Where vaptans do and do not fit in the treatment of hyponatremia

Transcription

1 & 2012 International Society of Nephrology Where vaptans do and do not fit in the treatment of hyponatremia Anna J. Jovanovich 1 and Tomas Berl 1 1 Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, USA The treatment of hyponatremia, an exceedingly common electrolyte disorder, has been a subject of controversy for many years. The advent of vasopressin antagonists (vaptans) has added to the treatment arsenal. This review focuses on why hyponatremia should be treated and the role of these antagonists in the treatment. Upon analysis of the available literature, we conclude that there is presently no role for vaptans in acute symptomatic hyponatremia. Although numerous therapeutic approaches are available for chronic symptomatic hyponatremia, vasopressin antagonists provide a simpler treatment option. Vaptans are efficacious in raising serum sodium in long-standing asymptomatic hyponatremia. However, the cost of the only Food and Drug Administration-approved oral agent (tolvaptan) makes its use prohibitive for most patients in this setting. Kidney International (2013) 83, ; doi: /ki ; published online 19 December 2012 KEYWORDS: hyponatremia; vasopressin; vasopressin antagonist Hyponatremia is said to be the most common electrolyte disorder in clinical medicine. Recent studies support that this may be the case, as 14.5% of patients are admitted to the hospital with a serum sodium (Na) o135 meq/l, and a number of those who are normonatremic become hyponatremic during their hospitalization. 1 Epidemiological studies consistently report an association with increased mortality in several disorders, such as heart failure, cirrhosis, cancer, chronic kidney disease, 2 and end-stage renal disease. 3 Whether treatment of hyponatremia improves mortality and other outcomes has yet to be elucidated. Nonetheless, uncertainties in its management make hyponatremia one of the most common terms of query in Up To Date (B Rose, personal communication). The advent of vasopressin (V 2 ) antagonists (vaptans) has added another tool to the treatment armamentarium. Vaptans are nonpeptide competitive inhibitors of the V 2 receptor located on the basolateral membrane of the collecting duct s principal cells. They bind to the V 2 receptor, preventing the hormone s downstream signaling pathway the generation of intracellular camp and the expression and insertion of aquaporin-2 on the apical membrane. This inhibits water reabsorption and results in the excretion of markedly dilute urine (aquaresis). Trials with vasopressin antagonists have consistently demonstrated increments in serum Na in euvolemic and hypervolemic hyponatremia. 4 In the United States, intravenous conivaptan and oral tolvaptan are approved for the treatment of euvolemic and hypervolemic hyponatermia. 5 In Europe, conivaptan and tolvaptan are approved for the treatment of euvolemic hyponatremia. This review will discuss why and how hyponatremia should be treated in various clinical settings, with emphasis on the role of vasopressin receptor antagonists. Correspondence: Tomas Berl, Division of Renal Diseases and Hypertension, University of Colorado, East 19th Avenue, Campus Box C281, Aurora, Colorado 80045, USA. tomas.berl@ucdenver.edu Received 25 June 2012; revised 31 August 2012; accepted 7 September 2012; published online 19 December 2012 ACUTE HYPONATREMIA Acute hyponatremia is arbitrarily defined as the decrement in serum Na over o48 h. When plasma osmolality decreases rapidly, brain cells gain water and activate protective mechanisms that mitigate against the increase in intracerebral pressure. This involves an increase in interstitial pressure that enhances the movement of extracellular fluid into the cerebrospinal fluid. Failure to adequately undergo this Kidney International (2013) 83,

2 AJ Jovanovich and T Berl: Hyponatremia and vaptans protective process results in cerebral edema. The risk factors for severe cerebral edema include concomitant hypoxemia, self-induced water intoxication in psychotic patients and marathon runners, and hospital-acquired hyponatremia, particularly in premenopausal women and children. Cerebral edema can lead to mental status changes, agitation, seizures, neurogenic pulmonary edema, and, in its most severe form, tentorial herniation and death. In symptomatic patients, particularly those with risk of complications, acute hyponatremia is a life-threatening medical emergency requiring immediate treatment. In the presence of hypoxia, intubation should be strongly considered. The primary goal of therapy is aimed at achieving a rapid increase in serum Na to reverse potentially lifethreatening cerebral edema. This can be achieved by the administration of hypertonic saline (3% ¼ 513 meq/l Na) at a dose of 1 2 ml/kg given rapidly, and repeated if necessary until symptoms, usually seizures, subside. Studies in patients with impending tentorial herniation have revealed that an increase in serum Na of 5 6 meq/l, achieved with 30 ml of 23.4% sodium chloride (NaCl), reduces intracranial pressure by 40% and prevents herniation in a great majority of patients. 6 Hypertonic saline is given to reverse cerebral edema and not to restore any Na deficits. Because patients who have developed hyponatremia acutely have not had time to fully undergo other adaptive changes, they are at a low risk of developing osmotic demyelination syndrome as the hyponatremia is corrected. In a retrospective survey of 18 patients with acute hyponatremia, with serum Na o105 meq/l, in 15 of whom the safety parameters were exceeded (412 meq/l in 24 h or 418 meq/l in 48 h), none had adverse neurological outcomes. 7 Nonetheless, even in this clinical setting, these safety parameters need not be exceeded. Although the tolvaptan trials (SALT) found a significant increase in serum Na in the first 8 h, 8 and intravenous conivaptan promptly increases serum Na, 9 these studies did not include patients with acute symptomatic hyponatremia. Patients with overt neurological findings were excluded from the SALT trials, and thus the observations cannot be extended to patients with acute hyponatremia. The absence of data and the proven benefit with hypertonic saline leads us to unequivocally state that there is no role for vaptans in symptomatic patients with acute hyponatremia. CHRONIC SYMPTOMATIC HYPONATREMIA Chronic symptomatic hyponatremia is characterized by low serum Na of 448 h duration accompanied by central nervous system symptoms. The symptoms of chronic hyponatremia are subtle and nonspecific. They include restlessness, disorientation, headache, nausea, vomiting, and muscle cramps. Seizures occur rarely and only when the serum Na is very low (o105 meq/l). The presence of these symptoms is evidence of cerebral dysfunction and requires therapy. Failure to correct chronic symptomatic hyponatremia is associated with higher morbidity and mortality. 10 In a study of 53 postmenopausal women (serum Na of 111±12 meq/l), the group that sustained an increase in serum Na of only 3 meq/l over 2 days, as well as the group that was overcorrected by 30 meq/l, resulted in worse outcomes (persistent vegetative state or death) as compared with the group that had an increase in serum Na of 22 meq/l in an unspecified period of time. 10 Nonetheless, the treatment has to be undertaken with great attention to the rate of correction. Following the initial response leading to increments in cerebrospinal fluid flow, further adaptive mechanisms, directed at decreasing brain water content, come into action. Potassium (K) is lost from cells, and over the ensuing 2 days, osmolytes inositol, taurine, sorbitol, glutamate, and glutamine are lost. The resulting trade-off culminates in a brain with minimal increased water content but depleted of important neurotransmitters such as glutamate. As serum Na is increased, this adapted brain loses water at a greater rate when compared with the normonatremic brain (Figure 1). 11 This results in astrocyte death as reflected in a high degree of apoptosis, 12 with the subsequent breakdown of white and gray matter interchanges causing activation of microglial cells and osmotic demyelination syndrome. 13 The increase in water loss is likely due to a delay in restoration of osmolytes into the brain. This may be mediated by the downregulation of the sodium-dependent neutral amino-acid transporter-2, an ubiquitous amino-acid transporter that is important for cell volume regulation. 14 The downregulation of sodiumdependent neutral amino-acid transporter-2 hinders aminoacid transport, thereby delaying its return to the brain and cell volume recovery. Brain water content (ml/100 g DW) From Verbalis et al...(28) in hyponatremic rats 100 From Cserr et al...(40) in normonatremic rats Plasma [Na + ] (meq/l) Figure 1 Effect of increasing Na concentration on brain water content in normonatremic animals (green) and animals with chronic hyponatremia (red). Reproduced from 11 with permission from Kidney International. 564 Kidney International (2013) 83,

3 AJ Jovanovich and T Berl: Hyponatremia and vaptans The goal of treatment is aimed at achieving resolution of symptoms, but care must be taken not to exceed well-defined goals. 7 As cerebral water is increased by p10%, this percentage increase in serum Na (or 10 meq/l) should be sufficient for resolution of symptoms. An appropriate goal of correction is B8 meq/l over 24 h. The limit of correction should not exceed 12 meq/l over the first day or 18 meq/l over 2 days. If exceeded, lowering of serum Na is indicated. 15,16 There are several approaches to correcting chronic symptomatic hyponatremia. Water restriction. Water restriction addresses the mechanism of hyponatremia by withholding free water. It is an inexpensive option, but the rate of correction is too slow to achieve the above goals. 17 Therefore, other corrective measures should be used. Loop diuretics with electrolyte repletion. Loop diuretics promote electrolyte-free water clearance. The composition of the urine [Na þ K] is approximately 75 meq/l. Thus, the administration of normal saline results in a net negative water clearance. For example, if the urine flow is 300 ml/h, the electrolyte-free water clearance would be 150 ml/h. This approach is very labor intensive. In addition to careful monitoring of serum Na, it requires monitoring of urine output, as well as urinary Na and K excretions, resulting in frequent adjustments in infusion rates of Na and K, and even water to prevent overcorrection. 18 Hypertonic saline (3% NaCl) and 1-deamino-8-D-arginine vasopressin. Many causes of hyponatremia are transient (drugs, polydipsia, and hypovolemia), and the onset of a water diuresis places a hyponatremic patient at risk for overcorrection. NaCl (3%) and 1-deamino-8-D-arginine vasopressin provide a predictable and controlled increase in serum Na concentration. 19,20 Although this method gives the clinician better control over the rate of Na correction, it does not address the excess in body water. In fact, if the patient is not water restricted, the serum Na may even decrease. Furthermore, 1-deamino-8-Darginine vasopressin prolongs the need for 3% NaCl. Finally, patients with cardiac dysfunction may not tolerate the Na load. Urea. Decaux et al. 21 reported on the treatment of euvolemic hyponatremia with urea in the intensive care setting. Fifty patients with moderate hyponatremia ( meq/l) who initially received isotonic or hypotonic saline sustained a decrease in serum Na concentration. The addition of urea ( g/day by gastric tube) resulted in an increase of 7 meq/l in 2 days. In another cohort of 35 patients with severe hyponatremia (o115 meq/l), the combination of isotonic saline (1 2 l/day) and urea (0.5 1 g/kg/d) increased serum Na from 111 to 122 meq/l in 1 day, resulting in the recovery of neurological symptoms. 21 The availability of urea is limited in most of Europe and North America. Given its low cost and apparent efficacy, more widespread use should be entertained. An alternative approach is the use of a V 2 receptor antagonist. This is more effective than water restriction. When compared with placebo, serum Na was significantly higher within the first 8 h after tolvaptan administration (SALT trials), which included patients with various causes of hyponatremia. 8 Conivaptan given to 18 patients increased serum Na by 7.5 meq/l in the first 24 h. 9 In a meta-analysis that included six randomized controlled trials, the serum Na increased by 6.29 meq/l in 3 7 days from the initiation of treatment in euvolemic hyponatremic patients (most of the increases occurred on day 1). 4 Another meta-analysis noted a 5.5 meq/l increase on day 1 in the same patient population. 22 Meta-analyses found no differences in mortality between groups treated with V 2 receptor antagonist versus placebo, and there were no cases of osmotic demyelination syndrome. 4,22 Because aquaretic agents generate urine that is very low in Na and K concentrations, the electrolyte-free water losses are greater than with loop diuretics. The repletion of electrolytes is unnecessary, thus making this a simpler approach. After the administration of the vasopressin antagonist, serum Na should be monitored every 3 4 h. Once serum Na has increased by 6 8 meq/l, urine output should be matched with 5% dextrose (D5W) to prevent further increases in serum Na. Oral water administration is an alternative, but some patients, particularly elderly patients, have decreased thirst perception and the intravenous route should be utilized. This approach also prevents net nocturnal water losses. It must be noted that the usual approach to rescue (relowering serum Na) after overcorrection with 1-deamino-8-D-arginine vasopressin and D5W may not be effective in vaptan therapy, as there may be resistance to 1-deamino-8-D-arginine vasopressin. CHRONIC ASYMPTOMATIC HYPONATREMIA Most patients with long-standing hyponatremia appear by most criteria to be asymptomatic. This is likely a reflection of the restoration of cell volume made possible by the loss of electrolytes and organic osmolytes. However, studies have questioned whether asymptomatic hyponatremia exists. 23 Renneboog et al. 24 demonstrated that older individuals presenting to the emergency department with falls were 67 times more likely to have hyponatremia (serum Na 126±5 meq/l) when compared with controls without falls. Hyponatremia was also significantly associated with poor attention and gait impairments. 24 Hyponatremia has been implicated as a risk factor for bone fractures, 25 an association supported by subsequent studies. 26,27 In a rat model, hyponatremia (serum Na 110 meq/l) caused a decrement in cortical and trabecular bone mass. 28 This disordered bone mineralization may be mediated by an effect of low serum Na concentrations to stimulate osteoclastic activity. 29 Taken together, chronic asymptomatic hyponatremia has significant morbidity, especially, in older adults who are already at high risk for falls and osteoporotic fractures. In this setting, also, several approaches are available. Kidney International (2013) 83,

4 AJ Jovanovich and T Berl: Hyponatremia and vaptans Water restriction. Water restriction has been the cornerstone of the treatment of hyponatremia. However, compliance with water restriction is poorly tolerated because fluid intake is in large measure determined by habit and cultural factors. Furthermore, water restriction is not always effective, particularly in the face of a severe diluting defect. As analyzed by Furst et al. 30, when urinary [Na þ K]4plasma Na, no electrolyte-free water is excreted and no amount of water restriction will increase serum Na. Only when the ratio is o0.50, a tolerable restriction of 1 l/day is likely to be of benefit. The response to water restriction is therefore variably effective. Demeclocycline. This drug targets the underlying pathogenesis of water-retaining disorders, as it appears to inhibit vasopressin-mediated adenylate cyclase. It should be considered in doses ranging between 600 and 1200 mg/day when water restriction is ineffective and the cause of hyponatremia is not reversible. The response rate is extremely variable. The drug carries frequent gastrointestinal side effects, can cause photosensitivity, and can be nephrotoxic in patients with liver disease. Hyponatremia is not an Food and Drug Administration-approved indication for this drug. Loop diuretics and NaCl tablets. This is an extension of the short-term approach described above in symptomatic patients, a setting in which it has been extensively used. In contrast, there is only one detailed report of its successful use in a patient for 6 months. 31 Frequent adjustments in the dose of the loop diuretic and NaCl and K are necessary to avoid both volume and K depletion, and even volume overload in patients with cardiac dysfunction. There are no studies comparing this therapeutic approach with the use of vasopressin antagonists. Urea. By increasing solute clearance and thereby urine flow rates, urea (30 90 g/day) can increase serum Na concentrations. It does so by decreasing the urinary concentration of Na and K, resulting in the excretion of electrolyte-free water. 32 A recent cross-over study in 13 patients with syndrome of inappropriate antidiuretic hormone found that tolvaptan and urea were equally efficacious in raising serum Na, and both were well tolerated over 1 year. 33 The use of urea may be limited by its unpalatability, potentially leading to poor adherence. Two studies have evaluated long-term V 2 receptor antagonist therapy in chronic hyponatremia. SALTWATER, an openlabel extension of SALT, followed up 111 patients receiving tolvaptan for a mean of 701 days. Serum Na increased from to 4135 meq/l for the duration of treatment without apparent loss of effectiveness. 34 Similarly, a study of satavaptan in which 10 out of 18 patients with syndrome of inappropriate antidiuretic hormone completed a 12-month observation achieved a mean increase in serum Na from 125 to 140 meq/l without escape or adverse events. 35 Adverse effects were uncommon in most trials and relate to the aquaretic effect of the drugs: polyuria, nocturia, thirst, and dry mouth. Excessive correction is more likely to occur with these drugs, 4 particularly in patients with serum Na o120 meq/l. 9 Data supporting a clear improvement in hard patient outcomes with these agents are sorely missing and needed. Tolvaptan did demonstrate a significant (P ¼ 0.015) improvement in the mental component, but not the physical component, of the SF-12 general medical survey. 8 However, studies designed to ascertain whether the drugs affect the length of hospitalization, morbidity, and mortality are needed to justify the long-term use of these extremely costly drugs. V 2 ANTAGONIST RESISTANCE V 2 antagonist resistance may be observed in certain clinical settings (Table 1). Very high circulating vasopressin levels The majority of patients with syndrome of inappropriate antidiuretic hormone have measurable levels of vasopressin at a time when their serum tonicity would call for complete suppression of secretion. Most of these patients have vasopressin levels within the normal range (1 10 pg/ml), but some display much higher levels. 36 Because vasopression antagonists are competitive inhibitors, it is conceivable that they would not respond to conventional doses of these drugs. Excessive water intake Water restriction is not necessary during the use of V 2 receptor antagonists, which themselves stimulate thirst. 8 This mitigates undesirable rapid correction rates. However, if water intake is excessive, equal to or greater than that generated by vaptans, serum Na will not decrease. Vasopressin-independent diluting defect In addition to vasopression, impaired renal hemodynamics (low glomerular filtration rate and enhanced proximal reabsorption) leads to decreased fluid delivery to the distal nephron. This occurs in advanced congestive heart failure and, particularly, in cirrhosis, and probably explains the more modest response to V 2 antagonists observed in SALT, 8 SALTWATER, 33 and even in a meta-analysis. 22 Nephrogenic syndrome of inappropriate antidiuresis Nephrogenic syndrome of inappropriate antidiuresis characterized by unmeasurable vasopressin levels is caused by an activating mutation of the arginine vasopressin V 2 receptor. 37 This missense mutation causes the V 2 receptor to be Table 1 Considerations in hyponatremic patients who are resistant to vaptans Very high circulating vasopressin levels Excessive water intake Vasopressin-independent diluting defect Nephrogenic syndrome of inappropriate antidiuresis 566 Kidney International (2013) 83,

5 AJ Jovanovich and T Berl: Hyponatremia and vaptans constitutively active. Although initially described in young children, it has also been reported in adults. 38 Female carriers of the gene may be susceptible to hyponatremia in the setting of high water intake. 39 CONCLUSION V 2 receptor antagonists are promising agents in the treatment of hypervolemic and euvolemic hyponatremias. Although they have no role in the treatment of acute symptomatic hyponatremia, they provide a simplified approach in the treatment of chronic symptomatic hyponatremia. V 2 receptor antagonists are proven to be efficacious and safe in the longterm treatment of chronic asymptomatic hyponatremia, but their high cost is a barrier to use in this setting. Unfortunately, there are no studies that show that the correction of serum Na improves the quality of life, length of hospitalization, morbidity, or overall mortality. This begs the hitherto unresolved critical question as to whether hyponatremia is itself the cause of morbidity and mortality or simply a marker for underlying serious disease. DISCLOSURE TB was on the speaker s bureau of Otsuka. AJJ declared no competing interests. REFERENCES 1. Waikar SS, Mount DB, Curhan GC. Mortality after hospitalization with mild, moderate, and severe hyponatremia. Am J Med 2009; 122: Kovesdy CP, Lott EH, Lu JL. Hyponatremia, hypernatremia, and mortality in patients with chronic kidney disease with and without congestive heart failure. Circulation 2012; 125: Waikar SS, Curhan GC, Brunelli SM. Mortality associated with low serum concentration in maintenance hemodialysis. Am J Med 2011; 124: Rozen-Zvi B, Yahav D, Gheorghiade M et al. Vasopressin receptor antagonists for the treatment of hyponatremia: systematic review and meta-analysis. Am J Kidney Dis 2010; 56: Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int 2006; 69: Koenig MA, Bryan M, Lewin JL III. Reversal of transtentorial herniation with hypertonic saline. Neurology 2008; 70: Sterns RH, Cappucio JD, Silver SM et al. Neurologic sequelae after treatment of severe hyponatremia: a multicenter perspective. J Am Soc Nephrol 1994; 4: Schrier RW, Gross P, Gheorghiade M et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006; 355: Velez JC, Dopson SJ, Sanders DS et al. Intravenous conivaptan for the treatment of hyponatremia caused by the syndrome of inappropriate secretion of antidiuretic hormone in hospitalized patients: a single-centre experience. Neprhol Dial Transplant 2010; 25: Ayus JC, Arieff AI. Chronic hyponatremic encephalopathy in postmenopausal women: association of therapies with morbidity and morality. JAMA 1999; 281: Berl T. Treating hyponatremia: damned if we do and damned if we don t. Kidney Int 1990; 37: Gangkam-Kengne F, Nicaise C, Soupart A et al. Astrocytes are an early target in osmotic demyelination syndrome. J Am Soc Nephrol 2011; 22: Gankam-Kengne F, Soupart A, Pochet R et al. Minocycline protects against neurologic complication of rapid correction of hyponatremia. J Am Soc Nephrol 2010; 21: Franchi-Gazzola R, Dall Asta V, Sala R et al. The role of the neutral amino acid transporter SNAT2 in cell volume regulation. Acta Physiol 2006; 187: Soupart A, Ngassa M, Decauz G. Therapeutic relowering of the serum sodium in a patient after excessive correction of hyponatremia. Clin Nephrol 1999; 51: Oya S, Tsutsumi K, Ueki K et al. Reinduction of hyponatremia to treat central pontine myelinolysis. Neurology 2001; 57: Schwartz WB, Bennet W, Curelop S et al. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med 1957; 23: Thurman JM, Berl T. Therapy of dysnatremic disorders. In: Wilcox C ed Therapy in Nephrology and Hypertension. Saunders Elsevier: Philadelphia, 2008, pp Perianayagam A, Sterns RH, Silver SM. DDAVP is effective in preventing and reversing inadvertent overcorrection of hyponatremia. Clin J Am Soc Nephrol 2008; 3: Sterns RH, Hix JK, Silver S. Treating profound hyponatremia: a strategy for controlled correction. Am J Kidney Dis 2010; 56: Decaux G, Andres C, Gankam Kengne F et al. Treatment of euvolemic hyponatremia in the intensive care unit by urea. Crit Care 2010; 14: R Jaber BL, Almarzouqi L, Borgi L et al. Short-term efficacy and safety of vasopressin receptor antagonists for treatment of hyponatremia. Am J Med 2011; 124: 977.e Schrier RW. Does asymptomatic hyponatremia exist? Nat Rev Nephrol 2010; 6: Renneboog B, Musch W, Vandemergel X et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med 2006; 119: 71.e Gankam Kengne F, Andres C, Sattar L et al. Mild hyponatremia and risk of fracture in the ambulatory elderly. QJM 2008; 101: Sandhu HS, Gilles E, DeVita MV et al. Hyponatremia associated with large-bone fracture in elderly patients. Int Urol Nephrol 2009; 41: Hoorn EJ, Rivadeneira F, van Meurs JB et al. Mild hyponatremia as a risk factor for fractures: the Rotterdam Study. J Bone Miner Res 2011; 26: Verbalis JG, Barsony J, Sugimura Y et al. Hyponatremia-induced osteoporosis. J Bone Miner Res 2010; 25: Barsony J, Sugimura Y, Verbalis JG. Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss. J Biol Chem 2011; 286: Furst H, Hallows KR, Post J et al. The urine/plasma electrolyute ratio: a predictive guide to water restriction. Am J Med Sci 2000; 319: Decaux G, Waterlot Y, Genette F et al. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with furosemide. NEnglJ Med 1981; 304: Berl T. Impact of solute intake on urine flow and water excretion. JAm Soc Nephrol 2008; 19: Soupart A, Coffernils M, Courturier B et al. Efficacy and tolerance of urea compared with vaptans for long-term treatment of patient with SIADH. Clin J Am Soc Nephrol 2012; 7: Berl T, Quittnat-Pelletier F, Verbalis JG et al. Oral Tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010; 21: Soupart A, Gross P, Legros JJ et al. Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist. Clin J Am Soc Nephrol 2006; 1: Robertson GL, Aycinena P, Zerbe RL. Neurogenic disorders of osmoregulation. Am J Med 1982; 72: Feldman BJ, Rosenthal SM, Vargas GA et al. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 2005; 352: Decaux G, Vandergheynst F, Bouko Y et al. Nephrogenic syndrome of inappropriate antidiuresis in adults: high phenotypic variability in men and women from a large pedigree. J Am Soc Nephrol 2007; 18: Ranchin B, Boury-Jamot M, Blanchard G et al. Familial nephrogenic syndrome of inappropriate antidiuresis: dissociation between aquaporin- 2 and vasopressin excretion. J Clin Endocrinol Metab 2010; 95: E37 E Cserr HF, Depasqualle M, Patlak CS. Regulation of brain water and electrolytes during acute hyponatremia in rats. Am J Physiol 1987; 254: F522 F529. Kidney International (2013) 83,