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The Nature of Renal Function
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
About 5% to 8% of filtered sodium is reabsorbed in the DCT. Apical sodium entry in this segment takes place via an electroneutral, thiazide-sensitive Na+-Cl− cotransporter (TSC). The gene is SLC12A3, located at 16q12–13. Mutations of this gene cause Gitelman’s syndrome, a variant of Bartter’s syndrome distinguished from the classical forms by milder clinical course, hypocalciuria and hypomagnesemia (59). As would be expected, inhibition of the TSC by thiazide diuretics mimics the features of Gitelman’s syndrome precisely. Because much less sodium is reabsorbed by the TSC than by NKCC2, thiazides are much weaker diuretics than loop diuretics. However, if a loop diuretic [such as furosemide (frusemide)] and a thiazide (such as metolazone) are used together, the two effects reinforce one another and massive diuresis results.
Novel mutations of the SLC12A3 gene in patients with Gitelman syndrome
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2021
Feng Wang, Manli Guo, Jing Li, Shaogang Ma
Gitelman syndrome (GS, OMIM 263800) is an autosomal recessive salt-wasting tubulopathy characterized by hypokalemia, hypomagnesemia and hypocalciuria. The disease is caused by inactivating mutations in the SLC12A3 gene, which is located on the long arm of chromosome 16 (16q13) and encodes a thiazide-sensitive sodium chloride cotransporter (NCC). GS is a hereditary disorder of potassium homeostasis without secondary hypertension. Although the long-term prognosis is considered to be favorable, hypokalemia is difficult to cure. Genetic research has become important in diagnosing GS [1–3].
The patient with metabolic alkalosis
Published in Acta Clinica Belgica, 2019
Valentine Gillion, Michel Jadoul, Olivier Devuyst, Jean-Michel Pochet
Na+ avidity in the collecting duct may primarily be increased through activation of the apical Na+ channel (ENaC), or secondarily through hyperaldosteronism either primary (Conn’s adenoma, adrenal hyperplasia, adrenal carcinoma) or secondary such as renal artery stenosis, renin secreting tumor, malignant hypertension, renal infarction, salt-losing tubulopathies including Bartter (Table 1) and Gitelman syndrome (SLC12A3; MIM# 263,800) or their phenocopy due to diuretics.
Molecular aspects of the altered Angiotensin II signaling in Gitelman’s syndrome
Published in Expert Opinion on Orphan Drugs, 2022
Verdiana Ravarotto, Giovanni Bertoldi, Lucia Federica Stefanelli, Laura Gobbi, Lorenzo A. Calò
GS is a rare inherited salt-wasting tubulopathy first described in 1966 as a familial disorder characterized by electrolytic alterations with concomitant hypomagnesemia and hypokalemia [3]. It is cataloged in the registry of the inherited rare Mendelian diseases (Online Mendelian Inherited In Man® – OMIM) with the code #263800; however, its estimated prevalence of 1:40000 makes it one of the most frequently inherited renal tubular disorders [4], and it is expected that a further portion of the population is affected by the syndrome without being aware [5]. The clinical characteristics and the severity of biochemical abnormalities reflect a gene-specific pattern: the etiology of GS is determined, in fact, by mutations in a gene that encodes for a cotransporter involved in the trafficking of electrolytes in the distal convoluted tubules (DCT) of the nephrons, the sodium chloride cotransporter (NCC). GS typical clinical features are saltcraving, muscle weakness, fatigue, and cramps with electrolyte imbalance associated with the side effects of treatment with thiazide diuretics that target the DCT specifically. The cloning and characterization of the gene SLC12A3 encoding for the NCC showed, in fact, that several mutations can be detected in GS patients impairing NCC function with ensuing sodium wasting and the activation of adaptive mechanisms such as the aldosterone-driven increased excretion of K+ in exchange for Na+ through the epithelial sodium channel (ENaC) [6–8]. Specifically, in the early portion of the DCT, the transport of Na+ is electrogenic for the concomitant release of Cl− through the NCC, while, in the late portion of the distal convoluted tubules (DCT2), the activation of the ENaC leaves a negative charge in the lumen in order to restore the water balance [9]. As a counterpart, to reestablish the neutral charge, the renal outer medullary potassium channel (ROMK) drives out K+-inducing hypokalemia. Hypocalciuria, besides hypokalemia, is another feature of GS [10]. Experimental evidence showed that specific mice lacking Ca2+ (TRPV5) channels in the early DCT have enhanced passive Ca2+ transport in the proximal tubule as a compensatory mechanism. This process is likely a response to the extracellular volume contraction arising from Na+ wasting in the DCT [11]. Studies on SLC12A3 knockout mice showed that they exhibit extracellular volume contraction and increased Na resorption in the proximal tubule [12]. Hypovolemia is therefore responsible for increased proximal Na+ reabsorption enhancing an electric gradient that drives passive Ca2+ transport in the proximal tubular segments [9]. Parallel to hypocalciuria, another characteristic of GS which resembles the chronic stimulation with thiazides is hypomagnesemia, likely due to reduced expression of the epithelial Mg2+ channels (TRPM6) in the DCT as it has been observed in animals lacking NCC [11]. This further supports the evidence that impaired function of the NCC leads to major structural remodeling of the distal convoluted tubule.