The pros and the cons of mTOR inhibitors in kidney transplantation

Abstract

Sirolimus and its derivate everolimus are two immunosuppressive drugs with similar chemical structure that inhibit the proliferation of T cells by interfering with a serine-threonine kinase, called mTOR. Apart from their immunosuppressive effects, these agents may also inhibit endothelial intimal proliferation, the replication of cytomegalovirus, and the development of certain cancers. The main dose-dependent adverse events of mTOR inhibitors are hyperlipidemia, thrombocytopenia, mucositis, edema, and proteinuria. The use of mTOR inhibitors in renal transplantation may allow to reduce the doses of calcineurin inhibitors. Withdrawal of calcineurin inhibitors is also possible and may improve renal function, but some patients do not tolerate this regimen because of side effects. Further studies are needed to assess the role of mTOR inhibitors in the long-term.

Keywords::

• everolimus
• kidney transplantation
• mTOR
• proliferation signal inhibitor
• rejection
• sirolimus

Financial & competing interests disclosure

C Ponticelli was a consultant of Novartis (Italy) until 31 December 2011. The author has no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• mTOR is the catalytic subunit of two complexes of serine–threonine kinase called mTORc1 and mTORc2.

• The mTORc1 is the downstream effector of phosphatidylinositol 3-kinase (PI3-k). In response to different stimuli, PI3-k (through the mediation of mTORc1) activates a cascade of kinases that transmit the signal to cells. In organ transplantation, this signaling pathway is activated by IL-2 and IL-15 and eventually provides the signal for T-cell proliferation.

• Sirolimus and everolimus are two macrocyclic lactones that after binding to a protein receptor, called FKBP12, inhibit the activity of mTORc1, which plays a central role in allotransplant rejection.

• The contact and costimulation with the antigen-presenting cell causes in the quiescent T cell, the activation of a system of phosphatases called calcineurin with consequent dephosphorylation of a family of transcription factors that allow their entrance into the nucleus where they participate to the synthesis of IL-2. After binding to its receptor IL-2, together with IL-15, activates PI3-k and its cascade of kinases that eventually give the signal for T-cell proliferation.

• In allotransplantation, the inhibition of mTORc1, the downstream effector of PI3-k, inhibits the phosphorylation of some kinases and cyclin-dependent kinases so preventing the signal for T-cell proliferation.

Notes