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Use of Sirolimus in Solid Organ Transplantation

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Abstract

Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor that inhibits cell cycle progression and has proven to be a potent immunosuppressive agent for use in solid organ transplant recipients. The drug was initially studied as an adjunct to ciclosporin (cyclosporine) to prevent acute rejection in kidney transplant recipients. Subsequent studies have shown efficacy when combined with a variety of other immunosuppressive agents. The most common adverse effects of sirolimus are hyperlipidaemia and myelosuppression. The drug has unique antiatherogenic and antineoplastic properties, and may promote immunological tolerance and reduce the incidence of chronic allograft nephropathy. Although sirolimus is relatively non-nephrotoxic when administered as monotherapy, it pharmacodynamically enhances the toxicity of calcineurin inhibitors. Ironically, the drug has been used to facilitate calcineurin inhibitor-free protocols designed to preserve renal function after solid organ transplantation. Whether sirolimus can be used safely over the long term with low doses of calcineurin inhibitors requires further study. The use of sirolimus as a corticosteroid-sparing agent also remains to be proven in controlled trials. Postmarketing studies have revealed a number of unforeseen adverse effects including impaired wound healing and possibly proteinuria, oedema, pneumonitis and thrombotic microangiopathy. Overall, sirolimus is a powerful agent when used judiciously with other available immunosuppressants. As is true for all immunosuppressive drugs available for treatment of solid organ transplant recipients, the efficacy of the drug must be balanced against its considerable adverse effects.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

References

  1. Sehgal SN. Immunosuppressive profile of rapamycin. Ann N Y Acad Sci 1993; 696: 1–8

    Article  PubMed  CAS  Google Scholar 

  2. Calne RY, Collier DS, Lim S, et al. Rapamycin for immunosup-pression in organ allografting. Lancet 1989; II: 227

    Article  Google Scholar 

  3. Morris RE, Meiser BM. Identification of a new pharmacologic action for an old compound. Med Sci Res 1989; 17: 877–81

    CAS  Google Scholar 

  4. Neuhas P, Klupp J, Langrehr JM. mTOR inhibitors: an overview. Liver Transpl 2001; 7: 473–84

    Article  Google Scholar 

  5. Cole OJ, Shehata M, Rigg KM. Effect of SDZ RAD on transplant arteriosclerosis in the rat aortic model. Transplant Proc 1998; 30: 2200–3

    Article  PubMed  CAS  Google Scholar 

  6. Salminen US, Alho H, Taskinen E, et al. Effects of rapamycin analogue SDZ RAD on obliterative lesions in a porcine heterotopic bronchial allograft model. Transplant Proc 1998; 30: 2204–5

    Article  PubMed  CAS  Google Scholar 

  7. Abraham RT, Wiederrrecht GJ. Immunopharmacology of rapamycin. Annu Rev Immunol 1996; 14: 483–510

    Article  PubMed  CAS  Google Scholar 

  8. Schuler W, Sedrani R, Cottens S, et al. SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 1997; 64: 36–42

    Article  PubMed  CAS  Google Scholar 

  9. Schmidbauer G, Hancock W, Wasowska B, et al. Abrogation by rapamycin of accelerated rejection in sensitized rats by inhibition of alloantibody responses and selective suppression of intragraft mononuclear and endothelial cell activation, cytokine production, and cell adhesion. Transplantation 1994; 57: 933–41

    Article  PubMed  CAS  Google Scholar 

  10. Li Y, Zheng X, Li X, et al. Combined costimulation blockade plus rapamycin but not cyclosporine produces permanent engraftment. Transplantation 1998; 66: 1387–8

    Article  PubMed  CAS  Google Scholar 

  11. Wells A, Li X, Li Y, et al. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 1999; 5: 1303–7

    Article  PubMed  CAS  Google Scholar 

  12. Li Y, Li X, Zheng X, et al. Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Nat Med 1999; 5: 1298–305

    Article  PubMed  CAS  Google Scholar 

  13. Kahan BD, Kramer WG. Median effect analysis of efficacy versus effects of immunosuppressants. Clin Pharmacol Ther 2001; 70: 74–81

    Article  PubMed  CAS  Google Scholar 

  14. Dumont FJ, Melino MR, Staruch MJ, et al. The immunosuppressive macrolides FK-506 and rapamycin act as reciprocal antagonists in murine T cells. J Immunol 1990; 144: 1418–24

    PubMed  CAS  Google Scholar 

  15. Chen H, Peng J, Luo H, et al. Compromised kidney graft rejection response in vervet monkeys after withdrawal of immunosuppressants tacrolimus and sirolimus. Transplantation 2000; 69: 1555–61

    Article  PubMed  CAS  Google Scholar 

  16. Khanna A, Plummer M, Bromberek K, et al. Immunomodulation in stable renal transplant recipients with concomitant tacrolimus and sirolimus therapy. Med Immunol 2002; 1: 3

    Article  PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  18. Yatscoff RW. Pharmacokinetics of rapamycin. Transplant Proc 1996; 38: 970–3

    Google Scholar 

  19. MacDonald A, Scarola J, Burke JT, et al. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther 2000; 22 Suppl. B: B101–21

    Article  PubMed  CAS  Google Scholar 

  20. Zimmerman JJ, Ferron GM, Lim HK, et al. The effect of a highfat meal on the oral bioavailability of the immunosuppressant sirolimus (rapamycin). J Clin Pharmacol 1999; 39: 1155–61

    PubMed  CAS  Google Scholar 

  21. Kelly PA, Napoli K, Kahan BD. Conversion from liquid to solid rapamycin formulations in stable renal allograft transplant recipients. Biopharm Drug Dispos 1999; 20: 249–53

    Article  PubMed  CAS  Google Scholar 

  22. Kahan BD, Napoli KL, Kelly PA, et al. Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity. Clin Transplant 2000; 14: 97–109

    Article  PubMed  CAS  Google Scholar 

  23. Gallant-Haidner HL, Trepanier DK, Freitag DG, et al. Pharmacokinetics and metabolism of sirolimus. Ther Drug Monit 2000; 22: 31–5

    Article  PubMed  CAS  Google Scholar 

  24. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. Lancet 2000; 356: 194–202

    Article  PubMed  CAS  Google Scholar 

  25. Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet 2001; 40: 573–85

    Article  PubMed  CAS  Google Scholar 

  26. Stenton SB, Partovi N, Ensom MH. Sirolimus: the evidence for clinical pharmacokinetic monitoring. Clin Pharmacokinet 2005; 44: 769–86

    Article  PubMed  CAS  Google Scholar 

  27. Brattstrom C, Sawe J, Tyden G, et al. Kinetics and dynamics of single oral doses of sirolimus in sixteen renal transplant recipients. Ther Drug Monit 1997; 19: 397–406

    Article  PubMed  CAS  Google Scholar 

  28. Kahan BD, Napoli KL. Role of therapeutic drug monitoring of rapamycin. Transplant Proc 1998; 30: 2189–91

    Article  PubMed  CAS  Google Scholar 

  29. Yatscoff R, LeGatt D, Kennan R, et al. Blood distribution of rapamycin. Transplantation 1993; 56: 1202–6

    Article  PubMed  CAS  Google Scholar 

  30. Streit F, Christians U, Scheibel HM, et al. Sensitive and specific quantification of sirolimus (rapamycin) and its metabolites in blood of kidney graft recipients by HPLC/electrospray-mass spectrometry. Clin Chem 1996; 42: 1417–25

    PubMed  CAS  Google Scholar 

  31. Napoli KL, Kahan BD. Sample clean-up and high-performance liquid Chromatographie techniques for measurement of whole blood rapamycin concentrations. J Chromatogr B Biomed Appl 1994; 654: 111–20

    Article  PubMed  CAS  Google Scholar 

  32. Jones K, Saadat-Lajevardi S, Lee T, et al. An immunoassay for the measurement of sirolimus. Clin Ther 2000; 22 Suppl. B: B49–61

    Article  PubMed  CAS  Google Scholar 

  33. Bai S, Stepkowski SM, Kahan BD, et al. Metabolic interaction between cyclosporine and sirolimus. Transplantation 2004; 77: 1507–12

    Article  PubMed  CAS  Google Scholar 

  34. McAlister VC, Mahalati K, Peltekian KM, et al. A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression comparing simultaneous to separated administration. Ther Drug Monit 2002; 24: 346–50

    Article  PubMed  CAS  Google Scholar 

  35. Kahan BD, Podbielski H, Napoli KL, et al. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination regimen for renal transplantation. Transplantation 1998; 66: 1040–6

    Article  PubMed  CAS  Google Scholar 

  36. Kahan BD, Julian BA, Pescovitz MD, et al. Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in Caucasian recipients of mismatched primary renal allografts: a phase II trial. Transplantation 1999; 68: 1526–32

    Article  PubMed  CAS  Google Scholar 

  37. MacDonald AS. A worldwide phase III randomised, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 2001; 71: 271–80

    Article  PubMed  CAS  Google Scholar 

  38. Podder H, Podbielski J, Hussein I, et al. Sirolimus improves the two-year outcome of renal allografts in African American patients. Transpl Int 2001; 14: 135–42

    Article  PubMed  CAS  Google Scholar 

  39. Formica RN, Lorber KM, Friedman AL, et al. Sirolimus-based immunosuppression with reduced dose cyclosporine or tacrolimus after renal transplantation. Transplant Proc 2003; 35 Suppl. 2: 95–8S

    Article  CAS  Google Scholar 

  40. Kahan BD, Knight R, Schonberg L, et al. Ten years of sirolimus therapy for human renal transplantation: the University of Texas at Houston experience. Transplant Proc 2003; 35: 25–34S

    Article  CAS  Google Scholar 

  41. McAlister VC, Gao Z, Peltekian K, et al. Sirolimus-tacrolimus combination immunosuppression. Lancet 2000; 355: 376–7

    Article  PubMed  CAS  Google Scholar 

  42. Shapiro R, Scantlebury VP, Jordan ML, et al. A pilot trial of tacrolimus, sirolimus, and steroids in renal transplant recipients. Transplant Proc 2002; 34: 1651–2

    Article  PubMed  CAS  Google Scholar 

  43. Hartwig T, Pridohl O, Witzigmann H, et al. Low-dose sirolimus and tacrolimus in kidney transplantation: first results of a single-center experience. Transplant Proc 2001; 33: 3226–8

    Article  PubMed  CAS  Google Scholar 

  44. Hricik DE, Anton HAS, Knauss TC, et al. Outcomes of African American kidney transplant recipients treated with sirolimus, tacrolimus, and corticosteroids. Transplantation 2002; 74: 189–93

    Article  PubMed  CAS  Google Scholar 

  45. Shapiro AMJ, Lakey JRT, Ryan EA, et al. Islet cell transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppression regimen. N Engl J Med 2000; 343: 230–8

    Article  PubMed  CAS  Google Scholar 

  46. van Hoof JP, Squifflet JP, Wlodarczyk Z, et al. A prospective randomized multicenter study of tacrolimus in combination with sirolimus in renal transplant recipients. Transplantation 2003; 75: 1934–9

    Article  CAS  Google Scholar 

  47. Gonwa T, Mendez R, Yang HC, et al. Randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 6 months. Transplantation 2003; 75: 1213–20

    Article  PubMed  CAS  Google Scholar 

  48. Mendez R, Gonwa T, Tang HC, et al. A prospective, randomized trial of tacrolimus in combination with sirolimus or mycophenolate mofetil in kidney transplantation: results at 1 year. Transplantation 2005; 80: 303–9

    Article  PubMed  CAS  Google Scholar 

  49. Ciancio C, Burke GW, Gaytnor JJ, et al. A randomized longterm trial of tacrolimus/sirolimus versus tacrolimus/mycophenolate mofetil versus cyclosporine (NEORAL)/sirolimus in renal transplantation. II. Survival, function, and protocol compliance at 1 year. Transplantation 2004; 77: 252–8

    Article  PubMed  CAS  Google Scholar 

  50. Meier-Kriesch HU, Schold JD, Srinivas TR, et al. Sirolimus in combination with tacrolimus is associated with worse renal allograft survival compared to mycophenolate mofetil combined with tacrolimus. Am J Transplant 2005; 5: 2273–80

    Article  CAS  Google Scholar 

  51. Dominguez J, Mahalati K, Kiberd B, et al. Conversion to Rapamycin immunosuppression in renal transplant recipients. Transplantation 2000; 70: 1244–7

    Article  PubMed  CAS  Google Scholar 

  52. Wyzgal J, Paczek L, Senatorski G, et al. Sirolimus rescue treatment in calcineurin-inhibitor nephrotoxicity after kidney transplantation. Transplant Proc 2002; 34: 3185–7

    Article  PubMed  CAS  Google Scholar 

  53. Diekmann F, Waiser J, Fritsche L, et al. Conversion to rapamycin in renal allograft recipients with biopsy-proven calcineurin-inhibitor nephrotoxicity. Transplant Proc 2001; 33: 3234–5

    Article  PubMed  CAS  Google Scholar 

  54. Egidi MF, Cowan PA, Naseer A, et al. Conversion to sirolimus in solid organ transplantation: a single center experience. Transplant Proc 2003; 35 Suppl. 3: 131–7S

    Article  CAS  Google Scholar 

  55. Schena FP, Wali RK, Pascoe MD, et al. Efficacy and safety of conversion from calcineurin inhibitors to sirolimus versus continued use of calcineurin inhibitors in renal allograft recipients: 12 month results from a large, randomized, open-label, comparative trial [abstract]. J Am Soc Nephrol 2005; 16: 32A

    Article  CAS  Google Scholar 

  56. Johnson RW, Kreis H, Oberbauer R, et al. Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation 2001; 72: 777–86

    Article  PubMed  CAS  Google Scholar 

  57. Gonwa TA, Hricik DE, Brinker K, et al. Sirolimus Renal Function Study Group: improved renal function in sirolimus treated renal transplant patients after early cyclosporine elimination. Transplantation 2002; 74: 1560–7

    Article  PubMed  CAS  Google Scholar 

  58. Baboolal K. A phase III prospective randomized study to evaluate concentration controlled sirolimus (Rapamune) with cyclosporine dose minimization or elimination at six months in de novo renal allograft recipients. Transplantation 2003; 75: 1404–8

    Article  PubMed  CAS  Google Scholar 

  59. Stallone G, Di Paolo S, Schena A, et al. Early withdrawal of cyclosporin A improves one year kidney graft structure and function in sirolimus treated patients. Transplantation 2003; 75: 998–1003

    Article  PubMed  CAS  Google Scholar 

  60. Jardine AG. Phase III prospective randomized study to evaluate the safety and efficacy of concentration controlled Rapamune (sirolimus) with cyclosporine dose minimization or elimination in denovo renal allograft recipients at 12 months [abstract]. Am J Transplant 2004; 4 Suppl. 8: S286

    Google Scholar 

  61. Grinyo JM, Campistol JM, Paul J, et al. Pilot randomized study of early tacrolimus withdrawal from a regimen with sirolimus plus tacrolimus in kidney transplantation. Am J Transplant 2004; 4: 1308–14

    Article  PubMed  CAS  Google Scholar 

  62. Oberauer R, Kreis H, Johnson RW, et al. Rapammune Maintenance Regimen Study Group: long term improvement in renal function with sirolimus after early cyclosporin withdrawal in renal transplant recipients: 2-year results of the Rapammune Maintenance Regimen Study. Transplantation 2003; 76: 364–70

    Article  CAS  Google Scholar 

  63. Mulay AV, Hussain N, Fergusson D, et al. Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: a systematic review of randomized trials. Am J Transplant 2005; 5: 1748–56

    Article  PubMed  CAS  Google Scholar 

  64. Groth CG, Backman L, Morales JM, et al. Sirolimus (Rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67: 1036–42

    Article  PubMed  CAS  Google Scholar 

  65. Kreis H, Cisterne JM, Land W, et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000; 69: 1252–60

    Article  PubMed  CAS  Google Scholar 

  66. Morales JM, Wrammer L, Kreis H, et al. Sirolimus does not exhibit nephrotoxicity compared to cyclosporine in renal transplant recipients. Am J Transplant 2002; 2: 436–42

    Article  PubMed  CAS  Google Scholar 

  67. Flechner SM, Goldfarb D, Modlin C, et al. Kidney transplantation without calcineurin inhibitor drugs: a prospective, randomized trial of sirolimus versus cyclosporine. Transplantation 2002; 74: 1770–6

    Article  Google Scholar 

  68. Flechner SM, Kurian SM, Solez K, et al. De novo kidney transplantation without use of calcineurin inhibitors preserves renal structure and function at two years. Am J Transplant 2004; 4: 1776–85

    Article  PubMed  CAS  Google Scholar 

  69. Lo A, Egidi MF, Gaber LW, et al. Comparison of sirolimusbased calcineurin inhibitor-sparing and calcineurin inhibitorfree regimens in cadaveric renal transplantation. Transplantation 2004; 77: 1228–35

    Article  PubMed  CAS  Google Scholar 

  70. Knechtle SJ, Pirsch J, Fechner J Jr, et al. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant 2003; 3: 722–30

    Article  PubMed  CAS  Google Scholar 

  71. Kirk A, Hale D, Mannon RB, et al. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (Campath-1H). Transplantation 2003; 76: 120–9

    Article  PubMed  CAS  Google Scholar 

  72. Flechner SM, Friend PJ, Brockman J, et al. Alemtuzumab induction and sirolimus plus mycophenolate mofetil maintenance for CNI and steroid-free transplant immunosuppression. Am J Transplant 2005; 5: 3009–14

    Article  PubMed  CAS  Google Scholar 

  73. Mahalati K, Kahan BD. A pilot study of steroid withdrawal from kidney transplant recipients on sirolimus-cyclosporine combination therapy. Transplant Proc 2001; 33: 1270–2

    Article  PubMed  CAS  Google Scholar 

  74. Woodle ES, Vincenti F, Lorber MI, et al. A multicenter pilot study of early (4-day) steroid cessation in renal transplant recipients under simulect, tacrolimus and sirolimus. Am J Transplant 2005; 5: 157–66

    Article  PubMed  CAS  Google Scholar 

  75. Hricik DE, Knauss TC, Bodziak KA, et al. Withdrawal of steroid therapy in African American kidney transplant recipients receiving sirolimus and tacrolimus. Transplantation 2003; 76: 938–42

    Article  PubMed  CAS  Google Scholar 

  76. Hricik DE, Knauss TC, Bodziak KA, et al. Suboptimal longterm outcomes after steroid withdrawal in African Americans receiving sirolimus and tacrolimus [abstract]. Am J Transplant 2005; 5 Suppl. 11: S287

    Google Scholar 

  77. Kumar AMS, Moritz MJ, Saaed MI, et al. Avoidance of chronic steroid therapy in African American kidney transplant recipients monitored by surveillance biopsy: 1-year results. Am J Transplant 2005; 5: 1976–85

    Article  PubMed  CAS  Google Scholar 

  78. Vincenti F, Stock P. De novo use of sirolimus in immunosuppression regimens in kidney and kidney-pancreas transplantation at the University of California, San Francisco. Transplant Proc 2003; 35 (3 Suppl.): 183–6S

    Article  CAS  Google Scholar 

  79. Rogers J, Ashcraft EE, Emovon OE, et al. Long-term outcome of sirolimus rescue in kidney-pancreas transplantation. Transplantation 2004; 78: 619–22

    Article  PubMed  CAS  Google Scholar 

  80. Lehmann R, Weber M, Berthold P, et al. Successful simultaneous islet-kidney transplantation using a steroid-free immunosuppression: two-year follow-up. Am J Transplant 2004; 4: 1117–23

    Article  PubMed  CAS  Google Scholar 

  81. Neff GW, Montalbano M, Tzakis AG. Ten years of sirolimus therapy in orthotopic liver transplant recipients. Transplant Proc 2003; 35 (3 Suppl.): 209–16S

    Article  CAS  Google Scholar 

  82. McAlister VC, Peltekian KM, Malatjalian DA, et al. Orthotopic liver transplantation using low-dose tacrolimus and sirolimus. Liver Transpl 2001; 7: 701–8

    Article  PubMed  CAS  Google Scholar 

  83. Trotter JF, Wachs M, Bak T, et al. Liver transplantation using sirolimus and minimal corticosteroids (3-day taper). Liver Transpl 2001; 7: 343–51

    Article  PubMed  CAS  Google Scholar 

  84. Kniepeiss D, Iberer F, Grasser B, et al. Sirolimus and mycophenolate mofetil after liver transplantation. Transpl Int 2003; 16: 504–9

    Article  PubMed  CAS  Google Scholar 

  85. Fairbanks KD, Eustace JA, Fine D, et al. Renal function improves in liver transplant recipients when switched from a calcineurin inhibitor to sirolimus. Liver Transpl 2003; 9: 1079–85

    Article  PubMed  Google Scholar 

  86. Sahin F, Kannangai R, Adegbola O, et al. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004; 10: 8421–5

    Article  PubMed  CAS  Google Scholar 

  87. Kneteman NM, Oberholzer J, Al Saghier M, et al. Sirolimusbased immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl 2004; 10: 1301–11

    Article  PubMed  Google Scholar 

  88. Augustine JJ, Hricik DE. Experience with everolimus. Transplant Proc 2004; 36 (2 Suppl.): 5000–33S

    Article  CAS  Google Scholar 

  89. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiactransplant recipients. N Engl J Med 2003; 349: 847–58

    Article  PubMed  CAS  Google Scholar 

  90. Keogh AM, the Sirolimus Cardiac Transplant Trial Group. Sirolimus immunotherapy reduces the rates of cardiac allograft rejection: 6-month results from a phase 2, open-label study [abstract]. Am J Transplant 2002; 2 Suppl. 3: S246

    Google Scholar 

  91. Groetzner J, Meiser B, Landehr P, et al. Mycophenolate mofetil and sirolimus as calcineurin inhibitor-free immunosuppression for late cardiac-transplant recipients with chronic renal failure. Transplantation 2004; 77: 568–74

    Article  PubMed  CAS  Google Scholar 

  92. Meiser B, Reichart B, Adamidis I, et al. First experience with de novo calcineurin-inhibitor-free immunosuppression following cardiac transplantation. Am J Transplant 2005; 5: 827–31

    Article  PubMed  Google Scholar 

  93. Poon M, Badimon JJ, Fuster V. Overcoming restenosis with sirolimus: from alphabet soup to clinical reality. Lancet 2002; 359: 619–22

    Article  PubMed  Google Scholar 

  94. Ikonen TS, Gummert JF, Serkova N, et al. Efficacies of sirolimus (rapamycin) and cyclosporine in allograft vascular disease in non-human primates: trough levels of sirolimus correlate with inhibition of progression of arterial intimai thickening. Transpl Int 2000; 13 Suppl. 1: S314–20

    Article  PubMed  Google Scholar 

  95. Eisen H, Kobashigawa J, Starling RC, et al. Improving outcomes in heart transplantation: the potential of proliferation signal inhibitors. Transplant Proc 2005; 37 (4 Suppl.): 4–17S

    Article  CAS  Google Scholar 

  96. King-Biggs MB, Dunitz JM, Park SJ, et al. Airway anastomotic dehiscence associated with use of sirolimus immediately after lung transplantation. Transplantation 2003; 75: 1437–43

    Article  PubMed  Google Scholar 

  97. Grotzner J, Kur F, Speisberg F, et al. Airway anastomosis complications in de novo lung transplantation with sirolimusbased immunosuppression. J Heart Lung Transplant 2004; 23: 632–8

    Article  Google Scholar 

  98. Shitrit D, Rahamimov R, Gidon S, et al. Use of sirolimus and low-dose calcineurin inhibitor in lung transplant recipients with renal impairment: results of a controlled pilot study. Kidney Int 2005; 67: 1471–5

    Article  PubMed  CAS  Google Scholar 

  99. Villanueva J, Boukhamseen A, Bhorade SM. Successful use in lung transplantation of an immunosuppressive regimen aimed at reducing target blood levels of sirolimus and tacrolimus. J Heart Lung Transplant 2005; 24: 421–5

    Article  PubMed  Google Scholar 

  100. Ussetti P, Laporta R, de Pablo A, et al. Rapamycin in lung transplantation: preliminary results. Transplant Proc 2003; 35: 1974–7

    Article  PubMed  CAS  Google Scholar 

  101. Venuta F, De Giacomo T, Rendina EA, et al. Recovery of chronic renal impairment with sirolimus after lung transplantation. Ann Thorac Surg 2004; 78: 1940–3

    Article  PubMed  Google Scholar 

  102. Hymes LC, Warshaw BL. Sirolimus in pediatric patients: results in the first 6 months post-renal transplant. Pediatr Transplant 2005; 9: 520–2

    Article  PubMed  CAS  Google Scholar 

  103. Sindhi R, Seward J, Mazariegos G, et al. Replacing calcineurin inhibitors with mTOR inhibitors in children. Pediatr Transplant 2005; 9: 391–7

    Article  PubMed  CAS  Google Scholar 

  104. Lobach NE, Pollock-Barziv SM, West LJ, et al. Sirolimus immunosuppression in pediatric heart transplant recipients: a single-center experience. J Heart Lung Transplant 2005; 24: 184–9

    Article  PubMed  Google Scholar 

  105. Kahan BD, Napoli KL, Kelly PA, et al. Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity. Clin Transplant 2000; 14: 97–109

    Article  PubMed  CAS  Google Scholar 

  106. Hoogeveen RC, Ballantyne CM, Pownall HJ, et al. Effect of sirolimus on the metabolism of apoB100-containing lipoproteins in renal transplant patients. Transplantation 2001; 72: 1244–50

    Article  PubMed  CAS  Google Scholar 

  107. Morrisett JD, Abdel-Fattah G, Hoogeveen R, et al. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. J Lipid Res 2002; 43: 1170–80

    PubMed  CAS  Google Scholar 

  108. Teutonico A, Schena PF, Di Paolo S. Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 2005; 16: 3128–35

    Article  PubMed  CAS  Google Scholar 

  109. Blum CB. Effects of sirolimus on lipids in renal allograft recipients: an analysis using the Framingham risk model. Am J Transplant 2002; 2: 551–9

    Article  PubMed  CAS  Google Scholar 

  110. Barshes NR, Goodpastor SE, Goss JA. Sirolimus-atorvastatin drug interaction in the pancreatic islet transplant recipient. Transplantation 2003 Dec 15; 76 (11): 1649–50

    Article  PubMed  Google Scholar 

  111. Gallo R, Padurean A, Jayaraman T, et al. Inhibition of intimai thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 1999; 99: 2164–70

    Article  PubMed  CAS  Google Scholar 

  112. Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2001; 103: 192–5

    Article  PubMed  CAS  Google Scholar 

  113. Elloso MM, Azrolan N, Sehgal SN, et al. Protective effect of the immunosuppressant sirolimus against aortic atherosclerosis in apo E-deficient mice. Am J Transplant 2003; 3: 562–9

    Article  PubMed  CAS  Google Scholar 

  114. Ikonen TS, Gummert JF, Serkova N, et al. Efficacies of sirolimus (rapamycin) and cyclosporine in allograft vascular disease in non-human primates: trough levels of sirolimus correlate with inhibition of progression of arterial intimai thickening. Transpl Int 2000; 13 Suppl. 1: S314–20

    Article  PubMed  Google Scholar 

  115. 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

    Article  PubMed  CAS  Google Scholar 

  116. Groth CG, Backman L, Morales JM, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67: 1036–42

    Article  PubMed  CAS  Google Scholar 

  117. Hong JC, Kahan BD. Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients: risk factors, incidence, progression, and management. Transplantation 2000; 69: 2085–90

    Article  PubMed  CAS  Google Scholar 

  118. Mix TC, Kazmi W, Khan S. Anemia: a continuing problem following kidney transplantation. Am J Transplant 2003; 3: 1426–33

    Article  PubMed  Google Scholar 

  119. Bouscary D, Pene F, Claessens YE. Critical role for PI 3-kinase in the control of erythropoietin-induced erythroid progenitor proliferation. Blood 2003; 101: 3436–43

    Article  PubMed  CAS  Google Scholar 

  120. Cruz R, Hedden L, Boyer D, et al. S6 kinase 2 potentiates interleukin-3-driven cell proliferation. J Leukoc Biol 2005; 78: 1378–85

    Article  PubMed  CAS  Google Scholar 

  121. Augustine JJ, Knauss TC, Schulak JA, et al. Comparative effects of sirolimus and mycophenolate mofetil on erythropoiesis in kidney transplant patients. Am J Transplant 2004; 4: 2001–6

    Article  PubMed  CAS  Google Scholar 

  122. Andoh TF, Lindsley J, Franceschini N, et al. Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model. Transplantation 1996; 62: 311–6

    Article  PubMed  CAS  Google Scholar 

  123. Podder H, Stepkowski SM, Napoli KL, et al. Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations. J Am Soc Nephrol 2001; 12: 1059–71

    PubMed  CAS  Google Scholar 

  124. Kahan BD. Two-year results of multicenter phase III trials on the effect of the addition of sirolimus to cyclosporine-based immunosuppressive regimens in renal transplantation. Transplant Proc 2003; 35 (3 Suppl.): 37–51S

    Article  CAS  Google Scholar 

  125. Masterson R, Leikis M, Perkovic V, et al. Sirolimus: a single center experience in combination with calcineurin inhibitors. Transplant Proc 2003; 35 (3 Suppl.): 99–104S

    Article  CAS  Google Scholar 

  126. Andoh TF, Burdmann EA, Fransechini N, et al. Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK 506. Kidney Int 1996; 50: 1110–7

    Article  PubMed  CAS  Google Scholar 

  127. Shihab FS, Bennett WM, Yi H, et al. Sirolimus increases transforming growth factor-betal expression and potentiates chronic cyclosporine nephrotoxicity. Kidney Int 2004; 65: 1262–71

    Article  PubMed  CAS  Google Scholar 

  128. Augustine JJ, Chang PC, Knauss TC, et al. Improved renal function after conversion from tacrolimus/sirolimus to tacrolimus/mycophenolate mofetil in kidney transplant recipients. Transplantation 2006; 81: 1004–9

    Article  PubMed  CAS  Google Scholar 

  129. Lieberthal W, Fuhro R, Andry CC, et al. Rapamycin impairs recovery from acute renal failure: role of cell-cycle arrest and apoptosis of tubular cells. Am J Physiol Renal Physiol 2001; 281: F693–706

    PubMed  CAS  Google Scholar 

  130. McTaggart RA, Gottlieb D, Brooks J, et al. Sirolimus prolongs recovery from delayed graft function after cadaveric renal transplantation. Am J Transplant 2003; 3: 416–23

    Article  PubMed  CAS  Google Scholar 

  131. Smith KD, Wrenshall LE, Nicosia RF, et al. Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use. J Am Soc Nephrol 2003; 14: 1037–45

    Article  PubMed  CAS  Google Scholar 

  132. Butani L. Investigation of pediatric renal transplant recipients with heavy proteinuria after sirolimus rescue. Transplantation 2004; 78: 1362–6

    Article  PubMed  Google Scholar 

  133. Saurina A, Campistol JM, Piera C, et al. Conversion from calcineurin inhibitors to sirolimus in chronic allograft dysfunction: changes in glomerular haemodynamics and proteinuria. Nephrol Dial Transplant. Epub 2005 Nov 9

  134. Dervaux T, Caillard S, Meyer C, et al. Is sirolimus responsible for proteinuria? Transplant Proc 2005; 37: 2828–9

    Article  PubMed  CAS  Google Scholar 

  135. Senior PA, Paty BW, Cockfield SM, et al. Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing. Am J Transplant 2005; 5: 2318–23

    Article  PubMed  Google Scholar 

  136. Diekmann F, Budde K, Oppenheimer F, et al. Predictors of success in conversion from calcineurin inhibitor to sirolimus in chronic allograft dysfunction. Am J Transplant 2004; 4: 1869–75

    Article  PubMed  CAS  Google Scholar 

  137. Flechner SM, Zhou L, Derweesh I, et al. The impact of sirolimus, mycophenolate mofetil, cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients. Transplantation 2003; 76: 1729–34

    Article  PubMed  CAS  Google Scholar 

  138. Valente JF, Hricik D, Weigel K, et al. Comparison of sirolimus vs. mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 2003; 3: 1128–34

    Article  PubMed  CAS  Google Scholar 

  139. Dean PG, Lund WJ, Larson TS, et al. Wound-healing complications after kidney transplantation: a prospective, randomized comparison of sirolimus and tacrolimus. Transplantation 2004; 77: 1555–61

    Article  PubMed  CAS  Google Scholar 

  140. Rogers CC, Hanaway M, Alloway RR, et al. Corticosteroid avoidance ameliorates lymphocele formation and wound healing complications associated with sirolimus therapy. Transplant Proc 2005; 37: 795–7

    Article  PubMed  CAS  Google Scholar 

  141. Kandaswamy R, Melancon JK, Dunn T, et al. A prospective randomized trial of steroid-free maintenance regimens in kidney transplant recipients: an interim analysis. Am J Transplant 2005; 5: 1529–36

    Article  PubMed  CAS  Google Scholar 

  142. Goel M, Flechner SM, Zhou L, et al. The influence of various maintenance immunosuppressive drugs on lymphocele formation and treatment after kidney transplantation. J Urol 2004; 171: 1788–92

    Article  PubMed  CAS  Google Scholar 

  143. Langer RM, Kahan BD. Incidence, therapy, and consequences of lymphocele after sirolimus-cyclosporine-prednisone immunosuppression in renal transplant recipients. Transplantation 2002; 74: 804–8

    Article  PubMed  CAS  Google Scholar 

  144. Gaben AM, Saucier C, Bedin M, et al. Rapamycin inhibits cdk4 activation, p 21(WAF1/CIP1) expression and G1-phase progression in transformed mouse fibroblasts. Int J Cancer 2004; 108: 200–6

    Article  PubMed  CAS  Google Scholar 

  145. Shegogue D, Trojanowska M. Mammalian target of rapamycin positively regulates collagen type I production via a phosphatidylinositol 3-kinase-independent pathway. J Biol Chem 2004; 279: 23166–75

    Article  PubMed  CAS  Google Scholar 

  146. Humar R, Kiefer FN, Berns H, et al. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 2002; 16: 771–80

    Article  PubMed  CAS  Google Scholar 

  147. Neff GW, Ruiz P, Madariaga JR, et al. Sirolimus-associated hepatotoxicity in liver transplantation. Ann Pharmacother 2004; 38: 1593–6

    Article  PubMed  CAS  Google Scholar 

  148. Montalbano M, Neff GW, Yamashiki N, et al. A retrospective review of liver transplant patients treated with sirolimus from a single center: an analysis of sirolimus-related complications. Transplantation 2004; 78: 264–8

    Article  PubMed  CAS  Google Scholar 

  149. Wadei H, Gruber SA, El-Amm JM, et al. Sirolimus-induced angioedema. Am J Transplant 2004; 4: 1002–5

    Article  PubMed  Google Scholar 

  150. Mahe E, Morelon E, Lechaton S, et al. Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. Transplantation 2005; 79: 476–82

    Article  PubMed  CAS  Google Scholar 

  151. Mohaupt MG, Vogt B, Frey FJ. Sirolimus-associated eyelid edema in kidney transplant recipients. Transplantation 2001; 72: 162–4

    Article  PubMed  CAS  Google Scholar 

  152. Aboujaoude W, Milgrom ML, Govani MV. Lymphedema associated with sirolimus in renal transplant recipients. Transplantation 2004; 77: 1094–6

    Article  PubMed  Google Scholar 

  153. Romagnoli J, Citterio F, Nanni G, et al. Severe limb lymphedema in sirolimus-treated patients. Transplant Proc 2005; 37: 834–6

    Article  PubMed  CAS  Google Scholar 

  154. van Gelder T, ter Meulen CG, Hene R, et al. Oral ulcers in kidney transplant recipients treated with sirolimus and mycophenolate mofetil. Transplantation 2003; 75: 788–91

    Article  PubMed  CAS  Google Scholar 

  155. Watson CJ, Firth J, Williams PF, et al. A randomized controlled trial of late conversion from CNI-based to sirolimus-based immunosuppression following renal transplantation. Am J Transplant 2005; 5: 2496–503

    Article  PubMed  CAS  Google Scholar 

  156. Kaczmarek I, Groetzner J, Adamidis I, et al. Sirolimus impairs gonadal function in heart transplant recipients. Am J Transplant 2004; 4: 1084–8

    Article  PubMed  CAS  Google Scholar 

  157. Tondolo V, Citterio F, Panocchia N, et al. Gonadal function and immunosuppressive therapy after renal transplantation. Transplant Proc 2005; 37: 1915–7

    Article  PubMed  CAS  Google Scholar 

  158. Meachem SJ, Ruwanpura SM, Ziolkowski J, et al. Developmentally distinct in vivo effects of FSH on proliferation and apoptosis during testis maturation. J Endocrinol 2005; 186: 429–46

    Article  PubMed  CAS  Google Scholar 

  159. Lecureuil C, Tesseraud S, Kara E, et al. Follicle-stimulating hormone activates p70 ribosomal protein S6 kinase by protein kinase A-mediated dephosphorylation of Thr 421/Ser 424 in primary Sertoli cells. Mol Endocrinol 2005; 19: 1812–20

    Article  PubMed  CAS  Google Scholar 

  160. Feng LX, Ravindranath N, Dym M. Stem cell factor/c-kit upregulates cyclin D3 and promotes cell cycle progression via the phosphoinositide 3-kinase/p70 S6 kinase pathway in spermatogonia. J Biol Chem 2000; 275: 25572–6

    Article  PubMed  CAS  Google Scholar 

  161. Robson M, Cote I, Abbs I, et al. Thrombotic microangiopathy with sirolimus-based immunosuppression: potentiation of calcineurin-inhibitor-induced endothelial damage? Am J Transplant 2003; 3: 324–7

    Article  PubMed  Google Scholar 

  162. Barone GW, Gurley BJ, Abul-Ezz SR, et al. Sirolimus-induced thrombotic microangiopathy in a renal transplant patient. Am J Kidney Dis 2003; 42: 202–6

    Article  PubMed  Google Scholar 

  163. Franco A, Hernandez D, Capdevilla L, et al. De novo hemolyticuremic syndrome/thrombotic microangiopathy in renal transplant patients receiving calcineurin inhibitors: role of sirolimus. Transplant Proc 2003; 35: 1764–6

    Article  PubMed  CAS  Google Scholar 

  164. Sartelet H, Toupance O, Lorenzato M, et al. Sirolimus-induced thrombotic microangiopathy is associated with decreased expression of vascular endothelial growth factor in kidneys. Am J Transplant 2005; 5: 2441–7

    Article  PubMed  Google Scholar 

  165. Garrean S, Massad MG, Tshibaka M, et al. Sirolimus-associated interstitial pneumonitis in solid organ transplant recipients. Clin Transplant 2005; 19: 698–703

    Article  PubMed  Google Scholar 

  166. Lindenfeld JA, Simon SF, Zamora MR, et al. BOOP is common in cardiac transplant recipients switched from a calcineurin inhibitor to sirolimus. Am J Transplant 2005; 5: 1392–6

    Article  PubMed  CAS  Google Scholar 

  167. Pham PT, Pham PC, Danovitch GM, et al. Sirolimus-associated pulmonary toxicity. Transplantation 2004; 77: 1215–20

    Article  PubMed  CAS  Google Scholar 

  168. Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999; 397: 530–4

    Article  PubMed  CAS  Google Scholar 

  169. Maluccio M, Sharma V, Lagman M, et al. Tacrolimus enhances transforming growth factor-βl expression and promotes tumor progression. Transplantation 2003; 76: 597–602

    Article  PubMed  CAS  Google Scholar 

  170. Luan FL, Hojo M, Maluccio M, et al. Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Transplantation 2002; 73: 1565–72

    Article  PubMed  CAS  Google Scholar 

  171. Luan FL, Ding R, Sharma VK, et al. Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 2003; 63: 917–26

    Article  PubMed  CAS  Google Scholar 

  172. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002; 8: 128–35

    Article  PubMed  CAS  Google Scholar 

  173. Nepomuceno RR, Balatoni CE, Natkunam Y, et al. Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Cancer Res 2003; 63: 4472–80

    PubMed  CAS  Google Scholar 

  174. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients; results from five multicenter studies. Clin Transplant 2004; 18: 446–9

    Article  PubMed  Google Scholar 

  175. Kauffman HM, Cherikh WS, Cheng Y, et al. Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation 2005; 80: 883–9

    Article  PubMed  CAS  Google Scholar 

  176. Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi’s sarcoma. Transplantation 2004; 77: 760–2

    Article  PubMed  Google Scholar 

  177. Sierka D, Kumar MS, Heifets M, et al. Successful minimization of immunosuppression and conversion to sirolimus in kidney transplant recipients with posttransplant lymphoproliferative disease (PTLD) and de novo nonskin malignancies [abstract]. Am J Transplant 2004; 4 Suppl. 8: 523

    Google Scholar 

  178. Ozaki KS, Camara NO, Galante NZ, et al. Decreased cytomegalovirus infection after antilymphocyte therapy in sirolimustreated renal transplant patients. Int Immunopharmacol 2005; 5: 103–6

    Article  PubMed  CAS  Google Scholar 

  179. Gruber SA, Garnick J, Morawski K, et al. Cytomegalovirus prophylaxis with valganciclovir in African-American renal allograft recipients based on donor/recipient serostatus. Clin Transplant 2005; 18: 273–8

    Article  Google Scholar 

  180. Trotter JF, Wollack A, Steinberg T. Low incidence of cytomegalovirus disease in liver transplant recipients receiving sirolimus primary immunosuppression with 3-day corticosteroid taper. Transpl Infect Dis 2003; 5: 174–80

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported, in part, by the Leonard Rosenberg Foundation. Drs Hricik, Bodziak and Augustine have each served as either principal investigators or co-investigators on grants sponsored by Wyeth Pharmaceuticals.

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  1. The Department of Medicine and the Transplantation Service, Case Western Reserve University, and University Hospitals of Cleveland, 11100 Euclid Avenue, Room 8124 Lakeside Building, Cleveland, Ohio, 44106, USA

    Joshua J. Augustine, Kenneth A. Bodziak &  Donald E. Hricik

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  1. Joshua J. Augustine
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Correspondence to Donald E. Hricik.

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Augustine, J.J., Bodziak, K.A. & Hricik, D.E. Use of Sirolimus in Solid Organ Transplantation. Drugs 67, 369–391 (2007). https://doi.org/10.2165/00003495-200767030-00004

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