Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome.
Renal vasoconstriction is a key factor in the development of hepatorenal syndrome (HRS) and may be secondary to increased activities of endothelin-1, a potent renal vasoconstrictor. To assess the effects of tezosentan, a nonselective endothelin receptor antagonist, on renal function in patients with type 2 HRS, six male patients, 56.3 +/- 2.5 years old, with cirrhosis and type 2 HRS were treated with tezosentan; ascending doses of 0.3, 1.0, and 3.0 mg/hour, each for 24 hours, were used for the initial 2 patients, but a constant dose of 0.3 mg/hour for up to 7 days was used for the remaining 4 patients. The glomerular filtration rate, renal plasma flow, 24-hour urinary volume, mean arterial pressure (MAP), heart rate, tezosentan levels, and vasoactive hormones were measured daily. Albumin was given as required. The study was stopped early because of concerns about the safety of tezosentan in type 2 HRS. Five patients discontinued the study early; one stopped within 4 hours because of systemic hypotension (MAP < 70 mm Hg), and 4 patients stopped at approximately 4 days because of concerns about worsening renal function (serum creatinine increased from 180 +/- 21 to 222 +/- 58 micromol/L, P > 0.05) and decreasing urine volume (P = 0.03) but without a significant change in MAP. The plasma tezosentan concentrations were 79 +/- 34 ng/mL at a steady state during infusion at 0.3 mg/hour. The plasma endothelin-1 concentrations increased from 2.7 +/- 0.3 pg/mL at the baseline to 19.1 +/- 7.3 pg/mL (P < 0.05).


CONCLUSIONS
An endothelin receptor blockade potentially can cause a deterioration in renal function in patients with cirrhosis and type 2 HRS. Caution should be taken in future studies using endothelin receptor antagonists in these patients.
Wong
Florence
F
Division of Gastroenterology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Canada. florence.wong@utoronto.ca
Moore
Kevin
K
Dingemanse
Jasper
J
Jalan
Rajiv
R
D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000097:blood; D006439:Hemodynamics / Q000187:drug effects; D006530:Hepatorenal Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007677:Kidney Function Tests; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D012964:Sodium / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D017211:Treatment Failure; D014867:Water / Q000378:metabolism
D019332:Endothelin-1; D011725:Pyridines; D013777:Tetrazoles; D014867:Water; C120582:tezosentan; D012964:Sodium