Immunosuppression after liver transplant, now and in future

Czech version

Authors: P. Trunečka
Authors‘ workplace: Transplantcentrum IKEM Praha, přednosta MU Dr. Pavel Trunečka, CSc.
Published in: Vnitř Lék 2013; 59(8): 671-677
Category:

Overview

The development of immunosuppression has significantly affected the development of liver transplantation and has helped to switch from the experimental method to a standard treatment of life threatening liver conditions. Tacrolimus is the basic immunosuppressant for patients after a liver transplant and thanks to its prolonged-release dosage form, which due to its simplicity and reliability of use, replaces tacrolimus twice daily early after the transplant and in the long‑term administration, will apparently, for a while, defend its position. Other widely used medicines include mycophenolic acid and mTOR inhibitors, sirolimus and everolimus. The induction with antilymphocyte antibodies is used in less than 10% of liver recipients. Only a few new immunosuppresants in this century have passed later stages of clinical studies; the last 2 medicines registered for patients after liver transplantation incude Advagraf (Astellas) and Certican (Novartis). Personalised immunosuppression should respect at least the following basic clinical situations: recipients renal function, hepatitis C virus infection, and hepatocellular carcinoma as the liver transplant indication. The results of immunotolerance biomarker research are necessary for a more successful conduct of protocols minimising immunosuppression and leading to immunotolerance, especially under the efforts of complete withdrawal of immunosupression.

Key words:
liver transplantation – immunosuppression – calcineurin inhibitors – mTOR inhibitors – viral hepatitis C – hepatocellular carcinoma

Sources

1. Merion RM. Current status and future of liver transplantation. Semin Liver Dis 2010; 30: 411– 421.

2. Millard CE. The NIH Consensus Development Conference on liver transplantation. R I Med J 1984; 67: 69– 71.

3. Jain A, Reyes J, Kashyap R et al. Long‑Term Survival After Liver Transplantation in 4,000 Consecutive Patients at a Single Center. Ann Surg 2000; 232: 490– 500.

4. Desai S, Hong JC, Saab S. Cardiovascular risk factors following orthotopic liver transplantation: predisposing factors, incidence and management. Liver Int 2010; 30: 948– 957.

5. Gautam M, Cheruvattath R, Balan V. Recurrence of autoimmune liver disease after liver transplantation: a systematic review. Liver Transpl 2006; 12: 1813– 1824.

6. Kahan BD, Ghobrial R. Immunosuppressive agents. Surg Clin North Am 1994; 74: 1029– 1054.

7. Levy G, Villamil F, Samuel D et al. LIS2T Study Group. Results of lis2t, a multicenter, randomized study comparing cyclosporine microemulsion with C2 monitoring and tacrolimus with C0 monitoring in de novo liver transplantation. Transplantation 2004; 77: 1632– 1638.

8. Kaufman DB, Shapiro R, Lucey MR et al. Immunosuppression: practice and trends. Am J Transplant 2004; 4 (Suppl 9): 38– 53.

9. Starzl TE, Todo S, Demetris AJ et al. Tacrolimus (FK506) and the pharmaceutical/ academic/ regulatory gauntlet. Am J Kidney Dis 1998; 31 (Suppl 1): S7– S14.

10. O’Grady JG, Burroughs A, Hardy P et al. UK and Republic of Ireland Liver Transplant Study Group. Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial. Lancet 2002; 360: 1119– 1125.

11. Trunečka P, Boillot O, Seehofer D et al. Tacrolimus Prolonged Release Liver Study Group. Once‑ daily prolonged‑ release tacrolimus (ADVAGRAF) versus twice‑ daily tacrolimus (PROGRAF) in liver transplantation. Am J Transplant 2010; 10: 2313– 2323.

12. Florman S, Alloway R, Kalayoglu M et al. Conversion of stable liver transplant recipients from a twice‑ daily Prograf‑based regimen to a once‑ daily modified release tacrolimus‑based regimen. Transplant Proc 2005; 37: 1211– 1213.

13. Dumortier J, Guillaud O, Boillot O. Conversion from twice daily tacrolimus to once daily tacrolimus in long‑term stable liver transplant recipients: a single‑center experience with 394 patients. Liver Transpl 2013; 19: 529– 533.

14. Beckebaum S, Iacob S, Sweid D et al. Efficacy, safety, and immunosuppressant adherence in stable liver transplant patients converted from a twice‑ daily tacrolimus‑based regimen to once‑ daily tacrolimus extended‑ release formulation. Transpl Int 2011; 24: 666– 675.

15. Levitsky J. Next level of immunosuppression: Drug/ Immune monitoring. Liver Transpl 2011; 17 (Suppl 3): S60– S65.

16. Lerut J, Bonaccorsi‑ Riani E, Finet P et al. Minimization of steroids in liver transplantation. Transpl Int 2009; 22: 2– 19.

17. Wiesner RH, Shorr JS, Steffen BJ et al. Mycophenolate mofetil combination therapy improves long‑term outcomes after liver transplantation in patients with and without hepatitis C. Liver Transpl 2005; 11: 750– 759.

18. McAlister VC, Gao Z, Peltekian K et al. Sirolimus‑ tacrolimus combination immunosuppression. Lancet 2000; 355: 376– 377.

19. Pengel LH, Liu LQ, Morris PJ. Do wound complications or lymphoceles occur more often in solid organ transplant recipients on mTOR inhibitors? A systematic review of randomized controlled trials. Transpl Int 2011; 24: 1216– 1230.

20. De Simone P, Nevens F, De Carlis L et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant 2012; 12: 3008– 3020.

21. Kirk AD. Induction immunosuppression. Transplantation 2006; 82: 593– 602.

22. Dhesi S, Boland B, Colquhoun S. Alemtuzumab and liver transplantation: a review. Curr Opin Organ Transplant 2009; 14: 245– 249.

23. Kamar N, Lavayssière L, Muscari F et al. Early plasmapheresis and rituximab for acute humoral rejection after ABO‑ compatible liver transplantation. World J Gastroenterol 2009; 15: 3426– 3430.

24. Toso C, Merani S, Bigam DL et al. Sirolimus‑based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology 2010; 51: 1237– 1243.

25. Webber A, Hirose R, Vincenti F. Novel strategies in immunosuppression: issues in perspective. Transplantation 2011; 91: 1057– 1063.

26. Turner AP, Knechtle SJ. Induction immunosuppression in liver transplantation: a review. Transpl Int 2013; 26: 673– 683.

27. Soliman T, Hetz H, Burghuber C et al. Short‑term induction therapy with anti‑thymocyte globulin and delayed use of calcineurin inhibitors in orthotopic liver transplantation. Liver Transpl 2007; 13: 1039– 44.

28. Ojo AO, Held PJ, Port FK et al. Chronic renal failure after transplantation of nonrenal organ. N Engl J Med 2003; 349: 931– 940.

29. Vajdic CM, McDonald SP, McCredie MR et al. Cancer incidence before and after kidney transplantation. JAMA 2006; 296: 2823– 2831.

30. Gutierrez‑ Dalmau A, Campistol JM. Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review. Drugs 2007; 67: 1167– 1198.

31. Gómez‑ Manero N, Herrero JI, Quiroga J et al. Prognostic model for early acute rejection after liver transplantation. Liver Transpl 2001; 7: 246– 254.

32. Zahn A, Schott N, Hinz U et al. Immunomonitoring of nuclear factor of activated T cells‑ regulated gene expression: the first clinical trial in liver allograft recipients. Liver Transpl 2011; 17: 466– 473.

33. Irish W, Arcona S, Bowers D et al. Cyclosporine versus Tacrolimus Treated Liver Transplant Recipients with Chronic Hepatitis C: outcomes Analysis of the UNOS/ OPTN Database. Am J Transplant 2011; 11: 1676– 1685.

34. McAlister VC, Haddad E, Renouf E et al. Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta‑analysis. Am J Transplant 2006; 6: 1578– 1585.

35. Samonakis DN, Triantos CK, Thalheimer Uet al. Immunosuppression and donor age with respect to severity of HCV recurrence after liver transplantation. Liver Transpl 2005; 11: 386– 395.

36. Neumann U, Samuel D, Trunečka P et al. A Randomized Multicenter Study Comparing a Tacrolimus‑ Based Protocol with and without Steroids in HCV‑ Positive Liver Allograft Recipients. J Transplant 2012; 2012: 894215.

37. Kawahara T, Asthana S, Kneteman NM. m‑ TOR inhibitors: what role in liver transplantation? J Hepatol 2011; 55: 1441– 1451.

38. Menon KV, Hakeem AR, Heaton ND. Meta‑analysis: recurrence and survival following the use of sirolimus in liver transplantation for hepatocellular carcinoma. Aliment Pharmacol Ther 2013; 37: 411– 419.

39. Lau C, Martin P, Bunnapradist S. Management of renal dysfunction in patients receiving a liver transplant. Clin Liver Dis 2011; 15: 807– 820.

40. Neuberger JM, Mamelok RD, Neuhaus P et al. ReSpECT Study Group. Delayed introduction of reduced‑dose tacrolimus, and renal function in liver transplantation: the “ReSpECT” study. Am J Transplant 2009; 9: 327– 336.

41. Saner FH, Cicinnati VR, Sotiropoulos G et al. Strategies to prevent or reduce acute and chronic kidney injury in liver transplantation. Liver Int 2012; 32: 179– 188.