Cardiac AMR has evolved over 25+ years from a controversial consideration to an established entity. In 1989, Hammond et al reported a pattern of "acute vascular (humoral)" rejection in 6 patients in Utah. The 1990 ISHLT Working Formulation (ISHLT WF) briefly addressed AMR but further study was needed. Reports from other centers followed, and in 2005 and 2006 the revised ISHLT WF AMR criteria were formally defined. The Banff 2009 conference highlighted a lack of uniformity in applying these criteria and variability in staining techniques for C4d. In 2010, a multidisciplinary effort by the ISHLT further refined the clinical and pathologic definitions of AMR. This work culminated in the current (2013) pathologic ISHLT WF.
Manifestations of AMR in tissue, serum, and patients each exist in a spectrum, and varying definitions have made it very difficult to compare "apples to apples" in the AMR literature. Much of the historic controversy around AMR has to do with semantics, terminology, and varying clinical and pathologic definitions. The 2013 ISHLT does not resolve all of these, but does standardize the diagnostic elements, with the aim of facilitating multicenter studies based on uniform criteria.
AMR is also dynamic, resulting from the complex interplay of several factors that each evolve over time. These include the magnitude (titer) and potency (isotype) of the inciting antibody, the efficiency of that antibody at fixing complement, and the influence of complement regulators in the graft. Because of this, several different "forms" of AMR are described, including:
Hyperacute rejection: Perhaps the first and best recognized form of AMR (or vascular/humoral rejection in the early literature). It is the most extreme end of the AMR spectrum and is the result of high titer pre-formed antibody immediately affecting an allograft after implantation. Because of the abundance and effectiveness of the pre-formed antibody, complement is activated immediately and severe damage to the endothelium ensues. Complement split product chemoattractants cause an influx of neutrophils and other leukocytes. The coagulation cascade is also initiated. The implanted grafts can turn dark and stop functioning before the surgeon's eyes. Histologically, hyperacute rejection is characterized by diffuse hemorrhage, transmural vascular inflammation and thrombosis, and abundant neutrophils. Thankfully, hyperacute rejection is vanishingly rare today thanks to more precise tissue typing methodologies and better graft-recipient matching practices.
Acute AMR: generally refers to a clinically significant (with graft dysfunction) episode of AMR either occurring shortly after transplantation or else as an abrupt change after a period of stable graft function. It is generally assumed (though not yet data supported) that these episodes are associated with high titers of anti-donor antibodies and that immunopathologic and morphologic features of AMR are more often present with this form. When all the features are present, this is the type of AMR for which there is greatest consensus and agreement.
Subclinical AMR: When immunopathologic and/or histopathologic, and/or donor specific antibody studies indicate AMR, but there is no graft dysfunction by clinical or imaging studies. This has also been referred to as silent, latent, or asymptomatic AMR. This situation is the source of some controversy and the implications for short and long term prognosis (and therefore the most appropriate treatment approach) are not clear. Many assume that the statistical association between AMR (defined variably in different studies) and Cardiac Allograft Vasculopathy (CAV) is explained by ongoing endothelial injury in subclinical AMR. Conclusive data supporting this are lacking.
Late AMR /Recurrent AMR: This refers to an AMR episode (with or without graft dysfunction) occurring either for the first time or as a recurrent episode at some significant duration after transplantation (often a year or more) or after a significant interval since the last AMR episode. Though not data supported, there is an assumption that this form of AMR results from de novo or latent memory type immune recognition of the graft rather than pre-formed antibody or presensitization. There is mounting evidence that AMR episodes occurring after the first year post-transplant almost always occur in patients who had some evidence of AMR shortly after transplant (or would have if studies had been done). Retrospectively staining an early biopsy for C4d may help clarify this if the question ever arises in a given patient.
Chronic AMR: This is a more nebulous term that has been used to define several different conditions. In some reports it is used synonymously with CAV, without respect to ISHLT WF features of AMR. Others have used the term to describe the scenario of late or recurrent AMR (as above) - equating acute with shortly after transplant and chronic with longer after transplant. This term has also been used to refer to morphologic findings seen at autopsy or explant (and less reliably in biopsies), often associated with CAV, in which there is increased fibrosis, reduced capillary density, and ultrastructural changes in capillary basement membranes. Complement staining is often negative when these changes are seen, but these patients frequently have had positive staining in the past. Clinically, there may be ventricular stiffening (diastolic failure) and a high incidence of sudden arrhythmic cardiac death. This entity is not well understood and not widely agreed upon.
Incorporating pathologic AMR diagnosis into the clinical picture
The 2013 ISHLT WF defines biopsy-based pathologic AMR , but this is only one factor in the clinical diagnosis and treatment of AMR. The presence of DSA, imaging and hemodynamic assessments of graft function, and other signs and symptoms of graft failure must all be considered by the clinical team. This integration is fundamental for patient management but challenging and remains open to debate between centers. One of the primary controversies revolves around treating patients with "asymptomatic/subclinical" AMR. In these patients with normally functioning grafts, the risk of intensifying immune suppression (further predisposing to infections and neoplasms) must be weighed against the potential benefit of preventing later cardiac allograft vasculopathy (CAV) and other complications.
An online survey of 184 ISHLT members showed greatest agreement for treating AMR with graft dysfunction regardless of pathologic AMR severity. Most centers also would treat AMR if DSA was present, with or without graft dysfunction and with any degree of pathologic AMR severity. In the absence of both graft dysfunction and DSA, pAMR1 would be treated by 30% of respondents, pAMR2 by 50% of respondents, and pAMR3 by 70% of respondents, so pathologic AMR (link for pAMR definitions below) is not entirely ignored.
Approaches to AMR surveillance
Unlike cellular rejection, AMR requires multiple inputs (histology, immunopathology, serum donor specific antibody (DSA) testing, and clinical measures) for diagnosis and treatment. These additional tests add expense and complexity, so their use in coordinated AMR surveillance strategies has varied from center to center. AMR surveillance strategy planning must account for the fact that individual morphologic, immunopathologic, serologic, and clinical features of AMR fluctuate over time and may not always coincide. The 2013 ISHLT WF recommends assessing all biopsy for AMR by histopathology, and outlines 3 indications for adding biopsy immunopathology:
The ISHLT WF also recommends an AMR surveillance schedule for biopsies in the 1st year after transplant:
The ISHLT WF also cautions about immunopathology at < 2 weeks since perioperative ischemic injury and other changes may cause false positive results. It also recommends more frequent testing for any patients with positive immunopathology; continuing on all biopsies until negative results are seen. Biopsies should ideally be spaced 2 weeks apart, given the clearance kinetics of complement staining. Since AMR may occur after the 1st year as well, many centers continue AMR surveillance into subsequent years, but this is not addressed in the 2013 ISHLT WF.
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