ANCA-associated glomerulonephritis is a pauci-immune necrotizing and crescentic glomerulonephritis caused by antineutrophil cytoplasmic antibodies directed against myeloperoxidase or proteinase 3, leading to rapidly progressive renal failure.

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

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.

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].

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.

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)

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.

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

^[2]^[3]^[4]^[10]

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].

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)

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

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

^[5]^[10]^[14]^[17]^[19]^[20]

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].

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]

Key Exam Point

All Hb-positive dipstick should be accompanied by urine microscopy to differentiate true haematuria from pigmenturia (myoglobin, haemoglobin). Furthermore, glomerular haematuria = dysmorphic RBCs / RBC casts; urological haematuria = isomorphic RBCs ± clots ^[19]^[21].

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

Renal biopsy is still essential for definitive diagnosis of ANCA-associated vasculitis ^[3]^[8]^[17].

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

The immunofluorescence pattern is the most helpful finding for diagnosis of the type of RPGN ^[5]^[10]. In ANCA-GN, IF is unremarkable ("pauci-immune") ^[3]. This is why biopsy is gold standard — serology alone cannot give you the IF pattern.

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)

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

Management Algorithm and Treatment Modalities for ANCA-Associated Glomerulonephritis

Before any immunosuppressive therapy, you must stabilise the patient. ANCA-GN presenting as RPGN is essentially an AKI + systemic vasculitis emergency ^[21]^[23].

Complication	Management	Why
Hyperkalaemia	IV calcium gluconate (cardioprotection); insulin-dextrose drip (shifts K+ intracellularly); oral/rectal calcium polystyrene sulfonate (eliminates K+); dialysis if refractory	Reduced GFR → impaired K+ excretion → risk of fatal arrhythmias. IV calcium stabilises the cardiac membrane (does not lower K+). Insulin activates Na+/K+-ATPase to shift K+ into cells ^[23].
Fluid overload / pulmonary oedema	IV loop diuretics (furosemide); fluid and salt restriction; dialysis if refractory	Oliguric AKI → sodium/water retention → volume expansion → pulmonary oedema. Furosemide acts on Na-K-2Cl cotransporter in thick ascending limb to promote natriuresis ^[23].
Metabolic acidosis	IV sodium bicarbonate; dialysis if pH < 7.1 refractory to bicarbonate	Impaired H+ excretion and reduced HCO3⁻ regeneration. Bicarbonate directly buffers H+ ^[23].
Diffuse alveolar haemorrhage	Urgent intubation if needed; high-dose IV methylprednisolone; consider plasma exchange	DAH is life-threatening — the same ANCA-mediated vasculitis attacking pulmonary capillaries. Needs immediate immunosuppression.
Uraemic symptoms	Dialysis (AEIOU indications)	Nausea, encephalopathy, pericarditis from nitrogenous waste accumulation

Haemodialysis indications (mnemonic: AEIOU): Acidosis (pH < 7.1 refractory), Electrolytes (hyperK > 6.5 refractory), Intoxication (drug overdose), Overload (fluid overload refractory to diuretics), Uraemia (pericarditis, neuropathy, encephalopathy) ^[23].

Phase 2: Induction Therapy

The goal of induction is to rapidly suppress the ANCA-mediated autoimmune attack and halt further glomerular destruction. This phase typically lasts 3–6 months.

Glucocorticoids are the backbone of induction — they suppress the acute inflammatory response while other slower-acting immunosuppressants take effect.

Regimen	Details	Mechanism
Pulse IV methylprednisolone	500–1000 mg IV daily × 3 days	Rapid, high-dose anti-inflammatory effect: suppresses NF-κB transcription → ↓ cytokine production (TNF-α, IL-1, IL-6); ↓ neutrophil activation, adhesion, and degranulation; stabilises endothelium
Oral prednisolone	Start 1 mg/kg/day (max 60–80 mg/day) after pulse; taper over 3–6 months	Continued anti-inflammatory and immunosuppressive effect during transition to steroid-sparing agents

Can give empirical pulse IV methylprednisolone before renal biopsy if clinically indicated ^[5]^[10] — this is a critical exam point. You do NOT wait for biopsy results if clinical RPGN is suspected.

Steroid Tapering — Why?

Long-term high-dose GC cause devastating side effects: osteoporosis, DM, cataracts, infections, AVN of femoral head, cushingoid features, adrenal suppression, growth retardation. The entire strategy of ANCA-GN management is to get the patient off steroids (or on the lowest possible dose) as quickly as safely possible by using steroid-sparing agents.

CYC = "cyclo" (ring) + "phosphamide" (nitrogen mustard derivative) — an alkylating agent that cross-links DNA, killing rapidly dividing cells (including lymphocytes that produce ANCA).

Route	Regimen	Advantages	Disadvantages
IV pulse CYC	15 mg/kg (max 1.2 g) every 2 weeks × 3, then every 3 weeks × 3–6 doses	Lower cumulative dose → fewer side effects; better compliance	Slightly less proven in PR3-ANCA/GPA
Oral CYC	2 mg/kg/day for 3–6 months	Historically the "standard"; well-studied	Higher cumulative dose → more toxicity (bladder, gonadal)

Side effects (important for exams):

Side Effect	Mechanism	Prevention
Bone marrow suppression (leucopaenia, thrombocytopaenia)	Alkylation of haematopoietic stem cell DNA	Regular CBC monitoring (every 1–2 weeks); dose adjustment for WBC < 3.0
Haemorrhagic cystitis	Acrolein (CYC metabolite) is excreted in urine and directly damages bladder urothelium	IV MESNA (2-mercaptoethane sulfonate — binds acrolein in urine, neutralising it); aggressive hydration; void frequently
Gonadal toxicity (infertility)	Alkylation destroys germ cells (ova, spermatocytes)	Sperm/oocyte cryopreservation before treatment; GnRH agonists in women (suppress ovarian function during CYC, making ova "quiescent" and less susceptible)
Increased malignancy risk (especially bladder cancer, haematological malignancies)	Cumulative DNA damage from alkylation	Limit cumulative lifetime dose; switch to maintenance agent after induction
Infections (opportunistic)	Immunosuppression: profound lymphopaenia	PJP prophylaxis (co-trimoxazole); infection monitoring

Rituximab = "ri" (chimeric) + "tuxi" + "mab" (monoclonal antibody) — a chimeric anti-CD20 monoclonal antibody that depletes B cells.

Feature	Details
Mechanism	Binds CD20 on pre-B and mature B lymphocytes → complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and direct apoptosis → B cell depletion → reduced ANCA production
Regimen	375 mg/m² IV weekly × 4 doses or 1000 mg IV × 2 doses (day 0 and day 14)
Evidence	RAVE trial (2010) and RITUXVAS trial (2010) established RTX as non-inferior to CYC for induction. RAVE showed RTX may be superior to CYC for relapsing disease and PR3-ANCA/GPA
Advantages	No gonadal toxicity; no haemorrhagic cystitis; no increased bladder cancer risk; may be superior for PR3-ANCA positive disease and relapsing disease
Disadvantages	Infusion reactions; late-onset neutropaenia; hypogammaglobulinaemia (↓IgG → infection risk); progressive multifocal leukoencephalopathy (PML — extremely rare); HBV reactivation risk

Current guideline position (KDIGO 2024, ACR/Vasculitis Foundation 2021): Rituximab is the preferred induction agent for GPA and MPA, especially in patients at high risk of CYC toxicity (young patients, women of child-bearing age) and in relapsing disease. CYC remains an acceptable alternative.

Avacopan = a small molecule inhibitor of the complement C5a receptor (C5aR1).

Feature	Details
Mechanism	Blocks the C5a receptor on neutrophils → prevents C5a-mediated neutrophil priming and activation → breaks the positive feedback loop (ANCA activates neutrophils → complement activated → C5a primes more neutrophils → more damage)
Evidence	ADVOCATE trial (2021): avacopan + reduced-dose GC was non-inferior to standard-dose GC for remission at week 26 and superior for sustained remission at week 52. Also better for GFR recovery.
Role	Glucocorticoid-sparing adjunct — allows faster and more complete GC tapering while maintaining efficacy. Given WITH RTX or CYC, but allows reduction/elimination of prednisone.
Regimen	30 mg PO twice daily
Side effects	Hepatotoxicity (monitor LFT), GI upset, upper respiratory infections
FDA/EMA approval	Approved for AAV in 2021

Why Avacopan Matters

The alternative complement pathway (C5a) was discovered to play a significant pathogenic role in ANCA-GN despite it being "pauci-immune." C5a primes neutrophils via the C5a receptor, amplifying ANCA-mediated damage. Blocking this receptor is a targeted approach that reduces reliance on broad-spectrum glucocorticoids, which cause most of the treatment-related morbidity in AAV.

Factor	Favours RTX	Favours CYC
Relapsing disease	RTX superior	—
PR3-ANCA / GPA	RTX may be superior	—
Young patient / fertility concerns	RTX (no gonadal toxicity)	—
Prior CYC exposure (high cumulative dose)	RTX	—
Severe renal disease (Cr > 500 or dialysis)	Less data	CYC historically more data
Cost / availability	More expensive	Less expensive
MPO-ANCA / MPA	Both equivalent	Both equivalent
HBV carrier	Caution (reactivation risk)	May be preferred with antiviral cover

Plasma exchange (plasmapheresis) physically removes circulating ANCA and complement components from the blood.

Feature	Details
Mechanism	Patient's plasma is separated from blood cells → discarded → replaced with albumin or FFP. This mechanically removes pathogenic ANCA, C5a, cytokines, and other inflammatory mediators
Regimen	Daily or alternate-day exchanges of 3–4 litres × 5–7 sessions over 2–3 weeks
Indications (current, post-PEXIVAS trial 2020)	Reserved for: (1) Diffuse alveolar haemorrhage (DAH) — strong indication; (2) Anti-GBM overlap ("double-positive" disease); (3) Possibly in severe renal disease (Cr > 500 or dialysis-dependent), though PEXIVAS showed no overall survival or ESRD benefit in the broad ANCA-GN population
NOT routinely indicated	PEXIVAS trial (2020) showed no benefit of PLEX over standard therapy for the primary composite endpoint of death or ESRD in the general ANCA-GN population. Current guidelines reserve PLEX for the above specific scenarios.

Plasma exchange for anti-GBM disease; plasma exchange for fulminant MPA/GPA or Goodpasture's syndrome ^[12]^[16].

PEXIVAS Trial — Exam Pearl

The PEXIVAS trial (NEJM 2020) was a landmark RCT that changed practice: it showed that in ANCA-GN, adding PLEX to standard immunosuppression did NOT reduce death or ESRD overall. It also showed that a reduced-dose GC regimen was non-inferior to a standard-dose GC regimen. This shifted the field toward less GC and no routine PLEX (except for DAH and anti-GBM overlap).

After achieving remission (typically 3–6 months of induction), the goal shifts to preventing relapse while minimising immunosuppression toxicity. Relapse is common in ANCA-GN: ~50% at 5 years for PR3-ANCA; ~20% for MPO-ANCA.

Agent	Regimen	Mechanism	Key Points
Rituximab	500 mg IV every 6 months (fixed dosing) or guided by CD19 count/ANCA titre	B cell depletion → sustained suppression of ANCA production	MAINRITSAN trial: RTX maintenance was superior to AZA for preventing relapse; now considered first-line maintenance for most patients
Azathioprine (AZA)	2 mg/kg/day orally	Purine analogue → inhibits DNA synthesis in lymphocytes → immunosuppression	Alternative if RTX unavailable/contraindicated; check TPMT genotype before starting (TPMT deficiency → severe myelosuppression)
Mycophenolate mofetil (MMF)	1–2 g/day orally	Inhibits inosine monophosphate dehydrogenase (IMPDH) → blocks de novo purine synthesis in lymphocytes	Alternative to AZA; higher relapse rate than RTX or AZA in some studies; useful if AZA intolerant
Methotrexate (MTX)	20–25 mg/week orally	Folate antagonist → inhibits dihydrofolate reductase → blocks DNA synthesis	Reserved for non-organ-threatening GPA (e.g., ENT-limited); contraindicated if GFR < 30 (renal excretion → accumulation → toxicity)
Low-dose prednisolone	5–7.5 mg/day, taper and aim to discontinue	Anti-inflammatory	Faster taper now supported by PEXIVAS and LoVAS trials; prolonged GC use adds toxicity without clear benefit

Duration of maintenance: at least 24–48 months (some experts recommend ≥36 months for PR3-ANCA due to higher relapse risk). The decision to stop must balance relapse risk vs cumulative immunosuppression toxicity ^[3]^[4]^[20].

Parameter	Frequency	Purpose
RFT (creatinine, eGFR)	Every 1–2 weeks during induction; monthly during maintenance	Track renal recovery or detect deterioration/relapse
Urinalysis (microscopy + protein)	Every visit	New active sediment (dysmorphic RBCs, RBC casts) may signal relapse
CBC with differential	Every 1–2 weeks during CYC; monthly during maintenance	Detect bone marrow suppression (leucopaenia, thrombocytopaenia) — dose-adjust CYC if WBC < 3.0
ANCA titres (anti-PR3 / anti-MPO)	Every 3–6 months	Rising ANCA may precede clinical relapse — but ANCA rise alone without clinical signs does NOT mandate treatment change; it prompts closer surveillance
CRP / ESR	Every visit	Track inflammation; rising levels may indicate relapse or infection
LFT	Regular	Monitor hepatotoxicity from AZA, MTX, avacopan
Immunoglobulin levels (IgG)	Every 6 months if on RTX	Hypogammaglobulinaemia → ↑ infection risk; may need IV immunoglobulin replacement if IgG < 3 g/L with recurrent infections

Immunosuppression dramatically increases infection risk. This is the leading cause of death in the first year of AAV treatment — not the vasculitis itself.

Infection	Prophylaxis	Why
Pneumocystis jirovecii pneumonia (PJP)	Co-trimoxazole (TMP-SMX) 480 mg daily or 960 mg three times weekly	PJP is a life-threatening opportunistic pneumonia in immunosuppressed patients; co-trimoxazole is highly effective prophylaxis. Continue for duration of immunosuppression.
Influenza	Annual influenza vaccination	Immunosuppressed patients at high risk of severe influenza
Pneumococcus	Pneumococcal vaccination (PCV13 + PPSV23)	Indicated for ALL patients with glomerulopathy ^[5]; immunosuppression increases susceptibility
COVID-19	COVID-19 vaccination (may have attenuated response on RTX)	RTX depletes B cells → impaired vaccine response; time vaccination ≥4 months after RTX dose
HBV reactivation	Check HBsAg/anti-HBc before RTX; if positive, start antiviral prophylaxis (entecavir)	RTX-mediated B cell depletion can reactivate latent HBV → fulminant hepatitis
Strongyloides	Screen in endemic areas; treat with ivermectin if positive before starting GC	GC-induced immunosuppression → hyperinfection syndrome (fatal disseminated strongyloidiasis)

Special Situations

Agent	Absolute Contraindications	Relative Contraindications
CYC	Pregnancy, lactation	Active infection; prior bladder cancer; very high cumulative lifetime dose; severe leucopaenia
RTX	Active severe infection (especially HBV without antiviral cover); severe hypogammaglobulinaemia	Pregnancy; recent live vaccination
AZA	TPMT homozygous deficiency (severe myelosuppression)	Allopurinol co-administration (inhibits AZA metabolism → toxicity); pregnancy is NOT a contraindication (AZA is safe)
MTX	GFR < 30 mL/min (renal excretion → accumulation); pregnancy; severe hepatic impairment	Alcohol excess; interstitial lung disease
MMF	Pregnancy (teratogenic)	Active GI disease
Avacopan	Severe hepatic impairment	—
GC (high dose)	No absolute contraindication in life-threatening disease	Uncontrolled DM, active TB, psychosis (relative — manage concomitantly)

Once the acute immunosuppressive treatment has been initiated and the patient is stabilised, general renoprotective measures should be continued long-term:

Measure	Mechanism	Details
ACEI / ARB	↓ intraglomerular pressure → ↓ proteinuria → ↓ rate of GFR decline	Indicated in ALL glomerulopathy ^[5]; titrate to reduce proteinuria < 1 g/day; monitor K+ and Cr (hold if Cr rises > 30% or hyperK develops)
Blood pressure control	Reduces haemodynamic glomerular injury	Target < 130/80 mmHg (or < 125/75 if proteinuria > 1 g/day)
Salt restriction	Reduces volume expansion and enhances ACEI/ARB efficacy	~2 g sodium/day
SGLT2 inhibitors	Emerging evidence for renoprotection in CKD (DAPA-CKD, EMPA-KIDNEY trials)	Increasingly used as adjunctive renoprotection in ANCA-GN with CKD; not yet in formal AAV guidelines but rapidly adopted
Statin	Treats hyperlipidaemia if persists after immunosuppressive treatment	Cardiovascular risk reduction in CKD patients

Phase	Duration	Regimen
Immediate	Hours–days	Stabilise AKI complications (hyperK, fluid overload, acidosis); empirical pulse IV methylprednisolone if clinical RPGN
Induction	3–6 months	GC (pulse MP × 3 then oral pred taper) + RTX or CYC ± avacopan ± PLEX (if DAH or anti-GBM overlap)
Maintenance	≥24–48 months	RTX (preferred) or AZA or MMF + low-dose prednisolone taper; PJP prophylaxis
Long-term	Indefinite	Renoprotection (ACEI/ARB, BP control, salt restriction); infection prophylaxis; relapse surveillance; prepare for RRT if progressing to ESRD

High Yield Summary — Management of ANCA-GN

Two-phase model: Induction (3–6 months) → Maintenance (≥24–48 months).
Empirical pulse IV methylprednisolone can be given BEFORE biopsy if clinical RPGN is suspected.
Induction: high-dose GC + RTX (preferred) or CYC. RTX is preferred for relapsing disease, PR3-ANCA/GPA, and fertility concerns.
Avacopan (C5aR1 inhibitor) is a new GC-sparing adjunct (ADVOCATE trial 2021).
PLEX is NOT routinely indicated (PEXIVAS 2020) — reserved for DAH and anti-GBM overlap.
Maintenance: RTX (first-line, MAINRITSAN trial) or AZA or MMF + taper GC.
PJP prophylaxis with co-trimoxazole for all immunosuppressed patients.
Check TPMT before AZA; check HBV status before RTX.
MTX is contraindicated if GFR < 30; CYC is contraindicated in pregnancy.
ACEI/ARB for ALL glomerulopathy — reduces proteinuria and slows GFR decline.
Infection is the leading cause of death in the first year — not the vasculitis.
Dialysis-dependent patients at presentation have guarded renal prognosis, but a trial of immunosuppression may still be warranted if biopsy shows cellular (not sclerotic) crescents.

Active Recall - Management of ANCA-GN

References

^[3] Senior notes: Ryan Ho Urogenital.pdf (Section 3.3.4 ANCA-associated GN — management, p.69) ^[4] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — ANCA-associated vasculitis management, p.333) ^[5] Senior notes: Ryan Ho Fundamentals.pdf (Section 3.5.5 RPGN management and general GN management, p.361, 368) ^[6] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (RPGN treatment, p.26–28) ^[7] Senior notes: Block A - I am losing weight and sweating all the time.pdf (PTU-induced ANCA vasculitis, p.20) ^[10] Senior notes: Adrian Lui Pediatrics Notes.pdf (RPGN management — empirical pulse MP, p.326) ^[11] Senior notes: Block A – Nephrology Data Interpretation.pdf (ANCA not conclusive; biopsy needed; Goodpasture treatment, p.14–15) ^[12] Senior notes: Ryan Ho Urogenital.pdf (Anti-GBM disease management — PLEX, prognosis, p.68) ^[16] Senior notes: Maksim Medicine Notes.pdf (Nephrology — RPGN management, PLEX indications, p.233) ^[17] Lecture slides: Nephrology - Introduction to Renal Investigation.pdf (Workup for GN slide) ^[20] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (GPA/MPA treatment — induction and maintenance, p.1772–1774) ^[21] Senior notes: Ryan Ho Critical Care.pdf (AKI management — immediate approach, p.25–27) ^[23] Senior notes: Ryan Ho Critical Care.pdf (Haemodialysis indications, hyperkalaemia management, p.26) ^[24] Senior notes: Block A - Drugs and the Kidney.pdf (Drug-induced vasculitis management, p.8–9)

Complications of ANCA-Associated Glomerulonephritis

Complications of ANCA-GN fall into two broad categories: disease-related complications (the direct consequences of the vasculitis and glomerular destruction) and treatment-related complications (the consequences of the immunosuppressive therapy). In clinical practice and exams, both are equally important — in fact, infection is the leading cause of death in the first year of AAV treatment, not the vasculitis itself.

Think of it this way: ANCA-GN is a disease where you must balance two opposing harms — undertreating leads to irreversible organ destruction, while overtreating leads to life-threatening immunosuppression toxicity. Understanding complications on both sides is essential for optimal management.

A. Complications of the Disease Itself

This is the most feared renal complication and the one that drives the urgency of treatment.

Feature	Explanation
Mechanism	Rapidly declining renal function leading to ESRD in days to weeks ^[5]^[10] — crescents compress the capillary tuft, obliterating the filtering surface. Once cellular crescents become fibrous crescents (unlikely to respond to immunosuppressive treatment) ^[5]^[10], the glomerulus is permanently destroyed. Cumulative glomerular loss → irreversible CKD → ESRD.
Risk factors for ESRD	Sclerotic Berden class on biopsy (≥50% globally sclerotic — worst prognosis) ^[3]; dialysis-dependent at presentation (patients who require immediate dialysis are unlikely to be dialysis-free in the long term) ^[12]; delayed treatment initiation; high initial serum creatinine
Incidence	Approximately 20–25% of ANCA-GN patients reach ESRD within 5 years despite treatment
Consequences of ESRD	Requires renal replacement therapy (haemodialysis, peritoneal dialysis, or renal transplantation) ^[6]^[25]

Chronic glomerulonephritis is an important cause of CKD ^[10]^[25]. In Hong Kong, vasculitis and SLE are among the listed causes of CKD, though diabetes and hypertension remain the top two ^[25].

When ANCA-GN progresses to CKD, the metabolic complications of CKD themselves become important:

CKD Complication	Pathophysiology
Anaemia (NcNc)	↓ erythropoietin production by damaged kidney + anaemia of chronic disease + uraemic suppression of erythropoiesis ^[6]^[25]
CKD-Mineral Bone Disease (CKD-MBD)	↓ 1,25-dihydroxyvitamin D activation → hypocalcaemia + hyperphosphataemia → secondary hyperparathyroidism → renal osteodystrophy + vascular calcification ^[25]
Metabolic acidosis (HAGMA)	↓ renal H⁺ excretion and ↓ HCO₃⁻ regeneration ^[6]
Hyperkalaemia	↓ distal tubular K⁺ secretion → risk of cardiac arrhythmia
Fluid overload	↓ sodium/water excretion → oedema, hypertension, pulmonary oedema
Cardiovascular disease	Accelerated atherosclerosis from CKD itself (chronic inflammation, dyslipidaemia, hypertension, vascular calcification) + the vasculitis
Uraemic symptoms	Nausea, anorexia, pruritus, fatigue, neuropathy, pericarditis, encephalopathy when GFR approaches < 15 mL/min ^[25]

Therapeutic objectives for CKD: delay kidney failure, control hypertension, reduce albuminuria, treat anaemia and MBD disorder, treat acidosis and high K, control lipid and CV risk ^[25].

Recurrence Post-Transplant

If an ANCA-GN patient reaches ESRD and receives a kidney transplant, there is a risk of recurrence of primary disease in the allograft. This is listed among the long-term complications of kidney transplant ^[26]. ANCA-GN can recur in the transplanted kidney, especially in PR3-ANCA positive patients. Transplantation is generally delayed until disease is in sustained remission and ANCA titres have fallen.

This is the most acutely life-threatening complication.

Feature	Explanation
Mechanism	The same ANCA-mediated neutrophilic vasculitis that damages glomerular capillaries also attacks pulmonary alveolar capillaries (capillaritis) → bleeding into the alveolar space ^[4]^[10]^[11]
Clinical presentation	Haemoptysis, dyspnoea, hypoxia, dropping haemoglobin, bilateral ground-glass infiltrates on CXR
Diagnosis	CXR showing bilateral infiltrates; bronchoscopy with BAL (progressively bloodier returns); paradoxically increased DLCO (blood in alveoli binds CO)
Severity	Can be rapidly fatal if not treated immediately — Goodpasture syndrome can cause pulmonary haemorrhage and death if not treated quickly ^[8] — the same applies to ANCA-associated DAH
Treatment	Urgent pulse IV methylprednisolone + rituximab/CYC + consider plasma exchange

Pulmonary-renal syndrome = haemoptysis + haematuria — the two most important causes are ANCA-associated vasculitis and Goodpasture syndrome ^[10]^[11]^[19].

Feature	Explanation
Mechanism	Reduced GFR → impaired sodium/water excretion → volume expansion; ischaemic glomeruli release renin → RAAS activation; chronic inflammation/endothelial dysfunction
Consequence	Accelerates further glomerular damage (haemodynamic injury) → vicious cycle; increases cardiovascular risk; can cause hypertensive encephalopathy or pulmonary oedema if severe
Relevance	Chronic GN is often associated with long-standing secondary hypertension ^[10]

ANCA-GN does not exist in isolation — it is usually part of a systemic vasculitis. Organ damage from vasculitis outside the kidney is a major source of morbidity:

Organ System	Complication	Mechanism	Disease
Lung	Pulmonary fibrosis (late complication), persistent nodules/cavities	Healing of granulomatous/vasculitic inflammation leaves fibrosis; cavitating nodules may become secondarily infected (aspergillus)	GPA
ENT	Saddle nose deformity, nasal septal perforation, subglottic stenosis (stridor)	Granulomatous destruction of nasal cartilage and subglottic tissue ^[4]^[27]	GPA
Eye	Visual loss from orbital granuloma or scleritis	Retro-orbital granulomatous mass compresses optic nerve; scleritis can lead to scleral thinning and perforation	GPA
Nervous system	Mononeuritis multiplex → permanent neurological deficit (foot drop, wrist drop)	Vasculitis of the vasa nervorum → ischaemic nerve infarction; if not treated promptly, Wallerian degeneration occurs and recovery is incomplete ^[4]	All AAV
Heart	Cardiomyopathy, myocarditis, pericarditis	Eosinophilic infiltration (EGPA); vasculitis of coronary arteries	EGPA primarily
GI	Mesenteric ischaemia, GI perforation	Vasculitis of mesenteric vessels → ischaemia	MPA, EGPA

Relapse is a hallmark complication of ANCA-GN and distinguishes it from anti-GBM disease (which rarely relapses, < 2%) ^[12].

Feature	PR3-ANCA / GPA	MPO-ANCA / MPA
5-year relapse rate	~50%	~20%
Common relapse pattern	Same organs or new organs	Usually same organs
Risk factors	PR3-ANCA serotype; rising ANCA titres; ear/nose/throat involvement (GPA); early discontinuation of maintenance therapy
Presentation	Return of haematuria, rising creatinine, new constitutional symptoms, recurrence of ENT/pulmonary symptoms
Management	Re-induction with same or alternative regimen; rituximab preferred for re-induction in relapsing disease

Rising ANCA ≠ Automatic Treatment Escalation

Rising ANCA titres may precede clinical relapse but should NOT trigger automatic escalation of immunosuppression in the absence of clinical or laboratory signs of active disease. Rising titres should prompt closer surveillance (more frequent urinalysis, RFT, clinical review) rather than empirical treatment changes. Treating serology alone leads to overtreatment.

This is critically important — the treatment itself is a major source of morbidity and mortality.

Feature	Explanation
Why	Profound immunosuppression from GC + CYC/RTX → severely impaired cellular and humoral immunity → susceptibility to opportunistic and conventional infections
Most dangerous period	First 3–6 months of induction (when immunosuppression is maximal)
Common infections	Bacterial pneumonia, UTI, bacteraemia, herpes zoster reactivation, CMV reactivation
Opportunistic infections	Pneumocystis jirovecii pneumonia (PJP) — the most feared; oral/oesophageal candidiasis; aspergillus (especially if lung cavities from GPA — fungus balls can colonise pre-existing cavities)
Prevention	PJP prophylaxis (co-trimoxazole) throughout immunosuppression; vaccination (pneumococcal, influenza, COVID-19); HBV screening before rituximab; strongyloides screening in endemic areas

PJP Prophylaxis is Non-Negotiable

Every patient on induction immunosuppression for ANCA-GN must receive co-trimoxazole (TMP-SMX 480 mg daily or 960 mg three times weekly) for PJP prophylaxis. PJP is rapidly fatal if not prevented or caught early. If the patient is allergic to sulfonamides, alternatives include dapsone, atovaquone, or pentamidine nebulisation.

Long-term GC use causes a constellation of complications that cumulatively represent a major burden:

Complication	Mechanism	Prevention/Management
Osteoporosis and fractures	GC suppress osteoblast function and promote osteoclast activity; also decrease intestinal calcium absorption and increase renal calcium excretion	Calcium + vitamin D supplementation; bisphosphonates (e.g., alendronate) if high fracture risk; DEXA scan baseline and follow-up
Diabetes mellitus (steroid-induced)	GC promote gluconeogenesis, increase insulin resistance, and impair pancreatic β-cell function	Monitor blood glucose; treat with insulin if needed
Cushing syndrome (iatrogenic)	Exogenous cortisol excess → moon face, central obesity, striae, buffalo hump, proximal myopathy	Taper GC as quickly as safely possible; use steroid-sparing agents
Avascular necrosis of femoral head	GC cause fat embolism in subchondral vessels → ischaemia of bone	Monitor for hip pain; MRI if suspected
Cataracts (posterior subcapsular)	Direct effect of GC on lens metabolism	Ophthalmology screening
Peptic ulcer disease	GC inhibit prostaglandin synthesis → reduced gastric mucosal protection (especially when combined with NSAIDs)	PPI prophylaxis if concomitant NSAID or high-risk
Adrenal suppression	Chronic exogenous GC suppresses hypothalamic-pituitary-adrenal axis; sudden withdrawal → adrenal crisis	Never abruptly stop GC; gradual taper
Increased infection risk	Broad immunosuppression — inhibits cytokine production, leukocyte migration, and phagocytosis	Minimise dose and duration; infection prophylaxis

The recognition that GC toxicity is a major problem has driven the development of avacopan (glucocorticoid-sparing) and the adoption of reduced-dose GC protocols (PEXIVAS, LoVAS trials).

Complication	Mechanism	Incidence/Management
Haemorrhagic cystitis	Acrolein (CYC metabolite) excreted in urine directly damages bladder urothelium → bleeding	Prevented by MESNA + hydration; present with painless haematuria
Bladder cancer	Chronic urothelial irritation by acrolein → mutagenesis	Risk increases with cumulative dose; long-term surveillance with urinalysis even after stopping CYC; limit cumulative dose
Gonadal failure / infertility	Alkylation destroys germ cells (ova, spermatocytes) — dose-dependent	Sperm/oocyte cryopreservation before starting; GnRH agonists in women
Bone marrow suppression	Alkylation of haematopoietic precursors → leucopaenia (nadir 7–14 days), thrombocytopaenia	CBC every 1–2 weeks; dose-adjust if WBC < 3.0
Haematological malignancy (myelodysplastic syndrome, leukaemia)	Cumulative alkylating DNA damage → mutagenesis in stem cells	Rare; risk increases with cumulative dose; long-term surveillance

Complication	Mechanism	Management
Hypogammaglobulinaemia	Sustained B cell depletion → reduced immunoglobulin production → ↓ IgG	Monitor IgG levels every 6 months; IV immunoglobulin replacement if IgG < 3 g/L with recurrent infections
Late-onset neutropaenia	Mechanism not fully understood; possibly T cell-mediated destruction of myeloid precursors in the setting of B cell depletion	Usually self-limiting; G-CSF if severe/symptomatic
Infusion reactions	Cytokine release from B cell lysis during first infusion	Pre-medicate with antihistamine, paracetamol, and methylprednisolone; slow infusion rate
HBV reactivation	B cell depletion disrupts immune containment of latent HBV → viral replication → fulminant hepatitis	Screen all patients for HBsAg and anti-HBc before RTX; start entecavir prophylaxis if positive
Progressive multifocal leukoencephalopathy (PML)	JC virus reactivation in severely immunocompromised — destroys oligodendrocytes → demyelination	Extremely rare ( < 1:10,000); no effective treatment; maintain high index of suspicion if new neurological symptoms

Agent	Key Toxicities
Azathioprine	Myelosuppression (especially if TPMT-deficient — check TPMT genotype before starting); hepatotoxicity; pancreatitis; interaction with allopurinol (xanthine oxidase inhibits AZA metabolism → toxic accumulation → severe pancytopaenia)
MMF	GI upset (diarrhoea, nausea); myelosuppression; teratogenicity
Methotrexate	Hepatotoxicity; pulmonary fibrosis; myelosuppression; contraindicated if GFR < 30 (renal excretion → accumulation)
Avacopan	Hepatotoxicity (monitor LFT); GI upset

Drug-Drug Interaction Alert: Azathioprine + Allopurinol

Never co-prescribe azathioprine with allopurinol without dose reduction. Allopurinol inhibits xanthine oxidase, which is a major pathway for AZA metabolism. Without this pathway, AZA's active metabolite (6-mercaptopurine) accumulates → severe, potentially fatal pancytopaenia. If both must be used, reduce AZA dose to 25% of standard and monitor CBC intensively ^[24].

If ANCA-GN progresses to ESRD despite treatment, the patient enters the world of chronic RRT with its own complications ^[25]^[26]:

Modality	Complications
Haemodialysis	Vascular access complications (thrombosis, infection, steal syndrome); hypotension during dialysis; disequilibrium syndrome; long-term: amyloidosis (β2-microglobulin), accelerated CVD
Peritoneal dialysis	Peritonitis; catheter-related infection; ultrafiltration failure; encapsulating peritoneal sclerosis
Kidney transplant	Recurrence of primary disease in allograft; rejection (antibody-mediated or T cell-mediated); infections (CMV, BK virus, PJP, MTB); drug toxicity (calcineurin inhibitor nephrotoxicity); malignancy (post-transplant lymphoproliferative disorder — PTLD, EBV-related B cell lymphoma); cardiovascular disease ^[26]

Category	Key Complications
Disease-related (renal)	ESRD (fibrous crescents → irreversible nephron loss); AKI complications (hyperK, fluid overload, acidosis, uraemia); hypertension; CKD metabolic complications (anaemia, CKD-MBD, CVD)
Disease-related (extrarenal)	DAH (life-threatening); saddle nose/subglottic stenosis (GPA); mononeuritis multiplex; myocarditis (EGPA); GI ischaemia
Disease-related (course)	Relapse (~50% at 5y for PR3-ANCA; ~20% for MPO-ANCA)
Treatment-related (GC)	Osteoporosis, DM, Cushing, AVN, cataracts, infections, adrenal suppression
Treatment-related (CYC)	Haemorrhagic cystitis, bladder cancer, gonadal failure, myelosuppression
Treatment-related (RTX)	Hypogammaglobulinaemia, HBV reactivation, infusion reactions, PML
Treatment-related (general)	Infections (leading cause of death in year 1); PJP; myelosuppression; malignancy (long-term)
RRT-related	Dialysis complications; transplant complications (rejection, recurrence, infections, PTLD)

High Yield Summary — Complications of ANCA-GN

ESRD is the most feared renal complication — driven by fibrous crescent formation (irreversible) and delayed treatment. Sclerotic Berden class has the worst prognosis (~32% 5-year renal survival).
Diffuse alveolar haemorrhage (DAH) is the most acutely life-threatening complication — same ANCA-mediated vasculitis attacking pulmonary capillaries; can be fatal within hours.
Relapse is common, especially in PR3-ANCA/GPA (~50% at 5 years). Rising ANCA titres should prompt closer surveillance but NOT automatic treatment escalation.
Infection is the #1 killer in the first year of treatment — PJP prophylaxis with co-trimoxazole is mandatory.
Glucocorticoid toxicity is cumulative and devastating — osteoporosis, DM, AVN, cataracts, infections, adrenal suppression — driving the shift towards GC-sparing strategies (avacopan, reduced-dose protocols).
CYC causes haemorrhagic cystitis (prevent with MESNA), gonadal failure (cryopreserve gametes), and bladder cancer (limit cumulative dose).
RTX causes hypogammaglobulinaemia (monitor IgG; replace if < 3 g/L with infections) and HBV reactivation (screen and prophylax).
Azathioprine + allopurinol = potentially fatal pancytopaenia — reduce AZA dose to 25% if co-prescribed.
If ESRD occurs, renal transplantation is possible but risk of recurrence of primary disease exists; transplant should be delayed until sustained remission.
Subglottic stenosis (GPA) can cause stridor — a late complication that may require surgical intervention even after systemic disease is controlled.

Active Recall - Complications of ANCA-GN

References

^[3] Senior notes: Ryan Ho Urogenital.pdf (Section 3.3.4 ANCA-associated GN — histological classification and prognosis, p.69) ^[4] Senior notes: Maksim Medicine Notes.pdf (Rheumatology — AAV clinical features and complications, p.333) ^[5] Senior notes: Ryan Ho Fundamentals.pdf (Section 3.5.5 RPGN — crescent formation pathogenesis and prognosis, p.361) ^[6] Senior notes: Block A - Glomerular and Tubulo-interstitial Diseases and Acute Kidney Injury.pdf (Chronic GN evaluation and CKD complications, p.26–28) ^[8] Senior notes: Block A - Nephrotology Teaching Clinic RTD.pdf (Goodpasture as emergency — pulmonary haemorrhage and death, p.3) ^[10] Senior notes: Adrian Lui Pediatrics Notes.pdf (RPGN — crescent progression, chronic GN as cause of CKD, p.326–327) ^[11] Senior notes: Block A – Nephrology Data Interpretation.pdf (Pulmonary-renal syndrome, RPGN leading to CKD, p.13–14) ^[12] Senior notes: Ryan Ho Urogenital.pdf (Anti-GBM disease — prognosis, dialysis dependence, rarely relapses, p.68) ^[19] Senior notes: Block A - Nephrology Interactive Tutorial.pdf (Pulmonary-renal syndrome — Goodpasture's and ANCA vasculitis, p.2) ^[24] Senior notes: Block A - Drugs and the Kidney.pdf (Drug-induced nephropathy, drug interactions, p.1, 8–9) ^[25] Senior notes: Block A - Chronic Kidney Disease and its Complications.pdf (Causes of CKD, therapeutic objectives, metabolic complications, p.3, 8, 17) ^[26] Senior notes: Block A - Renal Replacement Therapies.pdf (Long-term transplant complications — recurrence of primary disease, PTLD, infections, p.36) ^[27] Senior notes: Ryan Ho Respiratory.pdf (GPA — saddle nose, subglottic stenosis, pulmonary nodules, p.140)

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.

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.

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.

High Yield Summary — Management of ANCA-GN

Two-phase model: Induction (3–6 months) → Maintenance (≥24–48 months).
Empirical pulse IV methylprednisolone can be given BEFORE biopsy if clinical RPGN is suspected.
Induction: high-dose GC + RTX (preferred) or CYC. RTX is preferred for relapsing disease, PR3-ANCA/GPA, and fertility concerns.
Avacopan (C5aR1 inhibitor) is a new GC-sparing adjunct (ADVOCATE trial 2021).
PLEX is NOT routinely indicated (PEXIVAS 2020) — reserved for DAH and anti-GBM overlap.
Maintenance: RTX (first-line, MAINRITSAN trial) or AZA or MMF + taper GC.
PJP prophylaxis with co-trimoxazole for all immunosuppressed patients.
Check TPMT before AZA; check HBV status before RTX.
MTX is contraindicated if GFR < 30; CYC is contraindicated in pregnancy.
ACEI/ARB for ALL glomerulopathy — reduces proteinuria and slows GFR decline.
Infection is the leading cause of death in the first year — not the vasculitis.
Dialysis-dependent patients at presentation have guarded renal prognosis, but a trial of immunosuppression may still be warranted if biopsy shows cellular (not sclerotic) crescents.

High Yield Summary — Complications of ANCA-GN

ESRD is the most feared renal complication — driven by fibrous crescent formation (irreversible) and delayed treatment. Sclerotic Berden class has the worst prognosis (~32% 5-year renal survival).
Diffuse alveolar haemorrhage (DAH) is the most acutely life-threatening complication — same ANCA-mediated vasculitis attacking pulmonary capillaries; can be fatal within hours.
Relapse is common, especially in PR3-ANCA/GPA (~50% at 5 years). Rising ANCA titres should prompt closer surveillance but NOT automatic treatment escalation.
Infection is the #1 killer in the first year of treatment — PJP prophylaxis with co-trimoxazole is mandatory.
Glucocorticoid toxicity is cumulative and devastating — osteoporosis, DM, AVN, cataracts, infections, adrenal suppression — driving the shift towards GC-sparing strategies (avacopan, reduced-dose protocols).
CYC causes haemorrhagic cystitis (prevent with MESNA), gonadal failure (cryopreserve gametes), and bladder cancer (limit cumulative dose).
RTX causes hypogammaglobulinaemia (monitor IgG; replace if < 3 g/L with infections) and HBV reactivation (screen and prophylax).
Azathioprine + allopurinol = potentially fatal pancytopaenia — reduce AZA dose to 25% if co-prescribed.
If ESRD occurs, renal transplantation is possible but risk of recurrence of primary disease exists; transplant should be delayed until sustained remission.
Subglottic stenosis (GPA) can cause stridor — a late complication that may require surgical intervention even after systemic disease is controlled.

ANCA-Associated Glomerulonephritis

ANCA-Associated Glomerulonephritis

2. Epidemiology

3. Anatomy and Function — The Glomerular Filtration Barrier

4. Etiology (Focus on Hong Kong)

Step-by-Step Pathogenesis

Step 1: Aberrant Expression of ANCA Antigens

Step 2: Neutrophil Priming

Step 3: ANCA Binds and Activates Neutrophils

Step 4: Endothelial Injury

Step 5: Crescent Formation

Step 6: Complement Activation (Alternative Pathway)

6. Classification

7. Clinical Features

7.1 Symptoms

7.2 Signs

Active Recall - ANCA-Associated Glomerulonephritis (Definition to Clinical Features)

Differential Diagnosis of ANCA-Associated Glomerulonephritis

Tier 1: Differential Diagnosis of RPGN (the Clinical Syndrome)

Active Recall - Differential Diagnosis of ANCA-GN

References

Important Preface: There Are No "Diagnostic Criteria" in the Traditional Sense

Diagnostic Algorithm

Step-by-Step Approach

Investigation Modalities — Detailed Breakdown

C. Serological Panel — The "Sorting Hat"

E. Renal Biopsy — The Gold Standard

What the Biopsy Tells You

Active Recall - Diagnostic Criteria, Algorithm, and Investigations for ANCA-GN

Management Algorithm and Treatment Modalities for ANCA-Associated Glomerulonephritis

Phase 2: Induction Therapy

Special Situations

Active Recall - Management of ANCA-GN

References

Complications of ANCA-Associated Glomerulonephritis

A. Complications of the Disease Itself

Active Recall - Complications of ANCA-GN

References

On this page

ANCA-Associated Glomerulonephritis

1. Definition

2. Epidemiology

Incidence and Prevalence

Age and Sex

Risk Factors

3. Anatomy and Function — The Glomerular Filtration Barrier

Normal Glomerular Architecture

Why This Matters in ANCA-GN

4. Etiology (Focus on Hong Kong)

The ANCA Antigens

Hong Kong–Specific Epidemiological Pattern

Causes / Settings of ANCA-GN

5. Pathophysiology

6. Classification

By Systemic Disease Association

By Renal Histological Classification (Berden Classification, 2010)

By ANCA Serotype (Modern Approach)

7. Clinical Features

7.1 Symptoms

Renal Symptoms

Systemic / Constitutional Symptoms

Organ-Specific Symptoms by Disease Type

7.2 Signs

Renal Signs

Extrarenal / Systemic Signs

7.3 Urinalysis Findings (Bridge to Investigation)

8. Summary Table: ANCA-GN by Systemic Disease

Active Recall - ANCA-Associated Glomerulonephritis (Definition to Clinical Features)

References

Tier 1: Differential Diagnosis of RPGN (the Clinical Syndrome)

Type I: Anti-GBM Disease (Goodpasture Syndrome)

Type II: Immune-Complex Mediated RPGN

Non-Glomerular Mimics of RPGN

Tier 2: Distinguishing Within ANCA-Associated Conditions

The Diagnostic Thinking Process (Mermaid Diagram)

Key Serological and Histological Discriminators — Summary Table

Clues That Point Specifically Toward ANCA-GN

Important Differential Diagnosis Pitfalls

Differential Diagnosis of Pulmonary-Renal Syndrome

Active Recall - Differential Diagnosis of ANCA-GN

Diagnostic Criteria, Diagnostic Algorithm, and Investigations for ANCA-Associated Glomerulonephritis

Diagnostic Algorithm

Step-by-Step Approach

Step 1: Confirm Glomerulonephritis

Step 2: Assess Severity and Urgency

Step 3: Serological Panel to Narrow the Differential

Step 4: Empirical Treatment BEFORE Biopsy if Clinically Indicated

Step 5: Renal Biopsy — The Gold Standard

Step 6: Assess for Systemic (Extrarenal) Involvement

Complete Diagnostic Algorithm — Mermaid Diagram

Investigation Modalities — Detailed Breakdown

A. Urinalysis

B. Blood Tests — Baseline

C. Serological Panel — The "Sorting Hat"

ANCA Testing

Other Serological Tests

D. Imaging

E. Renal Biopsy — The Gold Standard

Indications

What the Biopsy Tells You

Light Microscopy (LM)

Immunofluorescence (IF) — The Defining Feature

Electron Microscopy (EM)

F. Other Investigations for Systemic Assessment

Key Diagnostic Interpretive Pitfalls

Summary: The Complete Investigation Panel for Suspected ANCA-GN

Active Recall - Diagnostic Criteria, Algorithm, and Investigations for ANCA-GN

References

Overarching Principles

Management Algorithm — Mermaid Diagram

Phase 1: Immediate / Supportive Management

Phase 2: Induction Therapy

A. Glucocorticoids (GC)

B. Cyclophosphamide (CYC)

C. Rituximab (RTX)

D. Avacopan (C5a Receptor Inhibitor) — New Agent

Choosing Between CYC and RTX for Induction

Phase 2b: Plasma Exchange (PLEX) — Adjunctive Therapy

Phase 3: Maintenance Therapy