MO032URINARY EXCRETION DISORDER IN 125 PATIENTS WITH GITELMAN SYNDROME

Abstract

Abstract Background and Aims Long-term oral prescription of thiazide diuretics, which can block the sodium chloride co-transporter (NCC) of the distal tubule, has been recognized to affect the function of the proximal tubule. But the underlying mechanism is largely unknown. Gitelman syndrome (GS) is a recessively inherited salt-losing tubulopathy due to the loss-of-function mutation of NCC, which can be used as a good model to understand the pathophysiological mechanism of thiazide-related disorders. In this study, we summarized the clinical characteristics of proximal tubular function in the cohort of patients with GS, and explore the possible mechanisms of proximal tubular dysfunction secondary to distal tubular disorder. Method Patients who were diagnosed with GS (confirmed by gene sequencing) in our hospital from August 1, 2005 to December 31, 2019 were enrolled, as well as the selected gender- and age-matched healthy controls. For patients whose SLC12A3 gene was sequenced as a single heterozygous mutation, further whole exome sequencing was performed to clarify the gene mutation. Clinical data including demographic information, symptoms, and hematuria tests were collected. The hydrochlorothiazide test was performed to assess the function of NCC. Characteristics of calcium and phosphate metabolism and uric acid of patients were analyzed. Results A total of 125 patients with genetic diagnosed GS were enrolled, and 33 patients (26.4%) were with only a single heterozygous mutation. Twenty-five patients completed whole exome sequencing, and 9 patients (36%) were finally diagnosed with compound heterozygous mutations. Seven mutation sites were newly detected by whole exome sequencing, including 3 missense mutations, 1 splice-site point mutation and 3 intron mutations. Serum uric acid in GS patients was significantly higher than that in healthy controls (347.5±91.7 vs 309.9±85.3μmol/L; P<0.001). The proportions of men and women with hyperuricemia were 19.4% and 34.5%, respectively. Urinary fraction excretion of uric acid in the hyperuricemia group was significantly lower than that of patients with normal serum uric acid. Compared with healthy controls, GS patients had higher blood calcium level (2.41±0.17 vs 2.32±0.09mmol/L; P<0.001). However, urinary calcium, parathyroid hormone (26.79±14.21 vs 33.18±11.58μmol/L; P=0.005), and 25-hydroxyvitamin D (15.88±6.46 vs 19.56±6.06 nmol/L; P=0.001) were lower in GS patients. Lower blood magnesium level was associated with lower parathyroid hormone level. Conclusion In GS patients, low urinary calcium, high serum calcium and high serum uric acid levels were related with the compensation of proximal tubular function.