Tacrolimus has less fibrogenic potential than cyclosporin A in a model of renal ischaemia-reperfusion injury.
BACKGROUND
Cyclosporin is associated with significant chronic nephrotoxicity, manifest in the long term mainly as renal fibrosis. There have been claims that tacrolimus is a less fibrotic drug than cyclosporin, and this study was designed to determine the effect of the two drugs on the expression of fibrosis-associated genes.


METHODS
Male Wistar rats underwent clamping of the right renal pedicle for 45 min together with left nephrectomy; this model has previously been shown to be associated with upregulation of fibrosis-associated genes. Experimental groups (six animals per group) received cyclosporin A 10 mg/kg daily, tacrolimus 0.2 mg/kg daily or no treatment. Animals were killed at 16 weeks, and the renal cortical expression of fibrosis-associated genes was studied by means of quantitative reverse transcriptase-polymerase chain reaction.


RESULTS
Tacrolimus-treated animals developed significantly less proteinuria and had lower serum creatinine levels than those receiving cyclosporin. Tacrolimus administration also significantly reduced the expression of transforming growth factor beta and tissue inhibitor of metalloproteinases 1, both the products of genes associated with fibrosis. Although cyclosporin treatment reduced levels of the matrix-degrading enzymes, matrix metalloproteinase (MMP) 2 and MMP-9, this was not statistically significant.


CONCLUSIONS
Tacrolimus has less nephrotoxicity than cyclosporin in this model. It also appears to have less fibrogenic potential, and this may have implications for the choice of long-term immunosuppressant in renal transplantation.
Jain
S
S
Department of Transplant Surgery, Leicester General Hospital, UK.
Bicknell
G R
GR
Nicholson
M L
ML
D000818:Animals; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000009:adverse effects*; D005355:Fibrosis; D015870:Gene Expression; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011507:Proteinuria / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar; D012077:Renal Artery; D015427:Reperfusion Injury / Q000139:chemically induced*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016559:Tacrolimus / Q000009:adverse effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D007166:Immunosuppressive Agents; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D003404:Creatinine; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D016559:Tacrolimus