Vessel Size and Associated Diseases

Large-Vessel Vasculitis (Aorta, Major Branches) - Takayasu arteritis (large arteries in young women; Asian predominance) - Giant cell (temporal) arteritis (>50 years; cranial vessels) - Polyarteritis nodosa (medium, not typically glomerulonephritis) - Renal involvement: Uncommon in glomerulonephritis; more often renal artery stenosis

Medium-Vessel Vasculitis - Polyarteritis nodosa (PAN) — small to medium arteries, NOT glomerulonephritis - Kawasaki disease (medium arteries in children; Japan) - Renal involvement: Uncommon glomerulonephritis; more often renal artery disease

Small-Vessel Vasculitis (Glomeruli, Arterioles, Small Arteries)

Focus of this handout: ANCA-associated vasculitis, anti-GBM disease, and C3-complement-mediated diseases.

Definition and Epidemiology

ANCA-associated vasculitis (AAV) is a pauci-immune, systemic, small-vessel necrotizing vasculitis characterized by: - Circulating ANCA (antineutrophil cytoplasmic antibodies) - Glomerulonephritis (necrotizing, pauci-immune pattern on immunofluorescence) - Pulmonary and systemic involvement depending on ANCA subtype

Incidence: 10–15 per million per year in Northern Europe/North America

Age of onset: Bimodal (peaks at 40–50 and 60–70 years)

Three Main Forms of AAV

Pathophysiology of AAV

ANCA-Antigen Interaction and Neutrophil Activation:

1. ANCA production: Immune response to ANCA antigens (PR3 in GPA, MPO in MPA/EGPA) generates circulating ANCA IgG
2. Neutrophil activation: ANCA binds to PR3/MPO on neutrophil surface (or in cytoplasm)
3. Complement activation: IgG-ANCA-antigen complexes activate classical complement cascade
4. Neutrophil degranulation: Activated neutrophils release proteases, ROS → endothelial damage
5. Vasculitis cascade: Endothelial injury → vessel wall necrosis, fibrinoid necrosis, crescents

Key point: Pauci-immune pattern means minimal Ig and complement deposits on immunofluorescence (despite circulating ANCA); deposits are scanty because most damage is from cellular mechanisms (ANCA-activated neutrophils), not immune complexes.

Diagnostic Approach to AAV

Suspected AAV (RPGN, upper resp, pulm hemorrhage)
  ↓
ANCA testing (by immunofluorescence + ELISA)
  ├─ c-ANCA/PR3 positive → GPA likely
  ├─ p-ANCA/MPO positive → MPA or EGPA (differentiate by clinical context)
  ├─ p-ANCA/ANCA-negative → Seronegative AAV or alternative diagnosis
  └─ If ANCA positive → Kidney biopsy to confirm

Definition and Epidemiology

Anti-GBM disease is a rare, autoimmune, small-vessel vasculitis characterized by: - Circulating anti-glomerular basement membrane (anti-GBM) antibodies (IgG) - Linear IgG deposition along the basement membrane of kidneys (and sometimes lungs, skin) - Rapidly progressive glomerulonephritis

Prevalence: Rare; <1% of glomerulonephritis cases; ~1 per 10 million per year

Age of onset: Young adults (20–30 years); can occur at any age

Male predominance: Slight (M:F = 1.2:1)

Forms of Anti-GBM Disease

Pathophysiology

Anti-GBM Antibody and Basement Membrane Attack:

1. Immune response to NC1 domain of alpha-3 chain of collagen IV (major component of GBM)
2. IgG anti-GBM antibodies bind to epitope on GBM and alveolar basement membrane
3. Linear IgG deposition along full length of GBM (pathognomonic pattern)
4. Complement activation: IgG-antigen complexes fix classical complement (C1q)
5. Membrane attack complex (C5b-9): Forms in basement membrane; creates pores, causes cell lysis
6. Neutrophil infiltration: Complement-driven recruitment of neutrophils → additional injury
7. Basement membrane rupture: From acute inflammation; creates crescents (fibrin, cells)

Result: Rapidly progressive glomerulonephritis with crescent formation; can cause ESRD within days to weeks if untreated.

Clinical Presentation

Renal manifestations: - Hematuria: Often visible; dark/cola-colored urine - Dysmorphic RBCs and RBC casts: Glomerular bleeding - Proteinuria: Usually mild (<1–2 g/day, less than immune complex GN) - Rapidly rising creatinine: RPGN pattern; Cr may double in days - Hypertension: Common; from fluid retention and HTN cascade

Pulmonary manifestations (Goodpasture): - Hemoptysis: Coughing up blood (can be bloody sputum or massive bleeding) - Dyspnea: From pulmonary hemorrhage and pulmonary edema - Chest pain: From pleural involvement - CXR findings: “Bat-wing” or diffuse infiltrates (alveolar hemorrhage) - Hypoxemia: From V/Q mismatch (blood in alveoli)

Systemic manifestations: - Constitutional: Fever, malaise, fatigue (from acute inflammation) - Joint pain: Arthralgia (less common than vasculitis) - Skin involvement: Rare; maculopapular rash - Notably ABSENT: Upper respiratory involvement (unlike GPA), granulomas, eosinophilia

Diagnostic Approach to Anti-GBM Disease

Suspected anti-GBM (pulmonary-renal, RPGN)
  ↓
Anti-GBM serology (ELISA)
  ├─ Anti-GBM positive → Very likely anti-GBM disease
  ├─ Anti-GBM negative → Kidney biopsy needed
  └─ Kidney biopsy confirms (linear IgG pattern)

Definition and Classification

C3 glomerulopathy (C3GN) is a group of glomerular diseases characterized by: - Predominant C3 deposition on immunofluorescence (without significant Ig co-deposition) - Dysregulation of alternative complement pathway - Progressive glomerulonephritis (hematuria, proteinuria, declining GFR)

Previously classified as: MPGN (membranoproliferative GN) Type II or III

Current classification (2013 update): C3 glomerulopathy is now distinguished from immune complex MPGN because pathophysiology is complement-driven, not Ig-driven.

Subtypes:

Focus: C3GN and DDD (acquired vs. genetic factors).

Pathophysiology of C3 Glomerulopathy

C3 Glomerulonephritis (C3GN)

Definition: C3GN is a glomerular disease with isolated or dominant C3 deposits without significant Ig on immunofluorescence.

Pathology: - Light microscopy: Proliferative glomerulonephritis - Endocapillary or membranoproliferative pattern - Cellularity with hypercellularity (endocapillary expansion) - Possible crescent formation (crescentic variant) - Immunofluorescence: C3-dominant or isolated C3 deposits - Granular pattern in capillary wall and mesangium - Minimal or NO IgG, IgA, IgM (distinguishes from immune complex disease) - Possible C1q, C4 (if classical pathway contribution) - Electron microscopy: - Electron-dense deposits in subendothelial space (in glomerular capillary wall) - Possible hump-like subepithelial deposits (post-infectious picture) - Possible organized dense material

Clinical presentation: - Hematuria: Microscopic or gross; RBC casts - Proteinuria: Mild to nephrotic range - Hypertension: Common; from glomerulonephritis - Progressive renal insufficiency: Decline in GFR over months to years - Age: Can occur at any age; both children and adults - Course: Variable; some progress to ESRD, others stable

Prognosis without treatment: - ~50% progress to ESRD within 10 years - Worse prognosis if: heavy proteinuria, crescents, Factor H mutations, Factor H autoantibodies

Dense Deposit Disease (DDD) — Formerly MPGN-IC Type II

Definition: DDD is a severe form of complement-mediated GN with characteristic “ribbon-like” electron-dense intramembranous deposits on electron microscopy.

Pathology: - Light microscopy: Membranoproliferative pattern - Increased mesangial cellularity - Capillary wall thickening (double contour/“tram-track”) - Possible crescents (more severe) - Immunofluorescence: C3-dominant (often isolated C3, may have minimal Ig) - Granular pattern; more prominent than in C3GN typically - Electron microscopy (diagnostic): - “Ribbon-like” or “organized,” electron-dense deposits - Located in intramembranous location (within the glomerular basement membrane) - Highly organized, often described as “organized” or “ribbon-like” appearance - This appearance is DIAGNOSTIC for DDD (formerly called MPGN-IC Type II)

Clinical features: - More aggressive than C3GN: Earlier progression to ESRD - Genetic basis common: Factor H mutations, Factor H autoantibodies, C3 mutations - Post-infectious: Can follow infection (post-streptococcal), though true DDD often has genetic basis - Age: Often in children/young adults; can occur at any age - Prognosis: ~50% ESRD within 5 years if untreated

Recurrence post-transplant: Very high recurrence rate (especially Factor H mutations); requires monitoring and preventive strategies.

Diagnostic Algorithm: Which Test First?

Suspected Glomerulonephritis (hematuria, RBC casts, proteinuria, rising Cr)
  ↓
Urinalysis (hematuria + RBC casts confirm GN)
Serum Cr, BUN (assess renal function)
  ↓
Rapid Serologic Screening:
  ├─ ANA (for lupus nephritis)
  ├─ ANCA (c-ANCA/PR3, p-ANCA/MPO for AAV)
  ├─ Anti-GBM (for anti-GBM disease)
  ├─ Anti-dsDNA, anti-Smith (if ANA positive, for lupus)
  ├─ Complement levels (C3, C4)
  ├─ Cryoglobulins (if appropriate)
  └─ ABO/Rh typing (if post-infectious suspected)
  ↓
Kidney biopsy (if diagnosis unclear from serology + clinical context)

Serologic Pattern Interpretation

Complement Protein Interpretation

Normal levels: - C3: 90–180 mg/dL - C4: 10–40 mg/dL

Low C3 + Low C4: - Classical pathway activated (IgG/IgM immune complex formation) - Diagnoses: Lupus nephritis, post-streptococcal GN, cryoglobulinemia, MPGN-Type I (IC) - Mechanism: Immune complexes consume classical pathway components (C1q, C4, C2); C3 consumed as substrate

Low C3 + Normal C4: - Alternative or lectin pathway activated (or classical pathway but more selective C3 consumption) - Diagnoses: C3GN, DDD, post-infectious GN with alternative pathway amplification - Mechanism: Alternative pathway (lacks C1q, C4) is dysregulated; C3 consumed; C4 spared

Normal C3 + Low C4: - Selective C4 consumption (unusual) - Consider: Early disease, activation via lectin pathway only, or laboratory artifact

Normal C3 + Normal C4: - Complement not significantly activated (or assays obtained late, after consumption resolved) - Consider: Early GN, IgA vasculitis (low complement uncommon), ANCA-associated vasculitis (pauci-immune, no significant complement deposition)

Acute AAV (ANCA-Associated Vasculitis)

Induction Therapy (remission induction, first 3–6 months):

Standard regimen: 1. High-dose corticosteroids: - IV methylprednisolone 500–1000 mg daily × 3 days, then - Prednisone 1 mg/kg daily (max 80 mg), tapered over weeks–months 2. Immunosuppression: - Cyclophosphamide (for severe/renal disease): - Pulse IV cyclophosphamide 500–1000 mg/m² monthly × 3–6 months OR - Oral cyclophosphamide 2 mg/kg daily - Monitor CBC; adjust for myelosuppression - Mesna (uroprotective agent) to prevent hemorrhagic cystitis - Rituximab (alternative, increasingly preferred): - IV infusions 375 mg/m² weekly × 4 weeks OR - 1000 mg IV × 2 doses 2 weeks apart - Less myelosuppression; preferable in older patients, reproductive concerns 3. Plasma exchange (for severe pulmonary hemorrhage, rapidly rising Cr, oliguria): - Daily or alternate-day plasma exchange × 7–14 sessions - Goal: Remove ANCA, immune complexes, inflammatory mediators

Maintenance Therapy (remission maintenance, months 6–24+): - Azathioprine 1.5–2 mg/kg daily or - Mycophenolate mofetil 1000–1500 mg BID or - Rituximab maintenance (re-dosing every 6–12 months) - Low-dose prednisone (taper goal: 0.1–0.2 mg/kg by 3–4 months)

Adjunctive measures: - Prophylactic antibiotics: Trimethoprim-sulfamethoxazole (TMP-SMX) reduces relapse risk (probably via Pneumocystis prophylaxis or anti-Staphylococcus effect) - Renal replacement therapy: If oliguric/anuric ARF, initiate dialysis early (does not preclude recovery) - Blood pressure control: ACE-I/ARB for reno-protection - Monitoring: ANCA titers (relative), CBC, CMP, LFTs (monthly during induction; periodic during maintenance)

Prognosis of AAV with treatment: - Remission rate: 70–90% with current regimens - Complete remission: 50–70% achieve ANDA-negativity - Relapse rate: 20–50% within 5 years; managed with re-induction - ESRD incidence: 10–20% if creatinine >3 mg/dL at diagnosis; lower if early recognition and treatment

Anti-GBM Disease

Urgent treatment required (can progress to dialysis-dependent ESRD in days):

Induction Therapy: 1. Plasma exchange: IMMEDIATE initiation - Daily plasma exchange × 10–14 sessions (or until anti-GBM serology negative) - Goal: Remove circulating anti-GBM antibodies - Urgent: Should begin within hours of diagnosis (any delay → progressive irreversible injury) 2. Corticosteroids: - IV methylprednisolone 500–1000 mg × 3 days, then - Prednisone 1 mg/kg daily, tapered over weeks–months 3. Immunosuppression: - Cyclophosphamide 2 mg/kg daily OR - Rituximab (increasingly used; may be superior to cyclophosphamide) - Goal: Suppress anti-GBM antibody production from B cells/plasma cells

Duration: - Continue plasma exchange until anti-GBM serology negative (usually 7–14 sessions) - Continue corticosteroids and immunosuppression × 3–6 months (similar to AAV) - Maintenance therapy: Azathioprine or mycophenolate for 12–24 months

Prognosis: - If treated urgently: Can prevent progression to ESRD in ~70% if Cr <3 mg/dL at diagnosis - If creatinine >3 mg/dL or oliguric at diagnosis: Only 10–20% recover renal function despite aggressive treatment - Pulmonary hemorrhage: Can be life-threatening; controlled with plasma exchange + steroids + immunosuppression - Recurrence: Rare (<5%) with adequate B-cell suppression

C3 Glomerulopathy (C3GN and DDD)

Current management (Evidence evolving):

First-line (supportive care): - ACE-I/ARB: To reduce proteinuria and slow progression - Blood pressure control: Target <120/80 or lower if tolerated - Statin: Possible pleiotropic effects (anti-inflammatory) - Prophylactic antibiotics (TMP-SMX): May reduce proteinuria/progression (controversial)

If progressive (rising Cr, heavy proteinuria, crescents): - Corticosteroids: Pulse methylprednisolone or oral prednisone - Immunosuppression (limited evidence): - Mycophenolate mofetil: 1000–1500 mg BID (some benefit in case series) - Cyclophosphamide: If rapidly progressive - Rituximab: Early data suggest benefit in Factor H-associated disease - Plasma exchange: If severe/rapidly progressive (potential benefit in some cases)

Targeted therapy (emerging): - Factor H (recombinant): For Factor H deficiency (rare; experimental) - Anti-C5 monoclonal (eculizumab, C5 inhibition): Shows promise in Factor H-associated and Factor H autoantibody disease (some case series; larger trials ongoing) - Factor D inhibitor: Blocks alternative pathway activation (experimental) - Factor B inhibitor: Blocks C3 convertase formation (experimental)

Transplantation considerations: - High recurrence rate: Especially DDD and Factor H-associated disease - Preventive measures: Some centers use prophylactic plasma exchange, immunosuppression, or complement-inhibition post-transplant - Outcome: Recurrence does not necessarily preclude graft survival; monitoring and management can prevent total graft loss

Related Student Handouts

• Nephritic and Nephrotic Syndromes
• Lupus Nephritis
• IgA Nephropathy
• Glomerular Treatment Principles
• Kidney Biopsy Essentials
• Immunosuppressive Therapy in Nephrology

Clinical Content (01-Clinical-Medicine/Nephrology)

• Glomerular Diseases Hub
• Essential Renal Laboratory Tests

Butler-COM Resources

• Butler COM - Nephrology Deep Dive

End of Handout

Last updated: 2026-02-12 | For medical students and residents in nephrology, internal medicine, and immunology