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Diagnosis and Treatment of : Compilation of the Guidelines

Ewout J. Hoorn and Robert Zietse

Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands

ABSTRACT Hyponatremia is a common water balance disorder that often poses a diagnostic or approach to hyponatremia, two sets of therapeutic challenge. Therefore, guidelines were developed by professional orga- guidelines have been developed, one by nizations, one from within the United States (2013) and one from within Europe professional organizations from within (2014). This review discusses the diagnosis and treatment of hyponatremia, com- the United States (“United States guide- paring the two guidelines and highlighting recent developments. Diagnostically, the line”) and one from within Europe (“Eu- initial step is to differentiate hypotonic from nonhypotonic hyponatremia. Hypo- ropean guideline,” in which the authors tonic hyponatremia is further differentiated on the basis of urine osmolality, urine of this review participated).6–9 The pro- sodium level, and volume status. Recently identified parameters, including fractional fessional organizations involved in the uric acid excretion and plasma copeptin concentration, may further improve the United States guideline were Tufts Uni- diagnostic approach. The treatment for hyponatremiaischosenonthebasisof versity Office of Continuing Education duration and symptoms. For acute or severely symptomatic hyponatremia, both and In 2 MedEd; the initiative was guidelines adopted the approach of giving a bolus of hypertonic saline. Although also supported by an unrestricted edu- fluid restriction remains the first-line treatment for most forms of chronic hypona- cational grant from Otsuka America tremia, therapy to increase renal free water excretion is often necessary. Vasopres- Pharmaceutical.9 The professional orga- sin receptor antagonists, urea, and loop diuretics serve this purpose, but received nizations involved in the European different recommendations in the two guidelines. Such discrepancies may relate to guideline were the European Renal As- different interpretations of the limited evidence or differences in guideline meth- sociation–European Dialysis and Trans- odology. Nevertheless, the development of guidelines has been important in ad- plantation Association, the European vancing this evolving field. Society of Endocrinology, and the Euro- pean Society of Intensive Care Medi- J Am Soc Nephrol 28: ccc–ccc, 2017. doi: 10.1681/ASN.2016101139 cine.6–8 The United States guideline refrained from using a quality-of-evidence scoring system due to the limited evi- dence. Instead, the guideline was on “ ” Hyponatremia (serum sodium [SNa] studies, because the patient with hypo- the basis of expert panel recommenda- , 136 mmol/L) is a common water bal- natremia does not exist. Instead, the un- tions, which relied on a critical evalua- ance disorder that often poses a diagnos- derlying disease that is complicated by tion of relevant literature by the panel 1 tic or therapeutic challenge. This may hyponatremia usually characterizes pa- members. The European guideline 4,5 explain why management of hyponatre- tients with hyponatremia. The most did perform systematic reviews of the mia is still suboptimal, as also recently common causes of hyponatremia are available evidence using the Grading of illustrated by a hyponatremia registry.2 the syndrome of inappropriate antidiu- Hyponatremia is not a disease but resis (SIAD), diuretic use, polydipsia, rather a pathophysiologic process indi- adrenal insufficiency, hypovolemia, 3 Published online ahead of print. Publication date cating disturbed water homeostasis. , and liver cirrhosis (the lat- available at www.jasn.org. Therefore, hyponatremia should be fur- ter two are often collectively referred to ther classified in order to provide direc- as “hypervolemic hyponatremia”). Al- Correspondence: Dr. Ewout J. Hoorn, Erasmus Medical Center, Internal Medicine – Nephrology, tions for diagnosis and treatment (Table though recent years have seen several Room D-438, PO Box 2040, 3000 CA, Rotterdam, 1). These classifications illustrate that developments in the diagnosis and treat- The Netherlands. Email: [email protected] hyponatremia is a very heterogeneous ment of hyponatremia, the evidence base Copyright © 2017 by the American Society of disorder. This has complicated clinical is still limited. To capture the current Nephrology

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Table 1. Classifications of hyponatremia Limitations of Classification Criteria Clinical Utility

Moderate (125–129 mmol/L) Absolute SNa concentration Symptoms do not always a versus severe/profound correlate with degree of hyponatremia (,125 mmol/L) Acute versus chronic Time of development (cutoff 48 h) Time of development not always known Symptomatic versus asymptomatic Presence of symptoms Many symptoms aspecific; chronic hyponatremia may be symptomatic Hypotonic, isotonic, or hypertonic Measured serum osmolality Ineffective osmoles (e.g., urea, ethanol) are also measured Hypovolemic, euvolemic, hypervolemic Clinical assessment of Clinical assessment of volume status volume status has low sensitivity and specificity a 7,9 SNa,125 mmol/L is defined as “severe hyponatremia” by the United States guideline, and as “profound hyponatremia” by the European guideline.

Recommendations Assessment Develop- or protein.16 The United States guide- less able to reabsorb sodium.7,22 In ad- ment and Evaluation scoring system. line subsequently divided hypotonic dition, advanced CKD usually impairs Both guideline committees were interdis- hyponatremia into hypovolemic, euvo- water excretion, complicating the eval- ciplinary, and the European guideline was lemic, and hypervolemic hyponatre- uation of the role of in water endorsed by the European societies of ne- mia.9 Although this represents the balance.23 These considerations prompted phrology, endocrinology, and intensive most traditional and commonly used the European guideline committee care.6–8 This brief review will compare approach to hypotonic hyponatremia, to propose an algorithm that prioritizes the two guidelines to discuss the diagnosis it deserves scrutiny. Hypovolemic and UOsm and UNa over volume status (Fig- and treatment of hyponatremia, while euvolemic hyponatremia are notori- ure 1). It also incorporates the limita- also highlighting recent developments. ously difficult to differentiate on the ba- tions of UNa. In addition, it recommends Because of the breadth of both guidelines, sis of physical examination,17 whereas early identification of acute or symp- this review will focus on the salient fea- hypervolemic hyponatremia is usually tomatic hyponatremia to identify pa- tures. Toplace both guidelines in perspec- clinically obvious (presence of edema tients in whom immediate treatment is tive we will integrate in our discussion the or ascites). Two studies that analyzed indicated. Two additional diagnostic pertinent comments published after their the diagnostic performance of the clin- tests for hyponatremia merit discussion, release.10–13 ical assessment of volume status in pa- including a trial of volume expansion tients with hyponatremia reported low and the fractional uric acid excretion sensitivity (50%–80%) and specificity (FEUA). A trial of volume expansion DIFFERENTIAL DIAGNOSIS OF (30%–50%).18,19 Previously, we showed with isotonic saline can be used to diag- HYPONATREMIA that clinicians often misclassify hypona- nose hypovolemic hyponatremia.18 tremia when using algorithms that start Although a rise in SNa in response to iso- Although the United States guideline did with clinical assessment of volume sta- tonic saline would be consistent with not present a diagnostic algorithm, the tus.20 Similarly, physicians in training hypovolemic hyponatremia, another classifications of hyponatremia on the had a better diagnostic performance possibility would be that the stimulus basis of tonicity and volume status than senior physicians when using an for vasopressin release in a patient with were discussed.9 The initial differentia- algorithm in which urine osmolality SIAD abated. Such stimuli are often tion in hypotonic and nonhypotonic (UOsm) and urine sodium (UNa)con- nonspecific and transient, including 14,24 hyponatremia is important, because centration are prioritized over assess- pain or nausea. In addition, SNa management is different.14 Nonhypo- ment of volume status.21 Because the has been shown to improve upon saline tonic hyponatremia is usually caused by kidneys will respond to hypovolemia infusion in patients with SIAD with 25 hyperglycemia, but may also be caused or a low effective arterial blood volume UOsm,500 mOsm/kg. Conversely, by the administration of mannitol or with sodium retention, UNa,30 mmol/L isotonic saline may sometimes worsen hypertonic radiocontrast.7 In these set- can be used to identify both hypovole- hyponatremia, a phenomenon called tings, management is usually conserva- mic and hypervolemic hyponatremia. “desalination.”26 In response to the tive, although a decrease in extracellular Three caveats, however, should be em- United States guideline, Gross raised 15 tonicity may occur during treatment. phasized: (1)UNa will also be low in pa- the issue of how to deal with mixed Nonhypotonic hyponatremia can also be tients consuming a low sodium diet forms of hyponatremia, for example caused by pseudohyponatremia, a labora- (rareinthewesternpopulations),(2) SIAD and hypovolemia.10 Indeed, we tory artifact that may occur with high con- the (recent) use of diuretics will increase previously showed that patients often centrations of triglycerides, cholesterol, UNa,and(3) patients with CKD may be have two to three possible causes for

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cerebral salt wasting, but normalizes in SIAD only during treatment.32 Of note, however, is that even in neurosurgical patients with hyponatremia, cerebral salt wasting is rare and has remained an enigmatic and not widely accepted clinical entity.33,34

VASOPRESSIN

Arginine vasopressin (the antidiuretic hormone) plays a central role in the path- ogenesis of hyponatremia. In one study, nonosmotic secretion of vasopressin was detected in 97% of patients with hypo- natremia.35 Because hypotonicity nor- mally suppresses vasopressin, the reasons for nonosmotic vasopressin release should be considered.36 “Appro- priate” vasopressin release is due to hy- povolemia or low effective arterial blood volume, both of which activate barore- ceptors to cause vasopressin release. Although one might expect thiazide- induced hyponatremia to be due to hypovolemia secondary to saliuresis, this is not the case.37 Instead, the path- ogenesis appears to be a combination of polydipsia and impaired urea-mediated water excretion.37,38 “Inappropriate” va- sopressin release is usually caused by the effect of an underlying disease or drugs on central osmoreceptors; alternatively, vasopressin can be produced ectopically (e.g., in small cell lung cancer or olfac- tory neuroblastoma).3,39,40 In addition, hypocortisolism increases vasopressin Figure 1. Diagnostic algorithm for hyponatremia. Based on the European guideline.7 ECF, release, because corticotropin-releasing extracellular fluid. hormone normally suppresses vasopres- sin.41 Although rare, secondary and even hyponatremia (although it was unclear of interest because it formally tested the primary adrenal insufficiency may if and to which extent each cause con- diagnostic performance of several pa- mimic SIAD and can be missed without tributed).27 In addition to a trial of vol- rameters using receiver operating appropriate testing.42–44 Although the ume repletion, an alternative approach curves. More recently, a larger study kidney usually limits the degree of hypo- to mixed pathogenesis would be to com- confirmed that FEUA.12% had the natremia in SIAD (“vasopressin es- bine hypertonic saline with desmopres- best sensitivity and specificity for cape”45), it can also cause antidiuresis sin.28,29 Although the literature on this SIAD.31 In absolute terms, however, the independent of vasopressin.46,47 Aspe- approach is limited, it offers a rational performance of FEUA was still moderate, cific example is gain-of-function muta- approach to prevent a rapid rise in SNa and UNa.30 mmol/L and FEUrea.55% tions of the vasopressin type 2 receptor that may occur once hypovolemia has had better sensitivity and specificity for causing hereditary hyponatremia been corrected. Fenske et al. found that SIAD, respectively. We frequently ana- (“nephrogenic SIAD”).48 Despite the FEUA.12% had the highest sensitivity lyze FEUA in patients with hyponatremia, pathogenetic role of vasopressin in hy- and specificity to diagnose SIAD with but mainly use it as supporting informa- ponatremia, plasma vasopressin is rarely 30 or without diuretic use. This study is tion. FEUA is high in both SIAD and measured in clinical practice. This has

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low effective arterial blood volume.53,54 Because hypovolemic hyponatremia is characterized by high plasma copeptin and low UNa, the plasma copeptin to UNa ratio may be especially useful to dif- ferentiate it from SIAD. Although the study by Fenske et al. did indeed dem- onstrate this,52 the specificity of copep- tin/UNa for SIAD in a more recent and larger study was less high.31 An interest- ing approach was the use of plasma copeptin to differentiate SIAD sub- types.55 Using hypertonic saline, SIAD subtypes were defined on the basis of their relationship between serum os- molality and plasma copeptin (Figure 2). As expected, low plasma copeptin levels are diagnostic for hyponatremia due to polydipsia.31,52 Arguably, the need for a novel diagnostic marker for this cause of hyponatremia is limited, as it is usually obvious from the clinical setting and the low UOsm.Inaddition to plasma copeptin, two additional cir- Figure 2. Copeptin-based classification of five subtypes of the syndrome of in- culating markers were recently evalu- appropriate antidiuresis (SIAD). The shaded gray area and the black dashed line show ated in patients with hyponatremia, the normal physiologic relationship between serum osmolality and plasma copeptin (as including apelin and midregional surrogate marker for vasopressin). In SIAD type B this relationship is intact, but the proatrial natriuretic peptide (MR- osmotic threshold for vasopressin release has decreased. In SIAD types A and C va- proANP).56,57 Physiologically, apelin sopressin release is no longer regulated by serum osmolality. In SIAD type D plasma and vasopressin are regulated in oppo- copeptinlevelsareundetectable.InSIADtypeEthenormalrelationshipbetweenserum site directions by volemic and osmotic osmolality and copeptin has reversed. This phenomenon has been coined “barostat stimuli.56 Apelin not only inhibits vaso- ” reset, as it may indicate increased sensitivity of baroreceptors to increased vaso- pressin release centrally, but also coun- pressin release. Percentages indicate how often each subtype was present in one study teracts the antidiuretic effect in the of 50 patients. Data on the basis of Fenske et al.55 and figure modified from Fenske kidney.58 However, in patients with hy- et al.116 with permission. ponatremia due to SIAD or heart failure, plasma apelin was insufficiently sup- two reasons. First, UOsm accurately re- pressin, but also neurophysin and copep- pressed, possibly contributing to anti- flects vasopressin activity, and, therefore, tin (also called C-terminal proarginine diuresis in these settings.56 Similar to this more readily available parameter can vasopressin).51 Because copeptin is plasma copeptin, MR-proANP levels be used instead. Second, vasopressin is more stable, it can be measured more were higher in patients with hypovole- difficult to measure reliably in nonexpert easily. Copeptin can therefore be used mic or hypervolemic hyponatremia laboratories, because it binds to platelets, as a surrogate marker for vasopressin. than in patients with SIAD (although it is unstable in isolated plasma, and com- Although both guidelines only briefly these levels were still higher than in mercial assays are not very sensitive for discuss copeptin, emerging data healthy subjects).57 High MR-proANP low concentrations.49 These limitations, justify a brief discussion on the diagnos- in hypovolemic hyponatremia is coun- however, have largely been resolved tic utility of this novel marker. Fenske terintuitive, but may be explained by by the development of an assay for et al. found that plasma copeptin levels lower GFR secondary to volume deple- copeptin.50 were higher in patients with hypo- or tion.59 Although plasma copeptin, ape- hypervolemic hyponatremia than in pa- lin, and MR-proANP increase insight tients with SIAD.52 This was demon- into the pathophysiology of hyponatre- COPEPTIN strated previously35 and likely reflects mia,thetruediagnosticpotential an “osmoreceptor gain,” the phenome- of these parameters remains to be de- Enzymatic cleavage of the vasopressin non in which angiotensin II amplifies termined. In addition, one single pa- prohormone produces not only vaso- vasopressin release in the context of a rameter is unlikely to achieve optimal

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Table 2. Comparison of the United States and European guidelines Subject United States Guideline European Guideline Acute or symptomatic Severe symptoms: Bolus 3% NaCl Severe symptoms: Bolus 3% hyponatremia (100 ml over 10 min 3 3 as needed) NaCl (150 ml over 20 min 2–3 times as needed) Moderate symptoms: Continuous Moderate symptoms: Bolus 3% infusion 3% NaCl (0.5–2 ml/kg per h) NaCl (150 ml 3% over 20 min once) Chronic hyponatremia SIAD Fluid restriction (first line) Fluid restriction (first line) , urea, or vaptan (second line) Urea or loop diuretics + oral NaCl (second line) Do not recommend or recommend a against vaptan Recommend against or demeclocycline Hypovolemic hyponatremia Isotonic saline Isotonic saline or balanced crystalloid solution Hypervolemic hyponatremia Fluid restriction Fluid restriction b Vaptans Recommend against vaptan Correction rates Minimum: 4–8 mmol/L per d, No minimum 4–6 mmol/L per d (high risk of ODS) Limits: 10–12 mmol/L per d, Limit: 10 mmol/L per d 8 mmol/L per d (high risk of ODS)

Management of overcorrection Baseline SNa$120 mmol/L: Start once limit is exceeded probably unnecessary

Baseline SNa,120 mmol/L: Consult an expert to discuss start relowering with electrolyte-free infusion containing electrolyte-free water or after water (10 ml/kg) with or without 2 mg correction exceeds 6–8 mmol/L per d desmopressin iv a “Do not recommend” when SNa,130 mmol/L, “recommend against” when SNa,125 mmol/L. bIn liver cirrhosis, restrict to patients where potential benefit outweighs risk of worsened liver function.9 discriminatory power. A relevant ques- Therefore, for each patient with profound have gradually become more conserva- tion is whether a combination of diag- hyponatremia (SNa,125 mmol/L), it is tive (with recommended correction rates nostic parameters might improve useful to consider whether cerebral as high as 20 mmol/L per day around management. edema or ODS should be suspected.62,63 1990).65 A subject directly related to cor- This automatically leads to the often rection rates is overcorrection. Both heated debate on optimal correction guidelines recommend frequent moni- 64 GENERAL APPROACH TO rates in hyponatremia. Both guidelines toring of SNa during the active correction TREATMENT reached consensus that the limit (not the phase (i.e., all treatments except fluid re- goal) should be around 10 mmol/L per striction). An aspect that was overlooked A cutoff of 48 hours is usually used to day for both acute and chronic hypona- by both guidelines is that the measure- 7,9 differentiate acute from chronic hypo- tremia (Table 2). Of note, the United ment of SNa may not offer the precision natremia (Table 1).7 This classification States guideline recommends a lower required for this monitoring. Tormey is useful because acute and chronic hy- limit of 8 mmol/L per day if there is a et al. calculated the so-called “reference ponatremia may be complicated by high risk of ODS (e.g., in patients with change value” for SNa using a common different neurologic conditions. Acute hypokalemia, alcoholism, malnutrition, analyzer and demonstrated that only 9 hyponatremia can cause cerebral or liver disease). In response to these changes in SNa $4 mmol/L were certain edema when cells have insufficient recommendations, Adrogué and Madias to be real.12 If overcorrection is detected, time to adapt to the hypotonic extra- proposed even more conservative limits both guidelines used different criteria for cellular environment. In chronic hy- of 6–8 mmol/L per day regardless of du- when to relower SNa: when initial SNa was ponatremia brain cell adaptation has ration or symptoms.11 Although we agree ,120 mmol/L (United States guideline) occurred and, in this setting, an acute that this is likely to be both sufficient and or when limits are exceeded (European increase in extracellular tonicity in- safe, the data to support this are still lim- guideline, Table 2). Both guidelines rec- duced by treatment can cause osmotic ited. It is of interest to see how over the ommend hypotonic fluids or desmopres- 60,61 demyelination syndrome (ODS). years the recommended correction rates sin for relowering SNa. A combination of

J Am Soc Nephrol 28: ccc–ccc, 2017 Hyponatremia 5 BRIEF REVIEW www.jasn.org hypotonic fluids and desmopressin may mild-to-moderate symptoms (Table TREATMENT OF CHRONIC be required for treating overcorrection 2).9 The European guideline based its HYPONATREMIA in hypovolemic hyponatremia, because recommendations primarily on the a persistent water diuresis may ensue presence and severity of symptoms Except for hypovolemic hyponatremia, after correction of hypovolemia.66 Ex- rather than on duration.7 Both guide- the treatment of chronic hyponatremia perimental data indicate improved lines recommend hypertonic saline relies on reducing free water intake outcomes with reinduction of hypona- (typically 3% NaCl) for acute or symp- and/or increasing renal free water excre- tremia after rapid overcorrection.67 tomatic hyponatremia.7,9 Hypertonic tion (Table 2). Fluid restriction (,1L/d) Another point that merits discussion saline is an effective and potentially is often the cornerstone of the therapy is the consistent association of hypona- life-saving treatment for cerebral edema for chronic hyponatremia.24 The urine 63,68 tremia with worse outcomes. This due to hyponatremia, as the high extra- to serum electrolyte ratio ([UNa +urine may indicate that hyponatremia has cellular sodium concentration immedi- potassium concentration]/SNa)indi- adverse effects beyond the classic neu- ately removes water from the intracellular cates if the patient is in an antidiuretic rologic symptoms.69,70 However, in the space. In patients with hypervolemic hy- or phase, and can also help absence of randomized intervention ponatremia, hypertonic saline may be estimate the degree of fluid restriction 9 3,11,24,82 studies indicating that correction of combined with loop diuretics. The re- required to increase SNa. For hyponatremia improves outcomes, it re- quired volume of hypertonic saline to patients with a ratio.1 (indicating con- , fl mains unclear whether these associations reach a predefined increase in SNa can centrated urine), 500 ml uid/d is rec- are causal.5 be estimated using the Adrogué–Madias ommended, which is difficult to adhere or Barsoum–Levine formulae.77,78 Al- to. Winzeler et al. recently showed that though predictions with these formulae in patients with SIAD fluid restriction is TREATMENT OF ACUTE are fairly accurate,66 aswitchtoward effective in 59% of patients.83 Predictors HYPONATREMIA giving hypertonic saline as fixed bolus of nonresponse were a UNa$130 mmol/L 79 83 has occurred in recent years. No stud- and UOsm$500 mOsm/kg. This im- Several settings predispose to acute hy- ies have systematically tested this ap- plies that in patients with chronic hypo- ponatremia, especially if combined with proach, but there are a number of natremia pharmacologic therapy is increased free water intake.71 Among appealing aspects. First, especially in pa- often required to increase renal free wa- others, these include the postoperative tients with cerebral edema, it is desirable ter excretion. This can be achieved by period, exercise, and the use of 3,4- to achieve a rapid partial correction in treatment with loop diuretics, urea, vaso- “ ” methylenedioxymethamphetamine SNa.Second,afixed bolus omits the need pressin receptor antagonists ( vaptans ), (“Ecstasy”), haloperidol, thiazide di- for calculations in a patient with an or demeclocycline. The two guidelines uretics, desmopressin, , or in- acute problem, limiting potential calcu- diverge in their recommendations re- travenous cyclophosphamide.71–74 A lation errors. Third, bolus therapy limits garding pharmacologic therapy for specific situation is the use of irrigants the risk of overcorrection, which does SIAD and hypervolemic hyponatremia (glycine, sorbitol, mannitol) during occur commonly with a continuous in- (Table 2). This was the case especially transurethral or hysteroscopic proce- fusion of hypertonic saline.80 On the for vaptans, which will therefore be dis- dures. Although absorption of the irri- basis of these considerations, both cussed in more detail below. gants glycine and sorbitol may cause guidelines recommend bolus therapy, hypotonic hyponatremia, the degree of albeit with slightly different specifica- Vaptans hypotonicity and therefore the risk tions (Table 2).7,9 Recently, Ayus and Vaptans block vasopressin type 2 recep- of cerebral edema depends on the type colleagues reported their experience tors in collecting duct principal cells and of irrigant and the time course in osmo- using a different protocol (500 ml 3% therefore induce aquaresis (for compre- lar shifts.75,76 In contrast, mannitol cau- NaCl over 6 hours) in 64 patients with hensive review, see Berl,84 Hoorn and 85 86 ses hypertonic hyponatremia without a hyponatremic encephalopathy (SNa,130 Zietse, Lehrich et al., Rozen-Zvi risk for cerebral edema. In daily practice, mmol/L and neurologic symptoms).81 On et al.,87 and Greenberg and Verbalis88). the distinction between acute and average, this protocol increased SNa with Several vaptans were developed, includ- chronic hyponatremia is difficult, be- 12and14mmol/Linthefirst 24–48 ing , , lixivaptan, cause the time in which hyponatremia hours, and improved symptoms without and (which also targets vaso- developed is usually unknown. The evidence of ODS.81 However, the severity pressin type 1a receptors). On the basis United States and European guidelines of hyponatremia (SNa frequently ,110 of their mechanism of action, vaptans approached this challenge differently. mmol/L) and the duration of symptoms are a logical and targeted therapy for hy- The United States guideline adhered to suggest that some of these patients had ponatremic patients with excess vasopres- acute versus chronic hyponatremia, but chronic hyponatremia. If so, these correc- sin. Indeed, several large clinical trials did subdivide acute hyponatremia on tion rates would exceed currently recom- have shown that vaptans are clearly effec- thebasisofthepresenceofsevereor mended limits (Table 2). tive in increasing SNa in patients with

6 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc,2017 www.jasn.org BRIEF REVIEW hyponatremia due to SIAD, heart failure, Urea evaluated all available international guide- or liver cirrhosis.89,90 Both guidelines Both guidelines suggest an interesting al- lines on hyponatremia and analyzed how agree that there is no place for vaptans ternative to vaptans for chronic hypona- well they met the Appraisal of Guidelines in patients with acute or severely symp- tremia due to SIAD, namely urea.102 Urea for Research and Evaluation criteria.114 tomatic hyponatremia, for which hyper- induces an osmotic diuresis, thereby in- They identified considerable variation in tonic saline is the treatment of choice.7,9 creasing renal free water excretion. methodologic rigor in the development of Still, it has been difficult to position vap- Decaux and colleagues pioneered the use guidelines, potentially explaining incon- tans in the therapeutic arsenal of chronic of urea in the 1980s for SIAD, but also for sistencies in recommendations.114 Be- hyponatremia.11,84,91,92 The United other forms of hyponatremia.103–109 More cause hyponatremia is a heterogeneous States guideline lists vaptans as one of recently, in 12 patients with SIAD, Soupart disorder rather than a clear-cut disease, the pharmacologic options, if fluid re- et al. compared the treatment with not all patients can be covered by guide- striction has failed (Table 2).9 The Eu- satavaptan to urea (both treatment periods lines. That said, which evidence does the ropean guideline did not recommend 1 year).110 Interestingly, both therapies field need for the coming years? First, it vaptans in moderate hyponatremia.7 had a similar efficacy and side-effect pro- would be useful to evaluate if a combina- The reason to do so was the absence of file. Although urea does not prevent over- tion of the traditional and newer diagnos- evidence for improved hard outcomes correction, it may reduce the risk of the tic tests would improve not only diagnosis with correction of SNa. Meanwhile, one associated brain damage. In a rat model but also outcomes. Second, the approach meta-analysis has suggested improved of experimental SIAD, Gankam Kenge of giving a bolus of hypertonic saline survival with correction of hyponatre- et al. compared the neurologic outcomes should be studied to address the optimal mia,93 although bias is difficult to exclude after overcorrection (approximately volume, whether this should be on the because no randomized controlled tri- 30 mmol/L per day) with hypertonic sa- basis of (ideal) body weight, and how of- als are available. Furthermore, there is line, lixivaptan, or urea.111 Quite strikingly, ten it should be repeated to reach the de- 115 evidence for potential harm of vaptans, neurologic scores and survival were better sired increase in SNa. Third, the role of including overcorrection, and liver tox- in the animals treated with urea. Histologic vaptans in the treatment of chronic hypo- icity.7,87,94–96 Because ODS has mainly analysis showed that, in comparison to the natremia remains a logical focus. For ex- been reported after overcorrection of two other treatments, urea reduced demy- ample, it would be important to analyze profound hyponatremia, the European elination, microglial activation, and whether the copeptin-based subtypes of guideline recommended against vap- changes in the blood-brain barrier, and in- SIAD respond differently to vaptans (Fig- tans in this setting.7 Recently, Tzoulis creased astrocyte viability.111 Although ure 2). Finally, studies analyzing the effect et al. reported “real-life experience” one should be careful to extrapolate these of a vaptan in comparison with another with tolvaptan in 61 patients with resis- findings to humans, this may explain why active treatment (rather than placebo) on tant hyponatremia due to SIAD.97 The patients with ESRD and hyponatremia do patient-relevant outcomes (rather than averageriseinSNa after 24 hours was not develop ODS after treatment with he- SNa) are warranted. 9.063.9 mmol/L. Excessive correction modialysis.112 One specific disadvantage of hyponatremia (.12 mmol/L per of urea used to be its palatability. This day) was observed in 23% of patients problem has been solved by developing a (all with profound hyponatremia), al- formulation in which urea is combined ACKNOWLEDGMENTS though none of them developed signs with sodium bicarbonate, citric acid, and of ODS.97 ODS was reported in one pa- sucrose (see European guideline for pre- E.J.H. is supported by the Dutch Kidney tient with heart failure in whom 15 mg scription7) and by the development of a Foundation (KSP-14OK19). tolvaptan caused SNa to increase from commercially available urea powder drink 126 to 142 mmol/L in the first day and mix (Ure-Na by Nephcentric). to further increase to 187 mmol/L in DISCLOSURES subsequent days.94 On the other hand, None. improvement of symptoms has been SUMMARY AND CONCLUSIONS shown with the use of vaptans. This in- REFERENCES cludes improvements in some neurocog- Our impression is that the development of 98 nitive symptoms, performance status in the United States and European guidelines 1. Adrogué HJ, Madias NE: The challenge of hy- 99 cancer patients, dyspnea in patients with has helped to standardize and improve the ponatremia. JAmSocNephrol23: 1140–1148, heart failure,100 and ascites in patients management of hyponatremia. The two 2012 with liver cirrhosis.101 Therefore, in our guidelines are more often in agreement 2. Greenberg A, Verbalis JG, Amin AN, Burst view, an unresolved question with regard than in disagreement. The discrepancies VR, Chiodo JA 3rd , Chiong JR, Dasta JF, Friend KE, Hauptman PJ, Peri A, Sigal SH: to the use of vaptans remains, of whether are likely related to the interpretation of Current treatment practice and outcomes. symptomatic improvement outweighs the the limited evidence and the methodology Report of the hyponatremia registry. Kidney risk of overcorrection, even if ODS is rare. used to draft the guidelines.113 Nagler et al. Int 88: 167–177, 2015

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3. Sterns RH: Disorders of plasma sodium– osmolality to minimize the likelihood of ce- inadvertent overcorrection of hypona- causes, consequences, and correction. N rebral edema during treatment of children tremia. Clin J Am Soc Nephrol 3: 331–336, Engl J Med 372: 55–65, 2015 with diabetic ketoacidosis. J Pediatr 150: 2008 4. Winzeler B, Jeanloz N, Nigro N, Suter- 467–473, 2007 30. Fenske W, Störk S, Koschker AC, Widmer I, Schuetz P, Arici B, Bally M, Blum 16. Turchin A, Seifter JL, Seely EW: Clinical Blechschmidt A, Lorenz D, Wortmann S, C, Bock A, Huber A, Mueller B, Christ-Crain problem-solving. Mind the gap. NEnglJ Allolio B: Value of fractional uric acid excre- M: Long-term outcome of profound hypo- Med 349: 1465–1469, 2003 tion in differential diagnosis of hyponatremic natremia: A prospective 12 months follow- 17. McGee S, Abernethy WB 3rd , Simel DL: patients on diuretics. J Clin Endocrinol Metab up study. Eur J Endocrinol 175: 499–507, The rational clinical examination. Is this pa- 93: 2991–2997, 2008 2016 tient hypovolemic? JAMA 281: 1022–1029, 31. Nigro N, Winzeler B, Suter-Widmer I, 5. Chawla A, Sterns RH, Nigwekar SU, 1999 Schuetz P, Arici B, Bally M, Blum CA, Nickel Cappuccio JD: Mortality and serum sodium: 18. Musch W, Thimpont J, Vandervelde D, CH, Bingisser R, Bock A, Huber A, Müller B, Do patients die from or with hyponatremia? Verhaeverbeke I, Berghmans T, Decaux G: Christ-Crain M: Evaluation of copeptin and Clin J Am Soc Nephrol 6: 960–965, 2011 Combined fractional excretion of sodium commonly used laboratory parameters for 6. Spasovski G, Vanholder R, Allolio B, Annane and urea better predicts response to saline the differential diagnosis of profound hy- D, Ball S, Bichet D, Decaux G, Fenske W, in hyponatremia than do usual clinical and ponatraemia in hospitalized patients: ‘The Hoorn EJ, Ichai C, Joannidis M, Soupart A, biochemical parameters. Am J Med 99: Co-MED Study’ [published online ahead of Zietse R, Haller M, van der Veer S, Van 348–355, 1995 print September 22, 2016]. Clin Endocrinol Biesen W, Nagler E; Hyponatraemia Guide- 19. Chung HM, Kluge R, Schrier RW, Anderson (Oxf) 10.1111/cen.13243 line Development Group: Clinical practice RJ:Clinicalassessmentofextracellularfluid 32. Maesaka JK, Imbriano LJ, Ali NM, Ilamathi guideline on diagnosis and treatment of volume in hyponatremia. Am J Med 83: E: Is it cerebral or renal salt wasting? Kidney hyponatraemia. Eur J Endocrinol 170: G1– 905–908, 1987 Int 76: 934–938, 2009 G47, 2014 20. Hoorn EJ, Halperin ML, Zietse R: Diagnostic 33. Sherlock M, O’Sullivan E, Agha A, Behan 7. Spasovski G, Vanholder R, Allolio B, Annane approach to a patient with hyponatraemia: LA, Owens D, Finucane F, Rawluk D, D, Ball S, Bichet D, Decaux G, Fenske W, Traditional versus physiology-based op- Tormey W, Thompson CJ: Incidence and Hoorn EJ, Ichai C, Joannidis M, Soupart A, tions. QJM 98: 529–540, 2005 pathophysiology of severe hyponatraemia Zietse R, Haller M, van der Veer S, Van 21. Fenske W, Maier SK, Blechschmidt A, in neurosurgical patients. Postgrad Med J Biesen W, Nagler E; Hyponatraemia Allolio B, Störk S: Utility and limitations of 85: 171–175, 2009 Guideline Development Group: Clinical the traditional diagnostic approach to hy- 34. Singh S, Bohn D, Carlotti AP, Cusimano M, practice guideline on diagnosis and treat- ponatremia: A diagnostic study. Am J Med Rutka JT, Halperin ML: Cerebral salt wast- ment of hyponatraemia. Nephrol Dial 123: 652–657, 2010 ing: Truths, fallacies, theories, and chal- Transplant 29[Suppl 2]: i1–i39, 2014 22. Hoorn EJ, Hotho D, Hassing RJ, Zietse R: lenges. Crit Care Med 30: 2575–2579, 2002 8. Spasovski G, Vanholder R, Allolio B, Annane Unexplained hyponatremia: Seek and you 35. Anderson RJ, Chung HM, Kluge R, Schrier D, Ball S, Bichet D, Decaux G, Fenske W, will find. Nephron, Physiol 118: 66–71, 2011 RW: Hyponatremia: A prospective analysis Hoorn EJ, Ichai C, Joannidis M, Soupart A, 23. Roussel R, Fezeu L, Marre M, Velho G, of its epidemiology and the pathogenetic Zietse R, Haller M, van der Veer S, Van Fumeron F, Jungers P, Lantieri O, Balkau B, role of vasopressin. Ann Intern Med 102: Biesen W, Nagler E: Clinical practice Bouby N, Bankir L, Bichet DG: Comparison 164–168, 1985 guideline on diagnosis and treatment of between copeptin and vasopressin in a 36. Hoorn EJ, Zietse R: Hyponatremia revisited: hyponatraemia. Intensive Care Med 40: population from the community and in Translating physiology to practice. Neph- 320–331, 2014 people with chronic kidney disease. JClin ron, Physiol 108: 46–59, 2008 9. Verbalis JG, Goldsmith SR, Greenberg A, Endocrinol Metab 99: 4656–4663, 2014 37. Friedman E, Shadel M, Halkin H, Farfel Z: Korzelius C, Schrier RW, Sterns RH, 24. Ellison DH, Berl T: Clinical practice. The Thiazide-induced hyponatremia. Reproduc- Thompson CJ: Diagnosis, evaluation, and syndrome of inappropriate antidiuresis. N ibility by single dose rechallenge and an treatment of hyponatremia: Expert panel Engl J Med 356: 2064–2072, 2007 analysis of pathogenesis. Ann Intern Med recommendations. Am J Med 126[Suppl 1]: 25. Musch W, Decaux G: Treating the syn- 110: 24–30, 1989 S1–S42, 2013 drome of inappropriate ADH secretion with 38. Frenkel NJ, Vogt L, De Rooij SE, Trimpert C, 10. Gross P: Panel recommendations on hypo- isotonic saline. QJM 91: 749–753, 1998 Levi MM, Deen PM, van den Born BJ: natremia. Am J Med 127: e29, 2014 26. Steele A, Gowrishankar M, Abrahamson S, Thiazide-induced hyponatraemia is associ- 11. Adrogué HJ, Madias NE: Diagnosis and Mazer CD, Feldman RD, Halperin ML: ated with increased water intake and im- treatment of hyponatremia. Am J Kidney Postoperative hyponatremia despite near- paired urea-mediated water excretion at Dis 64: 681–684, 2014 isotonic saline infusion: A phenomenon of low plasma antidiuretic hormone and urine 12. Tormey WP, Carney M, Cuesta M, Sreenan desalination. Ann Intern Med 126: 20–25, aquaporin-2. JHypertens33: 627–633, S: Reference change values for sodium are 1997 2015 ignored by the American and European 27. Hoorn EJ, Lindemans J, Zietse R: Develop- 39. Robertson GL: Regulation of arginine va- treatment guidelines for hyponatremia. Clin ment of severe hyponatraemia in hospital- sopressin in the syndrome of inappropriate Chem 61: 1430–1432, 2015 ized patients: Treatment-related risk factors antidiuresis. Am J Med 119[Suppl 1]: S36– 13. Avila M: The clinical practice guideline on and inadequate management. Nephrol Dial S42, 2006 diagnosis and treatment of hyponatraemia: Transplant 21: 70–76, 2006 40. Hoorn EJ, Monserez DA, Fenton RA, A response from Otsuka Pharmaceutical 28. Sood L, Sterns RH, Hix JK, Silver SM, Chen Overdevest I, Apperloo AJ, Zietse R, Europe Ltd. Eur J Endocrinol 171: L1–L3, L: Hypertonic saline and desmopressin: A Hardillo JA: Olfactory neuroblastoma with 2014 simple strategy for safe correction of severe hyponatremia. J Clin Oncol 33: e88–e92, 14. Cohen DM, Ellison DH: Evaluating hypo- hyponatremia. Am J Kidney Dis 61: 571– 2015 natremia. JAMA 313: 1260–1261, 2015 578, 2013 41.YamadaK,TamuraY,YoshidaS:Effectof 15. Hoorn EJ, Carlotti AP, Costa LA, MacMahon 29. Perianayagam A, Sterns RH, Silver SM, administration of corticotropin-releasing B, Bohn G, Zietse R, Halperin ML, Bohn D: Grieff M, Mayo R, Hix J, Kouides R: DDAVP hormone and glucocorticoid on arginine Preventing a drop in effective plasma is effective in preventing and reversing vasopressin response to osmotic stimulus in

8 Journal of the American Society of Nephrology J Am Soc Nephrol 28: ccc–ccc,2017 www.jasn.org BRIEF REVIEW

normal subjects and patients with hypo- 55. Fenske WK, Christ-Crain M, Hörning A, hyponatremia reduces mortality in rats. corticotropinism without overt diabetes in- Simet J, Szinnai G, Fassnacht M, Rutishauser Kidney Int 76: 614–621, 2009 sipidus. JClinEndocrinolMetab69: 396– J, Bichet DG, Störk S, Allolio B: A copeptin- 68. Liamis G, Rodenburg EM, Hofman A, Zietse 401, 1989 based classification of the osmoregulatory R, Stricker BH, Hoorn EJ: Electrolyte dis- 42. Cuesta M, Garrahy A, Slattery D, Gupta S, defects in the syndrome of inappropriate orders in community subjects: Prevalence Hannon AM, Forde H, McGurren K, Sherlock antidiuresis. JAmSocNephrol25: 2376– and risk factors. Am J Med 126: 256–263, M, Tormey W, Thompson CJ: The contribu- 2383, 2014 2013 tion of undiagnosed adrenal insufficiency to 56. Blanchard A, Steichen O, De Mota N, Curis 69. Hoorn EJ, Zietse R: Hyponatremia and euvolaemic hyponatraemia: Results of a large E, Gauci C, Frank M, Wuerzner G, mortality: How innocent is the bystander? prospective single-centre study. Clin Endo- Kamenicky P, Passeron A, Azizi M, Llorens- Clin J Am Soc Nephrol 6: 951–953, 2011 crinol (Oxf) 85: 836–844, 2016 Cortes C: An abnormal apelin/vasopressin 70. Schrier RW, Sharma S, Shchekochikhin D: 43. Smith JC, Siddique H, Corrall RJ: Mis- balance may contribute to water retention Hyponatraemia: More than just a marker of interpretation of serum cortisol in a patient in patients with the syndrome of in- disease severity? Nat Rev Nephrol 9: 37–50, with hyponatraemia. BMJ 328: 215–216, appropriate antidiuretic hormone (SIADH) 2013 2004 and heart failure. J Clin Endocrinol Metab 71. Hsu YJ, Chiu JS, Lu KC, Chau T, Lin SH: 44. van der Hoek J, Hoorn EJ, de Jong GM, 98: 2084–2089, 2013 Biochemical and etiological characteristics Janssens EN, de Herder WW: Severe hy- 57. Nigro N, Winzeler B, Suter-Widmer I, of acute hyponatremia in the emergency ponatremia with high urine sodium and os- Schuetz P, Arici B, Bally M, Blum CA, Nickel department. J Emerg Med 29: 369–374, molality. Clin Chem 55: 1905–1908, 2009 CH, Bingisser R, Bock A, Rentsch Savoca K, 2005 45. Ecelbarger CA, Nielsen S, Olson BR, Huber A, Müller B, Christ-Crain M: Mid-re- 72. Achinger SG, Arieff AI, Kalantar-Zadeh K, Murase T, Baker EA, Knepper MA, Verbalis gional pro-atrial natriuretic peptide and the Ayus JC: Desmopressin acetate (DDAVP)- JG: Role of renal aquaporins in escape from assessment of volaemic status and differ- associated hyponatremia and brain dam- vasopressin-induced antidiuresis in rat. J ential diagnosis of profound hypona- age: A case series. Nephrol Dial Transplant Clin Invest 99: 1852–1863, 1997 traemia. J Intern Med 278: 29–37, 2015 29: 2310–2315, 2014 46. de Bragança AC, Moyses ZP, Magaldi AJ: 58. Hus-Citharel A, Bodineau L, Frugière A, 73. Moses AM, Miller M: Drug-induced dilu- Carbamazepine can induce kidney water Joubert F, Bouby N, Llorens-Cortes C: tional hyponatremia. NEnglJMed291: absorption by increasing aquaporin 2 ex- Apelin counteracts vasopressin-induced 1234–1239, 1974 pression. Nephrol Dial Transplant 25: water reabsorption via cross talk between 74. Liamis G, Milionis H, Elisaf M: A review of 3840–3845, 2010 apelin and signaling drug-induced hyponatremia. Am J Kidney 47. Moyses ZP, Nakandakari FK, Magaldi AJ: pathways in the rat collecting duct. Endo- Dis 52: 144–153, 2008 Fluoxetine effect on kidney water re- crinology 155: 4483–4493, 2014 75. Agarwal R, Emmett M: The post-transurethral absorption. Nephrol Dial Transplant 23: 59. Tzikas S, Keller T, Wild PS, Schulz A, resection of prostate syndrome: Therapeutic 1173–1178, 2008 Zwiener I, Zeller T, Schnabel RB, Sinning C, proposals. Am J Kidney Dis 24: 108–111, 48. Feldman BJ, Rosenthal SM, Vargas GA, Lubos E, Kunde J, Münzel T, Lackner KJ, 1994 Fenwick RG, Huang EA, Matsuda-Abedini Blankenberg S: Midregional pro-atrial na- 76. Ayus JC, Arieff AI: Glycine-induced hypo- M, Lustig RH, Mathias RS, Portale AA, Miller triuretic peptide in the general population/ osmolar hyponatremia. Arch Intern Med WL, Gitelman SE: Nephrogenic syndrome Insights from the Gutenberg Health Study. 157: 223–226, 1997 of inappropriate antidiuresis. NEnglJMed Clin Chem Lab Med 51: 1125–1133, 2013 77. Adrogué HJ, Madias NE: Hyponatremia. N 352: 1884–1890, 2005 60. Sterns RH, Riggs JE, Schochet Jr. SS: Os- Engl J Med 342: 1581–1589, 2000 49. Moses AM, Clayton B: Impairment of os- motic demyelination syndrome following 78. Barsoum NR, Levine BS: Current prescrip- motically stimulated AVP release in patients correction of hyponatremia. N Engl J Med tions for the correction of hyponatraemia with primary polydipsia. Am J Physiol 265: 314: 1535–1542, 1986 and hypernatraemia: Are they too simple? R1247–R1252, 1993 61. Sterns RH, Silver SM: Brain volume regula- Nephrol Dial Transplant 17: 1176–1180, 50. Morgenthaler NG, Struck J, Alonso C, tion in response to hypo-osmolality and its 2002 Bergmann A: Assay for the measurement of correction. Am J Med 119[Suppl 1]: S12– 79. Moritz ML, Ayus JC: 100 cc 3% sodium copeptin, a stable peptide derived from the S16, 2006 chloride bolus: A novel treatment for hy- precursor of vasopressin. Clin Chem 52: 62. Berl T: Treating hyponatremia: Damned if ponatremic encephalopathy. Metab Brain 112–119, 2006 we do and damned if we don’t. Kidney Int Dis 25: 91–96, 2010 51. Christ-Crain M, Fenske W: Copeptin in the 37: 1006–1018, 1990 80. Mohmand HK, Issa D, Ahmad Z, Cappuccio diagnosis of vasopressin-dependent disor- 63. Hoorn EJ, Zietse R: Hyponatremia and JD, Kouides RW, Sterns RH: Hypertonic sa- ders of fluid homeostasis. Nat Rev Endo- mortality: Moving beyond associations. Am line for hyponatremia: Risk of inadvertent crinol 12: 168–176, 2016 JKidneyDis62: 139–149, 2013 overcorrection. Clin J Am Soc Nephrol 2: 52. Fenske W, Störk S, Blechschmidt A, Maier 64. Berl T: Treating hyponatremia: What is all 1110–1117, 2007 SG, Morgenthaler NG, Allolio B: Copeptin the controversy about? Ann Intern Med 81. Ayus JC, Caputo D, Bazerque F, Heguilen R, in the differential diagnosis of hypona- 113: 417–419, 1990 Gonzalez CD, Moritz ML: Treatment of hy- tremia. JClinEndocrinolMetab94: 123– 65. Martin RJ: Central pontine and extrapontine ponatremic encephalopathy with a 3% so- 129, 2009 myelinolysis: The osmotic demyelination dium chloride protocol: A case series. Am J 53. Robertson GL, Athar S: The interaction of syndromes. J Neurol Neurosurg Psychiatry Kidney Dis 65: 435–442, 2015 blood osmolality and blood volume in reg- 75[Suppl 3]: iii22–iii28, 2004 82. Rose BD: New approach to disturbances in ulating plasma vasopressin in man. JClin 66. Liamis G, Kalogirou M, Saugos V, Elisaf M: the plasma sodium concentration. Am J Endocrinol Metab 42: 613–620, 1976 Therapeutic approach in patients with dys- Med 81: 1033–1040, 1986 54. Zhang Z, Bourque CW: Amplification of natraemias. Nephrol Dial Transplant 21: 83. Winzeler B, Lengsfeld S, Nigro N, Suter- transducer gain by angiotensin II-mediated 1564–1569, 2006 Widmer I, Schütz P, Arici B, Bally M, Blum C, enhancement of cortical actin density in 67. Gankam Kengne F, Soupart A, Pochet R, Bock A, Huber A, Müller B, Christ-Crain M: osmosensory neurons. JNeurosci28: Brion JP, Decaux G: Re-induction of hy- Predictors of nonresponse to fluid restriction 9536–9544, 2008 ponatremia after rapid overcorrection of in hyponatraemia due to the syndrome of

J Am Soc Nephrol 28: ccc–ccc, 2017 Hyponatremia 9 BRIEF REVIEW www.jasn.org

inappropriate antidiuresis. JInternMed280: mechanistic model to evaluate putative 106. Cauchie P, Vincken W, Decaux G: Urea 609–617, 2016 mechanisms of tolvaptan drug-induced treatment for water retention in hypona- 84. Berl T: Vasopressin antagonists. NEnglJ liver injury and identify patient susceptibility tremic congestive heart failure. Int J Cardiol Med 372: 2207–2216, 2015 factors [published online ahead of print 17: 102–104, 1987 85. Hoorn EJ, Zietse R: Vasopressin-receptor an- September 21, 2016]. Toxicol Sci 10.1093/ 107. Verhoeven A, Musch W, Decaux G: Treat- tagonists. Future Cardiol 6: 523–534, 2010 toxsci/kfw193 ment of the polydipsia-hyponatremia syn- 86. Lehrich RW, Ortiz-Melo DI, Patel MB, 97. Tzoulis P, Waung JA, Bagkeris E, Carr H, drome with urea. J Clin Psychiatry 66: Greenberg A: Role of vaptans in the man- Khoo B, Cohen M, Bouloux PM: Real-life 1372–1375, 2005 agement of hyponatremia. Am J Kidney Dis experience of tolvaptan use in the treat- 108. Decaux G, Unger J, Brimioulle S, Mockel J: 62: 364–376, 2013 ment of severe hyponatraemia due to Hyponatremia in the syndrome of in- 87. Rozen-Zvi B, Yahav D, Gheorghiade M, syndrome of inappropriate antidiuretic appropriate secretion of antidiuretic hor- Korzets A, Leibovici L, Gafter U: Vasopressin hormone secretion. Clin Endocrinol (Oxf) mone. Rapid correction with urea, sodium receptor antagonists for the treatment of 84: 620–626, 2016 chloride, and water restriction therapy. hyponatremia: Systematic review and meta- 98. Verbalis JG, Ellison H, Hobart M, Krasa H, JAMA 247: 471–474, 1982 analysis. Am J Kidney Dis 56: 325–337, 2010 Ouyang J, Czerwiec FS; Investigation of 109. Decaux G, Mols P, Cauchie P, Flamion B, 88. Greenberg A, Verbalis JG: Vasopressin re- the Neurocognitive Impact of Sodium Delwiche F: Treatment of hyponatremic ceptor antagonists. Kidney Int 69: 2124– Improvement in Geriatric Hyponatremia: cirrhosis with ascites resistant to diuretics by 2130, 2006 Efficacy and Safety of Tolvaptan (INSIGHT) urea. Nephron 44: 337–343, 1986 89. Berl T, Quittnat-Pelletier F, Verbalis JG, Investigators: Tolvaptan and neurocognitive 110. Soupart A, Coffernils M, Couturier B, Schrier RW, Bichet DG, Ouyang J, Czerwiec function in mild to moderate chronic hypo- Gankam-KengneF,DecauxG:Efficacy and FS; SALTWATER Investigators: Oral tol- natremia: A randomized trial (INSIGHT). Am J tolerance of urea compared with vaptans vaptan is safe and effective in chronic hy- Kidney Dis 67: 893–901, 2016 for long-term treatment of patients with ponatremia. J Am Soc Nephrol 21: 705– 99. Petereit C, Zaba O, Teber I, Lüders H, Grohé SIADH. Clin J Am Soc Nephrol 7: 742–747, 712, 2010 C: A rapid and efficient way to manage hy- 2012 90. Schrier RW, Gross P, Gheorghiade M, Berl ponatremia in patients with SIADH and 111. Gankam Kengne F, Couturier BS, Soupart T, Verbalis JG, Czerwiec FS, Orlandi C; small cell lung cancer: Treatment with tol- A, Decaux G: Urea minimizes brain com- SALT Investigators: Tolvaptan, a selective vaptan. BMC Pulm Med 13: 55, 2013 plications following rapid correction of oral vasopressin V2-receptor antagonist, for 100. Konstam MA, Gheorghiade M, Burnett JC chronic hyponatremia compared with va- hyponatremia. NEnglJMed355: 2099– Jr ., Grinfeld L, Maggioni AP, Swedberg K, sopressin antagonist or hypertonic saline. 2112, 2006 Udelson JE, Zannad F, Cook T, Ouyang J, Kidney Int 87: 323–331, 2015 91. Gross PA, Wagner A, Decaux G: Vaptans are Zimmer C, Orlandi C; Efficacy of Vasopres- 112. Oo TN, Smith CL, Swan SK: Does uremia not the mainstay of treatment in hypona- sin Antagonism in Heart Failure Outcome protect against the demyelination associ- tremia: Perhaps not yet. Kidney Int 80: 594– Study With Tolvaptan (EVEREST) Investi- ated with correction of hyponatremia dur- 600, 2011 gators: Effects of oral tolvaptan in patients ing hemodialysis? A case report and 92. Borne RT, Krantz MJ: Lixivaptan for hypo- hospitalized for worsening heart failure: The literature review. Semin Dial 16: 68–71, natremia–the numbers game. JAMA 308: EVEREST outcome trial. JAMA 297: 1319– 2003 2345–2346, 2012 1331, 2007 113. Van Biesen W, Vanholder R: Clinical prac- 93.CoronaG,GiulianiC,VerbalisJG,FortiG, 101. Yan L, Xie F, Lu J, Ni Q, Shi C, Tang C, Yang tice guidelines on diagnosis and treatment Maggi M, Peri A: Hyponatremia improvement J: The treatment of vasopressin V2-receptor of hyponatraemia: Response to letter from is associated with a reduced risk of mortality: antagonists in cirrhosis patients with asci- Otsuka Ltd. Eur J Endocrinol 171: L5–L6, Evidence from a meta-analysis. PLoS One 10: tes: A meta-analysis of randomized con- 2014 e0124105, 2015 trolled trials. BMC Gastroenterol 15: 65, 114. Nagler EV, Vanmassenhove J, van der Veer 94. Malhotra I, Gopinath S, Janga KC, 2015 SN, Nistor I, Van Biesen W, Webster AC, Greenberg S, Sharma SK, Tarkovsky R: Un- 102. Sterns RH, Silver SM, Hix JK: Urea for hy- Vanholder R: Diagnosis and treatment of predictable nature of tolvaptan in treatment ponatremia? Kidney Int 87: 268–270, 2015 hyponatremia: A systematic review of clini- of hypervolemic hyponatremia: Case review 103. Decaux G, Brimioulle S, Genette F, Mockel J: cal practice guidelines and consensus on role of vaptans. Case Rep Endocrinol Treatment of the syndrome of inappropriate statements. BMC Med 12: 1, 2014 2014: 807054, 2014 secretion of antidiuretic hormone by urea. 115. Spital A: Treatment of hyponatremic en- 95. Sarges P, Steinberg JM, Lewis JH: Drug- Am J Med 69: 99–106, 1980 cephalopathy. Am J Kidney Dis 66: 540, induced liver injury: Highlights from a re- 104. Decaux G, Soupart A: Urea treatment for 2015 view of the 2015 literature. Drug Saf 39: exercise-associated hyponatremia. Clin J 116. Fenske W, Sandner B, Christ-Crain M: A 801–821, 2016 Sport Med 16: 276, author reply 276, 2006 copeptin-based classification of the os- 96. Woodhead JL, Brock WJ, Roth SE, Shoaf SE, 105. Decaux G, Andres C, Gankam Kengne F, moregulatory defects in the syndrome of Brouwer KL, Church R, Grammatopoulos Soupart A: Treatment of euvolemic hypo- inappropriate antidiuresis. Best Pract Res TN,StilesL,SilerSQ,HowellBA,Mosedale natremia in the intensive care unit by urea. Clin Endocrinol Metab 30: 219–233, M, Watkins PB, Shoda LK: Application of a Crit Care 14: R184, 2010 2016

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