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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., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of American Society of Nephrology.)

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.

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).

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.

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., (© 2021 S. Karger AG, Basel.)

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/kgH 2 O, and for SIADH/NSIAD we included only patients with a urine osmolality between 500 and 700 mOsm/kgH 2 O., 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.

Skin structure and function results from a dynamic interplay between dermal and epidermal cell types. Optimizing skin health through an effective and long-lasting skin care regime therefore requires a global approach, encompassing various mechanisms to stimulate this interplay beyond the action scope of a classical topical solution. This study evaluates the impact of a novel home-use device combining a topical serum, light-emitting diodes and massage on the clinical signs of extrinsic skin aging. The innovative principle relies on potentiating the effect of active ingredients contained in the topical serum with visible and near infra-red photons to prevent extracellular matrix degradation and promote its reconstruction. After in vitro and ex vivo investigations, a clinical study assessed the safety and efficacy of a daily treatment with the home-use device for 28 days. A significant increases in skin density and radiance while reducing the wrinkles was obtained with no side effects., (© 2020 LightInDerm. Journal of Biophotonics published by WILEY-VCH GmbH.)

Introduction : Hyponatremia is the most common fluid and electrolyte abnormality. It is associated with much higher morbidity and mortality rates than found in non hyponatremic patients. Areas covered : When the physician is faced to a hyponatremic patient he first has to confirm that hyponatremia is associated with hypoosmolality. Then he must answer to a series of questions: What is its origin? Is it acute or chronic? Which treatment is the most appropriate? We will discuss the various options for the treatment of hypotonic hyponatremia. For a better comprehensive approach of the treatment we will also discuss some pathophysiological data. The use of urea in euvolemic and hypervolemic hyponatremia will be particularly discussed. Literature was reviewed from Jan 1970 to Dec 2019. Expert opinion : Prospective studies showing the benefit in decreasing morbidity by increasing SNa in patients with chronic hyponatremia should be done. These studies should also compare the efficacy and side effects of urea therapy compare to vaptans.

Background: In hyponatremia, due to the inappropriate secretion of antidiuretic hormone (SIADH), a high versus low solute intake will affect the urine volume (UV) and, hence, the SNa level. The clinical implication of the fractional solute excretion is presented. Methods : In 35 normal controls and 24 patients with SIADH and urine osmolality higher than serum osmolality, we compared exact solute intake obtained from 24 h urine collection, with the estimated value obtained on a urine morning spot sample by the formula: eGFR (L/min) × Sosm × 1440 × FE.Osm (%) = mmol/24 h. The exact UV was compared with the estimated value given by the formula: eGFR × 1440 × S.Creat/U.Creat (for eGFR the MDRD was used). In 65 patients with chronic SIADH, from which a morning spot urine sample was available, we determined the estimated fluid and solute intake. Results : A good correlation was observed between the measured solute output or urine volume and the estimated values obtained from the controls ( r = 0.86) as well as in SIADH ( r = 0.91). Conclusion : Patients with low solute intake (FE.Osm <1.4%) and low diuresis (V/eCcr <0.8%) should increase their intake by taking oral urea, for example. Patients with high solute intake (FE.Osm >2.5%) and high diuresis (V/eCcr >1.5%) could usually be treated by mild water restriction (<1.5-21/24 h).

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.

The differential diagnosis between hypertonic, isotonic and hypotonic hyponatremia are presented. The help of some usual serum (urea, uric acid and TCO 2 ) 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.

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/kgH 2 O (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/kgH 2 O respectively and increased to 136.5±1mEq/l and 490±151mOsm/kgH 2 O (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/kgH 2 O and increased to 136.5±2mEq/l and 698±157mOsm/kgH 2 O (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/kgH 2 O., (Copyright © 2017. Published by Elsevier B.V.)

Background/aims: Hyponatremia secondary to distal diuretics intake could have a biochemical picture similar to the one observed in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In these patients, water retention is considered to be the main causal factor and solute depletion a secondary one., Methods: We compared the level of cation (Na + K) depletion and water balance in patients with high or low uric acid levels (< 4 mg/dL or 238 µmol/L) or with high or low (< 30 mg/dL or 5 mmol/L) urea levels. Data were collected from 15 consecutive patients treated in a similar way by a daily infusion of 2 L isotonic saline with potassium chloride until SNa reached at least 132 mmol/L. The same procedure was performed in 6 patients with hyponatremia due to salt depletion not related to diuretic intake., Results: Hyponatremia, associated with low or high uric acid level is mainly due to severe cation depletion (around 600 mmol) and not due to water retention, since body weight did not change significantly (SNa 122 ± 2.0 mEq/L). If patients were classified according to serum urea levels those with higher urea levels (≥30 mg/dL) presented with a mild increase in BW (0.84 ± 0.37 kg). In patients with salt depletion and hyponatremia not related to diuretic intake, we observe as expected an increase in BW (1.5 ± 0.3 kg) and similar cation retention with the treatment., Conclusion: We therefore suggest that diuretic induced hyponatremia with an SIADH-like biochemical profile, should be treated mainly by solute -repletion., (© 2018 S. Karger AG, Basel.)

Aims: Patients with diabetes mellitus experience a large number of falls and bone fractures that are not related solely to complications of the disease. The purpose of our study was to determine whether transient hyperglycemia affects attentional functions and gait., Methods: This was a case-control study. We asked 17 patients with type 1 or type 2 diabetes mellitus to perform three visual tests and one visual and auditory attention test (Phasic Alert A1-4 and A2-3, Go/No Go, Intermodal Comparison). Mean response time (ms) and total number of errors were assessed. Ten of the patients also performed a tandem gait test consisting of three steps. The total distance travelled (TDT, in mm) by the center of pressure was measured with a pressure-sensitive calibrated platform. Transient hyperglycemia was defined as blood glucose level greater than 13, 8 mmol/L at the time of the test. These same patients were retested 1-3 days later at a blood glucose level at least 5, 5 mmol/L lower than the initial values (T24-72h). Nineteen patients with diabetes mellitus were matched with the original participants and performed the same test under normoglycemic conditions., Results: During transient hyperglycemia, the mean response time (ms) and the TDT were significantly longer. The mean response time for the four tests increased by 53, 5 ms (P < 0.001). There was no increase in the number of errors. The TDT of the center of pressure increased significantly by 102 mm (P < 0.001)., Conclusions: Transient hyperglycemia alters attention and gait in patients with diabetes mellitus.

Hyponatremia is defined by low serum sodium concentration and is the most common electrolyte disorder encountered in clinical practice. Serum sodium is the main determinant of plasma osmolality, which, in turn, affects cell volume. In the presence of low extracellular osmolality, cells will swell if the adaptation mechanisms involved in the cell volume maintenance are inadequate. The most dramatic effects of hyponatremia on the brain are seen when serum sodium concentration decreases in a short period, allowing little or no adaptation. The brain is constrained inside a nonextensible envelope; thus, brain swelling carries a significant morbidity because of the compression of brain parenchyma over the rigid skull. Serum sodium concentration is an important determinant of several biological pathways in the nervous system, and recent studies have suggested that hyponatremia carries a significant risk of neurological impairment even in the absence of brain edema. The brain can also be affected by the treatment of hyponatremia, which, if not undertaken cautiously, could lead to osmotic demyelination syndrome, a rare demyelinating brain disorder that occurs after rapid correction of severe hyponatremia. This review summarizes the pathophysiology of brain complications of hyponatremia and its treatment.

Hyponatremia, defined as a serum sodium concentration <135mmol/l, is the most common water-electrolyte imbalance encountered in clinical practice. It can lead to a wide spectrum of clinical symptoms, from mild to severe or even life threatening, and is associated with increased mortality, morbidity and length of hospital stay. Despite this, the management of hyponatremia patients remains problematic. The prevalence of hyponatremia in a wide variety of conditions and the fact that hyponatremia is managed by clinicians with a broad variety of backgrounds have fostered diverse institution- and specialty-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 clinical practice guidelines on the diagnostic approach and treatment of hyponatremia as a joint venture of 3societies representing specialists with a natural interest in hyponatremia. In addition to a rigorous approach to the methodology and evaluation of the evidence, the document focuses on patient-positive outcomes and on providing a useful tool for clinicians involved in everyday practice. In this article, we present an abridged version of the recommendations and suggestions for the diagnosis and treatment of hyponatremia extracted from the full guide., (Copyright © 2017 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

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., (Copyright © 2017 by the American Society of Nephrology.)

Erdheim-Chester disease (ECD) is a non-Langerhans' histiocytosisand a veryrare multisystemic disease of unknown aetiology, with skeletal involvement of the long bones and in more than 50% of cases with extraskeletal involvement. The disease was described in 1930 by the anatomopathologist Jakob Erdheim and his student William Chester. More than 500 cases have since been reported. We report the case of a 77-year-old Italian woman with ECD who was admitted to hospital for acute cardiac tamponade. The patient presented with simultaneous cutaneous, retro-orbital, skeletal, cerebral and cardiovascular manifestations and was successfully treated with corticosteroids followed by interferon., Learning Points: Erdheim-Chester disease (ECD) is a non-Langerhans' histiocytosisand a very rare multisystemic disease that is thought to be associated with cytokine disturbances.ECD has a variable prognosis but is poorer in those with heart involvement.First-line treatment involves the administration of interferon alpha., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests.

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., (© 2016 Stichting European Society for Clinical Investigation Journal Foundation.)

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.

Oral urea has been used in the past to treat various diseases like gastric ulcers, liver metastases, sickle cell disease, heart failure, brain oedema, glaucoma, Meniere disease, etc. We have demonstrated for years, the efficacy of urea to treat euvolemic (SIADH) or hypervolemic hyponatremia. We briefly describe the indications of urea use in symptomatic and paucisymptomatic hyponatremic patients. Urea is a non-toxic, cheap product, and protects against osmotic demyelinating syndrome (ODS) in experimental studies. Prospective studies showing the benefit to treat mild chronic hyponatremia due to SIADH and comparing water restriction, urea, high ceiling diuretics, and antivasopressin antagonist antagonist should be done.

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.

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. Hyponatraemia is present in 15-20% of emergency admissions to hospital and occurs in up to 20% of critically ill patients. Symptomatology may vary from subtle to severe or even life threatening. Despite this, the management of patients remains problematic. Against this background, the European Society of Intensive Care Medicine, the European Society of Endocrinology and the European Renal Association-European Dialysis and Transplant Association, represented by European Renal Best Practice have developed a 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.

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.

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.

Delirium is common in older people. It is a crucial diagnosis because it raises the morbidity and the mortality. Diagnostic tools like Mini Mental State Examination (MMSE), the confusion assessment method (CAM), and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSMIV), can help with the diagnosis. We report a case of a woman with neurological symptoms which look like dementia. We diagnosed systemic lupus erythematosus (SLE). The apparition of late-onset SLE is more insidious, which leads to misdiagnosis. We will discuss about the difficulty of the differential diagnosis between delirium, depression and dementia in our patient and the difficulty to manage treatment of neurolupus in older people., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Hyponatremia occurring as a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting syndrome is a common complication in patients with subarachnoid hemorrhage (SAH). The efficacy and safety of urea as treatment for SIADH-induced hyponatremia has not been reported in this population., Methods: This is a retrospective analysis of all patients admitted to our department for nontraumatic SAH between January 2003 and December 2008 (n = 368). All patients with SIADH-induced hyponatremia (plasma sodium < 135 mEq/L, urine sodium > 20 mEq/L, and osmolality > 200 mOsm/kg; absence of overt dehydration or hypovolemia; no peripheral edema or renal failure; no history of adrenal or thyroid disease) routinely received urea per os when hyponatremia was associated with clinical deterioration or remained less than 130 mEq/L despite saline solution administration., Results: Forty-two patients developed SIADH and were treated with urea. Urea was started after a median of 7 (IQR, 5-10) days and given orally at doses of 15-30 g tid or qid for a median of 5 (IQR, 3-7) days. The median plasma sodium increase over the first day of treatment was 3 (IQR, 1-6) mEq/L. Hyponatremia was corrected in all patients, with median times to Na+ >130 and >135 mEq/L of 1 (IQR, 1-2) and 3 (IQR, 2-4) days, respectively. Urea was well tolerated, and no adverse effects were reported., Conclusions: Oral urea is an effective and well-tolerated treatment for SIADH-induced hyponatremia in SAH patients.

Background and Objectives: Vaptans (vasopressin V(2)-receptor antagonists) are a new approach for the treatment of hyponatremia. However, their indications remain to be determined, and their benefit compared with that of the usual treatments for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) have not been evaluated. This prospective, long-term study compared the efficacy, tolerability, and safety of two oral vaptans with those of oral urea in patients with SIADH., Design, Setting, Participants, & Measurements: Patients with chronic SIADH of various origins were treated first with vaptans for 1 year. After an 8-day holiday period, they received oral urea for an additional 1-year follow-up. Serum sodium was measured every 2 months, and drug doses were adjusted accordingly., Results: Thirteen participants were initially included in the study (serum sodium, 125±3 mEq/L); 12 completed the 2-year treatment period. Treatment with vaptans (satavaptan, 5-50 mg/d, n=10; tolvaptan, 30-60 mg/day, n=2) increased natremia (serum sodium, 135±3 mEq/L) during the 1-year vaptan period without escape. Hyponatremia recurred in the 12 participants when vaptans were stopped (holiday period). Urea improved the natremia with the same efficacy (serum sodium, 135±2 mEq/L) as vaptans during the 1-year urea treatment period. One participant treated with tolvaptan withdrew from the study early because of excessive thirst. Another patient receiving urea developed hypernatremia without complications., Conclusions: Urea has efficacy similar to that of vaptans for treatment of chronic SIADH. Tolerance is generally good for both agents.

The vaptans are non-peptide arginine-vasopressin-receptor antagonists, that are orally and intravenously active. A few vaptans have undergone sufficient clinical development to be on the market. In the EU only tolvaptan is accepted to treat hyponatremia related to SIADH. The place of this new treatment is compared with water restriction, demeclocyclin, furosemide and urea., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

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., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

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., (Copyright © 2012 S. Karger AG, Basel.)

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.

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.

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.

Introduction: Hyponatremia in the intensive care unit (ICU) is most commonly related to inappropriate secretion of antidiuretic hormone (SIADH). Fluid restriction is difficult to apply in these patients. We wanted to report the treatment of hyponatremia with urea in these patients., Methods: Two groups of patients are reported. The first one is represented by a retrospective study of 50 consecutive patients with mild hyponatremia treated with urea. The second group is presented by a series of 35 consecutive patients with severe hyponatremia acquired outside the hospital (≤ 115 mEq/L) who where treated by isotonic saline and urea (0.5 to 1 g/kg/day), administered usually by gastric tube., Results: In the first group with mild hyponatremia (128 ± 4 mEq/L) the serum sodium (SNa) increased to a mean value of 135 ± 4 mEq/L (P < 0.001) after two days of urea therapy (46 ± 25 g/day), despite a large fluid intake (> 2 L/day). The mean duration of urea therapy was six days (from 2 to 42 days). Six patients developed hyponatremia again once the urea was stopped, which necessitated its reintroduction. Six patients developed hypernatremia (maximum value 155 mEq/L). In the second group, SNa increased from 111 ± 3 mEq/L to 122 ± 4 mEq/L in one day (P < 0.001). All the patients with neurological symptoms made a rapid recovery. No side effects were observed., Conclusions: These data show that urea is a simple and inexpensive therapy to treat euvolemic hyponatremia in the ICU.

Objective: S100A8 and S100A9 are calcium binding proteins of the S100 family highly expressed in neutrophils and monocytes. S100 proteins are novel ligands of TLR4 important in modulating inflammation. High levels of S100A8/A9 found in human inflammatory diseases are a marker of disease activity in rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). We determined levels of S100A8/A9 in sera of patients with systemic lupus erythematosus (SLE) and analyzed their relation to clinical variables of disease activity., Methods: A group of 93 patients with SLE were studied over a period of 3 years, and 143 serum samples were analyzed. S100A8/A9 serum concentrations were determined by a sandwich ELISA. Sera from 10 primary Sjögren's syndrome (pSS) patients and 50 healthy volunteers were used as controls. Correlations to SLEDAI, ANA, anti-dsDNA, WBC, CH50, C4, and CRP were made. In addition, infections were recorded in all SLE patients., Results: Serum levels of S100A8/A9 were significantly (p = 0.04) higher in SLE patients (1412 +/- 664 ng/ml) versus healthy controls (339 +/- 35 ng/ml) and pSS patients (400 +/- 85 ng/ml). The only significant correlation (r = 0.219; p = 0.015) was found was between S100A8/A9 and SLEDAI. Further, SLE patients with concomitant infections had higher serum levels of S100A8/A9 (39300 +/- 13375 ng/ml) than those without infections (1150 +/- 422 ng/ml)., Conclusion: Serum levels of S100A8/A9 are significantly raised in SLE versus pSS patients and healthy controls and can be correlated to a disease activity index. S100A8/A9 is a more relevant marker of infection in SLE patients.

Osmotic demyelination syndrome is a devastating neurologic disorder often seen after the rapid correction of chronic hyponatremia. The permeability of the blood-brain barrier is increased in experimental osmotic demyelination, and some have suggested that corticosteroids protect against this disorder by keeping the permeability of the blood-brain barrier low. We previously reported that re-lowering of the serum sodium after rapid correction of chronic hyponatremia was beneficial if performed early in the course (12 to 24 h). Here we compared mortality, blood-brain barrier permeability, and microglial activation in rats after the rapid correction of chronic hyponatremia. We studied three groups of rats after correction of chronic hyponatremia: and treated them with sodium chloride, with or without dexamethasone; or with sodium chloride followed by re-induction of hyponatremia. We found that treatment with dexamethasone or re-induction of hyponatremia effectively prevented the opening of the blood-brain barrier, reduced neurological manifestations, and decreased microglial activation; however, only re-induction of hyponatremia resulted in a significant decrease in mortality 5 days after the correction of chronic hyponatremia. Restoring the permeability of the blood-brain barrier to normal levels did not decrease mortality. Our results suggest that after inadvertent rapid correction of hyponatremia, treatment options should favor re-lowering serum sodium. The increased permeability of blood-brain barrier seen in osmotic demyelination syndrome may not be a primary pathophysiologic insult of this syndrome.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of water balance characterized by hypotonic hyponatremia and impaired water excretion. The diagnosis of SIADH is based on the exclusion of other hyponatremic conditions, the presence of hyposmolality with inappropriate urine osmolality and a urine sodium concentration usually above 30 mEq/L. Some simple and readily available biologic parameters can be helpful in the diagnosis of SIADH (low urea and uric acid levels). The recent syndrome of nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is also discussed and the association of asymptomatic hyponatremia with falls and bone fractures.

Background: In most cases of hyponatremia, arginine vasopressin secretion is inappropriately high. This placebo-controlled, randomized, double-blind multicenter study evaluated the efficacy and safety of oral conivaptan, a V1A/V2-receptor antagonist, in patients with euvolemic or hypervolemic hyponatremia., Methods: Eighty-three patients with serum [Na] less than 130 mEq/L were stratified by volume status and randomly assigned to placebo or conivaptan 40 or 80 mg/d for 5 days., Results: Conivaptan increased the baseline-adjusted area under the serum [Na]-time curve significantly more than placebo (P = 0.0001). Patients given either dose of conivaptan demonstrated a serum [Na] of 4 mEq/L or greater above baseline significantly faster than those given placebo (P < 0.001) and maintained that increase for a greater total time (P = 0.0001). The least squares mean change in serum [Na] from baseline to end of treatment was also significantly greater with conivaptan 40 and 80 mg/d (6.8 and 8.8 mEq/L, respectively) (P = 0.0001) than that with placebo (1.2 mEq/L). The percentage of patients who obtained an increase from baseline in serum [Na] of 6 mEq/L or greater or normal serum [Na] was significantly higher among patients given conivaptan 40 and 80 mg/d (67% and 88%, respectively) than among those given placebo (20%; P < 0.001). Conivaptan was well tolerated; the most frequent adverse events were urinary tract infection, anemia, pyrexia, cardiac failure, hypotension, and hypokalemia., Conclusion: Oral conivaptan was effective in increasing serum [Na] in patients with euvolemic or hypervolemic hyponatremia and had a favorable safety profile.