Complete Avoidance of Calcineurin Inhibitors in Renal Transplantation: A Randomized Trial Comparing Sirolimus and Tacrolimus

Abstract

Calcineurin inhibitors have decreased acute rejection and improved early renal allograft survival, but their use has been implicated in the development of chronic nephrotoxicity. We performed a prospective, randomized trial in kidney transplantation comparing sirolimus-MMF-prednisone to tacrolimus-MMFprednisone. Eighty-one patients in the sirolimus group and 84 patients in the tacrolimus group were enrolled (mean follow-up = 33 months; range 13-47 months). At 1 year, patient survival was similar in the groups (98% with sirolimus, 96% with tacrolimus; p = 0.42) as was graft survival (94% sirolimus vs. 92% tacrolimus, p = 0.95). The incidence of clinical acute rejection was 10% in the tacrolimus group and 13% in the sirolimus group (p = 0.58). There was no difference in mean GFR measured by iothalamate clearance between the tacrolimus and sirolimus groups at 1 year (61 ± 19 mL/min vs. 63 ± 18 mL/min, p = 0.57) or 2 years (61 ± 17 mL/min vs. 61 ± 19 mL/min, p = 0.84). At 1 year, chronicity using the Banff schema showed no difference in interstitial, tubular or glomerular changes, but fewer chronic vascular changes in the sirolimus group. This study shows that a CNI-free regimen using sirolimus-MMF-prednisone produces similar acute rejection rates, graft survival and renal function 1-2 years after transplantation compared to tacrolimus-MMF-prednisone.

Long-term Efficacy and Safety of a Calcineurin Inhibitor-free Regimen in Live-Donor Renal Transplant Recipients

“…Based on intention-to-treat analysis, statistically significant higher renal function obtained at 2 yr among SRL/MMF patients, 14 was maintained until the last follow-up period, a finding that comes in accordance with all short-term 12,13,20 and long-term studies 16 ; however, more recently, Larson et al, 21 in a comparison of TAC/MMF versus SRL/MMF, showed that the iothalamate clearance at 1 mo was higher in the SRL/MMF than in the TAC/MMF group (67 Ϯ 18 ml/min versus 58 Ϯ 17 ml/min); however, this difference was lost at 1 yr because of the unexpected loss of GFR in the SRL/MMF group. Differences in renal function between Larson's and other studies may be explained by the different anti-calcineurinic drugs used in the control group because it seems that CsA induces more profound renal hemodynamic changes than TAC, at least at the current target levels for clinical immunosuppression.…”

“…21 Moreover, even in patients with high immunologic risk, Lo et al 20 reported 12-mo incidence of as low as 7%.…”

Five-Year Outcomes in Kidney Transplant Patients Converted From Cyclosporine to Everolimus: The Randomized ZEUS Study

“…CNI avoidance with mTOR inhibitor therapy from time of transplant was found to preserve efficacy and improve longterm renal function in early randomized trials (7)(8)(9), but more recent studies that have used lower-exposure sirolimus in an attempt to reduce toxicity have found efficacy to be compromised (10,11) and de novo CNI-free immunosuppression with sirolimus and mycophenolic acid (MPA) may be associated with inferior graft outcomes (10)(11)(12). Several randomized trials have compared the efficacy and safety of mTOR inhibitor therapy with reduced-exposure CNI from the time of kidney transplantation versus a standard CNI regimen with MPA therapy (13)(14)(15)(16).…”

Resolved

“…A recent head-to-head study of tacrolimus versus sirolimus in a steroid-maintenance protocol in which all patients received antithymocyte globulin induction therapy, showed no differences in measured GFR or rejection rates between the two groups. 12 Biopsy results showed fewer chronic vascular changes in the sirolimus group as compared with the tacrolimus group. Biopsy findings were significantly worse for tacrolimus patients in both the intention to treat groups (P ϭ 0.03) and when analyzed for patients remaining on the initial study drug.…”

“…11 For pediatric recipients, Sarwal et al also noted that an RDP protocol was associated with increased growth and increased compliance. 12 Success with RDP protocols has now been reported for both living and deceased donor recipients, for primary and secondary recipients, for white, black, and Asian recipients, for immunologically low-risk and highly sensitized recipients, and for recipients with potentially recurring diseases. 10 Clearly, the short-and mid-term goals of RDP have been achieved.…”