Renal transplantation sirolimus

Everolimus, a derivative of sirolimus, is a novel macrocyclic immunosuppressant. Risk of acute rejection increases when the everolimus trough level falls below 3 fig/L in renal transplant patients.46... 

Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal transplant patients should use sirolimus. Manage patients receiving the drug in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information needed for the follow-up of the patient. Liver transplantation-excess mortality, graft loss, and hepatic artery thrombosis (HAT) The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant recipients. Many of these patients had evidence of infection at or near the time of death. 

Organ rejection Prophylaxis of organ rejection in patients receiving renal transplants. It is recommended that sirolimus be used in a regimen with cyclosporine and corticosteroids. In patients at low to moderate immunological risk, cyclosporine should be withdrawn 2 to 4 months after transplantation and sirolimus dose should be increased to reach recommended blood concentrations. 

Absorption - Sirolimus is rapidly absorbed following oral administration, with a mean time-to-peak concentration of approximately 1 hour after a single dose in healthy subjects and approximately 2 hours after multiple oral doses in renal transplant recipients. The systemic bioavailability of sirolimus was estimated to be approximately 14%. 

Renal transplant patients have a higher prevalence of clinically significant hyperlipidemia. Accordingly, carefully consider the risk/benefit in patients with established hyperlipidemia before initiating an immunosuppressive regimen including sirolimus. 

Lymphocele Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in sirolimus-treated patients. Consider appropriate postoperative measures to minimize this complication. 

De novo transplant recipients, a loading dose of sirolimus of 3 times the maintenance dose should be given. A daily maintenance dose of 2 mg is recommended for use in renal transplant patients, with a loading dose of 6mg. 

Azathioprine is administered to patients who do not respond to calcineurin inhibitors, sirolimus and glucocorticoids. Daily doses of 3-10 mg/kg of azathioprine are administered 1 or 2 days before renal transplantation or on the day of surgery for prophylactic therapy. Mycophenolate mofetil is increasingly used in place of azathioprine for tissue transplantation since it is less myelotoxic and causes few opportunistic infections. 

Grinyo JM, Cruzado JM. 2006. Mycophenolate mofetil and sirolimus combination in renal transplantation. Am J Transplant. 6 1991-1999. 

Hong JC, Kahan BD. 2000. Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients Risk factors, incidence, progression and management. Transplantation. 69 2085-2090. 

In a 1-year follow-up of 40 renal transplant patients treated with various dosages of sirolimus (0.5-7 mg/m2/ day) in addition to a ciclosporin-based regimen, there were significant increases in serum cholesterol and triglycerides, and significant falls in white blood cell and platelet counts, compared with historical controls (1066). These effects correlated with sirolimus trough concentrations but not dosages. One patient had to discontinue sirolimus because of hyperlipidemia refractory to treatment. 

In six patients with renal transplants treated with sirolimus, mean total plasma cholesterol, triglyceride, and apolipoprotein concentrations increased (1067). The authors suggested that sirolimus increases lipase activity in adipose tissue and reduces lipoprotein lipase activity, resulting in increased hepatic synthesis of triglycerides, increased secretion of VLDL, and increased hypertriglyceridemia. 

Ciancio G, Burke GW, Gaynor JJ, Mattiazzi A, Roth D, Kupin W, Nicolas M, Ruiz P, Rosen A, Miller J. A randomized long-term trial of tacrolimus/sirolimus versus tacro-limus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. II. Survival, function, and protocol compliance at 1 year. Transplantation 2004 77(2) 252-8. 

Brattstrom C, Wilczek H, Tyden G, Bottiger Y, Sawe J, Groth CG. Hyperlipidemia in renal transplant recipients treated with sirolimus (rapamycin). Transplantation 1998 65(9) 1272 1. 

Kahan BD, Podbielski J, Napoli KL, Katz SM, Meier-Kriesche HU, Van Buren CT. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation 1998 66(8) 1040-6. 

Morrisett JD, Abdel-Fattah G, Hoogeveen R, Mitchell E, Ballantyne CM, Pownall HJ, Opekun AR, Jaffe JS, Oppermann S, Kahan BD. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res 2002 43(8) 1170-80. 

Chueh SC, Kahan BD. Dyslipidemia in renal transplant recipients treated with a sirolimus and cyclosporine-based immunosuppressive regimen incidence, risk factors, progression, and prognosis. Transplantation 2003 76 375-82. 

Kuypers DR. Benefit-risk assessment of sirolimus in renal transplantation. Drug Saf. 2005 28 153-181. 

Sirolimus (Rapamycin, Rapamune ), a natural macrocyclic lactone, is a potent immunosuppressive agent. It was developed by Wyeth-Ayerst Laboratories (Philadelphia, Pennsylvania, U.S.A.) and approved by the Food and Drug Administration for the prophylaxis of renal transplant rejection in 1999 (28,29). Sirolimus has its roots in Easter Island, where an actinomycete streptomyces hygroscopicus was found that produced a novel macrolide antibiotic with potent antibiotic, potent antifungal, immunosuppressive, and antimitotic activities. 

Jhonson RW, Kreis H, Oberbauer R, et al. Sirolimus allows eariy cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation 2001 72 777-786. 

Formica RN Jr, Lorber KM, Friedman AL, et al. Sirolimus-based immunosuppression with reduce dose cyclosporine or tacrolimus after renal transplantation. Transplant Proc 2003 35(3 suppl) 95S-98S. 

Easter Island (Rapa Nui) first discovered and characterized by Sehgal in 1975 (38), Initially identified as an antifungal agent, the compound was subsequently found to posses potent immunosuppressive activities, initially demonstrated through its ability to prevent adjuvant-induced arthritis and experimental allergic encephalomyelitis in rodent models. As a potent immunosuppressive agent, sirolimus has been developed and marketed by Wyeth Pharmaceuticals for the prevention of renal transplant rejection (Rapamune ) (39). 

Picard N, Premaud A, Rousseau A, et al. A comparison of the effect of ciclosporin and sirolimus on the pharmokinetics of mycophenolate in renal transplant patients. Br J Clin Pharmacol 2006 62(4) 477 484. 

Ibanez JP, Monteverde ML, Goldber J, Diaz MA,Turconi A. Sirolimus in pediatric renal transplantation. Transplant Proc 2005 37 682 1. 

Sirolimus is a substrate and inhibitor of CYP3A4 with a narrow therapeutic index and is associated with cognitive impairment and nephrotoxicity. There is a synergistic effect when it is co-administered with ciclosporin, possibly because both are substrates of CYP3A4 (and thus compete at metabolic sites) and are P-gp substrates that may competitively inhibit each other at the efflux pump. There is considerable interindividual variability, with a 10-fold range in plasma concentration in renal transplant recipients when it is given at a dosage of 5 mg per day. 

Bronchiohtis obliterans with organizing pneumonia has been attributed to sirolimus in two renal transplant patients (6). Both improved rapidly after sirohmus withdrawal or dosage reduction. 

Groth CG, Backman L, Morales JM, Caine R, Kreis H, Lang P, Touraine JL, Claesson K, Campistol JM, Durand D, Wramner L, Brattstrom C, Charpentier B. Sirohmus (rapamycin)-based therapy in human renal transplantation similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999 67(7) 1036-42. 

Morelon E, Stern M, Kreis H. Interstitial pneumonitis associated with sirolimus therapy in renal-transplant recipients. N Engl J Med 2000 343(3) 225-6. 

Johnson RW. Sirolimus (Rapamune) in renal transplantation. Curr Opin Nephrol Hypertens 2002 ll(6) 603-7. 

Attempts to minimize TAC-induced renal dysfunction by TAC switch to sirolimus [419, 744, 745] or use of low-dose maintenance TAC therapy associated with lymphocyte depleting agents, mycophenolate mofetil or sirolimus have been successfully achieved [746-750]. However, the association of TAC and sirolimus does not seem to be problem-free. Severe acute kidney injury in renal transplant recipients and thrombotic microangiopathy in intestinal transplant have been associated to combined use of TAC and sirolimus [751, 752], renal function improved in renal transplant recipients after conversion from TAC/ sirolimus to TAC/MMF therapy [753] and TAC/sirolimus combination was associated to worst renal allograft survival than TAC/MMF im-... 

Pescovitz MD, Govani M. Sirolimus and mycophenolate mofetil for calcineurin-free immunosuppression in renal transplant recipients. Am J Kidney Dis 2001 38 S16-S21. 

Watson CJ, Firth J, Williams PF, Bradley JR, Pritchard N, Chaudhry A, Smith JC, Palmer CR, Bradley JA. A randomized controlled trial of late conversion from CNI-based to sirolimus-base immunosuppression following renal transplantation. Am J Transplant 2005 5 2496-2503. 

McTaggart RA, Gottlieb D, Brooks J, Bacchetti P, Roberts JP, Tomlanovich S, Feng S. Sirolimus prolongs recovery from delayed graft function after cadaveric renal transplantation. Am J Transplant 2003 3 416-423. 

Tomlanovich SJ, Vincenti F. Sirolimus Defining nephrotoxicity in the renal transplant recipient. Clin J Am Soc Nephrol 2007 2 198-199. 

Leung LY, Lhn H-K, Hicks D, et al. Metabolite characterization in rat-and human liver microsomal incubations and trough whole blood of renal transplant patients treated with sirolimus, cyclosporine, and prednisone [Abstract]. ISSXProc 1996 10 366. 

Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol 1997 37 405-15. 

Kalian BD, Murgia MG, Slaton J, Napoli K. Potential applications of therapeutic drug monitoring of sirolimus immunosuppression in clinical renal transplantation. Ther Drug Monit 1995 17 672-5. 

Zochowska D, Wyzgal J, Paczek L (2012) Impact of CYP3A4 1B and CYP3A5 3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients. Ann Transplant 17 36 4... 

Oberbauer R, Kreis H, Johnson RWG, et al. Long-term improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients 2-year results of the Rapamune maintenance regimen study. Transplantation 2003 76 364-370. 

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