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Increased urinary prostaglandin E2 metabolite: A potential therapeutic target of Gitelman syndrome.

ABSTRACT: Gitelman syndrome (GS), an inherited autosomal recessive salt-losing renal tubulopathy caused by mutations in SLC12A3 gene, has been associated with normal prostaglandin E2 (PGE2) levels since 1995 by a study involving 11 clinically diagnosed patients. However, it is difficult to explain why cyclooxygenase-2 (COX2) inhibitors, which pharmacologically reduce PGE2 synthesis, are helpful to patients with GS, and few studies performed in the last 20 years have measured PGE2 levels. The relationships between the clinical manifestations and PGE2 levels were never thoroughly analyzed.This study involved 39 GS patients diagnosed by SLC12A3 gene sequencing. Plasma and 24-h urine samples as well as the clinical data were collected at admission. PGE2 and PGEM levels were detected in plasma and urine samples by enzyme immunoassays. The in vivo function of the sodium-chloride co-transporter (NCC) in GS patients was evaluated using a modified thiazide test. The association among PGE2 levels, clinical manifestations and the function of NCC in GS patients were analyzed.Significantly higher levels of urinary and plasma PGEM were observed in GS patients than in the healthy volunteers. Higher urinary PGEM levels indicated more severe clinical manifestations and NCC dysfunction estimated by the increase of Cl- clearance. A higher PGEM level was found in male GS patients, who showed earlier onset age and more severe hypokalemia, hypochloremia and metabolic alkalosis than female GS patients. No relationship between renin angiotensin aldosterone system activation and PGEM level was observed.Higher urinary PGEM levels indicated more severe clinical manifestations and NCC dysfunction in GS patients. COX2 inhibition might be a potential therapeutic target in GS patients with elevated PGEM levels.

SUBMITTER: Peng X

PROVIDER: S-EPMC5507263 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Increased urinary prostaglandin E2 metabolite: A potential therapeutic target of Gitelman syndrome.

Peng Xiaoyan X Jiang Lanping L Chen Chen C Qin Yan Y Yuan Tao T Wang Ou O Xing Xiaoping X Li Xuemei X Nie Min M Chen Limeng L

PloS one 20170710 7

<h4>Background</h4>Gitelman syndrome (GS), an inherited autosomal recessive salt-losing renal tubulopathy caused by mutations in SLC12A3 gene, has been associated with normal prostaglandin E2 (PGE2) levels since 1995 by a study involving 11 clinically diagnosed patients. However, it is difficult to explain why cyclooxygenase-2 (COX2) inhibitors, which pharmacologically reduce PGE2 synthesis, are helpful to patients with GS, and few studies performed in the last 20 years have measured PGE2 levels ...[more]

PMID: 28700713

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Project description:Gitelman syndrome (GS), also referred to as familial hypokalemia-hypomagnesemia, is characterized by hypokalemic metabolic alkalosis in combination with significant hypomagnesemia and low urinary calcium excretion. The prevalence is estimated at approximately 1:40,000 and accordingly, the prevalence of heterozygotes is approximately 1% in Caucasian populations, making it one of the most frequent inherited renal tubular disorders. In the majority of cases, symptoms do not appear before the age of six years and the disease is usually diagnosed during adolescence or adulthood. Transient periods of muscle weakness and tetany, sometimes accompanied by abdominal pain, vomiting and fever are often seen in GS patients. Paresthesias, especially in the face, frequently occur. Remarkably, some patients are completely asymptomatic except for the appearance at adult age of chondrocalcinosis that causes swelling, local heat, and tenderness over the affected joints. Blood pressure is lower than that in the general population. Sudden cardiac arrest has been reported occasionally. In general, growth is normal but can be delayed in those GS patients with severe hypokalemia and hypomagnesemia.GS is transmitted as an autosomal recessive trait. Mutations in the solute carrier family12, member 3 gene, SLC12A3, which encodes the thiazide-sensitive NaCl cotransporter (NCC), are found in the majority of GS patients. At present, more than 140 different NCC mutations throughout the whole protein have been identified. In a small minority of GS patients, mutations in the CLCNKB gene, encoding the chloride channel ClC-Kb have been identified.Diagnosis is based on the clinical symptoms and biochemical abnormalities (hypokalemia, metabolic alkalosis, hypomagnesemia and hypocalciuria). Bartter syndrome (especially type III) is the most important genetic disorder to consider in the differential diagnosis of GS. Genetic counseling is important. Antenatal diagnosis for GS is technically feasible but not advised because of the good prognosis in the majority of patients.Most asymptomatic patients with GS remain untreated and undergo ambulatory monitoring, once a year, generally by nephrologists. Lifelong supplementation of magnesium (magnesium-oxide and magnesium-sulfate) is recommended. Cardiac work-up should be offered to screen for risk factors of cardiac arrhythmias. All GS patients are encouraged to maintain a high-sodium and high potassium diet. In general, the long-term prognosis of GS is excellent.

Dataset Information

Increased urinary prostaglandin E2 metabolite: A potential therapeutic target of Gitelman syndrome.

Publications

Increased urinary prostaglandin E2 metabolite: A potential therapeutic target of Gitelman syndrome.

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