Skip to main content
SpringerLink
Log in

Immunosuppression in Simultaneous Pancreas-Kidney Transplantation

Progress to Date

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

Abstract

Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice for patients with end-stage renal failure due to type 1 diabetes mellitus. With advances in surgical techniques and immunosuppression management, outcomes have improved, with current 1- and 10-year pancreas graft survival rates of 86% and 53%, respectively. Induction therapy with either alemtuzumab or rabbit antithymocyte globulin (rATG) in combination with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) or sirolimus appears to be safe and effective in the setting of rapid steroid withdrawal (RSW), with excellent graft survival and low rejection rates. There are no large randomized trials between alemtuzumab and rATG to determine whether one is better than the other. Anti-interleukin (IL)-2 receptor antibody induction and no induction in combination with a CNI, MMF or sirolimus, and prednisone have demonstrated excellent graft survival rates but are associated with a higher incidence of acute rejection. The efficacy of anti-IL-2 receptor antibodies or no induction in the setting of RSW is unproven. Both of the CNIs, ciclosporin and tacrolimus, are effective in preventing acute rejection in SPKT recipients; however, pancreas allograft survival may be better with tacrolimus. MMF is more effective than azathioprine in preventing acute rejection. Sirolimus appears to be effective in preventing acute rejection, but the combination of sirolimus with a CNI may accentuate the nephrotoxicity of the CNI. RSW with induction therapy is safe and effective in SPKT recipients, but longer follow-up data on outcomes are needed. Recent analysis of registry data shows that most transplant centres are using an induction agent followed by a combination of tacrolimus, MMF and corticosteroids in SPKT recipients.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Fig. 1
Table III
Table IV

Similar content being viewed by others

References

  1. International Pancreas Transplant Registry. Pancreas transplants by category [online]. Available from URL: http://www.iptr.umn.edu/annual_reports/2004_annual_report/3_txs_cat/home.html [Accessed 2010 Mar 10]

  2. McCullough KP, Keith DS, Meyer KH, et al. Kidney and pancreas transplantation in the United States, 1998–2007: access for patients with diabetes and end-stage renal disease. Am J Transplant 2009; 9 (4 Pt 2): 894–906

    Article  PubMed  CAS  Google Scholar 

  3. White SA, Shaw JA, Sutherland DE. Pancreas transplantation. Lancet 2009; 373(9677): 1808–17

    Article  PubMed  CAS  Google Scholar 

  4. Cantarovich D, Vistoli F. Minimization protocols in pancreas transplantation. Transpl Int 2009; 22(1): 61–8

    Article  PubMed  Google Scholar 

  5. Stratta RJ, Alloway RR, Lo A, et al. Two-dose daclizumab regimen in simultaneous kidney-pancreas transplant recipients: primary endpoint analysis of a multicenter, randomized study. Transplantation 2003; 75(8): 1260–6

    Article  PubMed  CAS  Google Scholar 

  6. Stratta RJ, Alloway RR, Lo A, et al. A prospective, randomized, multicenter study evaluating the safety and efficacy of two dosing regimens of daclizumab compared to no antibody induction in simultaneous kidney-pancreas transplantation: results at 3 years. Transplant Proc 2005; 37(8): 3531–4

    Article  PubMed  CAS  Google Scholar 

  7. Kaufman DB, Iii GW, Bruce DS, et al. Prospective, randomized, multi-center trial of antibody induction therapy in simultaneous pancreas-kidney transplantation. Am J Transplant 2003; 3(7): 855–64

    Article  PubMed  Google Scholar 

  8. Burke 3rd GW, Kaufman DB, Millis JM, et al. Prospective, randomized trial of the effect of antibody induction in simultaneous pancreas and kidney transplantation: three-year results. Transplantation 2004; 77(8): 1269–75

    Article  PubMed  Google Scholar 

  9. Gruessner RW, Kandaswamy R, Humar A, et al. Calcineurin inhibitor- and steroid-free immunosuppression in pancreas-kidney and solitary pancreas transplantation. Transplantation 2005; 79(9): 1184–9

    Article  PubMed  CAS  Google Scholar 

  10. Thai NL, Khan A, Tom K, et al. Alemtuzumab induction and tacrolimus monotherapy in pancreas transplantation: one- and two-year outcomes. Transplantation 2006; 82(12): 1621–4

    Article  PubMed  CAS  Google Scholar 

  11. Kaufman DB, Leventhal JR, Gallon LG, et al. Alemtuzumab induction and prednisone-free maintenance immuno-therapy in simultaneous pancreas-kidney transplantation comparison with rabbit antithymocyte globulin induction: long-term results. Am J Transplant 2006; 6(2): 331–9

    Article  PubMed  CAS  Google Scholar 

  12. Clatworthy MR, Sivaprakasam R, Butler AJ, et al. Subcutaneous administration of alemtuzumab in simultaneous pancreas-kidney transplantation. Transplantation 2007; 84(12): 1563–7

    Article  PubMed  CAS  Google Scholar 

  13. Magliocca JF, Odorico JS, Pirsch JD, et al. A comparison of alemtuzumab with basiliximab induction in simultaneous pancreas-kidney transplantation. Am J Transplant 2008; 8(8): 1702–10

    Article  PubMed  CAS  Google Scholar 

  14. Muthusamy AS, Vaidya AC, Sinha S, et al. Alemtuzumab induction and steroid-free maintenance immunosuppression in pancreas transplantation. Am J Transplant 2008; 8(10): 2126–31

    Article  PubMed  CAS  Google Scholar 

  15. Pascual J, Pirsch JD, Odorico JS, et al. Alemtuzumab induction and antibody-mediated kidney rejection after simultaneous pancreas-kidney transplantation. Transplantation 2009; 87(1): 125–32

    Article  PubMed  CAS  Google Scholar 

  16. Farney AC, Doares W, Rogers J, et al. A randomized trial of alemtuzumab versus antithymocyte globulin induction in renal and pancreas transplantation. Transplantation 2009; 88(6): 810–9

    Article  PubMed  CAS  Google Scholar 

  17. Post DJ, Mazur MJ, Chakkera HA, et al. Outcomes of simultaneous kidney pancreas (SPK) transplant recipients with alemtuzumab induction and steroid avoidance immunosuppression: comparison of intravenous vs. subcutaneous administration [abstract]. Am J Transplant 2009; 9 Suppl. 2: 710

    Google Scholar 

  18. Farney A, Sundberg A, Moore P, et al. A randomized trial of alemtuzumab vs anti-thymocyte globulin induction in renal and pancreas transplantation. Clin Transplant 2008; 22(1): 41–9

    PubMed  Google Scholar 

  19. Cantarovich D, Giral-Classe M, Hourmant M, et al. Low incidence of kidney rejection after simultaneous kidney-pancreas transplantation after antithymocyte globulin induction and in the absence of corticosteroids: results of a prospective pilot study in 28 consecutive cases. Transplantation 2000; 69(7): 1505–8

    Article  PubMed  CAS  Google Scholar 

  20. Kaufman DB, Leventhal JR, Koffron AJ, et al. A prospective study of rapid corticosteroid elimination in simultaneous pancreas-kidney transplantation: comparison of two maintenance immunosuppression protocols. Tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus. Transplantation 2002; 73(2): 169–77

    Article  PubMed  CAS  Google Scholar 

  21. Freise CE, Kang SM, Feng S, et al. Excellent short-term results with steroid-free maintenance immunosuppression in low-risk simultaneous pancreas-kidney transplantation. Arch Surg 2003; 138(10): 1121–5; discussion 5-6

    Article  PubMed  Google Scholar 

  22. Aoun M, Eschewege P, Hamoudi Y, et al. Very early steroid withdrawal in simultaneous pancreas-kidney transplants. Nephrol Dial Transplant 2007; 22(3): 899–905

    Article  PubMed  CAS  Google Scholar 

  23. Rajab A, Pelletier RP, Ferguson RM, et al. Steroid-free maintenance immunosuppression with rapamune and low-dose neoral in pancreas transplant recipients. Transplantation 2007; 84(9): 1131–7

    Article  PubMed  CAS  Google Scholar 

  24. Bechstein WO, Malaise J, Saudek F, et al. Efficacy and safety of tacrolimus compared with cyclosporine micro-emulsion in primary simultaneous pancreas-kidney transplantation: 1-year results of a large multicenter trial. Transplantation 2004; 77(8): 1221–8

    Article  PubMed  CAS  Google Scholar 

  25. Rasaiah SB, Light JA, Sasaki TM, et al. A comparison of daclizumab to ATGAM induction in simultaneous pancreas-kidney transplant recipients on triple maintenance immunosuppression. Clin Transplant 2000; 14 (4 Pt 2): 409–12

    Article  PubMed  CAS  Google Scholar 

  26. Bruce DS, Sollinger HW, Humar A, et al. Multicenter survey of daclizumab induction in simultaneous kidney-pancreas transplant recipients. Transplantation 2001; 72(10): 1637–43

    Article  PubMed  CAS  Google Scholar 

  27. Lo A, Stratta RJ, Alloway RR, et al. Initial clinical experience with interleukin-2 receptor antagonist induction in combination with tacrolimus, mycophenolate mofetil and steroids in simultaneous kidney-pancreas transplantation. Transpl Int 2001; 14(6): 396–404

    Article  PubMed  CAS  Google Scholar 

  28. Chow FY, Polkinghorne K, Saunder A, et al. Historical controlled trial of OKT3 versus basiliximab induction therapy in simultaneous pancreas-renal transplantation. Nephrology (Carlton) 2003; 8(4): 212–6

    Article  CAS  Google Scholar 

  29. Zhang R, Florman S, Devidoss S, et al. The long-term survival of simultaneous pancreas and kidney transplant with basiliximab induction therapy. Clin Transplant 2007; 21(5): 583–9

    Article  PubMed  Google Scholar 

  30. Jordan ML, Chakrabarti P, Luke P, et al. Results of pancreas transplantation after steroid withdrawal under tacrolimus immunosuppression. Transplantation 2000; 69(2): 265–71

    Article  PubMed  CAS  Google Scholar 

  31. Reddy KS, Stratta RJ, Shokouh-Amiri H, et al. Simultaneous kidney-pancreas transplantation without antilym-phocyte induction. Transplantation 2000; 69(1): 49–54

    Article  PubMed  CAS  Google Scholar 

  32. Rigotti P, Baldan N, Cadrobbi R, et al. Antilymphocyte induction is no longer necessary in simultaneous pancreas and kidney transplantation. Transplant Proc 2002; 34(5): 1906–8

    Article  PubMed  Google Scholar 

  33. Becker LE, Nogueira VA, Abensur H, et al. No induction versus anti-IL2R induction therapy in simultaneous kidney pancreas transplantation: a comparative analysis. Transplant Proc 2006; 38(6): 1933–6

    Article  PubMed  CAS  Google Scholar 

  34. Kaufman DB, Leventhal JR, Koffron A, et al. Simultaneous pancreas-kidney transplantation in the mycophenolate mofetil/tacrolimus era: evolution from induction therapy with bladder drainage to noninduction therapy with enteric drainage. Surgery 2000; 128(4): 726–37

    Article  PubMed  CAS  Google Scholar 

  35. Meier-Kriesche HU, Li S, Gruessner RWG, et al. Immunosuppression: evolution in practice and trends, 1994–2004. Am J Transplant 2006; 6(5p2): 1111–31

    Article  PubMed  CAS  Google Scholar 

  36. Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357(25): 2562–75

    Article  PubMed  CAS  Google Scholar 

  37. 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(11): 1776–85

    Article  PubMed  CAS  Google Scholar 

  38. Woodle ES, First MR, Pirsch J, et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008; 248(4): 564–77

    PubMed  Google Scholar 

  39. Saudek F, Malaise J, Boucek P, et al. Efficacy and safety of tacrolimus compared with cyclosporin microemulsion in primary SPK transplantation: 3-year results of the Euro-SPK 001 trial. Nephrol Dial Transplant 2005; 20 Suppl. 2 (2): ii3–10, ii62

    Article  PubMed  CAS  Google Scholar 

  40. Boggi U, Vistoli F, Del Chiaro M, et al. Neoral versus prograf in simultaneous pancreas-kidney transplantation with portal venous drainage: three-year results of a single-center, open-label, prospective, randomized pilot study. Transplant Proc 2005; 37(6): 2641–3

    Article  PubMed  CAS  Google Scholar 

  41. Stegall MD, Simon M, Wachs ME, et al. Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine. Transplantation 1997; 64(12): 1695–700

    Article  PubMed  CAS  Google Scholar 

  42. Gruessner RW, Burke GW, Stratta R, et al. A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation. Transplantation 1996; 61(2): 261–73

    Article  PubMed  CAS  Google Scholar 

  43. Nankivell BJ, Borrows RJ, Fung CL, et al. Delta analysis of posttransplantation tubulointerstitial damage. Transplantation 2004; 78(3): 434–41

    Article  PubMed  Google Scholar 

  44. Nankivell BJ, Wavamunno MD, Borrows RJ, et al. Mycophenolate mofetil is associated with altered expression of chronic renal transplant histology. Am J Transplant 2007; 7(2): 366–76

    Article  PubMed  CAS  Google Scholar 

  45. Merville P, Berge F, Deminiere C, et al. Lower incidence of chronic allograft nephropathy at 1 year post-transplantation in patients treated with mycophenolate mofetil. Am J Transplant 2004; 4(11): 1769–75

    Article  PubMed  CAS  Google Scholar 

  46. Salvadori M, Holzer H, de Mattos A, et al. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2004; 4(2): 231–6

    Article  PubMed  CAS  Google Scholar 

  47. Budde K, Curtis J, Knoll G, et al. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study. Am J Transplant 2004; 4(2): 237–43

    Article  PubMed  CAS  Google Scholar 

  48. Bolin P, Tanriover B, Zibari GB, et al. Improvement in 3-month patient-reported gastrointestinal symptoms after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in renal transplant patients. Transplantation 2007; 84(11): 1443–51

    Article  PubMed  CAS  Google Scholar 

  49. Chan L, Mulgaonkar S, Walker R, et al. Patient-reported gastrointestinal symptom burden and health-related quality of life following conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium. Transplantation 2006; 81(9): 1290–7

    Article  PubMed  Google Scholar 

  50. Merion RM, Henry ML, Melzer JS, et al. Randomized, prospective trial of mycophenolate mofetil versus azathioprine for prevention of acute renal allograft rejection after simultaneous kidney-pancreas transplantation. Transplantation 2000; 70(1): 105–11

    PubMed  CAS  Google Scholar 

  51. MacDonald AS. A worldwide, phase III, randomized, 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(2): 271–80

    Article  PubMed  CAS  Google Scholar 

  52. 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(8): 1213–20

    Article  PubMed  CAS  Google Scholar 

  53. 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(5): 777–86

    Article  PubMed  CAS  Google Scholar 

  54. 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(8): 1070–6

    Article  PubMed  CAS  Google Scholar 

  55. Larson TS, Dean PG, Stegall MD, et al. Complete avoidance of calcineurin inhibitors in renal transplantation: a randomized trial comparing sirolimus and tacrolimus. Am J Transplant 2006; 6(3): 514–22

    Article  PubMed  CAS  Google Scholar 

  56. Gallon LG, Winoto J, Chhabra D, et al. Long-term renal transplant function in a recipient of simultaneous kidney and pancreas transplant maintained with two prednisone-free maintenance immunosuppressive combinations: tacrolimus/mycophenolate mofetil versus tacrolimus/ sirolimus. Transplantation 2007; 83(10): 1324–9

    Article  PubMed  CAS  Google Scholar 

  57. Knight RJ, Kerman RH, Zela S, et al. Pancreas transplantation utilizing thymoglobulin, sirolimus, and cyclosporine. Transplantation 2006; 81(8): 1101–5

    Article  PubMed  CAS  Google Scholar 

  58. Knight RJ, Kerman RH, McKissick E, et al. Selective corticosteroid and calcineurin-inhibitor withdrawal after pancreas-kidney transplantation utilizing thymoglobulin induction and sirolimus maintenance therapy. Clin Transplant 2008; 22(5): 645–50

    Article  PubMed  CAS  Google Scholar 

  59. Tanchanco R, Krishnamurthi V, Winans C, et al. Beneficial outcomes of a steroid-free regimen with thymoglobulin induction in pancreas-kidney transplantation. Transplant Proc 2008; 40(5): 1551–4

    Article  PubMed  CAS  Google Scholar 

  60. Axelrod D, Leventhal JR, Gallon LG, et al. Reduction of CMV disease with steroid-free immunosuppression in simultaneous pancreas-kidney transplant recipients. Am J Transplant 2005; 5(6): 1423–9

    Article  PubMed  CAS  Google Scholar 

  61. Cantarovich D, Karam G, Hourmant M, et al. Steroid avoidance versus steroid withdrawal after simultaneous pancreas-kidney transplantation. Am J Transplant 2005; 5(6): 1332–8

    Article  PubMed  CAS  Google Scholar 

  62. 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(2): 366–73

    Article  PubMed  Google Scholar 

  63. Gupta G, Shapiro R, Thai N, et al. Low incidence of BK virus nephropathy after simultaneous kidney pancreas transplantation. Transplantation 2006; 82(3): 382–8

    Article  PubMed  Google Scholar 

  64. Ison MG, Parker M, Stosor V, et al. Development of BK nephropathy in recipients of simultaneous pancreas-kidney transplantation. Transplantation 2009; 87(4): 525–30

    Article  PubMed  CAS  Google Scholar 

  65. Issa N, Amer H, Dean PG, et al. Posttransplant lympho-proliferative disorder following pancreas transplantation. Am J Transplant 2009; 9(8): 1894–902

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this review. Dr Heilman has received research grants from Genzyme Corporation and Wyeth Corporation. Drs Mazur and Reddy have no conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Medicine, Mayo Clinic Arizona, 5777 East Mayo Boulevard, Phoenix, Arizona, 85054, USA

    Raymond L. Heilman & Marek J. Mazur

  2. Department of Surgery, Mayo Clinic Arizona, Phoenix, Arizona, USA

    K. Sudhakar Reddy

Authors
  1. Raymond L. Heilman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marek J. Mazur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Sudhakar Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Raymond L. Heilman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heilman, R.L., Mazur, M.J. & Reddy, K.S. Immunosuppression in Simultaneous Pancreas-Kidney Transplantation. Drugs 70, 793–804 (2010). https://doi.org/10.2165/11535430-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11535430-000000000-00000

Keywords

Search

Navigation