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

• Published in: PloS one Vol. 9; no. 1; p. e86202
• Main Authors: Klawitter, Jelena, Klawitter, Jost, Schmitz, Volker, Shokati, Touraj, Epshtein, Ekaterina, Thurman, Joshua M, Christians, Uwe
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.01.2014; Public Library of Science (PLoS)
• Subjects: Anesthesiology; Animals; Biology; Blood pressure; Calcineurin; Chemistry; Cytochrome; Diabetes; Drug dosages; Drug Synergism; Enzymes; Glomerular filtration rate; Glomerular Filtration Rate - drug effects; Graft Rejection - prevention & control; Histology; Hypertension; Immunosuppressive agents; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacokinetics; Immunosuppressive Agents - therapeutic use; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney - physiopathology; Kidney diseases; Kidney Transplantation; Lipids; Magnetic resonance spectroscopy; Male; Medicine; Metabolism; Metabolites; Mycophenolate mofetil; Mycophenolic acid; Mycophenolic Acid - adverse effects; Mycophenolic Acid - analogs & derivatives; Mycophenolic Acid - pharmacokinetics; Mycophenolic Acid - therapeutic use; NMR; NMR spectroscopy; Nuclear magnetic resonance; Nuclear magnetic resonance spectroscopy; Oxidative stress; Physiological aspects; Rapamycin; Rats; Rats, Inbred WF; Renal function; Rodents; Sirolimus - adverse effects; Sirolimus - pharmacokinetics; Sirolimus - therapeutic use; Spectroscopy; Tacrolimus; Tacrolimus - adverse effects; Tacrolimus - pharmacokinetics; Tacrolimus - therapeutic use; Tissue Distribution; Transplants & implants; Trends; Urine; United States > US; Colorado
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0086202

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. 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). 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. 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.