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Pauci-immune Glomerulonephritis

Updated: Jun 7, 2023


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.

By Dr. Pravir Baxi

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:


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