NDT Advance Access originally published online on April 3, 2007
Nephrology Dialysis Transplantation 2007 22(8):2149-2155; doi:10.1093/ndt/gfm158
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Thrombin inhibition with melagatran does not attenuate renal ischaemia-reperfusion injury in rats
1Department of Anaesthesiology and Intensive Care, Institute of Clinical Sciences, 2Department of Nephrology, Institute of Medicine, 3Department of Physiology, Institute of Neurosciences and Physiology, The Sahlgrenska Academy at Göteborg University, Göteborg, Sweden and 4Department of Clinical Pathology, Odense University Hospital, Odense, Denmark
Correspondence and offprint requests to: Nicoletta Nitescu, MD, Department of Anaesthesiology and Intensive Care, Institute of Clinical Sciences, Sahlgrenska University Hospital, S-413 45 Göteborg, Sweden. Email: nicoletta.nitescu{at}vgregion.se
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Abstract |
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Background. Renal ischaemia-reperfusion (IR) is associated with activation of the coagulation system and inflammation within the kidney. The aim of the present study was to examine the effects of selective thrombin inhibition with melagatran on kidney morphology and function in rats subjected to renal IR.
Methods. Sprague–Dawley rats underwent renal IR (35 min of bilateral renal arterial clamping), or sham surgery. Treatment groups were: (i) IR–Saline, (ii) IR–Melagatran, (iii) Sham–Saline, and (iv) Sham–Melagatran. Twenty minutes prior to renal IR, the rats were administered a bolus dose of saline vehicle or melagatran [0.5 µmol/kg, subcutaneously (s.c.)] followed by a continuous infusion throughout (0.08 µmol/kg/h, s.c.). Forty-eight hours after IR, renal function was assessed in anaesthetized animals and kidney histology was analysed semi-quantitatively.
Results. Rats in group IR–Saline showed an approximate 85% reduction in glomerular filtration rate, 5-fold increases in fractional urinary excretion rates of sodium, potassium and water, and marked renal histological abnormalities, compared with sham (P < 0.05). Renal histopathological changes in the cortex and outer medulla were characterized by tubular necrosis and atrophy, tubular cast formation and interstitial inflammation. In addition, there was significant vascular congestion in the inner stripe of the outer medullary zone. Melagatran treatment had no significant effects on any of the abnormalities in kidney morphology or function in rats subjected to renal IR. Plasma melagatran concentrations were within a range known to exert significant antithrombotic effects, throughout the study period.
Conclusions. Thrombin inhibition with melagatran did not ameliorate abnormalities in kidney morphology or function 48 h after renal IR. These results indicate that melagatran is not renoprotective in rats subjected to renal IR.
Keywords: acute renal failure; coagulation; ischaemia-reperfusion; melagatran; thrombin; thrombin inhibitor
Received for publication: 31.10.06
Accepted in revised form: 2. 3.07