Electrolyte-free Water Excretion Research Articles

Evaluation and Management of Hyponatremia in Heart Failure.

To provide a contemporary overview of the pathophysiology, evaluation, and treatment of hyponatremia in heart failure (HF). Potassium and magnesium losses due to poor nutritional intake and treatment with diuretics cause an intracellular sodium shift in HF that may contribute to hyponatremia. Impaired renal blood flow leading to a lower glomerular filtration rate and increased proximal tubular reabsorption lead to an impaired tubular flux through diluting distal segments of the nephron, compromising electrolyte-free water excretion. Hyponatremia in HF is typically a condition of impaired water excretion by the kidneys on a background of potassium and magnesium depletion. While those cations can and should be easily repleted, further treatment should mainly focus on improving the underlying HF and hemodynamics, while addressing congestion. For decongestive treatment, proximally acting diuretics such as sodium-glucose co-transporter-2 inhibitors, acetazolamide, and loop diuretics are the preferred options.

Protocolo diagnóstico y terapéutico de los trastornos del sodio

The term dysnatremia is applied to alterations in the concentration of sodium in the plasma. Changes in the concentration of sodium in the plasma may cause fluid displacements between intracellular and extracellular compartments, In a healthy individual the osmoregulatory system of the organism maintains the concentration of sodium from 135 to 145 mEq/l. An alteration in this system leads to an imbalance between the intake and excretion of free water. When the intake of free water surpasses excretion, the concentration of sodium in the plasma falls to below 135 mEq/l, a condition known as hyponatremia. On the contrary, hypernatremia, which is defined as a concentration of sodium in serum higher than 145 mEq/l, arises when the excretion of electrolyte-free water surpasses intake.

Hypernatremia due to Urea-Induced Osmotic Diuresis: Physiology at the Bedside.

Hypernatremia secondary to urea-induced solute diuresis is due to the renal excretion of electrolyte-free water. This concept is explained here step-wise physiologically with the help of a clinical vignette.

Diagnosis and management of hyponatraemia in the older patient.

Hyponatraemia (serum sodium concentration below 135 mmol/L) is the most common electrolyte disturbance and occurs commonly in older people. The causes can be complex to diagnose and treat and many published guidelines do not focus on the issues in an older patient group. Here, we are principally concerned with diagnosis and management of euvolaemic and hypervolaemic hyponatraemia in hospitalised patients over 70 years old. We also aim to increase awareness of hyponatraemia in residential aged care facilities and the community. Hyponatraemia can have many causes; in older people, chronic hyponatraemia can often be the result of medications used to treat chronic disease, particularly thiazide or thiazide-like drugs (such as indapamide) or drugs acting on the central nervous system. Where a reversible trigger (such as drug-induced hyponatraemia) can be identified, hyponatraemia may be treated relatively simply. Chronic hyponatraemia due to an irreversible cause will require ongoing treatment. Fluid restriction can be an effective therapy in dilutional hyponatraemia, although poor compliance and the burdensome nature of the restrictions are important considerations. Tolvaptan is an oral vasopressin receptor antagonist that can increase serum sodium concentrations by increasing electrolyte-free water excretion. Tolvaptan use is supported by clinical trial evidence in patients with hypervolaemic or euvolaemic hyponatraemia below 125 mmol/L. Clinical trial evidence also supports its use after a trial of fluid restriction in patients with symptomatic hyponatraemia above 125 mmol/L. The use of tolvaptan is affected by regulatory restriction of chronic therapy due to safety concern and the non-subsidised cost of treatment.

Vasopressin and Vasopressin Antagonists in Heart Failure.

Despite the introduction of multiple new pharmacological agents over the past three decades in the field of heart failure (HF), overall prognosis remains poor. Hyponatremia is prevalent in HF patients and has been suggested as a contributor to poor response to standard therapy. Elevated levels of arginine vasopressin (AVP), a peptide hormone produced in the hypothalamus, play a role in development of hyponatremia, and AVP and its surrogate, copeptin, are related to changes in osmolality, hemodynamics, neuro-hormones as well as in overall outcome in HF patients. Of current pharmacological interest are the selective and non-selective vasopressin receptor antagonists (VRAs), which inhibit vasoconstriction and cardiac remodeling mediated by the V1a receptors in smooth blood vessels, and water retention (increased urine osmolality and decreased water excretion) by increasing aquaporin-2 water channels mediated by the V2 receptors in the renal collecting tubules. The optimal use of VRAs is yet to be determined, especially in patients with congestive HF. Although long-term effects on improvement in mortality have not been shown in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, the only long-term outcome trial to date, many short-term studies indicate beneficial aquaretic- and hemodynamic-effects of the VRAs. In contrast to loop diuretics, these new agents tend to increase urine flow and the excretion of electrolyte-free water (so-called aquaresis) in patients with HF, without substantial changes in sodium or potassium excretion. This chapter reviews the role of AVP and copeptin in HF, and the treatment potential of VRAs in HF.

Urine Osmolarity Predicts the Body Weight-Reduction Response to Tolvaptan in Chronic Kidney Disease Patients: A Retrospective, Observational Study

Background/Aims: Tolvaptan, a vasopressin V2 receptor antagonist, promotes the excretion of electrolyte-free water. Patients with heart failure or liver cirrhosis, whose urine osmolarity is high due to increased vasopressin, show a good response to tolvaptan; however, it remains dubious whether tolvaptan is also effective in patients with low urine osmolarity due to decreased renal function. The aim of this study was to investigate whether urine osmolarity predicts the effect of tolvaptan in patients with decreased renal function. Methods: In this retrospective, observational study, 17 overhydrated chronic kidney disease patients with heart failure or liver cirrhosis who were admitted to Osaka University Hospital were included. They were treated with sodium-excreting diuretics first, and then tolvaptan was added. The clinically relevant parameters were evaluated before and after the use of tolvaptan, and they, including urine osmolarity before use of tolvaptan, were compared between the responder group and the non-responder group. The definition of responder was based on the decrease of body weight by ≥5% in one week, which is a more rigorous indicator of the effectiveness of tolvaptan than the increase in urine output. Results: The parameter that showed a significant difference between the responder and non-responder groups was urine osmolarity before the use of tolvaptan. The cut-off point derived from the receiver operating characteristic (ROC) curve analysis was 279 mOsm/kg H₂O, with sensitivity of 0.86 and specificity of 0.80. Conclusions: In patients with decreased renal function, urine osmolarity before the use of tolvaptan predicted the effectiveness of diuretics in terms of body weight reduction.

Employment of vasopressin receptor antagonists in management of hyponatraemia and volume overload in some clinical conditions.

Hyponatraemia, the most common electrolyte imbalance occurring in hospitalized subjects, is usually classified as hypovolaemic, euvolaemic or hypervolaemic. Hyponatraemia is a predictor of death among subjects with chronic heart failure and cirrhosis. The inappropriate secretion of the antidiuretic hormone (AVP) seems to be of pivotal importance in the decline of serum sodium concentration in these clinical conditions. The objective of this review was to summarize recent progress in management of hyponatraemia in SIADH, cirrhosis and heart failure. Literature searches were conducted on the topics of hyponatraemia and vasopressin receptor antagonists, using PubMed, pharmaceutical company websites and news reports. The information was evaluated for relevance and quality, critically assessed and summarized. The initial treatment of severe hyponatraemia is directed towards the prevention or management of neurological manifestations and consists of an intravenous infusion of hypertonic saline. Fluid restriction is indicated in oedematous states. Diuretics alone or in combination with other specific drugs remain the main strategy in the management of volume overload in heart failure. In resistant cases, ultrafiltration can lead to effective removal of isotonic fluid preventing new episodes of decompensation; however, aquapheresis is associated with increased costs and other limits. In several trials, the efficacy of vasopressin receptor antagonists in euvolaemic patients (inappropriate antidiuretic hormone secretion) or in hypervolaemic hyponatraemia (chronic heart failure, cirrhosis) has been evaluated. It was found that vaptans, which promote aquaresis, were superior to a placebo in raising and maintaining serum sodium concentrations in these subjects. Combined with conventional therapy, vasopressin receptor antagonists (AVP-R antagonists) are able to increase the excretion of electrolyte-free water and the sodium concentration. Further studies are needed to assess efficacious outcomes of aquaresis compared with aquapheresis and with conventional therapy.

O-071 Salt-sparing Diuretic Action Of A Urea Analogue Inhibitor Of Urea Transporters Ut-a And Ut-b In Rats

Background and aims Urea is end metabolite of protein metabolism and is crucial for generation of hypertonic renal medulla. Urea transport to medullary interstitium is facilitated by urea transporters (UT-A and UT-B). UT inhibitors have potential use as a novel class of salt-sparing diuretics. Methods UT inhibitor effect of urea analogue dimethylthiourea (DMTU) was investigated and characterised in cell-based assays. Kidney function tests were investigated in both 1-day and 7-days DMTU-treated (500 mg/kg ip initially, then 125 mg/kg ip every 12h) rats. The effect of DMTU on maximum urine concentrating function was investigated in low (6%) and normal (20%) protein-fed rats. Results DMTU non-competitively inhibited UT-A and UT-B with IC 50 of ~3 mM. Following 500 mg/kg ip injection, plasma DMTU concentration was initially 10 mM (plasma elimination t 1/2 ~10 h) and urine DMTU concentration was >20 mM for 12 h. DMTU-treated rats showed reversible, sustained reduction in urine osmolality (>60%) and 3-fold increased daily urine output. DMTU increased renal electrolyte-free water excretion without altering solute excretion. DMTU impaired maximum urinary concentrating function only in normal protein-fed rats. Methylurea, a non-UT inhibitor urea analogue, had no effect on either urine volume or osmolality. DMTU-treated rats had greater diuresis and much reduced urinary salt loss compared to that of furosemide-treated rats. Conclusions These results establish a rat model of sustained UT inhibition and demonstrate remarkable diuretic efficacy of UT inhibition. Prominent effect of UT inhibitors on net renal water excretion implies a novel therapeutic strategy for treatment of oedema in hypervolemic diseases.

Cost-Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease

Letters21 January 2014Cost-Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney DiseaseChristopher M. Blanchette, PhD, MBA, Benjamin Gutierrez, PhD, and Keith Friend, MDChristopher M. Blanchette, PhD, MBAFrom Otsuka America Pharmaceutical, Princeton, New Jersey.Search for more papers by this author, Benjamin Gutierrez, PhDFrom Otsuka America Pharmaceutical, Princeton, New Jersey.Search for more papers by this author, and Keith Friend, MDFrom Otsuka America Pharmaceutical, Princeton, New Jersey.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L14-5001-6 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:We acknowledge Erickson and colleagues’ (1) effort to study ADPKD, for which no approved treatment is available. Compared with placebo, tolvaptan was found to slow the increase in total kidney volume and decline in kidney function and led to more incidents of aquaresis (excretion of electrolyte-free water) and hepatic adverse events over 3 years in patients with this condition (2). Although a cost-effectiveness analysis of tolvaptan is necessary, it is premature to complete at this time because several key data points are unknown.Tolvaptan is available in the United States (3) but is not approved for the ...

Role of Vaptans in the Management of Hyponatremia

Hyponatremia, the most commonly encountered electrolyte abnormality, affects as many as 30% of hospitalized patients. It is a powerful predictor of poor outcomes, especially in patients with congestive heart failure or cirrhosis. The failure to excrete electrolyte-free water that results from persistent secretion of antidiuretic hormone despite low serum osmolality usually underlies the development of hyponatremia. Treatment depends on several factors, including the cause, overall volume status of the patient, severity of hyponatremic symptoms, and duration of hyponatremia at presentation. This review focuses on the role of the vasopressin receptor antagonists, or vaptans, in the treatment of hyponatremia. These recently introduced agents have the unique ability to induce an aquaresis, the excretion of electrolyte-free water without accompanying solutes. After a brief historical perspective and discussion of pharmacologic characteristics of vaptans, we review the accumulated experience with vaptans for the treatment of hyponatremia. Vaptans have been shown to increase serum sodium concentrations in patients with euvolemic or hypervolemic hyponatremia in a reproducible manner, but their safe use requires full understanding of their indications and contraindications.

Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease

BackgroundThe course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V2-receptor antagonists inhibit cyst growth and slow the decline of kidney function.MethodsIn this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V2-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.ResultsOver a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, −2.61 [mg per milliliter]−1 per year vs. −3.81 [mg per milliliter]−1 per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).ConclusionsTolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.)

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Case Reports: A 40 year female presented with nausea, vomiting and diarrhea for 2 weeks. She also had diagnoses of fibromyalgia, chronic fatigue and depression. She complained of “dizziness” and a 3-day history of increasing lethargy. In the ED, initial electrolyte evaluation showed severe derangements including Na 97, K 2.0, Cl 55, bicarbonate 33, iCa 3.89, Mg 1.9. Her urine osmolality was <40 mOsm/kg and urine Na was <10 mmol/L. Hemodynamics and respiratory status were unremarkable. On further asking, she revealed she had been drinking lot of fluids at home as she was not able to keep solid food down. The liquid she had been ingesting was predominantly iced tea in excess of 6 L/day. She was started on iv fluid supplementation along with multiple electrolyte abnormality correction. On day 3, her Na was 125 and she was more ataxic. MRI of the brain was done and it revealed presence of subtle increased T2 signal in the caudate head and minimally within the putamen bilaterally along with mild hyperintensity on T2 weighted imaging in the hippocampi bilaterally, without any pontine abnormalities. Findings were suggestive of early osmotic demyelination syndrome. Subsequently the symptoms resolved and she did not have any sequelae. This case highlights the phenomenon which is better known as beer potomania – contributed by limited solute intake in combination with excess liquid consumption. Iced tea, like beer, has no protein and very limited to nil Na content. The limit on how much free water excretion can be achieved in a day is dependent on urine osmolality (urine flow rate = rate of solute excretion / urine osmolality). For an individual drinking predominantly iced tea, they are taking in very limited solute per day, which is then eliminated in the urine. This puts a cap of only about 4-5 Liters of electrolyte-free water excretion per day. Thus, if an individual drinks more than the foresaid quantity of liquid in a day, in the absence of additional solute, he/she will become hyponatremic. On top of this mechanism, the patient described also may have non-osmotic secretion of ADH as a result of nausea, vomiting and diarrhea. All of these seem to have contributed to her severely depressed sodium levels.

The use of vasopressin receptor antagonists in hyponatremia

Introduction: Considerable data have recently characterized hyponatremia as fairly common in the intensive care and general hospital settings. Moreover, mounting evidence suggests the association of mild degrees of hyponatremia with untoward neurocognitive and musculoskeletal outcomes. A key development in our ability to treat hyponatremia was the introduction and approval of aquaretics (vaptans). These vasopressin receptor antagonists work by increasing electrolyte-free water excretion and thus raising serum sodium concentration.Areas covered: This review presents a diagnostic approach for hyponatremia and discusses some therapeutic considerations. It displays new evidence linking mild chronic hyponatremia with unfavorable outcomes and examines the available treatment options and their limitations and strengths. New data on vaptans and their potential role to treat hyponatremia in different clinical settings are reviewed.Expert opinion: Vaptans are likely to play an important role in treating hyponatremia, given their clinical efficacy and tolerability. High cost remains an impediment for vaptans, and more studies are needed to further define their best use in hyponatremic patients.

The use of vaptan in hyponatremic patients with liver cirrhosis

The use of vaptan in hyponatremic patients with liver cirrhosis

Renal and Anti-Aldosterone Actions of Vasopressin-2 Receptor Antagonism and B-Type Natriuretic Peptide in Experimental Heart Failure

Hemodynamic and neurohumoral function can affect the efficacy of diuretic therapy in congestive heart failure. Arginine vasopressin increases water reabsorption through the V(2) receptor in the collecting duct, whereas B-type natriuretic peptide (BNP) decreases sodium reabsorption in the collecting duct. We hypothesized that combining BNP to the V(2)-receptor antagonist tolvaptan (TLV) would enhance renal excretory function by augmenting sodium excretion together with aquaresis without adversely affecting renal hemodynamics in experimental congestive heart failure. Congestive heart failure was induced in 3 groups (n=6 per group) of dogs by tachypacing. A acute experiment was done after 10 days. After baseline measurements, study groups received a 0.1 mg/kg IV bolus of TLV alone (TLV), TLV in combination with BNP (TLV+BNP; 50 ng/[kg . min]), or BNP alone (BNP). Mean arterial pressure increased with TLV, remained unchanged with TLV+BNP, and decreased with BNP (+5+/-1mm Hg versus -1+/-1 mm Hg versus -15+/-1 mm Hg; P<0.05). Renal blood flow and glomerular filtration rate were preserved with all regimens. Urine flow increased in all 3 groups but significantly more so with TLV+BNP (TLV: +0.4+/-0.1 mL/min versus TLV+BNP: +2.4+/-0.5 mL/min versus BNP: +0.8+/-0.3 mL/min; P<0.05). Only TLV+BNP and BNP were natriuretic (P<0.05), whereas only TLV and TLV+BNP increased electrolyte-free water excretion (P<0.05). Compared with TLV alone, TLV+BNP prevented an increase in aldosterone (P<0.05). Coadministration of TLV and BNP in experimental HF resulted in a beneficial profile of renal, neurohumoral, and hemodynamic actions, specifically potent diuresis with natriuresis, neutral effect on mean arterial pressure, and lack of aldosterone activation.

Diagnosis and management of hyponatremia in acute illness

Hyponatremia is the most common electrolyte disorder present in hospitalized patients. Acute and severe hyponatremia can cause significant morbidity and mortality. The present review discusses the epidemiology, causes, and a practical approach to the diagnosis and management of acute and chronic hyponatremia, including the appropriate use of hypertonic saline and potential future use of the new V2 vasopressin receptor antagonists in critically ill patients. The increasing knowledge of aquaporin water channels and the role of vasopressin in water homeostasis have enhanced our understanding of hyponatremic disorders. Increased vasopressin secretion due to nonosmotic stimuli leads to decreased electrolyte-free water excretion with resulting water retention and hyponatremia. Vasopressin receptor antagonists induce electrolyte-free water diuresis without natriuresis and kaliuresis. Phase three trials indicate that these agents predictably reduce urine osmolality, increase electrolyte-free water excretion, and raise serum sodium concentration. They are likely to become a mainstay of treatment of euvolemic and hypervolemic hyponatremia. The correct diagnosis and management of hyponatremia is complex and requires a systematic approach. Vasopressin receptor antagonists are potential tools in the management of hyponatremia. Further studies are needed to determine their role in the treatment of acute, severe, life-threatening hyponatremia as well as chronic hyponatremia.

Vasopressin and vasopressin antagonists in heart failure and hyponatremia

Increased synthesis of arginine vasopressin (AVP) plays a critical role in fluid retention and hyponatremia in patients with heart failure. The AVP receptor antagonists constitute a new class of agents that are promising in the management of hyponatremia and congestion. Three of these agents--conivaptan, tolvaptan, and lixivaptan--have been studied in clinical settings. All are effective in inducing aquaresis (ie, electrolyte-free water excretion) and normalizing serum sodium concentration. They are well tolerated without causing electrolyte disorders, hypotension, or renal impairment. Conivaptan has been approved by the US Food and Drug Administration for short-term intravenous treatment of euvolemic hyponatremia of variable etiology but has not been adequately studied in heart failure. The addition of tolvaptan to standard therapy in hospitalized patients with heart failure has led to symptomatic improvement and decreased body weight, but there is no long-term clinical benefit. Early data on lixivaptan in heart failure suggest a dose-dependent aquaresis effect, and larger studies are under way.

Conivaptan: a step forward in the treatment of hyponatremia?

Hyponatremia is one of the most common electrolyte abnormalities linked to adverse outcomes and increased mortality in hospitalized patients. While the differential diagnosis for hyponatremia is diverse, most cases stem from arginine vasopressin (AVP) dysregulation, where hypoosmolality fails to suppress AVP synthesis and release. The physiological effects of AVP are currently known to depend on its interaction with any of 3 receptor subtypes V1A, V2, and V1B. Activation of V2 by AVP is the key in renal water regulation and maintenance of total body volume and plasma tonicity. Despite the long-recognized problem with excess AVP in euvolemic and hypervolemic hyponatremia, traditional therapeutic options have relied on nonspecific and potentially problematic strategies. More recently, a new class of drugs, introduced as "aquaretics," has gained great attention among clinicians because of its ability to correct hyponatremia via direct competitive inhibition of AVP at V2 receptors to induce renal electrolyte-free water excretion. In this paper, we aim to review available clinical data on the only FDA-approved aquaretic, dual V1A/V2 receptor antagonist conivaptan, discuss its clinical indications, efficacy, safety profile, and comment on its clinical limitations.

Recent advances in the treatment of hyponatremia

Hyponatremia is a common and potentially serious electrolyte disorder, most often caused by excessive arginine vasopressin (AVP) secretion. Conventional management of hyponatremia is based on graded steps starting from water restriction in mild cases to administration of saline in symptomatic cases, which may not be effective. A major new approach in the treatment of hyponatremia is the development of AVP receptor antagonists that directly inhibit the effect of increased AVP which results in the excretion of electrolyte free water. This review summarizes pathophysiology, conventional treatment and future directions in the treatment of hyponatremia.

Vaptans: A promising therapy in the management of advanced cirrhosis

Hyponatremia (serum sodium concentration, <135 mmol/L) is a predictor of death among patients with chronic heart failure and cirrhosis. At present, therapy for acute and chronic hyponatremia is often ineffective and poorly tolerated. We investigated whether tolvaptan, an orally active vasopressin V(2)-receptor antagonist that promotes aquaresis--excretion of electrolyte-free water--might be of benefit in hyponatremia. In two multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptan was evaluated in patients with euvolemic or hypervolemic hyponatremia. 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 30 mg daily and then to 60 mg daily, if necessary, on the basis of serum sodium concentrations. The two primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. Serum sodium concentrations increased more in the tolvaptan group than in the placebo group during the first 4 days (P<0.001) and after the full 30 days of therapy (P<0.001). The condition of patients with mild or marked hyponatremia improved (P<0.001 for all comparisons). During the week after discontinuation of tolvaptan on day 30, hyponatremia recurred. Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. A planned analysis that combined the two trials showed significant improvement from baseline to day 30 in the tolvaptan group according to scores on the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey. In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V2-receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30. [Abstract reproduced by permission of N Engl J Med 2006;355:2099-2112].