Date Published: July 10, 2017
Publisher: Public Library of Science
Author(s): Xiaoyan Peng, Lanping Jiang, Chen Chen, Yan Qin, Tao Yuan, Ou Wang, Xiaoping Xing, Xuemei Li, Min Nie, Limeng Chen, Zhanjun Jia.
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.
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). Patients with GS are treated by oral potassium and magnesium supplementation and potassium-sparing diuretics. Due to its inhibition of prostaglandin E2 (PGE2) synthesis in the kidney, indomethacin was traditionally used in patients affected by Bartter syndrome (BS), another salt-losing 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 . Studies in several case series indicated that indomethacin, a nonselective inhibitor of cyclooxygenase (COX), can improve hypokalemia and developmental delays [2, 4–11]. Recently, an open-label, randomized, crossover study confirmed the efficiency of indomethacin treatment in GS patients via a significant decrease in renin activity and the estimated glomerular filtration rate (eGFR). However, no reliable laboratory measurements support indomethacin therapy. 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.
The study was approved by the Ethics Committee on Human Studies at Peking Union Medical College Hospital (PUMCH), Chinese Academy of Medical Sciences, Beijing, China. The authors adhered to the Declaration of Helsinki, and patients were included after providing informed consent.
GS has traditionally been thought to be a relatively benign disorder that could be treated by potassium and magnesium supplementation. Since the first report of normal PGE2 levels in patients diagnosed with GS by clinical manifestations in 1995, few studies have monitored the PGE2 levels associated with GS. Although no positive recommendation has been advocated by physicians, COX2 inhibitors, which are used to block PGE2 production, were reported to be helpful for GS patients[4, 5]. To the best of our knowledge, this is the first direct evidence of elevated PGEM levels in patients with genetically confirmed GS. After adjusting for the gender difference, urinary PGEM was correlated with plasma chloride and magnesium levels and urinary calcium excretion. The most interesting finding was that higher urinary PGEM levels indicated more severe clinical manifestations and NCC dysfunction.
Higher urinary PGE2 metabolite 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.