Terlipressin improves renal function in patients with cirrhosis and ascites without hepatorenal syndrome

Abstract

Patients with advanced cirrhosis and ascites are characterized by circulatory dysfunction with splanchnic vasodilatation and renal vasoconstriction, which often lead to ascites. The vasoconstrictor terlipressin improves renal function in hepatorenal syndrome (HRS). The aim of this study was to evaluate if terlipressin also improves renal function in patients with ascites without HRS. Twenty-three patients with cirrhosis participated; 15 with nonrefractory ascites were randomized to either terlipressin (N group, n ‫؍‬ 11) or a placebo (P group, n ‫؍‬ 4), and 8 had refractory ascites and received terlipressin (R group). The glomerular filtration rate (GFR), sodium clearance (C Na ), lithium clearance (C Li ), osmolal clearance (C Osm ), and urine sodium concentration (U Na ) were assessed before and after the injection of 2 mg of terlipressin or the placebo. GFR increased in the N group (69 ؎ 19 versus 92 ؎ 25 mL/min, P < 0.005) and in the R group (31 ؎ 19 versus 41 ؎ 31 mL/min, P < 0.05) after terlipressin. In the N group, terlipressin induced an increase in C Na (0.89 ؎ 0.21 versus 1.52 ؎ 1.45 mL/min, P < 0.05), C Li (17.3 ؎ 8.9 versus 21.5 ؎ 11.6 mL/min, P < 0.05), and C Osm (2.10 ؎ 0.81 versus 3.06 ؎ 2.0 mL/min, P < 0.05). In the R group, terlipressin induced an increase in C Na (0.11 ؎ 0.18 versus 0.35 ؎ 0.40 mL/min, P < 0.05) and C Li (5.5 ؎ 4.2 versus 9.5 ؎ 8.55 mL/min, P < 0.05). U Na increased in both groups after terlipressin (P < 0.005). Plasma norepinephrine (P < 0.05) and renin (P < 0.05) decreased after terlipressin. All parameters remained unchanged after the placebo. A scites is a serious complication of cirrhosis, occurring in about 50% of patients within 10 years after diagnosis, and it is associated with 50% mortality in 2 years. 1,2 Patients with ascites have hyperdynamic circulation, which is characterized by peripheral and splanchnic arterial vasodilatation and reduced arterial blood pressure and systemic vascular resistance. 3 Portal hypertension and splanchnic vasodilatation are major factors in the development of ascites. 4,5 Secondary to vasodilatation, vasoactive hormones, such as the reninangiotensin-aldosterone system and the sympathetic nervous system, are activated. This leads to renal vasoconstriction and reduced renal perfusion and filtration pressure. The current standard treatment of ascites involves diuretics and paracentesis, which are not designed to improve the underlying pathophysiology. The changes in the renal handling of water and salt seem to develop stepwise from a stage that can be controlled by diuretics to a stage refractory to diuretics and finally to full-blown renal failure, which is known as hepatorenal syndrome (HRS) type 1. 6 Several clinical studies have evaluated the efficacy of the long-term administration of terlipressin [a vasopressin 1 (V1) receptor agonist] in patients with HRS, [7][8][9][10][11][12][13] and there is evidence that terlipressin may improve renal

Effects of terlipressin on the aquaretic system: evidence of antidiuretic effects

“…The decrease in plasma sodium is the reflection of terlipressin's ability to retain water as shown in this study and to induce natriuresis as previously shown (9). In studies in HRS terlipressin has been shown to improve plasma sodium, however, only in combination with albumin (18,25).…”

“…This suggests that the V 2 receptor stimulation was intense, which corresponds with the observed increase in AQP2 excretion and in absolute distal water reabsorption. In contrast, terlipressin increases sodium excretion without affecting the distal sodium reabsorption (9).…”

“…Patients with HRS are characterized by avid sodium and water retention. Terlipressin is believed to selectively cause vasoconstriction by stimulation of V 1 receptors (9). The V 1 receptors are predominantly located in the smooth muscles of the arterial vasculature in the splanchnic region (6).…”

Treatment of type 2 hepatorenal syndrome in patients awaiting transplantation: Effects on kidney function and transplantation outcomes

“…[1][2][3][4]7 This treatment causes a marked increase in GFR in approximately 50% of patients and improves survival in type 1 HRS. [8][9][10][11][12] Therefore, this pharmacological treatment has become the standard of care for this condition. 13 Nonetheless, it is important to remark that short-term mortality remains elevated despite reversal of type 1 HRS and that liver transplantation (LT) remains the definitive therapy in candidate patients.…”

Pharmacological Therapy of Ascites

“…Vasoconstrictors such as the α1-adrenergic agonist midodrine or terlipressin improve circulatory and renal function in patients with and without refractory ascites. Terlipressin is given in intravenous boluses (1 mg at onset of paracentesis, 1 mg at 8 h and 1 mg at 16 h) in addition to oral midodrine (for 72 h post-paracentesis), which appear to be as good as albumin in suppressing plasma renin elevation in randomized trials; terlipressin is not commercially offered in the United States [51,68,69].…”