Mass spectrometry based metabolomics comparison of liver grafts from Donors after Circulatory Death (DCD) and Donors after Brain Death (DBD) used in human orthotopic liver transplantation

Use of marginal liver grafts, especially those from donors after circulatory death (DCD), has been considered as a solution to organ shortage. Inferior outcomes have been attributed to donor warm ischaemic damage in these DCD organs. Here we sought to profile the metabolic mechanisms underpinning donor warm ischaemia. Non-targeted Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry metabolomics was applied to biopsies of liver grafts from donors after brain death (DBD; n = 27) and DCD (n = 10), both during static cold storage (T1 ) as well as post-reperfusion (T2 ). Furthermore 6 biopsies from DBD donors prior to the organ donation (T0 ) were also profiled. Considering DBD and DCD together, significant metabolic differences were discovered between T1 and T2 (688 peaks) that were primarily related to amino acid metabolism, meanwhile T0 biopsies grouped together with T2 , denoting the distinctively different metabolic activity of the perfused state. Major metabolic differences were discovered between DCD and DBD during cold-phase (T1 ) primarily related to glucose, tryptophan and kynurenine metabolism, and in the post-reperfusion phase (T2 ) related to amino acid and glutathione metabolism. We propose tryptophan/ kynurenine and S-adenosylmethionine as possible biomarkers for the previously established higher graft failure of DCD livers, and conclude that the associated pathways should be targeted in more exhaustive and quantitative investigations.