Abstract
BackgroundGitelman 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.MethodsThis 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.ResultsSignificantly 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.ConclusionsHigher 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.
Highlights
Gitelman syndrome (GS, OMIM 263800) is an inherited autosomal recessive salt-losing renal tubulopathy
Higher levels of urinary and plasma prostaglandin E2 (PGE2) metabolites (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
Summary
Gitelman syndrome (GS, OMIM 263800) is an inherited autosomal recessive salt-losing renal tubulopathy. It is mainly caused by loss-of-function mutations in the SLC12A3 gene encoding the sodium-chloride co-transporter (NCC) in the distal convoluted tubule (DCT)[1]. Due to its inhibition of prostaglandin E2 (PGE2) synthesis in the kidney, indomethacin was traditionally used in patients affected by Bartter syndrome (BS)[2], another saltlosing tubulopathyies caused by mutations in genes coding for proteins responsible for salt reabsorption in the loop of Henle. It has long been believed that NCC disorders are not associated with markedly elevated renal PGE2 synthesis, especially in adult patients [3]. Direct evidence of plasma and urinary PGE2 levels is still limited to that reported in the study by Luthy et al from 11 GS patients in 1995[3]
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