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Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome
Author(s) -
Wong Florence,
Moore Kevin,
Dingemanse Jasper,
Jalan Rajiv
Publication year - 2008
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21940
Subject(s) - renal function , hepatorenal syndrome , medicine , urology , endothelin receptor , endothelin receptor antagonist , renal blood flow , creatinine , endocrinology , cirrhosis , receptor
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 ∼4 days because of concerns about worsening renal function (serum creatinine increased from 180 ± 21 to 222 ± 58 μmol/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). Conclusion: 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. (H EPATOLOGY 2007.)