*Purpose: Donor organ shortage has led to increased reliance on high-risk livers for transplantation. Furthermore, emergence of machine perfusion has led to a paradigm shift in organ preservation from functional suppression in static cold storage to full ex vivo metabolic support. The recently completed VITTAL trial demonstrated that normothermic machine perfusion (NMP-L) provides an opportunity to objectively assess graft quality and functional integrity pre-transplantation in order to safely transplant high-risk livers turned down by all transplant centres. This study investigated the potential of metabolic profiling to elucidate molecular signatures during NMP-L predictive of graft viability, post-reperfusion syndrome (PRS) and early allograft dysfunction (EAD) in these discarded livers.

*Methods: All livers were deemed marginal according to established high-risk criteria, and had been discarded by all transplant centres. 31 livers underwent NMP-L for a minimum of four hours, at which point a decision was made to transplant based on established viability criteria. Perfusate aliquots from commencement of graft perfusion to 4-hour time point were collected from all livers. Samples were centrifuged and the supernatant subjected to an untargeted metabolomics analysis using Ultra High Performance Liquid Chromatography-Mass Spectrometry.

*Results: 22 livers were transplanted after achieving viability criteria. Univariate statistical analyses revealed more than 20 metabolites (q<0.05) differentiating liver metabolic profiles according to viability criteria fulfilment following 4 hours of perfusion. Key changes were detected in metabolites relating to lipid, phospholipid and sphingolipid metabolism, notably upregulated in the non-viable group. In the transplanted cohort; 52 metabolites distinguished EAD (n=7) from non-EAD livers (n=15) after 4 hours of perfusion. The PRS group (n=10) revealed changes in 36 metabolites after 4 hours of perfusion compared to non-PRS group (n=12).

*Conclusions: This study reveals a metabolic signature of high-risk livers that correlates with VITTAL criteria for graft viability for transplantation during NMP-L. It also demonstrates the potential of NMP-L metabolic profiling as a clinical tool to objectively assess the quality and predict functional integrity of these livers pre-implantation.

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