Effects of Hydrochlorothiazide and Amiloride in Renal Hypophosphatemic Rickets

Abstract

The effects of thiazide diuretics on serum phosphate concentration, renal tubular threshold for phosphate, and urinary calcium excretion in children with renal hypophosphatemic rickets were studied. There were nine controlled acute studies conducted in five patients, and, in addition, seven long-term studies of up to 26 months were performed. During the acute studies, the children continued to receive the same doses of oral calcitriol and phosphate supplementation as at home. Hydrochlorothiazide, 1.50 to 2.25 mg/kg/d, was used alone in the first four studies; hydrochlorothiazide and amiloride at a dose of 1 mg for each 5 mg of hydrochlorothiazide were used in the other five studies. Administration of the diuretics for four days gave rise to a significant increase in serum phosphate concentration from 3.1 ± 0.4 mg/dL to 3.7 ± 0.9 mg/dL (P < .01) and in tubular threshold for phosphate from 1.31 ± 0.45 mg/dL to 1.74 ± 0.60 mg/dL (P < .01). These changes were accompanied by significant reductions in urinary sodium excretion from 135 ± 39 mEq/24 h during the control period to 99 ±42 mEq/24 h on the fourth day of therapy (P < .05), fractional sodium excretion from 0.99% ± 0.42% to 0.81% ± 0.42% (P < .05), and urinary calcium excretion from 57.3 ± 28.9 mg/24 h to 19.0 ± 13.1 mg/24 h (P < .01). Fractional excretion of phosphate divided by fractional excretion of sodium after the treatment with diuretics was not significantly different from that observed at the end of the control period. Increments in serum phosphate concentrations were correlated with elevations in serum albumin concentrations (r = .739; P <.02). As an additional index of intravascular volume contraction, the elevations in serum phosphate concentrations were correlated with the increase in BUN, (r = .793; P < .01). The addition of amiloride in the last five studies prevented the hypokalemia and alkalosis that had complicated the administration of hydrochlorothiazide. Long-term follow-up studies for a total of 119 therapy-months on six children and one adult, who continued to receive the diuretics concomitantly with calcitriol and phosphate supplementation, showed that they were free of complications except for a transient episode of hypercalcemia and hypercalciuria in one patient. In comparison with the previous period of treatment with calcitriol and phosphate without diuretics, linear growth velocity and healing of the rickets were not changed in two children and improved in the other four after the addition of hydrochlorothiazide and amiloride. Three patients who previously had hypercalciuria responded to thiazide administration by reverting to and maintaining normocalciuria. Ultrasonography showed no nephrocalcinosis throught the period of diuretic treatment of up to 3 years. It is concluded that some patients with renal hypophosphatemic rickets can benefit from the adjunct diuretic therapy by reducing the requirements for the large doses of phosphate supplementation and by providing a wider margin of safety for the currently accepted mode of therapy.