Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Acute cardiac allograft rejection: Treatment

Howard J Eisen, MD
Mariell Jessup, MD
Section Editor
Sharon A Hunt, MD
Deputy Editor
Susan B Yeon, MD, JD, FACC


Despite the use of potent immunosuppressive agents both immediately after cardiac transplantation and during long-term maintenance, acute rejection remains an important problem. The incidence of any rejection between discharge and one year has decreased from 30 percent for primary transplants in 2004 to 2006 to 25 percent in 2010 to 2011 [1]. Acute cellular rejection is most likely to occur in the first three to six months, with the incidence declining significantly after this time [2].

The diagnosis of acute cellular cardiac allograft rejection is generally made by endomyocardial biopsy performed either routinely or because of suggestive symptoms.

ISHLT grading system — The endomyocardial biopsy is graded using the International Society for Heart and Lung Transplantation (ISHLT) nomenclature adopted in 1990 and revised in 2004 [3-5]. For acute cellular rejection [5]:

Grade 0 – No rejection

Grade 1 R, mild – Interstitial and/or perivascular infiltrate with up to one focus of myocyte damage


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Sep 29, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Lund LH, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart and Lung Transplantation: thirty-first official adult heart transplant report--2014; focus theme: retransplantation. J Heart Lung Transplant 2014; 33:996.
  2. Hunt SA. Complications of heart transplantation. J Heart Transplant 1983; 3:70.
  3. Billingham ME, Cary NR, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant 1990; 9:587.
  4. Winters GL, Marboe CC, Billingham ME. The International Society for Heart and Lung Transplantation grading system for heart transplant biopsy specimens: clarification and commentary. J Heart Lung Transplant 1998; 17:754.
  5. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 2005; 24:1710.
  6. Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 1995; 270:283.
  7. Auphan N, DiDonato JA, Rosette C, et al. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 1995; 270:286.
  8. Schleimer RP, Jacques A, Shin HS, et al. Inhibition of T cell-mediated cytotoxicity by anti-inflammatory steroids. J Immunol 1984; 132:266.
  9. Knudsen PJ, Dinarello CA, Strom TB. Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol 1987; 139:4129.
  10. Snyder DS, Unanue ER. Corticosteroids inhibit murine macrophage Ia expression and interleukin 1 production. J Immunol 1982; 129:1803.
  11. Dinarello CA, Mier JW. Lymphokines. N Engl J Med 1987; 317:940.
  12. Burdick JF. The biology of immunosuppression with anti-lymphocyte antibodies. In: Kidney Transplant Rejection: Diagnosis and Treatment, Williams GM, Burdick JF, Solez K (Eds), Marcel Decker, New York 1988. p.307.
  13. Cosimi AB, Delmonico FL. Antilymphocyte antibody immunosuppressive therapy. In: Kidney Transplant Rejection: Diagnosis and Treatment, Williams GM, Burdick JF, Solez K (Eds), Marcel Decker, New York 1988. p.335.
  14. Abouna GM, al-Abdullah IH, Kelly-Sullivan D, et al. Randomized clinical trial of antithymocyte globulin induction in renal transplantation comparing a fixed daily dose with dose adjustment according to T cell monitoring. Transplantation 1995; 59:1564.
  15. Uber WE, Uber LA, VanBakel AB, et al. CD3 monitoring and thymoglobulin therapy in cardiac transplantation: clinical outcomes and pharmacoeconomic implications. Transplant Proc 2004; 36:3245.
  16. Bia MJ, Andiman W, Gaudio K, et al. Effect of treatment with cyclosporine versus azathioprine on incidence and severity of cytomegalovirus infection posttransplantation. Transplantation 1985; 40:610.
  17. Madaio MP, Spiegel JE, Levey AS. Life-threatening thrombocytopenia complicating antithymocyte globulin therapy for acute kidney transplant rejection. Evidence of in situ immune complex formation on the platelet surface. Transplantation 1988; 45:647.
  18. Kammer GM, Kurrasch R, Scillian JJ. Capping of the surface OKT3 binding molecule prevents the T-cell proliferative response to antigens: evidence that this molecule conveys the activation signal. Cell Immunol 1984; 87:284.
  19. Shield CF 3rd, Norman DJ. Immunologic monitoring during and after OKT3 therapy. Am J Kidney Dis 1988; 11:120.
  20. Caillat-Zucman S, Blumenfeld N, Legendre C, et al. The OKT3 immunosuppressive effect. In situ antigenic modulation of human graft-infiltrating T cells. Transplantation 1990; 49:156.
  21. Schroeder TJ, First MR. Monoclonal antibodies in organ transplantation. Am J Kidney Dis 1994; 23:138.
  22. Winters GL, Loh E, Schoen FJ. Natural history of focal moderate cardiac allograft rejection. Is treatment warranted? Circulation 1995; 91:1975.
  23. Lloveras JJ, Escourrou G, Delisle MB, et al. Evolution of untreated mild rejection in heart transplant recipients. J Heart Lung Transplant 1992; 11:751.
  24. Brunner-La Rocca HP, Sütsch G, Schneider J, et al. Natural course of moderate cardiac allograft rejection (International Society for Heart Transplantation grade 2) early and late after transplantation. Circulation 1996; 94:1334.
  25. Park MH, Starling RC, Ratliff NB, et al. Oral steroid pulse without taper for the treatment of asymptomatic moderate cardiac allograft rejection. J Heart Lung Transplant 1999; 18:1224.
  26. Hosenpud JD, Norman DJ, Pantely GA. Low-dose oral prednisone in the treatment of acute cardiac allograft rejection not associated with hemodynamic compromise. J Heart Transplant 1990; 9:292.
  27. Reed EF, Demetris AJ, Hammond E, et al. Acute antibody-mediated rejection of cardiac transplants. J Heart Lung Transplant 2006; 25:153.
  28. Berry GJ, Burke MM, Andersen C, et al. The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 2013; 32:1147.
  29. Taylor DO, Yowell RL, Kfoury AG, et al. Allograft coronary artery disease: clinical correlations with circulating anti-HLA antibodies and the immunohistopathologic pattern of vascular rejection. J Heart Lung Transplant 2000; 19:518.
  30. Michaels PJ, Espejo ML, Kobashigawa J, et al. Humoral rejection in cardiac transplantation: risk factors, hemodynamic consequences and relationship to transplant coronary artery disease. J Heart Lung Transplant 2003; 22:58.
  31. Grauhan O, Knosalla C, Ewert R, et al. Plasmapheresis and cyclophosphamide in the treatment of humoral rejection after heart transplantation. J Heart Lung Transplant 2001; 20:316.
  32. Hodges AM, Lyster H, McDermott A, et al. Late antibody-mediated rejection after heart transplantation following the development of de novo donor-specific human leukocyte antigen antibody. Transplantation 2012; 93:650.
  33. Bierl C, Miller B, Prak EL, et al. Antibody-mediated rejection in heart transplant recipients: potential efficacy of B-cell depletion and antibody removal. Clin Transpl 2006; :489.
  34. Almuti K, Haythe J, Dwyer E, et al. The changing pattern of humoral rejection in cardiac transplant recipients. Transplantation 2007; 84:498.
  35. Garrett HE Jr, Duvall-Seaman D, Helsley B, Groshart K. Treatment of vascular rejection with rituximab in cardiac transplantation. J Heart Lung Transplant 2005; 24:1337.
  36. Costanzo-Nordin MR, McManus BM, Wilson JE, et al. Efficacy of photopheresis in the rescue therapy of acute cellular rejection in human heart allografts: a preliminary clinical and immunopathologic report. Transplant Proc 1993; 25:881.
  37. Lehrer MS, Rook AH, Tomaszewski JE, DeNofrio D. Successful reversal of severe refractory cardiac allograft rejection by photopheresis. J Heart Lung Transplant 2001; 20:1233.
  38. Dall'Amico R, Livi U, Milano A, et al. Extracorporeal photochemotherapy as adjuvant treatment of heart transplant recipients with recurrent rejection. Transplantation 1995; 60:45.
  39. Barr ML, Meiser BM, Eisen HJ, et al. Photopheresis for the prevention of rejection in cardiac transplantation. Photopheresis Transplantation Study Group. N Engl J Med 1998; 339:1744.
  40. Frist WH, Winterland AW, Gerhardt EB, et al. Total lymphoid irradiation in heart transplantation: adjunctive treatment for recurrent rejection. Ann Thorac Surg 1989; 48:863.
  41. Salter MM, Kirklin JK, Bourge RC, et al. Total lymphoid irradiation in the treatment of early or recurrent heart rejection. J Heart Lung Transplant 1992; 11:902.
  42. Olsen SL, O'Connell JB, Bristow MR, Renlund DG. Methotrexate as an adjunct in the treatment of persistent mild cardiac allograft rejection. Transplantation 1990; 50:773.
  43. Costanzo MR, Koch DM, Fisher SG, et al. Effects of methotrexate on acute rejection and cardiac allograft vasculopathy in heart transplant recipients. J Heart Lung Transplant 1997; 16:169.
  44. Armitage JM, Kormos RL, Morita S, et al. Clinical trial of FK 506 immunosuppression in adult cardiac transplantation. Ann Thorac Surg 1992; 54:205.
  45. Yamani MH, Starling RC, Pelegrin D, et al. Efficacy of tacrolimus in patients with steroid-resistant cardiac allograft cellular rejection. J Heart Lung Transplant 2000; 19:337.
  46. Freudenberger R, Alexis J, Gass A, et al. Antithrombotic effect of FK506 vs cyclosporine in cardiac transplant recipients: potential implications in transplant arteriopathy. J Heart Lung Transplant 1999; 18:1228.
  47. Renlund DG, Gopinathan SK, Kfoury AG, Taylor DO. Mycophenolate mofetil (MMF) in heart transplantation: rejection prevention and treatment. Clin Transplant 1996; 10:136.
  48. Kobashigawa J, Miller L, Renlund D, et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators. Transplantation 1998; 66:507.
  49. Eisen HJ, Kobashigawa J, Keogh A, et al. Three-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in cardiac transplant recipients. J Heart Lung Transplant 2005; 24:517.
  50. Hosenpud JD, Bennett LE. Mycophenolate mofetil versus azathioprine in patients surviving the initial cardiac transplant hospitalization: an analysis of the Joint UNOS/ISHLT Thoracic Registry. Transplantation 2001; 72:1662.
  51. Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces acute rejection and prevents coronary artery disease at 2 years: a randomized clinical trial. Circulation 2004; 110:2694.
  52. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003; 349:847.
  53. Hiatt WR, Nissen SE, Cardiovascular and Renal Drugs Advisory Committee, US Food and Drug Administration. New drug application 21-628, Certican (everolimus), for the proposed indication of prophylaxis of rejection in heart transplantation: report from the Cardiovascular and Renal Drugs Advisory Committee, US Food and Drug Administration, November 16, 2005, Rockville, Md. Circulation 2006; 113:e394.