Acid-Base Status Determines Cyclosporine-Induced Hypercalciuria

Abstract

Objective Cyclosporine (CsA) causes tubular dysfunction characterized by polyuria, calcium wasting, distal tubular acidosis, and hyperkalemia. The hypercalciuria induced by CsA administration is associated with an inhibition of calbindin D 28k expression. It has also been shown that chronic metabolic alkalosis increased the expression of Ca 2+ transport proteins accompanied by diminished urine Ca 2+ excretion. The aim of this study, therefore, was to determine the effect of acid-base status on CsA-induced hypercalciuria. Methods Experiments were performed on male Sprague-Dawley rats. Metabolic alkalosis and acidosis were induced respectively by adding 0.28 mol/L NaHCO 3 and 0.28 mol/L NH 4Cl in the drinking water for 7 days; control rats received regular tap water. Seven days after NaHCO 3 or NH 4Cl administration, rats were treated with CsA (25 mg/kg, IP) daily for 14 days. To estimate glomerular filtration rate (GFR) over time, animals were placed in metabolic cages. Fractional urinary calcium excretion was determined by standard formula. Results The CsA group showed decreased serum calcium and increased fractional urinary calcium excretion compared with the control group. Creatinine clearance was also significantly reduced. Metabolic alkalosis alone did not affect GFR, but significantly prevented an increase in fractional urinary calcium excretion induced by CsA, whereas chronic metabolic acidosis resulted in the exact opposite effect. Conclusions It is essential for nephrologists to fully understand the mechanisms of CsA-induced renal injury. In this study, metabolic alkalosis reduced CsA-induced hypercalciuria. Further studies are needed to elucidate whether this effect may be achieved pharmacologically by the expression of Ca 2+ transport proteins.