Do vasopressin V2 receptor antagonists benefit cirrhotics with refractory ascites?

Abstract

Hyponatremia is a frequent complication of advanced cirrhosis with ascites associated with increased morbidity and mortality. It is caused by an impairment in the renal capacity to eliminate solute-free water and is considered to be related to persistent secretion of vasopressin despite low serum osmolality. This nonosmotic release of vasopressin is mediated by the autonomic nervous system, which senses the underfilling of arterial vascular component. This reduction of effective arterial blood volume is closely related to the development of ascites. Although the short-time effects of vasopressin V2 receptor antagonists (vaptans) on hyponatremia and ascites have been repeatedly reported, their effects on the long-term management of cirrhotic ascites have not been established yet. Considering that their effects on water diuresis and their safety are limited by severe underfilling state of patients, cautious approaches with adequate monitoring are needed to advanced cirrhosis. Proper indication, adequate doses and new possibility of combination therapy should be explored in the future controlled study. As hyponatremia is frequent obstacle to ascites management, judicious combination with low-dose diuretics may decrease the incidence of refractory ascites. Although vaptans show much promise in the treatment of advanced cirrhosis, the problem of high cost should be solved for the future.

Keywords: Ascites; Hyponatremia; Liver cirrhosis; Pathophysiology; V2 receptor antagonist.

Figure 1

Phatophysiologic backgrounds and main theories of ascites formation in liver cirrhosis. The pathogenetic events leading to ascites formation in patients with liver cirrhosis are multifactorial. They include hepatic venous outflow block, portal hypertension and hypoalbuminemia as hepatic factors, hyperdynamic circulation, peripheral arterial vasodilation, decreased effective circulating blood volume and altered neurohumoral systems as systemic circulatory factors, and enhanced salt and water reabsorption in proximal and distal nephron and convoluted duct related to intrarenal haemodynamic derangement as renal factors. They are closely interrelated and enhance salt and water reabsorption in the kidney. The activities of the two major vasoconstrictor and antinatriuretic systems, the renin-angiotensin-aldosteron system and the sympathetic nervous system, are increased in most cirrhotics with tense ascites. Increased plasma level of arginine vasopressin enhances water reabsorption in the collecting duct and contributes to water retention. Endothelin, an endothelial-derived peptide with marked vasoconstrictor activity, is also increased in advanced cirrhosis[86,87]. Increased endothelin levels were proven to be related to creatinine clearance, effective renal plasma flow[88], serum creatinine and blood pressure[89], and may also contribute to renal dysfunction in patients with cirrhosis[88]. Three main hypotheses, the underfilling theory, the overflow theory and the peripheral arterial vasodilation theory, are considered to explain variable pathophysiological changes occurred in a patient with advanced liver cirrhosis. VIP: Vasoactive intestinal peptide; CGRP: Calcitonin gene-related peptide; PG: Prostaglandin; TX; Thromboxane; LT: Leukotriene.