Antibody-Mediated Rejection in Cardiac Transplantation: Emerging Knowledge in Diagnosis and Management
2015; Lippincott Williams & Wilkins; Volume: 131; Issue: 18 Linguagem: Inglês
10.1161/cir.0000000000000093
ISSN1524-4539
AutoresMonica Colvin, Jennifer Cook, Patricia P. Chang, Gary L. Francis, Daphne T. Hsu, Matthew C. Kiernan, Jon Kobashigawa, JoAnn Lindenfeld, Sofia Carolina Masri, Dylan Miller, John B. OʼConnell, E. René Rodríguez, Bruce R. Rosengard, Sally Self, Connie White‐Williams, Adriana Zeevi,
Tópico(s)Viral Infections and Immunology Research
ResumoHomeCirculationVol. 131, No. 18Antibody-Mediated Rejection in Cardiac Transplantation: Emerging Knowledge in Diagnosis and Management Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBAntibody-Mediated Rejection in Cardiac Transplantation: Emerging Knowledge in Diagnosis and ManagementA Scientific Statement From the American Heart Association Monica M. Colvin, MD, MS, Jennifer L. Cook, MD, Patricia Chang, MD, Gary Francis, MD, FAHA, Daphne T. Hsu, MD, FAHA, Michael S. Kiernan, MD, Jon A. Kobashigawa, MD, FAHA, JoAnn Lindenfeld, MD, FAHA, Sofia Carolina Masri, MD, Dylan Miller, MD, John O'Connell, MD, E. Rene Rodriguez, MD, Bruce Rosengard, MD, Sally Self, MD, Connie White-Williams, RN, FAHA and Adriana Zeevi, PhDon behalf of the American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology, Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, Council on Cardiovascular Disease in the Young, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia Monica M. ColvinMonica M. Colvin , Jennifer L. CookJennifer L. Cook , Patricia ChangPatricia Chang , Gary FrancisGary Francis , Daphne T. HsuDaphne T. Hsu , Michael S. KiernanMichael S. Kiernan , Jon A. KobashigawaJon A. Kobashigawa , JoAnn LindenfeldJoAnn Lindenfeld , Sofia Carolina MasriSofia Carolina Masri , Dylan MillerDylan Miller , John O'ConnellJohn O'Connell , E. Rene RodriguezE. Rene Rodriguez , Bruce RosengardBruce Rosengard , Sally SelfSally Self , Connie White-WilliamsConnie White-Williams and Adriana ZeeviAdriana Zeevi and on behalf of the American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology, Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, Council on Cardiovascular Disease in the Young, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia Originally published2 Apr 2015https://doi.org/10.1161/CIR.0000000000000093Circulation. 2015;131:1608–1639Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2015: Previous Version 1 Antibody-mediated rejection (AMR) of the cardiac allograft is a poorly defined and challenging diagnosis for transplant recipients and their clinicians. Although even its very existence in heart transplantation was debated until relatively recently, improved immunopathologic and serological techniques to detect myocardial capillary complement deposition and circulating anti-HLA (human leukocyte antigen) antibodies have led to the detection of a spectrum of newly uncovered immunologic changes that characterize AMR. The earliest standardized clinical and pathological criteria for the diagnosis of AMR in heart transplantation became available in 2004, the result of a task force assembled by the International Society for Heart and Lung Transplantation (ISHLT). In 2006, the criteria were refined by the ISHLT Immunopathology Task Force (Table 1). These revisions provide 4 categories of diagnostic criteria: clinical, histopathologic, immunopathologic, and serological assessment.1 Despite these published criteria, currently >50% of heart transplant centers make the diagnosis of AMR based on cardiac dysfunction and the lack of cellular infiltrates on the heart biopsy (preconference survey included in the ISHLT consensus article).2 More recently, the ISHLT Consensus Conference on AMR has redefined the pathological diagnosis of AMR.3 The 2013 ISHLT "Working Formulation for the Standardization of Nomenclature in the Pathologic Diagnosis of Antibody-Mediated Rejection in Heart Transplantation" was published in December 2013. This document provided an update to the 2010 consensus conference.4 It is anticipated that this update to the definition of AMR will reduce variations in the diagnosis of AMR, providing a platform for the development of standardized therapies. The goal of the present scientific statement is to provide the heart transplant professional with an overview of the current status of the diagnosis and treatment of AMR in the cardiac allograft based on recent consensus conferences and the published literature. We include recommendations to facilitate evolving standardization and strategies for future study.Table 1. Findings in Acute AMR of the HeartRequired FindingsOptional1. Clinical evidence of acute graft dysfunctionRecommended in combination with other evidence to support diagnosis of AMR2. Histological evidence of acute capillary injury (a and b required)a. Capillary endothelial changesb. Macrophages in capillariesc. Neutrophils in capillaries (severe)d. Interstitial edema/hemorrhage (severe)3. Immunopathologic evidence for antibody-mediated injury (a or b or c required)a. IgG, IgM, and/or IgA + C3d and/or C4d or C1q (2–3+) by IFb. CD 68 for macrophages in capillaries (CD31 or CD34) and/or C4d (2–3+ intensity) in capillaries by paraffin IHc. Fibrin in vessels (severe)4. Serological evidence of anti-HLA or anti-donor antibodiesAnti-HLA class I and/or class II or other anti-donor antibody at time of biopsy (supportive of clinical and/or morphological findings)AMR indicates antibody-mediated rejection; HLA, human leukocyte antigen; IF, immunofluorescence; and IH, immunohistochemistry.Modified from Reed et al1 with permission from the International Society for Heart and Lung Transplantation. Copyright © 2006, International Society for Heart and Lung Transplantation.Historical Perspective: Evolving RecommendationsThe success of heart transplantation in the 1980s was enabled by the ability to diagnose rejection by transjugular right ventricular endomyocardial biopsy, a technique developed by Philip Caves in 1973. The diagnosis of acute cellular rejection (cytotoxic T-cell mediated) is made by histological identification of interstitial leukocyte infiltration with various degrees of myocyte damage. These features are sensitive and specific and correlate with allograft dysfunction. Furthermore, this immunopathologic and clinical state responds to anti–cellular rejection therapies with clinical improvement and resolution of histological rejection features. The subset of heart transplant recipients with graft failure and no evidence of cellular rejection were considered to have biopsy-negative rejection. Pathological changes observed in this setting were not included in the histological grading systems for cellular rejection, and these collective pathological changes were variably referred to as humoral, vascular, or antibody-mediated rejection (AMR).The first limited description of humoral rejection was included in the 1990 ISHLT criteria defined as positive immunofluorescence, vasculitis, or severe edema in the absence of cellular infiltrate5 (Table 2). By the time of the 2004 ISHLT revision, the immunologic process underlying AMR was better described in the literature.6 Routine screening was still not advocated; however, a recommendation was made for every endomyocardial biopsy specimen to undergo histological evaluation for AMR. At that time, the classification AMR 0 was assigned in the absence of histological or immunopathologic features. Confirmation of AMR or AMR 1 was defined as histological evidence with identification of antibodies (directed against CD68, CD31, C4d) and serum presence of donor-specific antibody (DSA; Table 2). With the publication of the 2004 working formulation, the field moved toward almost exclusive use of the term AMR and use of more precise histological descriptors. In 2006, the ISHLT Immunopathology Task Force provided an expanded description of the histological evidence of acute capillary injury, the minimum requirement for immunopathologic evidence of antibody-mediated injury, and an improved definition of serological evidence of circulating antibodies1 (Table 1).Table 2. Historical AMR Definitions19902004AMR 0Negative for AMRNo histological or immunopathologic features of AMRAMR 1Humoral rejection, positive IF, vasculitis or severe edema in the absence of cellular infiltratePositive for AMRHistological features of AMRPositive IF (C3d and/or C4d) or IP (CD68, C4d)AMR indicates antibody-mediated rejection; IF, immunofluorescence; and IP, immunoperoxidase.Modified from Stewart et al6 with permission from the International Society for Heart and Lung Transplantation. Copyright © 2005, International Society for Heart and Lung Transplantation.The persistent variations in the diagnosis and treatment of AMR were addressed in 2 related conferences: the Heart Session of the Tenth Banff Conference on Allograft Pathology (August 2009) and the ISHLT Consensus Conference on AMR (April 2010). These sessions undertook another revision in an attempt to refine the immunopathologic assessment of AMR. Our increased understanding of the pathological processes behind AMR enabled an evolution beyond the descriptive "biopsy-negative rejection" to AMR, a clinical entity with specific histopathologic, immunopathologic, and serological characteristics.2010 ISHLT Consensus Conference on AMRA consensus conference sponsored by the ISHLT convened transplant cardiologists, surgeons, pathologists, and immunologists on April 20, 2010, to advance the understanding of AMR.2 Participants represented 67 heart transplant centers from North America, Europe, and Asia. The most important issues included the need for a clinical definition of AMR, the significance of asymptomatic biopsy-proven AMR (without cardiac dysfunction), and the recognition that AMR may be caused by DSA as well as antibodies to non-HLA antigens. In cellular rejection, clinical descriptors such as recurrent, persistent, or hemodynamic compromise are used to illustrate clinical presentation or clinical severity. These clinical descriptors could also be used for AMR. Although AMR would be a pathological diagnosis, it was strongly recommended that at the time of suspected AMR, blood be drawn at biopsy and tested for the presence of donor-specific anti-HLA class I and class II antibodies. In the absence of detectable anti-HLA antibodies, the assessment of non-HLA antibodies may be indicated.In contrast to the 2004 revision, screening for AMR was recommended. Specifically, recommendations were made regarding the routine timing for specific staining of endomyocardial biopsy specimens and the frequency by which circulating antibodies should be assessed (Table 3). Finally, recommendations for management and future clinical trials were given.2 The ongoing work by pathologists to refine the classification of pathological AMR (as commissioned by the ISHLT board of directors) was published by Berry et al in 2011 and more recently in 2013.3,4 The 2013 ISHLT working formulation for pathological diagnosis of AMR is shown in Tables 4 and 5.Table 3. ISHLT Recommendations for Monitoring for AMREndomyocardial BiopsyCirculating AntibodyMethodologyHistological evaluationImmunoperoxidase: C4dImmunofluorescent staining: C4d and C3dSolid-phase assay and/or cell-based assays to assess for presence of DSA (and quantification if antibody present)IntervalsHistological evaluation of every protocol biopsyImmunoperoxidase/immunofluorescent staining: 2 wk and 1, 3, 6, and 12 mo after transplantationWhen AMR is suspected on the basis of histological, serological, or clinical findingsRoutine C4d(C3d) staining on subsequent biopsy specimens after a positive result until clearance2 wk and 1, 3, 6, and 12 mo, and then annually after transplantationWhen AMR is clinically suspectedAMR indicates antibody-mediated rejection; DSA, donor-specific antibody; and ISHLT, International Society for Heart and Lung Transplantation.Modified from Kobashigawa et al2 with permission from the International Society for Heart and Lung Transplantation. Copyright © 2011, International Society for Heart and Lung Transplantation.Table 4. Proposed Scoring System for Pathological AMRPositive BiopsyImmunohistochemistryImmunofluorescenceCapillary distribution and intensityMultifocal/diffuse weak or strong staining of C4dMultifocal/diffuse weak or strong staining of C4d/C3dIntravascular CD68 distribution>10% Focal/multifocal/diffuse intravascular macrophages…HLA-DR distribution and intensity…Multifocal/diffuse weak or strong stainingCaveatsFocal strong C4d staining is classified as negative but warrants close follow-upFocal strong C4d staining is classified as negative but warrants close follow-upAMR indicates antibody-mediated rejection; and HLA, human leukocyte antigen.Modified from Berry et al3 with permission from the International Society for Heart and Lung Transplantation. Copyright © 2011, International Society for Heart and Lung Transplantation.Table 5. Proposed Nomenclature for Pathological AMRCategoryDescriptionpAMR 0: Negative for pathological AMRBoth histological and immunopathologic studies are negativepAMR 1 (H+): Histopathologic AMR aloneHistological findings present and immunopathologic findings negativepAMR1 (I+): Immunopathologic AMR aloneHistological findings negative and immunopathologic findings positivepAMR 2: Pathological AMRBoth histological and immunopathologic findings are presentpAMR 3: Severe pathological AMRSevere AMR with histopathologic findings of interstitial hemorrhage, capillary fragmentation, mixed inflammatory infiltrates, endothelial cell pyknosis and/or karyorrhexis, and marked edemaAMR indicates antibody-mediated rejection; and pAMR, pathological antibody-mediated rejection category.Modified from Berry et al3 with permission from the International Society for Heart and Lung Transplantation. Copyright © 2011, International Society for Heart and Lung Transplantation.Pathogenesis and Immunopathologic Features of AMRPathogenesisAMR develops when recipient antibody is directed against donor HLA antigens on the endothelial layer of the allograft. Antibodies induce fixation and activation of the complement cascade, resulting in tissue injury. Complement activation, a key contributor to the pathogenesis of AMR, results in activation of the innate and adaptive immune responses. Complement and immunoglobulin are deposited within the allograft microvasculature, which results in an inflammatory process that is characterized by endothelial cell activation, upregulation of cytokines, infiltration of macrophages, increased vascular permeability, and microvascular thrombosis.7 This process ultimately manifests as allograft dysfunction.AMR may present as hyperacute rejection within 0 to 7 days after transplantation in patients who are sensitized to donor HLA antigens. Early AMR may occur during the first month after transplantation because of the development of de novo DSA or preexisting DSA. Early AMR tends to be associated with a higher prevalence of allograft dysfunction and hemodynamic compromise.8,9 The reported prevalence of late AMR, occurring months to years after transplantation, has increased, most likely because of heightened recognition.8,10–13 Approximately 50% of heart transplant recipients who develop rejection >7 years after transplantation have evidence of AMR.14 Finally, AMR has been reported concurrent with cellular rejection in up to 24% of cases.15 As the definition of AMR has evolved and more sensitive diagnostic modalities have become available, there is increasing evidence that AMR is a spectrum of immunologic injury that ranges from subclinical, histological, immunologic, and/or serological findings without graft dysfunction (ie, subclinical AMR) to overt AMR with hemodynamic compromise.Histopathologic FeaturesThe vascular endothelium is the point of first contact for anti-donor antibody in the allograft and the primary locus of activity in AMR. The myocardial capillaries, arterioles, and venules are readily sampled at biopsy; however, changes in the epicardial coronary arteries have also been noted at autopsy and in the explanted allograft.Enlarged or swollen endothelial cells, both cytoplasm and nuclei, are consistently seen, presumably reflecting endothelial activation as a consequence of intracellular signaling induced by antibody and subsequently complement, binding to surface antigen epitopes. The appearance of vasculitis or leukocytes infiltrating through the endothelium into the vessel wall demonstrates active humoral immunity with antibody-dependent cytotoxicity, cytokine- and chemoattractant-mediated homing, and circulating monocyte recruitment. Similar changes have been described in arterioles and venules, the closest contiguous segments upstream and downstream from myocardial capillaries, which are also lined by endothelium.16–18 Rarely, intravascular thrombi can be seen in these vessels, particularly in severe manifestations.6Interstitial edema and hemorrhage are also seen in AMR; however, interpretation of these findings is limited by the traumatic nature of procurement by the bioptome, which may present a challenge in distinguishing interstitial hemorrhage from biopsy-related artifact. Squeezing and distortion during biopsy removal and handling may also obscure edema.6,19–21Capillary changes indicative of AMR include endothelial cell swelling and intravascular macrophage accumulation coincident with pericapillary neutrophils.22Immunopathologic FeaturesThe primary evidence validating AMR as a distinct form of humoral immunity-induced rejection was the early demonstration of bound immunoglobulin and complement within the myocardial capillary bed. The role of immunoglobulins, complement activation, and the coagulation cascade in AMR is under constant study as diagnostic methods increase in sensitivity and specificity. Immunopathologic evidence, based on a variety of target antigens and immunopathologic assays, remains vital to the identification of AMR (Table 6).Table 6. Immunopathologic Features of AMRInterpretationAMRLimitationsIgG/IgMImmunoglobulin binding+Easily dissociatedShort half-lifeInterobserver variabilityC3, C1qComplement activation+Short half-lifeC3d/C4dComplement activation+Combination more predictive of AMR than C4d alone, long half-lifeHLA-DREndothelial integrity+Staining always present, but "frayed" pattern indicates capillary injuryFibrinThrombotic environment+Interstitial extravasation suggests more severe AMR episodeCD55, CD59Complement inhibitor−Long incubation and granular staining patternDifficult to interpretCD31, CD34, CD68Intravascular macrophages+CD68 confirms macrophage lineage of mononuclear cellsCD31/34 are endothelial markers which differentiate macrophages from endothelial cells and delineates intravascular localizationAMR indicates antibody-mediated rejection; and HLA, human leukocyte antigen.Immunoglobulin (IgG, IgM)For nearly a half a century, detection of tissue-bound immunoglobulin (and immune complexes) has been routine in kidney biopsies to diagnose immune complex glomerulonephritis. Detection assays for immunoglobulin heavy and light chains were therefore the first assays used to investigate AMR in cardiac transplant biopsies.17,22,23Before 2000, the detection of tissue immunoglobulin was a defining characteristic of AMR. This technique has limited utility because of the considerable intra-assay, interobserver, and interinstitutional variability. The sensitivity of this test is poor because of dissociation of immunoglobulin from antigen in vitro and rapid degradation in vivo. Specificity is limited because of the abundance of immunoglobulin in serum, where "serum contamination" of tissue leads to nonspecific staining.Complement ComponentsThe complement components C3 and C1q have been demonstrated in kidney AMR; however, their detection is limited by a short half-life in vivo and consequently a short window of detection during a rejection episode. Nevertheless, complement deposition is the sine qua non of AMR, and the presence of C4d and C3d has been proposed as a diagnostic criterion for AMR.The protein C4d is a complement split product that binds covalently to endothelium at the site of complement activation and persists longer than C3 or C1q (Figures 1 and 2). In 1998, this technique was adapted from experience in kidney transplantation and used to identify AMR.23–25 Currently, C4d is used frequently to diagnose AMR, and some authors suggest that C4d can be used as an immunopathologic surrogate for AMR.25–32 C4d positivity is also used in combination with histological features—with circulating DSA, or clinical graft dysfunction.23,33–36 Depending on how restrictive the pathological definition of AMR is (ie, number of criteria required), the reported incidence varies, with lower reported incidence with more criteria required. Early estimates using C4d alone ranged from 35% to 71%, whereas those using C4d in combination with other immunopathology markers, clinical graft dysfunction, and DSA reported AMR frequencies of 10%, 27%, and 12.5%, respectively.24,31,37–40Download figureDownload PowerPointFigure 1. A, C4d capillary staining by immunohistochemistry; B, C3d capillary staining by immunohistochemistry; C, C4d capillary staining by immunofluorescence; D, C3d, by immunofluorescence.Download figureDownload PowerPointFigure 2. A, C4d capillary staining by immunofluorescence; B, C3d capillary staining by immunofluorescence; C, CD31 staining by immunofluorescence.Although histological changes of AMR may be seen in any vessel type, C4d deposition is largely restricted to capillaries. Occasional staining of large-vessel endothelium (when present in a biopsy sample), perimyocytes, or sarcolemma may be seen; however, these patterns do not appear to indicate AMR.27,41Presence of C3d, a complement split product, is also used to diagnose AMR.23,38,42–46 (Figures 1 and 2). Like C4d, C3d persists in tissues longer than C3 and C1q, but because C3d cleavage occurs further downstream in the complement cascade, it indicates progression of complement activation.35 The combination of C4d and C3d detected by immunofluorescence predicts graft dysfunction and mortality better than C4d alone.47 Because C3d staining of arterioles may be seen in normal native tissue and likely represents artifactual nonspecific binding of the antibody to connective tissue components, only capillary staining with C3d is significant.39,48Immunoglobulin binding and complement activation are regulated in vivo by complement inhibitors. Two such regulators, CD59 and CD55 (decay accelerating factor), are used in conjunction with C4d and C3d to indicate aborted complement activation. The association with allograft function is unclear.47,49 Lengthy incubation times and a granular staining pattern render these assays impractical for clinical use.HLA-DR staining is helpful to delineate the capillary endothelium and highlight any compromise to individual capillary integrity, in which a frayed, disrupted, or feathery pattern indicates endothelial damage.50 Venular thrombosis is present in hyperacute rejection, and intravascular thrombi are noted in severe rejection.51 Fibrinogen (factor II) staining, although readily available and routinely used in kidney transplant immunopathology, is less specific.8,19,37,52Finally, the macrophage antigen CD68 allows identification of subtle accumulations of macrophages within vessels, which helps to differentiate intravascular/perivascular macrophages from lymphocytes, thereby excluding acute cellular rejection (ACR).17,39,53 Antigens CD34 and CD31 are endothelial cell markers, and like HLA-DR, they reflect the integrity of the capillary bed. CD34 and CD31 staining can be used to ascertain the intravascular location of macrophages/mononuclear cells, thereby supporting the diagnosis of AMR54 (Table 6; Figure 2).Posttransplantation AntibodiesThe development of anti-HLA antibodies after transplantation has been implicated in allograft injury. Tambur et al55 demonstrated that de novo production of antibodies during the first year after transplantation is significantly associated with cellular rejection and that class II antibodies significantly correlate with mortality and cardiac allograft vasculopathy (CAV). Posttransplantation panel reactive anti-HLA antibodies (PRAs) are associated with the development, frequency, and severity of CAV.56,57 Early and persistent anti-HLA antibody is associated with worse survival and CAV.58 DSAs, on the other hand, are associated with cellular rejection, AMR, and increased incidence of CAV.56,59–61 More recently, the demonstration of antibody specificity has provided greater prognostic determination. In a study of the relationship between complement deposition, HLA serology, and graft function, DSAs were found in 95% of biopsy samples that were positive for both C4d and C3d, compared with 35% in biopsy samples that were positive for C4d only. C4d+C3d+ biopsy samples demonstrated strong correlation with graft function and mortality; allograft dysfunction was present in 84% of patients with C4d+C3d+ compared with 5% of C4d+C3d− (P<0.0001). Combined positivity had a mortality of 37%.47 The presence of DSAs alone is not diagnostic of AMR; however, in the presence of complement deposition or graft dysfunction, their presence supports alloimmune activation.Non-HLA AntibodyNon-HLA and nontraditional antibodies may cause immune-mediated injury in the absence of detectable anti-HLA antibody. Non-HLA antibodies can be directed against autoantigens, polymorphic minor antigens, and polymorphic non-HLA antigens such as major histocompatibility complex class I chain–related antigens. These antibodies bind endothelium and result in apoptosis but not in complement-mediated lysis.1,62–65 Perhaps the most well described non-HLA antibodies are anti-endothelial cell antibodies, which have been implicated in acute humoral rejection, CAV, and poor graft survival in heart transplantation.66–68 Production of anti-endothelial cell antibodies appears to be stimulated by cytomegalovirus infection, increasing 1 to 4 weeks after detection of cytomegalovirus DNA. Vimentin, a well-described autoantigen, is the most abundant immunoreactive endothelial cell antigen.62,69 A type III intermediate filament cytoskeletal protein, it is elaborated by damaged endothelial cells, proliferating smooth muscle cells, fibroblasts, and leukocytes. One- and 2-year anti-vimentin titers predict the development of CAV.69 Anti-vimentin antibodies have been detected alone or in conjunction with anti-HLA antibodies and appear to be linked to HLA-DQ2 antibodies in particular. Alvarez-Márquez et al70 tested the association between various anti-cytoskeletal endothelial cell antibodies, including tubulin, vimentin, cytokeratin, and actin, and found that these antibodies were more frequent in heart transplant recipients who experienced rejection and that detection of these antibodies preceded the rejection episodes. Others have demonstrated an association between anti-vimentin antibodies and allograft injury.71 Both anti-myosin and anti-vimentin antibodies are significantly elevated in patients with AMR compared with those without AMR, preceding the episodes by 3 to 4 months.72Major histocompatibility complex class I chain–related antigens A and B (MICA and MICB) are polymorphic alloantigens that have been implicated as markers in transplantation, and MICA in particular has been linked with AMR. MICA is expressed on endothelial cell surfaces and can induce complement-lysing antibody. The appearance of anti-MICA antibodies after transplantation precedes the development of acute rejection and is more prevalent in patients who have rejection. Unfortunately, assays for measuring non-HLA antibodies are not widely available, which limits most centers' abilities to comprehensively assess suspected AMR. Nevertheless, non-HLA antibodies should be suspected in patients who have no evidence of DSA by solid phase assay but have pathological or clinical evidence of AMR.Clinical Features of AMRIncidenceThe true incidence of AMR is not known; because of the evolving diagnostic criteria and lack of routine screening by most programs, AMR is likely underreported. The reported incidence of AMR varies widely, between 3% and 85%, because of diverse diagnostic criteria and variations in screening frequency (Table 7). In published studies describing the incidence of AMR, the diagnostic criteria may include pathological findings, clinical findings, or both. To illustrate these disparities, Kfoury and colleagues15 evaluated histological and immunofluorescence findings in routine biopsy samples from 870 heart transplant recipients and reported an incidence of 85% at 100 days. This analysis included heart transplant recipients who received induction therapy with muromonab-CD3, which may have confounded the reported prevalence of AMR. Michaels and colleagues8 found AMR in 116 endomyocardial biopsy samples from 56 patients (≈600 patients followed up). Forty-four of the patients (77 biopsy samples) showed AMR without ACR (ISHLT grade 0). AMR was diagnosed by both immunofluorescence (immunoglobulin, C1q, and C3 deposition in capillaries or CD58+ cells on immunoperoxidase) and histological evidence as the criteria for AMR.8 Finally, Crespo-Leiro and colleagues11 reported an incidence of <3% when using the criteria of allograft dysfunction and C4d deposition. When ISHLT 2004 and 2006 criteria (ie, allograft dysfunction, serological evidence of DSA and biopsy evidence of complement deposition) were used, the incidence of AMR was 3% and 5%, respectively.38,47 It is anticipated that the establishment of standardized diagnostic criteria will improve consistency in the characterization of AMR.Table 7.
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