Transplantation Proceedings
Volume 39, Issue 10 , Pages 2937-2950 , December 2007

Proliferation Signal Inhibitors in Transplantation: Questions at the Cutting Edge of Everolimus Therapy

References 

  1. Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies?. Am J Transplant. 2004;4:1289
  2. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult heart transplant report-2005. J Heart Lung Transplant. 2006;25:869
  3. Briggs JD. Causes of death after renal transplantation. Nephrol Dial Transplant. 2001;16:1545
  4. Australia and New Zealand Dialysis and Transplant Registry. ANZDATA. http://www.anzdata.org.au/ 2006
  5. Collaborative Transplant Study. http://www.ctstransplant.org/public/citation.html K-15102-0207 March 2007
  6. Eisen H, Kobashigawa J, Starling RC, et al. Improving outcomes in heart transplantation: the potential of proliferation signal inhibitors. Transplant Proc. 2005;37(suppl 4):4S
  7. Nankivell BJ, Borrows RJ, Fung CL, et al. The natural history of chronic allograft nephropathy. N Engl J Med. 2003;349:2326
  8. Chapman JR, O’Connell PJ, Nankivell BJ. Chronic renal allograft dysfunction. J Am Soc Nephrol. 2005;16:3015
  9. Chapman JR. Longitudinal analysis of chronic allograft nephropathy: clinicopathologic correlations. Kidney Int. 2005;68(suppl 99):S108
  10. Aakhus S, Dahl K, Wideroe TE. Cardiovascular disease in stable renal transplant patients in Norway: morbidity and mortality during a 5-yr follow-up. Clin Transplant. 2004;18:596
  11. Opelz G, Dohler B. Improved long-term outcomes after renal transplantation associated with blood pressure control. Am J Transplant. 2005;5:2725
  12. Kobashigawa JA, Tobis JM, Starling RC, et al. Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years. J Am Coll Cardiol. 2005;45:1532
  13. Humar A, Gillingham KJ, Payne WD, et al. Association between cytomegalovirus disease and chronic rejection in kidney transplant recipients. Transplantation. 1999;68:1879
  14. Lowance D, Neumayer HH, Legendre CM, et al. Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation (International Valacyclovir Cytomegalovirus Prophylaxis Transplantation Study Group). N Engl J Med. 1999;340:1462
  15. Kasiske BL, Snyder JJ, Gilbertson DT, et al. Cancer after kidney transplantation in the United States. Am J Transplant. 2004;4:905
  16. Brennan DC. Cytomegalovirus in renal transplantation. J Am Soc Nephrol. 2001;12:848
  17. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant. 2003;4:222
  18. Ulrich C, Schmook T, Sachse MM, et al. Comparative epidemiology and pathogenic factors for nonmelanoma skin cancer in organ transplant patients. Dermatol Surg. 2004;30:622
  19. Kovarik JM. Everolimus: a proliferation signal inhibitor targeting primary causes of allograft dysfunction. Drugs Today (Barc). 2004;40:101
  20. Lee VWS, Chapman JR. Sirolimus: its role in nephrology. Nephrology. 2005;10:606
  21. Nashan B, Curtis J, Ponticelli C, et al. Everolimus and reduced-exposure cyclosporine in de novo renal transplant recipients: a three-year phase II, randomized, multicenter, open-label study. Transplantation. 2004;78:1332
  22. Webster AC, Lee VW, Chapman JR, et al. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systemic review and meta-analysis of randomized trials. Transplantation. 2006;81:1234
  23. Huang S, Liu LN, Hosoi H, et al. p53/p21(CIP1) cooperate in enforcing rapamycin-induced G(1) arrest and determine the cellular response to rapamycin. Cancer Res. 2001;61:3373
  24. Neshat MS, Mellinghoff IK, Tran C, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA. 2001;98:10031
  25. Podsypanina K, Lee RT, Politis C, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten +/− mice. Proc Natl Acad Sci USA. 2001;98:10320
  26. Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res. 2002;62:5027
  27. 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
  28. Morris RE. Rapamycins: antifungal, antitumor, antiproliferative and immunosuppressive macrolides. Transplant Rev. 1992;6:39
  29. Morris RE, Meiser B. A new pharmacologic action for an old compound. Med Sci Res. 1989;17:609
  30. Calne RY, Collier DS, Lim S, et al. Rapamycin for immunosuppression in organ allografting. Lancet. 1989;2:227
  31. Meiser BM, Wang J, Morris RE. Progress in Immunology. In:  Melchers F editors. Berlin: Springer Verlag; 1989;p. 1195;Proceedings of the 7th International Congress of Immunology
  32. Easton JB, Houghton PJ. Therapeutic potential of target of rapamycin inhibitors. Expert Opin Ther Targets. 2004;8:551
  33. Pascual J, Boletis IN, Campistol JM. Everolimus (Certican) in renal transplantation: a review of clinical trial data, current usage and future directions. Transplant Rev. 2006;20:1
  34. Ferron GM, Mishina EV, Zimmerman JJ, et al. Population pharmacokinetics of sirolimus in kidney transplant patients. Clin Pharmacol Ther. 1997;61:416
  35. MacDonald A, Scarola J, Burke JT, et al. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther. 2000;22:B101
  36. Christians U, Gottschalk S, Miljus J, et al. Alterations in glucose metabolism by cyclosporine in rat brain slices link to oxidative stress: interactions with mTOR inhibitors. Br J Pharmacol. 2004;143:388
  37. 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
  38. Schuurman HJ, Cottens S, Fuchs S, et al. SDZ RAD, a new rapamycin derivative: synergism with cyclosporine. Transplantation. 1997;61:32
  39. Schuurman HJ, Pally C, Weckbecker G, et al. SDZ RAD inhibits cold-ischemia-induced vascular remodelling. Transplant Proc. 1999;31:1024
  40. Gregory CR, Pratt R, Huie P, et al. Effects of treatment with cyclosporine, FK 506, rapamycin, mycophenolic acid, or deoxyspergualin on vascular smooth muscle proliferation in vitro and in vivo. Transplant Proc. 1993;25:770
  41. Gregory CR, Huie P, Billingham M, et al. Rapamycin inhibits arterial intimal thickening caused by both alloimmune and mechanical injury: its effect on cellular, growth factors, and cytokine responses in injured vessels. Transplantation. 1993;55:1409
  42. Ikonen TS, Gummert JF, Hayase M, et al. Sirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates. Transplantation. 2000;70:969
  43. Meiser BM, Billingham ME, Morris RE. Effects of cyclosporin, FK506, and rapamycin on graft- vessel disease. Lancet. 1991;338:1297
  44. Matsumoto Y, Hof A, Baumlin Y, et al. Differential effect of cyclosporine A and SDZ RAD on neointima formation of carotid allografts in apolipoprotein E-deficient mice. Transplantation. 2003;76:1166
  45. Gregory CR, Huang X, Pratt RE, et al. Treatment with rapamycin and mycophenolic acid reduces arterial intimal thickening produced by mechanical injury and allows endothelial replacement. Transplantation. 1995;59:655
  46. Nankivell BJ, Borrows RJ, Fung CLS, et al. Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. Transplantation. 2004;78:557
  47. Vitko S, Margreiter R, Weimar W, et al. Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients. Transplantation. 2004;78:1532
  48. Lorber MI, Mulgaonkar S, Butt KMH, et al. Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study. Transplantation. 2005;80:244
  49. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med. 2003;349:847
  50. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute allograft rejection: a randomised multicentre study. Lancet. 2000;356:194
  51. Mota A, Arias M, Taskinen EI, et al. Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant. 2004;4:953
  52. Oberbauer R, Segoloni G, Campistol JM, et al. Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation. Transpl Int. 2005;18:22
  53. Legrendre C, Morales JM, Brault Y, et al. Sirolimus (SRL) therapy following early cyclosporine (CsA) withdrawal: a multivariate analysis of factors influencing long-term renal function outcome. Transplantation. 2006;82(suppl 2):414
  54. Mulay AV, Hussain N, Fergusson D, et al. Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: a systemic review of randomized trials. Am J Transplant. 2005;5:1748
  55. Rapamune® Prescribing Information. Philadelphia: Wyeth Pharmaceuticals; 2006;
  56. Srinivas TR, Schold JD, Guerra G, et al. Mycophenolate mofetil/sirolimus compared to other common immunosuppressive regimens in kidney transplantation. Am J Transplant. 2006;6:1
  57. Pascual J. Concentration-controlled everolimus (Certican): combination with reduced dose calcineurin inhibitors. Transplantation. 2005;79:S76
  58. Vitko S, Tedesco H, Eris J, et al. Everolimus with optimised cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant. 2004;4:626
  59. Tedesco H, Pascual J, Magee J, et al. 36 M analysis on efficacy and safety of everolimus combined with reduced dose Neoral® in de novo kidney transplant recipients. Transplantation. 2006;82(suppl 2):499
  60. Whelchel J, Vitko S, Leone J, et al. 36 month result showing excellent graft function in de novo kidney transplant recipients treated with Certican, Simulect and reduced Neoral exposure. Transplantation. 2006;82(suppl 2):302
  61. Tedesco-Silva H, Vitko S, Pascual J, et al. 12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients. Transplant Int. 2007;20:27
  62. Stefoni S, Midtved K, Cole E, et al. Efficacy and safety outcomes among de novo renal transplant recipients managed by C2 monitoring of cyclosporine a microemulsion: results of a 12-month, randomized, multicenter study. Transplantation. 2005;79:577
  63. Lorber MI, Ponticelli C, Whelchel J, et al. Therapeutic drug monitoring for everolimus in kidney transplantation using 12-month exposure, efficacy, and safety data. Clin Transplant. 2005;19:145
  64. Budde K, Glander P, Schuhmann R, et al: Presented at the APSA/ASCEPT Annual Scientific Meeting, Melbourne, Australia, December 4–7, 2005, Poster 1–106
  65. Arns W, Glander P, Schuhmann R, et al: Presented at the APSA/ASCEPT Annual Scientific Meeting, Melbourne, Australia, December 4–7, 2005, Poster 1–108
  66. Ojo AO, Held PJ, Pork FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N Eng J Med. 2003;349:931
  67. Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation. 2004;110:2694
  68. Stepkowski SM, Napoli KL, Wang ME, et al. Effects of the pharmacokinetic interaction between orally administered sirolimus and cyclosporine on the synergistic prolongation of heart allograft survival in rats. Transplantation. 1996;62:986
  69. Fuchs U, Zittermann A, Tenderich G, et al. The role of everolimus in the improvement of renal function in heart transplant recipients. Transpl Int. 2005;18(suppl 1):PO094
  70. Snell GI, Levvey BJ, Chin W, et al. Sirolimus allows renal recovery in lung and heart transplant recipients with chronic renal impairment. J Heart Lung Transplant. 2002;21:540
  71. Lehmkuhl H, Ross H, Eisen H, et al. Everolimus (Certican) in heart transplantation-optimizing renal function through minimizing cyclosporine exposure. Transplant Proc. 2005;37:4145
  72. Lehmkuhl H, Mai D, Dandel M, et al. Observational study with everolimus (Certican) in combination with low-dose ciclosporin A in de novo heart transplant recipients. J Heart Lung Transplant. 2007;26:700
  73. 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
  74. 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. Bumbea V, Kamar N, Ribes D, et al. Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant. 2005;20:2517
  76. Morelon E, Kreis H. Sirolimus therapy without calcineurin inhibitors: Necker Hospital 8-year experience. Transplant Proc. 2003;35:52S
  77. Ruiz JC, Campistol JM, Sanchez-Fructuoso A, et al. Increase of proteinuria after conversion from calcineurin inhibitor to sirolimus-based treatment in kidney transplant patients with chronic allograft dysfunction. Nephrol Dial Transplant. 2006;21:3252
  78. Aliabadi AZ, Kammerstätter DP, Seebacher G, et al. Development of proteinuria after switch to sirolimus based immunosuppression in long-term cardiac transplant patients. Transplantation. 2006;82(suppl 2):562
  79. Fernandez-Fresnedo G, Plaza JJ, Sanchez-Plumed J, et al. Proteinuria: a new marker of long-term graft and patient survival in kidney transplantation. Nephrol Dial Transplant. 2004;19(suppl 3):iii47
  80. Viklicky O, Zou H, Muller V, et al. SDZ-RAD prevents manifestation of chronic rejection in rat renal allografts. Transplantation. 2000;69:497
  81. Straacke S, Mayer JM, Henne-Bruns D, et al. Elevated serum levels of vascular endothelial growth factor (VEGF) and proteinuria in renal allograft recipients treated with mTOR inhibitors. Transplantation. 2006;82(suppl 2):299
  82. Straathof-Galema L, Wetzels JF, Dijkman HB, et al. Sirolimus-associated heavy proteinuria in a renal transplant recipients: evidence for a tubular mechanism. Am J Transplant. 2006;6:429
  83. 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. 2006;21:488
  84. van den Akker JM, Wetzels JFM, Hoitsma AJ. Proteinuria following conversion from azathioprine to sirolimus in stable renal transplant recipients. Transplantation. 2006;82(suppl 2):238
  85. Dittrich E, Schmaldienst S, Soleiman A, et al. Rapamycin-associated post-transplantation glomerulonephritis and its remission after reintroduction of calcineurin-inhibitor therapy. Transpl Int. 2004;17:215
  86. Kobashigawa JA. What is the optimal prophylaxis for treatment of cardiac allograft vasculopathy?. Curr Control Trials Cardiovasc Med. 2000;1:166
  87. Kapadia SR, Nissen SE, Tuzcu EM. Impact of intravascular ultrasound in understanding transplant coronary artery disease. Curr Opin Cardiol. 1999;14:140
  88. Rickenbacher PR, Pinto FJ, Lewis NP, et al. Prognostic importance of intimal thickness as measured by intracoronary ultrasound after cardiac transplantation. Circulation. 1995;92:3445
  89. Dambrin C, Klupp J, Birsan T, et al. Sirolimus (rapamycin) monotherapy prevents graft vascular disease in nonhuman primate recipients of orthotopic aortic allografts. Circulation. 2003;107:2369
  90. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315
  91. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med. 2002;346:1773
  92. Tsuchiya Y, Lansky AJ, Costa RA, et al. Effect of everolimus-eluting stents in different vessel sizes (from pooled FUTURE I and II trials). Am J Cardiol. 2006;98:464
  93. Mancini D, Viganó M, Pulpon LA, et al. 24-month results of a multicenter study of everolimus for the prevention of allograft rejection and vasculopathy in de novo cardiac transplant recipients. 2003;Presented at the American Transplant Congress, Washington, DC, USA, May 30–June 4,
  94. Eisen H. Long-term cardiovascular risk in transplantation–insights from the use of everolimus in heart transplantation. Nephrol Dial Transplant. 2006;21:iii9
  95. Eisen H, Yang X. The impact of proliferation signal inhibitors on the healthcare burden of major adverse cardiac events following heart transplantation. Transplantation. 2006;82:S13
  96. Ruygrok PN, Webber B, Faddy S, et al. Angiographic regression of cardiac allograft vasculopathy after introducing sirolimus immunosuppression. J Heart Lung Transplant. 2003;22:1276
  97. Mancini D, Pinney S, Burkhoff D, et al. Use of rapamycin slows progression of cardiac transplantation vasculopathy. Circulation. 2003;108:48
  98. Frigerio M, Cipriani MG, Roubina E, et al. Case report: long-term outcome of a heart transplant recipient switched to everolimus after an acute myocardial infarction. Transplantation. 2006;82:S19
  99. Segovia J, Gómez-Bueno M, Alonso-Pulpón L. Treatment of allograft vasculopathy in heart transplantation. Expert Opin Pharmacother. 2006;7:2369
  100. Pascual M, Theruvath T, Kawai T, et al. Strategies to improve long-term outcomes after renal transplantation. N Engl J Med. 2002;346:580
  101. Paul LC. Chronic allograft nephropathy: an update. Kidney Int. 1999;56:783
  102. Halloran PF, Langone AJ, Helderman JH, et al. Assessing long-term nephron loss: Is it time to kick the CAN grading system. Am J Transplant. 2004;4:1729
  103. Marqués GG, Goenaga PE, Royo FJL, et al. Evolution of the renal function is a better predictor of long-term survival than serum creatinine. Transplant Proc. 2005;37:3701
  104. Arns W, Citterio F, Campistol JM. “Old-for-old” – new strategies for renal transplantation. Nephrol Dial Transplant. 2007;22:336
  105. Cohen B, Smits JM, Haase B, et al. Expanding the donor pool to increase renal transplantation. Nephrol Dial Transplant. 2005;20:34
  106. Oppenheimer F, Aljama P, Asensio PC, et al. The impact of donor age on the results of renal transplantation. Nephrol Dial Transplant. 2004;19(suppl 3):iii11
  107. Meier-Kriesche HU, Ojo AO, Cibrik DM, et al. Relationship of recipient age and development of chronic allograft failure. Transplantation. 2000;70:306
  108. Meier-Kriesche H, Ojo AO, Arndorfer JA, et al. Recipient age as an independent risk factor for chronic renal allograft failure. Transplant Proc. 2001;33:1113
  109. Rubin RH. Infectious disease complications of renal transplantation. Kidney Int. 1993;44:221
  110. Lipshutz GS, Mahanty H, Feng S, et al. BKV in simultaneous pancreas-kidney transplant recipients: a leading cause of renal graft loss in first 2 years post-transplant. Am J Transplant. 2005;5:366
  111. Lipshutz GS, Flechner SM, Govani MV, et al. BK nephropathy in kidney transplant recipients treated with a calcineurin inhibitor-free immunosuppression regimen. Am J Transplant. 2004;4:2132
  112. Hartmann A, Sagedal S, Hjelmesœth J. The natural course of cytomegalovirus infection and disease in renal transplant recipients. Transplantation. 2006;82:S15
  113. Ascherman JA, Hugo NE, Sultan MR, et al. Single-stage treatment of sternal wound complications in heart transplant recipients in whom pectoralis major myocutaneous advancement flaps were used. J Thorac Cardiovasc Surg. 1995;110:1030
  114. Baldwin RT, Radovancevic B, Sweeney MS, et al. Bacterial mediastinitis after heart transplantation. J Heart Lung Transplant. 1992;11:545
  115. Karwande SV, Renlund DG, Olsen SL, et al. Mediastinitis in heart transplantation. Ann Thorac Surg. 1992;54:1039
  116. 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
  117. Langer RM, Kahan BD. Incidence, therapy, and consequences of lymphocele after sirolimus-cyclosporine-prednisone immunosuppression in renal transplant recipients. Transplantation. 2002;74:804
  118. Troppmann C, Pierce JL, Gandhi MM, et al. Higher surgical wound complication rates with sirolimus immunosuppression after kidney transplantation: a matched-pair pilot study. Transplantation. 2003;76:426
  119. Kobashigawa JA, Miller LW, Russell SD, et al. Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report. Am J Transplant. 2006;6:1377
  120. Azzola A, Havryk A, Chhajed P, et al. Everolimus and mycophenolate mofetil are potent inhibitors of fibroblast proliferation after lung transplantation. Transplantation. 2004;77:275
  121. Kuppahally S, Al-Khaldi A, Weisshaar D, et al. Wound healing complications with de novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients. Am J Transplant. 2006;6:986
  122. 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
  123. Knight RJ, Villa M, Welsh M, et al. Risk factors for impaired wound healing in sirolimus treated renal transplant recipients. Am J Transplant. 2003;3:481
  124. Pascual J, Galeano C, Celemln D, et al. Uneventful thoracic healing with everolimus after aortic valve replacement. Ann Thoracic Surg. 2007;84:271
  125. Marcén R, Morales JM, Fernandez-Juarez G, et al. Risk factors of ischemic heart disease after renal transplantation. Transplant Proc. 2002;34:394
  126. Massy ZA. Hyperlipidemia and cardiovascular disease after organ transplantation. Transplantation. 2001;72:S13
  127. Barbagallo CM, Pinto A, Gallo S, et al. Carotid atherosclerosis in renal transplant recipients: relationships with cardiovascular risk factors and plasma lipoproteins. Transplantation. 1999;67:366
  128. Suwelack B, Witta J, Hausberg M, et al. Studies on structural changes of the carotid arteries and the heart in asymptomatic renal transplant recipients. Nephrol Dial Transplant. 1999;14:160
  129. Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis. 1998;32:S112
  130. Levey AS, Beto JA, Coronado BE, et al. Controlling the epidemic of cardiovascular disease in chronic renal disease: What do we know? What do we need to learn? Where do we go from here? National Kidney Foundation Task Force on Cardiovascular Disease. Am J Kidney Dis. 1998;32:853
  131. Ducloux D, Kazory A, Chalopin JM. Predicting coronary heart disease in renal transplant recipients: a prospective study. Kidney Int. 2004;66:441
  132. Kasiske BL, Chakkera HA, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol. 2000;11:1735
  133. Lentine KL, Brennan DC, Schnitzler MA. Incidence and predictors of myocardial infarction after kidney transplantation. J Am Soc Nephrol. 2005;16:496
  134. Rigatto C, Parfrey P, Foley R, et al. Congestive heart failure in renal transplant recipients: risk factors, outcomes, and relationship with ischemic heart disease. J Am Soc Nephrol. 2002;13:1084
  135. Winkelmayer WC, Lorenz M, Kramar R, et al. C-reactive protein and body mass index independently predict mortality in kidney transplant recipients. Am J Transplant. 2004;4:1148
  136. Kobashigawa JA, Starling RC, Mehra MR, et al. Multicenter retrospective analysis of cardiovascular risk factors affecting long-term outcomes of de novo cardiac transplant recipients. J Heart Lung Transplant. 2006;25:1063
  137. Rivero E, Varas C, Maguire AR, et al. 10-year predicted probability of coronary heart disease in renal transplant recipients treated with everolimus or MMF. Am J Transplant. 2002;2(suppl 3):417
  138. Sparacino V, Calabrese S. Conversion to a proliferation inhibitor in a patient with coronary artery disease – a case report. Nephrol Dial Transplant. 2006;21(suppl 3):iii34
  139. Pascual J, Fernández AM, Marcén R, et al. Conversion to everolimus in a patient with arterial hypertension and recurrent cutaneous neoplasia – a case report. Nephrol Dial Transplant. 2006;21(suppl 3):iii38
  140. Castro C, Campistol JM, Sancho D, et al. Rapamycin attenuates atherosclerosis induced by dietary cholesterol in apolipoprotein-deficient mice through a p27 Kip1-independent pathway. Atherosclerosis. 2004;172:31
  141. 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
  142. Bellosta S, Arnaboldi L, Canavesi M, et al: Presented at 7th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology. Denver, Co, USA, April 27–29, 2006
  143. Wenke K, Meiser B, Thiery J, et al. Simvastatin initiated early after heart transplantation: 8-year prospective experience. Circulation. 2003;107:93
  144. Vajdic CM, McDonald SP, McCredie MR, et al. Cancer incidence before and after kidney transplantation. JAMA. 2006;296:2823
  145. Kauffman HM, Cherikh WS, McBride MA, et al. Post-transplant de novo malignancies in renal transplant recipients: the past and present. Transpl Int. 2006;19:607
  146. Caillard S, Dharnidharka V, Agodoa L, et al. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation. 2005;80:1233
  147. Campistol JM, Eris J, Oberbauer R, et al. Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation. J Am Soc Nephrol. 2006;17:581
  148. 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
  149. Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med. 2005;352:1317
  150. Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi’s sarcoma. Transplantation. 2004;77:760
  151. Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999;397:530
  152. Maluccio M, Sharma V, Lagman M, et al. Tacrolimus enhances transforming growth factor-beta1 expression and promotes tumor progression. Transplantation. 2003;76:597
  153. Guba M, von BP, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8:128
  154. Koehl GE, Andrassy J, Guba M, et al. Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice. Transplantation. 2004;77:1319
  155. Suzaki N, Fuchimoto S, Iwagaki H, et al. Effects of cyclosporine A on experimental hepatic metastases of mouse colon-26 tumour. J Int Med Res. 1995;23:112
  156. Van de Vrie W, Marquet RL, Eggermont AM. Cyclosporine A enhances locoregional metastasis of the CC531 rate colon tumour. J Cancer Res Clin Oncol. 1997;123:123
  157. Freise CE, Ferrell L, Liu T, et al. Effect of systemic cyclosporine on tumor recurrence after liver transplantation in a model of hepatocellular carcinoma. Transplantation. 1999;67:510
  158. Boulay A, Zumstein-Mecker S, Stephan C, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res. 2004;64:252
  159. Beuvink I, Boulay A, Fumagalli S, et al. The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damage induced apoptosis through inhibition of p21 translation. Cell. 2005;120:747
  160. Majewski M, Korecka M, Kossev P, et al. The immunosuppressive macrolide RAD inhibits growth of human Epstein-Barr virus-transformed B lymphocytes in vitro and in vivo: A potential approach to prevention and treatment of posttransplant lymphoproliferative disorders. Proc Natl Acad Sci USA. 2000;97:4285
  161. Majewski M, Korecka M, Joergensen J, et al. Immunosuppressive TOR kinase inhibitor everolimus (RAD) suppresses growth of cells derived from posttransplant lymphoproliferative disorder at allograft-protecting doses. Transplantation. 2003;75:1710
  162. Liu X, Powlas J, Shi Y, et al. Rapamycin inhibits Akt-mediated oncogenic transformation and tumor growth. Anticancer Res. 2004;24:2697
  163. Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptopic and HIF-1-dependent pathways. Nat Med. 2004;10:594
  164. Andres V, Castro C, Campistol JM. Potential role of proliferation signal inhibitors on atherosclerosis in renal transplant patients. Nephrol Dial Transplant. 2006;21(suppl 3):iii1–iii4
  165. Yee KW, Zeng Z, Konopleva M, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res. 2006;12:5165
  166. Doherty L, Gigas DC, Kesari S, et al. Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Neurology. 2006;67:156
  167. Tabernero J, Rojo F, Burris H, et al. A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule of the oral mTOR-inhibitor everolimus (RAD001) in patients with advanced solid tumors. J Clin Oncol. 2005;23:Abstract 3007,
  168. Amato RJ, Misellati A, Khan M, et al. A phase II trial of RAD001 in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:18S Abstract 4530
  169. Abramowicz D, del Carmen Rial M, Vitko S, et al. Cyclosporine withdrawal from a mycophenolate mofetil-containing immunosuppressive regimen: results of a five-year, prospective, randomized study. J Am Soc Nephrol. 2005;16:2234
  170. Pascual J, Quereda C, Zamora J, et al. Steroid withdrawal in renal transplant patients on triple therapy with a calcineurin inhibitor and mycophenolate mofetil: a meta-analysis of randomized, controlled trials. Transplantation. 2004;78:1548
  171. Marcén R. Cardiovascular risk factors risk in transplantation–current controversies. Nephrol Dial Transplant. 2006;21:3
  172. Neumayer HH. Introducing everolimus (Certican) in organ transplantation: an overview of preclinical and early clinical developments. Transplantation. 2005;79(suppl 3):S72

 Authors received an honorarium for attending The PSI Forum “Proliferation signal inhibitors in transplantation: questions at the cutting edge,” held in Basel in May 2006, which was fully funded by Novartis Pharma AG.

PII: S0041-1345(07)01150-5

doi: 10.1016/j.transproceed.2007.09.008

Transplantation Proceedings
Volume 39, Issue 10 , Pages 2937-2950 , December 2007