Clinical and Genetic Factors Associated With Thiazide-Induced Hyponatremia.
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SUBMITTER: Huang CC
PROVIDER: S-EPMC4602917 | biostudies-literature | 2015 Aug
REPOSITORIES: biostudies-literature
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Clinical and Genetic Factors Associated With Thiazide-Induced Hyponatremia.
Huang Chin-Chou CC Chung Chia-Min CM Hung Shuen-Iu SI Pan Wen-Harn WH Leu Hsin-Bang HB Huang Po-Hsun PH Chiu Chun-Chih CC Lin Liang-Yu LY Lin Chih-Ching CC Yang Chih-Yu CY Li Szu-Yuan SY Chen Yen-Chia YC Wu Tao-Cheng TC Lin Shing-Jong SJ Chen Jaw-Wen JW
Medicine 20150801 34
Thiazide diuretics are associated with an increased risk of hyponatremia. The aim of this study was to investigate possible predictors of thiazide-induced hyponatremia.A total of 48 patients admitted to the ward or to the emergency department due to severe thiazide-induced hyponatremia (Na < 125 mmol/L) were enrolled in our study as the case group. Another 211 hypertensive patients with normal sodium levels after treatment with thiazide diuretics were selected as the control group. Twelve tag si ...[more]
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Project description:PURPOSE OF REVIEW:Hypertension affects more than 30% of the world's adult population and thiazide (and thiazide-like) diuretics are amongst the most widely used, effective, and least costly treatments available, with all-cause mortality benefits equivalent to angiotensin-converting enzyme inhibitors or calcium channel antagonists. A minority of patients develop thiazide-induced hyponatremia (TIH) and this is largely unpredictable at the point of thiazide prescription. In some cases, TIH can cause debilitating symptoms and require hospital admission. Although TIH affects only a minority of patients exposed to thiazides, the high prevalence of hypertension leads to TIH being the most common cause of drug-induced hyponatremia requiring hospital admission in the UK. This review examines current clinical and scientific understanding of TIH. Consideration is given to demographic associations, limitations of current electrolyte monitoring regimens, clinical presentation, the phenotype evident on routine clinical blood and urine tests as well as more extensive analyses of blood and urine in research settings, recent genetic associations with TIH, and thoughts on management of the condition. RECENT FINDINGS:Recent genetic and phenotyping analysis has suggested that prostaglandin E2 pathways in the collecting duct may have a role in the development of TIH in a subgroup of patients. Greater understanding of the molecular pathophysiology of TIH raises the prospect of pre-prescription TIH risk profiling and may offer novel insights into how TIH may be avoided, prevented and treated. The rising prevalence of hypertension and the widespread use of thiazides mean that further understanding of TIH will continue to be a pressing issue for patients, physicians, and scientists alike for the foreseeable future.
| S-EPMC5893690 | biostudies-literature
Project description:BackgroundHyponatremia is a frequent and potentially life-threatening adverse side effect of thiazide diuretics. This sub-analysis of the Hyponatremia Registry database focuses on current management practices of thiazide-associated hyponatremia (TAH) and compares differences between TAH and syndrome of inappropriate antidiuretic hormone secretion (SIADH).MethodsWe analyzed 477 patients from 225 US and EU sites with euvolemic hyponatremia ([Na+] ?130 mEq/L) who were receiving a thiazide diuretic. Of these, 118 met criteria for true thiazide-induced hyponatremia (TIH).ResultsThiazide was withdrawn immediately after hyponatremia was diagnosed only in 57% of TAH; in these patients, the median rate of [Na+] change (?daily[Na+]) was significantly higher than those with continued thiazide treatment (3.8 [interquartile range: 4.0] vs. 1.7 [3.8] mEq/L/day). The most frequently employed therapies were isotonic saline (29.6%), fluid restriction (19.9%), the combination of these two (8.2%), and hypertonic saline (5.2%). Hypertonic saline produced the greatest ?daily[Na+] (8.0[6.4] mEq/L/day) followed by a combination of fluid restriction and normal saline (4.5 [3.8] mEq/L/day) and normal saline alone (3.6 [3.5] mEq/L/day). Fluid restriction was markedly less effective (2.7 [2.7] mEq/L/day). Overly rapid correction of hyponatremia occurred in 3.1% overall, but in up to 21.4% given hypertonic saline. Although there are highly significant differences in the biochemical profiles between TIH and SIADH, no predictive diagnostic test could be derived.ConclusionsDespite its high incidence and potential risks, the management of TAH is often poor. Immediate withdrawal of the thiazide is crucial for treatment success. Hypertonic saline is most effective in correcting hyponatremia but associated with a high rate of overly rapid correction. We could not establish a diagnostic laboratory-based test to differentiate TIH from SIADH.
| S-EPMC5452281 | biostudies-literature
Project description:BackgroundThiazide, a first-line therapy for hypertension, lowers blood pressure, increases bone mineral density, and reduces the risk of fractures. However, hyponatremia, an adverse effect of thiazide, is associated with increased risk of osteoporosis and fractures. It is currently unclear whether thiazide-associated hyponatremia (TAH) outweighs the protective effects of thiazide.MethodsUsing data from Taiwan's National Health Insurance Research Database, we identified patients who were prescribed thiazide between 1998 and 2010. Those diagnosed with hyponatremia within three years after initiation of thiazide were selected for the TAH group. Thiazide users without hyponatremia were selected for the control group. The association between TAH and fracture risk was further evaluated using multivariable Cox regression models adjusted for comorbidities and medications. Subjects were followed up from the index date until the appearance of a fracture, death, or the end of a 3-year period.ResultsA total of 1212 patients were included in the TAH group, matched with 4848 patients in the control group. The incidence rate of fracture was higher in the TAH group than in the control group (31.4 versus 20.6 per 1000 person-years). TAH was associated with a higher risk of total fractures (adjusted hazard ratio [aHR]: 1.47, 95% confidence interval [CI] = 1.15-1.88), vertebra fractures (aHR: 1.84, 95% CI = 1.12-3.01), and hip fractures (aHR: 1.66, 95% CI = 1.12-2.46) after controlling for comorbidities and other medications.ConclusionsThiazide users with hyponatremia have a higher risk of fracture than thiazide users without hyponatremia. The fracture-protective effect of thiazide is attenuated by TAH.
| S-EPMC6285977 | biostudies-literature
Project description:Thiazide diuretics are among the most widely used treatments for hypertension, but thiazide-induced hyponatremia (TIH), a clinically significant adverse effect, is poorly understood. Here, we have studied the phenotypic and genetic characteristics of patients hospitalized with TIH. In a cohort of 109 TIH patients, those with severe TIH displayed an extended phenotype of intravascular volume expansion, increased free water reabsorption, urinary prostaglandin E2 excretion, and reduced excretion of serum chloride, magnesium, zinc, and antidiuretic hormone. GWAS in a separate cohort of 48 TIH patients and 2,922 controls from the 1958 British birth cohort identified an additional 14 regions associated with TIH. We identified a suggestive association with a variant in SLCO2A1, which encodes a prostaglandin transporter in the distal nephron. Resequencing of SLCO2A1 revealed a nonsynonymous variant, rs34550074 (p.A396T), and association with this SNP was replicated in a second cohort of TIH cases. TIH patients with the p.A396T variant demonstrated increased urinary excretion of prostaglandin E2 and metabolites. Moreover, the SLCO2A1 phospho-mimic p.A396E showed loss of transporter function in vitro. These findings indicate that the phenotype of TIH involves a more extensive metabolic derangement than previously recognized. We propose one mechanism underlying TIH development in a subgroup of patients in which SLCO2A1 regulation is altered.
| S-EPMC5669583 | biostudies-literature
Project description:BackgroundThiazide-associated hyponatremia (TAH) has been supposed to increase the risk of major adverse cardiovascular events (MACE) in the elderly. Therefore, this study aimed to evaluate the association of TAH with the risk of MACE in elderly Taiwanese patients.MethodsData from the longitudinal generation tracking database (LGTD 2010) of the Health and Welfare Data Science Center (HWDC) were retrospectively assessed. The TAH study group was defined as using > 30 cumulative daily defined doses (CDDDs) thiazide diuretics within one year before diagnosis of hyponatremia. The control group (1:3 propensity score matching) had no diagnosis of hyponatremia but had used > 30 CDDDs thiazide diuretics within one year. Data on MACE were extracted using International Classification of Diseases codes. Outcomes were assessed using a multivariable Cox proportional hazard model and Kaplan-Meier analysis.ResultsA total of 1155 and 3465 individuals were enrolled in the TAH and the control groups, respectively. The rates of MACE (11.1% vs. 7.3%) and death (22.8% vs.12.2%) were significantly higher in the TAH group than the control group. In the TAH group, the adjusted HRs were 1.29 (CI 1.01 ‒ 1.65) for MACE, 1.39 (CI 1.19 ‒ 1.63) for all-cause death, and 1.61 (CI 0.90 ‒ 2.92) for stroke.ConclusionTAH in patients above 65-years-old is associated with a 29% higher risk of MACE, 39% higher risk of all-cause death, and 61% higher risk of stroke. This work suggests that thiazides prescription in elderly patients should be more careful. However, further research is required to confirm our findings.
| S-EPMC10724905 | biostudies-literature
Project description:PurposeThiazide diuretics are the most common origin of drug-induced hyponatremia. However, population-based studies on clinical outcomes are lacking. We therefore explored the time course and absolute risk of thiazide-associated hospitalization due to hyponatremia in Sweden.MethodsPopulation-based case-control study including patients hospitalized with a principal diagnosis of hyponatremia (n = 11,213) compared with controls (n = 44,801). Linkage of registers was used to acquire data. Multivariable regression was applied to explore time-dependent associations between thiazide diuretics and hospitalization due to hyponatremia. Attributable risks were calculated assessing the disease burden attributable to thiazides.ResultsIndividuals initiating thiazide treatment were exposed to an immediate increase in risk for hospitalization with adjusted odds ratio (aOR) (95% CI) of 48 (28-89). The associations gradually declined reaching an aOR of 2.9 (2.7-3.1) for individuals treated for longer than 13 weeks. The attributable risk of hyponatremia-associated hospitalization due to thiazides of any treatment length was 27% (3095/11,213). Among 806 patients initiating treatment < 90 days before hospitalization, hyponatremia could be attributed to thiazides in 754. Based on nationwide data, 616,678 individuals were initiated on thiazides during the 8-year study period suggesting an absolute risk of 0.12% (754/661,678) for subsequent hospitalization with a main diagnosis of hyponatremia.ConclusionsThiazide diuretics attributed to more than one in four individuals hospitalized due to hyponatremia. The risk increase was very pronounced during the first month of treatment and then gradually declined, without returning to normal. However, the absolute risk for the development of hyponatremia demanding hospitalization may for most individuals be modest.
| S-EPMC8184529 | biostudies-literature
Project description:IntroductionThiazide diuretics are among the most widely used antihypertensive medications worldwide. Thiazide-induced hyponatremia (TIH) is 1 of their most clinically significant adverse effects. A priori TIH must result from excessive saliuresis and/or water reabsorption. We hypothesized that pathways regulating the thiazide-sensitive sodium-chloride cotransporter NCC and the water channel aquaporin-2 (AQP2) may be involved. Our aim was to assess whether patients with TIH would show evidence of altered NCC and AQP2 expression in urinary extracellular vesicles (UEVs), and also whether abnormalities of renal sodium reabsorption would be evident using endogenous lithium clearance (ELC).MethodsBlood and urine samples were donated by patients admitted to hospital with acute symptomatic TIH, after recovery to normonatremia, and also from normonatremic controls on and off thiazides. Urinary extracellular vesicles were isolated and target proteins evaluated by western blotting and by nanoparticle tracking analysis. Endogenous lithium clearance was assessed by inductively coupled plasma mass spectrometry.ResultsAnalysis of UEVs by western blotting showed that patients with acute TIH displayed reduced total NCC and increased phospho-NCC and AQP2 relative to appropriate control groups; smaller differences in NCC and AQP2 expression persisted after recovery from TIH. These findings were confirmed by nanoparticle tracking analysis. Renal ELC was lower in acute TIH compared to that in controls and convalescent case patients.ConclusionReduced NCC expression and increased AQP2 expression would be expected to result in saliuresis and water reabsorption in TIH patients. This study raises the possibility that UEV analysis may be of diagnostic utility in less clear-cut cases of thiazide-associated hyponatremia, and may help to identify patients at risk for TIH before thiazide initiation.
| S-EPMC6308385 | biostudies-literature
Project description:The urinary excretion of uromodulin is influenced by common variants in the UMOD gene, and it may be related to NaCl retention and hypertension. Levels of uromodulin are also dependent of the renal function, but other determinants remain unknown.We tested associations between the urinary excretion of uromodulin; medical history and medication; serum and urinary levels of electrolytes, glucose, and uric acid; and the genotype at the UMOD/Protein Disulfide Isomerase-Like, Testis Expressed locus (rs4293393 and rs12446492); 943 participants from the CARTaGENE Cohort, a random sample from the Canadian population of 20,004 individuals, were analyzed. Participants with available genotyping were obtained from a substudy addressing associations between common variants and cardiovascular disease in paired participants with high and low Framingham risk scores and vascular rigidity indexes.The population studied was 54±9 years old, with 51% women and eGFR of 9±14 ml/min per 1.73 m(2). Uromodulin excretion was 25 (11-42) mg/g creatinine. Using linear regression, it was independently higher among patients with higher eGFR, the TT genotype of rs4293393, and the TT genotype of rs12446492. The fractional excretions of urate and sodium showed a strong positive correlation with uromodulin, likely linked to the extracellular volume status. The presence of glycosuria and the use of uricosuric drugs, which both increased the fraction excretion of urate, were independently associated with a lower uromodulin excretion, suggesting novel interactions between uric acid and uromodulin excretion.In this large cohort, the excretion of uromodulin correlates with clinical, genetic, and urinary factors. The strongest associations were between uric acid, sodium, and uromodulin excretions and are likely linked to the extracellular volume status.
| S-EPMC4702232 | biostudies-literature
Project description:Background:Hypertension is the most common modifiable risk factor for cardiovascular disease, with an increasing prevalence with age, but with easily available medications to control it. Adverse effects of these medications do limit their use, in particular hyponatremia due to thiazide and thiazide-like diuretics. This is more common in the elderly patients due to a combination of inadequate protein intake and impaired urinary dilution capability, made worse by additional thiazide use. Limiting free water intake and increasing protein intake are often not successful resulting in thiazide avoidance. Daily protein supplement is a potential option in this clinical scenario. We describe the protocol for a feasibility study to explore this option. Methods:This is a single-arm, prospective, open-label proof-of-concept trial, including elderly patients with thiazide diuretic-induced hyponatremia. Forty patients will be enrolled and receive a bottle of a protein supplement daily, providing 120 mmol of solutes and permitting an extra 163 mL free water loss, for 4 weeks. The main outcome measures will be (1) feasibility for enrollment, (2) safety of the intervention, and (3) potential efficacy of the intervention in improving hyponatremia. Secondary outcome measures will include changes in urine osmolality, body weight, and urea measurements. Discussion:Thiazide diuretic-induced hyponatremia is an important adverse effect, with significant clinical impact, such as delirium and falls, and limits the use of these potent antihypertensive agents. There are little data on the effect or safety of protein supplementation and also on whether a trial of this is feasible. The results of this proof-of-concept feasibility trial will help plan and execute a larger definitive trial to test protein supplementation as an effective strategy in this condition. Trial registration:The trial is registered with Clinical trials, registration identifier: NCT02614807.
| S-EPMC5889541 | biostudies-literature
Project description:BackgroundPrior meta-analyses measuring thiazide-induced glycemic change have demonstrated an increased risk of incident diabetes; however, this measure's definition has changed over time.AimTo determine the magnitude of change in fasting plasma glucose (FPG) for thiazide diuretics.Data sourcesA research librarian designed and conducted searches in Medline®, EMBASE, and EBM Reviews-Cochrane Central Register of Controlled Trials (inception through July 2018) and International Pharmaceutical Abstracts (inception to December 2014).Study selectionRandomized, controlled trials comparing a thiazide or thiazide-like diuretic to any comparator reporting FPG were identified. Trials enrolling < 50 participants, those with a follow-up period of < 4 weeks, and conference abstracts were excluded.Data extractionIndependent duplicate screening of citations and full-text articles, data extraction, and assessment of risk of bias was conducted.Data synthesisNinety-five studies were included (N = 76,608 participants), with thiazides compared with placebo, beta-blockers, calcium channel blockers, renin-angiotensin-aldosterone-system inhibitors, potassium-sparing diuretic, and others alone or in combination. Thiazide diuretics marginally increased FPG (weighted mean difference 0.20 mmol/L (95% CI 0.15-0.25); I2 = 84%) (1 mmol/L = 18 mg/dL). Results did not change substantially when considering dose or duration, comparing thiazides with placebo or an active comparator, or using thiazides as monotherapy or combination therapy, even when combined with a potassium-correcting agent.ConclusionThiazide diuretics have a small and clinically unimportant impact on FPG.
| S-EPMC7280437 | biostudies-literature