DIVERSIFIED RENAL TUBULAR EPITHELIAL REMODELING AND WATER BALANCE IN GITELMAN'S SYNDROME AND THIAZIDE-TREATED HYPERTENSIVE PATIENTS

Abstract Background Gitelman's syndrome (GS) is a rare salt-losing renal tubular disorder associated with SLC12A3 gene mutations, which encodes the Na-Cl co-transporter (NCCT). GS is characterized by hypokalaemic metabolic alkalosis, hypomagnesemia, hypocalciuria and elevated renin-angiotensin-aldosterone (RAA) level. The variability of phenotypes is likely to be associated with the variety of SLC12A3 mutations. Methods In this study, we reported the clinical features and the genetic analysis of a GS family pedigree. Results We identified novel mutations of SLC12A3 , with c.433 C>T (p.Arg145Cys), c.1077 C>G (p.Asn359Lys), and c.1666 C>T (p.Pro556Ser). The proband exhibited hypokalaemia, hypomagnesemia, metabolic alkalosis, but hypercalcuria and kidney stone. The increased urinary calcium excretion made it confused to Bartter's syndrome (BS). The persistent renal potassium wasting associated renal tubular lesions finally affected urinary calcium reabsorption, leading to the increased calcium excretion. Genetic analysis revealed mutations of SLC12A3 with C433T (Arg145Cys, Het), C1077G (Asn359Lys, Het), and C1666T (Pro556Ser, Het). Those missense mutations led to the predicted amino acid change, caused differences of NCCT protein structures and function. One sister of the proband carried the same mutant sites, however, exhibited milder phenotypes including hypokalemia, hypomagnesemia, RAAS activation, but not elevated urinary calcium excretion. With administration of antisterone, potassium chloride and magnesium supplement, the serum potassium and magnesium were maintained in normal ranges. Conclusions In this study, we identified the novel mutations of SLC12A3 and the varieties of clinical features. Further efforts are needed to investigate the diversity in clinical manifestations of GS and its correlation with SLC12A3 mutations.

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Coexistence of normotensive primary aldosteronism in two patients with Gitelman's syndrome and novel thiazide-sensitive Na–Cl cotransporter mutations

Acta Endocrinologica ◽

10.1530/eje-09-0271 ◽

2009 ◽

Vol 161 (2) ◽

pp. 275-283 ◽

Cited By ~ 12

Author(s):

Zhimin Miao ◽

Yufang Gao ◽

René J M Bindels ◽

Wendong Yu ◽

Yanhua Lang ◽

...

Keyword(s):

Primary Aldosteronism ◽

Secondary Hypertension ◽

Control Group ◽

Protective Mechanism ◽

Missense Mutations ◽

Loss Of Function ◽

Functional Studies ◽

Gitelman's Syndrome ◽

Causal Genes ◽

Renal Tubular

BackgroundPrimary aldosteronism (PA) is the most common form of secondary hypertension, while Gitelman's syndrome (GS) is the most common inherited renal tubular disease. However, coexistence of these two diseases has never been previously reported.Aim and subjectsThe aim of our study was to describe the association of GS and PA in two unrelated patients and compare their clinical presentation with a group of patients with GS.MethodsTen subjects suspected to have only GS were assigned to the control group. Saline infusion test was used to confirm the diagnosis of PA. GS was confirmed by sequencing of the causal genes (SLC12A3 and CLCNKB) and functional analyses in Xenopus laevis oocytes.ResultsConfirmatory tests, gene analysis, and functional studies demonstrated the coexistence of GS and PA in both patients. In total, nine novel SLC12A3 gene variants, including seven missense mutations, one splice mutation, and one frameshift deletion, were found in 12 subjects. Four mutations (p.T60M, p.T304M, p.T465P, and p.N611T) harbored by the two patients with both PA and GS were revealed to be loss-of-function variants. Although both patients were normotensive, neither of them had normal nocturnal dip.ConclusionsTwo rare diseases GS and PA may occasionally coexist in one subject. In these patients, salt depletion and volume constriction might explain the absence of hypertension normally seen in PA patients. However, the protective mechanism against hypertension via down-regulation of renal sodium handling was probably not sufficient in those patients, since their normal circadian rhythm of blood pressure was disrupted.

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Studies on the Influence of Salt and Water Balance and Blood Pressure Regulation in Hypertensive Patients

Hypertension: Mechanisms and Management - International Boehringer Mannheim Symposia ◽

10.1007/978-3-642-67712-0_21 ◽

1980 ◽

pp. 219-227

Author(s):

H. Liebau ◽

M. Hilfenhaus ◽

O. Schober ◽

P. Mariss

Keyword(s):

Blood Pressure ◽

Water Balance ◽

Blood Pressure Regulation ◽

Pressure Regulation ◽

Hypertensive Patients ◽

Salt And Water Balance

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Gitelman's Syndrome: An unusual cause of Recurrent Attack of Quadriparesis

Journal of Medicine ◽

10.3329/jom.v16i1.22407 ◽

2015 ◽

Vol 16 (1) ◽

pp. 59-60

Author(s):

Sabrina Shahrin ◽

Rakesh Panday ◽

Kamal Uddin Sohel ◽

Nazmul Islam ◽

Motlabur Rahman ◽

...

Keyword(s):

Metabolic Alkalosis ◽

Autosomal Recessive ◽

Autosomal Recessive Inheritance ◽

Recessive Inheritance ◽

Recurrent Attack ◽

Gitelman's Syndrome ◽

Renal Tubular Disorder ◽

Renal Tubular

Gitelman'?s syndrome, discovered in 1966 by Gittleman,Graham and Welt, is an autosomal recessive renal tubular disorder and characterized by hypokalemic metabolic alkalosis, hypomagnesaemia, hypocalciuria. This is a rare cause of hypokalemia which has an autosomal recessive inheritance. Here we are reporting a case of a 35 years old lady presented with recurrent attacks of quadriparesis due to hypokalemia and pain in multiple joints. Later we diagnosed the case as Gitelman?'s syndrome.DOI: http://dx.doi.org/10.3329/jom.v16i1.22407 J MEDICINE 2015; 16 : 59-60

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Genotype/Phenotype Analysis in 67 Chinese Patients with Gitelman's Syndrome

American Journal of Nephrology ◽

10.1159/000448694 ◽

2016 ◽

Vol 44 (2) ◽

pp. 159-168 ◽

Cited By ~ 12

Author(s):

Ting Liu ◽

Cui Wang ◽

Jingru Lu ◽

Xiangzhong Zhao ◽

Yanhua Lang ◽

...

Keyword(s):

Fractional Excretion ◽

Chinese Patients ◽

Gitelman's Syndrome ◽

Abnormal Glucose Metabolism ◽

Renal Tubular Disorder ◽

Novel Variants ◽

Phenotype Analysis ◽

Male Patients ◽

Renal Tubular

Background: Gitelman's syndrome (GS) is an autosomal recessive renal tubular disorder, which is caused by the mutations in SLC12A3. This study was designed to analyze the characteristics of the genotype and phenotype, and follow-up in the largest group of Chinese patients with GS. Methods: Sixty-seven patients with GS underwent SLCl2A3 analysis, and their clinical characteristics and biochemical findings as well as follow-up were reviewed, aiming to achieve a better description of GS. Additionally, the association of genotype and phenotype was explored. Results: Forty-one different mutations were identified within these 67 GS patients, including 11 novel mutations and 5 recurrent ones. Typical hypocalciuria and hypomagnesemia were not found in 6 (9%) and 8 (11.9%) patients, respectively. Male patients and those harboring severe mutations in both alleles had significant higher urinary fractional excretion (FE) of potassium, magnesium and chlorine. In addition, there were 2 patients who had chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2) and 32 patients with abnormal glucose metabolism. Conclusions: We identified 41 mutations related to GS, containing 11 novel variants and 5 high-frequency ones, which should facilitate earlier and more accurate diagnosis of GS. FE of electrolytes in urine may be more sensitive in the phenotype evaluation and differential diagnosis than corresponding serum electrolytes. Hypokalemia and hypomagnesemia in GS were difficult to correct; however, spironolactone might be helpful for hypokalemia to some degree. Compared with normal people, patients with GS were at higher risk of developing type 2 diabetes.

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Physical Properties of Isolated Perfused Renal Tubular Basement Membranes

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100065997 ◽

1971 ◽

Vol 29 ◽

pp. 390-391

Author(s):

Jared Grantham ◽

Larry Welling

Keyword(s):

Basement Membrane ◽

Basement Membranes ◽

Transport Mechanisms ◽

Permeability Characteristics ◽

Peritubular Capillaries ◽

Strategic Location ◽

Tubular Lumen ◽

Glomerular Filtrate ◽

Urine Formation ◽

Renal Tubular

In the course of urine formation in mammalian kidneys over 90% of the glomerular filtrate moves from the tubular lumen into the peritubular capillaries by both active and passive transport mechanisms. In all of the morphologically distinct segments of the renal tubule, e.g. proximal tubule, loop of Henle and distal nephron, the tubular absorbate passes through a basement membrane which rests against the basilar surface of the epithelial cells. The basement membrane is in a strategic location to affect the geometry of the tubules and to influence the movement of tubular absorbate into the renal interstitium. In the present studies we have determined directly some of the mechanical and permeability characteristics of tubular basement membranes.

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