Nephrotoxicity of cyclosporine A in the rat. I. Specific intrarenal zonation of reduced succinate dehydrogenase activity.

The intranephronal distribution pattern of the activity of succinate dehydrogenase, a marker enzyme of mitochondrial inner membranes, was examined by histochemical investigation in the kidneys of 27 male Sprague-Dawley rats. The animals received cyclosporine A per os (15, 30 or 50 mg/kg.day) for 12 or 24 days. Six animals of the latter group remained untreated for a further 24 days. Five rats treated orally with 30 mg/kg.day olive oil served as controls. The kidneys of 2 normal male Sprague-Dawley rats were examined for comparison. Cyclosporine A reversibly induced a characteristic pattern of nephron segments with various degrees of reduced succinate dehydrogenase activity: in the proximal and distal tubules of subcapsular areas of the cortical labyrinth, of the medullary rays, and of the outer stripe of the outer medulla. The remaining areas contained tubules with normal succinate dehydrogenase activity, as confirmed by microphotometrical measurement. The number of these tubules appeared to be decreased under higher doses of cyclosporine A, irrespective of the duration of treatment. The finding of heterogeneous affection of tubular mitochondrial cristae membranes reflects direct tubulotoxicity of cyclosporine A.