Lack of renal improvement with nonselective endothelin antagonism with tezosentan in type 2 hepatorenal syndrome
Open Access
- 20 September 2007
- journal article
- clinical trial
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 47 (1), 160-168
- https://doi.org/10.1002/hep.21940
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.)Keywords
This publication has 37 references indexed in Scilit:
- Role of endothelin and endothelin receptor antagonists in renal diseaseEuropean Journal of Clinical Investigation, 2006
- Tezosentan, an endothelin receptor antagonist, limits liver injury in endotoxin challenged cirrhotic ratsGut, 2004
- The management of ascites in cirrhosis: Report on the consensus conference of the International Ascites ClubHepatology, 2003
- Tezosentan in patients with acuteheart failure and acute coronary syndromesJournal of the American College of Cardiology, 2003
- RITZ-5: randomized intravenousTeZosentan (an endothelin-A/B antagonist)for the treatment of pulmonary edemaJournal of the American College of Cardiology, 2003
- Systemic and regional changes in plasma endothelin following transient increase in portal pressureLiver Transplantation, 2003
- Plasma levels of endothelin-1 in patients with the hepatorenal syndrome after successful liver transplantationTransplant International, 2000
- Plasma endothelin-1 and -3 in cirrhosis: relationship with systemic hemodynamics, renal function and neurohumoral systemsJournal of Hepatology, 1996
- Effect of different endothelin receptor antagonists and of the novel non‐peptide antagonist Ro 46‐2005 on endothelin levels in rat plasmaFEBS Letters, 1993
- Fully Enzymatic Inulin Determination in Small Volume Samples without DeproteinizationNephron, 1992