Abstract
Access to liver transplantation continues to be hindered by the severe organ shortage. Extended-criteria donor livers could be used to expand the donor pool but are prone to ischemia-reperfusion injury (IRI) and post-transplant graft dysfunction. Ex situ machine perfusion may be used as a platform to rehabilitate discarded or extended-criteria livers prior to transplantation, though there is a lack of data guiding the utilization of different perfusion modalities and therapeutics. Since amino acid derivatives involved in inflammatory and antioxidant pathways are critical in IRI, we analyzed differences in amino acid metabolism in seven discarded non-steatotic human livers during normothermic- (NMP) and subnormothermic-machine perfusion (SNMP) using data from untargeted metabolomic profiling. We found notable differences in tryptophan, histamine, and glutathione metabolism. Greater tryptophan metabolism via the kynurenine pathway during NMP was indicated by significantly higher kynurenine and kynurenate tissue concentrations compared to pre-perfusion levels. Livers undergoing SNMP demonstrated impaired glutathione synthesis indicated by depletion of reduced and oxidized glutathione tissue concentrations. Notably, ATP and energy charge ratios were greater in livers during SNMP compared to NMP. Given these findings, several targeted therapeutic interventions are proposed to mitigate IRI during liver machine perfusion and optimize marginal liver grafts during SNMP and NMP.
Highlights
Liver transplantation (LT) remains the only definitive cure for end-stage liver diseases
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We found that livers undergoing normothermic machine perfusion (NMP) demonstrated significantly greater tryptophan metabolism via the kynurenine pathway, which has significant clinical implications and therapeutic value
Summary
Liver transplantation (LT) remains the only definitive cure for end-stage liver diseases. While numerous studies have demonstrated potential metabolic targets in the liver, renal, and intestinal IRI response [12,13,14,15,16], few studies have examined the metabolic changes that occur in the human liver during transplantation [12,17,18,19,20] and fewer still during ex situ machine perfusion [4,21] This is a critical area of research since the machine perfusion platform is the only setting for liver-specific adjunct therapies prior to transplantation. We hypothesized was that metabolic changes taking place in the liver driven by different perfusion modalities would identify potentially harmful and beneficial processes, which can be used to optimize future perfusion outcomes by mitigating IRI These insights provide valuable knowledge that can be used to generate new hypotheses and design therapeutic interventions to salvage or rehabilitate discarded or ECD livers for transplantation
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