Chronic cyclosporine nephrotoxicity: a pig model

Cyclosporine A (CsA) is one of the keystones in immunosuppressive treatment after solid organ transplantation, despite its major side effects such as nephrotoxicity. The chronic nephrotoxic effects of CsA seen in humans have been difficult to reproduce in small-animal models. The aim of the present study was to examine the chronic nephrotoxicity produced by therapeutic dosages of CsA in a pig model. Among 11 Gottingen minipigs included in the study, three died, yielding data from five animals given CsA (10 mg/kg/d, orally) for 6 months, and three controls. Body weight, blood pressure, glomerular filtration rate (GFR) by plasma clearance of (51)Cr-ethylenediamine-tetraacetic acid, CsA concentration, serum creatinine, and other values were measured every 5 weeks. Our results showed that the whole blood trough CsA levels were lower in pigs than in humans treated with similar CsA doses. Renal biopsies, which were obtained successfully, except one case of macroscopic hematuria, showed no histological changes in the kidney. No significant increase in serum creatinine or blood pressure was observed. Surprisingly, there was a significant increase in GFR during CsA treatment. We conclude that the pig model displays a hyperfiltration that warrants further investigation.