Clinical trial NCT02035046: Clinical Significance of Heterozygosity for Mutations of the SLC12A3 Gene Coding for the Thiazide Sensitive Na-Cl Cotransporter
Official title: Clinical Significance of Heterozygosity for Mutations of the SLC12A3 Gene Coding for the Thiazide Sensitive Na-Cl Cotransporter
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Heterozygous Carriers of Gitelman Syndrome
Keywords: Gitelman
Heterozygous SLC12A3 mutation
Blood pressure
Hypokalemia
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2014-01-14
Enrollment: 250
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: DIAGNOSTIC

Brief summary: 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.

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).

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

Primary outcomes:
measure: Systolic blood pressure evaluated by self-measurement
timeFrame: 3 days
Secondary outcomes:
measure: Salt balance
timeFrame: 1 day
measure: Potassium metabolism
timeFrame: 1 day
measure: Glucose and lipide metabolism
timeFrame: 1 day
measure: Oral glucose tolerance test
timeFrame: 1 day
measure: Mineral metabolism
timeFrame: 1 day
measure: Renal fonction
timeFrame: 1 day
measure: Vascular fonction evaluation
timeFrame: 1 day
Other outcomes:
Locations:
city: Limoges
country: France
facility: Nephrology Department. Centre Hospitalier Universitaire, Hôpital Dupuytren
city: Lyon
country: France
facility: Department of Functional Investigations. Hospices Civils de Lyon, Hôpital Edouard Herriot.
city: Paris
country: France
facility: Department of Functional Investigations. Assistance Publique Hôpitaux de Paris, Hôpital Tenon
city: Paris
country: France
facility: Clinical Research Center. Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou.
city: Toulouse
country: France
facility: Department of Functional Investigations. Centre Hospitalier Universitaire, Hôpital de Rangueil.
Study officials:
affiliation: Departement of Genetics. Assistance Publique Hôpitaux de Paris,Hôpital Européen Georges Pompidou.
name: Rosa Vargas-Poussou, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Research Center. Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou. Paris, France
name: Anne Blanchard, MD, PhD
role: STUDY_DIRECTOR
affiliation: Departement of Nephrology. Centre Hospitalier Universitaire. Limoges, France
name: Marie Essig, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Functional Investigations. Assistance Publique Hôpitaux de Paris, Hôpital Tenon, Paris, France
name: Jean Philippe Haymann, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Functional Investigations. Centre Hospitalier Universitaire, Hôpital de Rangueil. Toulouse, France
name: Ivan Tack, MD, PhD
role: STUDY_CHAIR
affiliation: Department of Functional Investigations. Hospices Civils de Lyon, Hôpital Edouard Herriot. Lyon, France
name: Laurence DUBOURG, MD, PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.