What is the role of sirolimus in immunosuppression after solid organ transplantation?

Updated: Jan 04, 2016
  • Author: Bethany Pellegrino, MD; Chief Editor: Mary C Mancini, MD, PhD, MMM  more...
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Mammalian target of rapamycin (mTOR) inhibitors

Sirolimus, also called rapamycin, is a macrolide product of a soil fungus found on Easter Island. This agent is used for maintenance immunosuppression and chronic rejection. Everolimus is a rapamycin analog with a similar mechanism of action and adverse effect profile.

The mode of action of sirolimus is to bind the cytosolic protein-FKBP12 in a way similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin, the sirolimus-FKBP12 complex inhibits the mTOR pathway by directly binding the mTOR Complex1 (mTORC1). This complex inhibits signal 3 by stopping translation of the RNA and preventing the progression from G1 phase to the S phase of DNA synthesis. It also inhibits IL-2– and IL–4-dependent proliferation of T and B cells.

Similarly, sirolimus inhibits proliferation of nonimmune cells and the pathways that could be involved in oncogenesis. The antiproliferative effects of sirolimus may have a role in treating cancer. Sirolimus was shown to inhibit the progression of dermal Kaposi sarcoma in patients with renal transplants. Sirolimus-based regimens have been associated with a reduced incidence of posttransplantation malignant neoplasms. It has been reported that a cyclosporine a–free immunosuppressant regimen based on sirolimus reduced aortic stiffness, plasma endothelin-1, and oxidative stress in renal transplant recipients enrolled in the CONCEPT trial.

Multiple drug interactions are possible, especially because of the extremely long half-life. Concomitant use with strong CYP3A4/P-gp inducers or strong CYP3A4/P-gp inhibitors decreases or increases sirolimus concentrations. When mTOR inhibitors are used simultaneously with cyclosporine, maximum concentration of the drug (Cmax) and area-under-the-curve (AUC) for both the compounds are increased. Thus, it is recommended that cyclosporine and mTOR inhibitors to be administered 4 hours apart.

Adverse effects associated with mTOR inhibitors are hyperlipidemia, thrombocytopenia, anemia, pneumonitis, oral ulcers, and diarrhea. Low testosterone levels may cause infertility. These agents can also cause poor wound healing and dehiscence formation of lymphoceles. When used combination with calcineurin inhibitors, sirolimus potentiates calcineurin nephrotoxicity. Sirolimus is associated with worsening of proteinuria. It may also cause delayed recovery from acute tubular necrosis.

Although successful pregnancies with sirolimus have been reported, it is not routinely used in pregnancy.

Finally, thrombotic angiopathy cases have been reported with sirolimus. Avoidance of calcineurin may be considered in patients with a primary etiology of atypical hemolytic uremic syndrome or other forms of thrombotic angiopathy, and use of sirolimus may "decrease" the incidence of hemolytic uremic syndrome recurrence.

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