Key points:

• Crescentic Glomerulonephritis (GN)
  • Histological marker for severe glomerular injury
    • Cellular proliferation (> 2 layers of parietal epithelial cells (=podocytes)) and inflammation within Bowman’s space
    • Disruption of the glomerular basement membranes (GBM) with fibrinoid necrosis
  • Major etiologies include: Immune complex mediated GN, Anti-GBM and Pauci-immune GN
• Pauci-immune glomerulonephritis (GN) is defined histologically by the presence of necrotizing and crescentic GN with few or no immune deposits on IF or EM
  • Most common cause of rapidly progressive GN (RPGN) especially in adults and elderly patients
  • 80-90% of pauci-immune GN cases are Anti-neutrophil cytoplasmic antibody (ANCA) positive
    • 10-20% are ANCA negative
      • Not detected in current assays; IgA ANCAs
      • Younger age, fewer extrarenal symptoms, poorer renal survival
  • ANCA vasculitis
    • Autoantibodies (typically IgG class) against lysosomal components of in neutrophils and monocytes
      • Specificity for myeloperoxidase (MPO) or proteinase 3 (PR3)
    • Pathogenesis
      • ANCAs are thought to be pathogenic: neutrophil priming by cytokines (e.g. TNF, C5a) à translocation of cytoplasmic antigens (MPO, PR3) à binding with ANCA Ab à neutrophil activation leading to endothelial injury and complement system activation
      • Triggers for ANCA production: environmental (infection and molecular mimicry), genetic predisposition (HLA Class II), defective neutrophil apoptosis, certain drugs
      • Drug-induced: propylthiouracil, hydralazine, minocycline, anti-TNF alpha, levamisole
        • Idiosyncratic, younger patients, better renal survival, high MPO titers
    • Diagnosis of ANCA vasculitis should specify the serotype and clinicopathological variant
    • Pathology
      • Does not discriminate between various clinicopathology conditions caused by ANCA
      • Glomeruli will show fibrinoid necrosis with crescents
        • Cellular (days-weeks, potentially reversible), fibrocellular (weeks) and fibrous (weeks-months)
      • Vasculature
        • Renal vasculitis in 5-35% of cases
        • Involves small arteries (interlobular > arcuate), arterioles, capillaries and venules with fibrinoid necrotizing lesions
        • Medullary angiitis: inflammation of the medullary vasa recta
          • Suggests the presence of systemic vasculitis but is not specific for ANCA GN (i.e. IgAN, cryoglobulinemic GN)
      • Granulomatous inflammation: rare in the kidney but seen more in the lung/upper respiratory tract
      • Histopathological Classification: allows for uniform reporting, prognostication and guiding treatment
        • Focal (> 50% with normal glomeruli, best renal prognosis), Crescentic (> 50% with cellular crescents), Sclerotic (> 50% globally sclerotic, worse renal prognosis)), Mixed (< 50 normal, < 50 crescents, < 50 globally sclerotic)
    • ANCA GN can be superimposed/co-existing in other diseases (i.e. LN, anti-GBM)
      • Crescents/necrosis out of proportion to immune complex deposition
      • Temporal heterogeneity of crescents/level of chronicity (i.e. anti-GBM)

• • Clinical Aspects
    • Granulomatosis with polyangiitis (formerly Wegener’s)
      • Necrotizing granulomatous inflammation primarily of lungs and nasal sinuses (saddle-nose deformity)
    • Eosinophilic granulomatosis with polyangiitis (previously Churg-Strauss)
      • Asthma, peripheral eosinophilia
    • Microscopic polyangiitis
      • Necrotizing vasculitis mostly affecting multiple sites
    • Type of ANCA does NOT permit specific diagnosis but ANCA antigen specificity is associated with disease phenotype/prognosis
      • PR3-ANCA: most often granulomatous inflammation, systemic features, higher relapse rate
      • MPO-ANCA: most often renal-limited, worse renal prognosis
    • Rough correlation of ANCA titers with response and relapse
    • 75% will achieve remission but 40% may relapse
    • Poor prognostic factors
      • Age >65, higher SCr or dialysis dependency at onset, proteinuria, higher chronic histologic indices
  • Treatment options
    • Induction: Corticosteroids with Rituximab OR Cyclophosphamide
    • Maintenance: Azathioprine OR Rituximab
    • Plasmapheresis: can be considered in severe/refractory cases however role may change with upcoming trial data (PEXIVAS)
    • Novel therapy under investigation: C5a receptor blockers

Selected References:

• https://www.ncbi.nlm.nih.gov/pubmed/28842398 2
• https://www.ncbi.nlm.nih.gov/pubmed/2683800