ANCA-Associated Glomerulonephritis
ANCA-associated glomerulonephritis is a pauci-immune necrotising and crescentic glomerulonephritis caused by small-vessel vasculitis, classically presenting as rapidly progressive glomerulonephritis.
ANCA-Associated Glomerulonephritis
ANCA-associated glomerulonephritis (ANCA-GN) is a form of small-vessel vasculitis that targets the glomerular capillaries, characterised histologically by pauci-immune necrotising and crescentic glomerulonephritis — meaning there is severe glomerular inflammation with little or no immunoglobulin/complement deposition on immunofluorescence (IF) microscopy [1][2][3].
Let's break the name down from first principles:
- ANCA = Anti-Neutrophil Cytoplasmic Antibodies — pathogenic autoantibodies directed against antigens within neutrophil cytoplasmic granules
- Associated — the disease is strongly linked to, though not exclusively caused by, these antibodies
- Glomerulonephritis — "glomerulo" = glomerulus (the filtering unit), "nephritis" = kidney inflammation; inflammation of the glomerular capillary tuft
ANCA-GN may occur as part of a systemic ANCA-associated vasculitis (AAV) — specifically Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), or Eosinophilic Granulomatosis with Polyangiitis (EGPA) — or as a renal-limited vasculitis (RLV) [2][3][4].
Key Concept — Pauci-immune
"Pauci-immune" literally means "few immune [deposits]." On immunofluorescence, you see little to no IgG, IgA, IgM, or complement staining in the glomerulus — this is the defining histological feature that separates ANCA-GN from anti-GBM disease (linear staining) and immune-complex GN (granular staining). The damage is neutrophil-mediated, not immune-complex-mediated.
Clinically, ANCA-GN sits within the spectrum of rapidly progressive glomerulonephritis (RPGN) — a syndrome of rapid renal function decline over days to weeks with crescent formation on biopsy. RPGN is classified into three types by IF pattern [3][5]:
| Type | IF Pattern | Cause |
|---|---|---|
| Type I | Linear | Anti-GBM disease (Goodpasture syndrome) |
| Type II | Granular | Immune-complex mediated (SLE, IgAN, PSGN) |
| Type III | Negative / Pauci-immune | ANCA-associated (GPA, MPA, EGPA, RLV) |
Type III (pauci-immune) is the most common cause of RPGN overall [1][3][5].
High Yield: When you see RPGN on an exam, think ANCA-GN first — it is the most common cause of RPGN. Type I (anti-GBM) is the least common but most dramatic.
2. Epidemiology
- ANCA-associated vasculitis has an annual incidence of approximately 13–20 per million population in Western cohorts [6].
- ANCA-GN (including renal-limited forms) accounts for the most common cause of RPGN and is a leading cause of new-onset dialysis-requiring AKI due to GN in adults [1][3].
- In Hong Kong and East Asian populations:
| Risk Factor | Mechanism / Explanation |
|---|---|
| Older age | Immunosenescence, epigenetic dysregulation of ANCA antigen expression |
| Genetic predisposition | HLA associations (HLA-DPB1*0401 for PR3-ANCA/GPA; HLA-DQ for MPO-ANCA/MPA) |
| Infections | Molecular mimicry — e.g., fimbriated bacteria may cross-react with PR3/MPO antigens [3] |
| Silica / occupite exposure | Silica dust, farming, hydrocarbons — occupational exposure triggers neutrophil priming |
| Drugs | Propylthiouracil (PTU) is a well-known trigger of MPO-ANCA vasculitis [7]; hydralazine, minocycline, levamisole (cocaine adulterant) |
| Smoking | Increases risk of PR3-ANCA/GPA, particularly upper airway disease |
Hong Kong Exam Pearl
PTU-induced ANCA vasculitis is a specifically tested association. The Block A thyroid lecture states: "ANCA-induced vasculitis — rare side effect more common with PTU than carbimazole" [7]. If a thyrotoxic patient on PTU develops haematuria and rising creatinine, think ANCA-GN.
3. Anatomy and Function — The Glomerular Filtration Barrier
To understand why ANCA-GN causes what it does, you need to understand the normal glomerular filtration barrier and the blood supply.
The glomerulus is a tuft of capillaries invaginated into Bowman's capsule. Blood enters via the afferent arteriole, passes through the capillary loops, and exits via the efferent arteriole. The filtrate (primary urine) passes through the glomerular filtration barrier (GFB) into Bowman's space [8].
The GFB has three layers (from blood side to urine side):
- Fenestrated endothelium — endothelial cells lining the capillary lumen with small fenestrae (~70 nm); blocks cells but allows plasma to pass
- Glomerular basement membrane (GBM) — a thick collagen IV-rich matrix; the main size and charge barrier (negatively charged due to heparan sulfate proteoglycans)
- Podocytes (visceral epithelial cells) — highly specialised cells with interdigitating foot processes connected by slit diaphragms (~40 nm); the final barrier to protein passage
Mesangial cells sit between capillary loops, providing structural support and participating in immune regulation (phagocytosis, cytokine release).
Parietal epithelial cells line Bowman's capsule — these are the cells that proliferate to form crescents in RPGN.
- Neutrophil-mediated damage to the endothelium and GBM → loss of barrier integrity → haematuria (RBCs pass through) and proteinuria (proteins pass through)
- Severe capillary wall disruption → fibrin leaks into Bowman's space → stimulates parietal epithelial cell proliferation → crescent formation [1][3][5]
- Crescents compress the capillary tuft from outside, obliterating the filtering surface → rapid GFR decline = RPGN
- If crescents become fibrotic (replaced by collagen), the damage is irreversible [5]
4. Etiology (Focus on Hong Kong)
Two forms of ANCA have been identified [2][3][4]:
| ANCA Type | Target Antigen | IF Pattern | Primary Disease Association |
|---|---|---|---|
| c-ANCA | Proteinase 3 (PR3) | Cytoplasmic | GPA (Wegener's) — ~80% c-ANCA positive |
| p-ANCA | Myeloperoxidase (MPO) | Perinuclear | MPA, EGPA, renal-limited vasculitis |
The "c" in c-ANCA = cytoplasmic staining pattern (diffuse granular throughout cytoplasm); the "p" in p-ANCA = perinuclear pattern (staining concentrated around the nucleus — an artefact of ethanol fixation causing MPO to redistribute to the nuclear membrane).
Both PR3 and MPO are present in azurophilic (primary) granules of neutrophils — normally these antigens are sequestered inside immature neutrophil granules and should be silenced in mature circulating neutrophils [3].
- In Hong Kong/East Asia, MPO-ANCA (p-ANCA) positivity predominates [4]
- MPA is the most common systemic ANCA-associated vasculitis in HK [4]
- GPA is relatively less common in Chinese populations
- Renal-limited vasculitis (no systemic features) accounts for a significant proportion — approximately 75–80% of renal-limited cases are MPO-ANCA positive [3]
- Drug-induced ANCA-GN (especially PTU) is particularly relevant in HK given the prevalence of Graves' disease treated with antithyroid drugs [7]
| Setting | Details |
|---|---|
| GPA (Granulomatosis with Polyangiitis) | Formerly Wegener's; necrotising granulomatous vasculitis; ENT + lung + kidney triad; c-ANCA/PR3 ~80% |
| MPA (Microscopic Polyangiitis) | Necrotising non-granulomatous vasculitis; no ENT involvement; p-ANCA/MPO predominant |
| EGPA (Eosinophilic GPA) | Formerly Churg-Strauss; eosinophil-rich necrotising vasculitis; asthma + eosinophilia + vasculitis phases; renal involvement less common; p-ANCA/MPO ~40% |
| Renal-limited vasculitis (RLV) | ANCA-GN without systemic vasculitic features; 75–80% MPO-ANCA positive |
| Drug-induced | PTU, hydralazine, minocycline, levamisole-adulterated cocaine |
| ANCA-negative pauci-immune GN | < 5% of pauci-immune crescentic GN; similar histology and prognosis to ANCA-positive disease [3] |
This is the crux of understanding ANCA-GN. The disease is driven by ANCA-mediated neutrophil activation against the glomerular endothelium.
Step-by-Step Pathogenesis
Step 1: Aberrant Expression of ANCA Antigens
- In healthy individuals, PR3 and MPO are sequestered within azurophilic granules of mature neutrophils and are not expressed on the cell surface [3].
- In ANCA-GN, epigenetic dysregulation (e.g., DNA hypomethylation of the PR3/MPO gene promoters) leads to aberrant surface expression of these antigens on mature neutrophils and monocytes.
- This creates a target for circulating ANCA to bind.
Step 2: Neutrophil Priming
- Priming refers to partial activation of neutrophils by cytokines (TNF-α, IL-1, IL-8) released during infections or inflammation.
- Primed neutrophils translocate PR3/MPO from intracellular granules to the cell surface, making them accessible to ANCA.
- This explains the clinical observation that infections often precede flares of ANCA vasculitis — the infection primes neutrophils, then ANCA completes the activation.
Step 3: ANCA Binds and Activates Neutrophils
- ANCA (IgG) binds to PR3 or MPO on the neutrophil surface via both:
- F(ab')2 binding to the antigen
- Fc receptor engagement (FcγRIIa) on the neutrophil
- This dual engagement fully activates the neutrophil, triggering:
- Degranulation — release of proteolytic enzymes (elastase, cathepsin G, MPO)
- Respiratory burst — production of reactive oxygen species (ROS)
- NETosis — release of neutrophil extracellular traps (NETs), which are web-like structures of DNA + PR3/MPO that perpetuate endothelial damage and serve as a nidus for further ANCA production
Step 4: Endothelial Injury
- Activated neutrophils adhere to the glomerular endothelium (via adhesion molecules upregulated by TNF-α).
- Degranulation and ROS release directly damage the endothelial cells and GBM — this is the "necrotising" component.
- Because the damage is direct (neutrophil-mediated) rather than immune-complex-mediated, there is little immunoglobulin deposition → pauci-immune pattern on IF.
Step 5: Crescent Formation
- Severe endothelial/GBM disruption causes breaks in the capillary wall → fibrinogen and other plasma proteins leak into Bowman's space.
- Fibrin acts as a scaffold and chemoattractant for monocytes/macrophages and parietal epithelial cells.
- Parietal epithelial cells proliferate and, together with infiltrating macrophages and T cells, form cellular crescents — the hallmark of RPGN [1][3][5].
- Over days to weeks, if untreated, cellular crescents undergo fibroblast infiltration and collagen deposition → fibrous crescents (irreversible scarring).
Step 6: Complement Activation (Alternative Pathway)
- Although ANCA-GN is "pauci-immune" (no classical/lectin pathway activation), recent research has shown that the alternative complement pathway plays a pathogenic role.
- C5a (a complement activation product) further primes neutrophils via the C5a receptor, creating a positive feedback loop: activated neutrophils → more complement → more neutrophil priming → more damage.
- This is the basis for the new drug avacopan (C5a receptor inhibitor), which has been approved as adjunctive therapy for ANCA-GN (KDIGO 2024/ADVOCATE trial).
Why 'Pauci-Immune'?
The damage in ANCA-GN is caused by direct neutrophil-mediated injury, not by immune complex deposition. The neutrophils are the effector cells activated by ANCA — they damage the endothelium through proteases and ROS. Since there are no immune complexes being deposited in the glomerulus, IF microscopy shows little to no immunoglobulin or complement staining. This is fundamentally different from Type II RPGN (e.g., lupus nephritis) where immune complexes deposit in the glomerulus and fix complement.
6. Classification
| Category | ANCA Type | Key Features |
|---|---|---|
| GPA | c-ANCA (anti-PR3) ~80%; p-ANCA ~20% | Granulomatous inflammation; ENT (sinusitis, epistaxis, saddle nose), lung (nodules/cavities), kidney [2][4] |
| MPA | p-ANCA (anti-MPO) predominant | Non-granulomatous necrotising vasculitis; NO ENT involvement; lung (diffuse alveolar haemorrhage), kidney [2][4] |
| EGPA | p-ANCA (anti-MPO) ~40% | Eosinophil-rich; three phases: asthma → eosinophilic infiltration → vasculitis [2] |
| Renal-limited vasculitis | p-ANCA (anti-MPO) ~75–80% | Pauci-immune crescentic GN without systemic vasculitis [3] |
The histological classification of ANCA-GN on renal biopsy predicts outcomes [3]:
| Class | Definition | Prognosis |
|---|---|---|
| Focal | ≥50% of glomeruli normal | Best prognosis |
| Crescentic | ≥50% of glomeruli with cellular crescents | Intermediate |
| Mixed | < 50% normal, < 50% crescentic, < 50% sclerotic | Intermediate |
| Sclerotic | ≥50% of glomeruli globally sclerotic | Worst prognosis (often irreversible) |
High Yield: The Berden classification is important because sclerotic class predicts poor renal survival regardless of treatment intensity, while focal class has excellent renal outcomes. This guides decisions about aggressiveness of immunosuppression — e.g., there may be less benefit to aggressive immunosuppression if biopsy shows predominantly sclerotic glomeruli.
There is increasing recognition that serotype (PR3-ANCA vs MPO-ANCA) may be more clinically meaningful than the traditional disease labels (GPA vs MPA):
| Feature | PR3-ANCA | MPO-ANCA |
|---|---|---|
| Predominant disease | GPA | MPA, RLV, EGPA |
| Geography | More common in Northern Europeans | More common in East Asia (including HK) |
| Relapse rate | Higher (~50% at 5 years) | Lower (~20% at 5 years) |
| Upper airway involvement | Common | Uncommon |
| Renal fibrosis on biopsy | Less chronic damage | More chronic fibrosis |
| Response to rituximab | May be superior to CYC for induction | Similar to CYC |
7. Clinical Features
ANCA-GN can present across a clinical spectrum from asymptomatic urinary abnormalities to fulminant RPGN with pulmonary haemorrhage (pulmonary-renal syndrome). The key is to think about it as two components: renal features (the GN itself) and extrarenal features (the systemic vasculitis).
7.1 Symptoms
| Symptom | Pathophysiological Basis |
|---|---|
| Haematuria (macroscopic — "smoky"/cola-coloured; or microscopic) | Breaks in glomerular capillary walls allow RBCs into Bowman's space and then urine. Dysmorphic RBCs result from mechanical distortion as they pass through damaged GBM. No clots — urokinase in glomerular filtrate lyses clots [9] |
| Frothy urine | Proteinuria — damaged GFB allows albumin to pass; protein in urine reduces surface tension → foam |
| Oliguria / anuria | Crescents compress the capillary tuft → drastically reduced GFR → reduced urine output |
| Peripheral oedema (ankle swelling, periorbital puffiness) | Reduced GFR → sodium and water retention → volume expansion → oedema; if nephrotic-range proteinuria coexists → hypoalbuminaemia → reduced oncotic pressure (but proteinuria in ANCA-GN is usually subnephrotic) |
| Dyspnoea | Fluid overload from oliguria/salt retention → pulmonary oedema; OR diffuse alveolar haemorrhage (DAH) — same ANCA-driven vasculitis affecting pulmonary capillaries |
| Fatigue / malaise | Uraemia (accumulation of waste products), anaemia (inflammatory + renal), and systemic inflammation |
| Nausea, loss of appetite | Uraemia — nitrogenous waste products stimulate the chemoreceptor trigger zone |
| Flank/loin pain | Acute renal swelling stretching the renal capsule [5] |
| Symptom | Pathophysiological Basis |
|---|---|
| Fever, night sweats, weight loss | Systemic inflammation — cytokine release (IL-1, IL-6, TNF-α); mimics malignancy/infection |
| Myalgia, arthralgia | Vasculitic inflammation of small vessels supplying muscles/joints |
| Haemoptysis | Pulmonary-renal syndrome — ANCA-driven vasculitis damages pulmonary alveolar capillaries → blood leaks into alveolar space. This is diffuse alveolar haemorrhage (DAH) — a medical emergency [1][5] |
| Organ System | Symptom | Disease | Mechanism |
|---|---|---|---|
| ENT / Upper airway | Nasal crusting, bloody nasal discharge, recurrent epistaxis, sinusitis, hearing loss (otitis media) | GPA | Granulomatous inflammation destroying nasal septum/sinuses/middle ear [2][4] |
| Lower airway | Cough, dyspnoea, haemoptysis | GPA (cavitating nodules), MPA (DAH) | Granulomas (GPA) or capillaritis (MPA) |
| Eye | Red eye (scleritis/episcleritis), visual loss (retro-orbital mass) | GPA | Granulomatous mass behind orbit or scleritis |
| Skin | Palpable purpura, skin ulcers, nail fold infarcts | All AAV | Leukocytoclastic vasculitis of dermal small vessels |
| Nervous system | Mononeuritis multiplex (e.g., foot drop, wrist drop), peripheral neuropathy | All AAV | Vasculitis of the vasa nervorum (small vessels supplying peripheral nerves) |
| Respiratory (EGPA-specific) | Asthma (often late-onset, severe), allergic rhinitis | EGPA | Eosinophilic infiltration of airways (precedes vasculitis phase) |
Pulmonary-Renal Syndrome
Haemoptysis + haematuria = pulmonary-renal syndrome until proven otherwise. The two most important causes are ANCA-associated vasculitis (usually MPA or GPA) and anti-GBM disease (Goodpasture syndrome). Both are medical emergencies requiring immediate immunosuppression. Always check ANCA AND anti-GBM simultaneously — they can coexist ("double positive") in ~5–10% of cases.
7.2 Signs
| Sign | Pathophysiological Basis |
|---|---|
| Hypertension (new-onset) | Reduced GFR → impaired sodium/water excretion → volume expansion → elevated BP. Also, ischaemic glomeruli release renin → RAAS activation |
| Peripheral oedema | Sodium/water retention; rarely due to hypoalbuminaemia (proteinuria usually subnephrotic in ANCA-GN) |
| Pulmonary crackles (basal) | Pulmonary oedema from fluid overload OR pulmonary haemorrhage from DAH |
| Flank tenderness | Renal capsular distension |
| Sign | Location | Disease | Mechanism |
|---|---|---|---|
| Palpable purpura | Lower limbs predominantly | All AAV | Leukocytoclastic vasculitis — neutrophilic inflammation and fibrinoid necrosis of dermal venules → extravasation of RBCs; "palpable" because of the accompanying oedema/inflammation [2][4] |
| Saddle nose deformity | Nose | GPA | Granulomatous destruction of nasal cartilage |
| Nasal ulceration / septal perforation | Nose | GPA | Granulomatous inflammation |
| Oral ulcers | Oral mucosa | GPA | Granulomatous/vasculitic inflammation |
| Scleritis / episcleritis | Eye (red, painful eye) | GPA | Vasculitis of scleral vessels |
| Proptosis | Eye (protruding eye) | GPA | Retro-orbital granulomatous mass |
| Subglottic stenosis | Larynx | GPA | Granulomatous inflammation below vocal cords — can cause stridor |
| Skin ulcers, livedo reticularis | Skin | All AAV | Vasculitic ischaemia of dermis |
| Nail fold infarcts | Fingers/toes | All AAV | Digital vessel vasculitis |
| Motor/sensory deficits in peripheral nerve distribution | Limbs | All AAV | Mononeuritis multiplex — vasculitis of vasa nervorum causing ischaemic neuropathy (asymmetric, named nerve distribution, e.g., common peroneal → foot drop) |
| Tachypnoea, reduced SpO2, diffuse crackles | Chest | MPA > GPA | Diffuse alveolar haemorrhage (DAH) |
High Yield: A classic exam scenario is an elderly patient with constitutional symptoms (fever, weight loss) + haematuria + rising creatinine + haemoptysis. This is pulmonary-renal syndrome, and the top differentials are ANCA-associated vasculitis (esp. MPA) and anti-GBM disease. Check ANCA, anti-GBM, complement, and get an urgent renal biopsy.
The urine sediment in ANCA-GN shows an "active sediment" [1][3][5]:
- Dysmorphic RBCs — RBCs distorted as they squeeze through damaged GBM (acanthocytes are the most specific morphology)
- RBC casts — cylindrical casts of RBCs formed in the renal tubules; pathognomonic of glomerulonephritis (not just haematuria from the bladder/ureter)
- Variable proteinuria — usually subnephrotic (< 3.5 g/day); heavy proteinuria should raise suspicion for a concurrent second glomerular disease [3]
- Sterile pyuria — WBCs in urine without bacterial infection, reflecting glomerular inflammation
Why is proteinuria usually subnephrotic in ANCA-GN?
Two reasons: (1) The GFR is drastically reduced by crescents compressing the capillary tuft — less filtrate means less protein can be filtered, even through a damaged barrier. (2) The primary injury is to the endothelium and GBM (leading to haematuria), rather than to the podocytes (which is what causes heavy proteinuria in nephrotic conditions like MCD or membranous nephropathy) [3][5].
| Feature | GPA | MPA | EGPA | Renal-Limited |
|---|---|---|---|---|
| ANCA type | c-ANCA (PR3) ~80% | p-ANCA (MPO) | p-ANCA (MPO) ~40% | p-ANCA (MPO) ~75–80% |
| Granulomas | Yes | No | Yes (eosinophilic) | No |
| ENT | Sinusitis, epistaxis, saddle nose | No | Allergic rhinitis | No |
| Lung | Nodules, cavities | DAH | Asthma, eosinophilic infiltrates | No |
| Kidney | Pauci-immune crescentic GN | Pauci-immune crescentic GN | Less common; pauci-immune GN | Pauci-immune crescentic GN |
| Skin | Palpable purpura | Palpable purpura | Palpable purpura | Usually no |
| Neuro | Mononeuritis multiplex | Mononeuritis multiplex | Mononeuritis multiplex | No |
| HK relevance | Less common | Most common AAV in HK | Rare | Significant proportion |
High Yield Summary
- ANCA-GN = pauci-immune necrotising crescentic glomerulonephritis; the most common cause of RPGN (Type III).
- Two ANCA types: c-ANCA/anti-PR3 (→ GPA) and p-ANCA/anti-MPO (→ MPA, EGPA, RLV). In HK, MPO-ANCA/MPA predominates.
- Pathogenesis: ANCA binds surface-expressed PR3/MPO on primed neutrophils → full activation → degranulation + ROS + NETosis → endothelial injury → fibrin leaks into Bowman's space → crescent formation → RPGN.
- Pauci-immune on IF because damage is neutrophil-mediated, NOT immune-complex-mediated.
- Clinical presentation: Active urine sediment (dysmorphic RBCs, RBC casts) + rapidly rising creatinine ± constitutional symptoms ± organ-specific vasculitic features (ENT in GPA, DAH in MPA, asthma in EGPA).
- Proteinuria is usually subnephrotic (limited by low GFR and endothelial rather than podocyte injury).
- Pulmonary-renal syndrome (haemoptysis + haematuria) = ANCA vasculitis or anti-GBM disease until proven otherwise.
- Drug-induced: PTU is a well-known trigger of MPO-ANCA vasculitis — high yield for HKUMed.
- Berden histological classification (focal, crescentic, mixed, sclerotic) predicts renal prognosis.
- Cellular crescents = potentially reversible with treatment; fibrous crescents = irreversible.
Active Recall - ANCA-Associated Glomerulonephritis (Definition to Clinical Features)
[1] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf [2] Lecture slides: GC 053. Fingers turn white and blue.pdf [3] Senior notes: Ryan Ho Urogenital.pdf (Section on ANCA-associated vasculitis, p.69) [4] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — Small vessel vasculitis, p.333) [5] Senior notes: Ryan Ho Fundamentals.pdf (Section 3.5.5 Acute Nephritic Syndrome and RPGN, p.359–361) [6] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (RPGN section, p.25–27) [7] Senior notes: Block A - I am losing weight and sweating all the time.pdf (Antithyroid drug side effects, p.20) [8] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Normal kidney histology and renal biopsy, p.3–4) [9] Senior notes: Maksim Surgery Notes.pdf (Haematuria section, p.308)
Differential Diagnosis of ANCA-Associated Glomerulonephritis
The clinical challenge with ANCA-GN is that it presents within the spectrum of acute nephritic syndrome and rapidly progressive glomerulonephritis (RPGN) — both of which have broad differential diagnoses. You are not really asking "does this patient have ANCA-GN?" in isolation; you are asking: "This patient has haematuria, rising creatinine, and perhaps haemoptysis — what is causing the glomerular injury, and how urgently do I need to act?"
The differential diagnosis is therefore structured in two tiers:
- Broad differential of RPGN / acute nephritic syndrome — what else could cause this clinical picture?
- Distinguishing within the pauci-immune category — if serological and biopsy data point towards ANCA-GN, which specific AAV entity is it?
Tier 1: Differential Diagnosis of RPGN (the Clinical Syndrome)
This is the most important framework. RPGN is classified by immunofluorescence (IF) staining pattern into three types [3][5][10][11]:
| IF Pattern | Type | Cause | Key Differentiating Features |
|---|---|---|---|
| Linear | Type I | Anti-GBM disease (Goodpasture syndrome if lung involvement) | Anti-GBM antibody positive; pulmonary haemorrhage (alveolar basement membrane cross-reactivity); young men or elderly; autoantibody production is transient and disease rarely relapses ( < 2%) [3][5][12] |
| Granular | Type II | Immune-complex mediated RPGN | Low complement (C3/C4); ANA/anti-dsDNA positive (lupus); ASO titre elevated (PSGN); serum IgA elevated (IgAN); cryoglobulins positive; HBV/HCV serology positive |
| Negative / Pauci-immune | Type III | ANCA-associated (GPA, MPA, EGPA, renal-limited); very few ( < 5%) ANCA-negative | ANCA positive (MPO or PR3); complement levels normal; no immune deposits on IF [3][5][10] |
GC 057 Lecture Slide — High Yield
The GC 057 lecture slide lists the differential diagnosis of haematuria as: urological conditions (stones, tumour), renal conditions (glomerulonephritis, acute interstitial nephritis, polycystic kidney disease), and infection (cystitis, TB, schistosomiasis) [1]. When approaching any patient with haematuria + rising creatinine, systematically exclude non-glomerular causes before narrowing within the GN differential.
- Why it mimics ANCA-GN: Both cause RPGN with crescents. Both can present with pulmonary-renal syndrome (haemoptysis + haematuria). Both are medical emergencies [10][12].
- How to differentiate:
- Anti-GBM antibody positive (by ELISA) — this is the definitive serological test [10][12]
- Linear IF staining on renal biopsy (anti-GBM antibody deposited along the entire GBM in a smooth line, like painting a wall — versus the "negative" IF in ANCA-GN)
- Complement levels are normal in anti-GBM disease (same as ANCA-GN — both differ from Type II)
- Transient autoantibody production → rarely relapses ( < 2%) [12] — unlike ANCA-GN (especially PR3-ANCA) which has a high relapse rate
- Serum Cr often > 250 μmol/L at diagnosis; T1 > T3 > T2 (anti-GBM disease tends to present with the most severe renal impairment at diagnosis) [5][10]
Double-Positive Disease
Approximately 5–10% of anti-GBM disease patients are also ANCA positive ("double positive"), and ~30% of ANCA-GN patients may have detectable anti-GBM. Always check BOTH ANCA AND anti-GBM simultaneously. Double-positive patients tend to behave more like ANCA-GN (relapsing course) but may have the severity of anti-GBM disease at presentation [3][10].
Goodpasture syndrome is a medical emergency — usually occurs in older patients. Antibodies cross-react with pulmonary alveolar basement membranes. Can cause pulmonary haemorrhage and death if not treated quickly [8].
These conditions deposit immune complexes in the glomerulus, activating the classical complement pathway → low C3 and/or C4 (the key distinguishing feature from ANCA-GN, where complement is normal).
| Condition | Key Differentiating Features |
|---|---|
| Lupus nephritis (SLE) | Young woman; malar rash, photosensitivity, oral ulcers, arthritis, serositis; ANA positive, anti-dsDNA positive, low C3/C4; granular IF ("full house" — IgG, IgA, IgM, C3, C1q); persistently low C3 > 8 weeks should raise suspicion [10][13][14] |
| Post-streptococcal GN (PSGN) | 1–3 weeks after pharyngitis, 3–6 weeks after skin infection; low C3 (normalises by 4–8 weeks); ASO titre elevated; granular "starry sky" IF; self-limiting in children; renal biopsy usually NOT done [10][13][15] |
| IgA nephropathy | Synpharyngitic haematuria (within 1–2 days of URTI) — contrasts with PSGN's 1–3 week latency; recurrent episodic haematuria; complement normal; serum IgA elevated in ~50%; mesangial IgA on IF [10][13][16] |
| Membranoproliferative GN (MPGN) | Persistently low C3 > 8 weeks (unlike PSGN which normalises); may be secondary to HBV/HCV, autoimmune disease, or malignancy; subendothelial deposits; "tram-track" GBM on LM [10][13][14] |
| Cryoglobulinaemia | Often secondary to HCV; palpable purpura, arthralgia, peripheral neuropathy; serum cryoglobulins positive; low C4 (classical pathway activation); granular IF [14][17] |
| Endocarditis-associated GN | Fever, new murmur, embolic phenomena; positive blood cultures; low C3/C4; granular IF [14] |
| Henoch-Schönlein purpura (IgA vasculitis) | Palpable purpura (buttocks/lower limbs), abdominal pain, arthralgia, GN; essentially systemic IgAN; complement normal; more common in children; mesangial IgA on IF [13][16] |
Complement Levels — The Great Differentiator
If complement (C3/C4) is low → think immune-complex mediated disease (Type II): SLE, PSGN, MPGN, cryoglobulinaemia, endocarditis-associated GN. If complement is normal → think anti-GBM (Type I) or ANCA-associated (Type III). This is the single most useful serological discriminator in the initial workup of RPGN.
Before you even enter the "which type of RPGN" algorithm, exclude conditions that mimic glomerulonephritis:
| Condition | Why It Mimics | How to Differentiate |
|---|---|---|
| Acute interstitial nephritis (AIN) | Rising creatinine + haematuria + pyuria | Drug history (antibiotics, NSAIDs, PPIs); sterile pyuria predominates; eosinophiluria; WBC casts (not RBC casts); no dysmorphic RBCs; drug rash + fever + eosinophilia triad [1][5] |
| Thrombotic microangiopathy (TMA) | Rising creatinine + haematuria | Microangiopathic haemolytic anaemia (MAHA): schistocytes on blood film, high LDH, low haptoglobin; thrombocytopaenia; no RBC casts |
| Atheroembolic disease | Elderly, post-vascular procedure + rising creatinine | Livedo reticularis, blue toes, eosinophilia; cholesterol clefts on biopsy |
| Urological causes | Haematuria | Isomorphic RBCs (not dysmorphic); blood clots present; CT urogram/cystoscopy needed; no RBC casts [9][16] |
| Acute tubular necrosis (ATN) | Rising creatinine + oliguria | Granular "muddy brown" casts; context of ischaemia/nephrotoxin; no dysmorphic RBCs or RBC casts |
Once serology (ANCA positive) and/or biopsy (pauci-immune crescentic GN) confirm ANCA-GN, the next question is: which systemic vasculitis, if any, is this part of? This matters because management and prognosis differ.
| Feature | GPA | MPA | EGPA | Renal-limited vasculitis |
|---|---|---|---|---|
| ANCA serotype | c-ANCA / anti-PR3 (~80%); p-ANCA (~20%) | p-ANCA / anti-MPO | p-ANCA / anti-MPO (~40%); ~60% ANCA-negative | p-ANCA / anti-MPO (~75–80%) |
| Upper airway | Yes: sinusitis, epistaxis, saddle nose, subglottic stenosis | No | Allergic rhinitis | No |
| Lower airway | Pulmonary nodules/cavities | Diffuse alveolar haemorrhage (DAH) | Asthma (late-onset, severe), eosinophilic pneumonia | No |
| Kidney | Pauci-immune GN | Pauci-immune GN (most common organ involved: 80–100%) | Pauci-immune GN (less common) | Pauci-immune GN (by definition) |
| Peripheral neuropathy | Mononeuritis multiplex | Mononeuritis multiplex | Mononeuritis multiplex | No |
| Skin | Palpable purpura | Palpable purpura | Palpable purpura | Usually no |
| Granulomas on biopsy | Yes (necrotising granulomatous) | No (non-granulomatous) | Yes (eosinophil-rich) | No |
| Relapse rate | High (especially PR3-ANCA) | Lower | Moderate | Low–moderate |
| HK predominance | Less common | Most common AAV in HK | Rare | Significant |
GC 053 Lecture Slide — High Yield: PAN vs MPA
The GC 053 lecture distinguishes PAN from MPA:
- PAN: renal involvement via vasculitis with infarcts/microaneurysms (NOT glomerulonephritis); HBV-associated in ~50%; abnormal angiogram with microaneurysms; ANCA negative; rarely relapses
- MPA: rapidly progressive glomerulonephritis; pulmonary haemorrhage; p-ANCA positive (50–80%); commonly relapses [2]
This is a critical distinction: PAN does NOT cause GN — it causes renal infarcts from medium-vessel vasculitis. If you see GN, it is NOT PAN.
This table is your "one-stop shop" for distinguishing the causes of RPGN:
| Test | ANCA-GN | Anti-GBM Disease | Lupus Nephritis | PSGN | IgAN | MPGN |
|---|---|---|---|---|---|---|
| ANCA | Positive (PR3 or MPO) | Usually negative | Usually negative | Negative | Negative | Negative |
| Anti-GBM | Usually negative | Positive | Negative | Negative | Negative | Negative |
| ANA / Anti-dsDNA | Negative | Negative | Positive | Negative | Negative | Negative |
| C3 / C4 | Normal | Normal | Low | Low C3 (normalises < 8w) | Normal | Low (persists > 8w) |
| ASO titre | Normal | Normal | Normal | Elevated | Normal | Normal |
| Serum IgA | Normal | Normal | Normal | Normal | Elevated (~50%) | Normal |
| IF pattern | Negative (pauci-immune) | Linear | Granular ("full house") | Granular ("starry sky") | Mesangial IgA | Granular |
| Onset relative to infection | Variable (may follow infection by days; infection primes neutrophils) | Not typically infection-related | Not typically infection-related | 1–3w post-pharyngitis; 3–6w post-skin infection | Synpharyngitic (within 1–2 days) | Variable |
[3][5][10][13][14][15][16][17]
High Yield Exam Point: The workup for glomerulonephritis includes: autoimmune markers (ANA, Anti-dsDNA, C3/4, ANCA, Anti-GBM, CRP, cryoglobulins); exclude infective causes (HBV/HCV/HIV/VDRL/malaria); malignancy screen (tumour markers, SIEP) especially in elderly; renal biopsy: LM/IF/EM findings → for diagnosis, guiding treatment decisions and prognosis [17].
In the clinical scenario, certain features should make you think "this is ANCA-GN and not one of the others":
- Elderly patient (peak 65–75 years) with RPGN — anti-GBM is bimodal (young men + elderly), lupus is young women, PSGN is children/young adults
- Normal complement — immediately excludes SLE, PSGN, MPGN, cryoglobulinaemia
- No latent period after infection — or if infection preceded, it was by days rather than the 1–6 week latency of PSGN. The infection "primed" neutrophils rather than generating immune complexes
- Constitutional symptoms (fever, weight loss, malaise) out of proportion — suggests systemic vasculitis
- Multisystem involvement: ENT symptoms (GPA), mononeuritis multiplex, palpable purpura, DAH — these point to systemic vasculitis rather than primary GN
- Drug history: PTU, hydralazine — drug-induced ANCA vasculitis [7]
- Subnephrotic proteinuria with active sediment — heavy proteinuria (nephrotic range) would more likely suggest membranous nephropathy, FSGS, or lupus nephritis class V
Don't Miss These
-
IgAN can mimic ANCA-GN clinically — both can cause asymptomatic haematuria that remit-relapses with normal RFT, and both can progress to RPGN. However, the risk of ESRD is much higher if ANCA-positive, so always check ANCA in patients with unexplained haematuria [3].
-
A patient with known diabetic nephropathy presenting with rapid GFR decline — don't assume it's just diabetic nephropathy progressing. Red flags for a superimposed GN (including ANCA-GN): active urine sediment (dysmorphic RBCs, RBC casts), sudden rise in creatinine, new-onset haemoptysis, constitutional symptoms. Don't miss a RPGN [18].
-
Membranous nephropathy can rarely be complicated by crescentic GN — some of these patients are ANCA-positive [5][10]. If a patient with known membranous nephropathy suddenly develops rapidly rising creatinine with active sediment, consider superimposed ANCA-GN.
-
ANCA can be falsely positive in infections (endocarditis, TB), inflammatory bowel disease, and other autoimmune conditions. ANCA is suggestive but not diagnostic — biopsy is the gold standard [3].
When a patient presents with haemoptysis + haematuria (pulmonary-renal syndrome), the differential narrows significantly [5][10][11][12]:
| Condition | Key Distinguishing Feature |
|---|---|
| ANCA-associated vasculitis (MPA, GPA) | ANCA positive; pauci-immune GN on biopsy; normal complement |
| Anti-GBM disease (Goodpasture syndrome) | Anti-GBM positive; linear IF on biopsy; transient; rarely relapses |
| SLE | ANA/anti-dsDNA positive; low C3/C4; full-house IF; young women |
| IgA vasculitis (HSP) | Palpable purpura (must!); abdominal pain; children; mesangial IgA |
| Cryoglobulinaemia | Cryoglobulins positive; low C4; HCV association |
| Infection-related | Endocarditis; Legionella; positive cultures |
High Yield Summary — Differential Diagnosis of ANCA-GN
- RPGN is classified by IF into Type I (linear — anti-GBM), Type II (granular — immune complex), Type III (pauci-immune — ANCA-associated). Type III is the most common.
- Complement levels are the great discriminator: Low → immune-complex disease; Normal → anti-GBM or ANCA-GN.
- Always check ANCA AND anti-GBM simultaneously — 5–10% are double positive.
- ANCA is suggestive but not diagnostic — can have false positives (infections, IBD) and false negatives. Biopsy is gold standard.
- Key clinical differentiators for ANCA-GN: elderly, normal complement, subnephrotic proteinuria, constitutional symptoms, multisystem vasculitic features.
- Don't miss RPGN in a patient with presumed diabetic nephropathy — look for red flags (active sediment, sudden creatinine rise, haemoptysis).
- PAN does NOT cause GN — it causes renal infarcts; if GN is present, think MPA not PAN.
- PTU-induced ANCA vasculitis is a specific and testable association.
Active Recall - Differential Diagnosis of ANCA-GN
References
[1] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (Slide: Differential diagnosis of haematuria) [2] Lecture slides: GC 053. Fingers turn white and blue.pdf (Slide: PAN vs MPA comparison table) [3] Senior notes: Ryan Ho Urogenital.pdf (Section 3.3.4 ANCA-associated Glomerulonephritis, p.68–69) [4] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — Small vessel vasculitis, p.333) [5] Senior notes: Ryan Ho Fundamentals.pdf (Section 3.5.5 RPGN classification and workup, p.361) [7] Senior notes: Block A - I am losing weight and sweating all the time.pdf (PTU-induced ANCA vasculitis, p.20) [8] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Goodpasture syndrome as emergency, p.3) [9] Senior notes: Maksim Surgery Notes.pdf (Haematuria differential, p.308) [10] Senior notes: Adrian Lui Pediatrics Notes.pdf (RPGN classification and workup, p.326) [11] Senior notes: Block A – Nephrology Data Interpretation.pdf (Pulmonary-renal syndrome differential, p.13–14) [12] Senior notes: Ryan Ho Urogenital.pdf (Anti-GBM disease management and prognosis, p.68) [13] Senior notes: Ryan Ho Urogenital.pdf (PSGN clinical and laboratory features, p.66) [14] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (Glomerular disease biochemical tests, p.1008) [15] Senior notes: Adrian Lui Pediatrics Notes.pdf (PSGN clinical features and lab findings, p.328) [16] Senior notes: Maksim Medicine Notes.pdf (Nephrology — IgAN, HSP, PSGN, anti-GBM table, p.233) [17] Lecture slides: Nephrology - Introduction to Renal Investigation.pdf (Workup for glomerulonephritis slide) [18] Senior notes: Block A - Nephrology Interactive Tutorial.pdf (Don't miss RPGN; red flags in diabetic nephropathy, p.5)
Important Preface: There Are No "Diagnostic Criteria" in the Traditional Sense
Unlike conditions such as SLE (SLICC/EULAR-ACR criteria) or rheumatic fever (Jones criteria), ANCA-GN does not have a single validated set of diagnostic criteria. Instead, the diagnosis is made by integrating:
- Clinical presentation (RPGN, nephritic syndrome, pulmonary-renal syndrome)
- Serological findings (ANCA positivity by immunoassay)
- Histopathological confirmation (renal biopsy showing pauci-immune necrotising/crescentic GN)
The overarching principle: serum ANCA is suggestive but not diagnostic — it can have both false positives and false negatives. Biopsy of the affected organ is the gold standard [3][11].
For the systemic vasculitis component (GPA, MPA, EGPA), classification criteria exist (ACR/EULAR 2022), but these are classification criteria for research purposes, not diagnostic criteria for clinical use. In clinical practice, we diagnose ANCA-GN by the combination of compatible clinical picture + serology + tissue biopsy.
Diagnostic Algorithm
The diagnostic approach to suspected ANCA-GN follows a systematic, stepwise process. The overarching clinical scenario is: a patient presenting with features of acute nephritic syndrome or RPGN (haematuria, rising creatinine, ± haemoptysis, ± constitutional symptoms).
Step-by-Step Approach
Before invoking any specific cause, confirm that the haematuria is glomerular in origin [1][5][10][19]:
- Urine dipstick: Blood ≥ 1+, Protein ≥ 1+
- Urine microscopy: dysmorphic RBCs and/or RBC casts → pathognomonic of GN
- Dysmorphic RBCs = RBCs distorted as they squeeze through the damaged GBM (acanthocytes are the most specific form)
- Isomorphic RBCs = uniform RBCs → suggests urological source (bladder, ureter, etc.)
- Blood clots are unusual in glomerular haematuria [1] — urokinase in glomerular filtrate lyses clots
GC 057 Lecture Slide — High Yield
The GC 057 slide emphasises differential diagnosis of haematuria: urologic conditions (stones, tumour), renal conditions (glomerulonephritis, acute interstitial nephritis, polycystic kidney disease), and infection (cystitis, TB, schistosomiasis) [1]. The urine microscopy is what separates glomerular from non-glomerular causes.
- RFT (renal function tests): serum creatinine, urea, eGFR
- Urine output monitoring: oliguria ( < 0.5 mL/kg/h) indicates severe disease
- Assess for life-threatening complications:
- Hyperkalaemia (ECG changes?)
- Pulmonary oedema (CXR)
- Diffuse alveolar haemorrhage (haemoptysis, dropping Hb, bilateral infiltrates on CXR, rising DLCO)
This is the critical "sorting" step. Order the following simultaneously — do NOT wait for one result before ordering the next, because RPGN can progress to irreversible renal failure in days [5][10][19][20]:
Workup for glomerulonephritis: Autoimmune markers (ANA, Anti-dsDNA, C3/4, ANCA, Anti-GBM, CRP, cryoglobulins); Exclude infective causes (HBV/HCV/HIV/VDRL/malaria); Malignancy screen (tumour markers, SIEP) especially in elderly; Renal biopsy: LM/IF/EM findings → Diagnosis, guide treatment decisions and prognosis [17].
| Test | What It Tests For | Expected in ANCA-GN | Expected if NOT ANCA-GN |
|---|---|---|---|
| ANCA (by ELISA: anti-PR3, anti-MPO) | ANCA-associated vasculitis | Positive (PR3 or MPO) | Negative (but ~5% pauci-immune GN is ANCA-negative) |
| Anti-GBM antibody | Anti-GBM disease | Negative (unless double-positive) | Positive in Goodpasture |
| C3, C4 | Complement consumption | Normal | Low in SLE, PSGN, MPGN, cryoglobulinaemia |
| ANA, Anti-dsDNA | Lupus nephritis | Negative | Positive in SLE |
| ASO titre | Recent streptococcal infection | Normal | Elevated in PSGN |
| Cryoglobulins | Cryoglobulinaemia | Negative | Positive (often HCV-associated) |
| HBV/HCV/HIV serology | Infection-associated GN | Negative (unless coincidental) | Positive → membranous (HBV), MPGN (HCV), FSGS (HIV) |
| ESR, CRP | Systemic inflammation | Elevated (often markedly) | Variable |
Complement as the Great Discriminator
Normal C3/C4 immediately narrows your differential to:
- Anti-GBM disease (Type I)
- ANCA-associated GN (Type III)
- IgA nephropathy (IgA-IgG immune complexes do NOT activate complement)
Low C3 ± low C4 → immune-complex mediated diseases (Type II): lupus nephritis, PSGN, MPGN, cryoglobulinaemia, endocarditis-associated GN [5][10][14].
Renal biopsy is necessary for most cases of nephritic syndrome and is essential for definitive diagnosis of ANCA-GN [3][5][8][10][17].
Why biopsy?
- Confirms the diagnosis: pauci-immune pattern on IF distinguishes from anti-GBM and immune-complex disease
- Guides treatment intensity: Berden classification (focal vs crescentic vs mixed vs sclerotic) predicts prognosis
- Assesses reversibility: proportion of cellular vs fibrous crescents determines how aggressively to treat
- Excludes concurrent disease: some patients have "double-positive" disease or superimposed pathology
Once ANCA-GN is confirmed, determine whether this is part of a systemic vasculitis or renal-limited:
- CXR / CT thorax: pulmonary nodules/cavities (GPA), diffuse alveolar haemorrhage (MPA)
- CT sinuses: sinusitis, bone erosions (GPA)
- DLCO: paradoxically increased in DAH (haemoglobin in alveoli binds CO)
- Nerve conduction studies: if mononeuritis multiplex suspected
- Skin biopsy: if palpable purpura — shows leukocytoclastic vasculitis
- Echocardiogram: rule out endocarditis if persistent fever + murmur (differential)
Investigation Modalities — Detailed Breakdown
| Investigation | Method | Key Findings in ANCA-GN | Interpretation / Why |
|---|---|---|---|
| Urine dipstick | Bedside colorimetric strips | Blood ≥ 1+, Protein ≥ 1+ | Screening test; cannot distinguish glomerular from urological haematuria; false positives from myoglobinuria/haemoglobinuria |
| Urine microscopy (light field) | Centrifuged urine sediment examined under microscope | Dysmorphic RBCs, RBC casts, sterile pyuria | RBC casts are pathognomonic of GN — they form when RBCs are trapped in Tamm-Horsfall protein within renal tubules; dysmorphic RBCs indicate passage through damaged GBM [1][5][10][19] |
| Urine protein quantification | 24-hour urine collection or spot ACR/PCR | Usually subnephrotic ( < 3.5 g/day) | Low GFR limits total protein filtered; primary injury is endothelial not podocyte; ↑↑ proteinuria should alert to concurrent second glomerular disease [3] |
| Investigation | Expected Findings | Clinical Significance |
|---|---|---|
| CBC with differential | NcNc anaemia (normocytic normochromic); ↑WBC may indicate infection triggering flare; eosinophilia in EGPA | Anaemia: dilutional (fluid overload) + anaemia of chronic disease + renal anaemia (↓EPO); eosinophilia > 1.5 × 10⁹/L strongly suggests EGPA [4][10][19][20] |
| RFT (urea, creatinine, eGFR) | ↑↑ creatinine; ↑ urea | Documents degree of renal impairment; urea:creatinine ratio > 100:1 may suggest pre-renal component; serial monitoring essential [5][10][19] |
| ESR | Usually elevated (often > 50 mm/hr) | Non-specific marker of systemic inflammation; important preliminary test [5][10] |
| CRP | Usually elevated | More specific for acute inflammation than ESR; tracks with disease activity [4][20] |
| Electrolytes | Hyperkalaemia, metabolic acidosis | Consequence of ↓GFR — reduced K⁺ and H⁺ excretion; may require urgent treatment |
| LFT | Usually normal unless hepatic involvement (rare) | Baseline before starting immunosuppression (many agents are hepatotoxic) |
| Blood glucose, HbA1c | To exclude DM nephropathy | Important to exclude DM as cause of proteinuria/renal impairment [10] |
C. Serological Panel — The "Sorting Hat"
This is the most important blood panel for determining the type of RPGN and the specific aetiology.
| Test | Method | Details |
|---|---|---|
| Indirect immunofluorescence (IIF) | Patient serum applied to ethanol-fixed neutrophils on glass slide; fluorescent anti-human IgG added | c-ANCA: diffuse granular cytoplasmic staining; p-ANCA: perinuclear staining (artefact — MPO redistributes to nuclear membrane during ethanol fixation). IIF is a screening test. |
| Antigen-specific ELISA | Measures antibodies against specific antigens (PR3 or MPO) | Anti-PR3 = c-ANCA pattern; Anti-MPO = p-ANCA pattern. ELISA is more specific than IIF. Modern practice: use ELISA as the primary screening test (2017 revised international consensus: high-quality immunoassays for PR3 and MPO can be used as primary screening without IIF). |
- Sensitivity of ANCA for AAV: ~90% for GPA, ~70% for MPA, ~40% for EGPA [4][20]
- Specificity: High when using ELISA, but false positives occur in infections (endocarditis, TB), IBD, and other autoimmune conditions [3][11]
- False negatives: ~10% of GPA and ~30% of MPA patients are ANCA-negative. A negative ANCA does NOT exclude ANCA-GN [3][11]
"Determination of anti-neutrophil cytoplasmic antibodies (ANCAs) can aid in the diagnosis, but positivity is not conclusive and negative ANCAs are not sufficient to reject the diagnosis" [11].
| Test | Purpose | Expected in ANCA-GN | Interpretation |
|---|---|---|---|
| Anti-GBM antibody (ELISA) | Rule out / rule in anti-GBM disease | Negative (unless double-positive ~5-10%) | Always check simultaneously with ANCA [5][10][14][20] |
| C3, C4 | Assess complement consumption | Normal | Low → Type II RPGN (SLE, PSGN, MPGN, cryoglobulinaemia). Persistently low C3 > 8 weeks → think lupus or MPGN, not PSGN [5][10][14] |
| ANA, Anti-dsDNA | Screen for SLE | Negative | Positive → lupus nephritis [14][20] |
| ASO titre | Evidence of recent strep infection | Normal | Elevated → PSGN [14] |
| Cryoglobulins | Cryoglobulinaemia | Negative | Positive → often HCV-associated; low C4 |
| HBV/HCV/HIV serology | Infection-associated GN | Negative (unless coincidental) | HBV → membranous; HCV → MPGN; HIV → collapsing FSGS [14] |
| SIEP / serum free light chains | Myeloma, amyloidosis | Normal | Monoclonal band → myeloma cast nephropathy or amyloid [14] |
Nephrology Interactive Tutorial — Workup for Acute Nephritic Syndrome
The Nephrology Interactive Tutorial teaches: for acute nephritic syndrome, order CBC, ANA, anti-dsDNA, C3/C4, ANCA, CRP for ANCA-associated vasculitis, and anti-GBM for Goodpasture's [19].
| Investigation | Indication | Key Findings | Interpretation |
|---|---|---|---|
| Chest X-ray (CXR) | All patients with suspected ANCA-GN | Bilateral lung infiltrates (DAH in MPA); pulmonary nodules ± cavitation (GPA) | DAH: bilateral ground-glass opacities; GPA: nodules/cavities may mimic malignancy or TB [4][11][20] |
| CT thorax (high-resolution) | If CXR abnormal or pulmonary symptoms present | Better delineation of nodules, cavities, ground-glass changes | More sensitive than CXR for early DAH or small nodules |
| CT sinuses | Suspected GPA with ENT symptoms | Sinusitis, mucosal thickening, bone erosions | Granulomatous destruction of sinuses [20] |
| Ultrasound kidneys | Best, most non-invasive way to assess and visualize kidneys | Normal-sized kidneys (10–12 cm) in acute disease | High creatinine + normal-sized kidneys = acute kidney injury → needs biopsy. Small kidneys = CKD (scarred/shrunken) → biopsy may not be helpful [22] |
| DLCO (diffusion capacity for CO) | Suspected DAH | Paradoxically increased DLCO | Haemoglobin within alveoli avidly binds CO → measured DLCO appears elevated despite respiratory impairment. This is a specific finding for intrapulmonary haemorrhage [5][6][10] |
For a patient presenting with RPGN, investigations include: full blood counts, biochemistry, urine protein quantification, urine sediments, autoimmune markers (ANCA, Anti-GBM, ANA, Anti-dsDNA, C3/C4), CXR, lung-function tests, DLCO [6].
E. Renal Biopsy — The Gold Standard
- All patients with suspected ANCA-GN should undergo renal biopsy unless:
- Contracted/small kidneys on ultrasound (suggests CKD — biopsy yields only fibrous tissue) [22]
- Solitary kidney (risk too high)
- Large cysts (bleeding risk)
- Uncorrectable bleeding diathesis
- If the person has signs of kidney involvement or cutaneous vasculitis, a biopsy is obtained [11]
What the Biopsy Tells You
Renal biopsy tissue is examined by three modalities (LM, IF, EM):
| Finding | Description | Significance |
|---|---|---|
| Necrotising lesions | Fibrinoid necrosis of glomerular capillary walls | Active disease — reflects ANCA-mediated neutrophil injury destroying the capillary wall |
| Cellular crescents | Proliferating parietal epithelial cells + macrophages filling Bowman's space in a crescent shape | Hallmark of RPGN; potentially reversible with immunosuppression [5][6][10] |
| Fibrous crescents | Crescents replaced by collagen/fibroblasts | Irreversible damage — unlikely to respond to immunosuppression [5][10] |
| Segmental sclerosis | Parts of glomeruli replaced by hyaline scar | Chronic damage — glomerulus permanently lost |
| Global sclerosis | Entire glomerulus replaced by scar | End-stage glomerular damage |
| Granulomatous inflammation | Multinucleated giant cells, epithelioid histiocytes | Specific to GPA — not seen in MPA or renal-limited vasculitis [3][4][20] |
| Variable interstitial inflammation | Lymphocytes, macrophages in interstitium | Accompanies glomerular injury; if severe → tubular atrophy |
Berden Histological Classification (prognostic, guides treatment intensity) [3]:
| Class | Definition | 1-Year Renal Survival | 5-Year Renal Survival |
|---|---|---|---|
| Focal | ≥50% glomeruli normal | ~93% | ~93% |
| Crescentic | ≥50% glomeruli with crescents | ~84% | ~76% |
| Mixed | < 50% normal, < 50% crescentic, < 50% sclerotic | ~80% | ~61% |
| Sclerotic | ≥50% globally sclerotic | ~50% | ~32% |
| Finding | Interpretation |
|---|---|
| Negative / Pauci-immune (no or minimal Ig/complement staining) | Confirms ANCA-GN (Type III RPGN) — damage is neutrophil-mediated, not immune-complex-mediated [3][5][10] |
| Linear IgG along GBM | Anti-GBM disease (Type I) |
| Granular deposits | Immune-complex disease (Type II) |
The IF Pattern Is the Single Most Important Biopsy Finding for Classification
- In ANCA-GN: no electron-dense deposits (consistent with pauci-immune pattern)
- This contrasts with:
- Anti-GBM: no deposits (linear IF is antibody bound directly to GBM, not deposited immune complexes)
- Immune-complex GN: electron-dense deposits in subepithelial (membranous), subendothelial (lupus class IV), or mesangial (IgAN) locations
| Investigation | Purpose | When to Order |
|---|---|---|
| ECG | Hyperkalaemia screening; baseline cardiac assessment | All patients with AKI |
| Arterial blood gas | Assess acid-base status; oxygenation if DAH suspected | If low SpO2 or respiratory distress [11] |
| Nerve conduction studies / EMG | Mononeuritis multiplex | If clinical suspicion of peripheral neuropathy |
| Echocardiogram | Rule out infective endocarditis (differential) | If persistent fever + murmur |
| Bronchoscopy with BAL | Confirm DAH | If haemoptysis present — progressively bloodier returns on serial lavage |
| Skin biopsy | Leukocytoclastic vasculitis | If palpable purpura present [4] |
| ENT biopsy | Granulomatous inflammation (GPA) | If ENT symptoms (crusting, epistaxis, saddle nose) |
Common Mistakes to Avoid
-
ANCA-positive ≠ ANCA-GN: False positives occur in infections (especially endocarditis, which can also cause GN and mimic pulmonary-renal syndrome), IBD, and other autoimmune diseases. Always biopsy.
-
ANCA-negative ≠ not ANCA-GN: ~5–30% of patients with histologically confirmed pauci-immune GN are ANCA-negative. These patients have similar biopsy findings and prognosis to ANCA-positive patients [3].
-
Do not wait for serology to start treatment: ANCA/anti-GBM results may take days. If clinical picture is RPGN (rapidly rising Cr + active sediment), start empirical pulse IV methylprednisolone while awaiting results [5][10].
-
Small kidneys on USS: Do not biopsy — they indicate CKD with irreversible damage. You'll only get fibrous tissue. Normal-sized kidneys with high creatinine = AKI, and a biopsy is needed [22].
-
Rising DLCO in a patient with haemoptysis: This is paradoxical and specific for diffuse alveolar haemorrhage — the blood in the alveoli binds CO, giving a falsely high DLCO reading.
| Category | Tests |
|---|---|
| Urine | Dipstick, microscopy (dysmorphic RBC, RBC casts), protein quantification (24h or ACR) |
| Baseline bloods | CBC D/C, RFT, ESR, CRP, electrolytes, LFT, glucose/HbA1c |
| Serological panel | ANCA (anti-PR3, anti-MPO), Anti-GBM, C3/C4, ANA, anti-dsDNA, ASO, cryoglobulins, HBV/HCV/HIV, SIEP |
| Imaging | USS kidneys (size, exclude obstruction), CXR, ± CT thorax, ± CT sinuses |
| Lung function | DLCO (↑ in DAH) |
| Biopsy | Renal biopsy: LM/IF/EM — gold standard for diagnosis, classification, and prognosis |
| Systemic | ECG, ABG, ± NCS/EMG, ± echocardiogram, ± bronchoscopy + BAL, ± skin/ENT biopsy |
High Yield Summary — Diagnosis of ANCA-GN
- No single diagnostic criteria set — diagnosis integrates clinical picture + serology + biopsy.
- Step 1: Confirm GN by urine microscopy (dysmorphic RBCs, RBC casts).
- Step 2: Assess severity (RFT, rate of Cr rise, oliguria).
- Step 3: Simultaneous serological panel — ANCA, anti-GBM, C3/C4, ANA/dsDNA are the minimum.
- Normal complement + ANCA positive = likely ANCA-GN; low complement = immune-complex disease.
- ANCA is suggestive but not diagnostic — can have false positives AND false negatives.
- Renal biopsy is the gold standard: pauci-immune IF confirms Type III RPGN; Berden classification (focal/crescentic/mixed/sclerotic) predicts prognosis.
- Do not delay treatment — empirical pulse IV methylprednisolone can be given before biopsy if RPGN is clinically suspected.
- DLCO paradoxically increases in diffuse alveolar haemorrhage (CO binds to alveolar blood).
- Normal-sized kidneys + high creatinine = AKI → biopsy needed. Small kidneys = CKD → biopsy often not helpful.
Active Recall - Diagnostic Criteria, Algorithm, and Investigations for ANCA-GN
[1] Lecture slides: GC 057. Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (Slide: Differential diagnosis of haematuria) [3] Senior notes: Ryan Ho Urogenital.pdf (Section 3.3.4 ANCA-associated Glomerulonephritis, p.69) [4] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — Small vessel vasculitis, p.333) [5] Senior notes: Ryan Ho Fundamentals.pdf (Section 3.5.5 RPGN classification and workup, p.360–361) [6] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (RPGN investigations, p.26) [8] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Renal biopsy for diagnosis, p.3–4) [10] Senior notes: Adrian Lui Pediatrics Notes.pdf (Evaluation of acute nephritic syndrome, p.325–326) [11] Senior notes: Block A – Nephrology Data Interpretation.pdf (ANCA not conclusive, biopsy needed, p.14–15) [14] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (Biochemical tests for GN diagnosis, p.415) [16] Senior notes: Maksim Medicine Notes.pdf (Nephrology — RPGN classification, p.233) [17] Lecture slides: Nephrology - Introduction to Renal Investigation.pdf (Workup for glomerulonephritis slide) [19] Senior notes: Block A - Nephrology Interactive Tutorial.pdf (Acute nephritic syndrome case and workup, p.1–2) [20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (GPA/MPA diagnosis — biochemical and radiological tests, p.1772–1774) [21] Senior notes: Ryan Ho Critical Care.pdf (AKI workup — urinalysis findings, p.27) [22] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (Kidney sizes on US, p.13)
Post-Streptococcal Glomerulonephritis
Post-streptococcal glomerulonephritis is an immune complex–mediated glomerulonephritis that develops as a delayed complication of nephritogenic Group A streptococcal infection, representing the prototypical acute nephritic syndrome.
Anti-GBM Disease
Anti-GBM disease is a small-vessel vasculitis caused by circulating autoantibodies directed against the alpha-3 chain of type IV collagen in glomerular and alveolar basement membranes, leading to rapidly progressive glomerulonephritis and, when pulmonary involvement occurs (Goodpasture syndrome), diffuse alveolar hemorrhage.