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


METHODS
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).


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.


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.
Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America ; Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, United States of America.
Jelena
J
Klawitter
Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America.
Jost
J
Klawitter
Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America ; Department of General-, Visceral- and Transplantation Surgery, Charité, Campus Virchow, Berlin, Germany.
Volker
V
Schmitz
Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America.
Touraj
T
Shokati
Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America.
Ekaterina
E
Epshtein
Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado, United States of America.
Joshua M
JM
Thurman
Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America.
Uwe
U
Christians
D000818:Animals; D004357:Drug Synergism; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006084:Graft Rejection / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016030:Kidney Transplantation; D008297:Male; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011920:Rats, Inbred WF; D020123:Sirolimus / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016559:Tacrolimus / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution
D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus