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Desensitization Strategies Pre- and Post-Cardiac Transplantation

  • Heart Failure (W Tang, Section Editor)
  • Published:
Current Treatment Options in Cardiovascular Medicine Aims and scope Submit manuscript

Opinion statement

Panel reactive antibody (PRA) testing has become standard in the evaluation of patients prior to cardiac transplant. Sensitizing events such as blood transfusions, which result in the accumulation of pre-transplant antibodies, should be avoided as clinically feasible. Desensitization therapy might be considered in sensitized patients with cPRA > 50 % although distinct cutoff PRA values for initiating therapy pre-transplant are patient and transplant program dependent. Post-cardiac transplant, quantitative antibodies should also be periodically analyzed, at intervals individualized to the patient. Donor-specific antibodies (DSA) after cardiac transplantation have been shown to be associated with worsened survival. It appears that complement fixing DSA confer the greatest risk for antibody-mediated rejection post-transplant. Desensitization strategies aim to reduce the number of clinically important antibodies prior to and after transplant, both by removal of antibodies and cessation of further production. Current desensitization regimens include pharmacologic, procedural, and surgical modalities, and must be individualized to the patient. Currently, most cardiac transplant programs tailor the post-transplant immunosuppressive regimen based on clinical factors and immunologic assays and may include the use of cytolytic induction and/or intravenous immune gammaglobulin in higher risk patients.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Kidambi S, Mohamedali B, Bhat G. Clinical outcomes in sensitized heart transplant patients bridged with ventricular assist devices. Clin Transplant. 2015;29(6):499–505.

    Article  CAS  PubMed  Google Scholar 

  2. Nwakanma LU et al. Annals Thoracic Surg. 2007;84:1556–63.

    Article  Google Scholar 

  3. Montgomery RA, Lonze BE, King KE, et al. Desensitization in HLA incompatible kidney recipients and survival. N Engl J Med. 2011;365:318.

    Article  CAS  PubMed  Google Scholar 

  4. Kobashigawa J, Mehra M, West L, et al. Report from a consensus conference on the sensitized patient awaiting heart transplantation. J Heart Lung Transplant. 2009;28:213–25. This paper summarizes a consensus conference focused on the evaluation and management of circulating antibodies and sensitization in the cardiac transplant patient.

    Article  PubMed  Google Scholar 

  5. Smith JD, Banner NR, Hamour IM, Ozawa M, Goh A, Robinson D, et al. De novo donor HLA-specific antibodies after heart transplantation are an independent predictor of poor patient survival. Am J Transplant. 2011;11(2):312–9.

    Article  CAS  PubMed  Google Scholar 

  6. O'Connor MJ, Keeshan BC, Lin KY, Monos D, Lind C, Paridon SM, Mascio CE, Shaddy RE, Rossano JW. Changes in the methodology of pre-heart transplant human leukocyte antibody assessment: an analysis of the United Network for Organ Sharing database. Clin Transplant. 2015.

  7. Altermann WW, Seliger B, Sel S, et al. Comparison of the established standard complement-dependent cytotoxicity and flow cytometric crossmatch assays with a novel ELISA-based HLA crossmatch procedure. Histol Histopathol. 2006;10:1115–24.

    Google Scholar 

  8. Smith JD, Hamour IM, Banner NR, et al. C4d fixing, Luminex binding antibodies—a new tool for prediction of graft failure after heart transplantation. Am J Transplant. 2007;7:2809–15.

    Article  CAS  PubMed  Google Scholar 

  9. Mahesh B, Leong HS, McCormack A, et al. Autoantibodies to vimentin cause accelerated rejection of cardiac allografts. Am J Pathol. 2007;170:1415–27.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Mizutani K, Terasaki P, Bignon JD, et al. Association of kidney transplant failure and antibodies against MICA. Hum Immunol. 2006;67:683–91.

    Article  CAS  PubMed  Google Scholar 

  11. Zou Y, Stastny P, Caner S, et al. Antibodies against MICA antigens and kidney-transplant rejection. N Engl J Med. 2007;357:1293–300.

    Article  CAS  PubMed  Google Scholar 

  12. Duquesnoy RJ, Kamoun M, Baxter-Lowe LA, Woodle ES, Bray RA, Claas FH, et al. Should HLA mismatch acceptability for sensitized transplant candidates be determined at the high-resolution rather than the antigen level? Am J Transplant. 2015;15:923–30.

    Article  CAS  PubMed  Google Scholar 

  13. Costanzo MR, Dichad A, Starling R, et al. The international society of heart and lung transplant guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29(8):914–56.

    Article  PubMed  Google Scholar 

  14. Pak SW, Uriel N, Burke E, Cappleman SA, Sutton EM, Takayama H, et al. High incidence of elevated panel reactive antibodies in patients supported with HeartMate II left ventricular assist devices sang. Circulation. 2010;122:A20395.

    Google Scholar 

  15. George I, Colley P, Russo MJ, Martens TP, Burke E, Oz MC, et al. Association of device surface and biomaterials with immunologic sensitization after mechanical support. J Thorac Cardiovasc Surg. 2008;135(6):1372–9.

    Article  PubMed  Google Scholar 

  16. Urban M, Gazdic T, Slimackova E, et al. Alloimmunosensitization in left ventricular assist device recipients and impact on posttransplantation outcome. ASAIO J. 2012;58:554–61.

    Article  CAS  PubMed  Google Scholar 

  17. Grinda JM, Bricourt MO, Amrein C, et al. Human leukocyte antigen sensitization in ventricular assist device recipients: a lesser risk with the DeBakey axial pump. Ann Thorac Surg. 2005;80:945–8.

    Article  PubMed  Google Scholar 

  18. Kwon MH, Zhang JQ, Schaenman JM, Cadeiras M, Gjertson DW, Krystal CA, et al. Characterization of ventricular assist device-mediated sensitization in the bridge-to-heart-transplantation patient. J Thorac Cardiovasc Surg. 2015;149(4):1161–6.

    Article  PubMed  Google Scholar 

  19. John R, Pagani FD, Naka Y, et al. Post-cardiac transplant survival after support with a continuous-flow left ventricular assist device: impact of duration of left ventricular assist device support and other variables. J Thorac Cardiovasc Surg. 2010;140:174–81.

    Article  PubMed  Google Scholar 

  20. Pagani FD, Dyke DB, Wright S, Cody R, Aaronson KD. Development of anti-major histocompatibility complex class I or II antibodies following left ventricular assist device implantation: effects on subsequent allograft rejection and survival. J Heart Lung Transplant. 2001;20:646–53.

    Article  CAS  PubMed  Google Scholar 

  21. Pamboukian SV, Costanzo MR, Dunlap S, et al. Relationship between bridging with ventricular assist device on rejection after heart transplantation. J Heart Lung Transplant. 2005;24:310–5.

    Article  PubMed  Google Scholar 

  22. Joyce DL, Southard RE, Torre-Amione G, et al. Impact of left ventricular assist device (LVAD)-mediated humoral sensitization on post-transplant outcomes. J Heart Lung Transplant. 2005;24:2054–9.

    Article  PubMed  Google Scholar 

  23. Gonzalez-Stawinski GV, Cook DJ, Chang AS, et al. Early and midterm risk of coronary allograft vasculopathy in patients bridged to orthotopic heart transplantation with ventricular assist devices. Transplantation. 2005;79:1175–9.

    Article  PubMed  Google Scholar 

  24. Ballow M. The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders. J Allergy Clin Immunol. 2011;127(2):315–23. quiz 24–5.

    Article  CAS  PubMed  Google Scholar 

  25. John R, Lietz K, Burke E, Ankersmit J, Mancini D, Suciu-Foca N, et al. Intravenous immunoglobulin reduces anti-HLA alloreactivity and shortens waiting time to cardiac transplantation in highly sensitized left ventricular assist device recipients. Circulation. 1999;100(19 Suppl):II229–35.

    CAS  PubMed  Google Scholar 

  26. Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited:09/18/2015), IVIg

  27. Jordan SC, Reinsmoen N, Lai CH, Vo A. Novel immunotherapeutic approaches to improve rates and outcomes of transplantation in sensitized renal allograft recipients. Discov Med. 2012;13:235–45.

    PubMed  Google Scholar 

  28. Vo AA, Lukovsky M, Toyoda M, et al. Rituximab and intravenous immune globulin for desensitization during renal transplantation. N Engl J Med. 2008;359:242–51. This randomized clinical trial was one of the first to highlight the efficacy of desensitization therapy prior to transplantation.

    Article  CAS  PubMed  Google Scholar 

  29. Reinsmoen NL, Lai CH, Vo A, Jordan SC. Evolving paradigms for desensitization in managing broadly HLA sensitized transplant candidates. Discov Med. 2012;13:267–73.

    PubMed  Google Scholar 

  30. Jordan SC, Tyan D, Stablein D, McIntosh M, Rose S, Vo A, et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol. 2004;15:3256–62.

    Article  PubMed  Google Scholar 

  31. Reinsmoen NL, Lai CH, Vo A, Cao K, Ong G, Naim M, et al. Acceptable donor-specific antibody levels allowing for successful deceased and living donor kidney transplantation after desensitization therapy. Transplantation. 2008;86(6):820–5.

    Article  CAS  PubMed  Google Scholar 

  32. Jordan SC, Toyoda M, Kahwaji J, Vo A. Clinical Aspects of intravenous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011;11(2):196–202.

    Article  CAS  PubMed  Google Scholar 

  33. Kobashigawa JA, Patel JK, Kittleson MM, Kawano MA, Kiyosaki KK, Davis SN, et al. The long-term outcome of treated sensitized patients who undergo heart transplantation. Clin Transpl. 2011;25(1):E61–7. This was the first long term study of desensitization therapy in cardiac transplantation, and revealed acceptable long term outcomes in treated sensitized patients after transplant.

    Article  Google Scholar 

  34. Bearden CM, Agarwal A, Book BK, Sidner RA, Gebel HM, Bray RA. Pronase treatment facilitates alloantibody flow cytometric and cytotoxic crossmatching in the presence of rituximab. Hum Immunol. 2004;65:803–9.

    Article  CAS  PubMed  Google Scholar 

  35. Book BK, Agarwal A, Milgrom AB, Bearden CM, Sidner RA, Higgins NG, et al. New crossmatch technique eliminates interference by humanized and chimeric monoclonal antibodies. Transplant Proc. 2005;37(2):640–2.

    Article  CAS  PubMed  Google Scholar 

  36. Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited:09/18/2015), Rituximab.

  37. Itescu S, Burke E, Lietz K, John R, Mancini D, Michler R, et al. Intravenous pulse administration of cyclophosphamide is an effective and safe treatment for sensitized cardiac allograft recipients. Circulation. 2002;105(10):1214–9.

    Article  CAS  PubMed  Google Scholar 

  38. Micromedex® 2.0, (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com/ (cited:09/18/2015), Cyclophosphamide.

  39. Higgins R, Kirklin JK, Brown RN, et al. To induce or not to induce: do patients at greatest risk for fatal rejection benefit from cytolytic induction therapy? J Heart Lung Transplant. 2005;24:392.

    Article  CAS  PubMed  Google Scholar 

  40. Penninga L, Moller CH, Gustafsson F, Gluud C, Steinbruchel DA. Immunosuppressive T-cell antibody induction for heart transplant recipients. Cochrane Database Syst Rev. 2013;12, CD008842.

    PubMed  Google Scholar 

  41. Kho MM, Bouvy AP, Cadogan M, Kraaijeveld R, Baan CC, Weimar W. The effect of low and ultra-low dosages Thymoglobulin on peripheral T, B and NK cells in kidney transplant recipients. Transpl Immunol. 2012;26:186.

    Article  CAS  PubMed  Google Scholar 

  42. Lund LH, Edwards LB, Kucheryavaya AY, et al. The registry of the international society for heart and lung transplantation: thirtieth official adult heart transplant report–2013; focus theme: age. J Heart Lung Transplant. 2013;32:951.

    Article  PubMed  Google Scholar 

  43. Zuckermann A, Schulz U, Deuse T, Ruhpawar A, Schmitto JD, Beiras-Fernandez A, et al. Thymoglobulin induction in heart transplantation: patient selection and implications for maintenance immunosuppression. Transpl Int. 2015;28(3):259–69.

    Article  PubMed Central  PubMed  Google Scholar 

  44. Brennan DC, Flavin K, Lowell JA, Howard TK, Shenoy S, Burgess S, et al. A randomized, double-blinded comparison of Thymoglobulin versus Atgam for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation. 1999;67(7):1011–8.

    Article  CAS  PubMed  Google Scholar 

  45. Hardinger KL, Schnitzler MA, Miller B, Lowell JA, Shenoy S, Koch MJ, et al. Five-year follow up of thymoglobulin versus ATGAM induction in adult renal transplantation. Transplantation. 2004;78(1):136–41.

    Article  CAS  PubMed  Google Scholar 

  46. Rafiei M, Kittleson M, Patel J, Osborne A, Chang D, Czer L, et al. Anti-thymocyte globulin may prevent antibody production after heart transplantation. Transplant Proc. 2014;46(10):3570–4. This retrospective study suggested the benefit of anti-thymocyte globulin in suppressing antibody production after cardiac transplant, supporting its utility in induction therapy.

    Article  CAS  PubMed  Google Scholar 

  47. Czer LS, Phan A, Ruzza A, Rafiei M, Setareh-Shenas S, Caceres M, et al. Antithymocyte globulin induction therapy adjusted for immunologic risk after heart transplantation. Transplant Proc. 2013;45(6):2393–8.

    Article  CAS  PubMed  Google Scholar 

  48. Brennan DC, Daller JA, Lake KD, et al. Rabbit antithymocyte globulin versus basiliximab in renal transplantation. N Engl J Med. 2006;355:1967.

    Article  CAS  PubMed  Google Scholar 

  49. Wang R, Moura LA, Lopes SV, Costa FD, Souza Filho NF, Fernandes TL, et al. Reduced progression of cardiac allograft vasculopathy with routine use of induction therapy with basiliximab. Arq Bras Cardiol. 2015;105(2):176–83.

    PubMed Central  PubMed  Google Scholar 

  50. Ansari D, Lund LH, Stehlik J, Andersson B, Höglund P, Edwards L, Nilsson J; Induction with anti-thymocyte globulin in heart transplantation is associated with better long-term survival compared with basiliximab. J Heart Lung Transplant. 2015.

  51. Pisani BA, Mullen GM, Malinowska K, Lawless CE, Mendez J, Silver MA, et al. Plasmapheresis with intravenous immunoglobulin G is effective in patients with elevated panel reactive antibody prior to cardiac transplantation. J Heart Lung Transplant: Off Public Int Soc Heart Transplant. 1999;18(7):701–6.

    Article  CAS  Google Scholar 

  52. Rummler S, Barz D. Plasma exchange and immunoadsorption of patients with thoracic organ transplantation. Transfus Med Hemother: Offizielles Organ Der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 2012;39(4):234–40.

    Article  Google Scholar 

  53. Sicard A, Phares TW, Yu H, Fan R, Baldwin 3rd WM, Fairchild RL, et al. The spleen is the major source of antidonor antibody-secreting cells in murine heart allograft recipients. Am J Transplant. 2012;12(7):1708–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Warren DS, Zachary AA, Sonnenday CJ, King KE, Cooper M, Ratner LE, et al. Successful renal transplantation across simultaneous ABO incompatible and positive crossmatch barriers. Am J Transplant: Off J Am Soc Transplant Am Soc Transplant Surg. 2004;4(4):561–8.

    Article  Google Scholar 

  55. 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: Off J Am Soc Transplant Am Soc Transplant Surg. 2009;9(1):201–9.

    Article  CAS  Google Scholar 

  56. Patel J, Everly M, Chang D, Kittleson M, Reed E, Kobashigawa J. Reduction of alloantibodies via proteasome inhibition in cardiac transplantation. J Heart Lung Transplant. 2011;30(12):1320–6.

    Article  PubMed  Google Scholar 

  57. Sacha L, et al. Carfilzomib for Refractory Antibody Mediated Rejection and Allosensitization in Heart Transplantation. The Journal of Heart and Lung Transplantation 33(Issue 4):S31.

  58. Stegall MD, Diwan T, Raghavaiah S, Cornell LD, Burns J, Dean PG, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant: Off J Am Soc Transplant Am Soc Transplant Surg. 2011;11(11):2405–13. This is the first clinical study demonstrating the efficacy of eculizumab in sensitized transplant patients.

    Article  CAS  Google Scholar 

  59. Patel J. Cedars-Sinai Medical Center. The De-novo Use of Eculizumab in Presensitized Patients Receiving Cardiac Transplantation (DUET) In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2015 Sep 28]. Available from: http://clinicaltrials.gov/ct2/show/NCT02013037 NLM Identifier: NCT02013037

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Correspondence to Jon A. Kobashigawa MD.

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Robert M. Cole declares no potential conflicts of interest.

Jon A. Kobashigawa reports grants and personal fees from Novartis Pharmaceuticals, grants and personal fees from CareDx, Inc., grants and personal fees from TransMedics Inc.

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Cole, R.M., Kobashigawa, J.A. Desensitization Strategies Pre- and Post-Cardiac Transplantation. Curr Treat Options Cardio Med 18, 8 (2016). https://doi.org/10.1007/s11936-015-0431-9

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  • DOI: https://doi.org/10.1007/s11936-015-0431-9

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