Abstract
As donor organ shortages persist, functional machine perfusion is under investigation to improve preservation of the donor liver. The transplantation of donation after circulatory death (DCD) livers is limited by poor outcomes, but its application may be expanded by ex vivo repair and assessment of the organ before transplantation. Here we employed subnormothermic (21 °C) machine perfusion of discarded human livers combined with metabolomics to gain insight into metabolic recovery during machine perfusion. Improvements in energetic cofactors and redox shifts were observed, as well as reversal of ischemia-induced alterations in selected pathways, including lactate metabolism and increased TCA cycle intermediates. We next evaluated whether DCD livers with steatotic and severe ischemic injury could be discriminated from ‘transplantable’ DCD livers. Metabolomic profiling was able to cluster livers with similar metabolic patterns based on the degree of injury. Moreover, perfusion parameters combined with differences in metabolic factors suggest variable mechanisms that result in poor energy recovery in injured livers. We conclude that machine perfusion combined with metabolomics has significant potential as a clinical instrument for the assessment of preserved livers.
Highlights
Liver transplantation is currently the only curative treatment option for patients suffering from end-stage liver disease
Innovative metabolomic analysis techniques have enabled the identification of key pathways and mechanisms involved in hepatobiliary disease and have revealed biomarkers associated with donor liver function[11,12,13]
40% of liver transplant candidates wait over 2 years for a liver transplant, while 10–15% of patients dies as a direct result of the insufficient supply of transplantable donor livers[20,21]
Summary
Liver transplantation is currently the only curative treatment option for patients suffering from end-stage liver disease. Alleviation of I/R injury as well as improved viability testing before the transplantation are likely to extend the utilization of otherwise suboptimal organs To this end, functional ex vivo machine perfusion is gaining clinical interest for the recovery and assessment of liver grafts prior to transplantation. Ex vivo assessment of organ quality prior to implantation could allow dynamic assessment of recovery during perfusion by providing an accurate indication of whether a liver has been sufficiently improved. This approach may replace the currently employed appraisal of liver viability with in-depth profiling of www.nature.com/scientificreports/. While metabolic recovery plays a vital role in clinically successful machine perfusion, the metabolomic signatures of ex vivo perfused livers remain underexplored
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