title: Hepatocyte-derived microRNAs as serum biomarkers of hepatic injury and rejection after liver transplantation.
abstract: Recent animal and human studies have highlighted the potential of hepatocyte-derived microRNAs (HDmiRs) in serum as early, stable, sensitive, and specific biomarkers of liver injury. Their usefulness in human liver transplantation, however, has not been addressed. The aim of this study was to investigate serum HDmiRs as markers of hepatic injury and rejection in liver transplantation. Serum samples from healthy controls and liver transplant recipients (n = 107) and peritransplant liver allograft biopsy samples (n = 45) were analyzed via the real-time polymerase chain reaction quantification of HDmiRs (miR-122, miR-148a, and miR-194). The expression of miR-122 and miR-148a in liver tissue was significantly reduced with prolonged graft warm ischemia times. Conversely, the serum levels of these HDmiRs were elevated in patients with liver injury and positively correlated with aminotransferase levels. HDmiRs appear to be very sensitive because patients with normal aminotransferase values (<50 IU/L) had 6- to 17-fold higher HDmiR levels in comparison with healthy controls (P < 0.005). During an episode of acute rejection, serum HDmiRs were elevated up to 20-fold, and their levels appeared to rise earlier than aminotransferase levels. HDmiRs in serum were stable during repeated freezing and thawing. In conclusion, this study shows that liver injury is associated with the release of HDmiRs into the circulation. HDmiRs are promising candidates as early, stable, and sensitive biomarkers of rejection and hepatic injury after liver transplantation.
authors.affiliation: Department of Surgery and Laboratory of Experimental Transplantation and Intestinal Surgery, Erasmus MC: University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Waqar R R
authors.initials: WR
authors.lastname: Farid
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
authors.forename: Adriaan J P
authors.initials: AJ
authors.lastname: van der Meer
authors.forename: Petra E
authors.initials: PE
authors.lastname: de Ruiter
authors.forename: Vedashree
authors.initials: V
authors.lastname: Ramakrishnaiah
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Jonge
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Tilanus
authors.forename: Geert
authors.initials: G
authors.lastname: Kazemier
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
mesh_terms: D000208:Acute Disease; D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D005260:Female; D006084:Graft Rejection / Q000097:blood* / Q000175:diagnosis; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007511:Ischemia / Q000097:blood; D008099:Liver / Q000098:blood supply; D008107:Liver Diseases / Q000097:blood* / Q000175:diagnosis; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D008875:Middle Aged; D014184:Transplantation, Homologous
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase