A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: A multicenter, randomized, placebo-controlled trial

Abstract

for The North American VPA-985 Study Group Hyponatremia in advanced cirrhosis and ascites or congestive heart failure (CHF) is the result of an inappropriate increase in vasopressin secretion, which acts through activation of specific V 2 receptors in the distal renal nephron to increase water reabsorption. This study investigates the efficacy and safety of 3 different doses of the V 2 receptor antagonist, VPA-985, in correcting hyponatremia over a 7-day inpatient study period. Forty-four hospitalized patients (33 patients with cirrhosis, 6 with CHF, and 5 with syndrome of inappropriate antidiuretic hormone (SIADH) were studied on a constant sodium intake, with VPA doses of 25, 125, and 250 mg twice daily or placebo. Serum sodium measurements were repeated after every daily dose, and the next dose withheld for excessive serum sodium rises. Fluid intake was adjusted according to previous 24-hour urinary outputs. Adverse events were based on clinical signs of dehydration or encephalopathy. VPA-985 produced a significant overall aquaretic response compared with placebo, with significant dose related increases in free water clearance (P < .05) and serum sodium (P < .05), without significant changes in orthostatic blood pressure or serum creatinine levels. Five patients (50%) on 250 mg twice daily had to have medication withheld on multiple occasions. End-of-study plasma vasopressin levels increased significantly in the 2 larger dose groups. In conclusion, VPA-985 appears effective and safe in appropriate doses in correcting abnormal renal water handling and hyponatremia in conditions associated with water retention. Higher doses of VPA-985 may produce significant dehydration and will require close monitoring with their use. (HEPATOLOGY 2003;37:182-191.)See Editorial on Page 13 P atients with advanced cirrhosis and ascites or with congestive heart failure (CHF) have a disturbance in water metabolism, resulting in decreased renal free water excretion and dilutional hyponatremia. 1 The presence of hyponatremia in hospitalized patients with alcoholic cirrhosis or CHF is associated with a significantly increased mortality. 2,3 The inability of these patients to excrete an appropriate amount of free water is related to many factors, the most important of which is the nonosmotic stimulation of vasopressin release. [4][5][6] Plasma vasopressin levels are increased despite low plasma osmolality, 7 reflecting the resetting of the osmostat to a lower osmolar threshold for vasopressin suppression. 8 Vasopressin exerts its effects on water metabolism through the activation of specific V 2 receptors, which are expressed on the cells of the ascending limb of the loop of Henle and on the cells of the collecting duct of the nephron. 9 In the collecting duct, the activation of the V 2 receptor increases water reabsorption directly through the insertion of water channels into the otherwise water-impermeable collecting duct cells. 10 V 2 receptor antagonists, by competitive binding to the V 2 receptor, can displace vasopressin and, the...

Aquaporin-1 and aquaporin-2 urinary excretion in cirrhosis: Relationship with ascites and hepatorenal syndrome

“…Finally, it would also be important to study aquaporin-2 excretion in patients with cirrhosis whose serum sodium concentration has been normalized by the administration of V2 receptor antagonists, drugs that increase solute-free water excretion and improve serum sodium levels. 32,33 In conclusion, patients with cirrhosis, particularly those with hyponatremia and hepatorenal syndrome, have decreased urinary aquaporin-2 excretion relative to healthy subjects, which suggests there is down-regulation of aquaporin-2 expression in the kidneys of those with cirrhosis. This may be a compensatory response to the hyponatremia and extracellular fluid volume expansion that patients with cirrhosis have.…”

Hyponatremia: Clinical Associations, Prognosis, and Treatment in Cirrhosis

“…Yet, an allocation system that incorporates a factor with such wide variability depending on the use of diuretics and fluid status may prevent pretransplant deaths, but also may increase posttransplant mortality, as patients with pretransplant hyponatremia have been shown to have more complications as previously noted. 60,61 Posttransplant Hyponatremia appears to have clinical implications after liver transplant. Patients with hyponatremia before transplant were more likely to develop delirium, renal failure, and infectious complications within the first months after transplant.…”

“…73,74 In addition, other studies such as Okita and associates have suggested a dose-dependent improvement in ascites, lower extremity edema and tolerance to diuretics with tolvaptan, but further research is needed to confirm these findings. 60,61,76,79,80 Conivaptan, approved for only 4 days of intravenous use in the hospital, for euvolemic and hypervolemic hyponatremia, 81 has limited data on its safety and efficacy. [82][83][84] In general, conivaptan was well tolerated with the most common adverse reaction being infusion-site reactions.…”

Vasopressin receptor antagonists

“…15 From the results of these studies, it has been concluded that lixivaptan is safe and effective at various doses at correcting abnormal renal water handling and hyponatremia in patients who are in a water-retentive state.…”