Direct thrombin inhibitor prevents delayed graft function in a porcine model of renal transplantation.
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.
Giraud
Sebastien
S
Inserm U927, Poitiers, France.
Thuillier
Raphael
R
Belliard
Aude
A
Hebrard
William
W
Nadeau
Cédric
C
Milin
Serge
S
Goujon
Jean-Michel
JM
Manguy
Emilie
E
Mauco
Gérard
G
Hauet
Thierry
T
Macchi
Laurent
L
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
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; C109573:melagatran; D003404:Creatinine; D013917:Thrombin