Solute-free Water Excretion Research Articles

Multiparametric renal function assessment in cirrhotic patients shows high prevalence of medically actionable changes in multiple modules.

Renal dysfunction is a common complication of cirrhosis, occurring either as part of multiorgan involvement in acute illness or secondary to advanced liver disease. To date, no study has comprehensively assessed multiple renal function parameters in hospitalized patients with cirrhosis through a multiparametric analysis of renal biochemistry markers. We conducted a retrospective, observational study including all consecutive patients hospitalized with cirrhosis who underwent a 43-multiparametric renal function assessment between January 1, 2021, and June 30, 2023. All patients showed at least one of the following renal abnormalities: Kidney Disease: Improving Global Outcomes stage G2 or higher, sodium and/or chloride excretion fraction <1%, electrolyte-free water clearance <0.4mL/min, or tubular maximum phosphate reabsorption capacity <0.8mmol/L. The estimated glomerular filtration rate equations significantly overestimated the measured creatinine clearance with median differences of +14mL/min/1.73m2 (95% CI 6-29) and +9mL/min/1.73m2 (95% CI 2-15) for European Kidney Function Consortium equations, respectively. Notably, 54% and 39% of patients demonstrated estimated glomerular filtration rates exceeding 30% of the measured creatinine clearance when the Chronic Kidney Disease - Epidemiology Collaboration and European Kidney Function Consortium formulas were employed, respectively. Substantial discrepancies in Kidney Disease: Improving Global Outcomes stage assignments were observed between the estimated glomerular filtration rate- and measured creatinine clearance-based assessments. This study underscores the value of a multiparametric renal function assessment as a routine tool for evaluating renal function in patients with cirrhosis. A high prevalence of medically actionable renal abnormalities spanning multiple renal function modules, including alterations in glomerular function, salt and solute-free water excretion, and proximal tubule phosphate reabsorption, has been demonstrated in hospitalized patients with cirrhosis.

Osmoregulation in children with cystic fibrosis.

Hyponatremia is not rare in cystic fibrosis and might be due to several mechanisms. An endocrine and renal imbalance in water and salt homeostasis was suggested. To address this hypothesis, we assessed the urinary concentrating and diluting ability in 12 cystic fibrosis patients (6 females, 6 males) and in two control groups: 14 children with pneumonia (9 females, 5 males) and in 13 healthy children (9 females, 4 males). Renal concentrating ability was evaluated following overnight water deprivation. Urine osmolality was not significantly different between groups. Renal diluting ability was assessed by means of a water-load test. This provoked a decrease in urine osmolality, as well as an increase in diuresis and solute-free water excretion. These changes were comparable among groups.Conclusion: Children with cystic fibrosis show a preserved renal concentrating and diluting capacity. A generalized endocrine and renal imbalance in water and salt homeostasis therefore appears unlikely.What is Known:•Hyponatremia sometimes occurs in cystic fibrosis.What is New:•Osmoregulation is normal in cystic fibrosis.

Effect of the Glucagon-like Peptide-1 Mimetic on Ion- and Osmoregulating Renal Functions in Normoglycemia and Hyperglycemia

Incretins are hormones with a wide range of biological activity. We studied the ratio of the glycemic effect of the glucagon-like peptide-1 mimetic and its effect on the renal excretion of sodium and water. It was found that both effects depend on the initial blood concentration of glucose. In normoglycemia, exenatide had no effect on blood sugar level, but it significantly increased urinary sodium excretion and reabsorption of solute-free water. In hyperglycemia the blood glucose concentration was normalized by exenatide, while the excretion of sodium by the kidneys and the reabsorption of solute-free water were increased to a small extent. This pattern was found both in patients with type 2 diabetes mellitus and in rats with hyperglycemia induced by intraperitoneal injection of glucose.

Correlation between Urinary Excretion of Arginine-Vasopressin and Renal Reabsorption of Sodium and Water.

We developed an approach for quantitative assay of injected vasopressin in urine samples by ELISA under conditions of physiological suppression of hormone secretion from the neurohypophysis into the blood. In experiments on unanesthetized rats, water load (5 ml/100 g body weight) almost completely blocked secretion of arginine-vasopressin. Injection of arginine-vasopressin in a dose of 0.1 nmol/100 g body weight after water load enhanced reabsorption of solute-free water and renal excretion of Na+, K+, and Mg2+ by 13.3, 5.5, and 5.0 times, respectively; urinary excretion of Ca2+ remained unchanged. It was found that urinary excretion of arginine-vasopressin directly correlated with reabsorption of solute-free water and renal sodium excretion.

Принципы изучения действия диуретиков

Дана характеристика диуретических средств и описаны подходы к доклиническому исследованию веществ с диуретической активностью. Изучение новых диуретиков на животных должно включать оценку их активности в сравнении с эталонным диуретиком, а также влияния на мочеотделение, клубочковую фильтрацию, экскрецию осмотически активных веществ и отдельных ионов. Описаны подходы к оценке локализации действия диуретика в нефроне с помощью клиренсовых методов, включающих определение клиренса и экскретируемых фракций различных органических веществ, ионов и осмотически свободной воды.

Ascites, refractory ascites and hyponatremia in cirrhosis.

Ascites is the most common complication related to cirrhosis and is associated with increased morbidity and mortality. Ascites is a consequence of the loss of compensatory mechanisms to maintain the overall effective arterial blood volume due to worsening splanchnic arterial vasodilation as a result of clinically significant portal hypertension. In order to maintain effective arterial blood volume, vasoconstrictor and antinatriuretic pathways are activated, which increase overall sodium and fluid retention. As a result of progressive splanchnic arterial vasodilation, intestinal capillary pressure increases and results in the formation of protein-poor fluid within the abdominal cavity due to increased capillary permeability from the hepatic sinusoidal hypertension. In some patients, the fluid can translocate across diaphragmatic fenestrations into the pleural space, leading to hepatic hydrothorax. In addition, infectious complications such as spontaneous bacterial peritonitis can occur. Eventually, as the liver disease progresses related to higher portal pressures, loss of a compensatory cardiac output and further splanchnic vasodilation, kidney function becomes compromised from worsening renal vasoconstriction as well as the development of impaired solute-free water excretion and severe sodium retention. These mechanisms then translate into significant clinical complications, such as refractory ascites, hepatorenal syndrome and hyponatremia, and all are linked to increased short-term mortality. Currently, liver transplantation is the only curative option for this spectrum of clinical manifestations but ongoing research has led to further insight on alternative approaches. This review will further explore the current understanding on the pathophysiology and management of ascites as well as expand on two advanced clinical consequences of advanced liver disease, refractory ascites and hyponatremia.

Pathogenesis of solute-free water retention in experimental ascitic cirrhosis: is vasopressin the only culprit?

Catecholamines trigger proximal tubular fluid retention and reduce renal excretion of solute-free water. In advanced cirrhosis, non-osmotic hypersecretion of vasopressin (antidiuretic hormone or ADH) is considered the cause of dilutional hyponatraemia, but ADH V2 receptor antagonists are not beneficial in long-term treatment of ascites. To test the hypothesis that water retention in experimental ascitic cirrhosis might depend primarily on adrenergic hyper-function, hormonal status, renal function and tubular free-water reabsorption (TFWR) were assessed in six groups of rats with ascitic cirrhosis: rats with cirrhosis due to 13-week CCl4 (carbon tetrachloride) administration (group G1); cirrhotic rats receiving daily diuretics (0.5 mg/kg furosemide plus 2 mg/kg K(+)-canrenoate) from the 11th to the 13th week of CCl4 (G2), diuretics associated with guanfacine oral prodrug (α2A-adrenergic receptor agonist and sympatholytic agent) at 2 (G3), 7 (G4) or 10 (G5) mg/kg, or with SSP-004240F1 (V2 receptor antagonist) at 1 mg/kg (G6). Natriuresis was lower in G1 than in G2, G4 and G6 (all P<0.05). Guanfacine, added to diuretics (i.e. G3 compared with G2), reduced serum noradrenaline from 423±22 to 211±41 ng/l (P<0.05), plasma renin activity (PRA) from 35±8 to 9±2 ng/ml/h (P<0.05) and TFWR from 45±8 to 20±6 μl/min (P<0.01). TFWR correlated with plasma aldosterone (r=0.51, P<0.01) and urinary potassium excretion (r=0.90, P<0.001). In ascitic cirrhosis, reduced volaemia, use of diuretics (especially furosemide) and adrenergic hyper-function cause tubular retention of water. Suitable doses of sympatholytic agents are effective aquaretics.

Kidney injury in cirrhosis: pathophysiological and therapeutic aspects of hepatorenal syndromes

Acute kidney injury (AKI) is frequent in patients with cirrhosis. AKI and hyponatraemia are major determinants of the poor prognosis in advanced cirrhosis. The hepatorenal syndrome (HRS) denotes a functional and potential reversible impairment of renal function. Type 1 HRS, a special type of AKI, is a rapidly progressive AKI, whereas the renal function in type 2 HRS decreases more slowly. HRS is precipitated by factors such as sepsis that aggravate the effective hypovolaemia in decompensated cirrhosis, by lowering arterial pressure and cardiac output and enhanced sympathetic nervous activity. Therefore, attempts to prevent and treat HRS should seek to improve liver function and to ameliorate arterial hypotension, central hypovolaemia and cardiac output, and to reduce renal vasoconstriction. Ample treatment of HRS is important to prevent further progression and death, but as medical treatment only modestly improves long-term survival, these patients should always be considered for liver transplantation. Hyponatraemia, defined as serum sodium <130 mmol/L, is common in patients with decompensated cirrhosis. From a pathophysiological point of view, hyponatraemia is related to an impairment of renal solute-free water excretion most likely caused by an increased vasopressin secretion. Patients with cirrhosis mainly develop hypervolaemic hyponatraemia. Current evidence does not support routine use of vaptans in the management of hyponatraemia in cirrhosis.

Hyponatraemia and cirrhosis.

Hyponatraemia is a common complication of advanced cirrhosis related to an impairment in the renal capacity for eliminating solute-free water, causing a retention of water that is disproportionate to the retention of sodium, thus leading to a reduction in serum sodium concentration and hypo-osmolality. The main pathogenic factor responsible for hyponatraemia is a non-osmotic hypersecretion of arginine vasopressin (AVP) or antidiuretic hormone from the neurohypophysis, related to circulatory dysfunction. Hyponatraemia in cirrhosis is associated with increased morbidity and mortality. Hyponatraemia is also associated with increased morbidity and impaired short-term survival after transplantation. The current standard of care based on restricting fluids to 1–1.5 L/day is rarely effective. Other approaches, such as albumin infusion and the use of vaptans—which act by specifically antagonizing the effects of AVP on the V2 receptors located in the kidney tubules—have been evaluated for their role in the management of hyponatraemia. The short-term treatment with vaptans is associated with a marked increase in renal solute-free water excretion and improvement of hyponatraemia; however their use in patients with end-stage liver disease is limited by hepatotoxic effects of some of these drugs. Long-term administration of vaptans seems to be effective in maintaining the improvement of serum sodium concentration, but the available information is still limited.

Physiological mechanisms for the increase in renal solute‐free water clearance by a glucagon‐like peptide‐1 mimetic

The aim of the present study was to clarify the mechanisms mediating the effect of a glucagon-like peptide-1 (GLP-1) mimetic on solute-free water excretion in rats. The GLP-1 mimetic exenatide (0.05-5.0nmol/kg, i.m.), alone and in combination with either a vasopressin V2 receptor antagonist (15nmol/kg, i.p.) or vasopressin (0.01nmol/kg, i.m.), was injected into control and water-loaded (water 10-50mL/kg, p.o., or 50mL/kg of 0.6% NaCl, i.p.) rats to evaluate the role of collecting duct water permeability in the hydrouretic effect. Urinary prostaglandin (PG) E2 excretion and the effects of diclofenac (5mg/kg, i.m.) and GLP-1 receptor antagonist (0.15μmol/kg, i.p.) on exenatide action were assessed. The hydrouretic effect of exenatide was equivalent following oral or intraperitoneal water loading, and was proportional to the volume of water administered. Injection of exenatide, under conditions of a maximal decrease in collecting duct water permeability (V2 receptor antagonist administration in water-loaded rats), additionally stimulated solute-free water formation. The GLP-1 receptor antagonist weakened the hydrouretic action of exenatide. Urinary PGE2 excretion increased following water loading (47±6 vs 24±4ng/kg over a 30min period) and was enhanced as a result of additional exenatide injection (69±10ng/kg). Diclofenac and vasopressin delayed the hydrouretic effect of exenatide. The effect of exenatide on solute-free water clearance in water-loaded rats is presumably mediated by stimulation of PGE2 secretion and reinforcement of tubular fluid influx from the proximal tubule to the distal segment of the nephron and collecting duct.

The hyponatremias

Introduction: Plasma sodium concentrations are commonly measured in hospitalized patients. In our department, hypernatremia (defined as a serum sodium &lt; 135 mmol/L) is usually an incidental finding. More rarely, however, clinical manifestations of hypernatremia occur. Symptoms depend on the magnitude and rapidity of onset of the hypernatremia. When acute, severe hyponatremia develops, brain edema may occur. Considerable morbidity and mortality can be associated with hyponatremic encephalopathy per se. Moreover, rapid correction of hyponatremia also carries a risk of neurological damage related to the osmotic demyelination syndromes. This review focuses on the epidemiology, pathophysiology, and therapy of hyponatremia. Materials and methods: We carried out a search of the literature in Medline, the Cochrane Library and Clinical Evidence using the search terms hypernatremia and sodium. Conclusions: Hyponatremia is the most common electrolyte disorder encountered in clinical practice, occurring in approximately 15% to 30% of hospitalized patients, and it is not uncommon in outpatients. When faced with a hyponatremic patient, the physician has to identify the cause, treat the defect, and take care of the patient, bearing in mind that hypernatremia and its correction are associated with significant morbidity and mortality. Hyponatremic encephalopathy following acute hypernatremia is well known to be a potentially life-threatening condition, especially in patients with concomitant diseases. In contrast, chronic hypernatremia is more common, and it is often considered to be a laboratory abnormality devoid of clinical consequences. Paradoxically, however, this is just the setting in which rapid correction of plasma sodium levels can cause severe neurologic defects and death. Despite substantial progress in understanding the pathophysiology of brain damage related to hyponatremia and its treatment, optimal, safe therapies have not been well defined yet. The imminent availability of aquaretic nonpeptide arginine vasopressin receptor antagonists could provide new insights into this field. However, because of their unique effects, i.e., selective increase of solute-free water excretion by the kidney, this new class of drugs cannot be used in patients with hypovolemic hyponatremia.

Management of Refractory Ascites

Ascites that does not respond or recurs after high-dose diuresis and sodium restriction should be considered refractory ascites. As cirrhosis advances, the escaping fluid overwhelms the lymphatic return. Decrease in renal plasma flow leads to increased sodium reabsorption at the proximal tubule leading to decreased responsiveness to loop diuretics and mineralocorticoid antagonists, which work distally. These complex hemodynamic alterations lead to refractory ascites. In refractory ascites, high-dose diuresis (400 mg of spironolactone and 160 mg of furosemide) and sodium restriction (<90 mmol/d) result in inadequate weight loss and sub optimal sodium excretion (<78 mmol/d). Further use of diuretics is limited by complications such as encephalopathy, azotemia, renal insufficiency, hyponatremia, and hyperkalemia. Therapy for refractory ascites is limited. The available therapies are repeated large volume paracentesis (LVP), transjugular intrahepatic portosystemic shunts, peritoneovenous shunts, investigational medical therapies, and liver transplantation. LVP with concomitant volume expanders is the initial treatment of choice. Transjugular intrahepatic portosystemic seems to be superior to LVP in reducing the need for repeated paracentesis and improves the quality of life. Several treatments that act at different steps in the pathogenesis of ascites are investigational, and some show promising results. Splanchnic and peripheral vasoconstrictors (Octreotide, Midodrine, and Terlipressin) increase effective arterial volume and decrease activation of the renin-angiotensin system with resultant increase in renal sodium excretion. Clonidine when given with spironolactone has been shown to cause rapid mobilization of ascites by significantly decreasing the sympathetic activity and renin-aldosterone levels. Natural aquaretics and synthetic V2 receptor antagonists (satavaptan) are being evaluated for mobilization of ascites by increasing the excretion of solute-free water. Liver transplantation remains the only definitive therapy for refractory ascites. Because refractory ascites is a poor prognostic sign, liver transplantation should be considered and incorporated early in the treatment plan.

Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis

Tolvaptan is a vasopressin V2-receptor antagonist that improves serum sodium concentration by increasing renal solute-free water excretion. Specific data on the safety and efficacy of tolvaptan in patients with cirrhosis and hyponatremia has not been exclusively evaluated. This sub-analysis of the Study of Ascending Levels of Tolvaptan trials examined cirrhotic patients with hyponatremia who received 15 mg oral tolvaptan (n=63; increased to 30 or 60 mg if needed) or placebo (n=57) once-daily for 30 days. At baseline, 44% had mild hyponatremia (serum sodium 130-134 mmol/L), 56% had marked hyponatremia (serum sodium <130 mmol/L), 85% had cirrhosis due to alcohol and/or hepatitis B/C, and 80% were Child-Pugh class B/C. Tolvaptan was effective in raising serum sodium. Average daily area under the curve for serum sodium was significantly greater in the tolvaptan group from baseline to day 4 (p<0.0001) and day 30 (p<0.0001). This superiority was maintained after stratification by baseline hyponatremia (mild and marked), estimated glomerular filtration rate (≤ 60 ml/min and >60 ml/min), or serum creatinine levels (<1.5mg/dl and ≥ 1.5mg/dl). Hyponatremia recurred 7 days after discontinuation of tolvaptan. Mean mental component summary scores of the SF-12 health survey improved from baseline to day 30 in the tolvaptan group but not the placebo group (4.68 vs. 0.08, p=0.02). Major side effects due to tolvaptan were dry mouth and thirst. Gastrointestinal bleeding occurred in 10% and 2% of patients in the tolvaptan and placebo group, respectively (p=0.11). Adverse event rates, withdrawals, and deaths were similar in both groups. One month of tolvaptan therapy improved serum sodium levels and patient-reported health status in cirrhotic patients with hyponatremia. Hyponatremia recurred in tolvaptan-treated patients after discontinuation.

Short-term effects of tolvaptan on renal function and volume in patients with autosomal dominant polycystic kidney disease

Tolvaptan and related V(2)-specific vasopressin receptor antagonists have been shown to delay disease progression in animal models of polycystic kidney disease. Slight elevations in serum creatinine, rapidly reversible after drug cessation, have been found in clinical trials involving tolvaptan. Here, we sought to clarify the potential renal mechanisms to see whether the antagonist effects were dependent on underlying renal function in 20 patients with autosomal dominant polycystic kidney disease (ADPKD) before and after 1 week of daily split-dose treatment. Tolvaptan induced aquaresis (excretion of solute-free water) and a significant reduction in glomerular filtration rate (GFR). The serum uric acid increased because of a decreased uric acid clearance, and the serum potassium fell, but there was no significant change in renal blood flow as measured by para-aminohippurate clearance or magnetic resonance imaging (MRI). No correlation was found between baseline GFR, measured by iothalmate clearance, and percent change in GFR induced by tolvaptan. Blinded post hoc analysis of renal MRIs showed that tolvaptan significantly reduced total kidney volume by 3.1% and individual cyst volume by 1.6%. Preliminary analysis of this small cohort suggested that these effects were more noticeable in patients with preserved renal function and with larger cysts. No correlation was found between changes of total kidney volume and body weight or estimated body water. Thus, functional and structural effects of tolvaptan on patients with ADPKD are likely due to inhibition of V(2)-driven adenosine cyclic 3',5'-monophosphate generation and its aquaretic, hemodynamic, and anti-secretory actions.

Le iponatremie

Introduction Plasma sodium concentrations are commonly measured in hospitalized patients. In our department, hypernatremia (defined as a serum sodium < 135 mmol/L) is usually an incidental finding. More rarely, however, clinical manifestations of hypernatremia occur. Symptoms depend on the magnitude and rapidity of onset of the hypernatremia. When acute, severe hyponatremia develops, brain edema may occur. Considerable morbidity and mortality can be associated with hyponatremic encephalopathy per se. Moreover, rapid correction of hyponatremia also carries a risk of neurological damage related to the osmotic demyelination syndromes. This review focuses on the epidemiology, pathophysiology, and therapy of hyponatremia. Materials and methods We carried out a search of the literature in Medline, the Cochrane Library and Clinical Evidence using the search terms hypernatremia and sodium. Conclusions Hyponatremia is the most common electrolyte disorder encountered in clinical practice, occurring in approximately 15% to 30% of hospitalized patients, and it is not uncommon in outpatients. When faced with a hyponatremic patient, the physician has to identify the cause, treat the defect, and take care of the patient, bearing in mind that hypernatremia and its correction are associated with significant morbidity and mortality. Hyponatremic encephalopathy following acute hypernatremia is well known to be a potentially life-threatening condition, especially in patients with concomitant diseases. In contrast, chronic hypernatremia is more common, and it is often considered to be a laboratory abnormality devoid of clinical consequences. Paradoxically, however, this is just the setting in which rapid correction of plasma sodium levels can cause severe neurologic defects and death. Despite substantial progress in understanding the pathophysiology of brain damage related to hyponatremia and its treatment, optimal, safe therapies have not been well defined yet. The imminent availability of aquaretic nonpeptide arginine vasopressin receptor antagonists could provide new insights into this field. However, because of their unique effects, i.e., selective increase of solute-free water excretion by the kidney, this new class of drugs cannot be used in patients with hypovolemic hyponatremia.

Tolvaptan: a vasopressin antagonist for the management of euvolemic and hypervolemic hyponatremia

Tolvaptan is a new vasopressin antagonist developed for the treatment of hypervolemic or euvolemic hyponatremia. It has greater affinity for the V2 receptor than native vasopressin or any other vasopressin antagonist. Blockade of the V2 receptor induces solute-free water excretion without affecting normal electrolyte excretion. The pharmacokinetics and pharmacodynamics of tolvaptan are suitable for once-daily dosing. Throughout all phases of clinical studies, it was shown to be safe for short- and long-term use. Tolvaptan effectively increases serum sodium levels in patients with heart failure, cirrhosis and syndrome of inappropriate secretion of antidiuretic hormone. In patients hospitalized owing to heart failure, tolvaptan decreased bodyweight, increased urine output and improved dyspnea compared with placebo. However, tolvaptan has not proven to be beneficial for the long-term management of heart failure. Currently, tolvaptan is the only oral agent in its class available in the USA and Europe.

Hiponatremia en la cirrosis hepática: patogenia y tratamiento

Hyponatremia is the most common electrolyte disorder in patients with cirrhosis. This disorder can be a result of substantial loss of extracellular fluid “hypotonic or hypovolemic hyponatremia” or develop in the context of an increase in extracellular fluid volume and in the absence of major sodium losses; this situation occurs in patients with advanced cirrhosis and is known as “dilutional or hypervolemic hyponatremia”. In dilutional or hypervolemic hyponatremia, serum sodium concentration is reduced, plasma volume is increased (although the effective plasma volume is decreased due to marked arterial vasodilation in the splanchnic circulation) and extracellular fluid volume is increased, with ascites and edema in the absence of signs of dehydration. This is a result of the marked deterioration in renal excretion of solute-free water, leading to disproportionate water retention in relation to sodium retention. Hypotonic hyponatremia represents 10% of all hyponatremias in patients with cirrhosis. Since hypervolemic hyponatremia is by far the most frequent form of this disorder, the present chapter will concentrate specifically on hypervolemic hyponatremia in cirrhosis.

Current and future treatment options in SIADH

The treatment of hyponatraemia due to SIADH is not always as straightforward as it seems. Although acute treatment with hypertonic saline and chronic treatment with fluid restriction are well established, both approaches have severe limitations. These limitations are not readily overcome by addition of furosemide, demeclocycline, lithium or urea to the therapy. In theory, vasopressin-receptor antagonists would provide a more effective method to treat hyponatraemia, by virtue of their ability to selectively increase solute-free water excretion by the kidneys (aquaresis). In this review we explore the limitations of the current treatment of SIADH and describe emerging therapies for the treatment of SIADH-induced hyponatraemia.

Treatment of Hyponatremia in Cirrhosis

Letter to the Editor In his review article, Dr. Mahesh [1] discussed the pathophysiology and management of hyponatremia in patients with cirrhosis and ascites. He noted hyponatremia as a problematic complication in cirrhotic patients. Recent studies strongly support this contention. Among patients with liver disease, hyponatremia is recognized as a predictive factor of poor quality-of-life and early death, independent of liver function tests, Child-Pugh criteria and Model for End-Stage Liver Disease scores [2, 3]. Dr. Mahesh presented a clear and stepwise approach in managing hyponatremia in this challenging patient population. His approach starts with modest water restriction, followed by withholding of loop diuretics and strict fluid restriction once plasma sodium drops below 126 meq/L [1]. He also briefly mentioned other treatment strategies. In the last paragraph, he stated: “vasopressin receptor analogues, demeclocycline etc have been tried, but no definite benefit”. I think the above statement is a typographical error. I believe that Dr. Mahesh was pertaining to vasopressin receptor antagonists and not to vasopressin receptor analogues, as published. Vasopressin receptor analogues have never been used to treat hyponatremia. On the other hand, vasopressin receptor antagonists, also called vaptans, are beginning to be recognized as effective and safe pharmacologic agents in euvolemic and hypervolemic hyponatremia such as in the case of cirrhosis with ascites [4]. Vaptans are non-peptide, argininevasopressin-receptor antagonists. They are orally and intravenously active. They work by antagonizing the effects of Arginine Vasopressin or Anti-Diuretic Hormone. This improves solute-free water excretion in the renal tubules [5]. Gines et al. [6] have shown improved serum sodium concentration in patients with cirrhosis after the first day of vaptan therapy. Correction of hyponatremia is observed in 27% to 54% of patients with cirrhosis [7]. Understandably, the correction of hyponatremia due to secondary causes such as cirrhosis and congestive heart failure is particularly difficult. The therapeutic approach must always address the underlying condition. In 2005, the U.S. Food and Drug Administration approved the use of conivaptan (Vaprisol®). Other vaptans in various phases of clinical or marketing development include: mozavaptan, lixivaptan, satavaptan and tolvaptan. There is still more to be learned regarding the use of vaptans in cirrhotic patients with hyponatremia. There has been no extensive investigation comparing clinical outcomes and effectiveness of vaptans against the usual interventions such as water restriction and withholding of loop diuretics. To end, the paper of Dr.Mahesh raises an important point regarding the prudence of slow and careful serum sodium correction. Chronic asymptomatic hyponatremia should be corrected at a slow rate of < 12 mmol/L/day. If ever vaptans would be employed in the treatment, their infusion should be stopped once serum sodium reaches 134 mmol/L, to avoid the risk of osmotic demyelination resulting to catastrophic central pontine myelinolysis [8].

Observations regarding the use of the aquaretic agent conivaptan for treatment of hyponatremia

The treatment of hyponatremia, especially euvolemic and hypervolemic hyponatremia, has changed with the development of drugs which function as vasopressin receptor antagonists. These agents increase solute-free water excretion by the kidney resulting in an aquaresis. Conivaptan, a vasopressin receptor antagonist, has recently been approved by the FDA in the United States for use in the therapy of both euvolemic and hypervolemic hyponatremia. This report summarizes one center's experience with ten patients treated with this new drug. The patients had euvolemic hyponatremia with serum sodium levels less than 128 mEq/l. The same protocol was used in all patients with the conivaptan being given as a 20-mg intravenous loading dose followed by a 20-mg continuous 24-h infusion. Review of the data revealed that six of the ten patients had an excellent response to the therapy, with serum sodium increasing by a mean of 8.5+/-0.8 mEq/l (increases ranged from 7 to 12 mEq/l over 24 h). No significant changes in serum potassium levels or mean arterial pressures were noted. Two of the ten patients experienced a decrease in urine osmolality without a significant increase in serum sodium. Two other patients had only slight decreases in urine osmolality, and no significant increase in serum sodium levels. The data reveal that conivaptan is useful in the management of significant hyponatremia. There were no significant untoward effects, with the exception of one patient whose blood pressure decreased during the conivaptan infusion and who responded to cessation of the infusion and saline replacement therapy. This new class of drugs holds great promise for the treatment of dilutional hyponatremic disorders.