Anti-thrombin therapy during warm ischemia and cold preservation prevents chronic kidney graft fibrosis in a DCD model.
Ischemia reperfusion injury (IRI) is pivotal for renal fibrosis development via peritubular capillaries injury. Coagulation represents a key mechanism involved in this process. Melagatran (M), a thrombin inhibitor, was evaluated in an autotransplanted kidney model, using Large White pigs. To mimic deceased after cardiac death donor conditions, kidneys underwent warm ischemia (WI) for 60 min before cold preservation for 24 h in University of Wisconsin solution. Treatment with M before WI and/or in the preservation solution drastically improved survival at 3 months, reduced renal dysfunction related to a critical reduction in interstitial fibrosis, measured by Sirius Red staining. Tissue analysis revealed reduced expression of transforming growth factor-beta (TGF-beta) and activation level of its effectors phospho-Smad3, Smad4 and connective tissue growth factor (CTGF) after M treatment. Fibrinolysis activation was also observed, evidenced by downregulation of PAI-1 protein and gene expression. In addition, M reduced S100A4 expression and vimentin staining, which are markers for epithelial mesenchymal transition, a major pathway to chronic kidney fibrosis. Finally, expression of oxidative stress markers Nox2 and iNOS was reduced. We conclude that inhibition of thrombin is an effective therapy against IRI that reduces chronic graft fibrosis, with a significantly positive effect on survival.
Favreau
F
F
Inserm U927, Ischémie-reperfusion en transplantation rénale, Poitiers, France.
Thuillier
R
R
Cau
J
J
Milin
S
S
Manguy
E
E
Mauco
G
G
Zhu
X
X
Lerman
L O
LO
Hauet
T
T
D000241:Adenosine; D000493:Allopurinol; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D001384:Azetidines / Q000627:therapeutic use*; D001483:Base Sequence; D001596:Benzylamines / Q000627:therapeutic use*; D002908:Chronic Disease; D017931:DNA Primers / Q000235:genetics; D005355:Fibrosis; D005978:Glutathione; D006801:Humans; D007328:Insulin; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects / Q000379:methods* / Q000473:pathology; D008297:Male; D023421:Models, Animal; D009926:Organ Preservation; D019188:Organ Preservation Solutions; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011887:Raffinose; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D013696:Temperature; D014019:Tissue Donors; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014182:Transplantation, Autologous
D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; D017931:DNA Primers; D007328:Insulin; D019188:Organ Preservation Solutions; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C055206:University of Wisconsin-lactobionate solution; C109573:melagatran; D000493:Allopurinol; D010959:Tissue Plasminogen Activator; D005978:Glutathione; D000241:Adenosine; D011887:Raffinose