Skip to main content
Log in

Malignancy in Kidney Transplant Recipients

  • Review Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Post-transplant malignancy morbidity and mortality are important limitations in kidney transplantation. The incidence of malignancy has been estimated at 20% after 10 years of chronic immunosuppression. The aetiology of post-transplant malignancy is multifactorial, with the increased risk for malignancy in transplant recipients correlating with overall exposure to immunosuppression. Strategies to understand and minimize the risk of developing malignancy in the transplant population are needed. Calcineurin inhibitors (CNIs) have been linked with posttransplant malignancies, while mammalian target of rapamycin (mTOR) inhibitors have shown antineoplastic activities. The dual efficacy of sirolimus as an immunosuppressive and antitumour agent has been demonstrated experimentally and clinically. Clinical studies have demonstrated a lower incidence of new malignancies after renal transplantation in recipients receiving immunosuppression with mTOR inhibitors compared with CNIs. Therapeutic protocols involving mTOR inhibitors may protect an allograft from immunological rejection, while at the same time addressing the problem of cancer in this high-risk population. Newer sirolimus analogues, such as temsirolimus, have become a focus in pure oncological research and are being evaluated for antineoplastic effects on a variety of malignancies in clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Table I
Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kauffman HM, Cherikh WS, McBride MA, et al. Post-transplant de novo malignancies in renal transplant recipients: the past and present. Transpl Int 2006 Aug; 19(8): 607–20

    Article  PubMed  Google Scholar 

  2. Adams PL. Long-term patient survival: strategies to improve overall health. Am J Kidney Dis 2006 Apr; 47 (4 Suppl. 2): S65–85

    Article  PubMed  Google Scholar 

  3. U.S. Renal Data System, USRDS 2006 annual data report. Atlas of end-stage renal disease in the United States. Bethesda (MD): National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2006 [online]. Available from URL: http://www.usrds.org/adr.htm [Accessed 2007 May 10]

  4. Sheil AG, Disney AP, Mathew TH, et al. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc 1993 Feb; 25 (1 Pt 2): 1383–4

    PubMed  CAS  Google Scholar 

  5. Buell JF, Gross TG, Woodle ES. Malignancy after transplantation. Transplantation 2005 Oct 15; 80 (2 Suppl.): S254–64

    Article  PubMed  Google Scholar 

  6. Koehl GE, Andrassy J, Guba M, et al. Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice. Transplantation 2004 May; 77(9): 1319–26

    Article  PubMed  CAS  Google Scholar 

  7. Kauffman HM. Malignancies in organ transplant recipients. J Surg Oncol 2006 Oct 1; 94(5): 431–3

    Article  PubMed  Google Scholar 

  8. Pedotti P, Cardillo M, Rossini G, et al. Incidence of cancer after kidney transplant: results from the North Italy transplant program. Transplantation 2003 Nov 27; 76(10): 1448–51

    Article  PubMed  Google Scholar 

  9. Vajdic CM, McDonald SP, McCredie MR, et al. Cancer incidence before and after kidney transplantation. JAMA 2006 Dec 20; 296(23): 2823–31 [Supplementary tables accessed at http://web.med.unsw.edu.au/nchecr]

    Article  PubMed  CAS  Google Scholar 

  10. Kasiske BL, Snyder JJ, Gilbertson DT, et al. Cancer after kidney transplantation in the United States. Am J Transplant 2004 Jun; 4(6): 905–13

    Article  PubMed  Google Scholar 

  11. Webster AC, Craig JC, Simpson JM, et al. Identifying high risk groups and quantifying absolute risk of cancer after kidney transplantation: a cohort study of 15,183 recipients. Am J Transplant 2007; 7(9): 2140–51

    Article  PubMed  CAS  Google Scholar 

  12. Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet 1998 Feb 28; 351(9103): 623–8

    Article  PubMed  CAS  Google Scholar 

  13. 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 Oct 15; 80(7): 883–9

    Article  PubMed  CAS  Google Scholar 

  14. Kahan BD, Yakupoglu YK, Schoenberg L, et al. Low incidence of malignancy among sirolimus/cyclosporine-treated renal transplant recipients. Transplantation 2005 Sep 27; 80(6): 749–58

    Article  PubMed  CAS  Google Scholar 

  15. Andrassy J, Graeb C, Rentsch M, et al. mTOR inhibition and its effect on cancer in transplantation. Transplantation 2005 Sep 27; 80 (1 Suppl.): S171–4

    Article  PubMed  CAS  Google Scholar 

  16. Koehl GE, Schlitt HJ, Geissler EK. Rapamycin and tumor growth: mechanisms behind its anticancer activity. Transplant Rev 2005 Jan; 19(1): 20–31

    Article  Google Scholar 

  17. Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999 Feb 11; 397(6719): 530–4

    Article  PubMed  CAS  Google Scholar 

  18. Maluccio M, Sharma V, Lagman M, et al. Tacrolimus enhances transforming growth factor-betal expression and promotes tumor progression. Transplantation 2003 Aug 15; 76(3): 597–602

    Article  PubMed  CAS  Google Scholar 

  19. Schumacher G, Oidtmann M, Rosewicz S, et al. Sirolimus inhibits growth of human hepatoma cells in contrast to tacrolimus which promotes cell growth. Transplant Proc 2002 Aug; 34(5): 1392–3

    Article  PubMed  CAS  Google Scholar 

  20. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangi-ogenesis: involvement of vascular endothelial growth factor. Nat Med 2002 Feb; 8(2): 128–35

    Article  PubMed  CAS  Google Scholar 

  21. Shihab FS, Bennett WM, Isaac J, et al. Nitric oxide modulates vascular endothelial growth factor and receptors in chronic cyclosporine nephrotoxicity. Kidney Int 2003 Feb; 63(2): 522–33

    Article  PubMed  CAS  Google Scholar 

  22. Walz G, Zanker B, Melton LB, et al. Possible association of the immunosuppressive and B cell lymphoma-promoting properties of cyclosporine. Transplantation 1990 Jan; 49(1): 191–4

    Article  PubMed  CAS  Google Scholar 

  23. Twentyman PR, Fox NE, White DJ. Cyclosporin A and its analogues as modifiers of adriamycin and vincristine resistance in a multi-drug resistant human lung cancer cell line. Br J Cancer 1987 Jul; 56(1): 55–7

    Article  PubMed  CAS  Google Scholar 

  24. Guba M, Graeb C, Jauch KW, et al. Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation 2004 Jun 27; 77(12): 1777–82

    Article  PubMed  CAS  Google Scholar 

  25. Sørensen HT, Mellemkjaer L, Nielsen GL, et al. Skin cancers and non-Hodgkin lymphoma among users of systemic glucocorticoids: a population-based cohort study. J Natl Cancer Inst 2004 May 5; 96(9): 709–11

    Article  PubMed  Google Scholar 

  26. Karagas MR, Cushing Jr GL, Greenberg ER, et al. Non-melanoma skin cancers and glucocorticoid therapy. Br J Cancer 2001 Sep 1; 85(5): 683–6

    Article  PubMed  CAS  Google Scholar 

  27. Kelly GE, Meikle W, Sheil AG. Effects of immunosuppressive therapy on the induction of skin tumors by ultraviolet irradiation in hairless mice. Transplantation 1987 Sep; 44(3): 429–34

    Article  PubMed  CAS  Google Scholar 

  28. Penn I. Malignant tumors in organ transplant recipients. Berlin: Springer, 1970

    Book  Google Scholar 

  29. McGeown MG, Douglas JF, Middleton D. One thousand renal transplants at Belfast City Hospital: post-graft neoplasia 1968–1999, comparing azathioprine only with cyclosporinbased regimes in a single centre. Clin Transpl 2000, 202

  30. Hiesse C, Rieu P, Kriaa F, et al. Malignancy after renal transplantation: analysis of incidence and risk factors in 1700 patients followed during a 25-year period. Transplant Proc 1997 Feb–Mar; 29(1–2): 831–3

    Article  PubMed  CAS  Google Scholar 

  31. Blaheta RA, Bogossian H, Beecken WD, et al. Mycophenolate mofetil increases adhesion capacity of tumor cells in vitro. Transplantation 2003 Dec 27; 76(12): 1735–41

    Article  PubMed  CAS  Google Scholar 

  32. Engl T, Makarevic J, Relja B, et al. Mycophenolate mofetil modulates adhesion receptors of the betal integrin family on tumor cells: impact on tumor recurrence and malignancy. BMC Cancer 2005 Jan 11; 5: 4

    Article  PubMed  Google Scholar 

  33. Wang K, Zhang H, Li Y, et al. Safety of mycophenolate mofetil versus azathioprine in renal transplantation: a systematic review. Transplant Proc 2004 Sep; 36(7): 2068–70

    Article  PubMed  CAS  Google Scholar 

  34. Ducloux D, Kazory A, Challier B, et al. Long-term toxicity of antithymocyte globulin induction may vary with choice of agent: a single-center retrospective study. Transplantation 2004 Apr 15; 77(7): 1029–33

    Article  PubMed  CAS  Google Scholar 

  35. Bustami RT, Ojo AO, Wolfe RA, et al. Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients. Am J Transplant 2004 Jan; 4(1): 87–93

    Article  PubMed  Google Scholar 

  36. Chapman TM, Keating GM. Basiliximab: a review of its use as induction therapy in renal transplantation. Drugs 2003; 63(24): 2803–35

    Article  PubMed  CAS  Google Scholar 

  37. Luan FL, Hojo M, Maluccio M, et al. Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Transplantation 2002 May 27; 73(10): 1565–72

    Article  PubMed  CAS  Google Scholar 

  38. Nourse J, Firpo E, Flanagan WM, et al. Interleukin-2-mediated elimination of the p27Kipl cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 1994 Dec 8; 372(6506): 570–3

    Article  PubMed  CAS  Google Scholar 

  39. 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 Aug 1; 63(15): 4472–80

    PubMed  CAS  Google Scholar 

  40. Eng CP, Sehgal SN, Vezina C. Activity of rapamycin (AY-22,989) against transplanted tumors. J Antibiot (Tokyo) 1984 Oct; 37(10): 1231–7

    Article  CAS  Google Scholar 

  41. Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc 2003 May; 35 (3 Suppi.): 7S–14S

    Article  PubMed  CAS  Google Scholar 

  42. Luan FL, Ding R, Sharma VK, et al. Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int 2003 Mar; 63(3): 917–26

    Article  PubMed  CAS  Google Scholar 

  43. Guba M, Yezhelyev M, Eichhorn ME, et al. Rapamycin induces tumor-specific thrombosis via tissue factor in the presence of VEGF. Blood 2005 Jun 1; 105(11): 4463–9

    Article  PubMed  CAS  Google Scholar 

  44. Sodhi A, Montaner S, Patel V, et al. Akt plays a central role in sarcomagenesis induced by Kaposi’s sarcoma herpesvirusencoded G protein-coupled receptor. Proc Natl Acad Sci U S A 2004 Apr 6; 101(14): 4821–6

    Article  PubMed  CAS  Google Scholar 

  45. 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 U S A 2000 Apr 11; 97(8): 4285–90

    Article  PubMed  CAS  Google Scholar 

  46. Campistol JM, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi’s sarcoma. Transplantation 2004 Mar 15; 77(5): 760–2

    Article  PubMed  Google Scholar 

  47. Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N Engl J Med 2005 Mar 31; 352(13): 1317–23

    Article  PubMed  CAS  Google Scholar 

  48. Garcia VD, Bonamigo Filho JL, Neumann J, et al. Rituximab in association with rapamycin for post-transplant lymphoproliferative disease treatment. Transpl Int 2003 Mar; 16(3): 202–6

    Article  PubMed  CAS  Google Scholar 

  49. Sierka K, Kumar MSA, Heifets M, et al. Successful minimization of immunosuppression (IM) and conversion to sirolimus (SLR) in kidney transplants recipients with post transplant lymphoproliferative disease (PTLD) and de novo nonskin malignancies (DNSM) [abstract no. 1331]. Am J Transplant 2004 Mar; 4 Suppl. 8: 523

    Google Scholar 

  50. 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 Aug; 18(4): 446–9

    Article  PubMed  Google Scholar 

  51. 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 Feb; 17(2): 581–9

    Article  PubMed  CAS  Google Scholar 

  52. Chan S, Scheulen ME, Johnston S, et al. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 2005 Aug 10; 23(23): 5314–22

    Article  PubMed  CAS  Google Scholar 

  53. Witzig TE, Geyer SM, Ghobrial I, et al. Phase II trial of singleagent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005 Aug 10; 23(23): 5347–56

    Article  PubMed  CAS  Google Scholar 

  54. Galanis E, Buckner JC, Maurer MJ, et al. on behalf of the North Central Cancer Treatment Group. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2005 Aug 10; 23(23): 5294–304

    CAS  Google Scholar 

  55. Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol 2004 Mar 1; 22(5): 909–18

    Article  PubMed  CAS  Google Scholar 

  56. Hudes G, Carducci M, Tomczak P, et al. Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007 May 31; 356(22): 2271–81

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The author would like to thank Dr Cathryn Jarvis, Dr Isabella Steffensen and Science & Medicine Canada for their editorial assistance in preparing this review. This work was supported by an unrestricted educational grant from Wyeth Canada. Dr Kapoor reports no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anil Kapoor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kapoor, A. Malignancy in Kidney Transplant Recipients. Drugs 68 (Suppl 1), 11–19 (2008). https://doi.org/10.2165/00003495-200868001-00003

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200868001-00003

Keywords

Navigation