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      A man with a worrying potassium deficiency

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          Summary

          Hypokalaemia may present as muscle cramps and Cardiac arrhythmias. This is a condition commonly encountered by endocrinologists and general physicians alike. Herein, we report the case of a 43-year-old gentleman admitted with hypokalaemia, who following subsequent investigations was found to have Gitelman's syndrome (GS). This rare, inherited, autosomal recessive renal tubular disorder is associated with genetic mutations in the thiazide-sensitive sodium chloride co-transporter and magnesium channels in the distal convoluted tubule. Patients with GS typically presents at an older age, and a spectrum of clinical presentations exists, from being asymptomatic to predominant muscular symptoms. Clinical suspicion should be raised in those with hypokalaemic metabolic alkalosis associated with hypomagnesaemia. Treatment of GS consists of long-term potassium and magnesium salt replacement. In general, the long-term prognosis in terms of preserved renal function and life expectancy is excellent. Herein, we discuss the biochemical imbalance in the aetiology of GS, and the case report highlights the need for further investigations in patients with recurrent hypokalaemic episodes.

          Learning points

          • Recurrent hypokalaemia with no obvious cause warrants investigation for hereditary renal tubulopathies.

          • GS is the most common inherited renal tubulopathy with a prevalence of 25 per million people.

          • GS typically presents at an older age and clinical suspicion should be raised in those with hypokalaemic metabolic alkalosis associated with hypomagnesaemia.

          • Confirmation of diagnosis is by molecular analysis for mutation in the SLC12A3 gene.

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          Most cited references8

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          Transgenic RNAi depletion of claudin-16 and the renal handling of magnesium.

          Tight junctions play a key role in mediating paracellular ion reabsorption in the kidney. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a human disorder caused by mutations in the tight junction protein claudin-16. However, the molecular mechanisms underlining the renal handling of magnesium and its dysfunction causing FHHNC are unknown. Here we show that claudin-16 plays a key role in maintaining the paracellular cation selectivity of the thick ascending limbs of the nephron. Using RNA interference, we have generated claudin-16-deficient mouse models. Claudin-16 knock-down (KD) mice exhibit chronic renal wasting of magnesium and calcium and develop renal nephrocalcinosis. Our data suggest that claudin-16 forms a non-selective paracellular cation channel, rather than a selective Mg(2+)/Ca(2+) channel as previously proposed. Our study highlights the pivotal importance of the tight junction in renal control of ion homeostasis and provides answer to the pathogenesis of FHHNC. We anticipate our study to be a starting point for more sophisticated in vivo analysis of tight junction proteins in renal functions. Furthermore, tight junction proteins could be major targets of drug development for electrolyte disorders.
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            Thiazide treatment of rats provokes apoptosis in distal tubule cells.

            We studied the effects of inhibition of apical NaCl entry on the structural correlates for electrolyte transport in the distal convoluted tubule (DCT) of rats. Thiazide diuretics were used to block NaCl entry specifically in the DCT. Metolazone or hydrochlorothiazide (HCTZ) were applied for three days subcutaneously via osmotic minipumps. The renal epithelial structure of control and treated rats was studied by light and electron microscopy. Distribution of the thiazide-sensitive NaCl cotransporter (rTSC1), calbindin D28K and Ca(2+)-Mg(2+)-ATPase was examined by immunohistochemistry, and the content of rTSC1 transcripts by Northern blot and in situ hybridization. In treated rats the DCT epithelium had lost the structural characteristics of electrolyte transporting epithelia and the cells were in different stages of apoptosis. In damaged cells calbindin D28K and Ca(2+)-Mg(2+)-ATPase were strongly decreased; the rTSC1 was shifted from the luminal membrane to the basal cell half and was found additionally in small membrane vesicles in intercellular and peritubular spaces. Transcripts of rTSC1 were drastically reduced in homogenates of kidney cortex and almost absent in damaged DCT cells. All other tubular segments were unaffected by the treatment. Focal inflammatory infiltrates were found to be specifically surrounding DCT profiles. Thus, inhibition by thiazides of apical NaCl entry into DCT cells is associated with apoptosis of DCT cells and focal peritubular inflammation.
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              Gitelman syndrome: pathophysiological and clinical aspects.

              Giltelman syndrome (GS) is a recessive salt-losing tubulopathy of children or young adults caused by a mutation of genes encoding the human sodium chloride cotransporters and magnesium channels in the thiazide-sensitive segments of the distal convoluted tubule. The plasma biochemical picture is characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis and hypereninemic hyperaldosteronism. However, patients with GS present some clinical and biochemical alterations resembling that observed in thiazide diuretics abuse. On the pathophysiological point of view, GS represents a useful and interesting human model to better understand the clinical consequences of plasma hydro-electrolytes and acid-base derangements, associated with multiple hormonal alterations. The impact of this complex disorder involves cardiovascular, muscle-skeletal and some other physiological functions, adversely affecting the patient's quality of life. This review tries to summarize and better explain the linkage between the electrolytes, neurohormonal derangements and clinical picture. Moreover, the differential diagnosis between other similar electrolyte-induced clinical disorders and GS is also discussed.
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                Author and article information

                Journal
                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                edm
                EDM Case Reports
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                2052-0573
                01 February 2014
                2014
                : 2014
                : 130067
                Affiliations
                [1 ]Diabetes and Endocrinology Cardiff and Vale NHS Trust Penlan Road, Penarth, CF64 2XX, Cardiff, CF14 4BGUK
                [2 ]Biochemistry Cardiff and Vale NHS Trust Penlan Road, Penarth, Cardiff CF64 2XXUK
                Author notes
                Correspondence should be addressed to A Tabasum Email: arshiyanaveed@ 123456yahoo.co.in
                Article
                EDM130067
                10.1530/EDM-13-0067
                3965273
                2750ee31-a9d3-4de2-b1da-feac99f5b0cb
                © 2014 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.

                History
                : 25 December 2013
                : 10 January 2014
                Categories
                Unique/Unexpected Symptoms or Presentations of a Disease

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