V2-antagonists for the treatment of hyponatraemia.

Hypotonic hyponatraemia results from an excess of total body water relative to the exchangeable sodium and potassium pool due to a decrease in electrolyte-free water (EFWC) excretion [1]. The decrease in free water excretion is mostly due to the secretion of the antidiuretic hormone (ADH), also called vasopressin. This secretion is either ‘appropriate’ when it is a result of volume stimuli, or ‘inappropriate’, as in the syndrome of inappropriate secretion of ADH (SIADH), when osmotic or volume stimuli are lacking. Vasopressin is involved in most cases of sustained hyponatraemia. Therefore, the use of specific blockers of vasopressin receptors is a logical approach in the treatment of patients with SIADH or hypervolemic hyponatraemia and may offer advantages over current available therapies (Table 1: treatment of SIADH). Selective non-peptide V2-receptor antagonists (V2RA, collectively known as the ‘vaptans’) are currently in development and in phase III trials:OPC41061 (Tolvaptan), VPA 985 (Lixivaptan), YM 087 (Conivaptan: V1aþV2 antagonists), OPC 31260 (Mozavaptan)) and SR 121463B (Satavaptan). Recently, Conivaptan (Vaprisol, Astellas) has been approved for parenteral use in the United States for SIADH and Mozavaptan for paraneoplastic SIADH in Japan. Some published studies with these ‘vaptans’ have been conducted in hyponatraemic patients with cirrhosis [3,4], congestive heart failure [5] and patients with SIADH [6], showing their effectiveness in increasing EFWC in various water-retention disorders. Recently, Schrier et al. reported the results of two large multicentre, randomized, placebo-controlled, double-blind trials of oral Tolvaptan in subjects with hyponatraemia and chronic heart failure, cirrhosis, SIADH or other causes. Patients were randomly assigned to oral placebo (223 patients) or oral Tolvaptan (225), at a dose of 15mg daily. The dose of Tolvaptan was increased to 30mg daily and then to 60mg daily, if sodium concentration remained <135mmol/l and had increased <5mmol//l during the 24 h after the initial dose. Tolvaptan was stopped after 30 days and serum sodium (SNa) was measured again one week later. Mild hyponatraemia was defined as 130–134mmol/l (50% of the patients) and marked hyponatraemia as <130mmol/l. All the patients seemed to be asymptomatic. One difference with other studies with V2RA was that water restriction was not prescribed to these patients. Urine output in the placebo group was, for example, 2079ml 1534ml and fluid intake 1492ml 945ml in the first day of the study. Therefore, many hyponatraemia patients had a fluid intake >2 l a day! This probably explains why the daily increase in SNa was lower than in other studies (the first day of treatment induced an SNa increase of about 2–3mmol/l and about 7mmol/l at the end of the study, on day 30). Around 55% of the patients in the Tolvaptan group had a normal SNa after one month of therapy and 25% in the placebo group. When Tolvaptan was stopped, SNa decreased again. The safety profile of the drug was excellent, except for an increased thirst, dry mouth and increased urination. A pre-specified combined analysis explored the effects of the drug on physical and mental health, using selfassessed scores on the Physical Component Summary and the Mental Component Summary (on a scale range going from 8 to 73 with higher score indicating better functioning) of the SF-12 Health Survey. Physical health did not improve, although mental health showed minimal (by two or three points), but significant improvement in the Tolvaptan group when comparing baseline to day 30. Most patients with chronic hyponatraemia and SNa >120mmol/l are usually considered asymptomatic [7], and while it is known that the presence of hyponatraemia is associated to an increase in morbidity and mortality [8–10], this is usually considered to be due to the severity of the underlying diseases. However, it has recently been shown that mild hyponatraemia is *Comments on Schrier RW, Gross P, Gheorghiade M et al. for the SALT investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatraemia. N Engl J Med 2006; 355: 2099–2112 Correspondence and offprint requests to: Guy Decaux, Department of General Internal Medicine, Erasme University Hospital, Brussels, Belgium. Email: guy.decaux@skynet.be Nephrol Dial Transplant (2007) 22: 1853–1855