Hydrochlorothiazide in CLDN16 mutation

Abstract

Background. Hydrochlorothiazide (HCT) is applied in the therapy of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) caused by claudin-16 (CLDN16) mutation. However, the shortterm efficacy of HCT to reduce hypercalciuria in FHHNC has not yet been demonstrated in a clinical trial. Methods. Four male and four female patients with FHHNC and CLDN16 mutation, under long-standing HCT therapy (0.4-1.2 mg/kg, median 0.9 mg/kg, dose according to calciuria), aged 0.7-22.4 years, were included in a clinical study to investigate the effect of HCT on calciuria. The study design consisted of three periods: continued therapy for 4 weeks, HCT withdrawal for 6 weeks and restart of therapy at the same dose for 4 weeks. Calciuria and magnesiuria were assessed weekly as Ca/creat and Mg/creat ratio, every 2 weeks in 24 h urine, and serum Mg, K and kaliuria (s-Mg, s-K and K/creat) at weeks 0, 6, 10 and 14. The data of each study period were averaged and analysed by Friedman and Wilcoxon test. Results. Ca/creat was significantly reduced by HCT (median before/at/after withdrawal 0.76/1.24/ 0.77 mol/mol creat; n ¼ 8, P<0.05). The reduction of Ca/24 h by HCT was not statistically significant (0.13/0.19/0.13 mmol/kg  24 h; n ¼ 5). Serum Mg (0.51/0.64/0.56 mmol/l; n ¼ 8, P<0.05) and Serum K (3.65/4.35/3.65 mmol/l; n ¼ 8, P<0.05) were significantly higher during withdrawal. However, Mg/creat (0.98/0.90/0.90 mol/mol creat; n ¼ 8), Mg/24 h (0.14/0.12/0.18 mmol/kg  24h; n ¼ 5) and K/creat (6.3/8.4/6.2 mol/mol creat; n ¼ 8) remained statistically unchanged during withdrawal. Conclusions. We demonstrated that HCT is effective in reducing hypercalciuria due to CLDN16 mutation on a short-term basis. However, the efficacy of HCT to attenuate disease progression remains to be elucidated.

Hereditary causes of kidney stones and chronic kidney disease

“…Unfortunately, thiazides neither yield a meaningful reduction in urinary calcium excretion nor delay the progression of CKD [76, 78, 93]. Moreover, thiazides can aggravate renal magnesium wasting, often leading to their discontinuation [5, 92, 94]. The serum magnesium level tends to remain low despite high-dose magnesium supplementation [78].…”

A Novel Mutation in the CLDN16 Gene in a Palestinian Family with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

“…5 Zimmermann et al studied the efficacy of hydrochlorothiazide (HCT) in FHHNC patients in a clinical trial, and concluded that HCT is effective in reducing hypercalciuria due to CLDN16 mutation on a shortterm basis; however, the efficacy of HCT to attenuate disease progression remains to be evaluated. 6 No functional studies were performed and we considered the amino acid change in the gene as pathogenic (i.e., mutation) based on the following: (1) positive segregation in the family as parents were heterozygous, (2) the amino acid change is in a region with a predilection to mutation, (3) the changed amino acid is in a conserved residue.…”

Claudins in Renal Physiology and Pathology

“…The effectiveness of these treatments on the course of nephrocalcinosis and on the decline of GFR in FHHNC is unknown. Hydrochlorothiazide has been shown to be effective in correcting hypercalciuria due to CLDN16 mutations in some [52,79] but not all patients [50][51][52]. Mg 2+ supplementation might also be ineffective to correct hypomagnesemia [50][51][52].…”