A NCA disease: pathology

1. ANCAdisease: 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. Necrotizingcrescentic 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 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

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

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

28. Comparison of histologic changes in the first renal biopsy and rebiopsies of 38 patients with ANCA vasculitis

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. Biopsyreportschemafor 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)

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