What are the salient histopathological features in Antibody-Mediated Rejection (AMR)?

From the Guidelines

The salient histopathological features in Antibody-Mediated Rejection (AMR) include C4d deposition along peritubular capillaries, microvascular inflammation, and the presence of complement components such as C3d, which are critical for diagnosing AMR. These features are characterized by the presence of C4d and C3d, which are complement split products that bind covalently to endothelium at the site of complement activation, as noted in a study published in Circulation in 2015 1. The histological changes of AMR may be seen in any vessel type, but C4d deposition is largely restricted to capillaries, with occasional staining of large-vessel endothelium, perimyocytes, or sarcolemma, although these patterns do not appear to indicate AMR 1. Some key points to consider in the diagnosis of AMR include:

• C4d positivity is used frequently to diagnose AMR, and some authors suggest that C4d can be used as an immunopathologic surrogate for AMR 1
• The combination of C4d and C3d detected by immunofluorescence predicts graft dysfunction and mortality better than C4d alone 1
• The presence of C3d, a complement split product, is also used to diagnose AMR, and it indicates progression of complement activation 1
• Histological changes of AMR may be seen in any vessel type, but C4d deposition is largely restricted to capillaries 1. Overall, the diagnosis of AMR relies on a combination of histological features, including C4d deposition, microvascular inflammation, and the presence of complement components, as well as clinical graft dysfunction and circulating donor-specific antibodies.

From the Research

Histopathological Features of Antibody-Mediated Rejection (AMR)

The salient histopathological features of AMR include:

• Microvascular inflammation, such as glomerulitis and peritubular capillaritis 2
• Thrombosis or neutrophils or mononuclear leukocytes in capillary lumens 3
• Edema, hemorrhage, necrosis, mild inflammation, and neutrophils or mononuclear leukocytes in the peritubular capillary lumens 3
• Thrombosis, thrombotic microangiopathy, fibrinoid necrosis, or transmural vasculitis in blood vessels 3
• Strong staining for C4d in the peritubular capillaries, which is characteristic of AMR 3, 4
• Transplant glomerulopathy (TG) and peritubular capillary basement membrane multilayering (PTCBMML) in chronic active AMR (CAAMR) 2

Diagnostic Criteria for AMR

A definitive diagnosis of AMR requires:

• Morphologic evidence of acute tissue injury 3
• Immunopathologic evidence for antibody action, such as C4d staining 3, 4
• Serologic evidence of circulating donor-specific antibodies 3, 5 In the absence of all three criteria, AMR should be suspected if some but not all criteria are met 3

Organ-Specific Features of AMR

AMR can occur in various organs, including:

• Kidney: characterized by microvascular inflammation, thrombosis, and C4d staining 3, 2, 5
• Liver: characterized by biliary obstruction-like features, C4d staining, and donor-specific antibodies 4
• Lung: characterized by microvascular inflammation, C4d staining, and acute lung injury 6