LAUSR

Bartter syndrome (BS) types 1–4 and Gitelman syndrome (GS) are caused by mutations in genes that encode renal ion transporters and channels located in the thick ascending limb of Henle’s loop (TALH) and distal convoluted tubules, respectively. There are at least three clinical phenotypes described for BS: (1) classic BS; (2) the hypocalciuric-hypomagnesemic Gitelman variant; and (3) the antenatal hypercalciuric variant. Each type of BS has been reported to correspond to one of these clinical phenotypes. However, recent advances in genetic testing using next-generation sequencing (NGS) have revealed that there is substantial overlap in phenotypes between these types of BS and GS. In this issue of Pediatrics International, Nozu et al. reviewed comprehensive analyses of diuretic loading tests performed in BS, GS, and pseudo-BS/GS patients as well as BSand GS-causative genes and other genes that can cause pseudo-BS/GS. Patients with type 2 BS responded to furosemide, indicating that the renal outer medullary potassium channel (ROMK) defects did not completely inactivate the Na-K-2Cl cotransporter (NKCC2), which may support the finding that renal potassium wasting in ROMK-deficiency mice was caused by both reduced reabsorption in the TALH and potassium secretion by the big potassium channels. Patients with type 3 BS responded to furosemide but not to thiazide, which indicated that secondary Na-Cl cotransporter dysfunction is the main molecular mechanism for the onset of type 3 BS. A clinical and genetic analysis of type 3 BS and GS showed that the two conditions cannot be distinguished by age at onset, serum magnesium levels, and urinary excretion of calcium. Other congenital renal tubular disorders such as autosomal dominant hypocalcemia, HNF1B-related nephropathy, nephronophthisis, and Dent disease can also be accompanied by BS/GS-like symptoms. Based on these findings, Nozu et al. suggested that the term “salt-losing tubulopathy” be used for BS, GS, and cases of tubulopathies accompanied by hypokalemia and metabolic alkalosis. Although approximately half of pseudo-BS/GS patients have a history of laxative or diuretic abuse, anorexia, excessive dieting, or alcoholism, there are many cases in which the mechanism of onset is unknown, which makes the precise diagnosis very difficult. They therefore also proposed to use the term “salt-losing disorder,” which includes BS, GS, and pseudo-BS/GS with and without congenital renal tubulopathy. As they describe in the review article, the disease names “Bartter syndrome” and “Gitelman syndrome” are already widely used, and cases with a genetic diagnosis that have already been genotyped can be called BS (types 1–5) or GS. Moreover, because the diagnosis may be the same after genetic testing in most antenatal/neonatal cases with “Bartter syndrome” as well as in most adult-onset “Gitelman syndrome” cases with hypomagnesemia, a diagnosis of “BS” or “GS” in such cases would generally be acceptable before genetic testing. Furthermore, the term “salt-losing tubulopathy” has been used in reference to broader renal tubular disorders including Fanconi syndrome and pseudohypoaldosteronism type I, which are caused by abnormalities in molecules associated with sodium handling in the proximal tubule and collecting duct, respectively. In summary, recent comprehensive analyses of clinical manifestations and genetic testing using NGS have enabled us to better understand the complexities of the genetic background and pathophysiology of so-called BS, GS, and pseudoBS/GS. “Salt-losing tubulopathy” may be a reasonable term used to refer to these disorders, although it is a future goal to reach a consensus on terminology in this field.