Telmisartan attenuates chronic ciclosporin A nephrotoxicity in a pig model.
BACKGROUND
We have previously demonstrated renal enlargement in pigs treated with ciclosporin A (CsA) 10 mg/kg/day orally for 6 months. The aim of the study was to investigate the effect of oral CsA (10 mg/kg/day) for 12 months on kidney structure and function and the potential renoprotective role of angiotensin II (Ang II) receptor blocker telmisartan on chronic CsA nephrotoxicity in pigs.


METHODS
Fourteen Göttingen minipigs aged 12-14 months were included: pigs received either CsA 10 mg/kg/day (n = 7) or CsA 10 mg/kg/day + telmisartan 40 mg/day (n = 7) orally for 12 months. At week 0, 12, 31, 38, 47 and 54, we measured body weight, mean arterial blood pressure (MAP), serum creatinine, whole blood trough CsA, plasma Ang II, haemoglobin and liver function parameters. Magnetic resonance imaging was used to estimate kidney length, volume, relative glomerular filtration rate (rGFR) and renal blood flow (RBF). Kidney tissue biopsies were used for conventional histological examination.


RESULTS
Plasma Ang II levels were significantly higher during telmisartan treatment. Interstitial fibrosis and glomerulosclerosis occurred in both groups, but were attenuated in the telmisartan-treated pigs (P = 0.064). A significant increase in renal volume was seen in both groups, but tended to be lower in the CsA + telmisartan pigs at 54 weeks (P = 0.097). Telmisartan did not reduce MAP, RBF or rGFR.


CONCLUSIONS
Long-term CsA treatment causes histopathological changes in the porcine kidney similar to those observed in humans and results in renal enlargement. Telmisartan attenuates the CsA-induced histopathological changes and enlargement in the pig kidney.
Cibulskyte
Donata
D
Clinical Institute, Skejby Hospital, Aarhus University Hospital, 8200 Aarhus N, Denmark.
Pedersen
Michael
M
Hørlyck
Arne
A
Marcussen
Niels
N
Hansen
Hans Erik
HE
Frøkiaer
Jørgen
J
Madsen
Melvin
M
Mortensen
Jens
J
D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use*; D001565:Benzoates / Q000627:therapeutic use*; D001706:Biopsy; D001783:Blood Flow Velocity / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D016572:Cyclosporine / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D008279:Magnetic Resonance Imaging; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D013552:Swine; D000077333:Telmisartan; D016896:Treatment Outcome
D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001565:Benzoates; D007166:Immunosuppressive Agents; D000804:Angiotensin II; D016572:Cyclosporine; D000077333:Telmisartan