The Journal of Heart and Lung Transplantation
Volume 29, Issue 4 , Pages 389-394, April 2010

Controversies in defining cardiac antibody-mediated rejection: Need for updated criteria

  • Abdallah G. Kfoury, MD

      Affiliations

    • Intermountain Medical Center and Intermountain Healthcare, Cardiac Transplant Program, Salt Lake City, Utah
    • Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah
    • Corresponding Author InformationReprint requests: Abdallah G. Kfoury, MD, Heart Failure Prevention and Treatment Program, Intermountain Medical Center, 5121 South Cottonwood Street, Salt Lake City, UT 84107. Telephone: 801-507-4637. Fax: 801-507-4811
    • ,
  • M. Elizabeth H. Hammond, MD

      Affiliations

    • Intermountain Medical Center and Intermountain Healthcare, Cardiac Transplant Program, Salt Lake City, Utah
    • Utah Transplantation Affiliated Hospitals (U.T.A.H.) Cardiac Transplant Program, Salt Lake City, Utah

published online 02 March 2010.

Article Outline

Recent years have seen a rising awareness of the significance of cardiac antibody-mediated rejection (AMR) as a result of its formal recognition by the International Society for Heart and Lung Transplantation. New insights on the pathology and clinical behavior of cardiac AMR are at odds with current diagnostic guidelines. This perspective examines some of the contentious and unresolved issues in cardiac AMR as the transplant community makes concrete steps towards updating its defining criteria.

Keywords: antibody-mediated rejection, heart transplantation, controversies, ISHLT, diagnostic criteria

 

First described in 1989 by Hammond et al in Utah, antibody-mediated rejection (AMR) of the cardiac allograft, also known as “vascular” or “humoral” rejection, remains a poorly understood and treated entity with documented adverse outcomes.1, 2, 3, 4, 5 The pathological hallmarks of cardiac AMR include capillary endothelial activation and macrophage and/or neutrophil infiltration with or without edema or hemorrhage, as well as vascular immunofluorescent deposition of immunoglobulin and complement.6, 7, 8 Serologic detection of preformed or de novo donor anti-HLA antibodies has been closely linked to AMR and poor outcomes.9, 10, 11, 12 In 2004, the International Society for Heart and Lung Transplantation (ISHLT) convened a multidisciplinary committee to formulate diagnostic criteria for AMR as part of the revision of the 1990 cardiac biopsy grading nomenclature.13, 14 This formal recognition was a major step forward that resulted in renewed interest in the field. Yet, since their publication in 2005, the AMR diagnostic guidelines have also been challenged by a steadily growing familiarity and knowledge base with new insights on the topic. This perspective focuses on some of the controversial questions in defining cardiac AMR (Figure 1).

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What specimens should be used to assess cardiac AMR? 

Early studies of AMR in cardiac allografts used frozen tissue samples obtained at the time of routine endomyocardial biopsy. Such samples were considered highly desirable for this purpose in the original ISHLT grading schema because they obviate the artifacts associated with routine formalin-fixed paraffin-embedded (FFPE) tissue processing, which includes tissue fixation, dehydration and lipid extraction associated with xylene infiltration prior to paraffinization.15 Furthermore, FFPE tissue processing for immunoperoxidase staining has been shown to be less desirable for detection of complement components on lipid-containing membranes, which are the hallmark of AMR.16 More recent experience suggests that these processing issues can be surmounted by using other fixatives and different immunohistochemical methods,17, 18 but recent comparative studies have highlighted the diminished sensitivity and differences in pattern found on FFPE tissue samples (Figure 2A).19, 20, 21 Inter-rater disparity in immunohistochemical studies has also recently been reported. The inter-rater concordance rate was much better for immunofluorescence staining than for staining on FFPE tissues (kappa 0.9 vs 0.3). Current efforts defined at the recent Tenth Banff Conference on Allograft Pathology focused on establishing acceptable processing requirements for cardiac biopsies, although both sample types will continue to be used until an obvious new standard emerges. It is significant that the Banff Conference on Renal Allograft Pathology continued the emphasis on use of frozen tissue for the detection of AMR in renal biopsy specimens.22

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  • Figure 2. 

    (A) False negative C4d by immunohistochemistry. Note the pale and interrupted pattern of the brown reaction product in capillaries affected by AMR (arrows). Controls for C4d by immunohistochemistry were positive. Immunofluorescent staining for C4d was strongly and diffusely positive on the same case (inset). (B) False positive C4d by immunofluorescence. In this slide, it is impossible to determine whether the pattern represents capillary and/or sarcolemmal membrane staining. The significance of the sarcolemmal staining pattern is unknown. Drying artifact involving the frozen tissue (arrow) may have contributed to this pattern. (C) Fibrin by immunofluorescence in mild AMR. Fibrin is usually not seen in acute AMR, except when it is severe or has been present for several weeks. This slide shows the fibrin pattern of rare perivascular foci in a case of mild acute AMR present for several weeks. The patient's previous AMR episode was negative for fibrin. The HLA-DR capillary staining in this case was bright and diffuse, as shown in (E). (D) Fibrin by immunofluorescence in severe AMR. Fibrin is often seen in patients with severe, long-standing AMR or in those who are not compliant with maintenance immunosuppression. The slide shows large aggregates of fibrin in areas of capillary damage. HLA-DR staining of these capillaries was paradoxically weak (F), consistent with capillary damage. (E) HLA-DR by immunofluorescence in mild AMR. Slide from a patient with mild acute AMR, positively staining for both C3d and C4d. This slide is stained with HLA-DR and highlights the bright uniform staining of upregulated capillary endothelium when AMR is present. (F) HLA-DR by immunofluorescence in severe AMR. This slide, taken from the same patient as in (D), shows the pattern of HLA-DR staining found in patients with long-standing or severe AMR. The pattern of HLA-DR staining is weak and not linear due to damaged vessel walls. Many capillaries do not show staining (arrows).

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What analytes should be measured? 

Original definitions of AMR involved finding the colocalization of immunoglobulin (IgG or IgM) and complement components (C3d, C1q and then C4d). From the early studies, it became obvious that interstitial staining with immunoglobulin reagents complicated this definition. Many investigators have rejected the value of staining for immunoglobulin as part of this definition. However, some reports, particularly where accommodation is being investigated, retain immunoglobulin staining to clarify alternative potential reasons for complement staining.23, 24 Immunoglobulin detection may also be helpful in situations of AMR where complement is not bound by antibodies involved.25

Recently, it has been reported that C4d staining alone is sufficient evidence of AMR if it is detected in a generalized and smooth distribution in all capillaries.26, 27 Others have disputed this claim and urge evaluation of both C3d and C4d to assure that the staining is related to AMR.28, 29, 30 At the recent Banff meeting, it was determined that the optimal staining by immunofluorescence should at least include both C3d and C4d. Non-immunologic causes of C4d expression have been reported, including viral infections, reperfusion injury and treatment with monoclonal antibodies and anti-thymocyte preparations (Figure 2B).31, 32, 33, 34, 35

The value of other analytes is still controversial. Based on experimental evidence in animal allografts, we and others have also urged evaluation of HLA-DR, which helps to define the location of capillaries by immunofluorescence and serves as further evidence of endothelial activation and/or capillary damage.8, 36, 37 The role of fibrin detection has also been disputed, although there have been numerous reports of the adverse impact of fibrin accumulation in endomyocardial biopsies, indicating the hypercoagulability of the vascular endothelium in such situations.38, 39 There are also recent reports detailing the interaction of platelets and endothelial cells in AMR in response to HLA alloantibody.40, 41 In the future, it may well be that other analytes, including regulator proteins and chemokines, will also need to be assessed to fully characterize this process in all its forms.30, 41, 42

The distribution and intensity of staining of these reactants have not been standardized in a grading scheme. There is a precedent in the renal transplant literature to consider only diffuse staining as significant,20, 21 but a recent report has challenged this assumption in a careful study using outcome as an endpoint.43

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Donor-specific antibodies: Diagnostic criterion or risk factor? 

Pre-sensitization to HLA Class I and/or Class II antibodies from various causes predisposes heart transplant recipients to higher rates of AMR and worse outcomes.44 New advances in solid-phase assays have allowed a more accurate and discriminate appraisal of preformed antibodies. As a result, sensitized patients awaiting suitable heart donors can now be better risk-stratified and screened by virtual cross-match. Similarly, the appearance of post-transplantation de novo antibodies, especially when donor-specific, increases the risk of AMR, allograft dysfunction and coronary allograft vasculopathy.9, 10, 11, 12 Yet, cardiac AMR has been diagnosed in the absence of anti-HLA antibodies, albeit much less commonly. Some of the clinically relevant non-HLA antibodies that have been incriminated in allograft rejection and/or bad outcomes comprise autoantibodies directed against cardiac proteins and vimentin or against antigens expressed on donor endothelial cells.45, 46 It is therefore still controversial whether to consider the detection of donor-specific antibodies in recipients as an early indicator of an immune response heralding AMR, or simply as a risk factor among others.

The progress in methodology in the field also brings to light some new unresolved issues in need of further exploration and consideration when formulating future diagnostic guidelines for cardiac AMR. These include: deciding which antibodies from a growing list are clinically pertinent for monitoring; understanding how their specificity and titer may influence whether they are protective or detrimental to the cardiac allograft; and elucidating mechanisms behind the apparent resistance of some allografts (accommodation) to humoral injury.47

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What is the incidence/prevalence of cardiac AMR? 

The true incidence of cardiac AMR is poorly characterized for a number of reasons. Screening for AMR in asymptomatic patients is not standard practice, especially since most transplant programs only define it when clinically manifest. It is therefore likely that cardiac AMR is underreported, that is if we accept the premise that AMR can be subclinical. If AMR exists as a subclinical entity as has been reported, it can present as acute self-limited or repetitive episodes or as chronic low-grade, ultimately leading to cardiac allograft vasculopathy or dysfunction and heart failure. Last, the incidence of AMR is not constant and varies decrementally over time after transplantation.

What has been reported to date in much of the literature is perhaps best described as prevalence of symptomatic AMR. The prevalence of lone symptomatic AMR ranges between 10% and 15%, whereas the prevalence of AMR when routinely being surveilled (symptomatic and asymptomatic) or when diagnosed concurrently with acute cellular rejection (mixed rejection) can surpass 40%.48, 49, 50, 51 This wide range is also the result of the lack of prior standardized diagnostic criteria as well as the diversity of the populations studied in their predisposition to AMR.

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Are histologic criteria alone adequate to screen for cardiac AMR? 

Screening criteria for AMR currently include the histologic findings of capillary endothelial swelling and macrophage activation and the presence of allograft dysfunction. If identified, confirming the diagnosis is carried on by immunofluorescence or immunoperoxidase staining. Therefore, our ability to diagnose or exclude cardiac AMR effectively rests on the assumption that histologic parameters alone have adequate specificity and sensitivity. In a large study of biopsy specimens with confirmed AMR by immunofluorescence, histologic changes were found to have acceptable specificity to rule out AMR. On the other hand, the sensitivities of capillary endothelial swelling (63%) and macrophage vascular adherence (30%) were disappointingly low.52 In further analyzing the data, a receiver operating characteristic (ROC) curve was plotted combining various semi-quantitative scores of both histologic parameters. Even then, the area under the curve was 0.759 indicating that up to roughly 25% of cases of cardiac AMR may be missed under the present recommended screening approach. It is generally accepted that cardiac AMR becomes manifest mostly early after transplantation.3, 4, 48, 49, 51 Heart transplant recipients without AMR during that period are usually less likely to develop it later on.53 Whether to include immunohistochemical testing on all endomyocardial biopsy specimens, at least in the first few weeks after transplantation, deserves serious consideration in future AMR diagnostic guidelines.

Issues concerning the requisite allograft dysfunction to diagnose cardiac AMR are debated in what follows.

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Should asymptomatic cardiac AMR be disregarded? 

The existing ISHLT guidelines questionably assume that cardiac AMR is always symptomatic or that it should not be diagnosed in the absence of allograft dysfunction. This definition is counterintuitive and conflicts with the proposed stages of AMR progression in solid-organ transplants,54, 55, 56 as well as with recently described experience relating asymptomatic AMR with worse cardiovascular mortality and higher likelihood of cardiac allograft vasculopathy.57, 58, 59 Cardiac AMR should be perceived as a pathologic continuum with potential ensuing clinical involvement. This paradigm change in our approach to cardiac AMR can be accomplished by eliminating the allograft dysfunction requisite from any future AMR diagnostic scheme. Alternatively, cardiac dysfunction or other clinical manifestations may be part of a constellation of pathologic, laboratory and clinical criteria, none of which alone are diagnostically definitive of AMR. Reconciling these diverse diagnostic elements of cardiac AMR is complex enough that it may lend itself nicely to a set of major and minor diagnostic criteria, similar to what has been done in other immunologic diseases.

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Should the severity of cardiac AMR be graded? 

The most up-to-date review of the grading system for cardiac biopsies designates acute AMR as either absent (AMR 0) or present (AMR 1), without any provision of grading its severity. Yet, more agree that the extent of histologic and immunopathologic features of AMR varies between biopsies.3, 4, 51, 52 With more severe AMR, histologic changes may progress from low-grade endothelial cell activation and macrophage vascular adherence to vascular permeability and, eventually, capillary damage with ensuing interstitial pleomorphic inflammation and myocyte necrosis. Immunofluorescent immunoglobulin and complement deposits may become more or less prominent and diffuse and can be seen in the interstitium along with fibrin as vessels get injured with more severe AMR (Figure 2C and D). The integrity of capillaries is important to assess, since, with severe injury and fibrin accumulation, they may be unable to express complement components diagnostic of AMR. Staining capillaries routinely with HLA-DR, which is upregulated during rejection, would be useful in this regard.42 HLA-DR staining in severe rejection is often diminished or expressed in patches because of capillary injury (Figure 2E and F). These diverse immunohistologic features of cardiac AMR based on severity were additionally found to be clinically relevant as they were linked to an incremental risk of cardiovascular mortality in one large series.60 Even in the absence of a clinical correlate, it would make sense to devise a consensus severity scale for cardiac AMR similar to what has been done for cellular rejection.

AMR of the cardiac allograft is a complex immunologic entity with pathologic and clinical characteristics that are difficult to standardize. Yet, it was encouraging to see pathologists and clinicians gather in the presence of a delegate from the Board of Directors of the ISHLT at the recent Banff Conference to lay the basis for what should hopefully develop into much-needed updated diagnostic guidelines for cardiac AMR.

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Disclosure statement 

The authors have no conflicts of interest to disclose.

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References 

  1. Hammond MEH, Yowell RL, Nunoda S, et al. Vascular (humoral) rejection in heart transplantation: pathologic observations and clinical implications. J Heart Lung Transplant. 1989;8:430–443
  2. 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;518–521
  3. 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;22:58–69
  4. Lones MA, Czer LS, Trento A, et al. Clinical–pathologic features of humoral rejection in cardiac allografts: a study in 81 consecutive patients. J Heart Lung Transplant. 1995;14:151–162
  5. Labarrere CA, Nelson DR, Faulk WP. Endothelial activation and development of coronary artery disease in transplanted human hearts. JAMA. 1997;278:1169–1175
  6. Ratliff NB, McMahon JT. Activation of intravascular macrophages within myocardial small vessels is a feature of acute vascular rejection in human heart transplants. J Heart Lung Transplant. 1995;14:338–345
  7. Hallgren R, Gerdin B, Tengblad A, et al. Accumulation of hyaluronan (hyaluronic acid) in myocardial interstitial tissue parallels development of transplantation edema in heart allografts in rats. J Clin Invest. 1990;85:668–673
  8. Hammond EH, Hansen JK, Spencer LS, et al. Vascular rejection in cardiac transplantation: histologic, immunopathologic, and ultrastructural features. Cardiovasc Pathol. 1993;2:21–34
  9. Petrossian GA, Nichols AB, Marboe CC, et al. Relation between survival and development of coronary artery disease and anti-HLA antibodies after cardiac transplantation. Circulation. 1989;80:III-122-5
  10. Reed EF, Hong B, Ho E, et al. Monitoring of soluble HLA alloantigens and anti-HLA antibodies identifies heart allograft recipients at risk of transplant-associated coronary artery disease. Transplantation. 1996;61:566–572
  11. Rose ML. Role of antibodies in rejection. Curr Opin Organ Transplant. 1999;4:227–233
  12. McKenna RM, Takemoto SK, Terasaki PI. Anti-HLA antibodies after solid organ transplantation. Transplantation. 2000;69:319–326
  13. Stewart S, Winters G, Fishbein M, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005;24:1710–1720
  14. Reed E, Demetris A, Hammond ME, et al. Acute antibody-mediated rejection of cardiac transplants. J Heart Lung Transplant. 2006;25:153–159
  15. Billingham ME, Cary NRB, Hammond EH, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection. J Heart Transplant. 1990;9:587–593
  16. Mölne J, Breimer ME, Svalander CT. Immunoperoxidase versus immunofluorescence in the assessment of human renal biopsies. Am J Kidney Dis. 2005;45:674–683
  17. Howie AJ, Gregory J, Thompson RA, et al. Technical improvements in the immunoperoxidase study of renal biopsy specimens. J Clin Pathol. 1990;43:257–259
  18. Chantranuat C, Qiao JH, Kobashigawa J, et al. Immunoperoxidase staining for C4d on paraffin-embedded tissue in cardiac allograft endomyocardial biopsies: comparison to frozen tissue immunofluorescence. Appl Immunhistochem Mol Morphol. 2004;12:166–171
  19. Ludovico-Martins H, Silva C, Teodoro WR, et al. Analysis of different staining techniques for C4d detection in renal allograft biopsies. Transplant Proc. 2009;41:862–865
  20. Seemayer CA, Gaspert A, Nickeleit V, et al. C4d staining of renal allograft biopsies: a comparative analysis of different staining techniques. Nephrol Dial Transplant. 2007;22:568–576
  21. Ludvico-Martins H, Silva C, Teodoro WR, et al. Analysis of different staining techniques for C4d detection in renal allograft biopsies. Transplant Proc. 2009;41:862–865
  22. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8:753–760
  23. Smith RN, Kawai T, Boskovic S, et al. Four stages and lack of stable accommodation in chronic alloantibody-mediated allograft rejection in Cynomolgus monkeys. Am J Transplant. 2008;8:1662–1672
  24. Shimizu A, Hisashi Y, Kuwaki K, et al. Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alpha1,3-galactosyltransferase gene-knockout pigs in baboons. Am J Pathol. 2008;172:1471–1481
  25. Murata K, Fox-Talbot K, Qian Z, et al. Synergistic deposition of C4d by complement-activating and non-activating antibodies in cardiac transplants. Am J Transplant. 2007;7:2605–2614
  26. Batal I, Girnita A, Zeevi A, et al. Clinical significance of the distribution of C4d deposits in different anatomic compartments of the allograft kidney. Mod Pathol. 2008;21:1490–1498
  27. Behr TM, Feucht HE, Richter K, et al. Detection of humoral rejection in human cardiac allografts by assessing the capillary deposition of complement fragment C4d in endomyocardial biopsies. J Heart Lung Transplant. 1999;18:904–912
  28. Rodriguez ER, Skojec DV, Tan CD, et al. Antibody-mediated rejection in human cardiac allografts: evaluation of immunoglobulins and complement activation products C4d and C3d as markers. Am J Transplant. 2005;5:2778–2785
  29. Murata K, Baldwin WM. Mechanisms of complement activation, C4d deposition, and their contribution to the pathogenesis of antibody-mediated rejection. Transplant Rev (Orlando). 2009;23:139–150
  30. Tan CD, Sokos GG, Pidwell DJ, et al. Correlation of donor-specific antibodies, complement and its regulators with graft dysfunction in cardiac antibody-mediated rejection. Am J Transplant. 2009;9:2075–2084
  31. Baldwin WM, Samaniego-Picota M, Kasper EK, et al. Complement deposition in early cardiac transplant biopsies is associated with ischemic injury and subsequent rejection episodes. Transplantation. 1999;68:894–900
  32. Spiller OB, Morgan BP. Antibody-independent activation of the classical complement pathway by cytomegalovirus-infected fibroblasts. J Infect Dis. 1998;178:1597–1603
  33. Van Strijp JA, Van Kessel KP, Miltenburg LA, et al. Attachment of human polymorphonuclear leukocytes to herpes simplex virus-infected fibroblasts mediated by antibodies-independent complement activation. J Virol. 1988;62:847–850
  34. Vallhonrat H, Williams WW, Cosimi AB, et al. In vivo generation of C4d, Bb, iC3b, and SC5b-9 after OKT3 administration in kidney and lung transplant recipients. Transplantation. 1999;67:253–258
  35. Martin S, Brenchley PE, O'Donoghue DJ, et al. The identification of allo- and auto-lymphocytotoxic antibodies in serum, in the presence of rabbit antithymocyte globulin. Tissue Antigens. 1988;31:26–32
  36. Manyak CL, Tse H, Fischer P, et al. Regulation of class II MHC molecules on human endothelial cells (Effects of IFN and dexamethasone). J Immunol. 1988;140:3817–3821
  37. McDouall RM, Batten P, McCormack A, et al. MHC class II expression on human heart microvascular endothelial cells: exquisite sensitivity to interferon-gamma and natural killer cells. Transplantation. 1997;64:1175–1180
  38. Labarrere CA, Torry RJ, Nelson DR, et al. Vascular antithrombin and clinical outcome in heart transplant patients. Am J Cardiol. 2001;87:425–431
  39. Shimizu A, Colvin RB. Pathological features of antibody-mediated rejection (Pathological features of antibody-mediated rejection). Curr Drug Targets Cardiovasc Haematol Disord. 2005;5:199–214
  40. Meehan SM, Limsrichamren S, Manaligod JR, et al. Platelets and capillary injury in acute humoral rejection of renal allografts. Hum Pathol. 2003;34:533–540
  41. Kirk AD, Morrell CN, Baldwin WM. Platelets influence vascularized organ transplants from start to finish. Am J Transplant. 2009;9:14–22
  42. Tay SS, McCormack A, Rose ML. Effect of cognate human CD4+ T cell and endothelial cell interactions upon chemokine production. Transplantation. 2004;78:987–994
  43. Kedainis RL, Koch MJ, Brennan DC, et al. Focal C4d+ in renal allografts is associated with the presence of donor-specific antibodies and decreased allograft survival. Am J Transplant. 2009;9:812–819
  44. Nwakanma LU, Williams JA, Weiss ES, et al. Influence of pretransplant panel-reactive antibody on outcomes in 8,160 heart transplant recipients in recent era. Ann Thorac Surg. 2007;84:1556–1562
  45. Jurcevic S, Ainsworth ME, Pomerance A, et al. Antivimentin antibodies are an independent predictor of transplant-associated coronary artery disease after cardiac transplantation. Transplantation. 2001;71:886–892
  46. Fredrich R, Toyoda M, Czer LS, et al. The clinical significance of antibodies to human vascular endothelial cells after cardiac transplantation. Transplantation. 1999;67:385–391
  47. Kobashigawa J, Mehra M, West L, et al. Report form a consensus conference on the sensitized patient awaiting heart transplantation. J Heart Lung Transplant. 2009;28:213–225
  48. Michaels PJ, Fishbein MC, Colvin RB. Humoral rejection of human organ transplants. Springer Semin Immunopathol. 2003;25:119–140
  49. Kfoury AG, Hammond EH, Snow GL, et al. Early screening for antibody-mediated rejection in heart transplant recipients. J Heart Lung Transplant. 2007;26:1264–1269
  50. Almuti K, Haythe J, Dwyer E, et al. The changing pattern of humoral rejection in cardiac transplant recipients. Transplantation. 2007;84:498–503
  51. Fishbein MC, Kobashigawa J. Biopsy-negative cardiac transplant rejection: etiology, diagnosis, and therapy. Curr Opin Cardiol. 2004;19:166–169
  52. Hammond ME, Stehlik J, Snow G, et al. Utility of histologic parameters in screening for antibody-mediated rejection of the cardiac allograft: a study of 3,170 biopsies. J Heart Lung Transplant. 2005;24:2015–2021
  53. Hammond MEH, Renlund DG. Cardiac allograft vascular (microvascular) rejection. Curr Opin Organ Transplant. 2002;7:233–239
  54. Mueller A, Schnuelle P, Waldherr R, et al. Impact of the Banff'97 classification for histological diagnosis of rejection on clinical outcome and renal function parameters after kidney transplantation. Transplantation. 2000;69:1123–1127
  55. Mauiyyedi S, Crespo M, Collins AB, et al. Acute humoral rejection in kidney transplantation: II (Morphology, immunopathology, and pathologic classification). J Am Soc Nephrol. 2002;13:779–787
  56. Takemoto SK, Zeevi A, Feng S, et al. National conference to assess antibody-mediated rejection in solid organ transplantation. Am J Transplant. 2004;4:1033–1041
  57. Kfoury AG, Stehlik J, Renlund DG, et al. Impact of repetitive episodes of antibody-mediated or cellular rejection on cardiovascular mortality in cardiac transplant recipients: defining rejection patterns. J Heart Lung Transplant. 2006;25:1277–1282
  58. Wu GW, Kobashigawa JA, Fishbein MC, et al. Asymptomatic antibody-mediated rejection after heart transplantation predicts poor outcomes. J Heart Lung Transplant. 2009;28:417–422
  59. Kfoury AG, Hammond ME, Snow GL, et al. Cardiovascular mortality among heart transplant recipients with asymptomatic antibody-mediated or stable mixed cellular and antibody-mediated rejection. J Heart Lung Transplant. 2009;28:781–784
  60. Kfoury AG, Renlund DG, Snow GL, et al. A clinical correlation study of severity of antibody-mediated rejection and cardiovascular mortality in heart transplantation. J Heart Lung Transplant. 2009;28:51–57

PII: S1053-2498(09)00849-3

doi:10.1016/j.healun.2009.10.016

The Journal of Heart and Lung Transplantation
Volume 29, Issue 4 , Pages 389-394, April 2010

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