A metabolically stable apelin-17 analog decreases AVP-induced antidiuresis and improves hyponatremia.

Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.

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.

Osmoregulation in children with cystic fibrosis.

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

Urea for Chronic Hyponatremia.

BACKGROUND: Hyponatremia is the most common electrolyte disorder encountered clinically. While acute and/or severe hyponatremia is commonly associated with significant symptoms, milder and more chronic forms of hyponatremia remain clinically inconspicuous. Recent evidence suggests that even milder forms of hyponatremia are associated with increased morbidity and mortality. Despite this, currently available treatments for chronic hyponatremia lack data on efficacy and/or have important limitations related to patient nonadherence, adverse side effects, and/or significant costs. Consequently, there is a clear need for investigation of alternative treatments for this common condition. SUMMARY: Small case series conducted in Europe since the early 1980s suggest that urea, an oral osmotic diuretic that increases urinary water excretion, is safe and effective for the treatment of chronic hyponatremia. In 2016, a novel formulation of urea became available in the United States. Our group recently reported the first and only study describing the efficacy and safety of this American formulation of oral urea among hospitalized patients with hyponatremia. Key Messages: Oral urea appears to be an effective, safe, and well-tolerated therapeutic strategy in the management of chronic hyponatremia.

Comparison between Urine Sodium and Clinical Evaluation to Assess Saline Responsiveness in Severe Hyponatremia - A Prospective Study.

INTRODUCTION AND BACKGROUND: Hyponatremia is a commonly encountered electrolyte disturbance seen in diverse clinical settings. The recently published European guidelines comprehensively summarize the present status of evaluation for hyponatremia. The guidelines emphasize the poor predictability of clinical criteria and instead suggest that the urine sodium (UNa) may be a better way to initially evaluate the cause of hyponatremia. AIMS AND OBJECTIVES: Aim of the study is to comparison between urine sodium and clinical evaluation to assess saline responsiveness in severe hyponatremia. MATERIALS AND METHODS: Prospective Cross sectional study carried out in Departments of Nephrology, Kerala Institute of Medical Sciences, Thiruvananthapuram, Kerala. Study Period between October 2014 to October 2016 (2 years), Patients diagnosed as Severe hyponatremia S.Sodium < 125mEq/L based on clinical and laboratory evaluations. INCLUSION CRITERIA: All clinically and lab confirmed cases of severe hyponatremia, Age >18 years. Outpatients, Inpatients admitted to medical wards and ICU, who give informed consent and serum sodium of less than 125mEq/L constitute the study population. These patients meeting the following criteria: blood glucose level less than 200mg/dl would be included. EXCLUSION CRITERIA: Patients with overt hypervolemia due to cardiac, hepatic, and renal disease with gross edema were excluded. RESULTS: Among 50 patients in the study 70% were found at age group > 60 yrs. 30% patients were < 60 years age group. Youngest patient was 14 yrs old and oldest patient was 83 yrs old. 21 (42%) were Females and Males were 29 (58%). Majority of the cases were symptomatic at time of presentation n=38 (76%). All were having hypotonic hyponatremia among them 14 patients (28%) were euvolemic, 3 patients (6%) were hypervolemic and 33 patients (66%) were hypovolemic. 31 patients (62%) had serum Sodium levels between 115-125mEq/L and 19 patients (38%) had serum Sodium levels between 100-114mEq/L. Among the 33 patients (66%) Hyponatremia due to volume depletion by clinical assessment by the Nephrologist and who were given saline 26 (78%) were saline responsive and 7 patients (22%) were saline non responsive. Among the 7 patients who are saline non responders 6 patients (85.7%) had UNa > 20 and 1 patient (14.3%) had UNa < 20, which is statistically not significant (p=0.840). Among the 44 patients who are saline responders 18 patients are saline responsive. Among the 44 patients 20 (76.9%) had UNa > 20 and 6 (23.1%) had UNa < 20, statistically not significant (p=0.604). Duration for normalizing sodium was noted during the study 17 cases, 1-3 days were needed, 22 cases needed 4-7 days. CONCLUSION: Volume status of patients with hyponatremia can be assessed clinically with a high degree of reliability if the hyponatremia is severe. Thus we re-emphasize the importance of measuring volume status in patients with hyponatremia and classify patients on basis of volume status prior to triaging management. The measurement of UNa had a poor correlation with saline responsiveness and this shows that the laboratory measure is subject to errors due to prior treatments given to the patient and has to be interpreted with the prior clinical scenario in mind.

Hyponatremia secondary to transient renal salt wasting (TRSW): A not so uncommon observation in the elderly
.

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.

Hypovolemic Hyponatremia.

The etiology of hyponatremia is often multifactorial. The most common causes include hypovolemia from gastrointestinal (GI) or other fluid losses, thiazide diuretics, and SIAD [1]. In this chapter, we will discuss hypovolemic hyponatremia, as well as the clinical parameters that help distinguish between hypovolemic and euvolemic states. These include not only the urine [Na+] concentration but also the fractional uric acid excretion, a parameter that can be employed even when diuretics have been prescribed [2,3,4,5,6,7]. Among the common causes of hypovolemic hyponatremia are GI fluid loss, a range of endocrinopathies [7], and thiazide-induced hyponatremia, which is best considered as a distinct entity, in particular because recent data suggest that it has a genetic predisposition. Also, the discontinuation of thiazide is a key step in treatment [2,7]. The management of hypovolemic hyponatremia starts with confirming its presence and determining the underlying cause. Correction focuses on the appropriate use of isotonic fluid to effect volume repletion while avoiding an overly rapid rise in serum [Na+] concentration.

Approach to and management of abnormalities in plasma sodium.

The differential diagnosis between hypertonic, isotonic and hypotonic hyponatremia are presented. The help of some usual serum (urea, uric acid and TCO2) and urine parameters (mainly osmolality and sodium concentration) are discussed and help to determine the best treatment. Morbidity associated with untreated hyponatremia and with the different treatment available is also discussed. Who to prevent and treat ODS (osmotic demyelating syndrome) is recalled. The pathophysiology and treatment of hypernatremia are also discussed.

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.

Mechanism of Hyponatremia in Community-Acquired Pneumonia: Does B-type Natriuretic Peptide Play a Causative Role?

OBJECTIVE: Hyponatremia is a well-known sequela of community-acquired pneumonia (CAP). B-type natriuretic peptide (BNP) has a natriuretic effect and was found to be elevated in patients with CAP. We investigated whether BNP has a role in the pathophysiology of hyponatremia in pediatric CAP. METHODS: Serum and urine electrolytes and osmolality, as well as NT-pro-BNP (N-BNP), were obtained in 49 hospitalized pediatric patients with CAP (29 with hyponatremia, 20 with normal sodium levels. RESULTS: Urine sodium levels were lower in the hyponatremic group compared with the normonatremic group (24.3 meq/L vs 66.7 meq/L, P = 0.006). No difference in N-BNP levels was found between groups (median, 103.8 vs 100.1; P = 0.06; interquartile range, 63.7-263.3 pg/mL vs 47.4-146.4 pg/mL). N-BNP was not associated with serum or urinary sodium levels. CONCLUSIONS: These results indicate that BNP is unlikely to play a causative role in the mechanism of hyponatremia in CAP.

Urine sodium concentrations are predictive of hypoadrenocorticism in hyponatraemic dogs: a retrospective pilot study.

OBJECTIVES: To determine if a urine sodium concentration could be used to rule out hypoadrenocorticism in hyponatraemic dogs. MATERIALS AND METHODS: Medical records were reviewed for hyponatraemic dogs (serum sodium<135 mmol/L) that had recorded urine sodium concentrations. Twenty hyponatraemic dogs were included: 11 diagnosed with classical hypoadrenocorticism and nine with non-adrenal causes of hyponatraemia. A Wilcoxon rank-sum test was used to compare results between groups. RESULTS: No dog with hypoadrenocorticism had a urine sodium concentration less than 30 mmol/L. Urine sodium concentration in dogs with hypoadrenocorticism was significantly higher (median 103 mmol/L, range: 41 to 225) than in dogs with non-adrenal illness (median 10 mmol/L, range: 2 to 86) (P<0·0005). Serum sodium concentrations were not significantly different between dogs with hypoadrenocorticism and dogs with non-adrenal illness. CLINICAL SIGNIFICANCE: These results suggest that urine sodium concentrations can be used to prioritise a differential diagnosis of hypoadrenocorticism in hyponatraemic dogs. A urine sodium concentration less than 30 mmol/L in a hyponatraemic dog makes classical hypoadrenocorticism an unlikely cause of the hyponatraemia. Nevertheless, because of the small sample size our results should be interpreted with caution and a larger follow-up study would be valuable.

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.

Effects of Tolvaptan Addition to Furosemide in Normo- and Hyponatremia Patients with Heart Failure and Chronic Kidney Disease Stages G3b-5: A Subanalysis of the K-STAR Study.

BACKGROUND: Tolvaptan increases free water clearance (aquaresis) and thereby improves hyponatremia. Although hyponatremia on admission is common in patients with congestive heart failure (CHF), little is known regarding the response to tolvaptan in those who also have chronic kidney disease (CKD) with or without hyponatremia. The aim of this subanalysis was to investigate the differences in treatment response between normo- and hyponatremia patients with CHF and CKD stages G3b-5. METHODS: The Kanagawa Aquaresis Investigators Trial of Tolvaptan on HF Patients with Renal Impairment (K-STAR) was a multicenter, open-label, randomized, controlled prospective clinical trial that included 81 Japanese patients with CHF and residual signs of congestion despite oral furosemide treatment (≥40 mg/day). All patients were randomly assigned to 7-day treatment with either ≤15 mg/day of new add-on tolvaptan or ≤40 mg/day of increased furosemide. A subanalysis was conducted for 73 patients, who were classified into 2 groups according to their assigned treatment, then further stratified into 2 subgroups according to their serum sodium concentration [Na+]. The differences between the urine and serum parameters from day 1 to 3 were compared between the groups and between the subgroups in each group. RESULTS: The change (Δ) in urine volume (ΔUV) and Δurine osmolality were greater in the tolvaptan group than in the furosemide group; however, ΔUV and Δurine osmolality did not show significant differences between the normonatremia subgroup and the hyponatremia subgroup in each group. In addition, Δserum [Na+] was greater in the tolvaptan group, although the change was not clinically significant. In contrast, Δserum [Na+] did not show significant differences between the normo- and hyponatremia subgroups in each group. CONCLUSION: Tolvaptan added to furosemide resulted in a greater diuretic effect than increased furosemide, even in normonatremia patients with CHF complicated by CKD stages G3b-5 in the very early treatment phase.

Cerebral Salt-Wasting Syndrome: Diagnosis by Urine Sodium Excretion.

BACKGROUND: Cerebral salt-wasting syndrome (CSWS) was initially described over 60 years ago in hyponatremic patients with a cerebral lesion. However, the diagnostic criteria for CSWS have not been fully established. Thus, when hyponatremia is observed in patients with CSWS, they may be misdiagnosed as having the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Thus, it is critical to differentiate between these 2 conditions because their treatments are diametrically opposed. MATERIALS AND METHODS: We carried out a retrospective study of 45 patients with CSWS and compared them to 60 normonatremic control patients, and 28 patients with SIADH. All patients had their 24-hour urine volumes and sodium (Na) excretion measured. RESULTS: In patients with CSWS, urinary Na excretion was 394 ± 369mmol/24 hours and urinary volume was 2,603 ± 996mL/24 hours; both values significantly greater than in controls (P < 0.01). By contrast, in patients with SIADH, the urine Na excretion was only 51 ± 25mmol/24 hours and urine volume was 745 ± 298mL/24 hours; values significantly lower than in patients with CSWS (P < 0.01). CONCLUSIONS: CSWS was diagnosed in patients with cerebral lesion who had (1) symptomatic hyponatremia, (2) urine Na excretion 2 standard deviations above controls and (3) increased urine volume. Patients with SIADH also had symptomatic hyponatremia but, in contrast to patients with CSWS, they had decreased Na excretion and urine volume. Thus urine Na excretion and volume are very important for diagnosing the cause of hyponatremia in patients with cerebral lesions.

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.

Secreción inadecuada de hormona antidiurética secundaria a tratamiento antiparkinsoniano / Inappropriate antidiuretic hormone hypersecretion associated with treatment of Parkinson's disease

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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.

[Causes, diagnosis and differential diagnosis of hyponatremia]. / Hyponatriämie.

Hyponatremia is a common electrolyte disorder that arises from disturbances in water metabolism. In cases of acute advanced hyponatremia, serious symptoms are predominant, while chronic mild hyponatremia causes minor symptoms such as slowness, depression or unsteadiness of gait. Any therapy of hyponatremia depends on the severity of its symptoms and on its specific etiology and diagnosis. Concerning the differential diagnosis of the type of hyponatremia, it is initially helpful to distinguish between euvolemic, hypervolemic and hypovolemic forms of hyponatremia. In order to distinguish between these 3 types of hyponatremia, it is best to assess the spontaneous urinary sodium concentration and to consider evidence from the medical history and the physical examination. Once the type of hyponatremia has been diagnosed, the next step is to decide which of the known etiologies of hyponatremia applies. Diagnostic problems may arise in mixed hyponatremia, a condition in which different types and etiologies of hyponatremia occur at the same time. In such cases it may be best to determine what appears to be the leading diagnosis. Another kind of diagnostic difficulty often occurs in simultaneous diuretic use. It may help to distinguish to which extracellular volume the types of hyponatremia relate on the basis of the fractional excretion of uric acid rather than on the urinary sodium concentration.