Urinary excretion of the water channel aquaporin 2 correlated with the pharmacological effect of tolvaptan in cirrhotic patients with ascites
Urinary excretion of the water channel aquaporin 2 correlated with the pharmacological effect of tolvaptan in cirrhotic patients with ascites
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DOI：
10.1007/s00535-015-1143-3
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发表时间：
2016-06-01
影响因子：
6.3
通讯作者：
Izumi, Namiki
中科院分区：
文献类型：
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作者：
Nakanishi, Hiroyuki;Kurosaki, Masayuki;Izumi, Namiki
肾脏集合管细胞顶端膜上的水通道水通道蛋白2（AQP 2）介导水重吸收。AQP 2在顶膜的表达受到加压素的严格调节，并通过最近开发的ELISA法测量尿型进行定量。托伐普坦，一种血管加压素2型受体拮抗剂，抑制肝硬化的水重吸收。本研究的目的是确定托伐普坦的药理作用与尿AQP 2水平动态之间的相关性。托伐普坦用于41例标准利尿剂治疗无效的腹水患者。分别于治疗前、治疗后4、8、24 h测定尿AQP 2排泄量和尿渗透压，发现治疗前腹水型糖尿病患者尿AQP 2/肌酐比值显著高于健康对照组（P < 0.0001）。托伐普坦给药后，尿AQP 2/肌酐比值在4 h和8 h分别下降45.0%和77.0%。同样，尿渗透压在4 h和8 h分别下降42.0%和41.5%。尿AQP 2水平和尿渗透压在基线和托伐普坦给药后的所有时间点均显著相关。4 h时尿AQP 2水平下降程度与尿渗透压下降程度显著相关（r = 0.452，P = 0.009）和8h（r = 0.384，P = 0.030）。这些结果表明，AQP 2系统在肝硬化的液体潴留中起主要作用，并且可以通过测量尿AQP 2水平的动态来监测托伐普坦抑制水重吸收的药理作用。
The water channel aquaporin 2 (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 24 h 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 4 h and 77.0 % at 8 h. Similarly, urinary osmolarity decreased by 42.0 % at 4 h and 41.5 % at 8 h. 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 4 h (r = 0.452, P = 0.009) and 8 h (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.