Preoperative Management (Desensitization)

  • Chan-Duck KimEmail author


The identification of suitable donor kidneys for transplant candidates with high levels of circulating antibodies against human leukocyte antigen (HLA) is a major challenge and sensitized patients have a reduced chance of receiving a crossmatch-negative organ. For many highly sensitized renal transplant candidates, an acceptable donor is never identified, and the patient remains on dialysis indefinitely. In an attempt to improve the probability of transplant in the highly sensitized patients, several desensitization protocols have been developed that permit positive-crossmatch kidney transplantation. Alloantibodies are removed from the patient’s circulation by plasmapheresis or immunoadsorption in pretransplantation and their production is suppressed by T cell immunosuppression, intravenous immunoglobulins (IVIG), rituximab, or the proteasome inhibitor (bortezomib) based on the rationale that depletion of B lymphocytes or plasma cells may reduce anti-HLA antibodies production. Additional novel approaches are the blockage of complement activation by administration of the complement C5 inhibitor (eculizumab) or C1 esterase inhibitor, anti-IL-6 receptor blockers and the administration of immunoglobulin G (IgG)-degrading enzyme derived from Streptococcus pyogenes (IdeS) in highly sensitized patients. These new interventions aimed at the prevention of donor-specific antibodies (DSA)-mediated allograft injury and are somewhat promising therapeutic avenues currently still under investigation and much work remains to determine optimal protocols. Moreover, at present, there are no prospective and randomized trials comparing different desensitization protocols and no clear scientific data to recommend a certain protocol. In summary, although diverse desensitization protocols for positive-crossmatch kidney transplantations have improved access to transplantation for highly sensitized patients, more clinical experiences are clearly needed.


Desensitization Plasmapheresis Intravenous immunoglobulin (IVIG) Rituximab Eculizumab C1 esterase inhibitor Anti-IL-6 receptor blockers IdeS 


  1. 1.
    Pesavento TE. Kidney transplantation in the context of renal replacement therapy. Clin J Am Soc Nephrol. 2009;4(12):2035–9. Scholar
  2. 2.
    Gloor J, Stegall MD. Sensitized renal transplant recipients: current protocols and future directions. Nat Rev Nephrol. 2010;6(5):297–306. Scholar
  3. 3.
    Amrouche L, Aubert O, Suberbielle C, Rabant M, Van Huyen JD, Martinez F, et al. Long-term outcomes of kidney transplantation in patients with high levels of preformed DSA: the Necker high-risk transplant program. Transplantation. 2017;101(10):2440–8. Scholar
  4. 4.
    Orandi BJ, Garonzik-Wang JM, Massie AB, Zachary AA, Montgomery JR, Van Arendonk KJ, et al. Quantifying the risk of incompatible kidney transplantation: a multicenter study. Am J Transplant. 2014;14(7):1573–80. Scholar
  5. 5.
    Orandi BJ, Luo X, Massie AB, Garonzik-Wang JM, Lonze BE, Ahmed R, et al. Survival benefit with kidney transplants from HLA-incompatible live donors. N Engl J Med. 2016;374(10):940–50. Scholar
  6. 6.
    Hodge EE, Klingman LL, Koo AP, Nally J, Hobbs RE, Stewart RW, et al. Pretransplant removal of anti-HLA antibodies by plasmapheresis and continued suppression on cyclosporine-based therapy after heart-kidney transplant. Transplant Proc. 1994;26(5):2750–1.PubMedGoogle Scholar
  7. 7.
    Biesenbach P, Eskandary F, Ay C, Wiegele M, Derfler K, Schaden E, et al. Effect of combined treatment with immunoadsorption and membrane filtration on plasma coagulation--results of a randomized controlled crossover study. J Clin Apher. 2016;31(1):29–37. Scholar
  8. 8.
    Hakim RM, Milford E, Himmelfarb J, Wingard R, Lazarus JM, Watt RM. Extracorporeal removal of anti-HLA antibodies in transplant candidates. Am J Kidney Dis. 1990;16(5):423–31.CrossRefGoogle Scholar
  9. 9.
    Lorenz M, Regele H, Schillinger M, Kletzmayr J, Haidbauer B, Derfler K, et al. Peritransplant immunoadsorption: a strategy enabling transplantation in highly sensitized crossmatch-positive cadaveric kidney allograft recipients. Transplantation. 2005;79(6):696–701.CrossRefGoogle Scholar
  10. 10.
    Schwaiger E, Eskandary F, Kozakowski N, Bond G, Kikic Z, Yoo D, et al. Deceased donor kidney transplantation across donor-specific antibody barriers: predictors of antibody-mediated rejection. Nephrol Dial Transplant. 2016;31(8):1342–51. Scholar
  11. 11.
    Klein K, Susal C, Schafer SM, Becker LE, Beimler J, Schwenger V, et al. Living donor kidney transplantation in patients with donor-specific HLA antibodies enabled by anti-CD20 therapy and peritransplant apheresis. Atheroscler Suppl. 2013;14(1):199–202. Scholar
  12. 12.
    Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001;345(10):747–55. Scholar
  13. 13.
    Watanabe J, Scornik JC. IVIG and HLA antibodies. Evidence for inhibition of complement activation but not for anti-idiotypic activity. Am J Transplant. 2005;5(11):2786–90. Scholar
  14. 14.
    Jordan SC, Toyoda M, Vo AA. Intravenous immunoglobulin a natural regulator of immunity and inflammation. Transplantation. 2009;88(1):1–6. Scholar
  15. 15.
    Tjon AS, Tha-In T, Metselaar HJ, van Gent R, van der Laan LJ, Groothuismink ZM, et al. Patients treated with high-dose intravenous immunoglobulin show selective activation of regulatory T cells. Clin Exp Immunol. 2013;173(2):259–67. Scholar
  16. 16.
    Paquin Proulx D, Aubin E, Lemieux R, Bazin R. Inhibition of B cell-mediated antigen presentation by intravenous immunoglobulins (IVIg). Clin Immunol. 2010;135(3):422–9. Scholar
  17. 17.
    Stegall MD, Gloor J, Winters JL, Moore SB, Degoey S. A comparison of plasmapheresis versus high-dose IVIG desensitization in renal allograft recipients with high levels of donor specific alloantibody. Am J Transplant. 2006;6(2):346–51. Scholar
  18. 18.
    Montgomery RA, Lonze BE, King KE, Kraus ES, Kucirka LM, Locke JE, et al. Desensitization in HLA-incompatible kidney recipients and survival. N Engl J Med. 2011;365(4):318–26. Scholar
  19. 19.
    Jin MK, Cho JH, Kwon O, Hong KD, Choi JY, Yoon SH, et al. Successful kidney transplantation after desensitization using plasmapheresis, low-dose intravenous immunoglobulin, and rituximab in highly sensitized patients: a single-center experience. Transplant Proc. 2012;44(1):200–3. Scholar
  20. 20.
    Lim JH, Cho JH, Jung HY, Choi JY, Park SH, Kim YL, Kim HK, Huh S, Yoo ES, Won DI, Kim CD. Excellent outcome after desensitization in high immunologic risk kidney transplantation. PLoS One. 2019;14(9):e0222537. eCollection 2019.CrossRefGoogle Scholar
  21. 21.
    Pescovitz MD. Rituximab, an anti-cd20 monoclonal antibody: history and mechanism of action. Am J Transplant. 2006;6(5 Pt 1):859–66. Scholar
  22. 22.
    Vo AA, Lukovsky M, Toyoda M, Wang J, Reinsmoen NL, Lai CH, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. 2008;359(3):242–51. Scholar
  23. 23.
    Vo AA, Peng A, Toyoda M, Kahwaji J, Cao K, Lai CH, et al. Use of intravenous immune globulin and rituximab for desensitization of highly HLA-sensitized patients awaiting kidney transplantation. Transplantation. 2010;89(9):1095–102. Scholar
  24. 24.
    Vo AA, Choi J, Cisneros K, Reinsmoen N, Haas M, Ge S, et al. Benefits of rituximab combined with intravenous immunoglobulin for desensitization in kidney transplant recipients. Transplantation. 2014;98(3):312–9. Scholar
  25. 25.
    Marfo K, Ling M, Bao Y, Calder B, Ye B, Hayde N, et al. Lack of effect in desensitization with intravenous immunoglobulin and rituximab in highly sensitized patients. Transplantation. 2012;94(4):345–51. Scholar
  26. 26.
    van den Hoogen MW, Kamburova EG, Baas MC, Steenbergen EJ, Florquin S, HJ MK, 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(2):407–16. Scholar
  27. 27.
    Perry DK, Burns JM, Pollinger HS, Amiot BP, Gloor JM, Gores GJ, et al. Proteasome inhibition causes apoptosis of normal human plasma cells preventing alloantibody production. Am J Transplant. 2009;9(1):201–9. Scholar
  28. 28.
    Everly MJ, Everly JJ, Susskind B, Brailey P, Arend LJ, Alloway RR, et al. Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection. Transplantation. 2008;86(12):1754–61. Scholar
  29. 29.
    Diwan TS, Raghavaiah S, Burns JM, Kremers WK, Gloor JM, Stegall MD. The impact of proteasome inhibition on alloantibody-producing plasma cells in vivo. Transplantation. 2011;91(5):536–41. Scholar
  30. 30.
    Woodle ES, Shields AR, Ejaz NS, Sadaka B, Girnita A, Walsh RC, et al. Prospective iterative trial of proteasome inhibitor-based desensitization. Am J Transplant. 2015;15(1):101–18. Scholar
  31. 31.
    Moreno Gonzales MA, Gandhi MJ, Schinstock CA, Moore NA, Smith BH, Braaten NY, 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(6):1222–7. Scholar
  32. 32.
    Kwun J, Burghuber C, Manook M, Iwakoshi N, Gibby A, Hong JJ, et al. Humoral compensation after bortezomib treatment of allosensitized recipients. J Am Soc Nephrol. 2017;28(7):1991–6. Scholar
  33. 33.
    Philogene MC, Sikorski P, Montgomery RA, Leffell MS, Zachary AA. Differential effect of bortezomib on HLA class I and class II antibody. Transplantation. 2014;98(6):660–5. Scholar
  34. 34.
    Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, et al. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant. 2012;12(12):3337–54. Scholar
  35. 35.
    Lonze BE, Zachary AA, Magro CM, Desai NM, Orandi BJ, Dagher NN, et al. Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation. Am J Transplant. 2014;14(2):459–65. Scholar
  36. 36.
    Cornell LD, Schinstock CA, Gandhi MJ, Kremers WK, Stegall MD. Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year. Am J Transplant. 2015;15(5):1293–302. Scholar
  37. 37.
    Lefaucheur C, Viglietti D, Hidalgo LG, Ratner LE, Bagnasco SM, Batal I, et al. Complement-activating anti-HLA antibodies in kidney transplantation: allograft gene expression profiling and response to treatment. J Am Soc Nephrol. 2018;29(2):620–35. Scholar
  38. 38.
    Vo AA, Zeevi A, Choi J, Cisneros K, Toyoda M, Kahwaji J, et al. A phase I/II placebo-controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in HLA sensitized patients. Transplantation. 2015;99(2):299–308. Scholar
  39. 39.
    Jones SA, Fraser DJ, Fielding CA, Jones GW. Interleukin-6 in renal disease and therapy. Nephrol Dial Transplant. 2015;30(4):564–74. Scholar
  40. 40.
    Kang S, Tanaka T, Kishimoto T. Therapeutic uses of anti-interleukin-6 receptor antibody. Int Immunol. 2015;27(1):21–9. Scholar
  41. 41.
    Vo AA, Choi J, Kim I, Louie S, Cisneros K, Kahwaji J, et al. A phase I/II trial of the interleukin-6 receptor-specific humanized monoclonal (tocilizumab) + intravenous immunoglobulin in difficult to desensitize patients. Transplantation. 2015;99(11):2356–63. Scholar
  42. 42.
    Wenig K, Chatwell L, von Pawel-Rammingen U, Bjorck L, Huber R, Sondermann P. Structure of the streptococcal endopeptidase IdeS, a cysteine proteinase with strict specificity for IgG. Proc Natl Acad Sci U S A. 2004;101(50):17371–6. Scholar
  43. 43.
    Jarnum S, Bockermann R, Runstrom A, Winstedt L, Kjellman C. The bacterial enzyme ides cleaves the IgG-type of B cell receptor (BCR), abolishes BCR-mediated cell signaling, and inhibits memory B cell activation. J Immunol. 2015;195(12):5592–601. Scholar
  44. 44.
    Jordan SC, Lorant T, Choi J, Kjellman C, Winstedt L, Bengtsson M, et al. IgG endopeptidase in highly sensitized patients undergoing transplantation. N Engl J Med. 2017;377(5):442–53. Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Division of Nephrology, Department of Internal Medicine, School of MedicineKyungpook National University, Kyungpook National University HospitalDaeguSouth Korea

Personalised recommendations