Acute cyclosporine A-induced nephrotoxicity: a rabbit model

Chronic cyclosporine A (CsA) nephrotoxicity has been widely assessed but only few studies have described acute nephrotoxicity. As CsA is now used for short periods, we developed an experimental model of acute CsA-induced nephrotoxicity. Renal clearances of inulin and para-aminohippurate were assessed in 35 New Zealand rabbits. Group 1: control, no treatment; group 2: CsA 25 mg/kg per day in 0.5 ml/kg per day for 5 days; group 3: vehicle Cremophor-EL, 0.5 ml/kg per day for 5 days; group 4: follow-up, the same as group 2, then CsA discontinuation for 31 days. Compared with group 1, CsA significantly decreased glomerular filtration rate (GFR), renal blood flow (RBF), and diuresis, with a significant increase in renal vascular resistance (RVR). The proportional fall in GFR (-32.3%) and RBF (-33.1%) suggests both pre- and postglomerular vasoconstriction. Discontinuation of CsA in group 4 led to normalization of RVR with improvement of other renal function parameters. Compared with group 1, Cremophor-EL induced no significant changes but an increased RBF. Microvacuolization of proximal tubule epithelial cells was the sole histological abnormality observed only in group 2. The overall results suggest that CsA induced a vasomotor acute renal failure which was not due to Cremophor-EL. This effect was partly reversible after discontinuation of treatment.