The role and value of sirolimus administration in kidney and liver transplantation

Abstract

Enormous advancements in visceral transplantation have led to significant improvements in the quality of life of patients. However, despite these developments, the average graft half-life after transplantation has remained almost unchanged and chronic rejection is still considered a major problem. In this regard, more concerns have shifted to factors influencing long-term graft survival, patient survival, and quality of life. To achieve this goal, detrimental effects of immunosuppressive (IS) agents, which have deleterious influence on the quality of life and/or patient survival, should be reduced. In the course of recent years, the transplant community has worked on reducing these side effects by developing new ISs, employing new combination regimens, or finding and adjusting optimal dosages and blood level concentrations. Among the IS agents, the antifungal, antitumoral and IS activity of mammalian target of rapamycin (mTOR) inhibitors without nephrotoxicity, have received special attention regarding this new class of IS. Sirolimus (SRL), as the first member of mTOR inhibitors, has been utilized in many clinical trials with respect to its benefit-risk assessment. In our review, the clinical evolution of SRL, as well as the evidence-based clinical benefits of SRL in kidney and liver transplantation (KTx, LTx), are summarized. Various studies of SRL in KTx and LTx have shown that combination therapy with SRL will enrich the variety of IS modalities. It also can be regarded as a safe base therapy to which other necessary drugs can be added. In addition to the enhanced acute rejection prophylaxis, and in contrast to the calcineurin inhibitors (CNI) and steroids, this drug solely does not have common side effects such as nephrotoxicity, neurotoxicity, diabetes mellitus and hypertension. Moreover, this agent might diminish vasculopathic processes that mediate chronic allograft nephropathy (CAN). Therefore, by reducing the likelihood of CAN it can decrease the rate of long-term organ failure. One possibly desirable characteristic of SRL is its antiproliferative effect, which could provoke antitumoral or antiatherogenic activity following transplantation. Despite all promising impacts of SRL in organ transplantation, there are some concerns regarding the adverse effects of this drug, for instance dyslipidemia, pneumonitis and wound healing problems. However, the majority of these side effects can be reduced or ceased by careful dose adjustments and correct timing of use. In conclusion, after a decade of both in vivo and in vitro studies on SRL, it can be advocated that SRL is a promising, potent and effective IS agent as it reduces the rate of acute rejection episodes in de novo transplants. It could improve the quality of life, graft and patient survival rate, and achieve excellent outcomes with few adverse effects when wisely used in combination with other immunosuppressants.

Rapamycin Protects Against High Fat Diet–Induced Obesity in C57BL/6J Mice

“…Subsequently, RAPA was shown to have potent immunosuppressive and antiproliferative effects (11). As an immunosuppressant drug, it is used extensively following kidney, liver, and heart transplants to prevent acute graft rejection (12,13). In addition, because of its antiproliferactive action, RAPA holds promise as a novel anticancer agent (14).…”

Acute Rejection Features in Dual Kidney Transplant Recipients from Elderly Donors: Comparison of Calcineurin Inhibitor-Based and Calcineurin Inhibitor-Free Immunosuppressive Protocols

“…In previous reports on single kidney transplant recipients from standard donors, when sirolimus was added to CIs the number of ATCMRs was lower than that observed using CI-based protocols (22). In the absence of CIs, however, it was similar or higher (23-24) depending on number, type and doses of the other irnmunosupressive drugs used in combination with sirolimus (25)(26)16).…”

“…Kidneys from elderly donors may have a reduced renal reserve, and chronic CItoxicity can further impair their function. Sirolimus, administered alone to animals, was devoid of nephrotoxicity, (20)(21) and, when included in Cl-sparing and CI-free protocols, preserved renal function in humans (16). In previous reports on single kidney transplant recipients from standard donors, when sirolimus was added to CIs the number of ATCMRs was lower than that observed using CI-based protocols (22).…”

“…It has been recently shown that graft loss in recipients of grafts from donors over 70 years of age was higher than in recipients of grafts from donors 60 to 69 years of age (15) Calcineurin inhibitor-free immunosuppressive therapy based on sirolimus can preserve renal function and decrease the likelihood ofIF/TA (16). Thus, in this context it might be particularly advantageous.…”

Impaired Lower Extremity Wound Healing Secondary to Sirolimus After Kidney Transplantation

“…The half-life is between 57 and 63 hours, and excretion is mostly fecal. 8,9 Sirolimus has found its place in immunosuppression after transplant for several reasons. It has been found to increase the potency of immunosuppression when added with other drug regimens.…”