LIVER EXPERT FORUM – CONFERENCE REPORT EDUCATION “IL-2RA or rATG induction does not increase risk of infection and the available evidence does not suggest an effect on malignancy or post-transplant lymphoproliferative disease.” Conclusions The place of induction in the management of liver transplant patients is becoming established. Universal application of induction therapy as an ”add-on” to standard therapy is not justified, but for patients at high risk for rejection (e.g. re-transplantation or transplants with a positive T-cell cross-match), addition of induction appears advisable. Predominantly, the role of induction is now to support the reduction or elimination of CNI therapy or steroids in order to minimize complications such as renal dysfunction and infection. Steroid-free regimens are feasible and safe when accompanied by effective induction. Delayed CNI introduction requires induction to cover the interval until adequate CNI blood concentrations are reached, and if early CNI withdrawal is undertaken induction is strongly advisable. Where low-exposure CNI therapy is employed, induction is not essential but potentially useful, especially in higher-risk cases. This tailored approach targets induction to certain categories of patients and specific protocols, harnessing the potency of induction to minimize short- and long-term complications of chronic immunosuppression. Report prepared by Caroline Dunstall, UK. Kindly supported by Sanofi-Aventis Deutschland GmbH. References 1. OPTN National Data Report. Available at: https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/. Accessed 20th September 2017. 2. European Liver Transplant Registry. Available at: http://www. eltr.org/Donor-data.html. Accessed 20th September 2017. 3. Zhu JZ, Dai YN, Wang YM, Zhou QY, Yu CH, Li YM. Prevalence of nonalcoholic fatty liver disease and economy. Dig Dis Sci 2015;60:3194–202. 4. de Graaf EL, Kench J, Dilworth P, et al. Grade of deceased donor liver macrovesicular steatosis impacts graft and recipient outcomes more than the Donor Risk Index. J Gastroenterol Hepatol 2012;27:540–6. 5. Kim WR, Lake JR, Smith JM, et al. OPTN/SRTR 2015 Annual Data Report: Liver. Am J Transplant 2017;17(Suppl 1):174– 251. 6. Goldberg D, Ditah IC, Saeian K, et al. Changes in the prevalence of hepatitis C virus infection, nonalcoholic steatohepatitis, and alcoholic liver disease among patients with cirrhosis or liver failure on the waitlist for liver transplantation. Gastroenterology 2017;152:1090–9. 7. Gaynor JJ, Moon JI, Kato T, et al. A cause-specific hazard rate analysis of prognostic factors among 877 adults who received primary orthotopic liver transplantation. Transplantation 2007;84:155–65. 8. Abad CL, Lahr BD, Razonable RR. Epidemiology and risk factors for infection after living donor liver transplantation. Liver Transpl 2017;23:465–77. 9. Saliba F, Delvart V, Ichaï P, et al. Fungal infections after liver transplantation: outcomes and risk factors revisited in the MELD era. Clin Transplant 2013;27:E454–61. 10. Wong RJ, Cheung R, Perumpail RB, Holt EW, Ahmed A. Diabetes mellitus, and not obesity, is associated with lower survival following liver transplantation. Dig Dis Sci 2015;60:1036– 44. 11. European Liver Transplant Registry. Available at: http://www. eltr.org/Overall-indication-and-results.html. Accessed 20th September 2017. 12. Tanemura A, Mizuno S, Wada H, Yamada T, Nobori T, Isaji S. Donor age affects liver regeneration during early period in the graft liver and late period in the remnant liver after living donor liver transplantation. World J Surg 2012;36:1102–11. 13. Ono Y, Kawachi S, Hayashida T, et al. The influence of donor age on liver regeneration and hepatic progenitor cell populations. Surgery 2011;150:154–61. 14. Kulik U, Lehner F, Klempnauer J, Borlak J. Primary non-function is frequently associated with fatty liver allografts and high mortality after re-transplantation. Liver Int 2017;37:1219– 28. 56
LIVER EXPERT FORUM – CONFERENCE REPORT 15. Stahl JE, Kreke JE, Malek FA, Schaefer AJ, Vacanti J. Consequences of cold-ischemia time on primary nonfunction and patient and graft survival in liver transplantation: a meta-analysis. PLoS One 2008;3:e2468. 16. Penninga L, Wettergren A, Wilson CH, Chan AW, Steinbrüchel DA, Gluud C. Antibody induction versus placebo, no induction, or another type of antibody induction for liver transplant recipients. Cochrane Database Syst Rev 2014;(6):CD010253. 17. Crins ND, Röver C, Goralczyk AD, Friede T. Interleukin-2 receptor antagonists for pediatric liver transplant recipients: a systematic review and meta-analysis of controlled studies. Pediatr Transplant 2014;18:839–50. 18. Moonka DK, Kim D, Kapke A, Brown KA, Yoshida A. The influence of induction therapy on graft and patient survival in patients with and without hepatitis C after liver transplantation. Am J Transplant 2010;10:590–601. 19. Uemura T, Schaefer E, Hollenbeak CS, Khan A, Kadry Z. Outcome of induction immunosuppression for liver transplantation comparing anti-thymocyte globulin, daclizumab, and corticosteroid. Transplant Int 2011;24:640–50. 20. Segev DL, Sozio SM, Shin EJ, et al. Steroid avoidance in liver transplantation: meta-analysis and meta-regression of randomized trials. Liver Transpl 2008;14:512–25. 21. Otero A, Varo E, de Urbina JO, et al. A prospective randomized open study in liver transplant recipients: daclizumab, mycophenolate mofetil, and tacrolimus versus tacrolimus and steroids. Liver Transpl 2009;15:1542–52. 22. Klintmalm GB, Washburn WK, Rudich SM, et al. Corticosteroid-free immunosuppression with daclizumab in HCV(+) liver transplant recipients: 1-year interim results of the HCV-3 study. Liver Transpl 2007;13:1521–31. 23. Eason JD, Nair S, Cohen AJ, Blazek JL, Loss GE Jr. Steroid-free liver transplantation using rabbit antithymocyte globulin and early tacrolimus monotherapy. Transplantation 2003;75:1396–9. 24. Montenovo MI, Jalikis FG, Li M et al. Superior patient and graft survival in adult liver transplant with rabbit antithymocyte globulin induction: experience with 595 patients. Exp Clin Transplant 2017; 4: 425-432 25. Sharma P, Welch K, Eikstadt R, Marrero JA, Fontana RJ, Lok AS. Renal outcomes after liver transplantation in the model for end-stage liver disease era. Liver Transpl 2009;15:1142– 8. 26. Leithead JA, Ferguson JW, Hayes PC. Modifiable patient factors are associated with the late decline in renal function following liver transplantation. Clin Transplant 2012;26:E316–23. 27. Nankivell BJ, P'Ng CH, O'Connell PJ, Chapman JR. Calcineurin inhibitor nephrotoxicity through the lens of longitudinal histology: comparison of cyclosporine and tacrolimus eras. Transplantation 2016;100:1723–31. 28. Varo E, Bañares R, Guilera M. Underestimation of chronic renal dysfunction after liver transplantation: ICEBERG study. World J Transplant 2015;5:26–33. 29. Calmus Y, Kamar N, Gugenheim J, et al. Assessing renal function with daclizumab induction and delayed tacrolimus introduction in liver transplant recipients. Transplantation 2010;89:1504–10. 30. Neuberger JM, Mamelok RD, Neuhaus P, et al. Delayed introduction of reduced-dose tacrolimus, and renal function in liver transplantation: the ‚ReSpECT‘ study. Am J Transplant 2009;9:327–36. 31. Yoshida EM, Marotta PJ, Greig PD, et al. Evaluation of renal function in liver transplant recipients receiving daclizumab (Zenapax), mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: a multicenter randomized clinical trial. Liver Transpl 2005;11:1064–72. 32. Bajjoka I, Hsaiky L, Brown K, Abouljoud M. Preserving renal function in liver transplant recipients with rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitors. Liver Transpl 2008;14;66–72. 33. 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. 34. Boudjema K, Camus C, Saliba F, et al. Reduced-dose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation: a randomized study. Am J Transplant 2011;11:965–76. 35. De Simone P, Nevens F, De Carlis L, et al; H2304 Study Group. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant 2012;2:3008–20. 36. Fischer L, Klempnauer J, Beckebaum S, et al. A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation--PROTECT. Am J Transplant 2012;12:1855–65. 37. Masetti M, Montalti R, Rompianesi G, et al. Early withdrawal of calcineurin inhibitors and everolimus monotherapy in de novo liver transplant recipients preserves renal function. Am J Transplant 2010;10:2252–62. 38. Teperman L, Moonka D, Sebastian A, et al. Calcineurin inhibitor-free mycophenolate mofetil/sirolimus maintenance in liver transplantation: the randomized spare-the-nephron trial. Liver Transpl 2013;19:675–89. 39. Bogetti D, Sankary HN, Jarzembowski TM, et al. Thymoglobulin induction protects liver allografts from ischemia/reperfusion injury. Clin Transplant 2005;19:507–11. 40. Halldorson JB, Bakthavatsalam R, Montenovo M, et al. Differential rates of ischemic cholangiopathy and graft survival associated with induction therapy in DCD liver transplantation. Am J Transplant 2015;15:251–8. EDUCATION 57
