Mammalian Target of Rapamycin Inhibitors Combined With Calcineurin Inhibitors as Initial Immunosuppression in Renal Transplantation: A Meta-analysis

Abstract

Background: The current standard of care immunosuppressive regimen in kidney transplantation (KT) includes a combination of mycophenolates (MMF/MPA) with a calcineurin inhibitor (CNI). Methods:We designed a systematic review including all randomized clinical trials (RCTs) assessing the outcomes in KT recipients receiving mTORi+CNI compared with regimens containing MMF/MPA or azathioprine with CNI.Results: A total of 24 studies with 7356 participants were included. The comparison of mTORi-CNI versus MMF/MPA-CNI did not show differences in acute rejection, mortality or graft loss rates. Better graft function was observed using MMF/MPA-CNI than using mTORi+CNI, but this difference was not evident when the mTORi was associated with reduced dose CNI in more recent studies with everolimus.Dyslipidemia, lymphoceles and impaired wound healing were more frequent with mTORi-CNI and diarrhea and leukopenia more frequent with MMF/MPA-CNI. Viral infections at any time and malignant neoplasia beyond 2 years were less frequent with mTORi-CNI. Rates of discontinuation due to adverse effects in the mTORi groups varied between 17% and 46% compared to 0-26.6% in MMF/MPA groups. The current use of lower mTORi dosage has decreased discontinuation rates. Conclusions:Efficacy is similar with mTORi+CNI and MMF/MPA-CNI. The safety profile is the predominant difference between the two regimens.

Risks and benefits of everolimus

“…Thus, in summary, this trial together with the results of other recent data provides further evidence, that MPA/tacrolimus remains current standard of care in de‐novo renal allograft recipients, despite all the well known‐limitations of this combination therapy. Everolimus is a well‐proven second‐line treatment option in case of MPA intolerability, such as severe viral infections, which are difficult to treat.…”

“…Finally, frequent rejections followed by intense rejection treatment, severe infections, and aggravated nephrotoxicity caused renal problems, graft loss, and death in this trial. Again, this trial, like many other clinical trials and meta‐analyzes demonstrates, that renal dysfunction is more frequent in patients treated with combination of mTOR inhibitors and CNIs, especially if CNI levels are not adequately lowered . A thorough pharmacodynamic analysis from a large registration trial showed that already tacrolimus levels of 4 ng/ml increased the risk of low and/or decreasing renal function as early as 12 months post‐transplant.…”

“…Because of reimbursement issues in Brazil for the expensive valganciclovir prophylaxis, drug‐related side effects, and only 6% CMV high‐risk patients, the Sao Paolo group explored the option of a preemptive CMV treatment strategy with tight CMV monitoring together with the use of mTOR inhibitors . The observation of lower CMV infection rates under mTOR inhibitors compared with MPA dates back from early clinical trials and was confirmed in recent trials and meta‐analyzes .…”

“…Besides underimmunosuppression, typical drug‐related side effects (hyperlipidemia, stomatitis, edema, proteinuria, wound‐healing, and lymphoceles), remain a major concern in everolimus‐treated patients, leading to frequent discontinuations. All clinical trials and recent meta‐analyzes clearly demonstrate inferior tolerability of everolimus compared with MPA, as evidenced by higher discontinuation rates due to adverse events. Contrary to everolimus, MPA has a wide therapeutic range.…”

Mycophenolates: The latest modern and potent immunosuppressive drugs in adult kidney transplantation: What we should know about them?

“…Will mycophenolate continue to be part of the postKT triple therapy, or will it be replaced by a new molecule, or by older ones such as the mammalian target of rapamycin inhibitors (mTORi), that are increasingly finding their place in KT, especially in smaller doses. A large and recent systematic review included 24 randomized clinical trials assessing the outcomes in 7356 KT recipients receiving mTORi + CNI compared with regimens containing MMF/MPA or AZA with CNI . This systematic review did not show differences in acute rejection, mortality, or graft loss rates.…”