Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome

Authors

  • Florence Wong,

    Corresponding author
    1. Division of Gastroenterology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Canada
    • 9th Floor, North Wing, Room 983, Toronto General Hospital, 200 Elizabeth Street, Toronto M5G2C4, Ontario, Canada
    Search for more papers by this author
    • fax: 416-340-5019

  • Kevin Moore,

    1. Institute of Hepatology and Centre for Hepatology, Department of Medicine, Royal Free and University College Medical School, University College London, London, United Kingdom
    Search for more papers by this author
  • Jasper Dingemanse,

    1. Clinical Development, Actelion Pharmaceuticals, Ltd., Allschwil, Switzerland
    Search for more papers by this author
  • Rajiv Jalan

    1. Liver Failure Group, Institute of Hepatology, Division of Medicine, University College London, London, United Kingdom
    Search for more papers by this author

  • Potential conflict of interest: Nothing to report.

  • Part of this work was undertaken at University College London Hospitals/University College London, which received a proportion of its funding from the United Kingdom Department of Health through the National Institute for Health Research Biomedical Research Centres. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health.

Abstract

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. (HEPATOLOGY 2007.)

Ancillary