¹University of Bern, University Hospital Lausanne, University Hospital Bern, Five Office, Brunner-Naga Consulting, Jerini AG, Bern, Switzerland

Abstract

Purpose: Patients with hepatic insufficiency are known to cope less efficiently with Na load. In a rat CCl₄-induced liver cirrhosis model, Icatibant, a potent bradykinin-2 receptor antagonist, prevented Na retention, improved diuresis, and reduced microvascular leakage (Wirth et al Eur J Pharmacol 1997; 37: 45-53). Methods: In a randomized, double-blind, proof-of-concept study, 8 patients with liver cirrhosis (Child Pugh score 5-8) and 8 healthy subjects on standardized diet received a constant 3 day infusion of Icatibant (0.15 mg/kg/day) or vehicle (placebo), with Na load on Day 2 (2L NaCl 0.9% i.v.). Results: Using sinistrine clearance, renal function did not change during treatment while the baseline extracellular body water (Vd) was higher in patients than volunteers (12.4 vs. 10.2 L/m², p=0.05). In patients, 6-12h after NaCl load, Icatibant increased Na excretion vs. placebo by 6.9 mmol/h (p=0.02), K excretion by 1.24 mmol/h (p=0.04), urine osmolarity by 18.54 mmol/h (p=0.01), and urine flow by 41.4 mL/h (p=0.05) while on Day 3 cumulative Na excretion was higher (+85.9 mmol, p=0.09) and body weight lower (|[minus]|0.53 kg, p=0.04). In volunteers, response to Na load was prompt and nearly similar for both periods. Icatibant was safe and well tolerated. Conclusion: Icatibant increases the natriuretic response in cirrhotic patients after Na load. Its potential for treating patients with refractory ascites should be investigated further.