Urinary excretion of the water channel aquaporin2 correlated with the pharmacological effect of tolvaptan in cirrhotic patients with ascites.

Abstract

The water channel aquaporin2 (AQP2) at the apical membrane of renal collecting duct cells mediates water reabsorption. The expression of AQP2 at the apical membrane is tightly regulated by vasopressin and was quantitated by measurement of the urinary form by a recently developed ELISA. Tolvaptan, an antagonist of vasopressin type 2 receptor, inhibits water reabsorption in cirrhosis. The aim of this study was to determine the correlation between the pharmacological effect of tolvaptan and the dynamics of urinary AQP2 levels. Tolvaptan was administered to 41 cirrhotic patients with ascites unresponsive to standard diuretic therapy. Urinary excretion of AQP2 and urinary osmolarity were measured at the baseline and at 4, 8, and 24h after administration of tolvaptan. At the baseline, urinary AQP2/creatinine ratios were significantly higher in cirrhotic patients with ascites than in healthy controls (P<0.0001). After administration of tolvaptan, urinary AQP2/creatinine ratios decreased by 45.0% at 4h and 77.0% at 8h. Similarly, urinary osmolarity decreased by 42.0% at 4h and 41.5% at 8h. Urinary AQP2 levels and urinary osmolarity significantly correlated at the baseline and at all time points after tolvaptan administration. The degree of the decrease in urinary AQP2 levels and degree of the decrease in urinary osmolarity correlated significantly at 4h (r=0.452, P=0.009) and 8h (r=0.384, P=0.030) after tolvaptan administration. These results indicate that the vasopressin-AQP2 system plays a major role in fluid retention in cirrhosis and that the pharmacological effect of tolvaptan to inhibit water reabsorption can be monitored by measurement of the dynamics of urinary AQP2 levels.