1. ANCA disease: pathology Dušan Ferluga Institute of Pathology, Faculty of Medicine, University of Ljubljana Ljubljana, Slovenia

2. 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)

4. 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

5. Necrotizing crescentic glomerulonephritis (NC-GN) Focal ( 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%

10. 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.

11. Histopathologic hallmarks of ANCA glomerulonephritis / vasculitis Pauci-immune pattern by immunofluorescence Fibrinoid necrosis Extracapillary crescents without significant glomerular proliferation Residual scarring glomerulosclerosis (segmental, global)

16. CD68

19. Clinico-pathologic diagnosis in 135 patients with ANCA renal disease Diagnosis PR3-ANCA (n=55) MPO-ANCA (n=74) Other ANCA antigens (n=6) Wegener’s granulomatosis 47/568/561/56 Microscopic polyangiitis 6/5042/502/50 Renal limited vasculitis 2/2823/283/28 Churg Strauss syndrome 0/11/10/1

20. 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)

26. Renal histologic changes in 135 patients with ANCA-associated GN Histologic changes PR3-ANCA (n=55) MPO-ANCA (n=74) Other ANCA antigens (n=6) GN focal - diffuse31 - 24*18 - 56*4 - 2 Glom necrosis1.8 ± 1.3*1.3 ± 1.2*0.8 ± 0.9 Glom exud react1.2 ± 1.20.8 ± 0.90.5 ± 0.8 Crescents38.5%43.6%37.5% Glob GSCL11.5%*24.0%*17.7% Seg GSCL7.0%*13.9%*4.2% Interst fibrosis1.3 ± 1.1*2.2 ± 1.2*2.2 ± 1.0 P<0.05 Vizjak A et al. Am J K id Dis 2003

27. Selected demographic and clinical data of 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/female33/2222/522/4 Serum creatinine (µmol/L) 368.9455.9361.3 Duration of disease (months) 14.88.516.8 Duration of renal disease (months) 3.0*6.9*3.6 *P<0.05 Vizjak et al. Am J Kid Dis 2003

28. 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 (n = 45) P value GN - active11 (28.9%)0 <0.005 - active/chronic24 (63.2%)16 (35.6%) <0.005 - chronic3 (7.9%)29 (64.4%) <0.005 Glom necrosis1.7 ± 1.10.3 ± 0.6 <0.005 Extracap crescents47.2 ± 24.118.6 ± 23.7 <0.005 Glob GSCL15.7 ± 15.439.2 ± 23.9 <0.005 Seg GSCL9.2 ± 10.215.2 ± 12.3 0.016 Interstitial fibrosis1.8 ± 1.32.6 ± 1.1 0.004

29. 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.

31. 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. 1 st MCP, Ohrid 2011)

32. Collaborators and contributors Alenka Vizjak (immunopathology) Anastazija Hvala (electron microscopy) Jelka Lindič (nephrology)