title: Direct thrombin inhibitor prevents delayed graft function in a porcine model of renal transplantation.
abstract: BACKGROUND
  Kidney transplantations from donors after cardiac arrest (DCA) are characterized by an increase in the occurrence of delayed graft function and primary nonfunction. In this study, Melagatran, a selective reversible direct thrombin inhibitor was used to limit renal injury in a DCA pig kidney transplantation model.
  
  
  METHODS
  We used a porcine model of DCA to study the effects of treatment with Melagatran in the peri-conservation period. Thromboelastography was used to check Melagatran antithrombin effect on in vitro clot formation. Reverse-transcriptase polymerase chain reaction was used to analyze the peripheral immune cells activation status. Renal function and morphologic study were performed at days 1 and 7. Finally, we analyzed the mechanisms of Melagatran protection on kidney microvasculature primary endothelial cells.
  
  
  RESULTS
  Prolongation of coagulation time (Ex-Tem) was observed 10 min after injection; however, Melagatran did not modulate increases of thrombin-antithrombin complexes following reperfusion. Melagatran significant treatment lowered the proinflammatory status of circulating immune cells. Animal's survival was increased in Melagatran-treated groups (9 of 10 in Melagatran groups vs. 4 of 10 in controls at day 7). Renal injury and inflammation were also significantly reduced in treated groups. We also demonstrated a direct protective effect of Melagatran against endothelial cell activation and inflammation in vitro.
  
  
  CONCLUSIONS
  Direct thrombin inhibitor administration in the periconservation period improved graft outcome and reduced renal injury in a model of DCA.
authors.affiliation: Inserm U927, Poitiers, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Giraud
authors.forename: Raphael
authors.initials: R
authors.lastname: Thuillier
authors.forename: Aude
authors.initials: A
authors.lastname: Belliard
authors.forename: William
authors.initials: W
authors.lastname: Hebrard
authors.forename: Cédric
authors.initials: C
authors.lastname: Nadeau
authors.forename: Serge
authors.initials: S
authors.lastname: Milin
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Goujon
authors.forename: Emilie
authors.initials: E
authors.lastname: Manguy
authors.forename: Gérard
authors.initials: G
authors.lastname: Mauco
authors.forename: Thierry
authors.initials: T
authors.lastname: Hauet
authors.forename: Laurent
authors.initials: L
authors.lastname: Macchi
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001384:Azetidines / Q000627:therapeutic use*; D001596:Benzylamines / Q000627:therapeutic use*; D001926:Brain Death; D002470:Cell Survival / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D006323:Heart Arrest; D016030:Kidney Transplantation / Q000502:physiology*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D023421:Models, Animal; D010314:Partial Thromboplastin Time; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013552:Swine; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014182:Transplantation, Autologous / Q000502:physiology; D014184:Transplantation, Homologous / Q000502:physiology
chemical_list: D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; C109573:melagatran; D003404:Creatinine; D013917:Thrombin