Mycophenolate Mofetil Enhances the Negative Effects of Sirolimus and Tacrolimus on Rat Kidney Cell Metabolism

Jelena Klawitter,Touraj Shokati,Volker Schmitz,Joshua M Thurman,Jost Klawitter,Ekaterina Epshtein,Uwe Christians,Leighton R James

doi:10.1371/journal.pone.0086202

Jelena Klawitter, Touraj Shokati + Show 6 more

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https://doi.org/10.1371/journal.pone.0086202

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Background and PurposeMycophenolate 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.Experimental ApproachIt 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 (1H-NMR spectroscopy) and comparing these markers to renal function (glomerular filtration rate (GFR)) and morphologic alterations (histology).Key ResultsWhile 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.ConclusionsIn 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.

Highlights

The introduction of calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus (TAC) in kidney transplantation has made transplantation a standard therapeutic intervention for end-stage renal diseases [1,2]
Experimental Approach: It was our aim to study the effects of TAC, SRL and mycophenolate mofetil (MMF) alone and evaluate their interactions when combined on the rat kidney
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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Introduction

The introduction of calcineurin inhibitors (CNIs) cyclosporine (CsA) and tacrolimus (TAC) in kidney transplantation has made transplantation a standard therapeutic intervention for end-stage renal diseases [1,2]. The combination of low dose CNIs with MMF/MPA or SRL seems to be an attractive option for long-term maintenance immunosuppressive drug regimens after kidney transplantation [15,16,17,18,19]. 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 (1H-NMR spectroscopy) and comparing these markers to renal function (glomerular filtration rate (GFR)) and morphologic alterations (histology)

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