Pauci-immune Glomerulonephritis – Nephropathology Essentials

Pauci-immune Glomerulonephritis – Nephropathology Essentials

In this GlomCon Conference Dr. Kammi Henriksen shared her expertise with us and reviewed the pathology of pauci-immune glomerulonephritis. Our Moderator’s Notes are derived from her live presentation which you can watch here: https://glomcon.org/anca/the-pathology-of-pauci-immune-gn/

Moderator’s Notes

Author: Dr. Pravir V. Baxi
Editors: Dr. Ali Poyan Mehr, Dr. Swati Arora

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: