mTOR inhibitors in pancreas transplant: adverse effects and drug-drug interactions.

INTRODUCTION: Patient and pancreas allograft survival improved following reductions in surgical complications, tighter donor selection and optimization in immunosuppressive protocols. However, long-term survival of pancreas allografts is adversely affected by rejection and immunosuppressive regimen toxicity. Areas covered: This article reviews the existing literature and knowledge of mammalian target of rapamycin inhibitors (mTORi). Some clinically relevant drug-drug interactions are highlighted. We summarize the nephrotoxic and diabetogenic mechanisms of mTORi after pancreas transplant, the alternatives to minimize these effects, and report on other adverse events. Expert opinion: Calcineurin inhibitor (CNI)-based regimens remain the mainstay treatment after pancreas-kidney transplant. However, long-term use of CNIs may be associated with nephrotoxicity. Switching from CNIs to mTORi (sirolimus/SRL and everolimus/EVR) may preserve kidney function, mainly EVR conversion. However, mTORi promote an imbalance of mTOR signaling during long-term follow-up and may ultimately contribute to proteinuria and hyperglycemia. These drugs disrupt autophagy, inhibit cell proliferation, and downregulate VEGF. Therefore, it is important to comprehend and interpret the experimental data. It is equally important to critically analyze clinical studies. Of importance, minimization of side effects, based on safe approaches, can prolong kidney allograft survival. Additional randomized-controlled studies are required to assess the impact of mTORi on pancreas allograft survival.