What is focal necrotizing perinuclear anti‑neutrophil cytoplasmic antibody (p‑ANCA) vasculitis?

What is Focal Necrotizing p-ANCA Vasculitis?

Focal necrotizing p-ANCA vasculitis refers to pauci-immune focal and segmental necrotizing glomerulonephritis associated with perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA), most commonly directed against myeloperoxidase (MPO), representing a kidney-limited or systemic manifestation of ANCA-associated vasculitis. 1

Pathologic Definition

• The kidney lesion is characterized by pauci-immune focal and segmental necrotizing and crescentic glomerulonephritis (NCGN), meaning there is minimal immune complex deposition on immunofluorescence despite severe inflammatory damage. 1

• "Focal" indicates that only some glomeruli are affected (not all), while "necrotizing" refers to fibrinoid necrosis of the capillary walls with disruption of the glomerular architecture. 1

• The p-ANCA pattern on immunofluorescence testing corresponds to perinuclear staining around the nucleus of ethanol-fixed neutrophils. 2

Antibody Specificity and Disease Association

• About 90% of patients with small-vessel vasculitis affecting the kidneys have ANCA, with p-ANCA most commonly directed against myeloperoxidase (MPO-ANCA). 1

• p-ANCA/MPO-ANCA is most strongly associated with microscopic polyangiitis (MPA), which presents as vasculitis without granulomatous inflammation. 3

• High-quality antigen-specific immunoassays (ELISA) for MPO are the preferred screening method to confirm that p-ANCA represents true vasculitis-associated antibodies rather than atypical ANCA seen in non-vasculitic conditions. 1, 4

Clinical Presentation

The renal manifestations include:

• Microscopic hematuria with dysmorphic red blood cells and red cell casts on urinalysis, indicating glomerular bleeding. 1

• Moderate proteinuria (1-3 g/day), which is less severe than nephrotic-range proteinuria. 1

• Rapidly declining glomerular filtration rate (GFR) over days to weeks, presenting as rapidly progressive glomerulonephritis. 1

• Patients may have isolated renal disease (pauci-immune focal necrotizing glomerulonephritis alone) or systemic involvement with pulmonary hemorrhage, skin lesions (palpable purpura), or other organ manifestations. 1, 5

Diagnostic Approach

• Diagnosis relies on the combination of clinical findings (rapidly progressive renal failure), positive MPO-ANCA serology, and kidney biopsy confirmation. 1

• Kidney biopsy remains the gold standard with a diagnostic yield as high as 91.5% in ANCA-associated vasculitis, showing focal necrotizing glomerulonephritis with crescent formation and minimal immune deposits. 1, 4

• However, do not delay immunosuppressive therapy while awaiting kidney biopsy when clinical presentation strongly suggests AAV with positive ANCA serology, especially in rapidly deteriorating patients. 1

Disease Classification Context

• This pathologic pattern falls under the umbrella of ANCA-associated vasculitides (AAV), which comprise granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). 3

• The focal necrotizing pattern with p-ANCA/MPO positivity most commonly indicates MPA or kidney-limited vasculitis, as opposed to GPA which is more commonly associated with c-ANCA/PR3 antibodies. 3, 6

Pathophysiologic Mechanism

• These antibodies can activate neutrophils and the complement system, resulting in vessel wall inflammation and necrotizing damage to small vessels in the kidney glomeruli. 6, 7

• The "pauci-immune" designation means there is an absence of significant immune complex or complement deposition on immunofluorescence, distinguishing it from immune complex-mediated glomerulonephritis. 1

Treatment Implications

• The American College of Rheumatology recommends immediate initiation of remission induction therapy with rituximab or cyclophosphamide plus high-dose glucocorticoids in patients with severe, organ-threatening disease. 1

• Plasma exchange should be considered in patients with severe acute kidney injury to improve renal outcomes. 1

• The presence of focal necrotizing changes on biopsy indicates active, aggressive disease requiring urgent immunosuppressive intervention to prevent irreversible kidney damage and progression to end-stage renal disease. 1, 8