Tacrolimus has less fibrogenic potential than cyclosporin A in a model of renal ischaemia-reperfusion injury

Background: Cyclosporin is associated with significant chronic nephrotoxici ty, manifest in the long term mainly as renal fibrosis. There have been cla ims that tacrolimus is a less fibrotic drug than cyclosporin, and this stud y was designed to determine the effect of the two drugs on the expression o f 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 show n to be associated with upregulation of fibrosis-associated genes. Experime ntal groups (str 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 studie d by means of quantitative reverse transcriptase-polymerase chain reaction. Results: Tacrolimus-treated animals developed significantly less proteinuri a and had lower serum creatinine levels than those receiving cyclosporin. T acrolimus administration also significantly reduced the expression of trans forming growth factor beta and tissue inhibitor of metalloproteinases 1, bo th the products of genes associated with fibrosis. Although cyclosporin tre atment reduced levels of the matrix-degrading enzymes, matrix metalloprotei nase (MMP) 2 and MMP-9, this was not statistically significant. Conclusion: Tacrolimus has less nephrotoxicity than cyclosporin in this mod el. It also appears to have less fibrogenic potential, and this may have im plications for the choice of long-term immunosuppressant in renal transplan tation.