Renal tubular transport of cyclosporine A (CSA) and associated changes in renal function

In an effort to understand the mechanisms of nephrotoxicity of cyclosporine A (CSA), this study has been undertaken to evaluate the CSA clearance by the kidney and its tubular transport, with simultaneous studies on the multiple renal functional parameters. New Zealand white rabbits weighing approximately 2.5 kg were used in the study. Rabbits were infused with 14C labelled inulin to determine GFR. Blood pressure was monitored throughout the study via ear artery cannula. The rabbits were catheterized by the bladder and remained conscious throughout the entire study. When an infusional steady state was achieved, three clearance periods of 15 minutes were undertaken, followed then by a bolus of 10 mg/kg CSA, followed by an infusion of 1 mg/kg. A further three clearance periods were undertaken, studying the clearance of CSA at the same time as the GFR. Additional studies were made of plasma renin activity, aldosterone, 6-keto-PGF1 alpha, urinary sodium excretion and urinary potassium excretion rate. CSA was determined in whole blood and urine by HPLC. The results indicate that CSA, as determined by HPLC, has a whole blood renal clearance of 0.029 +/- 0.011 ml/min/kg body weight. Glomerular filtration rate showed no difference in animals pretreated with an infusion of mannitol when comparing pre- and post-CSA administration. Without mannitol, there was a significant decrease in the GFR following administration of CSA. CSA administration was accompanied by a rise in plasma renin activity in animals treated with mannitol and without mannitol. The rate of 6-keto-PGF1 alpha excretion without pretreatment with mannitol showed a significant rise following CSA administration.(ABSTRACT TRUNCATED AT 250 WORDS)