ANCA-Associated Vasculitis & Pulmonary-Renal Syndromes

The pulmonary-renal syndrome — simultaneous diffuse alveolar haemorrhage (DAH) and rapidly progressive glomerulonephritis (RPGN) — is a recurring NEET PG image-and-vignette favourite. This note dissects the three classical culprits (GPA, MPA, anti-GBM/Goodpasture), their ANCA serology, histology, and the steroid-cyclophosphamide-plasmapheresis backbone of treatment.

Definition & classification

A pulmonary-renal syndrome is the combination of diffuse alveolar haemorrhage and glomerulonephritis. The big three causes that examiners want are the ANCA-associated vasculitides (AAV) and anti-GBM (Goodpasture) disease.

ANCA-associated vasculitis is a group of small-vessel, pauci-immune, necrotising vasculitides characterised by circulating Anti-Neutrophil Cytoplasmic Antibodies. The 2012 Chapel Hill Consensus classification recognises three entities:

Entity	Old eponym	ANCA pattern	Target antigen	Hallmark organs
Granulomatosis with polyangiitis (GPA)	Wegener granulomatosis	c-ANCA	PR3 (proteinase-3)	Upper + lower airway + kidney
Microscopic polyangiitis (MPA)	—	p-ANCA	MPO (myeloperoxidase)	Lung + kidney (RPGN)
Eosinophilic GPA (EGPA)	Churg-Strauss	p-ANCA (~40%)	MPO	Asthma, eosinophilia, neuropathy

Anti-GBM disease is not a vasculitis — it is an antibody-mediated disease against the alpha-3 chain of type IV collagen. When it affects both lung and kidney it is called Goodpasture syndrome; isolated renal involvement is anti-GBM glomerulonephritis.

High-yield: c-ANCA / PR3 → think GPA. p-ANCA / MPO → think MPA (and EGPA). Linear IgG on immunofluorescence → think anti-GBM. These three pairings are the most repeated single facts in this topic.

ANCA — the serology you must know

ANCA are detected by indirect immunofluorescence (IIF) on ethanol-fixed neutrophils, then confirmed by antigen-specific ELISA.

Feature	c-ANCA	p-ANCA
IIF pattern	Cytoplasmic, granular	Perinuclear
Antigen	Proteinase-3 (PR3)	Myeloperoxidase (MPO)
Classic disease	GPA	MPA, EGPA
Artefact note	True	Perinuclear pattern is a fixation artefact of ethanol

High-yield: The perinuclear (p-ANCA) staining is an ethanol-fixation artefact — MPO is actually cytoplasmic but its positive charge migrates around the nucleus during ethanol fixation. On formalin-fixed neutrophils both PR3 and MPO give a cytoplasmic pattern.

Pitfall: atypical p-ANCA (against lactoferrin, elastase, cathepsin G) occurs in IBD (ulcerative colitis), autoimmune hepatitis, RA and drug-induced vasculitis — these are MPO-negative and not true AAV.

Mnemonic — "C goes with the C's; P goes with the P's":

• c-ANCA → PR3 → Wegener/GPA (the odd one out; remember c-ANCA → GPA).
• p-ANCA → MPO → Microscopic Polyangiitis.

Etiology & pathophysiology

The unifying lesion of AAV is pauci-immune necrotising small-vessel inflammation. "Pauci-immune" means scanty or absent immune-complex deposition on immunofluorescence and electron microscopy — distinguishing AAV from lupus nephritis and post-infectious GN.

Stepwise pathogenesis of AAV (the ANCA cytokine sequence):

1. Priming: infection/cytokines (TNF-alpha, C5a) prime neutrophils → translocation of PR3 and MPO to the cell surface.
2. Activation: circulating ANCA bind these surface antigens and engage Fc-gamma receptors → full neutrophil activation.
3. Degranulation & respiratory burst: release of reactive oxygen species and lytic enzymes damages the endothelium.
4. Alternative complement amplification: C5a generation recruits and primes more neutrophils — a feed-forward loop (basis for the C5a-receptor antagonist avacopan).
5. NETosis & necrosis: neutrophil extracellular traps perpetuate injury and expose more autoantigen → fibrinoid necrosis and crescent formation.

So the flow is: Priming → ANCA binding → neutrophil burst → C5a amplification → endothelial necrosis → crescentic GN / capillaritis.

In GPA the additional feature is granulomatous inflammation (necrotising granulomas of the respiratory tract). MPA has no granulomas — that single difference separates the two on biopsy.

Anti-GBM pathogenesis is distinct: antibodies against the NC1 domain of the alpha-3 chain of type IV collagen (the Goodpasture antigen) bind the basement membrane of glomeruli and alveoli → complement-mediated, linear injury. Smoking, infection, hydrocarbon exposure and cocaine unmask the antigen in the lung, explaining why lung haemorrhage occurs mainly in smokers.

High-yield: Drug-induced ANCA vasculitis — hydralazine, propylthiouracil (PTU), minocycline, cocaine adulterated with levamisole — classically gives high-titre MPO/p-ANCA, often with dual ANCA positivity and anti-elastase antibodies (levamisole). Stopping the drug is the cornerstone of treatment.

Clinical features

Constitutional: fever, weight loss, arthralgia, fatigue — a "vasculitis prodrome" often precedes organ damage by weeks.

GPA (Granulomatosis with polyangiitis)

The classic triad is upper airway + lower airway + kidney ("ELK" — ENT, Lung, Kidney).

• Upper respiratory tract: chronic sinusitis, nasal crusting/epistaxis, saddle-nose deformity (collapse of nasal bridge from cartilage destruction), otitis media, subglottic stenosis.
• Lower respiratory tract: lung nodules (often cavitating), pulmonary infiltrates, haemoptysis from capillaritis.
• Renal: pauci-immune crescentic (RPGN) glomerulonephritis.
• Eye: scleritis, episcleritis, orbital pseudotumour/proptosis (retro-orbital granuloma).
• Skin: palpable purpura.

High-yield: Saddle-nose deformity + cavitating lung nodules + haematuria + c-ANCA = GPA until proven otherwise. Other causes of saddle nose: relapsing polychondritis, congenital syphilis, leprosy, cocaine.

MPA (Microscopic polyangiitis)

• Dominant presentation is RPGN with rapidly rising creatinine.
• Pulmonary haemorrhage (DAH) is common; no granulomas, no upper-airway destruction.
• Mononeuritis multiplex, palpable purpura, GI involvement.
• Most common cause of pulmonary-renal syndrome overall.

EGPA (Churg-Strauss)

Three phases: (1) allergic (asthma, allergic rhinitis) → (2) eosinophilic (eosinophilia, eosinophilic pneumonia, gastroenteritis) → (3) vasculitic (neuropathy, purpura, cardiac involvement). Cardiac disease is the leading cause of death. Late-onset asthma + peripheral eosinophilia + mononeuritis multiplex is the buzzphrase.

Anti-GBM / Goodpasture

• Pulmonary haemorrhage + RPGN, typically in a young male smoker (bimodal: 20-30 yr men, and 60-70 yr either sex).
• Haemoptysis + dyspnoea + iron-deficiency anaemia (recurrent alveolar bleeds) + acute kidney injury with haematuria and red-cell casts.
• Renal-limited disease in older patients.

High-yield: Diffuse alveolar haemorrhage is suggested by haemoptysis (may be absent), falling haemoglobin, diffuse alveolar infiltrates and a rising DLCO/KCO on lung-function testing (extra haemoglobin in alveoli takes up CO). A rising DLCO is the classic answer for active alveolar bleeding.

Diagnosis & investigation of choice

Serology

• ANCA (IIF + ELISA) for PR3 and MPO.
• Anti-GBM antibody (ELISA) — order alongside ANCA in any pulmonary-renal presentation.
• Note: ~10-15% of anti-GBM patients are also p-ANCA/MPO positive ("double-positive"). These patients behave like vasculitis (relapse-prone) and need maintenance therapy.

Urine & renal panel

• Active urinary sediment: dysmorphic RBCs, red-cell casts, proteinuria; rising creatinine = RPGN.

Imaging

• GPA: CT chest — nodules, cavities, ground-glass haemorrhage; CT/MRI sinuses.

Biopsy — the investigation of choice for confirmation

Renal biopsy is the gold standard to confirm and stage disease.

Disease	Light microscopy	Immunofluorescence
AAV (GPA/MPA)	Focal necrotising crescentic GN	Pauci-immune (negative/scanty)
Anti-GBM	Diffuse crescentic GN	Linear IgG along GBM
Lupus nephritis	Proliferative GN	"Full-house" granular (IgG, IgA, IgM, C3, C1q)

High-yield: Crescents = RPGN. The three immunofluorescence patterns define the three RPGN types:

• Type I — Linear → anti-GBM
• Type II — Granular (immune complex) → lupus, post-infectious, IgA, HSP
• Type III — Pauci-immune → ANCA-associated (GPA/MPA), the commonest cause of RPGN

A nasal/lung biopsy in GPA shows the triad of necrosis, granulomatous inflammation, and vasculitis.

Diagnostic flow for a pulmonary-renal syndrome: Haemoptysis + AKI/haematuria → send ANCA + anti-GBM + ANA/dsDNA + complement → urgent renal biopsy (LM + IF) → classify (linear vs granular vs pauci-immune) → start immunosuppression without waiting if rapidly deteriorating.

Management / drug of choice

Treatment has two phases: remission induction then maintenance.

Remission induction (severe / organ-threatening disease)

• Glucocorticoids (IV methylprednisolone pulses → oral prednisolone taper) PLUS
• Rituximab (anti-CD20) OR cyclophosphamide. Rituximab is now preferred (non-inferior in RAVE/RITUXVAS, better for relapsing and PR3 disease, avoids gonadotoxicity).
• Avacopan (oral C5a-receptor antagonist) is steroid-sparing and approved as add-on induction (ADVOCATE trial).

Plasma exchange (plasmapheresis)

• Mandatory for anti-GBM disease, and used in AAV with severe DAH or severe renal failure / dialysis dependence.
• The PEXIVAS trial tempered routine plasma exchange in AAV (no overall benefit on death/ESRD) but it is still used for life-threatening haemorrhage and anti-GBM.

Anti-GBM / Goodpasture — the classic triad of therapy

Plasmapheresis + cyclophosphamide + corticosteroids — started urgently because untreated disease leads to irreversible renal failure within days.

High-yield: For Goodpasture syndrome the textbook answer is plasmapheresis + cyclophosphamide + steroids, begun before biopsy if needed. Plasma exchange removes the pathogenic anti-GBM antibody; cyclophosphamide stops its synthesis.

Maintenance

• Rituximab (preferred) or azathioprine for 18-24 months (longer for PR3/relapsing disease). Methotrexate or mycophenolate are alternatives.
• Anti-GBM needs no long-term maintenance because relapse is rare once antibody is cleared (unless double-positive with ANCA).

Supportive / prophylaxis

• Co-trimoxazole for Pneumocystis jirovecii prophylaxis (also reduces GPA relapse) while immunosuppressed.
• Bone protection, vaccination, contraception with cyclophosphamide.

Disease	Induction	Maintenance	Plasma exchange
GPA / MPA	Steroids + rituximab (or cyclophosphamide) ± avacopan	Rituximab / azathioprine 18-24 mo	Only for severe DAH / dialysis-dependent AKI
Anti-GBM	Steroids + cyclophosphamide + plasmapheresis	Usually none	Always
EGPA	Steroids ± rituximab; mepolizumab (anti-IL-5) if eosinophilic/relapsing	Steroid taper / mepolizumab	Rarely

Complications

• End-stage renal disease — especially if creatinine is high or dialysis needed at presentation (worst prognostic factor).
• Diffuse alveolar haemorrhage → respiratory failure — a leading cause of early death.
• Subglottic / tracheal stenosis (GPA) — may need surgical dilatation.
• Infection — the major cause of death during treatment (immunosuppression + steroids); PCP, fungal, bacterial.
• Cyclophosphamide toxicity: haemorrhagic cystitis (give mesna + hydration), bladder cancer, infertility, marrow suppression.
• Relapse — much higher in PR3/GPA than MPO/MPA; relapse often heralded by rising ANCA titre (though titre alone should not drive treatment).
• EGPA: eosinophilic myocarditis / cardiomyopathy — top cause of mortality.

Key differentials

• Anti-GBM vs AAV: linear IgG + anti-GBM antibody vs pauci-immune + ANCA. Order both; remember double-positives.
• Lupus nephritis: young woman, low complement, ANA/anti-dsDNA, "full-house" granular IF — not pauci-immune.
• IgA vasculitis (Henoch-Schönlein): child, palpable purpura on buttocks/legs, abdominal pain, IgA mesangial deposits — immune-complex, ANCA-negative.
• Polyarteritis nodosa (PAN): medium-vessel, ANCA-negative, microaneurysms on angiography, HBV association, spares the lung, no glomerulonephritis (causes renal infarcts/hypertension instead).
• Cryoglobulinaemic vasculitis: HCV, low C4, palpable purpura, membranoproliferative GN.
• Infective endocarditis / cocaine-levamisole: can mimic AAV with low-titre ANCA.

Vasculitis	Vessel size	ANCA	Lung	Distinguishing clue
GPA	Small	c-ANCA/PR3	Yes (cavitating nodules)	Saddle nose, ENT, granulomas
MPA	Small	p-ANCA/MPO	Yes (DAH)	RPGN, no granulomas
EGPA	Small	p-ANCA (~40%)	Asthma/eosinophilia	Late-onset asthma, eosinophilia
PAN	Medium	Negative	No	HBV, microaneurysms, spares lung
Anti-GBM	(Not vasculitis)	Usually neg	DAH	Linear IgG, young smoker male

Recently asked / exam angle

• Image-based: CXR/CT showing cavitating lung nodules → asked the antibody (answer: c-ANCA/PR3, GPA) or the deformity (saddle nose).
• Histology slide: crescentic GN with linear IF → anti-GBM; with pauci-immune IF → ANCA vasculitis; full-house → lupus.
• Single-best-answer: "Commonest cause of RPGN / pulmonary-renal syndrome" → pauci-immune (ANCA-associated), specifically MPA.
• Mechanism MCQ: p-ANCA perinuclear pattern is an ethanol-fixation artefact; target antigen is MPO.
• Treatment: Goodpasture → plasmapheresis + cyclophosphamide + steroids; newer steroid-sparing C5a-receptor blocker → avacopan; EGPA biologic → mepolizumab (anti-IL-5).
• Drug-induced: PTU and hydralazine → MPO/p-ANCA vasculitis; levamisole-adulterated cocaine → dual ANCA with retiform purpura of ears.
• Lung function: active alveolar haemorrhage raises DLCO/KCO.
• Prophylaxis: co-trimoxazole for PCP and reduced GPA relapse; mesna with cyclophosphamide.

Rapid revision

1. c-ANCA → PR3 → GPA; p-ANCA → MPO → MPA/EGPA.
2. p-ANCA perinuclear pattern is an ethanol-fixation artefact; MPO is truly cytoplasmic.
3. GPA = ELK (ENT + Lung + Kidney) with granulomas; MPA has no granulomas and no upper-airway destruction.
4. Saddle-nose + cavitating nodules + haematuria + c-ANCA = GPA.
5. Pauci-immune crescentic GN (Type III) is the commonest cause of RPGN; AAV is pauci-immune on IF.
6. Anti-GBM = linear IgG on IF; antigen is the alpha-3 chain of type IV collagen (NC1 domain).
7. Goodpasture = anti-GBM + lung + kidney, classically a young male smoker; treat with plasmapheresis + cyclophosphamide + steroids.
8. Rituximab is now the preferred induction/maintenance agent in AAV; avacopan is the C5a-receptor antagonist that spares steroids.
9. PEXIVAS reduced routine plasma exchange in AAV; reserve it for severe DAH, dialysis-dependent AKI, and all anti-GBM.
10. PTU, hydralazine, minocycline, levamisole-cocaine cause drug-induced MPO/p-ANCA vasculitis (often dual-positive).
11. EGPA = asthma + eosinophilia + neuropathy; cardiac involvement is the chief killer; biologic is mepolizumab.
12. Active alveolar haemorrhage raises DLCO; give co-trimoxazole (PCP prophylaxis) and mesna (cyclophosphamide cystitis prophylaxis).