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.
Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Toulouse. rostaing.l@chu-toulouse.fr
Lionel
L
Rostaing
Nassim
N
Kamar
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