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Induction and Maintenance Immunosuppressants in Sensitized Renal Allograft Recipients

  • Jin Min Kong
Chapter

Abstract

Induction and maintenance immunosuppression for sensitized allograft recipients having immune memory cells should be different from those for standard/low-immunologic risk patients, as memory cells elicit immunologic recall responses that can result in early and often severe antibody-mediated rejection. The peri-transplant period, when donor-specific T and B memory cells rapidly expand in response to antigen (allograft) challenge, appears to be a unique window of chance to reduce the size of donor-specific clones more selectively by cell-depleting induction agents. Induction with antithymocyte globulin has been shown to reduce the incidence of antibody-mediated rejection in sensitized kidney transplant recipients. It predominantly depletes T cells but it also has immune modulatory effects on other cell lineages such as dendritic cells, and interferes with the generation of plasmablasts by blocking T cell help. Plasmablasts rapidly proliferate during the early posttransplant period by immunologic recall response in sensitized patients. Because these cells retain CD20 on the cell surface and are susceptible to rituximab-induced cytolysis, induction with rituximab can be a valuable tool for depletion of donor-specific plasma cell precursors in sensitized patients. Bortezomib is a nonspecific inhibitor of proteasome and can induce apoptosis of actively dividing and immunoglobulin-producing cells, such as plasmablasts. It has been suggested that long-lived plasmacytes are resistant to bortezomib-induced cytolysis, while young plasmablasts are more susceptible. Thus, bortezomib may also have a role as an induction agent in sensitized patients. One, or a combination of two or more, of these drugs can be used for induction in sensitized renal allograft recipients. Currently available literature indicates that the tacrolimus-based triple regimen including mycophenolate and prednisolone is the most appropriate maintenance immunosuppression for sensitized patients, and that the overall potency of immunosuppression including the tacrolimus drug-level should be appropriately maintained, as both the incidence of immunologic rejection and patient loss secondary to over-immunosuppression is higher in these patients.

Keywords

Induction immunosuppression Maintenance immunosuppression Sensitized recipients Kidney transplantation Antithymocyte globulin Rituximab Bortezomib Tacrolimus level 

References

  1. 1.
    Wrammert J, Smith K, Miller J, et al. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature. 2008;453:667–71.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Chong AS, Ansari MJ. Heterogeneity of memory B cells. Am J Transplant. 2018;18:779–84.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Bonnefoy-Berard N, Vincent C, Revillard JP. Antibodies against functional leukocyte surface molecules in polyclonal antilymphocyte and antithymocyte globulins. Transplantation. 1991;53:669.CrossRefGoogle Scholar
  4. 4.
    Zand MS, Vo T, Huggins J, Felgar R, et al. Polyclonal rabbit antithymocyte globulin triggers B-cell and plasma cell apoptosis by multiple pathways. Transplantation. 2005;79:1507–15.PubMedCrossRefGoogle Scholar
  5. 5.
    Thibaudin D, Alamartine E, de Filippis JP, et al. Advantage of antithymocyte globulin induction in sensitized kidney recipients: a randomized prospective study comparing induction with and without antithymocyte globulin. Nephrol Dial Transplant. 1998;13:711–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Brennan DC, Daller JA, Lake KD, et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006;355:1967–77.PubMedCrossRefGoogle Scholar
  7. 7.
    Noel C, Abramowicz D, Durand D, et al. Daclizumab versus antithymocyte globulin in high-immunological-risk renal transplant recipients. J Am Soc Nephrol. 2009;20:1385–92.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Hellemans R, Hazzan M, Durand D, et al. Daclizumab versus rabbit antithymocyte globulin in high-risk renal transplants: five-year follow-up of a randomized study. Am J Transplant. 2015;15:1923–32.PubMedCrossRefGoogle Scholar
  9. 9.
    Pilch NA, Taber DJ, Moussa O, et al. Prospective randomized controlled trial of rabbit antithymocyte globulin compared with IL-2 receptor antagonist induction therapy in kidney transplantation. Ann Surg. 2014;259:888–93.PubMedCrossRefGoogle Scholar
  10. 10.
    Lebranchu Y, Bridoux F, Büchler M, et al. Immunoprophylaxis with basiliximab compared with antithymocyte globulin in renal transplant patients receiving MMF-containing triple therapy. Am J Transplant. 2002;2:48–56.PubMedCrossRefGoogle Scholar
  11. 11.
    Mourad G, Rostaing L, Legendre C, et al. Sequential protocols using basiliximab versus antithymocyte globulins in renal-transplant patients receiving mycophenolate mofetil and steroids. Transplantation. 2004;78:584–90.PubMedCrossRefGoogle Scholar
  12. 12.
    Abou-Ayache R, Büchler M, Lepogamp P, et al. CMV infections after two doses of daclizumab versus thymoglobulin in renal transplant patients receiving mycophenolate mofetil, steroids and delayed cyclosporine a. Nephrol Dial Transplant. 2008;23:2024–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Ciancio G, Gaynor JJ, Guerra G, et al. Randomized trial of three induction antibodies in kidney transplantation: long-term results. Transplantation. 2014;97:1128–38.PubMedCrossRefGoogle Scholar
  14. 14.
    Emami S, Huang E, Kuo H-T, et al. Multivariate analysis of antibody induction therapy and their associated outcomes in live donor kidney transplantation in the recent era. Clin Transpl. 2012;26:351–8.CrossRefGoogle Scholar
  15. 15.
    Brokhof MM, Sollinger HW, Hager DR, et al. Antithymocyte globulin is associated with a lower incidence of de novo donor-specific antibodies in moderately sensitized renal transplant recipients. Transplantation. 2014;97:612–7.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Gurk-Turner C, Airee R, Philosophe B, et al. Thymoglobulin dose optimization for induction therapy in high risk kidney transplant recipients. Transplantation. 2008;85:1425–30.PubMedCrossRefGoogle Scholar
  17. 17.
    Klem P, Cooper JE, Weiss AS, et al. Reduced dose rabbit anti-thymocyte globulin induction for prevention of acute rejection in high-risk kidney transplant recipients. Transplantation. 2009;88:891–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Sood P, Hariharan S. Anti-CD20 blocker rituximab in kidney transplantation. Transplantation. 2018;102:44–58.PubMedCrossRefGoogle Scholar
  19. 19.
    Zachary AA, Lucas DP, Montgomery RA, et al. Rituximab prevents an anamnestic response in patients with cryptic sensitization to HLA. Transplantation. 2013;95:701–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Jackson AM, Kraus ES, Orandi BJ, et al. A closer look at rituximab induction on HLA antibody rebound following HLA-incompatible kidney transplantation. Kidney Int. 2015;87:409–16.PubMedCrossRefGoogle Scholar
  21. 21.
    Tydén G, Genberg H, Tollemar J, et al. A randomized, double blind, placebo-controlled, study of single-dose rituximab as induction in renal transplantation. Transplantation. 2009;87:1325–9.PubMedCrossRefGoogle Scholar
  22. 22.
    van den Hoogen MW, Kamburova EG, Baas MC, et al. Rituximab as induction therapy after renal transplantation: a randomized, double-blind, placebo-controlled study of efficacy and safety. Am J Transplant. 2015;15:407–16.CrossRefPubMedGoogle Scholar
  23. 23.
    Kohei N, Hirai T, Omoto K, et al. Chronic antibody-mediated rejection is reduced by targeting B-cell immunity during an introductory period. Am J Transplant. 2012;12:469–76.PubMedCrossRefGoogle Scholar
  24. 24.
    Ashimine S, Watarai Y, Yamamoto T, et al. Neither pretransplant rituximab nor splenectomy affects de novo HLA antibody production after renal transplantation. Kidney Int. 2014;85:425–30.PubMedCrossRefGoogle Scholar
  25. 25.
    Eskandari SK, Seelen MAJ, Lin G, et al. The immunoproteasome: an old player with a novel and emerging role in alloimmunity. Am J Transplant. 2017;17:3033–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Sadaka B, Ejaz NS, Shields AR, et al. A banff component scoring-based histologic assessment of bortezomib-based antibody-mediated rejection therapy. Transplantation. 2015;99:1691–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Moreno Gonzales MA, Gandhi MJ, et al. 32 doses of bortezomib for desensitization is not well tolerated and is associated with only modest reductions in anti-HLA antibody. Transplantation. 2017;101:1222–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Eskandary F, Regele H, Baumann L, et al. A Randomized trial of bortezomib in late antibody-mediated kidney transplant rejection. J Am Soc Nephrol. 2018;29:591–605.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Ejaz NS, Shields AR, Alloway RR, et al. Randomized controlled pilot study of B cell-targeted induction therapy in HLA sensitized kidney transplant recipients. Am J Transplant. 2013;13:3142–54.PubMedCrossRefGoogle Scholar
  30. 30.
    Burghuber CK, Manook M, Ezekian B, et al. Dual targeting: combining costimulation blockade and bortezomib to permit kidney transplantation in sensitized recipients. Am J Transplant. 2018:1–13.Google Scholar
  31. 31.
    Hanaway MJ, Woodle ES, Mulgaonkar S, et al. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011;364:1909.PubMedCrossRefGoogle Scholar
  32. 32.
    Sureshkumar KK, Thai NL, Hussain SM, et al. Influence of induction modality on the outcome of deceased donor kidney transplant recipients discharged on steroid-free maintenance immunosuppression. Transplantation. 2012;93:799.PubMedCrossRefGoogle Scholar
  33. 33.
    Guerra G, Ciancio G, Gaynor JJ, et al. Randomized trial of immunosuppressive regimens in renal transplantation. J Am Soc Nephrol. 2011;22:1758.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Webster AC, Woodroffe RC, Taylor RS, et al. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ. 2005;331:810.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007;357:2562.PubMedCrossRefGoogle Scholar
  36. 36.
    Knight SR, Morris PJ. Steroid avoidance or withdrawal after renal transplantation increases the risk of acute rejection but decreases cardiovascular risk. A meta-analysis. Transplantation. 2010;89:1.PubMedCrossRefGoogle Scholar
  37. 37.
    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;248:564.PubMedGoogle Scholar
  38. 38.
    Lim WH, Eris J, Kanellis J, et al. A systematic review of conversion from calcineurin inhibitor to mammalian target of rapamycin inhibitors for maintenance immunosuppression in kidney transplant recipients. Am J Transplant. 2014;14:2106–19.PubMedCrossRefGoogle Scholar
  39. 39.
    de Graav GN, Baan CC, Clahsen-van Groningen MC, et al. A randomized controlled clinical trial comparing belatacept with tacrolimus after de novo kidney transplantation. Transplantation. 2017;101:2571.PubMedCrossRefGoogle Scholar
  40. 40.
    Ferguson R, Grinyó J, Vincenti F, et al. Immunosuppression with belatacept-based, corticosteroid-avoiding regimens in de novo kidney transplant recipients. Am J Transplant. 2011;11:66.PubMedCrossRefGoogle Scholar
  41. 41.
    Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005;353:770.PubMedCrossRefGoogle Scholar
  42. 42.
    Wiebe C, Rush DN, Nevins TE, et al. Class II eplet mismatch modulates tacrolimus trough levels required to prevent donor-specific antibody development. J Am Soc Nephrol. 2017;28:3353–62.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Davis S, Gralla J, Klem P, et al. Lower tacrolimus exposure and time in therapeutic range increase the risk of de novo donor-specific antibodies in the first year of kidney transplantation. Am J Transplant. 2018;18:907–15.PubMedCrossRefGoogle Scholar
  44. 44.
    van Hest RM, Mathot RA, Pescovitz MD, et al. Explaining variability in mycophenolic acid exposure to optimize mycophenolate mofetil dosing: a population pharmacokinetic meta-analysis of mycophenolic acid in renal transplant recipients. J Am Soc Nephrol. 2006;17:871.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  • Jin Min Kong
    • 1
  1. 1.Division of NephrologyHanseo General HospitalBusanSouth Korea

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