Renal effects of long-term ciclosporin A treatment in a large animal model.
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
Gottingen 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.


CONCLUSIONS
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.
Cibulskyte
Donata
D
Department of Nephrology, Skejby Hospital, Aarhus University Hospital, Aarhus, Denmark.
Samsoe Engberg
Anne
A
Hanefelt Kristensen
Daniel
D
Ellingsen
Anne Ringer
AR
Ringer Ellingsen
Anne
A
Pedersen
Michael
M
Hoerlyck
Arne
A
Flyvbjerg
Allan
A
Marcussen
Niels
N
Hansen
Hans Erik
HE
Madsen
Melvin
M
Mortensen
Jens
J
D000284:Administration, Oral; D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D007677:Kidney Function Tests; D008137:Longitudinal Studies; D013552:Swine; D013556:Swine, Miniature
D016572:Cyclosporine