ANCA disease:
pathology
Dušan Ferluga
Institute of Pathology,
Faculty of Medicine, University of Ljubljana
Ljubljana, Slovenia
Systemic vasculitides
International Consensus Conference,
Chapel Hill, USA, 1993
(proposal in Arthritis&Rheumatism 1994, 37: 187-192)
- Terminology (names of diseases = diagnostic terms)
- Definition of diseases (abnormalities that warrant
assignement of the diagnostic terms)
- Diagnostic criteria? (not yet defined)
Small vessel vasculitides
• Frequent affection of kidneys (up to 100%)
Glomerulonephritis, extraglomerular
vasculitis, tubulointerstitial involvement
• Important contribution of kidney biopsy to
establish diagnosis and to evaluate
activity, chronicity and severity (extent)
• Final diagnosis clinical (immunoserology!)pathological
Necrotizing crescentic
glomerulonephritis (NC-GN)
• Focal (<50%) or diffuse (>50%)
• Isolated (primary), in systemic vasculitides,
in autoimmune connective tissuee diseases
• Immunopathogenetic categories:
1. Immune complex NC-GN
2. Anti-GBM NC-GN
3. Pauci-immune ANCA NC-GN
98/285 – 34,4%
40/285 – 14,0%
147/285 – 51,6%
Significance of kidney biopsy in
ANCA disease
To confirm diagnosis - why?
ANCA specificity and sensitivity are
not absolute.
Not all ANCA positive patients have
ANCA vasculitis and ANCA negative
results do not exclude ANCA disease.
Histopathologic hallmarks of ANCA
glomerulonephritis / vasculitis
• Pauci-immune pattern by immunofluorescence
• Fibrinoid necrosis
• Extracapillary crescents without significant
glomerular proliferation
• Residual scarring glomerulosclerosis
(segmental, global)
CD68
Clinico-pathologic diagnosis in
135 patients with ANCA renal disease
PR3-ANCA
MPO-ANCA
(n=55)
(n=74)
Other ANCA
antigens
(n=6)
Wegener’s
granulomatosis
47/56
8/56
1/56
Microscopic
polyangiitis
6/50
42/50
2/50
Renal limited
vasculitis
2/28
23/28
3/28
Churg Strauss
syndrome
0/1
1/1
0/1
Diagnosis
Significance of kidney biopsy in
differential diagnosis of ANCA
vasculitides
• Underdiagnosed extraglomerular focal
necrotizing vasculitis (5 - 35%), suggesting
systemic vasculitides, because of biopsy
sampling inspite of serial sections
• Limited significance of kidney biopsy in
distinguishing between MPA, WG and CS (limited
specificities of eosinophilic infiltration, absence
of true interstitial geographic type granulomas as
typically seen in respiratory tract)
Renal histologic changes in 135 patients
with ANCA-associated GN
PR3-ANCA
MPO-ANCA
(n=55)
(n=74)
Other ANCA
antigens
(n=6)
GN focal - diffuse
31 - 24*
18 - 56*
4-2
Glom necrosis
Glom exud react
Crescents
Glob GSCL
1.8 ± 1.3*
1.2 ± 1.2
38.5%
11.5%*
1.3 ± 1.2*
0.8 ± 0.9
43.6%
24.0%*
0.8 ± 0.9
0.5 ± 0.8
37.5%
17.7%
7.0%*
13.9%*
4.2%
1.3 ± 1.1*
2.2 ± 1.2*
2.2 ± 1.0
Histologic
changes
Seg GSCL
Interst fibrosis
•P<0.05
Vizjak A et al. Am J K id Dis 2003
Selected demographic and clinical data
of 135 patients with ANCA-associated GN
PR3-ANCA
MPO-ANCA
(n=55)
(n=74)
Other ANCA
antigens
(n=6)
Age (years)
55.9*
63.3*
63.2*
Male/female
33/22
22/52
2/4
Serum creatinine
368.9
455.9
361.3
14.8
8.5
16.8
3.0*
6.9*
3.6
Feature
(µmol/L)
Duration of disease
(months)
Duration of renal
disease (months)
*P<0.05
Vizjak et al. Am J Kid Dis 2003
Comparison of histologic changes in the
first renal biopsy and rebiopsies of 38
patients with ANCA vasculitis
Histologic changes
First renal
biopsy
(n = 38)
Rebiopsies
11 (28.9%)
24 (63.2%)
3 (7.9%)
0
16 (35.6%)
29 (64.4%)
P
value
(n = 45)
<0.005
GN - active
- active/chronic
- chronic
Glom necrosis
Extracap crescents
Glob GSCL
1.7 ± 1.1
0.3 ± 0.6 <0.005
47.2 ± 24.1 18.6 ± 23.7 <0.005
15.7 ± 15.4 39.2 ± 23.9 <0.005
Seg GSCL
9.2 ± 10.2
15.2 ± 12.3
0.016
Interstitial fibrosis
1.8 ± 1.3
2.6 ± 1.1
0.004
<0.005
<0.005
Significance of kidney biopsy in ANCA
disease
• Major significance for planning therapy,
monitoring response and detecting
recurrences.
Pathologist has to provide exact
information – quantitative data about
active therapeutically accesible lesions
(necrotizing, crescentic), about
irreversible chronic sclerotic changes, as
well as about preserved nephrons.
Classification schema for ANCA-associated glomerulonephritis
Class
Focal
Crescentic
Mixed
Sclerotic
Inclusion Criteria
≥50% normal glomeruli
≥50% glomeruli with cellular crescents
<50% normal, <50% crescentic, <50% globally
sclerotic glomeruli
≥50% globally sclerotic glomeruli
Pauci-immune staining pattern on immunofluorescence microscopy (IM) and ≥1
glomerulus with necrotizing or crescentic glomerulonephritis on light
microscopy (LM) are required for inclusion in all four classes.
(Berden, AE et al. JASN 2010; 21: 1628-36)
Biopsy report schema for ANCA glomerulonephritis (GN)
1. Focal (≤50%; indicating percentage of normal glomeruli)
1.1. Focal active (A): necrosis (%), crescents (%: cellular, fibrocellular)
1.2. Focal chronic (C): sclerosis – global (%), segmental (%), crescents (%: fibrous)
1.3. Focal active and chronic (A/C): as in 1.1+1.2.
2. Diffuse (≥50%; indicating percentage of normal glomeruli)
2.1. Diffuse active (A): necrosis (%), crescents (%: cellular, fibrocellular)
2.2. Diffuse chronic (C): sclerosis – global (%), segmental (%), crescents (%: fibrous)
2.3. Diffuse active and chronic (A/C): as in 2.1+2.2
____________________________________________________________________
*Inclusion criteria: pauci-immune GN and ≥1 glomerulus with necrosis and/or crescent
(cellular, fibrocellular, fibrous) in all six classes
____________________________________________________________________
(Ferluga D. et al. 1st MCP, Ohrid 2011)
Collaborators and
contributors
Alenka Vizjak (immunopathology)
Anastazija Hvala (electron microscopy)
Jelka Lindič (nephrology)