Klawitter Jelena, Klawitter Jost, Schmitz Volker, Shokati Touraj, Epshtein Ekaterina, Thurman Joshua M, Christians Uwe
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.
Department of Anesthesiology, University of Colorado, Aurora, Colorado, United States of America.
PLoS One. 2014 Jan 30;9(1):e86202. doi: 10.1371/journal.pone.0086202. eCollection 2014.
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.
已知霉酚酸酯（MMF）本身对肾脏没有负面影响。MMF单独使用或与西罗莫司联合使用，可作为无钙调神经磷酸酶抑制剂（CNI）、保护肾脏的药物方案的基础。然而，由于同种免疫反应风险增加，接受MMF/西罗莫司（SRL）治疗的患者的长期预后似乎不如接受包含CNI他克莫司（TAC）的方案治疗的患者。有趣的是，从未考虑过MMF可能增强SRL和TAC对肾脏的负面影响。
我们的目的是研究TAC、SRL和MMF单独的作用，并评估它们联合使用时对大鼠肾脏的相互作用。为此，我们采用了一种综合分子标记方法，包括测量尿8-异前列腺素浓度（氧化应激标记物）和尿代谢物模式的变化（氢核磁共振波谱法），并将这些标记物与肾功能（肾小球滤过率（GFR））和形态学改变（组织学）进行比较。
虽然单独使用MMF不会影响GFR，但它与SRL和TAC的相互作用导致大鼠肾功能显著下降。这种下降与尿异前列腺素浓度的显著增加以及对尿代谢物模式的负面影响增强同时发生。
概括而言，本研究表明MMF可能增强TAC对肾功能的负面影响，甚至在与SRL联合使用时可能表现出肾毒性。
