The purine pathway in liver tissue biopsies from donors for transplantation is associated to immediate graft function and survival

Abstract

Background & Aims: The current shortage of livers for transplantation has increased the use of organs sourced from donation after circulatory death (DCD). These organs are prone to higher incidence of graft failure, but the underlying mechanisms are largely unknown. Here we aimed to find biomarkers of liver function before transplantation to better inform clinical evaluation. Methods: Matched pre- and post-transplant liver biopsies from DCD (n=24) and donation after brain death (DBD, n=70) were collected. Liver biopsies were analysed using mass spectroscopy molecular phenotyping. First, a discrimination analysis DCD vs DBD was used to parse metabolites associated to DCD. Then a data-driven approach was used to predict Immediate Graft Function (IGF). The metabolites were tested in models to predict survival. Results: Five metabolites in the purine pathway were selected and investigated. The ratios of: adenine monophosphate (AMP), adenine, adenosine and hypoxanthine to urate, differed between DBD and DCD biopsies at pre- transplantation stage (q<0.05). The ratios of AMP and adenine to urate also differed in biopsies from recipients undergoing IGF (q<0.05). Using random forest a panel composed by alanine aminotransferase (ALT) and AMP, adenine, hypoxanthine ratio to urate predicted IGF with AUC 0.84 (95% CI [0.71, 0.97]). In comparison AUC 0.71 (95%CI [0.52, 0.90]) was achieved by clinical measures. Survival analysis revealed that the metabolite classifier could stratify 6-year survival outcomes (p = 0.0073) while clinical data and donor class could not. Conclusions: At liver pre-transplantation stage, a panel composed of purine metabolites and ALT in tissue could improve prediction of IGF and survival.