mTOR inhibitor/proliferation signal inhibitors: entering or leaving the field?

Abstract

Background: The mammalian target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that controls cell growth and metabolism in response to nutrients, growth factors, cellular energy and stress, and has pleiotropic effects. Its blockade, by mTOR inhibitors (mTOR-Is), such as sirolimus or everolimus, leads to antiproliferative effects.

Methods: We have reviewed the major studies that deal with the utilization of mTOR-Is after kidney transplant and the outcomes.

Results: Calcineurin-inhibitor (CNI) avoidance, under the umbrella of sirolimus-based immunosuppression in de novo kidney-transplant (KT) patients, is associated with worse results compared with those observed in patients receiving CNI-based immunosuppression. Conversely, using mTOR-Is in the context of CNI minimization and CNI-free protocols is safe and efficient when used after 3 months post-transplant. If cyclosporin A (CsA) is used in combination with mTOR-I, considerable dose reduction of both drugs is required. A better choice may be withdrawal of CsA from this combination after 3-12 months. Later withdrawal or conversion to an mTOR-I may not be beneficial. Kidney transplant recipients given mTOR-Is have reduced incidence of de novo posttransplant malignancies. Posttransplant Kaposi's sarcoma and nonmelanotic skin malignancies frequently undergo remission/regression after conversion to mTOR-I immunosuppression. The associated side effects of mTOR-Is are numerous and may lead to significant drug cessation.

Conclusion: mTOR-Is could be more widely used in kidney transplant patients due to reduced nephrotoxicity and de novo cancer compared with CNIs.