Search Results (13)

Objective: The objective of this study was to compare the effectiveness of urea and tolvaptan in the treatment of plasma sodium levels in patients with hypotonic hyponatremia. Methods: This was an observational, longitudinal, and retrospective study including all adult patients who received treatment with urea or tolvaptan for hypotonic hyponatremia from 1 April 2014 to 31 October 2023 at the Department of Internal Medicine, Virgen del Rocío University Hospital, Seville, Spain. Results: Forty-seven (55.3%) patients received urea and 38 (44.7%) tolvaptan. The drugs were prescribed for the treatment of syndrome of inappropriate antidiuresis (SIAD) in 59 (69.4%) patients. The mean blood sodium level at the start of treatment was 123.5 ± 6.2 mEq/L. Overall, 61.7% and 63.2% of patients treated with urea and tolvaptan, respectively, achieved a normal blood sodium level (p = 0.89), although the time to have their sodium levels corrected differed between both groups: 41.7 ± 76 days with urea and 21 ± 23.9 days with tolvaptan (p = 0.038). The following were significant in the multivariate study: Initial sodium value (p = 0.037), absolute sodium improvement (p = 0.041), and percentage sodium improvement (p = 0.033). Among patients with SIAD, 69.5% achieved a normal sodium level; this figure was 45.5% for patients with heart failure. Three patients reported side adverse events in the urea group and none in the tolvaptan group. Conclusions: Our data, reflecting real-world practice and follow-up of patients with hypotonic hyponatremia, suggest that both urea and tolvaptan are safe, well-tolerated, and have a similar effectiveness in correcting blood sodium levels in patients with hypotonic hyponatremia, overall and secondary to SIAD, though treatment with tolvaptan achieved this goal earlier than urea. Full article

Traumatic brain injuries (TBIs) cause direct central nervous system injury. The presentation depends on the location, the type, and the severity of the injury. Additional injury may develop secondary to compression, the disruption of cerebral perfusion, and changes in sodium levels, resulting in either cellular edema or dehydration. Plasma osmolality (Posm) is a critical parameter influenced by solute concentrations, including sodium, glucose, and urea, and is a relevant concern when considering sodium levels in these patients. While Posm can be calculated using a standard formula, direct measurements via osmometry offer better accuracy. It is essential to differentiate between osmolality and tonicity; the latter refers specifically to effective solutes that drive water movement in the extracellular fluid. Sodium and its anions are effective solutes, whereas urea and glucose have variable effects due to their permeability and insulin dependence. Following TBI, the dysregulation of osmoregulation may occur and affect neurological outcomes. Osmoreceptors in the brain regulate arginine vasopressin secretion in response to changes in effective solute concentrations, with sodium chloride and mannitol being potent stimuli. The regulation of plasma osmolality, typically maintained within ±5% of the 280–295 mOsm/kg H₂O range, is crucial for homeostasis and relies on antidiuresis and thirst mechanisms. This review narrative underscores the complexities of osmoregulation in the context of TBIs and their clinical implications, particularly concerning the development of conditions such as diabetes insipidus, the syndrome of inappropriate antidiuretic hormone secretion, and abnormal thirst. Full article

Antidepressants, including duloxetine, are a significant cause of drug-induced hyponatremia, which can disrupt the continuation of medication. Tolvaptan is beneficial for correcting hyponatremia caused by the syndrome of inappropriate antidiuresis, but its impact on duloxetine-induced hyponatremia remains unknown. We used male Sprague-Dawley rats to examine the impact of duloxetine treatment on lithium-induced nephrogenic diabetes insipidus (Li-NDI) and to evaluate whether the results were reversed by co-treatment with tolvaptan. To induce Li-NDI, lithium chloride (40 mmol lithium/kg dry food) was administered for 2 weeks. Duloxetine (50 mg/kg/day) and tolvaptan (10 mg/kg/day) were also administered in food to assess their individual effects over the same period. At the end of each animal experiment, kidneys were harvested to measure levels of cAMP, vasopressin-2 receptor (V2R), cAMP-responsive element binding protein 1 (CREB-1), aquaporin-2 (AQP2), and prostaglandin E2 (PGE2). Water diuresis was induced in the Li-NDI rats, and duloxetine treatment reduced polyuria while increasing urine osmolality. Duloxetine treatment prevented the decrease in total AQP2, AQP2 phosphorylation at serine 256, and CREB-1 phosphorylation in Li-NDI rats. The V2R mRNA level was also reduced in Li-NDI rats and restored by duloxetine treatment. In the subsequent experiment, the decreased water diuresis in Li-NDI rats treated with duloxetine was reversed by co-treatment with tolvaptan. Tolvaptan co-treatment also reversed the changes in AQP2 protein and CREB-1 phosphorylation in the renal cortex and medulla. The decreased cAMP levels in Li-NDI rat kidneys were elevated by duloxetine treatment, and this elevation was reversed by co-treatment with tolvaptan. However, the elevated PGE2 levels in Li-NDI rat kidneys were not affected by either duloxetine alone or tolvaptan co-treatment. In conclusion, antidiuresis was induced by duloxetine in Li-NDI and reversed by tolvaptan co-treatment through alterations in the V2R-cAMP-AQP2 pathway. These findings could underlie the mechanism of duloxetine-induced hyponatremia and suggest the potential usefulness of tolvaptan in treating drug-induced hyponatremia. Full article

Background: Hyponatremia is common, particularly among the elderly. Reset osmostat (RO) serves as an alternative diagnosis to the syndrome of inappropriate antidiuresis (SIAD). There is limited information available regarding the prevalence of RO in outpatient clinics and hospital wards. The water-diluting test is considered the gold standard for the diagnosis of RO. The recent identification of copeptin provides an additional diagnostic marker alongside the utilization of fractional uric acid excretion. Methods: This single-center, prospective, observational study involved eight patients undergoing a water-diluting test over a study period of 2 years. Results: Reset osmostat was diagnosed in 50% of cases, while SIAD was confirmed in one patient. The tests were inconclusive for the remaining three patients. Conclusions: Our findings suggest that reset osmostat, despite its rarity, is a plausible diagnosis in chronic hyponatremia. The relevance of copeptin could not be confirmed in this study. Moreover, fractional uric acid excretion might be as effective as the water-diluting test in diagnosing reset osmostat. Full article

In cancer patients, hyponatremia is detected in about 40% of cases at hospital admission and has been associated to a worse outcome. We have previously observed that cancer cells from different tissues show a significantly increased proliferation rate and invasion potential, when cultured in low extracellular [Na⁺]. We have recently developed an animal model of hyponatremia using Foxn1nu/nu mice. The aim of the present study was to compare tumor growth and invasivity of the neuroblastoma cell line SK-N-AS in hyponatremic vs. normonatremic mice. Animals were subcutaneously implanted with luciferase-expressing SK-N-AS cells. When masses reached about 100 mm³, hyponatremia was induced in a subgroup of animals via desmopressin infusion. Tumor masses were significantly greater in hyponatremic mice, starting from day 14 and until the day of sacrifice (day 28). Immunohistochemical analysis showed a more intense vascularization and higher levels of expression of the proliferating cell nuclear antigen, chromogranin A and heme oxigenase-1 gene in hyponatremic mice. Finally, metalloproteases were also more abundantly expressed in hyponatremic animals compared to control ones. To our knowledge, this is the first demonstration in an experimental animal model that hyponatremia is associated to increased cancer growth by activating molecular mechanisms that promote proliferation, angiogenesis and invasivity. Full article

Pituitary apoplexy (PA) is a rare medical emergency. The sudden pressure increase in the sella turcica may determine compression on the surrounding structures determining the classical symptomatology associated, especially visual field impairment and/or ocular palsies and hypopituitarism; hypotonic hyponatremia may occur too, even if it is not common. Although already described in the literature, cases of isolated III cranial nerve palsies are extremely rare events. We report the case of a mid-60-year-old man with a known pituitary adenoma accessing the Emergency Department (ED) for worsening headaches unresponsive to analgesics, with a morphological picture consistent with ischemic PA, despite no dimensional increase of the pituitary lesion; upon ED access, a mild paucisymptomatic hyponatremia was also observed. Dexamethasone and mannitol were empirically introduced upon neurosurgical indication and tramadol and ketorolac were promptly administered as well, but without benefit. In the next days, a severe hypotonic hyponatremia was evidenced and a clear left III cranial nerve palsy developed, but no clear signs of cerebral bleeding or ischemia, nor a significant compression on the homolateral cavernous sinus, were observed. Upon ruling out other possible causes, a likely diagnosis of syndrome of inappropriate antidiuresis (SIAD) was made, confirmed by the quick response to fluid restriction. Overall, the sudden fall in tonicity plasma levels seemed to contribute to the exacerbation of the neurological deficit since the normalization of sodium levels was associated with a rapid and complete reversion of the III cranial nerve palsy. Full article

The utilization of vasopressin receptor antagonists, known as vaptans, in the management of hyponatremia among patients afflicted with the syndrome of inappropriate antidiuretic hormone (SIADH) remains a contentious subject. This meta-analysis aimed to evaluate the safety and efficacy of vaptans for treating chronic hyponatremia in adult SIADH patients. Clinical trials and observational studies were identified by a systematic search using MEDLINE, EMBASE, and Cochrane Database from inception through September 2022. The inclusion criteria were the studies that reported vaptans’ safety or efficacy outcomes compared to placebo or standard therapies. The study protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD 42022357307). Five studies were identified, comprising three RCTs and two cohort studies, enrolling a total of 1840 participants. Regarding short-term efficacy on days 4–5, vaptans exhibited a significant increase in serum sodium concentration from the baseline in comparison to the control group, with a weighted mean difference of 4.77 mmol/L (95% CI, 3.57, 5.96; I² = 34%). In terms of safety outcomes, the pooled incidence rates of overcorrection were 13.1% (95% CI 4.3, 33.6; I² = 92%) in the vaptans group and 3.3% (95% CI 1.6, 6.6; I² = 27%) in the control group. Despite the higher correction rate linked to vaptans, with an OR of 5.72 (95% CI 3.38, 9.70; I² = 0%), no cases of osmotic demyelination syndrome were observed. Our meta-analysis comprehensively summarizes the efficacy and effect size of vaptans in managing SIADH. While vaptans effectively raise the serum sodium concentration compared to placebo/fluid restriction, clinicians should exercise caution regarding the potential for overcorrection. Full article

Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients. This applies also to cancer patients. Multiple causes can lead to hyponatremia, but most frequently this electrolyte disorder is due to the syndrome of inappropriate antidiuresis. In cancer patients, this syndrome is mostly secondary to ectopic secretion of arginine vasopressin by tumoral cells. In addition, several chemotherapeutic drugs induce the release of arginine vasopressin by the hypothalamus. There is evidence that hyponatremia is associated to a more negative outcome in several pathologies, including cancer. Many studies have demonstrated that in different cancer types, both progression-free survival and overall survival are negatively affected by hyponatremia, whereas the correction of serum [Na⁺] has a positive effect on patient outcome. In vitro studies have shown that cells grown in low [Na⁺] have a greater proliferation rate and motility, due to a dysregulation in intracellular signalling pathways. Noteworthy, vasopressin receptors antagonists, which were approved more than a decade ago for the treatment of euvolemic and hypervolemic hyponatremia, have shown unexpected antiproliferative effects. Because of this property, vaptans were also approved for the treatment of polycystic kidney disease. In vitro evidence indicated that this family of drugs effectively counteracts proliferation and invasivity of cancer cells, thus possibly opening a new scenario among the pharmacological strategies to treat cancer. Full article

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. Full article

Serum uric acid levels are altered by kidney disorders because the kidneys play a dominant role in uric acid excretion. Here, major kidney disorders which accompany hyperuricemia or hypouricemia, including their pathophysiology, are discussed. Chronic kidney disease (CKD) and hyperuricemia are frequently associated, but recent clinical trials have not supported the pathogenic roles of hyperuricemia in CKD incidence and progression. Diabetes mellitus (DM) is often associated with hyperuricemia, and hyperuricemia may be associated with an increased risk of diabetic kidney disease in patients with type 2 DM. Sodium-glucose cotransporter 2 inhibitors have a uricosuric effect and can relieve hyperuricemia in DM. Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an important hereditary kidney disease, mainly caused by mutations of uromodulin (UMOD) or mucin-1 (MUC-1). Hyperuricemia and gout are the major clinical manifestations of ADTKD-UMOD and ADTKD-MUC1. Renal hypouricemia is caused by URAT1 or GLUT9 loss-of-function mutations and renders patients susceptible to exercise-induced acute kidney injury, probably because of excessive urinary uric acid excretion. Hypouricemia derived from renal uric acid wasting is a component of Fanconi syndrome, which can be hereditary or acquired. During treatment for human immunodeficiency virus, hepatitis B or cytomegalovirus, tenofovir, adefovir, and cidofovir may cause drug-induced renal Fanconi syndrome. In coronavirus disease 2019, hypouricemia due to proximal tubular injury is related to disease severity, including respiratory failure. Finally, serum uric acid and the fractional excretion of uric acid are indicative of plasma volume status; hyperuricemia caused by the enhanced uric acid reabsorption can be induced by volume depletion, and hypouricemia caused by an increased fractional excretion of uric acid is the characteristic finding in syndromes of inappropriate anti-diuresis, cerebral/renal salt wasting, and thiazide-induced hyponatremia. Molecular mechanisms by which uric acid transport is dysregulated in volume or water balance disorders need to be investigated. Full article

Drug-induced hyponatremia caused by renal water retention is mainly due to syndrome of inappropriate antidiuresis (SIAD). SIAD can be grouped into syndrome of inappropriate antidiuretic hormone secretion (SIADH) and nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The former is characterized by uncontrolled hypersecretion of arginine vasopressin (AVP), and the latter is produced by intrarenal activation for water reabsorption and characterized by suppressed plasma AVP levels. Desmopressin is useful for the treatment of diabetes insipidus because of its selective binding to vasopressin V2 receptor (V2R), but it can induce hyponatremia when prescribed for nocturnal polyuria in older patients. Oxytocin also acts as a V2R agonist and can produce hyponatremia when used to induce labor or abortion. In current clinical practice, psychotropic agents, anticancer chemotherapeutic agents, and thiazide diuretics are the major causes of drug-induced hyponatremia. Among these, vincristine and ifosfamide were associated with sustained plasma AVP levels and are thought to cause SIADH. However, others including antipsychotics, antidepressants, anticonvulsants, cyclophosphamide, and thiazide diuretics may induce hyponatremia by intrarenal mechanisms for aquaporin-2 (AQP2) upregulation, compatible with NSIAD. In these cases, plasma AVP levels are suppressed by negative feedback. In rat inner medullary collecting duct cells, haloperidol, sertraline, carbamazepine, and cyclophosphamide upregulated V2R mRNA and increased cAMP production in the absence of vasopressin. The resultant AQP2 upregulation was blocked by a V2R antagonist tolvaptan or protein kinase A (PKA) inhibitors, suggestive of the activation of V2R-cAMP-PKA signaling. Hydrochlorothiazide can also upregulate AQP2 in the collecting duct without vasopressin, either directly or via the prostaglandin E2 pathway. In brief, nephrogenic antidiuresis, or NSIAD, is the major mechanism for drug-induced hyponatremia. The associations between pharmacogenetic variants and drug-induced hyponatremia is an area of ongoing research. Full article

Hyponatremia is the most common electrolyte disorder, commonly affecting older hospitalized individuals; however, the literature is not clear regarding its effect on mortality. The aim of this 2-year observational prospective cohort study was to evaluate the mortality and re-admission rates, the clinical and laboratory characteristics and the causes of hyponatremia in patients older than 65 years admitted with a corrected serum sodium of 130 mEq/L or less in an internal medicine ward of a tertiary Greek university hospital. During the observation period, 138 patients (mean age 80.5 years, 36.2% male) fulfilled the inclusion criteria and were prospectively followed for 1 year after admission. Symptoms of hyponatremia were present in 59.4% of patients. Hypovolemia was the main sole cause of hyponatremia, but in about one third of patients, hyponatremia was multifactorial. Only a low proportion of patients (12.3%) fulfilled the criteria of the syndrome of inappropriate antidiuresis (SIAD) at admission according to the current guidelines. The re-admission rates at 3- and 12-months following discharge was 34.2% and 51.8%, respectively. Mortality during hospitalization was 17.4% and was higher compared to non-hyponatremic admitted older patients, while the total mortality at 1 year after admission was 28.3%, indicating that hyponatremia at admission is a marker of significant mortality during and after hospitalization in elderly patients. Full article

NSIAD is a rare X-linked condition, caused by activating mutations in the AVPR2 gene coding for the vasopressin V2 receptor (V2R) associated with hyponatremia, despite undetectable plasma vasopressin levels. We have recently provided in vitro evidence that, compared to V2R-wt, expression of activating V2R mutations R137L, R137C and F229V cause a constitutive redistribution of the AQP2 water channel to the plasma membrane, higher basal water permeability and significantly higher basal levels of p256-AQP2 in the F229V mutant but not in R137L or R137C. In this study, V2R mutations were expressed in collecting duct principal cells and the associated signalling was dissected. V2R-R137L and R137C mutants had significantly higher basal pT269-AQP2 levels -independently of S256 and PKA-which were reduced to control by treatment with Rho kinase (ROCK) inhibitor. Interestingly, ROCK activity was found significantly higher in V2R-R137L along with activation of the Gα12/13–Rho–ROCK pathway. Of note, inhibition of ROCK reduced the basal elevated osmotic water permeability to control. To conclude, our data demonstrate for the first time that the gain-of-function mutation of the V2R, R137L causing NSIAD, signals through an alternative PKA-independent pathway that increases AQP2 membrane targeting through ROCK-induced phosphorylation at S/T269 independently of S256 of AQP2. Full article