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1.
[Sodium metabolism: An update in 2019].
Robert, A, Cheddani, L, Ebel, A, Vilaine, E, Seidowsky, A, Massy, Z, Essig, M
Nephrologie & therapeutique. 2020;(2):77-82
Abstract
The classical theory of sodium metabolism considers mostly its role on the extracellular volume according to a daily response to the variations of salt intake, correlated to the variations of water volume. Recent works consider sodium tissular storage. This non-osmotic pool could play a role in blood pressure regulation and in immunity mechanisms. The regulation modalities could be more complex, organised over the long term, with a modification of the sodium-water relationship. The aim of this article is to give a new insight on sodium metabolism, based on recent works, especially on the role and regulation of non osmotic tissular sodium.
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Dietary potassium restriction attenuates urinary sodium wasting in the generalized form of pseudohypoaldosteronism type 1.
Adachi, M, Tajima, T, Muroya, K
CEN case reports. 2020;(2):133-137
Abstract
Owing to its rarity and severe nature, the treatment for generalized pseudohypoaldosteronism type 1 (PHA1), a genetic disorder in the epithelial sodium channel (ENaC), is exclusively experience-based. In particular, the usefulness of dietary potassium restriction in PHA1 remains unclear with the absence of theoretical background to elucidate its utility. First, we demonstrated the effect of potassium restriction in a 13-month-old patient with ENaC γ-subunit gene mutations via a retrospective chart review; reduction of daily dietary potassium intake from 40 to 20 mEq induced rapid restoration of volume depletion, as evidenced by weight gain, elevation of the serum sodium level from 133 to 141 mEq/L, decreased urinary sodium excretion, and normalized renin activity. The serum potassium level decreased from 5.6 to 4.5 mEq/L. Next, we attempted to elucidate the pathophysiological basis of the usefulness of potassium restriction, leveraged by the increased knowledge regarding the roles of with-no-lysine kinases (WNKs) in the distal nephron. When potassium is restricted, the WNK signal will turn "on" in the distal nephron via reduction in the intracellular chloride level. Consequently, the sodium reabsorption from the Na+Cl- cotransporter (NCC) in the distal convoluted tubule and possibly from pendrin in the β-intercalated cell will increase. Thus, potassium restriction causes NCC and pendrin to compensate for the non-functional ENaC in the collecting duct. In conclusion, dietary potassium restriction is one of the indispensable treatments for generalized PHA1.
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3.
Vasopressin receptor subtypes and renal sodium transport.
Natochin, YV, Golosova, DV
Vitamins and hormones. 2020;:239-258
Abstract
In mammals, three subtypes of V-receptors have been identified in the kidney. The effects of vasopressin, a hormone synthesized in the hypothalamus, are triggered by three distinct receptor isoforms: V2, V1a, and V1b. Stimulation of V2-receptors regulates urine osmotic concentration by increasing sodium reabsorption in the thick ascending limb of the loop of Henle and enhancing osmotic permeability of the epithelium cells in the collecting duct. Stimulation of V1a-receptors inhibits renal sodium reabsorption and induces natriuresis, comparable to the effect of the diuretic furosemide, in the thick ascending limb of the loop of Henle. Stimulation of V1b-receptors induces potassium secretion in the final parts of the distal segments and initial parts of the collecting ducts. In this review, we discuss the role of vasopressin and its interaction with V-receptor subtypes in natriuresis and for stabilizing the physicochemical parameters of the internal environment and water-salt homeostasis in humans. A better understanding of these systems and their regulation is necessary to facilitate identification of additional system components and mechanisms, clarify their contribution during various normal and pathological functional states, and suggest novel strategies for the development of therapeutic interventions.
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4.
Evolution and evolving resolution of controversy over existence and prevalence of cerebral/renal salt wasting.
Maesaka, JK, Imbriano, LJ, Miyawaki, N
Current opinion in nephrology and hypertension. 2020;(2):213-220
Abstract
PURPOSE OF REVIEW The topic of hyponatremia is in a state of flux. We review a new approach to diagnosis that is superior to previous methods. It simplifies identifying the causes of hyponatremia, the most important issue being the differentiation of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) from cerebral/renal salt wasting (RSW). We also report on the high prevalence of RSW without cerebral disease in the general wards of the hospital. RECENT FINDINGS We applied our new approach to hyponatremia by utilizing sound pathophysiologic criteria in 62 hyponatremic patients. Seventeen (27%) had SIADH, 19 (31%) had a reset osmostat, 24 (38%) had RSW with 21 having no evidence of cerebral disease, 1 had Addison's disease, and 1 was because of hydrochlorothiazide. Many had urine sodium concentrations (UNa) less than 30 mmol/l. SUMMARY RSW is much more common than perceived in the general wards of the hospital. It is important to change the terminology from cerebral to RSW and to differentiate SIADH from RSW. These changes will improve clinical outcomes because of divergent therapeutic goals of water-restricting in SIADH and administering salt and water to a dehydrated patient with RSW. The present review will hopefully spur others to reflect and act on the new findings and different approaches to hyponatremia.
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5.
The challenges of diagnosis and management of Gitelman syndrome.
Urwin, S, Willows, J, Sayer, JA
Clinical endocrinology. 2020;(1):3-10
Abstract
Gitelman syndrome is an inherited tubulopathy characterized by renal salt wasting from the distal convoluted tubule. Defects in the sodium chloride cotransporter (encoded by SLC12A3) underlie this autosomal recessive condition. This article focuses on the specific challenges of diagnosing and treating Gitelman syndrome, with use of an illustrative case report. Symptoms relate to decreased serum potassium and magnesium levels, which include muscle weakness, tetany, fatigue and palpitations. Sudden cardiac deaths have been reported. Making a diagnosis may be difficult given its rarity but is important. A knowledge of the serum and urine biochemical picture is vital to distinguish it from a broad differential diagnosis, and application of genetic testing can resolve difficult cases. There is a group of Gitelman syndrome heterozygous carriers that experience symptoms and electrolyte disturbance and these patients should be managed in a similar way, though here genetic investigations become key in securing a difficult diagnosis. Potassium and magnesium replacement is the cornerstone of treatment, though practically this can be hard for patients to manage and often does not fully relieve symptoms even when serum levels are normalized. Challenges arise due to the lack of randomized controlled trials focussing on treatment of this rare disease; hence, clinicians endorse strategies in line with correction of the underlying pathophysiology such as sodium loading or pharmacological treatments, which seem to help some patients. Focussed dietary advice and knowing the best tolerated preparations of potassium and magnesium medications are useful tools for the physician, as well as an awareness of the specific burdens that this patient group face in order to signpost appropriate support.
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6.
Clinical impact of tissue sodium storage.
Olde Engberink, RHG, Selvarajah, V, Vogt, L
Pediatric nephrology (Berlin, Germany). 2020;(8):1373-1380
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Abstract
In recent times, the traditional nephrocentric, two-compartment model of body sodium has been challenged by long-term sodium balance studies and experimental work on the dermal interstitium and endothelial surface layer. In the new paradigm, sodium can be stored without commensurate water retention in the interstitium and endothelial surface layer, forming a dynamic third compartment for sodium. This has important implications for sodium homeostasis, osmoregulation and the hemodynamic response to salt intake. Sodium storage in the skin and endothelial surface layer may function as a buffer during periods of dietary depletion and excess, representing an extra-renal mechanism regulating body sodium and water. Interstitial sodium storage may also serve as a biomarker for sodium sensitivity and cardiovascular risk, as well as a target for hypertension treatment. Furthermore, sodium storage may explain the limitations of traditional techniques used to quantify sodium intake and determine infusion strategies for dysnatraemias. This review is aimed at outlining these new insights into sodium homeostasis, exploring their implications for clinical practice and potential areas for further research for paediatric and adult populations.
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Thiazide-Associated Hyponatremia: Clinical Manifestations and Pathophysiology.
Filippone, EJ, Ruzieh, M, Foy, A
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2020;(2):256-264
Abstract
Hyponatremia can complicate thiazide use in a minority of susceptible individuals and can result in significant morbidity and even mortality. Risk factors for thiazide-associated hyponatremia include age, female sex, and possibly low body mass. A genetic susceptibility has recently been uncovered. Although frequently developing early after thiazide treatment initiation, many cases of hyponatremia present after months or years of use. Many cases are asymptomatic or have mild symptoms, but seizures and/or coma may develop, especially in those with acute onset. The pathophysiology is incompletely understood and includes some combination of excessive fluid intake, cation (sodium and potassium) depletion, osmotic inactivation of sodium, and reduced ability to excrete free water. Reduced distal delivery of filtrate, reduced solute load (urea), direct inhibition of the sodium-chloride cotransporter, and increased collecting duct permeability to water mediated by some combination of antidiuretic hormone, prostaglandins, and thiazides themselves may contribute to this diluting defect. The predominant pathophysiologic mechanism(s) varies from patient to patient. The cornerstone of therapy is cessation of thiazide use, cation repletion, and oral fluid restriction. If severely symptomatic, 3% saline solution may be indicated. Overly rapid correction of chronic hyponatremia must be avoided in all cases.
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Expansion of the "Sodium World" through Evolutionary Time and Taxonomic Space.
Kozlova, MI, Bushmakin, IM, Belyaeva, JD, Shalaeva, DN, Dibrova, DV, Cherepanov, DA, Mulkidjanian, AY
Biochemistry. Biokhimiia. 2020;(12):1518-1542
Abstract
In 1986, Vladimir Skulachev and his colleagues coined the term "Sodium World" for the group of diverse organisms with sodium (Na)-based bioenergetics. Albeit only few such organisms had been discovered by that time, the authors insightfully noted that "the great taxonomic variety of organisms employing the Na-cycle points to the ubiquitous distribution of this novel type of membrane-linked energy transductions". Here we used tools of bioinformatics to follow expansion of the Sodium World through the evolutionary time and taxonomic space. We searched for those membrane protein families in prokaryotic genomes that correlate with the use of the Na-potential for ATP synthesis by different organisms. In addition to the known Na-translocators, we found a plethora of uncharacterized protein families; most of them show no homology with studied proteins. In addition, we traced the presence of Na-based energetics in many novel archaeal and bacterial clades, which were recently identified by metagenomic techniques. The data obtained support the view that the Na-based energetics preceded the proton-dependent energetics in evolution and prevailed during the first two billion years of the Earth history before the oxygenation of atmosphere. Hence, the full capacity of Na-based energetics in prokaryotes remains largely unexplored. The Sodium World expanded owing to the acquisition of new functions by Na-translocating systems. Specifically, most classes of G-protein-coupled receptors (GPCRs), which are targeted by almost half of the known drugs, appear to evolve from the Na-translocating microbial rhodopsins. Thereby the GPCRs of class A, with 700 representatives in human genome, retained the Na-binding site in the center of the transmembrane heptahelical bundle together with the capacity of Na-translocation. Mathematical modeling showed that the class A GPCRs could use the energy of transmembrane Na-potential for increasing both their sensitivity and selectivity. Thus, GPCRs, the largest protein family coded by human genome, stem from the Sodium World, which encourages exploration of other Na-dependent enzymes of eukaryotes.
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Diagnosis and Management of Disorders of Body Tonicity-Hyponatremia and Hypernatremia: Core Curriculum 2020.
Seay, NW, Lehrich, RW, Greenberg, A
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2020;(2):272-286
Abstract
Overall body fluid concentration is regulated within a narrow range by the concerted action of the hypothalamic-pituitary axis to influence water intake through thirst and water excretion via the effect of vasopressin, or antidiuretic hormone, on renal collecting duct water permeability. Sodium is the principal extracellular cation; abnormalities in overall effective body fluid concentration, or tonicity, manifest as disturbances in serum sodium concentration. Depending on its severity and chronicity, hyponatremia can lead to significant symptoms, primarily related to central nervous system function. Failure to correct hyponatremia can lead to permanent neurologic damage, as can over rapid correction. It is thus essential to stay within specific limits for correction, particularly for chronic hyponatremia. Hypernatremia also leads to central nervous system dysfunction, although goals for its correction rate are less well established. This Core Curriculum article discusses the normal regulation of tonicity and serum sodium concentration and the diagnosis and management of hypo- and hypernatremia.
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10.
Sodium, volume and pressure control in haemodialysis patients for improved cardiovascular outcomes.
Pinter, J, Chazot, C, Stuard, S, Moissl, U, Canaud, B
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(Suppl 2):ii23-ii30
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Abstract
Chronic volume overload is pervasive in patients on chronic haemodialysis and substantially increases the risk of cardiovascular death. The rediscovery of the three-compartment model in sodium metabolism revolutionizes our understanding of sodium (patho-)physiology and is an effect modifier that still needs to be understood in the context of hypertension and end-stage kidney disease. Assessment of fluid overload in haemodialysis patients is central yet difficult to achieve, because traditional clinical signs of volume overload lack sensitivity and specificity. The highest all-cause mortality risk may be found in haemodialysis patients presenting with high fluid overload but low blood pressure before haemodialysis treatment. The second highest risk may be found in patients with both high blood pressure and fluid overload, while high blood pressure but normal fluid overload may only relate to moderate risk. Optimization of fluid overload in haemodialysis patients should be guided by combining the traditional clinical evaluation with objective measurements such as bioimpedance spectroscopy in assessing the risk of fluid overload. To overcome the tide of extracellular fluid, the concept of time-averaged fluid overload during the interdialytic period has been established and requires possible readjustment of a negative target post-dialysis weight. 23Na-magnetic resonance imaging studies will help to quantitate sodium accumulation and keep prescribed haemodialytic sodium mass balance on the radar. Cluster-randomization trials (e.g. on sodium removal) are underway to improve our therapeutic approach to cardioprotective haemodialysis management.