Variations in daily urine solute output in patients with NDI, CDI, SIADH, and NSIAD: Clinical implications.

INTRODUCTION: We aimed to study the effects of daily variation in solute intake on urine volume in patients with syndrome of inappropriate secretion of antidiuretic hormone secretion (SIADH), syndrome of nephrogenic antidiuresis (NSIAD), central diabetes insipidus (CDI), or nephrogenic diabetes insipidus (NDI). MATERIALS AND METHODS: In 6 patients with CDI, 7 patients with NDI, 7 patients with SIADH, and 2 patients with NSIAD we had the opportunity to have 24-hour urine collections during normal diet before any treatment. We had two 24-hour urine collections with a difference of at least 20% in solute output (measured by the formula urine osmolality × urine volume). In 1 patient with NDI taking a high protein diet we analyzed the effect of a normal protein intake on diuresis. With respect to patients with NDI and CDI we included only patients with a urine osmolality lower than 110 mOsm/kgH2O, and for SIADH/NSIAD we included only patients with a urine osmolality between 500 and 700 mOsm/kgH2O. RESULTS: When the data of the patients with CDI/NDI were pooled, a high correlation between urine volume and solute output was observed (R = 0.83; p < 0.001). In 1 patient with X-linked NDI, we decreased urine volume simply by decreasing protein intake. If we pooled the data concerning SIADH/NSIAD, a correlation was observed between urine volume and solute output (R = 0.94; p < 0.001). As expected, increasing solute intake is beneficial in SIADH/NSIAD, while decreasing it decreases diuresis in NDI. CONCLUSION: Daily variations in solute output affect urine volume in NDI/CDI/SIADH/NSIAD, this could affect serum sodium (SNa) despite no variation in fluid intake. In SIADH, if solute intake is lower than usual for a few days it may significantly influence the SNa level despite no variation in fluid intake.

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.

Osmotic Stress-Induced Defective Glial Proteostasis Contributes to Brain Demyelination after Hyponatremia Treatment.

Adequate protein folding is necessary for normal cell function and a tightly regulated process that requires proper intracellular ionic strength. In many cell types, imbalance between protein synthesis and degradation can induce endoplasmic reticulum (ER) stress, which if sustained, can in turn lead to cell death. In nematodes, osmotic stress induces massive protein aggregation coupled with unfolded protein response and ER stress. In clinical practice, patients sustaining rapid correction of chronic hyponatremia are at risk of osmotic demyelination syndrome. The intense osmotic stress sustained by brain cells is believed to be the major risk factor for demyelination resulting from astrocyte death, which leads to microglial activation, blood-brain barrier opening, and later, myelin damage. Here, using a rat model of osmotic demyelination, we showed that rapid correction of chronic hyponatremia induces severe alterations in proteostasis characterized by diffuse protein aggregation and ubiquitination. Abrupt correction of hyponatremia resulted in vigorous activation of both the unfolded protein response and ER stress accompanied by increased autophagic activity and apoptosis. Immunofluorescence revealed that most of these processes occurred in astrocytes within regions previously shown to be demyelinated in later stages of this syndrome. These results identify osmotic stress as a potent protein aggregation stimuli in mammalian brain and further suggest that osmotic demyelination might be a consequence of proteostasis failure on severe osmotic stress.

Impact of hyponatremia on nerve conduction and muscle strength.

BACKGROUND: Hyponatremia is associated with unstable gait and propensity to falls. The potential contribution of peripheral nervous system dysfunction induced by hyponatremia has not yet been addressed by prospective studies. DESIGN: In the first part of this prospective study, we performed two tests evaluating muscle strength (grip test and quadriceps isometric contraction test) together with a timed up and go (TUG) test in 11 patients with chronic mild-to-moderate hyponatremia before and after the normalization of natremia. In the second part, we measured nerve conduction velocities and F-wave latencies in nine patients with profound hyponatremia (< 125 mmol/L) before and after the normalization of natremia. RESULTS: No significant change in muscle strength was observed when natremia was corrected from 127·7 ± 2·5 to 136·1 ± 1·8 mmol/L, contrary to a significant improvement in TUG from 14·9 ± 5·1 to 12·5 ± 4·7 s (P = 0·006). Nerve conduction velocities and F-wave latencies showed significant improvement in most of the studied nerves when natremia was corrected from 121·9 ± 2·4 to 135·5 ± 3·4 mmol/L (e.g. mean increase of 14·3% for motor nerve conduction and mean decrease of 21·6% for F-wave latency of left peroneal nerve). CONCLUSION: Whereas chronic mild-to-moderate hyponatremia has no impact on muscle strength, we demonstrate for the first time an impact of profound hyponatremia on nerve conduction studies. Further studies are needed to ascertain the contribution of these latter results on gait disturbances, propensity to falls and attention deficits associated with hyponatremia.

Urea minimizes brain complications following rapid correction of chronic hyponatremia compared with vasopressin antagonist or hypertonic saline.

Hyponatremia is a common electrolyte disorder that carries significant morbidity and mortality. However, severe chronic hyponatremia should not be corrected rapidly to avoid brain demyelination. Vasopressin receptor antagonists (vaptans) are now being widely used for the treatment of hyponatremia along with other alternatives like hypertonic saline. Previous reports have suggested that, in some cases, urea can also be used to correct hyponatremia. Correction of severe hyponatremia with urea has never been compared to treatment with a vaptan or hypertonic saline with regard to the risk of brain complications in the event of a too rapid rise in serum sodium. Here, we compared the neurological outcome of hyponatremic rats corrected rapidly with urea, lixivaptan, and hypertonic saline. Despite similar increase in serum sodium obtained by the three drugs, treatment with lixivaptan or hypertonic saline resulted in a higher mortality than treatment with urea. Histological analysis showed that treatment with urea resulted in less pathological change of experimental osmotic demyelination than was induced by hypertonic saline or lixivaptan. This included breakdown of the blood-brain barrier, microglial activation, astrocyte demise, and demyelination. Thus, overcorrection of hyponatremia with urea resulted in significantly lower mortality and neurological impairment than the overcorrection caused by lixivaptan or hypertonic saline.

Clinical practice guideline on diagnosis and treatment of hyponatraemia.

Hyponatraemia, defined as a serum sodium concentration <135 mmol/l, is the most common disorder of body fluid and electrolyte balance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from subtle to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay in patients presenting with a range of conditions. Despite this, the management of patients remains problematic. The prevalence of hyponatraemia in widely different conditions and the fact that hyponatraemia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and speciality-based approaches to diagnosis and treatment. To obtain a common and holistic view, the European Society of Intensive Care Medicine (ESICM), the European Society of Endocrinology (ESE) and the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA), represented by European Renal Best Practice (ERBP), have developed the Clinical Practice Guideline on the diagnostic approach and treatment of hyponatraemia as a joint venture of three societies representing specialists with a natural interest in hyponatraemia. In addition to a rigorous approach to methodology and evaluation, we were keen to ensure that the document focused on patient-important outcomes and included utility for clinicians involved in everyday practice.

Morbidity Associated with Chronic Hyponatremia.

This article will discuss the consequences of chronic hyponatremia. In conditions such as cancer, heart failure, liver cirrhosis, or chronic kidney disease, the presence and magnitude of hypotonic hyponatremia are considered to reflect the severity of the underlying disease and are associated with increased morbidity as well as mortality. Hyponatremia can be acute (<48 h) or chronic (>2-3 days). Chronic hyponatremia is associated with attention deficit, dizziness, tiredness, gait disturbance, falls, sarcopenia, bone fractures, osteoporosis, hypercalciuria (in the syndrome of inappropriate antidiuresis-SIADH), and kidney stones. In vitro studies have shown that cells grown in a low concentration of extracellular sodium have a greater proliferation rate and motility. Patients with chronic hyponatremia are more likely to develop cancer. We will not review the clinical consequences of respiratory arrest and osmotic demyelination syndrome (ODS) of the too-late or excessive treatment of hyponatremia.

Normonatremic Transient Renal Salt Wasting (TRSW) Is Not Rare in a Department of Internal Medicine.

Background: We previously reported that for around 5% of patients hospitalized with hyponatremia, it was related to what is called "transient renal salt wasting" (TRSW). In the present study we ask whether TRSW can also be observed in patients without hyponatremia. Methods: In this observational retrospective study we analyze the urine solute excretion of 200 consecutive normonatremic patients with normal kidney function and admitted in our department over one year. Patients were selected for analyses of FE.K, UCa/UCr and FE.PO4 if FE.Na was higher than 2% (N < 1.6%) before any treatment, and only if they were not taking diuretics. Result: Eleven normonatremic patients presented with transient high FE.Na > 2% on admission (2.9 ± 0.6% with a high FE.K of 28 ± 6.4%; a high UCa/UCr of 0.37 ± 0.13 and a high FE.PO4 of 23.2 ± 9.6%). All of these patients were elderly. Seven were female and four were male. Neurological disorders were observed in six patients (three strokes, one transient ischemic attack, one syncope and one epileptic attack). Heart problems were observed in three patients (all angina pectoris, two of which also had HBP). One patient presented with rectal bleeding with HBP, and another presented COPD with a pneumothorax. One patient with angina pectoris showed a transient relapse after four days of hospitalization (FE.Na 3.6%). The urine electrolyte excretion in these patients are similar to those observed after furosemide intake. Conclusion: Normonatremic TRSW is not a rare observation, particularly in patients with neurological or cardiac problems.

The Urine Calcium/Creatinine Ratio and Uricemia during Hyponatremia of Different Origins: Clinical Implications.

Background: Chronic hyponatremia is known to be associated with osteoporosis. It has been shown that chronic hyponatremia increases bone resorption in an attempt to release body stores of exchangeable sodium by different mechanisms. We wanted to know the calciuria of patients with hyponatremia of different origins. Material and Methods: We made a retrospective study of 114 consecutive patients with asymptomatic hyponatremia of different origins with the usual serum and urine chemistry. Result: In hyponatremia due to SIADH, we had a high urine calcium/creatinine ratio of 0.23 ± 0.096 while in patients with salt depletion the UCa/UCr ratio was low (0.056 ± 0.038), in patients with hyponatremia secondary to thiazide intake the value was also low (0.075 ± 0.047) as in hypervolemic patients (0.034 ± 0.01). In hyponatremia due to polydipsia, the value was high (0.205 ± 0.10). Correction of hyponatremia in the euvolemic patients was associated with a significant decrease in the UCa/UCr ratio. In patients with hyponatremia secondary to thiazide intake, we noted that in the patients with low uric acid levels (<4 mg/dL, suggesting euvolemia) we also observed a low UCa/UCr (<0.10). In nine patients with chronic SIADH (SNa 125.1 ± 3.6 mEq/L), the 24 h urine calcium excretion was 275 ± 112 mg and decreased to 122 ± 77 mg (p < 0.01) after at least 2 weeks of treatment. Conclusions: Patients with chronic hyponatremia due to SIADH usually have a high UCa/UCr ratio (>0.15). This is also observed in hyponatremia secondary to polydipsia. Patients with thiazide-induced hyponatremia usually have low UCa/UCr levels and this is the case even among those with a biochemistry similar to that in SIADH (uric acid < 4 mg/dL).

Treatment Guidelines for Hyponatremia: Stay the Course.

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.

Oral lixivaptan effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia.

Hyponatremia is the most common electrolyte disorder in clinical practice. Its incidence increases with age and it is associated with increased morbidity and mortality. Recently, the vaptans, antagonists of the arginine vasopressin pathway, have shown promise for safe treatment of hyponatremia. Here we evaluated the efficacy, safety, and tolerability of oral lixivaptan, a selective vasopressin V2-receptor antagonist, for treatment of nonhospitalized individuals with euvolemic hyponatremia (sodium less than 135 mmol/l) in a multicenter, randomized, double-blind, placebo-controlled, phase III study. About half of the 206 patients were elderly in a chronic care setting. Of these patients, 52 were given a placebo and 154 were given 25-100 mg per day lixivaptan, titrated based on the daily serum sodium measurements. Compared with placebo (0.8 mmol/l), the serum sodium concentration significantly increased by 3.2 mmol/l from baseline to day 7 (primary efficacy endpoint) with lixivaptan treatment. A significantly greater proportion of patients that received lixivaptan achieved normal serum sodium (39.4%) by day 7 relative to placebo (12.2%). Overall, lixivaptan was considered safe and well-tolerated. Thus, oral lixivaptan can be safely initiated in the outpatient setting and effectively increases serum sodium concentrations in outpatients with euvolemic hyponatremia.

Lack of responsiveness to 1-desamino-D arginin vasopressin (desmopressin) in male patients with nephrogenic syndrome of inappropriate antidiuresis: from bench to bedside.

BACKGROUND: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently described entity, linked to gain-of-function mutations (R137C and R137L) in arginine vasopressin (AVP) gene leading to chronic activation of tubular V2 AVP receptor (V2R) and thus free water reabsorption. In addition to collecting duct cells, the V2R is also expressed in endothelial cells, where it mediates the rise in circulating levels of von Willebrand factor (vWF) and coagulation factor VIII (fVIII). Recent in vitro data showed that these mutant receptors are resistant to vasopressin-stimulated cAMP production. We aimed to explore by clinical observations the sensitivity to vasopressin of the R137C-V2R mutant in vivo. MATERIAL AND METHODS: We performed a stimulation test with 1-desamino-D arginin vasopressin (dDAVP) 0·3 µg/kg of bodyweight in three patients (two hemizygous male and one heterozygous female) with NSIAD with R137C mutation and measured on the one hand the levels of vWF and fVIII and the other hand urine osmolality and albumin excretion (UAE). RESULTS: Whereas the female heterozygous patient displayed normal response to simulation by dDAVP (except for UAE), no increase in vWF, fVIII, urinary osmolality and UAE was observed among hemizygous male patients. CONCLUSIONS: Coherent with in vitro observation in transfected cells, our clinical observations demonstrate that the R137C-V2R mutant is resistant to vasopressin stimulation in its physiological sites of expression.

Astrocytes are an early target in osmotic demyelination syndrome.

Abrupt osmotic changes during rapid correction of chronic hyponatremia result in demyelinative brain lesions, but the sequence of events linking rapid osmotic changes to myelin loss is not yet understood. Here, in a rat model of osmotic demyelination syndrome, we found that massive astrocyte death occurred after rapid correction of hyponatremia, delineating the regions of future myelin loss. Astrocyte death caused a disruption of the astrocyte-oligodendrocyte network, rapidly upregulated inflammatory cytokines genes, and increased serum S100B, which predicted clinical manifestations and outcome of osmotic demyelination. These results support a model for the pathophysiology of osmotic brain injury in which rapid correction of hyponatremia triggers apoptosis in astrocytes followed by a loss of trophic communication between astrocytes and oligodendrocytes, secondary inflammation, microglial activation, and finally demyelination.

Low Creatininuria due to Hyponatremia Is Reversible in Many Patients.

BACKGROUND: Chronic hyponatremia has been reported to be associated with low solute intake and low creatinine excretion (reflecting likely sarcopenia). We wanted to study the effect, on the long term, of correction of hyponatremia on solute and creatinine excretion in chronic SIADH. METHODS: We made a retrospective review of clinical and biochemical data of patients with euvolemic hyponatremia. We analyzed 24-h urine solute and creatinine excretion in volunteers with hyponatremia induced by dDAVP over 4 days, in 12 patients with chronic SIADH (>1 month) before and after a few days of SNa correction and in 12 patients (6 women and 6 men) before and after 3 months of SNa correction by a vaptan or urea. RESULTS: We confirm a low urine creatinine and solute excretion only in patients with chronic hyponatremia (>1 month). Correction of SNa (from 127 ± 2.3 mEq/L to 139 ± 2.8 mEq/L) for >3 months, in the 12 patients (mean age 58 ± 18), was associated with an increase in 24-h creatinine excretion (from 986 ± 239 to 1,238 ± 220 mg; p < 0.02) and in patients treated with a vaptan (n = 5) solute excretion increased from 656 ± 207 mmol/24 h to 960 ± 193 mmol/24 h (p < 0.02). Sodium excretion increased also in the 12 patients (from 100 ± 53 mEq/24 h to 169 ± 38 mEq/24 h; p < 0.01). CONCLUSION: Chronic hyponatremia (>1 month) is associated with a decrease in solute output (or intake) and in creatinine excretion. In many patients, these abnormalities are reversible in the long term.

Vaptans are not the mainstay of treatment in hyponatremia: perhaps not yet.

Two vasopressin antagonists ('vaptans') are now in the market for the treatment of euvolemic (Europe) or euvolemic and hypervolemic (United States) hyponatremia: conivaptan for intravenous use and tolvaptan for oral application. Although their specificity and effectiveness are considered established, their indications are not. At present, we do not know which symptoms of hyponatremia and which degree of hyponatremia should serve as indications for vaptans. Other areas of uncertainty relate to the following unanswered questions: do vaptans shorten the duration of hospitalization? Is it justifiable to use them to prevent relapse of hyponatremia in (chronic) SIAD(H)? (In this text we use the abbreviation SIAD(H) instead of the recently proposed abbreviation SIAD to emphasize that vaptans will work only in the presence of ADH ('SIADH') but not in the syndrome of nephrogenic antidiuresis.) Do they decrease the high mortality associated with hyponatremia? How do we justify the cost of chronic vaptan therapy? The optimal vaptan regimen (dose, timing of controls) to treat SIAD(H) is currently not established, as is the procedure to be recommended in a too rapid correction rate of (chronic) hyponatremia. Until these requirements shall be met by additional studies, we are hesitant to consider vaptans a treatment of choice for the appropriate hyponatremias.

Minocycline protects against neurologic complications of rapid correction of hyponatremia.

Osmotic demyelination syndrome is a devastating neurologic condition that occurs after rapid correction of serum sodium in patients with hyponatremia. Pathologic features of this injury include a well-demarcated region of myelin loss, a breakdown of the blood-brain barrier, and infiltration of microglia. The semisynthetic tetracycline minocycline is protective in some animal models of central nervous system injury, including demyelination, suggesting that it may also protect against demyelination resulting from rapid correction of chronic hyponatremia. Using a rat model of osmotic demyelination syndrome, we found that treatment with minocycline significantly decreases brain demyelination, alleviates neurologic manifestations, and reduces mortality associated with rapid correction of hyponatremia. Mechanistically, minocycline decreased the permeability of the blood-brain barrier, inhibited microglial activation, decreased both the expression of IL1α and protein nitrosylation, and reduced the loss of GFAP immunoreactivity. In conclusion, minocycline modifies the course of osmotic demyelination in rats, suggesting its possible therapeutic use in the setting of inadvertent rapid correction of chronic hyponatremia in humans.