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268 Elizabeth J. Brant, Julie G. McGregor, J. Charles Jennette et al.

glomerulonephritis. However, presentation can be influenced to some extent by the type of
disease be it GPA or MPA, as well as, duration of disease prior to presentation. In terms of
kidney involvement, both GPA and MPA can present with severe kidney failure, at times
requiring dialysis. EGPA less commonly involves the kidneys, and when it does, kidney
disease tends to be less severe than in GPA or MPA. Dysmorphic hematuria with or without
red blood cell casts, proteinuria, and an elevated creatinine are all clues to the diagnosis.
Proteinuria is typically within the nephritic range (<3g/day), but nephrotic-range proteinuria
does not exclude the diagnosis. Kidney disease can occur absent other clinical manifestations.

Laboratory Diagnosis

Any testing for AAV begins with clinical suspicion of disease. This typically prompts
non-specific studies, such as blood tests and urine microscopy, to look for elevated creatinine
and dysmorphic hematuria with or without red blood cell casts, respectively, as evidence of
kidney involvement. Similarly, chest radiograph or computed tomography (CT) may be used
to screen for pathological changes if present. In those with otolaryngologic symptoms,
endoscopic examination with biopsy is preferred, followed by more specific avenues of
investigation if necessary. Tissue biopsy is the gold standard for diagnosis of AAV. In the
acute setting, the lesion common to all affected tissues is segmental inflammation with
fibrinoid necrosis (Figure 1), often with accompanying neutrophil infiltration initially,
followed in quick succession by mononuclear leukocyte infiltration [59, 60]. As disease
progresses, the lesions become sclerotic. The finding of pauci-immune necrotizing crescentic
glomerulonephritis strongly supports a diagnosis of AAV. However, lesions can be detected
at various stages of development, so mild segmental fibrinoid necrosis with or without an
adjacent crescent is common (Figure 1). If the acute lesion is severe, the glomerular tuft may
have global necrosis with a circumferential crescent. In patients with granulomatous disease,
GPA and EGPA, granulomatous inflammation most often affects the respiratory tract,
including the lungs, rather than the kidneys, and is present concomitantly with small-vessel
vasculitis. Lesions appear histologically as necrotic zones with surrounding mixed cellular
infiltrate of neutrophils, lymphocytes, monocytes, macrophages, and often multinucleated
giant cells. Eosinophils may also be present, but are more obvious, although not
pathognomonic, in EGPA.

Anti-neutrophil cytoplasmic autoantibodies, first described by Davies and colleagues
[61], have become routine in the diagnostic armamentarium of AAV. Treatment should not be
delayed while awaiting results. A serologically-negative form of AAV is recognized in which
current clinical assays do not detect MPO-ANCA or PR3-ANCA. By using highly sensitive
epitope excision with mass spectrometry, Roth and coworkers identified a single small linear
MPO epitope with high pathogenicity that was undetectable by usual assays due to
obfuscation in serum by ceruloplasmin, the endogenous inhibitor of myeloperoxidase activity
[62].

Patients presenting with clinical signs and symptoms consistent with disease, but who are
serologically negative, may have this or another as yet unidentified epitope that is not readily
detected by currently available means. There are ANCA that occur in healthy individuals in
very low titer that are not detected by routine serologic assays [63]. These are considered

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