Mycophenolate mofetil enhances the negative effects of sirolimus and tacrolimus on rat kidney cell metabolism

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Abstract

BACKGROUND AND PURPOSE: Mycophenolate mofetil (MMF) per se is not known to have negative effects on the kidney. MMF alone or in combination with sirolimus, can be the basis of calcineurin inhibitor (CNI)-free, kidney sparing drug protocols. However, long-term outcomes in patients on MMF/SRL seem to be inferior to those treated with regimens that include the CNI tacrolimus (TAC) due to an increased risk of allo-immune reactions. Interestingly, potential enhancement of the negative effects of SRL and TAC on the kidney by MMF has never been considered.<br /><br />EXPERIMENTAL APPROACH: It was our aim to study the effects of TAC, SRL and MMF alone and evaluate their interactions when combined on the rat kidney. For this purpose we used a comprehensive molecular marker approach including measurements of urinary 8-isoprostane concentrations (oxidative stress marker) and changes of urinary metabolite patterns ((1)H-NMR spectroscopy) and comparing these markers to renal function (glomerular filtration rate (GFR)) and morphologic alterations (histology).<br /><br />KEY RESULTS: While MMF alone did not impact GFR, its interaction with SRL and TAC led to a significant decrease of rats' renal function. The decline went in parallel with a significant increase in urinary isoprostane concentrations and an enhancement of negative effects on urinary metabolite patterns.<br /><br />CONCLUSIONS: In broad summary, the present study showed that MMF may enhance the negative effects of TAC on kidney function and may even display nephrotoxic properties when combined with SRL.

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Klawitter, J., Klawitter, J., Schmitz, V., Shokati, T., Epshtein, E., Thurman, J. M., & Christians, U. (2014). Mycophenolate mofetil enhances the negative effects of sirolimus and tacrolimus on rat kidney cell metabolism. PLoS ONE, 9(1). https://doi.org/10.1371/journal.pone.0086202

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