Study of Urinary Electrolytes and Fractional Excretion of Uric Acid in Evaluating Hyponatremia.

INTRODUCTION: Serum sodium levels <135 mmol/L are known as hyponatremia. The syndrome of inappropriate antidiuresis (SIAD), which is described by a drop in the effective arterial blood volume (EABV), is the most common cause of hyponatremia. This study was carried out to categorize hyponatremia based on volume status and on parameters like fractional excretion of uric acid (FE-UA), fractional excretion of sodium (FE-Na), urine uric acid (U-UA), and serum uric acid (SR-UA) values. MATERIALS AND METHODS: Sixty-one patients admitted to the Department of Medicine at Rajendra Institute of Medical Sciences (RIMS), Ranchi, with hyponatremia were included in the study by applying random sampling. Routine urine and blood samples were collected for biochemical tests. Institutional ethical clearance was obtained for this study. Data were analyzed using Statistical Package for the Social Sciences (SPSS) (version 21). Frequency, central tendency, receiver operating characteristic (ROC), and nonparametric Mann-Whitney U test analysis tools were utilized for analysis. RESULTS: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) was found in nearly 50.82% of hyponatremic patients. Approximately, 70% of non-SIADH patients were hypovolemic. When compared to the non-SIADH group, patients in the SIADH group had significantly higher systolic blood pressure (SBP) and diastolic blood pressure (DBP), lower pulse rates, and lower urine creatinine levels and urine creatinine to serum creatinine ratio. The non-SIADH group had significantly higher SR-UA levels (p < 0.0001), but the SIADH group had significantly higher U-UA levels and significantly lower SR-UA levels. Among the studied parameters, FE-UA was the most accurate in diagnosing SIADH. FE-UA (>12%) is a better diagnostic marker for distinguishing SIADH patients from non-SIADH patients. CONCLUSION: FE-uric acid was found to be the most superior in diagnosing SIADH, followed by FE-Na.

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.

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.

[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.

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.

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.

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.

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.

Diagnostic value of urine sodium concentration in hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion versus hypovolemia.

BACKGROUND: We are often left with the differential diagnosis of syndrome of inappropriate antidiuretic hormone secretion (SIADH) versus hypovolemic hyponatremia. It is difficult to tell who will respond to isotonic saline infusion and who will not, if the urine sodium value is not completely suppressed (>10 mEq/L). AIM: To examine the diagnostic accuracy of the urine sodium value. DESIGN: A retrospective observation. METHODS: The diagnostic accuracy of the urine sodium value was compared to that of a complete work-up and hospital course, including a response to saline infusion in patients with a final diagnosis of SIADH or hypovolemic hyponatremia. We also examined the diagnostic value of urine sodium-to-BUN ratio which should improve separation between SIADH and hypovolemia since the urine sodium and BUN move in opposite directions in these two conditions. RESULTS: The urine sodium value of 50 mEq/L was the most accurate in separating SIADH from hypovolemic hyponatremia: sensitivity 0.89, specificity 0.69, and accuracy 0.82. The diagnostic utility for SIADH versus hypovolemia, as quantified by the areas under the ROC curves, was not statistically different between urine sodium alone (0.89, 95% CI 0.77-0.96) and urine sodium-to-BUN ratio (0.93, 95% CI 0.83-0.98); p-value 0.33. CONCLUSIONS: When the underlying cause is inconclusive between SIADH and hypovolemia, and when only basic laboratory results are available at the time of initial evaluation, the urine sodium alone will be adequate to guide initial fluid management. In contrast to traditional teaching, elevated urine sodium levels up to 50 mEq/L demonstrated clinically meaningful responses to isotonic saline infusion.

Diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone.

BACKGROUND: Hyponatremia is a frequent condition in elderly patients. In diagnostic workup, a 24-hour urine sample is used to measure urinary osmolality and urinary sodium concentration necessary to confirm the diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This study was undertaken to test the hypothesis that a spot urine sample would be sufficient for urinalysis. METHODS: In nine patients with SIADH, morning spot and 24-hour urine samples were examined for osmolality and sodium concentration. Levels of arginine vasopressin, atrial natriuretic and brain natriuretic peptides, renin, and aldosterone were measured in the supine and upright positions of patients and compared with nine healthy age-matched control patients. RESULTS: The patients had low plasma osmolality (median 266 mOsm/kg) and measurable levels of arginine vasopressin (median 1.8 pg/mL). Values of osmolality in the spot urine (median 298 mOsm/kg) and in the 24-hour urine (median 215 mOsm/kg) did not differ significantly; neither did sodium concentration (medians 80 mmol/L in the spot urine versus 45 mmol/L in the 24-hour urine). Patients had significantly elevated plasma levels of brain natriuretic peptide (P = 0.007), elevated mean arterial blood pressure (P = 0.03), and lower plasma levels of creatinine (P = 0.002) compared to the controls. CONCLUSION: A spot urine sample seems to be sufficient to confirm the diagnosis of SIADH.

Syndrome of inappropriate secretion of antidiuretic hormone after chemotherapy with vinorelbine.

PURPOSE: To describe a case of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after administration of vinorelbine (VNB) for recurrence of lung cancer. CASE: A 76-year-old man underwent bronchial arterial infusion (BAI) of VNB for postoperative recurrence of lung cancer. Seven days later, hyponatremia and natriuresis developed. Based on his clinical and laboratory findings, we diagnosed him with SIADH. He improved within a couple of days with fluid restriction only. CONCLUSIONS: Administration of VNB may potentially cause SIADH. This is the second report of the SIADH caused by VNB. It is important to monitor the serum sodium level and clinical findings after chemotherapy with VNB.

Lack of elevation of urinary albumin excretion among patients with chronic syndromes of inappropriate antidiuresis.

BACKGROUND: A recent study has revealed that acute and chronic administration of the vasopressin V2 receptor (V2R) agonist dDAVP induced a marked increase of urinary albumin excretion (UAE) in healthy rats and humans (Bardoux P et al. Nephrol Dial Transplant 2003; 18: 497-506). The occurrence of an elevation of UAE among patients with chronic syndromes of inappropriate antidiuresis has not been reported. METHODS: We looked for the elevation of UAE in 24-h urine samples of the following patients: nine chronic SIADH patients, two patients with acute post-operative SIADH, three patients of the same family with nephrogenic syndrome of inappropriate antidiuresis (NSAID) and two patients with hyponatraemia due to surdosage of dDAVP in the setting of central diabetes insipidus. RESULTS: There was no elevation of UAE in our patients (whether they presented with hyponatraemia or not), apart from a patient treated with supra-physiological doses of dDAVP. When she received 80 microg/day of dDAVP, her UAE was 42 mg/day. In this patient, UAE returned to the normal range (21 mg/day) when doses of dDAVP were tapered (20 microg/day). CONCLUSION: The present study shows that chronic V2R stimulation generally does not result in a rise in UAE. The discrepancy between our results and those of the above-mentioned study could be explained by a dose-dependent effect of V2R stimulation on UAE.

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.

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.

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.

Renal handling of urate in the syndrome of inappropriate secretion of antidiuretic hormone.

Three patients with the syndrome of inappropriate secretion of antidiuretic hormone had elevated uric acid clearances. Their uric acid clearances decreased markedly after the administration of pyrazinamide. Probenecid was given to two of them and it produced large increases in uric acid clearance. These data suggest that enhanced secretion in the renal tubules was responsible for the increased clearance of uric acid. This article provides evidence that hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone is due to increased tubular urate secretion.