Can mTOR inhibitors reduce the risk of late kidney allograft failure?
The most frequent causes of late kidney allograft failure are chronic rejection, nonalloimmune injury and death, all of which may depend on the characteristics of the donor and recipient, but may also be influenced by the type of immunosuppression. Combining calcineurin inhibitors (CNIs) and corticosteroids offers potent immunosuppression, but may also cause side effects leading to progressive graft dysfunction or an increased risk of death. New immunosuppressive strategies may come from the availability of inhibitors of mTOR, a downstream effector of phosphatidylinositol-3 kinase that provides the signal for cell proliferation by phosphorylating a cascade of kinases. Recent trials have shown that it is possible to minimize the dose or withdraw CNIs a few weeks after transplantation when they are combined with mTOR inhibitors and their combination may also make it possible to minimize or avoid the use of corticosteroids. Moreover, by inhibiting the signal for cell proliferation, mTOR inhibitors may reduce the replication of cytomegalovirus inside host cells, prevent transplant vasculopathy, and exert anti-oncogenic activity. All of these characteristics offer a ray of hope for reducing the risk of long-term allograft failure.
Ponticelli
Claudio
C
Department of Immunology, Istituto Auxologico Italiano, Milano, Italy. ponticelli@fastwebnet.it
D000818:Animals; D065095:Calcineurin Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation; D011494:Protein Kinases / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus