Kidney nontumor
Vascular diseases-Anti-neutrophil cytoplasmic antibody (ANCA) associated renal disease
ANCA related GN (general)


Topic Completed: 1 July 2019

Revised: 3 July 2019

Copyright: 2019, PathologyOutlines.com, Inc.

PubMed Search: ANCA-related glomerulonephritis

Ana Belén Larqué, M.D., Ph.D.
Page views in 2019 to date: 341
Cite this page: Larqué A. ANCA related GN (general). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/kidneyANCArelatedgngen.html. Accessed September 18th, 2019.
Definition / general
  • Pauci-immune necrotizing crescentic glomerulonephritis related to or caused by anti-neutrophil cytoplasmic antibody (ANCA)
Essential features
  • Pauci-immune necrotizing crescentic glomerulonephritis (renal biopsy: gold standard)
  • Rapidly progressive glomerulonephritis with hematuria and proteinuria
  • Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis: granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis or renal-limited vasculitis (J Am Soc Nephrol 2010;21:1628)
Terminology
  • Pauci-immune glomerulonephritis
  • Pauci-immune crescentic glomerulonephritis
  • ANCA-associated vasculitis
ICD coding
  • ICD10: NO1.7 - rapidly progressive nephritic syndrome with diffuse crescentic glomerulonephritis
Epidemiology
Sites
  • Kidney-glomeruli
Pathophysiology
  • ANCA is a primary pathogenic factor mainly by augmenting leukocyte endothelial interactions (Mod Rheumatol 2010;20:54)
  • In vitro evidence:
    • ANCA IgG can activate cytokine primed neutrophils by interacting with myeloperoxidase (MPO) or PR3 at the surface of the cells
    • Endothelial injury by ANCA-activated neutrophils and disruption of glomerular capillary walls
    • Alternative complement pathway activation by ANCA-activated neutrophils (Nat Rev Rheumatol 2014;10:463)
Etiology
Clinical features
Diagnosis
  • Rapidly progressive glomerulonephritis clinically
  • Pauci-immune crescentic glomerulonephritis pathologically
  • Positivity for ANCA (Clin Rheumatol 2017;36:1949)
Laboratory
  • Positive ANCA test by indirect immunofluorescence plus ELISA in serum
    • Sensitivity of 80% and specificity of 96% for pauci-immune glomerulonephritis
    • Negative ANCA in ~ 20% of pauci-immune glomerulonephritis
  • Type of ANCA does not permit specific diagnosis
    • MPO ANCA most common in pauci-immune glomerulonephritis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (50 - 60%)
    • PR3 ANCA most common in granulomatosis with polyangiitis (~ 75%)
  • Other ("atypical") ANCA specificities described
    • React with lactoferrin, elastase and P-cathepsin-G in serum
    • Found in variety of conditions with chronic inflammation or infection
  • Negative ANCA associated with absence of disease activity
  • Normal complement levels in serum (Kidney Int 2000;57:846, Clin Rev Allergy Immunol 2013;45:109)
Prognostic factors
  • ~ 75% achieve remission
  • ~ 30% relapse, frequently with PR3-ANCA
  • 60 - 75% 5 year patient and kidney survival
  • Risk factors for early death
  • Pathological prognostic features
    • Number of normal glomeruli (strong predictor of renal function)
    • Active lesions are associated with renal recovery: active glomerular necrosis and crescents, higher in granulomatosis with polyangiitis
    • Chronic lesions are associated with poor renal prognosis: glomerulosclerosis higher in MPA or MPO-ANCA than in granulomatosis with polyangiitis or PR3-ANCA patients (Clin Rheumatol 2017;36:1949, Nephrol Dial Transplant 2005;20:96)
Case reports
Treatment
  • Cyclophosphamide and prednisolone to induce remission
  • Maintenance therapy with less toxic drugs such as mycophenolate mofetil, azathioprine
  • Plasmapheresis or plasma exchange in refractory cases
  • Rituximab (anti-CD20) for induction or relapses (Nat Rev Rheumatol 2014;10:484)
Microscopic (histologic) description
  • Pathological classification (J Am Soc Nephrol 2010;21:1628)
    • Focal (> 50% normal glomeruli)
    • Crescentic (> 50% cellular or fibrocellular crescents):
      • Crescents containing > 10% cellularity included
      • Fibrous crescents not counted
    • Mixed (heterogeneous glomerular lesions, none predominating as > 50%)
    • Sclerotic (> 50% global glomerulosclerosis, defined as > 80% of capillary tuft sclerosed)
  • Focal segmental fibrinoid necrosis (glomerular basement membrane is disrupted in areas of necrosis)
  • Extracapillary proliferation with the accumulation of macrophages and epithelial cells in Bowman space (Age of crescents: cellular, fibrocellular, fibrous)
  • Karyorrhectic debris and fibrin thrombi are frequently seen within the affected glomerular capillary lumens
  • Active periglomerular inflammation and rupture of Bowman capsule
  • Sometimes periglomerular granulomatous inflammation
  • Normal glomeruli usually present
  • Endocapillary hypercellularity, typical of immune complex-mediated glomerulonephritides, is lacking
  • Variable inflammation, predominantly composed of lymphocytes, histiocytes, plasma cells and sometimes brisk number of eosinophils
  • Granulomas suggest the possibility of underlying granulomatous with polyangiitis or eosinophilic granulomatous with polyangiitis
    • Note that an apparent interstitial granuloma adjacent to a disrupted Bowman capsule does not carry the same connotation
  • Vasculitis 5 - 35%
  • Involves small arteries, arterioles, capillaries, venules
  • Leukocytoclastic vasculitis pattern (neutrophils, fibrinoid necrosis)
  • Necrotizing, leukocytoclastic angiitis of the medullary vasa recta (frequently associated with interstitial hemorrhage and the presence of neutrophilic tubulitis and neutrophils within tubular lumens) (Colvin: Diagnostic Pathology: Kidney Diseases, 2nd Edition, 2015, Zhou: Silva's Diagnostic Renal Pathology, 2nd Edition, 2017)
Microscopic (histologic) images

Contributed by Ana Belén Larqué, M.D, Ph.D.
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Arterial wall with fibrinoid necrosis

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Cellular crescent

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Crescents

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Segmental fibrinoid necrosis of glomerular tufts

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Interstitial inflammation

Immunohistochemistry
  • Immunohistochemistry not used for diagnosis
  • PAS, Jones silver and trichrome are used to evaluate morphology but are not specific for the type of glomerular disease
Immunofluorescence description
  • Pauci-immune glomerular pattern (weak ≤ 1+) granular staining for IgG, IgM, IgA, C3 and C1q)
  • There is no evidence of glomerular immunodeposits
  • Active crescents and fibrinoid necrosis stain for fibrin
Immunofluorescence images

Contributed by Ana Belén Larqué, M.D, Ph.D.
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Segmental staining for fibrinogen

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Arterial wall staining for fibrinogen

Electron microscopy description
  • Electron microscopy generally contributes little, mainly recapitulating the changes seen on light microscopy
  • Subendothelial edema, microthrombosis and degranulation of neutrophils are present but immune deposits are absent (J Am Soc Nephrol 2010;21:1628)
Sample pathology report
  • Left kidney, biopsy:
    • Focal necrotizing and crescentic ANCA glomerulonephritis
      • Adequacy: adequate (cortex 80%, medulla 20%)
      • Microscopic description: Thirteen glomeruli, 5 of these exhibited crescents (one with fibrinoid necrosis), including 2 cellular crescents and 3 fibrocellular crescents. Fibrosis occupying 30% of the interstitium with minimal lymphoplasmacytic infiltrate. There was no evidence of extraglomerular arteritis.
      • Immunofluorescence microscopy: Number of glomeruli: 3. There were no deposits of IgA, IgM, IgG, C3, C1q or fibrin.
Differential diagnosis
  • ANCA-negative crescentic glomerulonephritis
    • Serologic testing for ANCA negative
  • Anti-glomerular basement membrane disease (anti-GBM)
    • Bright, linear staining of glomerular basement membranes for IgG
    • Vasculitis absent
  • Immune complex-mediated crescentic glomerulonephritis
    • 2+ or greater of Ig and complement
    • Some due to specific diseases such as lupus, cryoglobulinemia, IgA nephropathy, membranoproliferative glomerulonephritis
  • ANCA superimposed on other diseases
    • Membranous glomerulonephritis, IgA nephropathy, lupus nephritis may have crescents and necrosis due to superimposed ANCA-glomerulonephritis
  • Drug induced pauci-immune crescentic glomerulonephritis (CEN Case Rep 2016;5:188)
  • Thrombotic microangiopathies
    • Subendothelial widening along the glomerular capillaries, with endothelial cell swelling and loss of fenestration by ultrastructural examination
Board review question #1

    What is the most likely diagnosis on this biopsy?

  1. Focal segmental glomerulosclerosis
  2. Minimal changes disease
  3. Myeloma cast nephropathy
  4. Pauci-immune necrotizing and crescentic glomerulonephritis, ANCA associated
Board review answer #1
D. Pauci-immune necrotizing and crescentic glomerulonephritis, ANCA associated

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Reference: ANCA related GN (general)
Board review question #2
    Which of the following signs and symptoms are common in ANCA-related glomerulonephritis?

  1. Edema
  2. Lipiduria
  3. Nephrotic-range proteinuria
  4. Rapidly progressive renal failure
Board review answer #2
D. Rapidly progressive renal failure

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Reference: ANCA related GN (general)
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