Management of Side Effects of Sirolimus Therapy Giovanni Stallone, 1,3 Barbara Infante, 1 Giuseppe Grandaliano, 2 and Loreto Gesualdo 1 Sirolimus (SRL) has been shown to improve long-term graft survival in several calcineurin inhibitor avoidance/ minimization protocols. Although SRL has been suggested to reduce the progression of chronic renal graft damage and to prevent the development of neoplasia, two of the most prominent challenges in the field of transplantation, its use is significantly limited by an extremely high incidence of side effects. Some of the side effects are directly linked to the antiproliferative action of SRL, whereas the mechanisms underlying most of the undesired effects of the drug are still far from being clarified. Nevertheless, there is an increasing body of evidence linking most these drug-associated events to SRL dose. In addition, it is now possible to identify well-defined risk factors for most of these effects. Thus, to limit SRL-related side effects the two golden rules are (1) accurate selection of patients to be treated and (2) avoidance of high SRL doses. Keywords: Sirolimus, Side effects, Kidney transplant. (Transplantation 2009;87: S23–S26) S irolimus (SRL) is a macrolide lactone with a novel mech- anism of immunosuppression (1). After administration, SRL enters the cells and binds to a specific cytoplasmic recep- tor, FK506-binding protein (FKBP-12). The drug-receptor complex blocks the activity of a cytoplasmic serine-threonine kinase known as mammalian target of rapamycin (mTOR). This kinase is the downstream effector of the phosphatidylinositol 3 kinase (PI3K)-Akt signaling pathway, and it is a key check-point in several cell functions, including cell growth and proliferation (1). The mTOR is also involved in the modulation of cell metabolism, sensing the availability of extracellular nutrients. A number of different stimuli, including interleukin-2, -15, on- cogenic proteins, vascular endothelial growth factor, may acti- vate mTOR. The inhibition of this pivotal cytoplasmic kinase by SRL in T cells hampers their clonal expansion in response to alloantigen and represents the basis of the immunosup- pressive effect of the drug. The inhibition of mTOR has been suggested to be involved in the antifibrotic effects of SRL as well as in its ability to reduce the incidence and progression of several posttransplant neoplasia (1, 2). On the basis of these molecular effects and with the support of several clinical observations, SRL has been sug- gested as an alternative to calcineurin inhibitors (CNI) in the long-term immunosuppressive regimen of kidney transplan- tation. The use of SRL, however, has been significantly lim- ited by an extremely high incidence of side effects. Indeed, in most of the clinical trials testing this immunosuppressive drug the rate of drop out caused by side effects was almost invariably higher in the treatment arm including SRL. Al- though the central role of mTOR in several cell functions may explain this observation, the fine molecular mechanisms un- derlying most of the SRL-associated undesired effects are still poorly defined. The aim of this review was to analyze the most common SRL side effects, focusing on their management, in the at- tempt to define the best approach to use this drug. Metabolic Effects Because mTOR plays a pivotal role in the modulation of cell metabolism it is not surprising that SRL exerts several undesired metabolic effects. Hyperlipidemia The most frequent SRL side effect is represented by hyperdyslipidemia (3). The drug may increase the serum levels of total cholesterol, triglycerides, and apolipoprotein C-III. Lipid abnormalities are probably the result of complex inter- ferences of SRL on lipid metabolism (3). Several studies dem- onstrate that SRL may up-regulate apolipoprotein C-III, reduce the catabolism of very low density lipoprotein (VLDL) apo B100-containing lipoprotein, and alter the insulin signal- ing pathway with increased hepatic synthesis of triglycerides and increased secretion of VLDL (3). The co-administration of CsA and corticosteroids may aggravate lipid abnormalities. Long-term studies with SRL showed that hyperlipidemia tends to improve over time (4). Immunosuppressive strategies min- imizing doses of SRL, CNIs or corticosteroids may help in controlling hyperlipidemia. The administration of statins and fibrates are effective in reducing hypercholesterolemia and hypertrygliceridemia, respectively (3). Impaired Glucose Tolerance and Posttransplant Diabetes Mellitus Posttransplantation glucose intolerance or overt post- transplant diabetes mellitus may result from a combination of insulin resistance and dysfunctional insulin secretion, as in the general population. However, the relative contribution of either mechanism may vary largely among patients, in rela- tion to several pathogenic factors, including age, body mass index, ethnicity, time from transplant, and use of different immunosuppressive regimens (5). Among immunosuppres- sant, steroids are well known to affect glucose tolerance by increasing peripheral insulin resistance, whereas CNIs may alter insulin release. A recent report suggests that SRL might have a role in the development of posttransplant diabetes G.G. and G.S. have received honoraria within the last three years from Wyeth. B.I. and L.G. declare no conflict of interest. 1 Department of Biomedical Sciences, Section of Nephrology, University of Foggia, Foggia, Italy. 2 Department of Emergency and Organ Transplantation, Nephrology, Dial- ysis and Transplantation Unit, University of Bari, Bari, Italy. 3 Address correspondence to: Giovanni Stallone, M.D., Department of Bio- medical Sciences, Division of Nephrology, University of Foggia, Viale Luigi Pinto, 1, 71100 Foggia, Italy. E-mail: g.stallone@unifg.it Received 30 October 2008. Revision requested 4 December 2008. Accepted 3 February 2009. Copyright © 2009 by Lippincott Williams & Wilkins ISSN 0041-1337/09/8708S-23 DOI: 10.1097/TP.0b013e3181a05b7a Transplantation • Volume 87, Number 8S, April 27, 2009 S23