Clinical Significance of Heterozygosity for Mutations of the SLC12A3 Gene Coding for the Thiazide Sensitive Na-Cl Cotransporter (HEPHYGI)

Gitelman syndrome is a salt wasting tubulopathy caused by mutations in the SLC12A3 gene coding for the thiazide sensitive sodium chloride cotransporter. This disease mimics the chronic treatment with thiazide diuretics and is characterized by renal hypokalemia, low to normal blood pressure, hypocalciuria and hypomagnesemia. The purpose of this study is to determine whether the heterozygous carriers present the metabolic risks and/or the benefits of this disease.

Study Overview

• Status: Completed
• Conditions: Heterozygous Carriers of Gitelman Syndrome
• Intervention / Treatment: Procedure: Samplings of blood; Procedure: Sampling of urine; Procedure: Measure of the blood pressure; Procedure: glycemia test

Detailed Description

Gitelman syndrome (GS), is an autosomal recessive salt wasting tubulopathy caused mainly by loss of function mutations in the SLC12A3 gene coding for the thiazide sensitive sodium-chloride cotransporter (NCC). Thus, GS mimics a chronic treatment with high doses of thiazide diuretics. NCC is expressed in the distal convoluted tubule, which is responsible for 7% of NaCl reabsorption. GS is the more frequent hereditary tubulopathie with estimated prevalence of 1/40000, which implicates that 1% of general population are heterozygous carriers (600 000 in France). Previous publications suggest that the apparently asymptomatic heterozygous carriers could present some clinical traits of GS or chronic thiazide treatment. These including: beneficial aspects (low blood pressure, low urinary calcium excretions) or metabolic risks (hypokalemia, insulin resistance). Nevertheless, these studies do not evaluate all the aspects and blood pressure was evaluated once in hospital setting. This study aims to compare home monitoring blood pressure; salt balance; potassium, glucose lipid and mineral metabolism and vascular function in 80 heterozygous carriers, 80 GS patients and 80 controls persons (without mutations in SLC12A3 gene).

• Study Type: Interventional
• Enrollment (Anticipated): 250
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Limoges, France, 87042 Limoges cedex
    • Nephrology Department. Centre Hospitalier Universitaire, Hôpital Dupuytren
  • Lyon, France, 69437 Lyon
    • Department of Functional Investigations. Hospices Civils de Lyon, Hôpital Edouard Herriot.
  • Paris, France, 75020
    • Department of Functional Investigations. Assistance Publique Hôpitaux de Paris, Hôpital Tenon
  • Paris, France, 75908
    • Clinical Research Center. Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou.
  • Toulouse, France, 31059 TOULOUSE cedex 9
    • Department of Functional Investigations. Centre Hospitalier Universitaire, Hôpital de Rangueil.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Gitelman syndrome patients, relatives carrying heterozygous mutations and relatives or healthy voluntarees without mutations.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: study's population	Procedure: Samplings of blood; Procedure: Sampling of urine; Procedure: Measure of the blood pressure; Procedure: glycemia test

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic blood pressure evaluated by self-measurement	self-measurement at home, 3 times a day during 3 consecutive days	3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Salt balance	Blood renin and aldosterone measurements, 24h urinary sodium and aldosterone excretion	1 day
Potassium metabolism	Dietary intake, blood potassium and 24 h urinary potassium excretion	1 day
Glucose and lipide metabolism	BMI, blood glucose, insulin, cholesterol, LDL, HDL and triglycerides.	1 day
Oral glucose tolerance test		1 day
Mineral metabolism	Blood and urinary calcium, magnesium and phosphate. bone remodeling markers	1 day
Renal fonction	Estimated GFR, proteinuria and albuminuria	1 day
Vascular fonction evaluation	Pulse wave analysis and central blood pressure. Blood and urinary vascular fonction markers	1 day

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Ministry of Health, France
• Investigators: Principal Investigator: Rosa Vargas-Poussou, MD, PhD, Departement of Genetics. Assistance Publique Hôpitaux de Paris,Hôpital Européen Georges Pompidou.; Study Director: Anne Blanchard, MD, PhD, Clinical Research Center. Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou. Paris, France; Study Chair: Marie Essig, MD, PhD, Departement of Nephrology. Centre Hospitalier Universitaire. Limoges, France; Study Chair: Jean Philippe Haymann, MD, PhD, Department of Functional Investigations. Assistance Publique Hôpitaux de Paris, Hôpital Tenon, Paris, France; Study Chair: Ivan Tack, MD, PhD, Department of Functional Investigations. Centre Hospitalier Universitaire, Hôpital de Rangueil. Toulouse, France; Study Chair: Laurence DUBOURG, MD, PhD, Department of Functional Investigations. Hospices Civils de Lyon, Hôpital Edouard Herriot. Lyon, France

Publications and helpful links

General Publications

• Tago N, Kokubo Y, Inamoto N, Naraba H, Tomoike H, Iwai N. A high prevalence of Gitelman's syndrome mutations in Japanese. Hypertens Res. 2004 May;27(5):327-31. doi: 10.1291/hypres.27.327.
• Fava C, Montagnana M, Rosberg L, Burri P, Almgren P, Jonsson A, Wanby P, Lippi G, Minuz P, Hulthen LU, Aurell M, Melander O. Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure. Hum Mol Genet. 2008 Feb 1;17(3):413-8. doi: 10.1093/hmg/ddm318. Epub 2007 Nov 1.
• Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008 May;40(5):592-599. doi: 10.1038/ng.118. Epub 2008 Apr 6.
• Hsu YJ, Yang SS, Chu NF, Sytwu HK, Cheng CJ, Lin SH. Heterozygous mutations of the sodium chloride cotransporter in Chinese children: prevalence and association with blood pressure. Nephrol Dial Transplant. 2009 Apr;24(4):1170-5. doi: 10.1093/ndt/gfn619. Epub 2008 Nov 25.
• Ren H, Qin L, Wang W, Ma J, Zhang W, Shen PY, Shi H, Li X, Chen N. Abnormal glucose metabolism and insulin sensitivity in Chinese patients with Gitelman syndrome. Am J Nephrol. 2013;37(2):152-7. doi: 10.1159/000346708. Epub 2013 Jan 31.
• Cruz DN, Simon DB, Nelson-Williams C, Farhi A, Finberg K, Burleson L, Gill JR, Lifton RP. Mutations in the Na-Cl cotransporter reduce blood pressure in humans. Hypertension. 2001 Jun;37(6):1458-64. doi: 10.1161/01.hyp.37.6.1458.

Study record dates

Study Major Dates

• Study Start: December 1, 2013
• Primary Completion (Actual): September 1, 2016
• Study Completion (Actual): September 1, 2016

Study Registration Dates

• First Submitted: December 18, 2013
• First Submitted That Met QC Criteria: January 10, 2014
• First Posted (Estimate): January 14, 2014

Study Record Updates

• Last Update Posted (Estimate): January 16, 2017
• Last Update Submitted That Met QC Criteria: January 13, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Blood pressure; Hypokalemia; Gitelman; Heterozygous SLC12A3 mutation
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Genetic Diseases, Inborn; Renal Tubular Transport, Inborn Errors; Gitelman Syndrome
• Other Study ID Numbers: P120111