title: Metabolomics discloses donor liver biomarkers associated with early allograft dysfunction.
abstract: OBJECTIVE
  Early allograft dysfunction (EAD) dramatically influences graft and patient outcome after orthotopic liver transplantation and its incidence is strongly determined by donor liver quality. Nevertheless, objective biomarkers, which can assess graft quality and anticipate organ function, are still lacking. This study aims to investigate whether there is a preoperative donor liver metabolomic biosignature associated with EAD.
  
  
  METHODS
  A comprehensive metabolomic profiling of 124 donor liver biopsies collected before transplantation was performed by mass spectrometry coupled to liquid chromatography. Donor liver grafts were classified into two groups: showing EAD and immediate graft function (IGF). Multivariate data analysis was used to search for the relationship between the metabolomic profiles present in donor livers before transplantation and their function in recipients.
  
  
  RESULTS
  A set of liver graft dysfunction-associated biomarkers was identified. Key changes include significantly increased levels of bile acids, lysophospholipids, phospholipids, sphingomyelins and histidine metabolism products, all suggestive of disrupted lipid homeostasis and altered histidine pathway. Based on these biomarkers, a predictive EAD model was built and further evaluated by assessing 24 independent donor livers, yielding 91% sensitivity and 82% specificity. The model was also successfully challenged by evaluating donor livers showing primary non-function (n=4).
  
  
  CONCLUSIONS
  A metabolomic biosignature that accurately differentiates donor livers, which later showed EAD or IGF, has been deciphered. The remarkable metabolomic differences between donor livers before transplant can relate to their different quality. The proposed metabolomic approach may become a clinical tool for donor liver quality assessment and for anticipating graft function before transplant.
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria - Fundación Hospital La Fe, Valencia, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Cortes
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria - Fundación Hospital La Fe, Valencia, Spain.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Pareja
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria - Fundación Hospital La Fe, Valencia, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, CIBERehd, Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas, FIS, Spain.
authors.forename: Juan C
authors.initials: JC
authors.lastname: García-Cañaveras
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria - Fundación Hospital La Fe, Valencia, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, CIBERehd, Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas, FIS, Spain.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Donato
authors.affiliation: Unidad Analítica, Instituto de Investigación Sanitaria - Fundación Hospital La Fe, Valencia, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Montero
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria - Fundación Hospital La Fe, Valencia, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Mir
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria - Fundación Hospital La Fe, Valencia, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, CIBERehd, Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas, FIS, Spain.
authors.forename: José V
authors.initials: JV
authors.lastname: Castell
authors.affiliation: Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria - Fundación Hospital La Fe, Valencia, Spain. Electronic address: agustin.lahoz@uv.es.
authors.forename: Agustín
authors.initials: A
authors.lastname: Lahoz
mesh_terms: D064591:Allografts; D001647:Bile Acids and Salts / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D005260:Female; D006084:Graft Rejection / Q000453:epidemiology* / Q000503:physiopathology*; D006639:Histidine / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016031:Liver Transplantation; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D055432:Metabolomics / Q000379:methods*; D008875:Middle Aged; D010743:Phospholipids / Q000378:metabolism; D011237:Predictive Value of Tests; D012307:Risk Factors; D013109:Sphingomyelins / Q000378:metabolism; D014019:Tissue Donors
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D008246:Lysophospholipids; D010743:Phospholipids; D013109:Sphingomyelins; D006639:Histidine
keywords: Lipidomics; Liver dysfunction; Liver transplant; Mass spectrometry; Primary non-function