cold storage or NMP. Samples were collected immediately prior to implantation and 30 min after hepatic arterial reperfusion. Untargeted liquid chromatography-mass spectrometry was performed, and energy charge was calculated as (ATP + 1/2 ADP)/(ATP + ADP + AMP). Univariate and receiver operating characteristic analysis identified metabolites correlated with EAD and assessed predictive accuracy. Results: Hepatic concentrations of adenine nucleotides and calculated energy charge did not differ between outcome groups either before implantation or after reperfusion. In contrast, trans-urocanate was significantly enriched in IGF livers across both time points, and additional histidine catabolism pathway metabolites were preferentially increased in IGF grafts. Trans-urocanate demonstrated discriminatory performance for EAD with 80% sensitivity and 80% specificity, confirmed as the single strongest predictive feature among >1600 detected metabolites. Conclusions: These data identify histidine catabolism as a novel metabolic pathway associated with early graft function and a potential indicator of allograft resilience to ischemia-reperfusion injury. Integration of histidine pathway metabolites into perfusion-era viability assessment may serve as a discriminative biomarker of EAD and support future metabolite-guided graft optimization strategies.