Sirolimus for calcineurin inhibitors in organ transplantation: contra.
Sirolimus (SRL) is an antiproliferative agent inhibiting the mammalian target of rapamycin (mTOR) proposed as a non-nephrotoxic alternative to calcineurin inhibitors for the prevention of acute rejection in renal transplantation. Despite initial encouraging results, enthusiasm faded with large trials showing an increased risk of acute rejection with this molecule that did not provide superior graft function over cyclosporin or tacrolimus. Recent data showed that SRL, along with an immunosuppressive activity on CD4+ T cells, exerts a paradoxical stimulatory effect on innate immunity, which may explain its incomplete control of alloimmune response. Moreover, SRL therapy is burdened by a concerning safety profile including high risk of delayed graft function and onset of proteinuria. This adds to many other adverse effects, including dyslipidemia, diabetes, myelosuppression, delayed wound healing, infertility, ovarian cysts, and mouth ulcers, that further limit the use of this molecule. Severe cases of interstitial pneumonia have also been reported with this therapy, raising additional concerns. Incomplete control of immune response, along with a poor tolerability, makes SRL far from being the ideal antirejection drug. Progressive restrictions of SRL indication in renal transplantation have, however, been paralleled by evidence showing mTOR abnormalities involved in many pathogenic conditions, thus opening the avenue to new possible applications of this molecule.
Cravedi
Paolo
P
Mario Negri Institute for Pharmacological Research, Bergamo--Unit of Nephrology, Azienda Ospedaliera Ospedali Riuniti, Bergamo, Italy.
Ruggenenti
Piero
P
Remuzzi
Giuseppe
G
D000818:Animals; D065095:Calcineurin Inhibitors; D051799:Delayed Graft Function / Q000139:chemically induced; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016377:Organ Transplantation / Q000009:adverse effects; D011507:Proteinuria / Q000139:chemically induced; D018570:Risk Assessment; D012307:Risk Factors; D020123:Sirolimus / Q000009:adverse effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus