Sirolimus for solid organ transplantation in children Solid organ transplantation in children has seen significant improvement in outcomes in recent years. Liver, kidney, heart and small bowel/multi- organ transplantation have all demonstrated improvements in both pediatric patient and graft survivals (1, 2). These continuing improvements are due in part to improved patient and organ selection, operative techniques and patient man- agement. However, a critical factor has also been the recent introduction of a variety of newer agents for immunosuppression with efficacy in children. One such promising agent has been sirolimus, initially called rapamycin, first derived from the soil of the island Rapa Nui or Easter Island in 1969 (3). This agent has demonstrated safety and efficacy in children, initially used as rescue therapy and more recently as maintenance immunosup- pression. Advantages include an improved toxic- ity profile compared with calcineurin inhibitors, making it a choice agent utilized to attenuate such side-effects as nephrotoxicity and neurotoxicity. Below follows a review of the most important experience to date with this exciting agent for solid organ transplantation in children. Mechanism of action and pharmacokinetics of sirolimus (Fig. 1) Sirolimus or rapamycin is a macrocyclic lactone produced by a strain of Streptomyces hygroscop- icus (3). Sirolimus is a potent inhibitor of antigen-induced proliferation of T cells, B cells, and antibody production (4, 5). Sirolimus also blocks mesenchymal cell response to growth factors, smooth muscle cell proliferation, and intimal thickening (6). Sirolimus binds to intra- cellular protein, FKBP12. This complex blocks the activation of the cell-cycle–specific kinase, TOR. Mammalian TOR activates S6K1 (p70 ribosomal S6 kinase). Inactivation of TOR by sirolimus results in the blockage of cell-cycle progression at the juncture of G1 and S phase (7). Because apoptosis is independent of TOR activity, sirolimus, unlike calcineurin inhibitors, preserves apoptosis of T cells (8). Sirolimus was initially approved in combination with cortico- steroids and cyclosporine for prevention of rejection after renal transplantation by the Food Gupta P, Kaufman S, Fishbein TM. Sirolimus for solid organ transplantation in children. Pediatr Transplantation 2005: 9: 269–276. Ó 2005 Blackwell Munksgaard Abstract: Sirolimus represents a major advancement in the field of solid organ transplantation and is being used as a rescue agent for acute and chronic rejection as well as for primary immunosuppression with good graft outcome. Although initial studies with sirolimus were in adults, now significant data have accumulated on the role of sirolimus in pediatric solid organ transplantation. This article reviews the current status of sirolimus in pediatric transplantation. Puneet Gupta, Stuart Kaufman and Thomas M. Fishbein Georgetown University Hospital, Transplant Institute, Washington, DC, USA Key words: pediatric transplantation – immunosuppression – sirolimus Puneet Gupta, Georgetown University Hospital, Transplant Institute, 3800 Reservoir Road, NW, 2nd Floor Main Building East Wing, Washington, DC 20007, USA Tel.: 202 444 3700 Fax: 202 444 7304 E-mail: pg63@gunet.georgetown.edu Accepted for publication 1 December 2004 Abbreviations: AUC, area under the curve; EBV, Epstein– Barr virus; FK, tacrolimus; FKBP12, FK binding protein; GVHD: graft-vs.-host; HAT, hepatic artery thrombosis; HCM, hypertrophic cardiomyopathy; HOCM, hypertrophic obstruct ive cardiomyopathy; PDGF, platelet-derived growth factor; PTLD, post-transplant lymphoproliferative disorder; SRL, sirolimus; TMA, thrombotic microangiopa- thy; TOR, target of rapamycin. Pediatr Transplantation 2005: 9: 269–276. Copyright Ó 2005 Blackwell Munksgaard Pediatric Transplantation DOI: 10.1111/j.1399-3046.2005.00305.x 269