# ANCA-Associated Vasculitis and Renal Involvement

## Introduction

ANCA-associated vasculitis encompasses three related small-vessel necrotizing vasculitides: granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome). These diseases share the hallmark of pauci-immune glomerulonephritis, characterized by scant or absent immune deposits on immunofluorescence, distinguishing them from immune complex-mediated and anti-GBM forms of glomerulonephritis. AAV is the most common cause of rapidly progressive glomerulonephritis in adults over 50 years of age. Without treatment, mortality approaches 80 percent at 1 year, but with modern immunosuppressive therapy, 5-year survival has improved to 70 to 85 percent.

## Classification and ANCA Associations

### Granulomatosis with Polyangiitis (GPA)

Granulomatosis with polyangiitis is characterized by involvement of the upper airway, lower airway, and kidneys. Upper airway manifestations include chronic sinusitis, saddle nose deformity from nasal cartilage destruction, and subglottic stenosis. Lower airway disease presents with pulmonary nodules, cavitary lesions, and diffuse alveolar hemorrhage. Approximately 75 to 80 percent of GPA patients are positive for c-ANCA with anti-proteinase 3 (anti-PR3) specificity, while 10 to 15 percent demonstrate p-ANCA with anti-myeloperoxidase (anti-MPO) positivity. Tissue biopsy reveals necrotizing granulomatous inflammation, which is the pathologic hallmark distinguishing GPA from MPA. Renal involvement occurs at some point during the disease course in 70 to 80 percent of patients.

### Microscopic Polyangiitis (MPA)

Microscopic polyangiitis is a non-granulomatous necrotizing vasculitis in which p-ANCA with anti-MPO specificity is found in 60 to 70 percent of patients, while c-ANCA with anti-PR3 is present in 20 to 30 percent. Renal involvement is very common, occurring in 80 to 100 percent of patients and frequently serving as the presenting feature of the disease. Pulmonary manifestations include capillaritis with diffuse alveolar hemorrhage and, in some MPO-positive patients, pulmonary fibrosis in a usual interstitial pneumonia pattern. The absence of granulomatous inflammation is the key pathologic distinction from GPA.

### Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Eosinophilic granulomatosis with polyangiitis is distinguished by its association with adult-onset severe asthma, peripheral eosinophilia exceeding 10 percent or 1500 per microliter, and tissue eosinophilic infiltration. P-ANCA with anti-MPO specificity is positive in 40 to 50 percent of cases, with ANCA positivity being more common in patients with renal and peripheral nerve involvement. ANCA-negative EGPA demonstrates a predilection for cardiac involvement, including eosinophilic cardiomyopathy, which is the leading cause of mortality in this variant. Renal involvement is less common in EGPA, affecting approximately 25 percent of patients, and is generally less severe than in GPA or MPA.

| Feature | GPA (Wegener) | MPA | EGPA (Churg-Strauss) |
|---------|--------------|-----|---------------------|
| Predominant ANCA | c-ANCA/anti-PR3 (75–80%) | p-ANCA/anti-MPO (60–70%) | p-ANCA/anti-MPO (40–50%) |
| Granulomas | Yes (necrotizing) | No | Yes (eosinophilic) |
| Upper airway involvement | Sinusitis, saddle nose, subglottic stenosis | Rare | Nasal polyps, allergic rhinitis |
| Lower airway involvement | Cavitary nodules, DAH | DAH, pulmonary fibrosis (UIP) | Asthma (severe, adult-onset) |
| Renal involvement | 70–80% | 80–100% | ~25% |
| Distinctive feature | Granulomatous inflammation | Renal-dominant; non-granulomatous | Eosinophilia >1500/μL; cardiac involvement (ANCA-negative) |
| 5-year relapse rate | ~50% (PR3) | 20–30% (MPO) | Lower |

### Reclassification: PR3-AAV vs MPO-AAV

An emerging consensus supports reclassifying AAV based on ANCA specificity rather than clinical phenotype, as PR3 versus MPO status carries greater prognostic and therapeutic implications than the distinction between GPA and MPA. PR3-AAV is associated with a higher relapse rate of approximately 50 percent at 5 years and a greater prevalence of upper airway granulomatous disease. MPO-AAV demonstrates a lower relapse rate of 20 to 30 percent at 5 years but is associated with more renal-limited disease and more chronic renal damage at the time of presentation.

## Pathogenesis

### ANCA-Mediated Neutrophil Activation

The pathogenesis of AAV centers on the interaction between ANCA and primed neutrophils. In the priming step, cytokines such as TNF-alpha and IL-1, along with complement factor C5a, cause neutrophils to translocate PR3 or MPO from their cytoplasmic azurophilic granules to the cell surface. ANCA IgG then binds to these surface-expressed antigens, simultaneously engaging Fc-gamma receptors, resulting in full neutrophil activation. The activated neutrophils undergo degranulation, generate a respiratory burst producing reactive oxygen species, and release neutrophil extracellular traps. These activated neutrophils adhere to glomerular endothelium, producing necrotizing injury with fibrinoid necrosis of the capillary walls.

### Complement Activation (Alternative Pathway)

The alternative complement pathway, particularly the C5a-C5aR1 axis, plays a critical role in AAV pathogenesis. Murine models have demonstrated that C5a primes neutrophils, amplifying the ANCA-mediated activation loop and creating a self-perpetuating cycle of inflammation. This mechanistic understanding forms the basis for the therapeutic efficacy of avacopan, a selective C5a receptor inhibitor.

### Genetic and Environmental Factors

Genetic susceptibility to AAV is conferred by specific HLA associations, with HLA-DPB1 linked to GPA and HLA-DQ linked to MPA. Environmental triggers include infections, notably Staphylococcus aureus nasal carriage in GPA, where molecular mimicry with complementary PR3 may initiate the autoimmune response. Silica exposure has been identified as an occupational risk factor. Drug-induced ANCA vasculitis can be triggered by hydralazine, propylthiouracil, and minocycline, all of which predominantly induce anti-MPO ANCA.

<image>Pathogenesis diagram of ANCA-associated vasculitis showing the sequence of events in glomerular injury. Panel 1: Cytokine priming (TNF-alpha, C5a) causes neutrophil translocation of PR3 or MPO from azurophilic granules to the cell surface. Panel 2: ANCA IgG binds to surface PR3/MPO, simultaneously engaging Fc-gamma receptors, causing full neutrophil activation. Panel 3: Activated neutrophils adhere to glomerular endothelium, undergo degranulation and NET formation, releasing proteases and reactive oxygen species. Panel 4: Endothelial damage leads to fibrinoid necrosis of the capillary wall, disruption of Bowman's capsule, and crescent formation from proliferation of parietal epithelial cells and macrophages. Show the C5a amplification loop with the alternative complement pathway generating C5a that further primes neutrophils.</image>

## Renal Involvement

### Clinical Presentation

Renal involvement in AAV typically manifests as rapidly progressive glomerulonephritis, with serum creatinine rising over days to weeks and oliguria developing in severe cases. The urine sediment is active, demonstrating dysmorphic red blood cells and red blood cell casts. Proteinuria is usually in the subnephrotic range, typically less than 3 grams per day. Hypertension is variably present. The pulmonary-renal syndrome, with concurrent diffuse alveolar hemorrhage and RPGN, is a life-threatening presentation whose differential diagnosis includes both AAV and anti-GBM disease.

### Renal Biopsy Findings

Light microscopy reveals focal segmental necrotizing and crescentic glomerulonephritis with fibrinoid necrosis of the capillary walls and crescents that may be cellular, fibrocellular, or fibrous depending on the stage of disease. Immunofluorescence demonstrates the hallmark pauci-immune pattern, with no or only scant immune deposits, which distinguishes AAV from anti-GBM disease (linear IgG staining) and immune complex-mediated RPGN (granular deposits). Electron microscopy confirms the absence of electron-dense deposits and reveals endothelial injury with breaks in the glomerular basement membrane.

### Berden Histopathologic Classification (2010)

The Berden classification system categorizes renal biopsies into four prognostic classes based on the predominant histologic pattern. The focal class, defined by 50 percent or more normal glomeruli, carries the best renal prognosis. The crescentic class, with 50 percent or more cellular crescents, represents potentially reversible disease with appropriate treatment. The mixed class demonstrates a combination of normal, crescentic, and sclerosed glomeruli. The sclerotic class, defined by 50 percent or more globally sclerosed glomeruli, carries the worst renal prognosis and offers limited benefit from aggressive immunosuppression. This classification has been validated as an independent predictor of renal survival, providing critical prognostic information beyond clinical parameters such as eGFR and proteinuria.

## Diagnosis

### ANCA Testing

Direct ELISA testing for anti-PR3 and anti-MPO antibodies is now recommended as the first-line screening approach, based on the 2017 international consensus statement. Indirect immunofluorescence patterns (c-ANCA and p-ANCA) are less specific and can be positive in other conditions. Anti-PR3 or anti-MPO antibodies are positive in approximately 90 percent of AAV patients with active renal disease. ANCA-negative AAV accounts for approximately 10 percent of cases, and renal biopsy is essential for establishing the diagnosis in this subset. The role of rising ANCA titers in predicting relapse remains controversial, and current guidelines recommend against basing treatment decisions on ANCA titer changes alone.

### Differential Diagnosis of Pauci-Immune RPGN

The differential diagnosis of pauci-immune RPGN includes drug-induced AAV, which can be triggered by hydralazine, propylthiouracil, minocycline, or cocaine contaminated with levamisole. Anti-GBM disease with concurrent ANCA positivity occurs in 10 to 30 percent of anti-GBM patients, who typically carry anti-MPO antibodies and have a worse prognosis than either disease alone. Polyarteritis nodosa is a medium-vessel vasculitis that is ANCA-negative and must be distinguished from AAV.

## Treatment

### Induction Therapy

#### Rituximab + Glucocorticoids (First-Line)

Rituximab combined with glucocorticoids is the preferred first-line induction therapy for most patients with AAV, as recommended by KDIGO 2024 and ACR/VF 2021 guidelines. The RAVE trial, published in 2010, demonstrated that rituximab at 375 mg/m2 weekly for 4 doses was non-inferior to cyclophosphamide for remission induction and superior for relapsing disease. The RITUXVAS trial, also from 2010, showed that rituximab combined with 2 doses of intravenous cyclophosphamide was equivalent to standard cyclophosphamide. Concurrent glucocorticoid therapy consists of pulse methylprednisolone 500 to 1000 mg intravenously for 3 days, followed by oral prednisone at 1 mg/kg with a maximum of 80 mg, with rapid tapering.

#### Avacopan (C5a Receptor Inhibitor)

Avacopan is a selective oral C5a receptor inhibitor that targets the complement-mediated amplification loop central to AAV pathogenesis. The ADVOCATE trial, published in 2021, demonstrated that avacopan at 30 mg twice daily combined with rituximab or cyclophosphamide was non-inferior to a standard prednisone taper for achieving remission at 26 weeks and was superior for sustained remission at 52 weeks. This agent enables steroid-free or steroid-minimized induction, representing a significant advance in reducing the morbidity of chronic glucocorticoid therapy. Avacopan received FDA approval in 2021 as adjunctive treatment for AAV. It is important to recognize that avacopan does not eliminate the need for rituximab or cyclophosphamide as the backbone of induction therapy.

#### Cyclophosphamide + Glucocorticoids

Cyclophosphamide-based induction therapy can be administered as either intravenous pulses following the Euro-Vasculitis protocol, with 15 mg/kg at a maximum of 1.2 grams every 2 to 3 weeks for 3 to 6 months, or as daily oral dosing at 2 mg/kg for 3 to 6 months following the NIH protocol. The oral route results in higher cumulative doses and greater toxicity. Cyclophosphamide is now generally reserved for severe disease refractory to rituximab or in resource-limited settings. Cumulative dose-dependent toxicities include infections, cytopenias, malignancy with an increased risk of bladder cancer at cumulative doses exceeding 36 grams, infertility, and hemorrhagic cystitis, for which MESNA prophylaxis is recommended with oral cyclophosphamide regimens.

#### Plasma Exchange (PLEX)

The role of plasma exchange in AAV has evolved significantly. The MEPEX trial, published in 2007, suggested benefit in patients with severe renal disease and serum creatinine above 5.8 mg/dL, showing reduced dialysis dependence at 12 months. However, the larger and more definitive PEXIVAS trial, published in 2020, demonstrated that plasma exchange did not reduce the composite endpoint of death or end-stage renal disease in AAV overall, including patients with severe renal disease. Importantly, PEXIVAS also showed that a reduced-dose glucocorticoid regimen was non-inferior to the standard dose, further supporting steroid minimization strategies. The current approach reserves plasma exchange for patients with diffuse alveolar hemorrhage or anti-GBM overlap disease, and routine use for severe renal AAV is no longer supported.

<image>Treatment algorithm for ANCA-associated vasculitis with renal involvement. Start with confirmed diagnosis (positive ANCA + renal biopsy showing pauci-immune crescentic GN). Assess severity: life-threatening (DAH, severe RPGN requiring dialysis) versus organ-threatening (rising creatinine, active GN without immediate dialysis need). For all patients: pulse methylprednisolone 500-1000 mg x 3 days. Then first-line induction: rituximab 375 mg/m2 weekly x 4 + avacopan 30 mg BID (allows steroid reduction/elimination) OR rituximab + prednisone taper. Alternative: cyclophosphamide (Euro-Vasculitis protocol) + prednisone. For life-threatening DAH: add PLEX. For anti-GBM overlap: PLEX essential. Transition to maintenance at remission (typically 3-6 months): rituximab 500 mg every 6 months for ≥2-4 years (MAINRITSAN trials). Show monitoring: ANCA titers, creatinine, urinalysis, CRP/ESR every 1-3 months.</image>

### Maintenance Therapy

Rituximab is the preferred maintenance agent, with 500 mg intravenously every 6 months. The MAINRITSAN trial, published in 2014, and the MAINRITSAN-2 trial demonstrated the superiority of rituximab over azathioprine for relapse prevention. Maintenance therapy should be continued for a minimum of 2 to 4 years, with longer duration recommended for PR3-AAV given its higher relapse rate. The RITAZAREM trial, published in 2023, showed that rituximab at 1000 mg every 4 months was superior to azathioprine for relapse prevention in patients with relapsing AAV. Azathioprine at 2 mg/kg/day, with TPMT testing before initiation, serves as an alternative when rituximab is unavailable. Mycophenolate mofetil is a second-line alternative, as the IMPROVE trial demonstrated a higher relapse rate with MMF compared to azathioprine. The glucocorticoid taper should target complete discontinuation by 4 to 6 months, supported by the PEXIVAS data showing no harm with reduced-dose protocols.

### Treatment of Relapse

Rituximab is the preferred agent for treatment of relapse, based on the RAVE trial's demonstration that rituximab was superior to cyclophosphamide specifically in patients with relapsing disease. Repeat induction-intensity dosing should be employed, and clinicians should assess for drug-induced ANCA vasculitis or other secondary causes contributing to the relapse.

## Special Considerations

### Dialysis-Dependent AAV

Approximately 20 to 30 percent of patients with AAV are dialysis-dependent at presentation. Renal recovery is possible in approximately 50 percent of these patients with appropriate treatment, with better outcomes predicted when renal biopsy shows predominantly cellular rather than fibrous crescents. In patients with a Berden sclerotic class biopsy, the chance of renal recovery is minimal, and the risks of aggressive immunosuppression may outweigh the potential benefits. The treatment decision should therefore be guided by the renal biopsy findings: immunosuppression is warranted when active cellular crescentic disease is present but should be withheld when the biopsy reveals predominantly sclerotic changes.

### Dual ANCA + Anti-GBM Positivity

Concurrent ANCA and anti-GBM positivity occurs in 10 to 30 percent of anti-GBM patients, with anti-MPO being the more common ANCA specificity in this overlap population. These patients are more prone to relapse than those with pure anti-GBM disease. Treatment follows the anti-GBM disease protocol with plasmapheresis, cyclophosphamide, and corticosteroids, with the addition of long-term monitoring for AAV relapse given the presence of ANCA.

### Drug-Induced AAV

Drug-induced AAV can be triggered by hydralazine, propylthiouracil, minocycline, and cocaine contaminated with levamisole. These patients are often characterized by multi-ANCA positivity, testing positive for anti-MPO, anti-PR3, anti-histone, and anti-elastase antibodies. Treatment centers on discontinuation of the offending drug, with immunosuppressive therapy reserved for severe disease. Drug-induced AAV generally carries a better prognosis than primary AAV and may not require prolonged maintenance therapy.

## Key Clinical Pearls

- ANCA specificity (PR3 vs MPO) is more clinically relevant than phenotype (GPA vs MPA): PR3-AAV relapses more frequently and requires longer maintenance therapy
- Avacopan (ADVOCATE trial) enables steroid-free or steroid-minimized induction; it is an add-on, not a replacement, for rituximab or cyclophosphamide
- PEXIVAS changed practice: plasma exchange does NOT reduce death or ESRD in AAV with severe renal disease; reserve PLEX for DAH and anti-GBM overlap
- Rituximab-based maintenance (MAINRITSAN, RITAZAREM) is superior to azathioprine for relapse prevention and is now preferred
- The Berden histologic classification provides critical prognostic information: predominantly sclerotic class has minimal chance of renal recovery, informing treatment intensity decisions

## References
1. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE). *N Engl J Med*. 2010;363(3):221-232.
2. Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the Treatment of ANCA-Associated Vasculitis (ADVOCATE). *N Engl J Med*. 2021;384(7):599-609.
3. Walsh M, Merkel PA, Peh CA, et al. Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS). *N Engl J Med*. 2020;382(7):622-631.
4. Guillevin L, Pagnoux C, Karras A, et al. Rituximab versus Azathioprine for Maintenance in ANCA-Associated Vasculitis (MAINRITSAN). *N Engl J Med*. 2014;371(19):1771-1780.
5. Berden AE, Ferrario F, Hagen EC, et al. Histopathologic Classification of ANCA-Associated Glomerulonephritis. *J Am Soc Nephrol*. 2010;21(10):1628-1636.