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Evaluation and management of hyponatremia: an emerging role for vasopressin receptor antagonists

A Corrigendum to this article was published on 01 April 2007


Vasopressin-2 receptor antagonists, collectively known as the 'vaptans', provide a new approach to the treatment of hyponatremia; therefore, an updated Review of the pathophysiology of hyponatremia is particularly timely. After briefly defining hyponatremia and introducing its clinical aspects and complications, we present an approach to the diagnosis and evaluation of hyponatremia that is based primarily on the often-underused concept of free water clearance and, more specifically, the electrolyte-free water clearance. Then we review the use of vasopressin receptor antagonists in the management of hyponatremia from the standpoint of their pharmacology, their mechanism of action, and available efficacy data from clinical trials.

Key Points

  • Pathogenesis of hyponatremia involves an imbalance between water intake and water output

  • Hyponatremia is categorized according to severity, chronicity and patient volume status; there are therapeutic ramifications associated with each category

  • Calculating the electrolyte-free water clearance—especially the urine:plasma electrolyte ratio—can help to guide prescription of water restriction and response to other therapies

  • Vasopressin receptor antagonists (aquaretics) seem to be safe and effective for treatment of euvolemic and hypervolemic hyponatremia

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Figure 1: Correlation between solute-free water clearance and urinary AQP-2 excretion during the first 2 h of urine collection in chronic heart failure patients after administration of lixivaptan (VPA-985).
Figure 2: Effect of administration of lixivaptan (VPA-985) at different doses on urinary AQP-2 excretion.
Figure 3: Effect of conivaptan (YM087) on least-squares mean ± standard error change from baseline in (A) FWC and (B) EFWC.
Figure 4: Change in average daily area under the curve for serum sodium concentration (A) from baseline to day 4 and (B) from baseline to day 30 in patients who received either tolvaptan or placebo.


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We acknowledge the classic studies by Schrier and co-workers, and the recent work on vaptans. It is impossible to be inclusive, but we would like to collectively recognize the countless investigators who have advanced our understanding of hyponatremia and its treatment. S Chen and N Jalandhara declared no competing interests.

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Correspondence to Daniel Batlle.

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Competing interests

D Batlle has received consultation fees from Astellas. He will receive a grant from Otsuka as part of a multicenter study on PKD using tolvaptan, and possibly from Astellas for a study on hyponatremia using conivaptan. S Chen and N Jalandhara declared no competing interests.

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Chen, S., Jalandhara, N. & Batlle, D. Evaluation and management of hyponatremia: an emerging role for vasopressin receptor antagonists. Nat Rev Nephrol 3, 82–95 (2007).

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