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

ABSTRACT

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.

KEYWORDS:

• Pancreas transplant
• mTOR inhibitors
• proteinuria
• hyperglycemia
• autophagy

Article highlights

• mTORi is used in immunosuppressive maintenance regimen in ~ 20% of SPKT recipients. In PTA, mTORi did not adversely affect pancreas allograft survival.

• Side effects occurring in ≥ 10% of patients treated with mTORi include dyslipidemia, peripheral edema, cytopenia, acne, proteinuria, and oral ulcers. Other adverse events attributed to mTORi include hyperglycemia, wound healing complications, interstitial pneumonitis, infertility, and diarrhea.

• Successful control of dyslipidemia and cytopenia can be achieved without discontinuing mTORi. Most other side effects are harder to manage.

• Cardiovascular disease is the leading cause of mortality among pancreas transplant recipients and it accounts for a significant amount of death with a functioning allograft. Treatment of mTORi-induced dyslipidemia may have a potential benefit of lowering LDL and decreasing cardiovascular risks.

• Experimental studies highlight the importance of tight mTOR regulation in podocytes and β-cells function and suggest that the use of mTORi to treat renal and pancreatic disease must be considered with caution.

• Switching from CNIs to mTORi is associated with worsening or de novo proteinuria in the post-transplant setting. Low risk immunologic risk patients with estimated glomerular filtration ratio > 40 ml/min and no significant proteinuria (< 500 mg/day) are potentially good candidates for conversion. DSA monitoring is a key aspect after conversion to mTORi for antibody-mediated rejection screening.

• mTORi can cause DM by reducing β-cell mass and function, promoting apoptosis and decreasing β-cell proliferation and regeneration. Strategies of ‘resting’ β-cells using insulin and anti-hyperglycemic agents (insulin, glitazones, DPP-4 inhibitors, and metformin) combined to therapeutic lifestyle changes may preserve β-cell function and β-cell mass, contributing to prolong pancreatic allograft survival and, ultimately, patient survival.

• Autophagy may be a promising therapeutic target to treat renal and pancreatic disease, but further studies are required to address this strategy in the post-transplant setting.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.