Untitled - Roche Trasplantes

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:
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