A NCA disease: pathology

AANCANCA disease: disease: pathologypathology

Dušan Ferluga

Institute of Pathology, Faculty of Medicine, University of Ljubljana

Ljubljana, Slovenia

SSystemic vasculitidesystemic 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 vasculitidesSmall 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

NeNecrotizingcrotizing crescentic crescentic glomerulonephritisglomerulonephritis (NC-GN) (NC-GN)

• Focal (<50%) or diffuse (>50%)

• Isolated (primary), in systemic vasculitides, in autoimmune connective tissuee diseases

• Immunopathogenetic categories:1. Immune complex NC-GN 98/285 – 34,4%2. Anti-GBM NC-GN 40/285 – 14,0% 3. Pauci-immune ANCA NC-GN 147/285 – 51,6%

Significance of kidney biopsy in Significance of kidney biopsy in ANCA diseaseANCA 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 Histopathologic hallmarks of ANCA glomerulonephritis / ANCA glomerulonephritis /

vasculitisvasculitis

• Pauci-immune pattern by immunofluorescence• Fibrinoid necrosis• Extracapillary crescents without significant

glomerular proliferation• Residual scarring glomerulosclerosis

(segmental, global)

CD68

Clinico-pathologic diagnosis in Clinico-pathologic diagnosis in 135 patients with ANCA renal disease135 patients with ANCA renal disease

Diagnosis PR3-ANCA

(n=55)

MPO-ANCA

(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

Significance of kidney biopsy in Significance of kidney biopsy in differential diagnosis of ANCA differential diagnosis of ANCA

vasculitidesvasculitides

• 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 Renal histologic changes in 135 patients with ANCA-associated GNwith ANCA-associated GN

Histologic changes

PR3-ANCA

(n=55)

MPO-ANCA

(n=74)

Other ANCA antigens

(n=6)

GN focal - diffuse 31 - 24* 18 - 56* 4 - 2

Glom necrosis 1.8 ± 1.3* 1.3 ± 1.2* 0.8 ± 0.9

Glom exud react 1.2 ± 1.2 0.8 ± 0.9 0.5 ± 0.8

Crescents 38.5% 43.6% 37.5%

Glob GSCL 11.5%* 24.0%* 17.7%

Seg GSCL 7.0%* 13.9%* 4.2%

Interst fibrosis 1.3 ± 1.1* 2.2 ± 1.2* 2.2 ± 1.0•P<0.05Vizjak A et al. Am J K id Dis 2003

Selected demographic and clinical data Selected demographic and clinical data of 135 patients with ANCA-associated GNof 135 patients with ANCA-associated GN

Feature PR3-ANCA

(n=55)

MPO-ANCA

(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 (µmol/L)

368.9 455.9 361.3

Duration of disease (months)

14.8 8.5 16.8

Duration of renal disease (months)

3.0* 6.9* 3.6

*P<0.05

Vizjak et al. Am J Kid Dis 2003

Comparison of histologic changes in the Comparison of histologic changes in the first renal biopsy and rebiopsies of 38 first renal biopsy and rebiopsies of 38

patients with ANCA vasculitispatients with ANCA vasculitisHistologic changes First renal

biopsy (n = 38)

Rebiopsies

(n = 45)

Pvalue

GN - active 11 (28.9%) 0 <0.005

- active/chronic 24 (63.2%) 16 (35.6%) <0.005

- chronic 3 (7.9%) 29 (64.4%) <0.005

Glom necrosis 1.7 ± 1.1 0.3 ± 0.6 <0.005

Extracap crescents 47.2 ± 24.1 18.6 ± 23.7 <0.005

Glob GSCL 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

Significance of kidney biopsy in ANCA Significance of kidney biopsy in ANCA diseasedisease

• 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 Inclusion Criteria

Focal ≥50% normal glomeruli

Crescentic ≥50% glomeruli with cellular crescents

Mixed <50% normal, <50% crescentic, <50% globally sclerotic glomeruli

Sclerotic ≥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)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 Collaborators and contributorscontributors

Alenka Vizjak (immunopathology)

Anastazija Hvala (electron microscopy)

Jelka Lindič (nephrology)