Acute Nephrotoxicity of Tacrolimus and Sirolimus in Renal Isografts: Differential Intragraft Expression of Transforming Growth Factor-??1 and ??-Smooth Muscle Actin

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Abstract
Background. Renal dysfunction early after kidney transplantation has multiple causes including ischemia-reperfusion (I/R) injury and drug-induced nephrotoxicity. This study assesses the acute nephrotoxicity of tacrolimus (Tac) and sirolimus (Sir) in a rat renal isograft model. Methods. Lewis renal isografts and uninephrectomized rats that did not undergo transplantation were treated with various doses of Tac (0.5–5.0 mg/kg/d) or Sir (0.5–6.5 mg/kg/d). Kidneys were examined on day 14 by routine histology and immunohistochemistry for transforming growth factor (TGF)-β1 and α-smooth muscle actin (SMA). Results. Both Tac and Sir demonstrated evidence of nephrotoxicity in the early posttransplant period including increased serum creatinine and morphologic changes in the graft including interstitial inflammation, fibrosis, and tubular vacuolization. Nephrotoxicity was most prominent in the high-dose treatment groups for both drugs and was more severe in transplanted kidneys than in uninephrectomized animals that did not undergo transplantation, suggesting an additive effect of I/R injury and drug nephrotoxicity. Both Tac and Sir increased intragraft TGF-β1 and α-SMA, but there were distinct differences in the patterns of TGF-β1 expression. Both demonstrated TGF-β1 in tubular epithelial cells, but Sir was associated with proximal tubular TGF-β1 localization in a bright granular pattern, whereas Tac was associated with diffuse distal tubular staining. Conclusions. Both Tac and Sir may be nephrotoxic in the early posttransplant period, especially at high doses and when combined with I/R injury. Immunohistochemical localization of TGF-β1 in the tubular cells was distinctly different with each drug, suggesting possible differences in the mechanism(s) of nephrotoxicity requiring further study.