Untitled - Roche Trasplantes

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PROTOCOL BIOPSIES AND THE DIAGNOSIS OF HUMORAL REJECTION • Clinical evidence of acute allograft dysfunction. • Histological evidence of acute allograft injury, i.e. neutrophils, macrophages, or thrombi in capillaries (peritubular and/or glomerular capillaries), fibrinoid necrosis of arterioles, acute tubular injury. • Immunological evidence for the action of antibodies, i.e., C4d deposition in peritubular capillaries, or antibodies or C3 in arteries. • Serological evidence of donor-specific-antibodies at the time of biopsy. At least three of the four criteria should be given to make the diagnosis of acute humoral rejection. In this setting the biopsy has a central role since it can provide two (specific pathology and C4d) of the four diagnostic criteria. In this setting diagnostic pioneer work was done by Feucht and colleagues already in the early nineties. This group was the first to describe C4d as an in situ marker of acute antibody-mediated rejection in renal allografts showing a highly significant correlation to the presence of donor-specific antibodies in the patient’s serum. However, it took more than a decade to finally implement the entity of AHR, although the characteristic morphological changes of antibodymediated allograft injury were well described by several groups, mostly from cases of hyperacute rejection in pre-sensitized patients with high titers of preformed antibodies. These pathological features comprise capillary congestion with neutrophils and/or macrophages (=capillaritis), glomerulitis, microthrombi, fibrinoid arterial necrosis, and acute tubular necrosis. Rarely all features are present simultaneously. From our experiences the most frequent morphological findings in C4d positive biopsies are acute tubular injury and capillaritis (Figure 1), followed by glomerulitis (Figure 2), whereas microthrombi and fibrinoid arterial necrosis are very rare nowadays. The up-date of the Banff classification recommends a C4d stain to be obligatory for all renal allograft biopsies. However, the consecutively published incidence of C4d detection in renal allograft biopsies by immunohistochemistry and immunofluorescence varies between 21-51% in various transplant centers. Herewith the incidence is higher in biopsies with simultaneous signs of acute cellular rejection than in those without. A retrospective multicenter study conducted in three European transplants centers revealed that differences in the percentage of pre-sensitized, mostly re-transplanted patients is one explanation for a variable incidence of C4d detection. Furthermore, up to date no internationally accepted cut-off levels to call a case C4d positive by immunohistochemistry or immunofluorescence are established, and therefore, methodological issues might explain for different incidences in C4d-positive cases as well. In contrast, criteria defining the specificity of a C4d stain as a marker of AHR are exactly defined by the Banff community for frozen as well as paraffin-embedded tissue sections: 53
BIOPSIA DE PROTOCOLO EN EL TRASPLANTE RENAL Figure 1. Capillaritis in a case with acute humoral rejection. Peritubular capillaries (arrow) are crowded by neutrophils and mononuclear cells, mostly macrophages. • Only a linear circumferential staining pattern at the endothelial site of peritubular capillaries should be considered as a specific stain (Figure 3). • Only peritubular capillaries of cortex and medulla in non-scared and non-necrotic areas should be evaluated. • Staining intensity is not relevant in paraffin sections, but intensive, diffuse staining pattern should be present in frozen sections to be regarded as specific. • In frozen section glomeruli are always positive and can therefore serve as internal controls, but have to be regarded as non-specific concerning the diagnosis of acute humoral rejection. • Membranous glomerulonephritis is suitable as positive control for immunohistochemistry in paraffin sections, while in allograft biopsies without acute humoral rejection glomeruli are negative in formalin fixed specimens. 54
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