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1.
Bartter and Gitelman syndromes: Questions of class.
Besouw, MTP, Kleta, R, Bockenhauer, D
Pediatric nephrology (Berlin, Germany). 2020;(10):1815-1824
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Abstract
Bartter and Gitelman syndromes are rare inherited tubulopathies characterized by hypokalaemic, hypochloraemic metabolic alkalosis. They are caused by mutations in at least 7 genes involved in the reabsorption of sodium in the thick ascending limb (TAL) of the loop of Henle and/or the distal convoluted tubule (DCT). Different subtypes can be distinguished and various classifications have been proposed based on clinical symptoms and/or the underlying genetic cause. Yet, the clinical phenotype can show remarkable variability, leading to potential divergences between classifications. These problems mostly relate to uncertainties over the role of the basolateral chloride exit channel CLCNKB, expressed in both TAL and DCT and to what degree the closely related paralogue CLCNKA can compensate for the loss of CLCNKB function. Here, we review what is known about the physiology of the transport proteins involved in these disorders. We also review the various proposed classifications and explain why a gene-based classification constitutes a pragmatic solution.
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Association Between Estimated 24-h Urinary Sodium Excretion and Metabolic Syndrome in Korean Adults: The 2009 to 2011 Korea National Health and Nutrition Examination Survey.
Won, JC, Hong, JW, Noh, JH, Kim, DJ
Medicine. 2016;(15):e3153
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Abstract
High sodium intake is 1 of the modifiable risk factors for cardiovascular disease, but in Korea, daily sodium intake is estimated to be double the level recommended by World Health Organization. We investigated the association between the estimated 24-h urinary sodium excretion (24hUNaE) and metabolic syndrome using nationwide population data. In total, 17,541 individuals (weighted n = 33,200,054; weighted men, 52.5% [95% confidence interval, CI = 51.8-53.3]; weighted age, 45.2 years [44.7-45.7]) who participated in the Korean Health and Nutrition Examination Survey 2009 to 2011 were investigated. NCEP-ATP III criteria for metabolic syndrome were used, and sodium intake was estimated by 24hUNaE using Tanaka equation with a spot urine sample. The weighted mean 24hUNaE values were 3964 mg/d (95% CI = 3885-4044) in men and 4736 mg/d (4654-4817) in women. The weighted age-adjusted prevalence of metabolic syndrome was 22.2% (21.4-23.0), and it increased with 24hUNaE quartile in both men and women (mean ± standard error of the mean; men: 22.5 ± 1.0%, 23.0 ± 1.0%, 26.0 ± 1.2%, and 26.0 ± 1.2%; P = 0.026; women: 19.4 ± 0.8%, 17.7 ± 0.8%, 19.8 ± 1.0%, and 23.0 ± 1.1%; P = 0.002, for quartiles 1-4, respectively). Even after adjustment for age, daily calorie intake, heavy alcohol drinking, regular exercise, college graduation, and antihypertensive medication, the weighted prevalence of metabolic syndrome increased with the increase in 24hUNaE in men and women. The weighted 24hUNaE was positively associated with the number of metabolic syndrome components after adjustment for confounding factors in men and women. In subjects without antihypertensive medication, the odds ratio for metabolic syndrome in quartile 4 of 24hUNaE compared with quartile 1 was 1.56 (1.33-1.84, P < 0.001) in the total population, 1.66 (1.34-2.06, P < 0.001) in men, and 1.94 (1.49-2.53, P < 0.001) in women. In this nationwide population study, we observed a significant independent association between high sodium intake, estimated by spot urine sodium excretion, and the presence of metabolic syndrome in men and women.
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Correction of hyponatremia and osmotic demyelinating syndrome: have we neglected to think intracellularly?
Pham, PM, Pham, PA, Pham, SV, Pham, PT, Pham, PT, Pham, PC
Clinical and experimental nephrology. 2015;(3):489-95
Abstract
BACKGROUND Osmotic demyelination syndrome (ODS) is a complication generally associated with overly rapid correction of hyponatremia. Traditionally, nephrologists have been trained to focus solely on limiting the correction rate. However, there is accumulating evidence to suggest that the prevention of ODS is beyond achieving slow correction rates. METHODS We (1) reviewed the literature for glial intracellular protective alterations during hyperosmolar stress, a state presumed equivalent to the rapid correction of hyponatremia, and (2) analyzed all available hyponatremia-associated ODS cases from PubMed for possible contributing factors including correction rates and concurrent metabolic disturbances involving hypokalemia, hypophosphatemia, hypomagnesemia, and/or hypoglycemia. RESULTS In response to acute hyperosmolar stress, glial cells undergo immediate extracellular free water shift, followed by active intracellular Na(+), K(+) and amino acid uptake, and eventual idiogenic osmoles synthesis. At minimum, protective mechanisms require K(+), Mg(2+), phosphate, amino acids, and glucose. There were 158 cases of hyponatremia-associated ODS where both correction rates and other metabolic factors were documented. Compared with the rapid correction group (>0.5 mmol/L/h), the slow correction group (≤0.5 mmol/L/h) had a greater number of cases with concurrent hypokalemia (49.4 vs. 33.3 %, p = 0.04), and a greater number of cases with any concurrent metabolic derangements (55.8 vs. 38.3 %, p = 0.03). CONCLUSION Glial cell minimizes volume changes and injury in response to hyperosmolar stress via mobilization and/or utilization of various electrolytes and metabolic factors. The prevention of ODS likely requires both minimization of correction rate and optimization of intracellular response during the correction phase when a sufficient supply of various factors is necessary.
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Atrial natriuretic peptide and renal dopaminergic system: a positive friendly relationship?
Choi, MR, Rukavina Mikusic, NL, Kouyoumdzian, NM, Kravetz, MC, Fernández, BE
BioMed research international. 2014;:710781
Abstract
Sodium metabolism by the kidney is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Renal dopamine plays a central role in this interactive network. The natriuretic hormones, such as the atrial natriuretic peptide, mediate some of their effects by affecting the renal dopaminergic system. Renal dopaminergic tonus can be modulated at different steps of dopamine metabolism (synthesis, uptake, release, catabolism, and receptor sensitization) which can be regulated by the atrial natriuretic peptide. At tubular level, dopamine and atrial natriuretic peptide act together in a concerted manner to promote sodium excretion, especially through the overinhibition of Na+, K+-ATPase activity. In this way, different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome or hypertension, are associated with impaired action of renal dopamine and/or atrial natriuretic peptide, or as a result of impaired interaction between these two natriuretic systems. The aim of this review is to update and comment on the most recent evidences demonstrating how the renal dopaminergic system interacts with atrial natriuretic peptide to control renal physiology and blood pressure through different regulatory pathways.
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Monogenic forms of hypertension.
Simonetti, GD, Mohaupt, MG, Bianchetti, MG
European journal of pediatrics. 2012;(10):1433-9
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Abstract
Arterial hypertension in childhood is less frequent as compared to adulthood but is more likely to be secondary to an underlying disorder. After ruling out more obvious causes, some patients still present with strongly suspected secondary hypertension of yet unknown etiology. A number of these children have hypertension due to single gene mutations inherited in an autosomal dominant or recessive fashion. The finding of abnormal potassium levels (low or high) in the presence of suppressed renin secretion, and metabolic alkalosis or acidosis should prompt consideration of these familial diseases. However, mild hypertension and the absence of electrolyte abnormalities do not exclude hereditary conditions. In monogenic hypertensive disorders, three distinct mechanisms leading to the common final pathway of increased sodium reabsorption, volume expansion, and low plasma renin activity are documented. The first mechanism relates to gain-of-function mutations with a subsequent hyperactivity of renal sodium and chloride reabsorption leading to plasma volume expansion (e.g., Liddle's syndrome, Gordon's syndrome). The second mechanism involves deficiencies of enzymes that regulate adrenal steroid hormone synthesis and deactivation (e.g., subtypes of congenital adrenal hyperplasia, apparent mineralocorticoid excess (AME)). The third mechanism is characterized by excessive aldosterone synthesis that escapes normal regulatory mechanisms and leading to volume-dependent hypertension in the presence of suppressed renin release (glucocorticoid remediable aldosteronism). Hormonal studies coupled with genetic testing can help in the early diagnosis of these disorders.
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Salt excretion in normotensive individuals with metabolic syndrome: a population-based study.
Rodrigues, SL, Baldo, MP, de Sá Cunha, R, Andreão, RV, Del Carmen Bisi Molina, M, Gonçalves, CP, Dantas, EM, Mill, JG
Hypertension research : official journal of the Japanese Society of Hypertension. 2009;(10):906-10
Abstract
The objective of this study was to investigate the association between sodium intake and metabolic syndrome (MS) in individuals free from the confounding effects of increased blood pressure (BP). In all, a total of 1655 individuals (45.8% men) who participated in the MONICA-WHO/Vitoria Project, mean age 45+/-11 years were investigated. According to NCEP-ATP lll criteria, MS prevalence was 32.9 and 85% of these individuals had BP >130/85 mm Hg. Thus, high BP represents the main MS risk factor. Twelve-hour nocturnal urine (1900 to 0700 hours) was used to measure urinary sodium and potassium excretion. Sodium excretion was associated with BP. From the optimal BP level up to stage lll hypertension, the mean (median) sodium excretion increased from 99 (89) to 128 (134) mEq and from 81 (69) to 112 (103) mEq in men and women, respectively (P<0.001 for trend; median). However, when 781 individuals with BP <130/85 mm Hg (including 80 drug-free normotensive individuals with MS) were stratified according to the gender and number of MS components, no significant differences were observed either in the urinary volume or in the sodium or potassium excretion. For each of the four MS components, sodium excretion was 96+/-48, 97+/-53, 108+/-65 and 97+/-49 mEq for men, and 83+/-51, 83+/-58, 80+/-49 and 93+/-45 mEq for women, respectively. No differences were found in urinary sodium excretion in normotensive individuals, regardless of the presence of MS. Therefore, it seems that high sodium intake is not an MS predictor per se as suggested earlier.
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Inherited sodium avid states.
Achard, JM, Hadchouel, J, Faure, S, Jeunemaitre, X
Advances in chronic kidney disease. 2006;(2):118-23
Abstract
Several familial forms of hypertension have been identified, in which the mendelian pattern of inheritance indicated that hypertension results from the alteration of a single gene. This short review focuses on those rare monogenic disorders characterized by a low-renin profile. This common feature reflects that the causative mutations responsible for these disorders all result in an excessive sodium reabsorption in the aldosterone-dependent nephron. Low-renin familial hypertensions with hypokalemia encompass familial hyperaldosteronisms, in which aldosterone levels are elevated, and familial pseudohyperaldosteronisms, mimicking aldosteronism despite appropriately suppressed aldosterone levels. In these disorders, the avidity of the kidney for sodium is because of dysregulated sodium reabsorption through the epithelial sodium channel ENaC and results in potassium wasting and metabolic alcalosis. Familial hypertension with hyperkalemia is a specific syndrome resulting from mutations in at least 3 different genes, among which 2 have been recently identified. These genes encode members of a new family of kinase, the WNK kinases, involved in the regulation of sodium and potassium excretion by the kidney.
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Abnormalities of renal sodium handling in the metabolic syndrome. Results of the Olivetti Heart Study.
Strazzullo, P, Barbato, A, Galletti, F, Barba, G, Siani, A, Iacone, R, D'Elia, L, Russo, O, Versiero, M, Farinaro, E, et al
Journal of hypertension. 2006;(8):1633-9
Abstract
OBJECTIVE The mechanisms underlying high blood pressure in the framework of metabolic syndrome (MS) are not clarified: we thus analyzed the relationship of MS and its components to renal tubular sodium handling among participants of the Olivetti Heart Study, an epidemiological investigation of a representative sample of adult white male population in southern Italy. METHODS Proximal (FPRNa) and distal (FDRNa) fractional sodium reabsorption were estimated by the clearance of exogenous lithium in 702 participants aged 25-75 years examined in 1994-1995. Blood pressure and relevant anthropometric and biochemical variables were also measured. The diagnosis of MS was based on modified National Cholesterol Education Program (NCEP)-Adult Treatment Panel III (ATP III) criteria. RESULTS FPRNa, but not FDRNa, was directly associated with body mass index (BMI), waist circumference, diastolic pressure, serum triglyceride and uric acid, independently of age and of antihypertensive treatment. After adjustment for age, FPRNa, but not FDRNa, was significantly greater in individuals with MS, as compared to those without [77.6% (95% confidence interval = 76.7-80.1) versus 74.4% (73.7-75.1), P < 0.001]. A similar difference was observed after the exclusion of participants on current antihypertensive treatment (P = 0.018). In untreated individuals, a significant interaction was observed between obesity and insulin resistance as related to FPRNa (P = 0.002): the highest age-adjusted levels of FPRNa were detected in obese hypertensive and obese insulin-resistant participants. CONCLUSION In this sample of an adult male population, MS was associated with an increased rate of FPRNa. This finding is relevant to the pathophysiology of MS and possibly to the prevention of its cardiovascular and renal consequences.
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Renal sodium handling study in an atypical case of Bartter's syndrome associated with mitochondriopathy and sensorineural blindness.
Menegon, LF, Amaral, TN, Gontijo, JA
Renal failure. 2004;(2):195-7
Abstract
Bartter's syndrome is a disorder that has been linked to mutations in one of three ion transporter proteins: NKCC2 (type I), ROMK (type II) and CCLNKB (type III), which affects a final common pathway that participates in ion transport by thick ascending limb cells. We present an atypical case of mitochondriopathy combined with tubule functional disturbances compatible with Bartter's syndrome and definitive sensorineural blindness. Our patient had a peculiar clinical presentation with signs of salt and volume depletion, low blood pressure and secondary hyperaldosteronism, associated with hypokalemic metabolic alkalosis, hypocalcemia and severe hypomagnesemia, uncommon in genetic forms of Bartter's syndrome. The enhanced absolute and fractional sodium excretion in our patient compared to volunteers was accompanied by increased post-proximal sodium rejection, suggesting a striking ion transport dysfunction in these nephron segments. These findings lead to the Bartter's syndrome diagnosis, accompanied by a suppose mitochondrial tick ascending loop of Henle epithelium dysfunction that may reflect the high energy supplied by mitochondria electron transport chain, required for this nephron segment to maintain normal ion transport.
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10.
Disorders of body water homeostasis.
Verbalis, JG
Best practice & research. Clinical endocrinology & metabolism. 2003;(4):471-503
Abstract
Disorders of body fluids are among the most commonly encountered problems in the practice of clinical medicine. This is in large part because many different disease states can potentially disrupt the finely balanced mechanisms that control the intake and output of water and solute. It therefore behoves clinicians treating such patients to have a good understanding of the pathophysiology, the differential diagnosis and the management of these disorders. Because body water is the primary determinant of the osmolality of the extracellular fluid, disorders of body water homeostasis can be divided into hypo-osmolar disorders, in which there is an excess of body water relative to body solute, and hyperosmolar disorders, in which there is a deficiency of body water relative to body solute. The classical hyperosmolar disorder is diabetes insipidus (DI), and the classical hypo-osmolar disorder is the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This chapter first reviews the regulatory mechanisms underlying water and sodium metabolism, the two major determinants of body fluid homeostasis. The major disorders of water metabolism causing hyperosmolality and hypo-osmolality, DI and SIADH, are then discussed in detail, including the pathogenesis, differential diagnosis and treatment of these disorders.