Differentiating syndrome of inappropriate ADH, reset osmostat, cerebral/renal salt wasting using fractional urate excretion.

OBJECTIVES: Clinical and laboratory data of reset osmostat (RO) and cerebral/renal salt wasting (C/RSW) mimic syndrome of inappropriate antidiuretic hormone (SIADH) and can pose diagnostic challenges because of significant overlapping between clinical and laboratory findings. Failure to correctly diagnose hyponatremia may result in increased mortality risk, longer hospital stay, and is cost-effective. We aim to illustrate clinical and laboratory similarities and difference among patients with hyponatremic disorders and discuss the diagnostic value of factional uprate excretion (FEurate) to differentiate SIADH from RO and C/RSW. CASE PRESENTATIONS: We report the use of FEurate in the evaluation of three patients with hyponatremia and elevated urine osmolality in the absence of edema or clinical evidence of dehydration to differentiate SIADH from RO and C/RSW. CONCLUSIONS: Measurement of FEurate may offset in part the diagnostic confusion imparted by the diagnoses of SIADH, RO, and C/RSW.

Hyponatremia secondary to transient renal salt wasting (TRSW): A not so uncommon observation in the elderly
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AIMS: We attempted to classify 115 consecutive nonedematous hyponatremic patients according to their history and saline responsiveness. We hereby describe 6 out of them presenting a transient renal salt wasting (TRSW) state of unknown origin. MATERIALS AND METHODS: Six patients with an initial SNa of 126 ± 3 mEq/L were included in the study. They were treated with 2 L isotonic saline infusion over 24 hours. The evolution of the biochemical data of 5 patients were compared to 6 patients with syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH), 6 hyponatremias following the use of thiazides, and to 5 salt-depleted hyponatremic patients of similar age and body weight, treated in the same way. RESULTS: The mean values of FEurea and FEuric acid in the 6 described patients, together with a clearly inappropriate natriuresis suggested SIADH. However, the high mean fractional potassium excretion (FEK = 34 ± 15%) was not observed in SIADH (13 ± 3%) (p < 0.01). Plasma sodium levels improved quickly after saline infusion in most of these patients, while fractional solute excretions and diuresis decreased. Calciuria is increased in patients with renal salt waisting (RSW), while low calciuria values are observed in the thiazide group. Four of the 6 hyponatremic patients were admitted for syncopal malaise or fall. CONCLUSION: We observed in 6 out of 115 consecutive hyponatremic patients a TRSW. RSW as a diagnosis has to be considered when in hyponatremia with excessive natriuresis, high FEK and an intake of diuretics is ruled out. This hyponatremia is saline-responsive, but relapse can be frequently observed.

High Prevalence of Renal Salt Wasting Without Cerebral Disease as Cause of Hyponatremia in General Medical Wards.

BACKGROUND: The approach to hyponatremia is in a state of flux, especially in differentiating syndrome of inappropriate antidiuretic hormone secretion (SIADH) from cerebral-renal salt wasting (RSW) because of diametrically opposite therapeutic goals. Considering RSW can occur without cerebral disease, we determined the prevalence of RSW in the general hospital wards. METHODS: To differentiate SIADH from RSW, we used an algorithm based on fractional excretion (FE) of urate and nonresponse to saline infusions in SIADH as compared to excretion of dilute urines and prompt increase in serum sodium in RSW. RESULTS: Of 62 hyponatremic patients, (A) 17 patients (27%) had SIADH, 11 were nonresponsive to isotonic saline, and 5 normalized a previously high FEurate after correction of hyponatremia; (B) 19 patients (31%) had a reset osmostat based on normal FEurates and spontaneously excreted dilute urines; (C) 24 patients (38%) had RSW, 21 had no clinical evidence of cerebral disease, 19 had saline-induced dilute urines; 2 had undetectable plasma ADH levels when urine was dilute, 10 required 5% dextrose in water to prevent rapid increase in serum sodium, 11 had persistently increased FEurate after correction of hyponatremia and 10 had baseline urinary sodium < 20 mEq/L; (D) 1 patient had Addison disease with a low FEurate and (E) 1 patient (1.6%) had hyponatremia due to hydrochlorothiazide. CONCLUSIONS: Of the 24 patients with RSW, 21 had no cerebral disease, supporting our proposal to change cerebral-renal salt wasting to renal salt wasting. Application of established pathophysiological standards and a new algorithm based on determination of FEurate were superior to the volume approach for determination of urinary sodium when identifying the cause of hyponatremia.

Mild water restriction with or without urea for the longterm treatment of syndrome of inappropriate antidiuretic hormone secretion (SIADH): Can urine osmolality help the choice?

BACKGROUND: Treatment options for chronic SIADH include water restriction (WR) and urea. The usefulness of urine osmolality to guide the choice of the treatment option is not clearly defined. We hypothesized that urine osmolality can indicate whether treatment with mild water restriction alone could be successful. METHODS: Retrospective Review of clinical and biochemical (blood and urine) data of patients with chronic SIADH treated for at least one year with mild WR (1.5-2l/day) either with or without urea. RESULTS: Twenty nine patients were included. Nine patients were treated by mild WR. Mean serum sodium (SNa) and mean Uosm were 129±2mEq/l and 274±78mOsm/kgH2O respectively before WR, and increased to 138.5±3mEq/l and 505±87mOsm/kgH2O (P<0.001). Eight patients were treated with mild WR and 15g urea daily, the SNa and Uosm before treatment were 127.5±3mEq/l and 340±100mOsm/kgH2O respectively and increased to 136.5±1mEq/l and 490±151mOsm/kgH2O (P<0.001). Four of the eight patients had a permanent low solute intake which contributed to hyponatremia. Twelve patients needed 30g urea daily combined with mild WR. The SNa and Uosm were respectively 126±2mEq/l and 595±176mOsm/kgH2O and increased to 136.5±2mEq/l and 698±157mOsm/kgH2O (P<0.05). Uosm increased in most of the treated patients. CONCLUSIONS: About 30% of patients could be treated by moderate WR alone. All these patients presented an initial urine osmolality lower than 400mOsm/kgH2O.

Artificial Syndrome of Inappropriate Antidiuresis Model as Potential Use for Diagnostic and Therapeutic Strategies.

Hyponatremia is the most frequent electrolyte disorder with the syndrome of inappropriate antidiuresis (SIADH) being its predominant cause. Physiological studies in patients with SIADH are difficult to interpret due to usually several comorbidities and polymedication. Therefore, a SIADH model in healthy volunteers would be very helpful to allow insight in this complex disease and to test new therapeutic approaches. The aim of the study was to create a SIADH model with evaluation of subsequent physiological changes.The prospective interventional study on 14 healthy volunteers was carried out at the University Hospital Basel. The intervention was done by induction of hypotonic hyponatremia through hydration and administration of desmopressin. Clinical and laboratory parameters in a SIADH model were the main outcome of the measure.14 participants (64% males), BMI 23.1 kg/m2 (±2.4), aged 28.6 years (±9), completed the study. Through the intervention, serum sodium level decreased from 140 mmol/l (±1.3) to 132 mmol/l (±2.0) and serum osmolality from 286 mmol/kg (±4.7) to 267 mmol/kg (±3.5). Simultaneously urine osmolality increased to 879 mmol/kg (±97.7) and urine sodium to 213 mmol/l (±51.5) verifying the artificial SIADH model. A significant decrease of copeptin (5 pmol/l (±1.9) to 2.6 pmol/l (±0.5), p 0.002), aldosterone (314.7 pmol/l (±154.1) to 86.7 pmol/l (±23.6), p 0.019), and renin (21.2 ng/l (±26.7) to 3.6 ng/l (3.2), p 0.035) were noted, while NT-proBNP and MR-proANP significantly increased (31.7 ng/l (±18.6) to 50.5 ng/l (±33.0), p 0.001; 48.4 pmol/l (±16.8) to 56.8 pmol/l (±9.0), p 0.003).In conclusion, we were able to induce an artificial SIADH in healthy volunteers and study the changes of various hormonal biomarkers involved. This SIADH model could be helpful in evaluating diagnostic and therapeutic approaches.

Low-dose tolvaptan PK/PD: comparison of patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion to healthy adults.

PURPOSE: Tolvaptan (TLV) is indicated to treat hyponatremia due to syndrome of inappropriate diuretic hormone (SIADH) in Europe. Treatment is to be initiated at 15 mg QD but post-approval reporting indicates increasing use of 7.5 mg as the starting dose. Physicians believe 7.5 mg is effective and has a lower incidence of overly rapid correction of serum sodium. METHODS: Single TLV doses of 3.75, 7.5, and 15 mg were administered to 14 healthy adults in a crossover design and to 29 subjects ≥18 years with SIADH and serum sodium between 120 and 133 mmol/L in a parallel-group design. Pharmacodynamics and TLV plasma concentrations were assessed for 24 h post-dose. RESULTS: In SIADH subjects, corrections of serum sodium (Δ of ≥8 mmol/L in the first 8 h or ≥12 mmol/L in the first 24 h) were observed in one, one, and two subjects in the 3.75-, 7.5-, and 15-mg dose groups. Fluid balance (FB) for 0-6 h post-dose was correlated (r 2 = 0.37) with maximum increases in serum sodium; subjects with large corrections had large (~1 L) negative FB. Compared to healthy adults, subjects with SIADH did not drink in response to their negative FB and had larger increases in serum sodium at 24 h. Median time of maximum increase in healthy adults was 6 h, with no rapid corrections, and FB was near 0 mL by 24 h. CONCLUSION: Starting titration with 7.5 mg TLV will not eliminate the risk of rapid corrections in serum sodium. Monitoring FB may indicate that a subject is at risk for over correction.

Identifying Different Causes of Hyponatremia With Fractional Excretion of Uric Acid.

BACKGROUND: There is controversy over the prevalence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and cerebral or renal salt wasting (RSW), 2 syndromes with identical common clinical and laboratory parameters but different therapies. The traditional approach to the hyponatremic patient relies on volume assessment, but there are limitations to this method. METHODS: We used an algorithm that relies on fractional excretion of urate (FEurate) to evaluate patients with hyponatremia and present 4 illustrative cases. RESULTS: Overall, 2 patients had increased FEurate [normal: 4-11%], as is seen in SIADH and RSW. A diagnosis of SIADH was made in 1 patient by correcting the hyponatremia with 1.5% saline and observing a characteristic normalization of an elevated FEurate that is characteristic of SIADH as compared to FEurate being persistently increased in RSW. A patient with T-cell lymphoma had symmetrical leg edema due to lymphomatous obstruction of the inferior vena cava, postural hypotension, pleural effusion, ascites, decreased cardiac output and urine sodium level of 10mmol/L. Saline-induced excretion of dilute urines and undetectable plasma antidiuretic hormone were consistent with RSW. Furosemide, given for presumed heart failure, induced a profound diuresis that required large volumes of fluid resuscitation. A normal FEurate identified a reset osmostat in a transplant patient with a slowly developing pneumocystis carinii pneumonia. A volume-depleted hyponatremic patient with Addison׳s disease had a low FEurate of 1.4%. CONCLUSIONS: These illustrative cases suggest that an approach to hyponatremia using FEurate may be a useful alternative to traditional volume-based approaches.

Clinical analysis of brain trauma-associated SIADH.

The objective of this study was to analyze the clinical features of brain trauma associated syndrome of inappropriate antidiuretic hormone secretion. A retrospective analysis was performed for the electrolytes and osmolality of blood and urine samples of brain injury patients, which have been collected in our department since last 20 years. Four cases of brain injury patients met the criteria of SIADH, and three of them were cured but one patient died. In conclusion, the pathogenesis and treatment of SIADH associated with brain injury are different from hyponatremia. Early diagnosis and treatment can reduce the morbidity and mortality of patients with traumatic brain injury.

[Difficulties in the differential diagnosis of hyponatremia presenting with severe neuropsychiatric symptoms]. / Súlyos neuropszichiátriai tünetekkel járó hyponatraemia differenciáldiagnosztikai nehézségei.

Hyponatremia is the most frequent eletrolyte imbalance in hospitalized geriatric patient. The accompanying signs and symptoms can run a wide range and, therefore, these patients are usually admitted to various departments, i.e. neurology and/or traumatology first. Directed laboratory investigations demonstrate severe hyponatremia. Differential diagnosis can be very difficult and complex in the clinical settings. Firstly, spurious forms of hyponatremia have to be excluded, then the underlying cause should elucidated based on the patients hydration status and serum osmolarity. Hyponatremia can be divided into hyper-, hypo- and normovolemic forms. Moreover, it can be further classified as hypo-, iso- and hyperosmolar hyponatremias. The differentiation between renal and extrarenal salt wasting forms is hinged on the urine sodium concentration. Syndrome of inappropriate antidiuretic hormone secretion is the most common cause of normovolemic, hypoosmolar forms (named also as Schwartz-Bartter syndrome). The authors aimed to shed light on the often insurmountable difficulties of the diagnosis, differential diagnosis and appropriate treatment of this very frequent electrolyte imbalance by presenting a clinical case report. Their purported aim reflects upon the wide array of ethiopathogenesis of hyponatremia: various endocrine, renal diseases, inappropriateness of antidiuretic hormone secretion as well as the role of different medications (e.g. diuretics). This fine-tuned and intricate physiology of sodium metabolism could fortuitously be overturned by these mechanisms.

Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports.

BACKGROUND: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a disorder of water balance linked to gain-of-function mutation of arginine vasopressin receptor type 2 (AVPR2) resulting in free water reabsorption and episodes of hyponatremia. AIMS: To review the long-term treatment of NSIAD. METHODS: In the first part of this paper, we report 3 cases of male patients presenting with hyponatremia due to NSIAD. The second part consists of a comprehensive review of all published case reports. RESULTS: In our experience, long-term fluid restriction (FR) and treatment with low doses of urea are efficient and well tolerated. Episodic intake of urea seems sufficient in some patients. Treatment data were available for 13 of the 16 hyponatremic patients reported in the literature. Each of these 13 patients had regulated fluid intake. Six of the patients received urea with no reported failure to correct hyponatremia and 5 received NaCl supplementation with varying efficacy. The AVPR2 antagonists tolvaptan and satavaptan (prescribed before the diagnosis of NSIAD was made) showed no efficacy in 1 patient. CONCLUSIONS: NSIAD is quite easy to treat with FR and urea in adults as well as in children, with good compliance and efficacy. Of note, FR is well tolerated, suggesting that NSIAD may differ from other causes of syndrome of inappropriate antidiuretic hormone secretion by reduction of thirst intensity due to lower levels of AVP (which stimulates thirst). In eventual refractory cases, furosemide (associated with NaCl supplementation) would represent a valuable therapeutic option by analogy of its efficacy in syndrome of inappropriate antidiuretic hormone secretion.

Ecstasy (MDMA)-induced hyponatraemia is associated with genetic variants in CYP2D6 and COMT.

We hypothesised that genetically determined poor metabolism of 3,4-methylene dioxymetamphetamine (MDMA) due either to the presence of CYP2D6 genotypes giving absent or low CYP2D6 enzyme activity, or a COMT genotype predicting low COMT enzyme activity would be associated with a greater degree of MDMA-induced reduction in plasma sodium and osmolality than other genotypes at these genes following consumption of 'ecstasy' tablets by clubbers. Of the 48 subjects who returned to the test site post-clubbing, 30 provided samples for measurement of vasopressin (AVP), plasma sodium, urea and plasma and urine osmolality. Genotyping was performed for functional variants in CYP2D6 (n = 29) and COMT (Val158Met, n = 30). In subjects with urinary MDMA detected post-clubbing, there was a significant association between change in plasma osmolality (p = 0.009) and in plasma sodium (p = 0.012) and CYP2D6 genotypic category. Individuals with the low-activity but readily inhibitable CYP2D6 extensive metaboliser/intermediate metaboliser (EM/IM) genotype showed greater reductions in these measures than all other CYP2D6 genotypic categories. COMT low-activity genotypes (Met/Met and Val/Met) were also significantly associated with reductions in plasma osmolality (p = 0.028) and in plasma sodium (p = 0.003). On conservative Bonferroni correction for two independent genes, the CYP2D6 and COMT plasma sodium findings remain significant. The relatively high frequency of the low-activity CYP2D6 and COMT genotypes in the population warrants further attention, since consumption of free water following ingestion of MDMA in these individuals may trigger dilutational hyponatraemia and increased risk of syndrome of inappropriate antidiuretic hormone secretion.

Normal fractional urate excretion identifies hyponatremic patients with reset osmostat.

BACKGROUND: Reset osmostat (RO) occurs in 36% of patients with syndrome of inappropriate antidiuretic hormone secretion (SIADH) and is not often considered when evaluating hyponatremic patients. Patients with RO are not usually treated, but recent awareness that symptoms are associated with mild hyponatremia creates a therapeutic dilemma. We encountered patients with hyponatremia, hypouricemia and high urine sodium concentration (UNa), who had normal fractional excretion (FE) of urate and excreted dilute urines that were consistent with RO. We decided to test whether a normal FEurate in nonedematous hyponatremia irrespective of UNa or serum urate would identify patients with RO. METHODS: We determined FEurate in nonedematous hyponatremic patients. A diagnosis of RO was made if urine osmolality (Uosm) was <200 mOsm/kg in a random urine. We performed a modified water-loading test in patients with a normal FEurate whose random Uosm was >200 mOsm/kg. RESULTS: All nonedematous hyponatremic patients with FEurate of 4%-11% had RO, as determined by Uosm <200 mOsm/kg on a random urine collection in 8 patients, or after a modified water-loading test in 6 patients. Plasma antidiuretic hormone (ADH) in 4 patients was undetectable at <1 pg/mL during water-loading. Nine patients had baseline concentrated urine, 12 had UNa >20 mmol/L, 9 were hypouricemic, yet all had a normal FEurate. Comorbidities were similar to those reported in RO. CONCLUSIONS: RO, a benign form of SIADH, occurs commonly. A normal FEurate in a nonedematous hyponatremic patient is highly suggestive of RO. Determining FEurate is superior to serum urate. The therapeutic dilemma for RO must be resolved.

Serum and urine responses to the aquaretic agent tolvaptan in hospitalized hyponatremic patients.

Tolvaptan, an oral, selective arginine vasopressin (AVP) V2 receptor antagonist has been approved for the treatment of euvolemic and hypervolemic hyponatremia in the United States. This report summarizes our center's experience with thirteen patients treated for hyponatremia with one 15-mg dose of tolvaptan. The patients had euvolemic or hypervolemic hyponatremia with decreased serum osmolality and serum sodium (SNa) levels less than 129 mEq/L. Eight patients had a diagnosis of the syndrome of inappropriate antidiuretic hormone (SIADH), and five patients had a diagnosis of congestive heart failure (CHF). Results revealed an increase in SNa in all patients from 122.5 ± 4.2 to 128.9 ± 4.1 mEq/L (P < 0.05). The mean increase in SNa of 6.4 mEq/L (range 2-10 mEq/L) 24 h post-tolvaptan was not different in the two groups of patients, but SIADH patients had higher pre and post-tolvaptan SNa levels than CHF patients. Urine osmolalities (UOsm) decreased in all patients, and the patients with SIADH had significantly higher baseline UOsm and a larger decrease in UOsm 12 h post-tolvaptan administration when compared with the CHF patients. AVP levels did not change post-tolvaptan administration. However, the magnitude of increase in SNa levels was inversely related to pretolvaptan AVP levels in the SIADH subgroup (r = -0.7, P = 0.01). Three SIADH patients received small amounts of D5W to attenuate changes in SNa. No significant changes in mean arterial pressure, serum potassium, serum glucose, and blood urea nitrogen or serum creatinine were observed. The data show that tolvaptan is effective for the treatment of hyponatremia and may produce differing responses in disparate patient groups.

A family with hyponatremia and the nephrogenic syndrome of inappropriate antidiuresis.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an X-linked disorder caused by activating mutations in arginine vasopressin receptor 2 (AVPR2), resulting in persistently concentrated urine. We report on a family affected by NSIAD with the known mutation R137C, an arginine to cysteine substitution at amino acid 137. The spectrum of symptoms varied markedly and ranged from infrequent voiding to incidentally noted hyponatremia to recurrent admissions with hyponatremic seizures. There was evidence for physiologic compensatory mechanisms: most affected members intuitively compensated for the concentrated urine by curtailing their fluid intake. Before the genetic diagnosis, these members had recognized each other by their infrequent voiding, which especially suited one patient, a London cab driver. Interestingly, after water deprivation, urine osmolality was significantly lower in patients compared with unaffected members, suggesting desensitization of the downstream signaling pathway with persistent AVPR2 activation. Urine osmolality was as low as 241 mOsm/kg (241 mmol/kg) in patients, which could obfuscate the diagnosis. The development of symptoms of hyponatremia was strikingly different in the 2 male patients: one patient was asymptomatic with a plasma sodium level of 120 mEq/L (120 mmol/L), whereas another experienced seizures with similar values. Investigations of such genetically defined patients show clues for the understanding of human physiology and inform diagnosis and clinical management.

Efficacy and safety of oral tolvaptan therapy in patients with the syndrome of inappropriate antidiuretic hormone secretion.

OBJECTIVE: Tolvaptan, an oral antagonist of the vasopressin V(2) receptor, has been found to improve hyponatremia in patients with mixed etiologies. This study analyzed a subgroup of patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) to evaluate the efficacy and safety of tolvaptan in this group. DESIGN AND PATIENTS: Hyponatremic patients in the SALT-1 and SALT-2 studies with a diagnosis of SIADH were identified based on clinical diagnosis by individual study investigators. Subjects were randomized to receive oral placebo (n=52) or tolvaptan 15 mg daily, with further titration to 30 and 60 mg daily, if necessary, based on the response of serum [Na(+)] (n=58). RESULTS: In patients with SIADH, improvement in serum [Na(+)] was significantly greater (P<0.0001) with tolvaptan than placebo over the first 4 days of therapy as well as the entire 30-day study, with minimal side effects of increased thirst, dry mouth, and urination. Only 5.9% of tolvaptan-treated patients had overly rapid correction of hyponatremia as defined by current guidelines. After discontinuation of tolvaptan, serum [Na(+)] declined to values similar to placebo. A significant positive treatment effect favoring tolvaptan on the physical component, and a near-significant trend on the mental component, was found using the SF-12 Health Survey. Tolvaptan was associated with a significantly reduced incidence of fluid restriction. CONCLUSIONS: Results for the SIADH subgroup were analogous to those of the combined SALT population regarding efficacy and safety but demonstrated a greater improvement in the physical component of the SF-12 Health Survey than in the full mixed etiology SALT patient group.

Unexplained hyponatremia: seek and you will find.

BACKGROUND: Hyponatremia is a common diagnostic challenge. METHODS: An index case is presented to discuss the diagnostic approach to chronic and unexplained hyponatremia. RESULTS: The index case concerns a 60-year-old man with chronic hepatitis C and previous alcohol use who was referred because of weight loss, poor dietary intake, dizzy spells, and unexplained hyponatremia (serum sodium 124-129 mmol/l). A low urine sodium concentration (20 mmol/l) and a low fractional sodium excretion (0.07%) were observed repeatedly, while urine osmolality was high (>400 mosm/kg). The central questions in this case are: what is the differential diagnosis, which tests are needed to confirm or exclude a diagnosis, and how would you proceed if no obvious cause is found? CONCLUSIONS: The diagnosis of this case of unexplained hyponatremia was unexpected, but important because it was treatable. The challenges and caveats of the diagnostic approach to hyponatremia are discussed. A diagnostic algorithm to guide clinicians who are confronted with similar cases is presented.

Familial nephrogenic syndrome of inappropriate antidiuresis: dissociation between aquaporin-2 and vasopressin excretion.

CONTEXT: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD), the X-linked disease resulting from activating mutation of the vasopressin V2 receptor gene (AVPR2), is a recently described condition causative of episodes of hyponatremia in boys and male and female adults. OBJECTIVE: The objective of the study was the pathophysiological characterization of NSIAD. DESIGN: A family with NSIAD was identified and investigated for hyponatremic episodes and degrees of urine dilution defects. For the first time, the impact of the mutated V2R on aquaporin 2 (AQP2) excretion is reported. SETTING: The study was conducted at a referral center. PATIENTS: Five patients of seven carriers (two young brothers and their mother and her two sisters) were investigated together with age-matched controls. INTERVENTIONS: There were no interventions. RESULTS: In NSIAD patients, urinary AQP2 excretion occurred independently of concomitant vasopressin excretion and strongly correlated with urine osmolality, confirming direct AQP2 involvement in urine concentration. Water loading was followed by a very slow and incomplete elimination in the asymptomatic hemizygous boy with no suppression of AQP2 excretion and a delayed elimination in the heterozygous women because of an incomplete suppression of AQP2, and it induced hyponatremia in all NSIAD patients. Two hemizygous carriers presented with severe hyponatremia-induced seizures, and the repetition in one of them led to mental retardation. CONCLUSIONS: Hyponatremia was a constant and characteristic aspect of the abnormal response to even mild water-loading tests in an asymptomatic hemizygous child as well as heterozygous adults. We confirm the phenotypic variability of NSIAD, a disease that should be regarded in pediatric intensive care units in presence of severe and/or recurrent hyponatremia, and also in adults, because carriers are prone to hyponatremia.