title: Biomarker differences between cadaveric grafts used in human orthotopic liver transplantation as identified by coulometric electrochemical array detection (CEAD) metabolomics.
abstract: Metabolomics in systems biology research unravels intracellular metabolic changes by high throughput methods, but such studies focusing on liver transplantation (LT) are limited. Microdialysate samples of liver grafts from donors after circulatory death (DCD; n=13) and brain death (DBD; n=27) during cold storage and post-reperfusion phase were analyzed through coulometric electrochemical array detection (CEAD) for identification of key metabolomics changes. Metabolite peak differences between the graft types at cold phase, post-reperfusion trends, and in failed allografts, were identified against reference chromatograms. In the cold phase, xanthine, uric acid, and kynurenine were overexpressed in DCD by 3-fold, and 3-nitrotyrosine (3-NT) and 4-hydroxy-3-methoxymandelic acid (HMMA) in DBD by 2-fold (p<0.05). In both grafts, homovanillic acid and methionine increased by 20%-30% with each 100 min increase in cold ischemia time (p<0.05). Uric acid expression was significantly different in DCD post-reperfusion. Failed allografts had overexpression of reduced glutathione and kynurenine (cold phase) and xanthine (post-reperfusion) (p<0.05). This differential expression of metabolites between graft types is a novel finding, meanwhile identification of overexpression of kynurenine in DCD grafts and in failed allografts is unique. Further studies should examine kynurenine as a potential biomarker predicting graft function, its causation, and actions on subsequent clinical outcomes.
authors.affiliation: 1 The Liver Unit, Queen Elizabeth Hospital Birmingham , Edgbaston, Birmingham, United Kingdom .
authors.forename: M Thamara P R
authors.initials: MT
authors.lastname: Perera
authors.forename: Roger
authors.initials: R
authors.lastname: Higdon
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Richards
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silva
authors.forename: Nick
authors.initials: N
authors.lastname: Murphy
authors.forename: Eugene
authors.initials: E
authors.lastname: Kolker
authors.forename: Darius F
authors.initials: DF
authors.lastname: Mirza
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D007737:Kynurenine / Q000378:metabolism; D016031:Liver Transplantation / Q000379:methods*; D055432:Metabolomics / Q000379:methods*; D008715:Methionine / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism; D019820:Xanthine / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019820:Xanthine; D014527:Uric Acid; D007737:Kynurenine; C002744:3-nitrotyrosine; D014443:Tyrosine; D008715:Methionine; D006719:Homovanillic Acid