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Urinary excretion of the water channel aquaporin 2 correlated with the pharmacological effect of tolvaptan in cirrhotic patients with ascites

  • Original Article—Liver, Pancreas, and Biliary Tract
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Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgment

This study was supported by a Grant-in-Aid from the Japan Agency for Medical Research and Development.

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Author notes

    Authors and Affiliations

    1. Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Kyonancho 1-26-1, Musashino-shi, Tokyo, 180-8610, Japan

      Hiroyuki Nakanishi, Masayuki Kurosaki, Takanori Hosokawa, Yuka Takahashi, Jun Itakura, Shoko Suzuki, Yutaka Yasui, Nobuharu Tamaki, Natsuko Nakakuki, Hitomi Takada, Mayu Higuchi, Yasuyuki Komiyama, Tsubasa Yoshida, Kenta Takaura, Tsuguru Hayashi, Konomi Kuwabara & Namiki Izumi

    2. Department of Nephrology, Tokyo Medical and Dental University, Tokyo, Japan

      Sei Sasaki

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    1. Hiroyuki Nakanishi
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    Correspondence to Namiki Izumi.

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    Conflict of interest

    Namiki Izumi received grants from the Japanese Ministry of Welfare, Health, and Labor and the Japanese Ministry of Education, Culture, Sports, and Science during the conduct of this study, and has received lecture fees from MSD, Chugai Pharmaceutical Company, Ltd.; Daiichi-Sankyo Company, Ltd.; Bayer AG; and Janssen Pharmaceutical K.K. Masayuki Kurosaki has received lecture fees from Chugai Pharmaceutical Company, Ltd; and Janssen Pharmaceutical K.K.

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    H. Nakanishi and M. Kurosaki contributed equally to this work.

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    Nakanishi, H., Kurosaki, M., Hosokawa, T. et al. Urinary excretion of the water channel aquaporin 2 correlated with the pharmacological effect of tolvaptan in cirrhotic patients with ascites. J Gastroenterol 51, 620–627 (2016). https://doi.org/10.1007/s00535-015-1143-3

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    • DOI: https://doi.org/10.1007/s00535-015-1143-3

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