Systemic and Nonrenal Adverse Effects Occurring in Renal Transplant Patients Treated with mTOR Inhibitors

Abstract

The mammalian target of rapamycin inhibitors (mTOR-I), sirolimus and everolimus, are immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR), a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2, and PI3K confers the antineoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are valid option to calcineurine inhibitors (CNIs) for maintenance immunosuppression in renal transplant recipients with chronic allograft nephropathy. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects that need to be early recognized and treated to avoid severe illness in renal transplant patients. In particular, mTOR-I may induce systemic nonnephrological side effects including pulmonary toxicity, hematological disorders, dysmetabolism, lymphedema, stomatitis, cutaneous adverse effects, and fertility/gonadic toxicity. Although most of the adverse effects are dose related, it is extremely important for clinicians to early recognize them in order to reduce dosage or discontinue mTOR-I treatment avoiding the onset and development of severe clinical complications.

m-TOR Inhibitors in the Current Practice

“…In the pre-clinical models; m-TORI had exhibited growth inhibition of tumoral cells by increasing expression of E-cadherin and p27-kip1, also it decrease cyclin-d1 expression, causing arrest in cellular progression from G1 to S-phase [1,4,6,7,15]. Recent reports demonstrated that sirolimus inhibits UV-B activation of several metalloproteinases that can enhance tumor development and premature skin aging [34].…”

“…• Fever (23% to 34%), chest pain, headache, insomnia, fatigue, Arthralgia, alterations in taste, and asthenia are common side effects and can be managed by reducing the drug dose [1,3,15].…”

“…Hyperlipidemia was reported in 8% to 57%, M-TORI increases high-density lipoproteins (HDL), low density lipoproteins (LDL), cholesterol, and triglycerides in approximately 40 to 75% of patients receiving this therapy, it affects the up-regulation of adipocyte fatty acid-binding protein (aP2) expressed in monocytes and macrophages which plays a key role in the increased accumulation of triglycerides [3,15].…”

“…In contrast to SRL, everolimus (EVR/RAD/Certican) is considered as a derivative of sirolimus, structurally looks similar to SLR but with additional extra hydroxyethyl chain substitution at position-40 on the sirolimus molecule, which make it more hydrophilic and bioavailable than sirolimus (figure 2) [1,4,5,[7][8][9][10][11][12][13][14][15]. Similarly EVR/FKBP-12 multiplexes acts directly to mTOR, leading to inhibition of T-cell progression from the G1 to the S stage of cell cycle, thus results in inhibition of IL-2-induced protein synthesis and cellular proliferation and inhibition of IL-4-dependent multiplications of T-and B-cells [1,4,15,16].…”

“…Similarly EVR/FKBP-12 multiplexes acts directly to mTOR, leading to inhibition of T-cell progression from the G1 to the S stage of cell cycle, thus results in inhibition of IL-2-induced protein synthesis and cellular proliferation and inhibition of IL-4-dependent multiplications of T-and B-cells [1,4,15,16]. Moreover, B-cell activation, proliferation, differentiation into antibody-producing cells, and antibody release are also inhibited [5,6,17].…”