Drugs

, Volume 67, Issue 3, pp 369–391 | Cite as

Use of Sirolimus in Solid Organ Transplantation

  • Joshua J. Augustine
  • Kenneth A. Bodziak
  • Donald E. Hricik
Review Article

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.

References

  1. 1.
    Sehgal SN. Immunosuppressive profile of rapamycin. Ann N Y Acad Sci 1993; 696: 1–8PubMedCrossRefGoogle Scholar
  2. 2.
    Calne RY, Collier DS, Lim S, et al. Rapamycin for immunosup-pression in organ allografting. Lancet 1989; II: 227CrossRefGoogle Scholar
  3. 3.
    Morris RE, Meiser BM. Identification of a new pharmacologic action for an old compound. Med Sci Res 1989; 17: 877–81Google Scholar
  4. 4.
    Neuhas P, Klupp J, Langrehr JM. mTOR inhibitors: an overview. Liver Transpl 2001; 7: 473–84CrossRefGoogle Scholar
  5. 5.
    Cole OJ, Shehata M, Rigg KM. Effect of SDZ RAD on transplant arteriosclerosis in the rat aortic model. Transplant Proc 1998; 30: 2200–3PubMedCrossRefGoogle Scholar
  6. 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: 2204–5PubMedCrossRefGoogle Scholar
  7. 7.
    Abraham RT, Wiederrrecht GJ. Immunopharmacology of rapamycin. Annu Rev Immunol 1996; 14: 483–510PubMedCrossRefGoogle Scholar
  8. 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: 36–42PubMedCrossRefGoogle Scholar
  9. 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: 933–41PubMedCrossRefGoogle Scholar
  10. 10.
    Li Y, Zheng X, Li X, et al. Combined costimulation blockade plus rapamycin but not cyclosporine produces permanent engraftment. Transplantation 1998; 66: 1387–8PubMedCrossRefGoogle Scholar
  11. 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: 1303–7PubMedCrossRefGoogle Scholar
  12. 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: 1298–305PubMedCrossRefGoogle Scholar
  13. 13.
    Kahan BD, Kramer WG. Median effect analysis of efficacy versus effects of immunosuppressants. Clin Pharmacol Ther 2001; 70: 74–81PubMedCrossRefGoogle Scholar
  14. 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: 1418–24PubMedGoogle Scholar
  15. 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: 1555–61PubMedCrossRefGoogle Scholar
  16. 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: 3PubMedCrossRefGoogle Scholar
  17. 17.
    Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol 1997; 37: 405–15PubMedGoogle Scholar
  18. 18.
    Yatscoff RW. Pharmacokinetics of rapamycin. Transplant Proc 1996; 38: 970–3Google Scholar
  19. 19.
    MacDonald A, Scarola J, Burke JT, et al. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther 2000; 22 Suppl. B: B101–21PubMedCrossRefGoogle Scholar
  20. 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: 1155–61PubMedGoogle Scholar
  21. 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: 249–53PubMedCrossRefGoogle Scholar
  22. 22.
    Kahan BD, Napoli KL, Kelly PA, et al. Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity. Clin Transplant 2000; 14: 97–109PubMedCrossRefGoogle Scholar
  23. 23.
    Gallant-Haidner HL, Trepanier DK, Freitag DG, et al. Pharmacokinetics and metabolism of sirolimus. Ther Drug Monit 2000; 22: 31–5PubMedCrossRefGoogle Scholar
  24. 24.
    Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. Lancet 2000; 356: 194–202PubMedCrossRefGoogle Scholar
  25. 25.
    Mahalati K, Kahan BD. Clinical pharmacokinetics of sirolimus. Clin Pharmacokinet 2001; 40: 573–85PubMedCrossRefGoogle Scholar
  26. 26.
    Stenton SB, Partovi N, Ensom MH. Sirolimus: the evidence for clinical pharmacokinetic monitoring. Clin Pharmacokinet 2005; 44: 769–86PubMedCrossRefGoogle Scholar
  27. 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: 397–406PubMedCrossRefGoogle Scholar
  28. 28.
    Kahan BD, Napoli KL. Role of therapeutic drug monitoring of rapamycin. Transplant Proc 1998; 30: 2189–91PubMedCrossRefGoogle Scholar
  29. 29.
    Yatscoff R, LeGatt D, Kennan R, et al. Blood distribution of rapamycin. Transplantation 1993; 56: 1202–6PubMedCrossRefGoogle Scholar
  30. 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: 1417–25PubMedGoogle Scholar
  31. 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: 111–20PubMedCrossRefGoogle Scholar
  32. 32.
    Jones K, Saadat-Lajevardi S, Lee T, et al. An immunoassay for the measurement of sirolimus. Clin Ther 2000; 22 Suppl. B: B49–61PubMedCrossRefGoogle Scholar
  33. 33.
    Bai S, Stepkowski SM, Kahan BD, et al. Metabolic interaction between cyclosporine and sirolimus. Transplantation 2004; 77: 1507–12PubMedCrossRefGoogle Scholar
  34. 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: 346–50PubMedCrossRefGoogle Scholar
  35. 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: 1040–6PubMedCrossRefGoogle Scholar
  36. 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: 1526–32PubMedCrossRefGoogle Scholar
  37. 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: 271–80PubMedCrossRefGoogle Scholar
  38. 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: 135–42PubMedCrossRefGoogle Scholar
  39. 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: 95–8SCrossRefGoogle Scholar
  40. 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: 25–34SCrossRefGoogle Scholar
  41. 41.
    McAlister VC, Gao Z, Peltekian K, et al. Sirolimus-tacrolimus combination immunosuppression. Lancet 2000; 355: 376–7PubMedCrossRefGoogle Scholar
  42. 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: 1651–2PubMedCrossRefGoogle Scholar
  43. 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: 3226–8PubMedCrossRefGoogle Scholar
  44. 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: 189–93PubMedCrossRefGoogle Scholar
  45. 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: 230–8PubMedCrossRefGoogle Scholar
  46. 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: 1934–9CrossRefGoogle Scholar
  47. 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: 1213–20PubMedCrossRefGoogle Scholar
  48. 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: 303–9PubMedCrossRefGoogle Scholar
  49. 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: 252–8PubMedCrossRefGoogle Scholar
  50. 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: 2273–80CrossRefGoogle Scholar
  51. 51.
    Dominguez J, Mahalati K, Kiberd B, et al. Conversion to Rapamycin immunosuppression in renal transplant recipients. Transplantation 2000; 70: 1244–7PubMedCrossRefGoogle Scholar
  52. 52.
    Wyzgal J, Paczek L, Senatorski G, et al. Sirolimus rescue treatment in calcineurin-inhibitor nephrotoxicity after kidney transplantation. Transplant Proc 2002; 34: 3185–7PubMedCrossRefGoogle Scholar
  53. 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: 3234–5PubMedCrossRefGoogle Scholar
  54. 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: 131–7SCrossRefGoogle Scholar
  55. 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: 32ACrossRefGoogle Scholar
  56. 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: 777–86PubMedCrossRefGoogle Scholar
  57. 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: 1560–7PubMedCrossRefGoogle Scholar
  58. 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: 1404–8PubMedCrossRefGoogle Scholar
  59. 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: 998–1003PubMedCrossRefGoogle Scholar
  60. 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: S286Google Scholar
  61. 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: 1308–14PubMedCrossRefGoogle Scholar
  62. 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: 364–70CrossRefGoogle Scholar
  63. 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: 1748–56PubMedCrossRefGoogle Scholar
  64. 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: 1036–42PubMedCrossRefGoogle Scholar
  65. 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: 1252–60PubMedCrossRefGoogle Scholar
  66. 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: 436–42PubMedCrossRefGoogle Scholar
  67. 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: 1770–6CrossRefGoogle Scholar
  68. 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: 1776–85PubMedCrossRefGoogle Scholar
  69. 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: 1228–35PubMedCrossRefGoogle Scholar
  70. 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: 722–30PubMedCrossRefGoogle Scholar
  71. 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: 120–9PubMedCrossRefGoogle Scholar
  72. 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: 3009–14PubMedCrossRefGoogle Scholar
  73. 73.
    Mahalati K, Kahan BD. A pilot study of steroid withdrawal from kidney transplant recipients on sirolimus-cyclosporine combination therapy. Transplant Proc 2001; 33: 1270–2PubMedCrossRefGoogle Scholar
  74. 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: 157–66PubMedCrossRefGoogle Scholar
  75. 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: 938–42PubMedCrossRefGoogle Scholar
  76. 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: S287Google Scholar
  77. 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: 1976–85PubMedCrossRefGoogle Scholar
  78. 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.): 183–6SCrossRefGoogle Scholar
  79. 79.
    Rogers J, Ashcraft EE, Emovon OE, et al. Long-term outcome of sirolimus rescue in kidney-pancreas transplantation. Transplantation 2004; 78: 619–22PubMedCrossRefGoogle Scholar
  80. 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: 1117–23PubMedCrossRefGoogle Scholar
  81. 81.
    Neff GW, Montalbano M, Tzakis AG. Ten years of sirolimus therapy in orthotopic liver transplant recipients. Transplant Proc 2003; 35 (3 Suppl.): 209–16SCrossRefGoogle Scholar
  82. 82.
    McAlister VC, Peltekian KM, Malatjalian DA, et al. Orthotopic liver transplantation using low-dose tacrolimus and sirolimus. Liver Transpl 2001; 7: 701–8PubMedCrossRefGoogle Scholar
  83. 83.
    Trotter JF, Wachs M, Bak T, et al. Liver transplantation using sirolimus and minimal corticosteroids (3-day taper). Liver Transpl 2001; 7: 343–51PubMedCrossRefGoogle Scholar
  84. 84.
    Kniepeiss D, Iberer F, Grasser B, et al. Sirolimus and mycophenolate mofetil after liver transplantation. Transpl Int 2003; 16: 504–9PubMedCrossRefGoogle Scholar
  85. 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: 1079–85PubMedCrossRefGoogle Scholar
  86. 86.
    Sahin F, Kannangai R, Adegbola O, et al. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004; 10: 8421–5PubMedCrossRefGoogle Scholar
  87. 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: 1301–11PubMedCrossRefGoogle Scholar
  88. 88.
    Augustine JJ, Hricik DE. Experience with everolimus. Transplant Proc 2004; 36 (2 Suppl.): 5000–33SCrossRefGoogle Scholar
  89. 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: 847–58PubMedCrossRefGoogle Scholar
  90. 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: S246Google Scholar
  91. 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: 568–74PubMedCrossRefGoogle Scholar
  92. 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: 827–31PubMedCrossRefGoogle Scholar
  93. 93.
    Poon M, Badimon JJ, Fuster V. Overcoming restenosis with sirolimus: from alphabet soup to clinical reality. Lancet 2002; 359: 619–22PubMedCrossRefGoogle Scholar
  94. 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: S314–20PubMedCrossRefGoogle Scholar
  95. 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.): 4–17SCrossRefGoogle Scholar
  96. 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: 1437–43PubMedCrossRefGoogle Scholar
  97. 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: 632–8CrossRefGoogle Scholar
  98. 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: 1471–5PubMedCrossRefGoogle Scholar
  99. 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: 421–5PubMedCrossRefGoogle Scholar
  100. 100.
    Ussetti P, Laporta R, de Pablo A, et al. Rapamycin in lung transplantation: preliminary results. Transplant Proc 2003; 35: 1974–7PubMedCrossRefGoogle Scholar
  101. 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: 1940–3PubMedCrossRefGoogle Scholar
  102. 102.
    Hymes LC, Warshaw BL. Sirolimus in pediatric patients: results in the first 6 months post-renal transplant. Pediatr Transplant 2005; 9: 520–2PubMedCrossRefGoogle Scholar
  103. 103.
    Sindhi R, Seward J, Mazariegos G, et al. Replacing calcineurin inhibitors with mTOR inhibitors in children. Pediatr Transplant 2005; 9: 391–7PubMedCrossRefGoogle Scholar
  104. 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: 184–9PubMedCrossRefGoogle Scholar
  105. 105.
    Kahan BD, Napoli KL, Kelly PA, et al. Therapeutic drug monitoring of sirolimus: correlations with efficacy and toxicity. Clin Transplant 2000; 14: 97–109PubMedCrossRefGoogle Scholar
  106. 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: 1244–50PubMedCrossRefGoogle Scholar
  107. 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: 1170–80PubMedGoogle Scholar
  108. 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: 3128–35PubMedCrossRefGoogle Scholar
  109. 109.
    Blum CB. Effects of sirolimus on lipids in renal allograft recipients: an analysis using the Framingham risk model. Am J Transplant 2002; 2: 551–9PubMedCrossRefGoogle Scholar
  110. 110.
    Barshes NR, Goodpastor SE, Goss JA. Sirolimus-atorvastatin drug interaction in the pancreatic islet transplant recipient. Transplantation 2003 Dec 15; 76 (11): 1649–50PubMedCrossRefGoogle Scholar
  111. 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: 2164–70PubMedCrossRefGoogle Scholar
  112. 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: 192–5PubMedCrossRefGoogle Scholar
  113. 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: 562–9PubMedCrossRefGoogle Scholar
  114. 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: S314–20PubMedCrossRefGoogle Scholar
  115. 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: 375–82PubMedCrossRefGoogle Scholar
  116. 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: 1036–42PubMedCrossRefGoogle Scholar
  117. 117.
    Hong JC, Kahan BD. Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients: risk factors, incidence, progression, and management. Transplantation 2000; 69: 2085–90PubMedCrossRefGoogle Scholar
  118. 118.
    Mix TC, Kazmi W, Khan S. Anemia: a continuing problem following kidney transplantation. Am J Transplant 2003; 3: 1426–33PubMedCrossRefGoogle Scholar
  119. 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: 3436–43PubMedCrossRefGoogle Scholar
  120. 120.
    Cruz R, Hedden L, Boyer D, et al. S6 kinase 2 potentiates interleukin-3-driven cell proliferation. J Leukoc Biol 2005; 78: 1378–85PubMedCrossRefGoogle Scholar
  121. 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: 2001–6PubMedCrossRefGoogle Scholar
  122. 122.
    Andoh TF, Lindsley J, Franceschini N, et al. Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model. Transplantation 1996; 62: 311–6PubMedCrossRefGoogle Scholar
  123. 123.
    Podder H, Stepkowski SM, Napoli KL, et al. Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations. J Am Soc Nephrol 2001; 12: 1059–71PubMedGoogle Scholar
  124. 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.): 37–51SCrossRefGoogle Scholar
  125. 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.): 99–104SCrossRefGoogle Scholar
  126. 126.
    Andoh TF, Burdmann EA, Fransechini N, et al. Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK 506. Kidney Int 1996; 50: 1110–7PubMedCrossRefGoogle Scholar
  127. 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: 1262–71PubMedCrossRefGoogle Scholar
  128. 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: 1004–9PubMedCrossRefGoogle Scholar
  129. 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: F693–706PubMedGoogle Scholar
  130. 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: 416–23PubMedCrossRefGoogle Scholar
  131. 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: 1037–45PubMedCrossRefGoogle Scholar
  132. 132.
    Butani L. Investigation of pediatric renal transplant recipients with heavy proteinuria after sirolimus rescue. Transplantation 2004; 78: 1362–6PubMedCrossRefGoogle Scholar
  133. 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 9Google Scholar
  134. 134.
    Dervaux T, Caillard S, Meyer C, et al. Is sirolimus responsible for proteinuria? Transplant Proc 2005; 37: 2828–9PubMedCrossRefGoogle Scholar
  135. 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: 2318–23PubMedCrossRefGoogle Scholar
  136. 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: 1869–75PubMedCrossRefGoogle Scholar
  137. 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: 1729–34PubMedCrossRefGoogle Scholar
  138. 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: 1128–34PubMedCrossRefGoogle Scholar
  139. 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: 1555–61PubMedCrossRefGoogle Scholar
  140. 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: 795–7PubMedCrossRefGoogle Scholar
  141. 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: 1529–36PubMedCrossRefGoogle Scholar
  142. 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: 1788–92PubMedCrossRefGoogle Scholar
  143. 143.
    Langer RM, Kahan BD. Incidence, therapy, and consequences of lymphocele after sirolimus-cyclosporine-prednisone immunosuppression in renal transplant recipients. Transplantation 2002; 74: 804–8PubMedCrossRefGoogle Scholar
  144. 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: 200–6PubMedCrossRefGoogle Scholar
  145. 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: 23166–75PubMedCrossRefGoogle Scholar
  146. 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: 771–80PubMedCrossRefGoogle Scholar
  147. 147.
    Neff GW, Ruiz P, Madariaga JR, et al. Sirolimus-associated hepatotoxicity in liver transplantation. Ann Pharmacother 2004; 38: 1593–6PubMedCrossRefGoogle Scholar
  148. 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: 264–8PubMedCrossRefGoogle Scholar
  149. 149.
    Wadei H, Gruber SA, El-Amm JM, et al. Sirolimus-induced angioedema. Am J Transplant 2004; 4: 1002–5PubMedCrossRefGoogle Scholar
  150. 150.
    Mahe E, Morelon E, Lechaton S, et al. Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. Transplantation 2005; 79: 476–82PubMedCrossRefGoogle Scholar
  151. 151.
    Mohaupt MG, Vogt B, Frey FJ. Sirolimus-associated eyelid edema in kidney transplant recipients. Transplantation 2001; 72: 162–4PubMedCrossRefGoogle Scholar
  152. 152.
    Aboujaoude W, Milgrom ML, Govani MV. Lymphedema associated with sirolimus in renal transplant recipients. Transplantation 2004; 77: 1094–6PubMedCrossRefGoogle Scholar
  153. 153.
    Romagnoli J, Citterio F, Nanni G, et al. Severe limb lymphedema in sirolimus-treated patients. Transplant Proc 2005; 37: 834–6PubMedCrossRefGoogle Scholar
  154. 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: 788–91PubMedCrossRefGoogle Scholar
  155. 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: 2496–503PubMedCrossRefGoogle Scholar
  156. 156.
    Kaczmarek I, Groetzner J, Adamidis I, et al. Sirolimus impairs gonadal function in heart transplant recipients. Am J Transplant 2004; 4: 1084–8PubMedCrossRefGoogle Scholar
  157. 157.
    Tondolo V, Citterio F, Panocchia N, et al. Gonadal function and immunosuppressive therapy after renal transplantation. Transplant Proc 2005; 37: 1915–7PubMedCrossRefGoogle Scholar
  158. 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: 429–46PubMedCrossRefGoogle Scholar
  159. 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: 1812–20PubMedCrossRefGoogle Scholar
  160. 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: 25572–6PubMedCrossRefGoogle Scholar
  161. 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: 324–7PubMedCrossRefGoogle Scholar
  162. 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: 202–6PubMedCrossRefGoogle Scholar
  163. 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: 1764–6PubMedCrossRefGoogle Scholar
  164. 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: 2441–7PubMedCrossRefGoogle Scholar
  165. 165.
    Garrean S, Massad MG, Tshibaka M, et al. Sirolimus-associated interstitial pneumonitis in solid organ transplant recipients. Clin Transplant 2005; 19: 698–703PubMedCrossRefGoogle Scholar
  166. 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: 1392–6PubMedCrossRefGoogle Scholar
  167. 167.
    Pham PT, Pham PC, Danovitch GM, et al. Sirolimus-associated pulmonary toxicity. Transplantation 2004; 77: 1215–20PubMedCrossRefGoogle Scholar
  168. 168.
    Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999; 397: 530–4PubMedCrossRefGoogle Scholar
  169. 169.
    Maluccio M, Sharma V, Lagman M, et al. Tacrolimus enhances transforming growth factor-βl expression and promotes tumor progression. Transplantation 2003; 76: 597–602PubMedCrossRefGoogle Scholar
  170. 170.
    Luan FL, Hojo M, Maluccio M, et al. Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Transplantation 2002; 73: 1565–72PubMedCrossRefGoogle Scholar
  171. 171.
    Luan FL, Ding R, Sharma VK, et al. Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 2003; 63: 917–26PubMedCrossRefGoogle Scholar
  172. 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: 128–35PubMedCrossRefGoogle Scholar
  173. 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: 4472–80PubMedGoogle Scholar
  174. 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: 446–9PubMedCrossRefGoogle Scholar
  175. 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: 883–9PubMedCrossRefGoogle Scholar
  176. 176.
    Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi’s sarcoma. Transplantation 2004; 77: 760–2PubMedCrossRefGoogle Scholar
  177. 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: 523Google Scholar
  178. 178.
    Ozaki KS, Camara NO, Galante NZ, et al. Decreased cytomegalovirus infection after antilymphocyte therapy in sirolimustreated renal transplant patients. Int Immunopharmacol 2005; 5: 103–6PubMedCrossRefGoogle Scholar
  179. 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: 273–8CrossRefGoogle Scholar
  180. 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: 174–80PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Joshua J. Augustine
    • 1
  • Kenneth A. Bodziak
    • 1
  • Donald E. Hricik
    • 1
  1. 1.The Department of Medicine and the Transplantation ServiceCase Western Reserve University, and University Hospitals of ClevelandClevelandUSA

Personalised recommendations