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NEPHROPATHOLOGY
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: