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

Controversies in the diagnostic algorithm for AMR based on current ISHLT guidelines.

(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).