Zahmatkesh M, Kadkhodaee M, Ghaznavi R, Mahdavi-Mazdeh M
Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Transplant Proc. 2007 May;39(4):1231-2. doi: 10.1016/j.transproceed.2007.02.040.
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.
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(4)Cl in the drinking water for 7 days; control rats received regular tap water. Seven days after NaHCO(3) or NH(4)Cl 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.
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.
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.
环孢素（CsA）可导致肾小管功能障碍，其特征为多尿、钙流失、远端肾小管酸中毒和高钾血症。CsA给药诱导的高钙尿症与钙结合蛋白D（28k）表达受抑制有关。研究还表明，慢性代谢性碱中毒可增加Ca（2+）转运蛋白的表达，同时尿Ca（2+）排泄减少。因此，本研究的目的是确定酸碱状态对CsA诱导的高钙尿症的影响。
对雄性Sprague-Dawley大鼠进行实验。分别通过在饮用水中添加0.28mol/L NaHCO（3）和0.28mol/L NH（4）Cl 7天来诱导代谢性碱中毒和酸中毒；对照大鼠饮用普通自来水。给予NaHCO（3）或NH（4）Cl 7天后，大鼠每天腹腔注射CsA（25mg/kg），持续14天。为了估计不同时间的肾小球滤过率（GFR），将动物置于代谢笼中。通过标准公式测定尿钙排泄分数。
与对照组相比，CsA组血清钙降低，尿钙排泄分数增加。肌酐清除率也显著降低。单独的代谢性碱中毒不影响GFR，但可显著防止CsA诱导的尿钙排泄分数增加，而慢性代谢性酸中毒则产生相反的效果。
肾病学家必须充分了解CsA诱导肾损伤的机制。在本研究中，代谢性碱中毒减少了CsA诱导的高钙尿症。是否可以通过Ca（2+）转运蛋白的表达在药理学上实现这种效果，还需要进一步研究阐明。
