Responsiveness of Hypercalciuria to Thiazide in Dent’s Disease

Abstract

Abstract. Hypercalciuria is the major risk factor promoting stone formation in Dent's disease, also known as X-linked recessive nephrolithiasis, but the effects of diuretics on calcium excretion and other stone risk factors in this disease are unknown. This study examined urine composition in eight male patients with Dent's disease, ages 6 to 49 yr, all of whom were hypercalciuric and had inactivating mutations of CLCN5. Eight males, ages 7 to 34 yr, with idiopathic hypercalciuria (IH) served as controls. Patients were instructed to maintain a consistent intake of sodium, potassium, calcium, and protein.Two consecutive 24-h urine collections were obtained after a baseline period and after 2 wk of chlorthalidone (25 mg), amiloride (5 mg), and the two diuretics in combination, with a week off drug separating the treatment periods in a randomized crossover design. Doses were reduced by half in boys under age 12 yr. Chlorthalidone alone (P Ͻ 0.002) and the combination of chlorthalidone and amiloride (P Ͻ 0.003) reduced calcium excretion significantly in either patient group. With chlorthalidone, calcium excretion fell to normal (Ͻ4.0 mg/kg per d) in all but one patient in each group. Amiloride alone had no significant effect on urinary calcium excretion, in either patient group. In patients with Dent's disease during chlorthalidone therapy, the supersaturation ratios for calcium oxalate and calcium phosphate fell by 25% and 35%, respectively. Mean citrate excretion was reduced by chlorthalidone (P Ͻ .04) and by chlorthalidone in combination with amiloride (P Ͻ .02). There were no significant differences in the responses to these diuretics between the patient groups in any of the urinary parameters. The intact hypocalciuric response to a thiazide diuretic indicates that inactivation of the ClC-5 chloride channel does not impair calcium transport in the distal convoluted tubule and indicates that thiazides should be useful in reducing the risk of kidney stone recurrence in patients with Dent's disease.

Uso a longo prazo de enalapril e hidroclorotiazida em dois pacientes com novas mutações com doença de Dent tipo 1

“…High doses of thiazides can reduce calciuria and the risk of nephrolithiasis; however, they are poorly tolerated for long periods in these polyuric patients, frequently associated with hypovolemia and hypokalemia. 12,13 In addition, calcium concentration in the urine can be halved just by doubling the water intake, avoiding the effects of thiazide. In addition to LMW proteinuria, the glomerular component may increase during follow-up, and enalapril could be useful.…”

Investigação de nefrolitíase no Oeste do Paraná

“…CLCN5 gene mutations are related to the so called Dent's Disease. Hypercalciuria may be associated with hypophosphatemia due to mutations in phosphorus /sodium cotransporter proteins, encoded by the NPT2a gene [23][24][25] . In children with hypercalciuria, the prevalence of renal lithiasis in the family ranges from 46 to 49% [26][27][28] .…”

Clinical utility gene card for: Dent disease (Dent-1 and Dent-2)

“…Potential medical interventions include high fluid intake, thiazide diuretics 18 and potassium citrate supplementation. 19 Animal studies suggest a positive effect of citrate suppletion in a Clcn5 knockout mouse model (on kidney function and calcium deposits).…”

“…19 Animal studies suggest a positive effect of citrate suppletion in a Clcn5 knockout mouse model (on kidney function and calcium deposits). 19 Human data have documented a decrease in hypercalciuria with thiazide diuretics, 18 yet at the expense of hypokalemia in some patients. The long-term efficacy on the progression of renal failure has not been studied, however.…”