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


CONCLUSIONS
mTOR-Is could be more widely used in kidney transplant patients due to reduced nephrotoxicity and de novo cancer compared with CNIs.
Rostaing
Lionel
L
Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Toulouse. rostaing.l@chu-toulouse.fr
Kamar
Nassim
N
D065095:Calcineurin Inhibitors; D049109:Cell Proliferation / Q000187:drug effects*; D004359:Drug Therapy, Combination; D019317:Evidence-Based Medicine; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016030:Kidney Transplantation / Q000009:adverse effects; D009369:Neoplasms / Q000209:etiology / Q000517:prevention & control; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D013997:Time Factors; D016896:Treatment Outcome
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases