A Comparative, Randomized Trial of Concentration-Controlled Sirolimus Combined With Reduced-Dose Tacrolimus or Standard-Dose Tacrolimus in Renal Allograft Recipients

Abstract

Background. The clinical safety and efficacy of sirolimus plus reduced-dose tacrolimus was evaluated in de novo renal allograft recipients enrolled in a comparative, open-label study. Methods. One hundred twenty-eight renal allograft recipients were randomly assigned (1:1) to receive reduced-dose tacrolimus plus sirolimus (rTAC) or standard-dose tacrolimus and sirolimus (sTAC) for 6 months. The primary efficacy endpoint was calculated creatinine clearance values at 6 months. Results. Demographic variables were similar between groups. At 6 months, mean (AE standard deviation) calculated creatinine clearance was significantly improved in the rTAC group (63.8 vs 52.7 mL/min, P ¼ .005), although mean serum creatinine values were not significantly different. Patient survival (95.2% and 96.9%) and graft survival (93.7% and 98.5%) were similar between the rTAC and sTAC groups, respectively. Acute rejection rates were 17.5% with rTAC and 7.7% with sTAC (P ¼ .095). Conclusions. The rTAC regimen provided effective immunosuppression and was associated with improved creatinine clearance. Adequate immunosuppressant exposure must be achieved in the early postoperative period to minimize the risk of acute rejection.

Calcineurin Inhibitor Minimization, Conversion, Withdrawal, and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta‐Analysis

“…The most widely reported strategy identified by our literature search was CNI minimization, implemented by reducing target trough levels. Thirty‐six RCTs (Table S4) examining dose minimization were identified: 22 studies used CsA, 7 used tacrolimus and 7 incorporated both. Mycophenolic acid formulations (mycophenolate mofetil [MMF] or enteric‐coated mycophenolate sodium [MPS]) were used as adjuvant agents in 19 studies, and 14 used mammalian target of rapamycin (mTOR) inhibitors in addition to CNI.…”

Impact on Autophagy and Ultraviolet B Induced Responses of Treatment with the MTOR Inhibitors Rapamycin, Everolimus, Torin 1, and pp242 in Human Keratinocytes

“…Rapamycin is also known as another denomination sirolimus [69] and is used in combination with the calcineurin inhibitor tacrolimus as maintenance immunosuppressants in transplantation to selectively block the transcriptional activation of cytokines [43, 70, 71]. Importantly, Rapamycin binds two proteins, the FK506- (tacrolimus-) binding protein (FKBP) and FKBP-Rapamycin-associated protein (FRAP, the primal nomination of MTOR), in regulating cellular signaling [72, 73].…”

Protective effects of tacrolimus on podocytes in early diabetic nephropathy in rats

“…Tacrolimus is a potent immunosuppressant, and several animal experiments and clinical applications have demonstrated that it has a similar immunosuppressive effect to cyclosporin A (Cys A), with more potent immunosuppressive effects, compared with CysA (10-100-fold higher) and fewer side effects (25). Previous studies have found that tacrolimus not only forms a basis for immunosuppression to prevent kidney transplant rejection, but also for the treatment of chronic allograft nephropathy and lupus nephritis, which can significantly delay glomerulosclerosis and tubulointerstitial damage (26,27). Studies have shown that tacrolimus inhibits transforming growth factor-β-induced kidney tubular epithelial cell transdifferentiation, which may be an important mechanism of tacrolimus in treating organ rejection post-transplantation, and which also provides a theoretical basis for the prevention and treatment of renal fibrosis (28).…”