Research advances in hypokalemic salt-losing tubulopathies / 上海交通大学学报（医学版）

Hereditary tubular disorders play an important role in the ion transport mechanism of kidney. Hypokalemic salt-losing tubulopathies (SLTs) are a set of rare hereditary diseases, which accompany with hypokalaemic metabolic alkalosis, normo or hypotension, and are associated with high plasma renin activity and hyperaldosteronemia. Bartter syndrome and Gitelman syndrome, characterized by the disability of the thick ascending limb of Henle's loop and/or the distal convoluted tubule, respectively, are two common types of SLTs. Some types of SLTs share similar clinical manifestations, making them difficult to diagnose. Besides, with the development of molecular genetics, new disease-causing genes have been discovered. It's inconvenient for clinicians to refer to the old classification of SLTs. The review mainly covered the newly discovered pathogenic genes of SLTs and the corresponding pathogenic mechanisms. In addition, a new system for classification of SLTs based on physiology and pharmacology was introduced.

Mutations in SLC12A3 and CLCNKB and Their Correlation with Clinical Phenotype in Patients with Gitelman and Gitelman-like Syndrome

Gitelman's syndrome (GS) is caused by loss-of-function mutations in SLC12A3 and characterized by hypokalemic metabolic alkalosis, hypocalciuria, and hypomagnesemia. Long-term prognosis and the role of gene diagnosis in GS are still unclear. To investigate genotype-phenotype correlation in GS and Gitelman-like syndrome, we enrolled 34 patients who showed hypokalemic metabolic alkalosis without secondary causes. Mutation analysis of SLC12A3 and CLCNKB was performed. Thirty-one patients had mutations in SLC12A3, 5 patients in CLCNKB, and 2 patients in both genes. There was no significant difference between male and female in clinical manifestations at the time of presentation, except for early onset of symptoms in males and more profound hypokalemia in females. We identified 10 novel mutations in SLC12A3 and 4 in CLCNKB. Compared with those with CLCNKB mutations, patients with SLC12A3 mutations were characterized by more consistent hypocalciuria and hypomagnesemia. Patients with 2 mutant SLC12A3 alleles, compared with those with 1 mutant allele, did not have more severe clinical and laboratory findings except for lower plasma magnesium concentrations. Male and female patients did not differ in their requirement for electrolyte replacements. Two patients with concomitant SLC12A3 and CLCNKB mutations had early-onset severe symptoms and showed different response to treatment. Hypocalciuria and hypomagnesemia are useful markers in differentiation of GS and classical Bartter's syndrome. Gender, genotypes or the number of SLC12A3 mutant alleles cannot predict the severity of disease or response to treatment.