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Thiazide Responsiveness Testing in Patients With Renal Magnesium Wasting and Correlation With Genetic Analysis: A Diagnostic Test Study.

To the Editor: Electrolyte disorders such as hypomagnesemia and hypokalemia can result from excessive urinary losses. Rarely, this is due to loss-of-function mutations in genes such as those encoding tubular transporters or ion channels. In Gitelman syndrome (GS), mutant NCCT (encoded by SLC12A3) in the distal convoluted tubule leads to hypokalemia, metabolic alkalosis, hypomagnesemia, and hypocalciuria. Because thiazide diuretics block NCCT, thiazide challenge can probe NCCT function in patients thought to have GS. This thiazide test differentiates well between the salt-losing nephropathies GS and Bartter syndrome (BS). However, the differential diagnosis of GS includes more disorders characterized by renal magnesium wasting (Item S1). The clinical value of the thiazide test in these renal magnesium-wasting disorders is not known. We performed a diagnostic study in patients with renal magnesium wasting, using thiazide responsiveness as the index test and genetic analysis as the reference standard. All patients with renal magnesium wasting (FeMg . 2.7% with hypomagnesemia) and clinical suspicion of GS who had a thiazide test at our institute between 2010 and 2014 were included (detailed methods in Item S1). Thiazide tests were performed as described by Colussi et al. A normal response was considered DFeCl . 2.3%. Genetic testing was done by Sanger sequencing and multiplex ligation–dependent probe amplification. Patient characteristics at the time of presentation to our clinic are given in Table 1. Most patients were receiving magnesium and/or potassium salts at referral. As shown in the thiazide test findings in Fig 1, the 3 patients with an SLC12A3 mutation had a blunted response to hydrochlorothiazide administration, whereas the patient with BS with heterozygous mutations in CLCNKB and KCNJ1 had a normal to increased response. The 5 patients with HNF1B mutations had responses ranging from normal to completely unresponsive. The patient with an FXYD2 mutation showed a clearly blunted response. Thus, a blunted response to thiazide diuretics is not specific for GS because it can also occur in patients with a GS-like syndrome (including magnesiuria and hypocalciuria) who have other underlying genetic causes of renal magnesium wasting (eg, HNF1B or FXYD2 mutations). This could indicate that NCCT function is also affected in these patients. This is remarkable because mutations in FXYD2 are thought to cause isolated renal hypomagnesemia and mutations in HNF1B cause a multisystem phenotype often consisting of renal cysts, diabetes, and reduced kidney function, but its tubulopathy is characterized by an isolated magnesium reabsorption defect as well. The underlying mechanism of presumed NCCT dysfunction in these diseases is unresolved. It could be due to the magnesiuria itself, but both we and others have shown that patients with BS who have magnesiuria respond normally to thiazide diuretics. Therefore, an interaction between tubular transporters or a tubular development defect seems more likely.