Renal Effects of Long-Term Ciclosporin A Treatment in a Large Animal Model

Abstract

Background: Most experimental studies of chronic ciclosporin A (CsA) nephrotoxicity have been performed in rodents; however, the pig possesses several advantages. The aim of this study was to investigate renal functional and structural changes during CsA treatment with 20 mg/kg/day for 6 months in a pig model. Methods: Göttingen minipigs were randomized to oral CsA treatment or as controls. At 0, 5, 10, 15, 20 and 25 weeks body weight, blood pressure, serum creatinine, and whole blood CsA levels were measured. Magnetic resonance imaging was used to estimate relative glomerular filtration rate (rGFR), renal blood flow (RBF), kidney length and volume. Renal vascular resistance (RVR) was calculated. Kidney tissue biopsies were taken and volume fraction of cortical interstitial tissue estimated by a stereology-based method. Results: CsA induced significant increases in serum creatinine, blood pressure, RVR, and a significant decrease in RBF. Furthermore, renal volume increased significantly. This finding was inversely related to the decrease in RBF and initially followed by an increase in rGFR, which then decreased. No significant histopathological kidney changes were observed. Conclusion: CsA treatment with 20 mg/kg/day for 6 months causes increased serum creatinine, blood pressure, RVR, and renal volume along with a decrease in RBF in accordance with data obtained in humans. The initial temporal changes in renal volume and function during CsA administration have similarities to the functional changes seen in early diabetes.