**5. Stages of antibody-mediated rejection**

At a National Institutes of Health (United States) consensus conference, draft criteria were established for antibody-mediated rejection and for four theoretical stages in the development of CAMR (Takemoto et al., 2004) as shown in FIG. 1 (Colvin & Smith, 2005).

allograft biopsies, including both routine histologic evaluation and immunohistology to

Current and Future Directions in Antibody-Mediated Rejection Post Kidney Transplantation

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As pathologists have become increasingly adept at diagnosing antibody-mediated rejection (AMR) on allograft biopsies, substantial progress has been made in the treatment of AMR and in successful renal transplantation in recipients with pre-existing antibodies against donor blood group (ABO) and/or major histocompatibility (HLA) antigens. It has become critical to

The diagnostic criteria for acute humoral rejection (AMR; acute antibody-mediated rejection). Patients with AHR present with an acute loss of graft function that often arises in the first few weeks after transplantation and cannot be distinguished from cell-mediated rejection on clinical grounds (Halloran et al., 1992; Takemoto et al., 2004). AMR can also develop years after transplantation, often triggered by a decrease in immunosuppression (iatrogenic, noncompli‐ ance, or malabsorption). Presensitization is the major risk factor, but most of the patients with AMR had a negative cross-match. AMR has occurred with all immunosuppression regimens, even profoundly depleting therapy (Lorenz et al., 2004). The first clue that circulating anti– class I HLA antibody caused a different pattern of acute rejection came from the studies of Halloran's group in Edmonton (Halloran et al., 1992). These investigators showed that neutrophils in peritubular capillaries (PTC) and glomerular capillaries are strongly associated with circulating anti-donor HLA antibodies. Other features, such as fibrinoid necrosis of arteries and microthrombi, are also more common. However, none of these features is specific.

The pathology of AMR has a wide spectrum and can easily be missed by histologic criteria alone. Renal biopsies may show acute cellular rejection, acute tubular injury, or thrombotic microangiopathy. Neutrophils in capillaries are characteristically but not always found. Macrophages are now recognized as a common intracapillary cell in AMR in kidney (Tinckam et al., 2005) and heart (Lepin et al., 2006) allografts. Typically, the PTC are dilated. Fibrinoid necrosis is found in a minority of cases (approximately 10 to 20%). A component of acute cellular rejection may also be present, as manifested by a prominent mononuclear infiltrate, tubulitis, or endarteritis. These lesions are generally not attributable to antibody alone. Treg cells (FOXP3+) are rarer in the infiltrate than in cell-mediated rejection, perhaps contributing to the poorer prognosis in AMR (Veronese et al., 2007). Microthrombi and interstitial hemor‐ rhage also sometimes occur. The PTC and glomerular endothelium shows a variety of ultrastructural changes, including loss of fenestrations, detachment from the basement membrane, lysis, and apoptosis; complete destruction of capillaries can occur, leaving thickened laminated basement membranes (Liptak et al., 2005). Immunofluorescence (IF) curiously does not often show antibody or C3 deposition in the vessels. However, IF does show C4d in the majority of the PTC as a bright ring pattern, using a mAb in cryostat sections (Collins et al., 1999; Mauiyyedi et al., 2001, 2002). Immunohistochemistry (IHC) works in formalinfixed, paraffin-embedded tissues with a polyclonal antibody (Lorenz et al., 2004). By immu‐ noelectron microscopy, C4d is detected on the surface of the endothelial cells and in intracytoplasmic vesicles (Regele et al., 2002). Antibodies that react to non-C4d portions of the

develop standardized criteria for the pathological diagnosis of AMR.

detect complement split products.

**6.1. Acute antibody mediated rejection**

**Figure 1.** Proposed stages of antibody-mediated rejection (Reproduced with permission from Nature Publishing Group).

According to this model, the first evidence of an antibody-mediated response is the de novo generation of donor-reactive antibodies (stage I). In many circumstances and for unknown reasons, donor-reactive antibodies do not elicit AAMR.

The next stage (stage II) shows evidence of antibody reactivity and complement activation in the graft, with C4d deposition in peritubular or glomerular capillary endothelium. At this stage, there is no evidence of pathological or clinical injury in the graft. Both stage I and stage II fit the criteria for accommodation and are therefore not necessarily predestined to lead to graft injury. In stage III, in addition to positive staining for C4d, there are identifiable patho‐ logical changes, but graft function is still normal (that is, there is subclinical rejection). Finally, in stage IV, in addition to positive staining for C4d and pathological changes, graft dysfunction occurs. The interval between stages can be long and variable, and it is not known whether progression is inexorable (Colvin & Smith, 2005).
