NephrologyTier 1Disease (DEADMAN)

Anti-GBM disease

Description

Autoantibody against the glomerular and alveolar basement membrane -> RPGN +/- pulmonary haemorrhage
The most aggressive glomerulonephritis - untreated, ESKD or death in weeks

Nomenclature

Term	Meaning
Goodpasture syndrome	RPGN + pulmonary haemorrhage from any cause (ANCA vasculitis, SLE, IgA vasculitis, anti-GBM)
Goodpasture disease	RPGN + pulmonary haemorrhage + anti-GBM antibody - accounts for 20-40% of Goodpasture syndrome
Anti-GBM disease	The antibody-defined disease, with or without lung involvement

Distribution: pulmonary + renal 60-80%, renal only 20-40%, pulmonary only <10%
A monophasic, one-hit disease - unlike ANCA vasculitis it rarely relapses

Rare: ~0.5-1.8 per million per year
Bimodal: 20-30 yrs (M>F, pulmonary-renal) and 60-70 yrs (F>=M, renal-limited)
*HLA-DRB1\15:01 in ~80%** (protective: DR1, DR7)
Of pulmonary-renal syndrome overall: ANCA vasculitis ~56-78%, anti-GBM ~12-18%

Autoantibody (usually IgG1) against the non-collagenous NC1 domain of the alpha-3 chain of type IV collagen - alpha-3(IV)NC1, the Goodpasture antigen
- Normally a cryptic epitope hidden within the collagen hexamer
- Requires a conformational change to expose it -> loss of tolerance -> complement fixation, neutrophil recruitment, capillary wall rupture -> crescents
Distribution of the antigen explains the phenotype: glomerular BM, alveolar BM, cochlea, choroid plexus, eye
Why the lung is only sometimes involved: alveolar endothelium is non-fenestrated, so antibody access requires a second hit that injures alveolar capillaries
- **Smoking (the strongest), hydrocarbon exposure, cocaine inhalation, infection, pulmonary oedema, high inspired O2, lithotripsy**
Double-positive disease: 10-40% are also ANCA-positive (usually MPO/p-ANCA)
- Behave like anti-GBM acutely, but relapse like ANCA vasculitis - so they need long-term maintenance immunosuppression
Alport patients can develop de novo anti-GBM disease against the transplanted kidney (the alpha-3/4/5 chains are foreign to them)

Presentation

Haemoptysis is the most common presenting feature (65-94%); cough, dyspnoea, iron deficiency anaemia
Constitutional: fatigue, fever, nausea/vomiting, chest pain; prodrome common
Renal: oliguria, gross haematuria, rapidly rising creatinine, HTN uncommon and mild
Half already need dialysis at presentation

Serology - do not wait for it to treat

Serum anti-GBM antibody: sensitivity >95%, specificity 91-100%
- False negatives if the assay uses whole GBM rather than recombinant alpha-3(IV)NC1
Always send ANCA at the same time - 10-40% double-positive
Complement normal (contrast with SLE and post-infectious GN)

Renal biopsy - gold standard

LM: focal segmental necrotising GN with crescents, typically all of the same age (ANCA crescents are of mixed ages)
IF: LINEAR IgG (+/- C3) along the capillary loops - the diagnostic finding
- Also seen in diabetic nephropathy and monoclonal disease, but without necrosis or crescents
% crescents on biopsy is the single best predictor of renal recovery

Lung

CXR/CT: bilateral alveolar infiltrates sparing the apices and costophrenic angles
DLCO increased - haemoglobin in the alveolus takes up CO; detects occult haemorrhage
Bronchoscopy: progressively bloodier lavage, haemosiderin-laden macrophages

Differential of pulmonary-renal syndrome

ANCA vasculitis (commonest), anti-GBM, SLE, IgA vasculitis, cryoglobulinaemia, APS, severe cardiac failure with volume overload plus AKI, legionella/leptospirosis

A medical emergency - start treatment on clinical suspicion, before the biopsy result

Triple therapy - all three, together

1. Plasma exchange - daily or alternate-day, ~14 sessions or until anti-GBM undetectable
- 4 L exchange with 5% albumin; FFP if pulmonary haemorrhage or recent biopsy
- The only GN in which plasma exchange has an unambiguous role
2. Corticosteroids - methylprednisolone 500-1000 mg IV daily x3, then prednisolone 1 mg/kg tapering over 3-6 months
3. Cyclophosphamide - 2-3 mg/kg/day PO (or IV pulses), for ~3 months
- Reduce dose for age >55 and renal impairment

Adjuncts

Rituximab - if cyclophosphamide contraindicated or refractory; increasingly used
*Imlifidase (IgG-degrading enzyme of Streptococcus pyogenes)* - cleaves circulating IgG within hours; conditionally approved in Europe for severe anti-GBM disease
PJP prophylaxis, gastric protection, bone protection, fertility counselling

Who to treat aggressively - the hardest decision

Dialysis-dependent + 100% crescents + no pulmonary haemorrhage -> renal recovery is very unlikely
- Immunosuppression may not be justified for the kidney alone
BUT treat regardless if there is pulmonary haemorrhage - it is immediately life-threatening and fully reversible

Transplantation

Wait until anti-GBM has been undetectable for at least 6 months (usually ~12 months from diagnosis)
Recurrence then rare

Stop the second hit

Predictors of renal outcome

	Renal survival
Creatinine <500 micromol/L at presentation	~90-95% independent at 1 yr
Creatinine >500, not dialysis-dependent	~50%
Dialysis-dependent at presentation	<10%
100% crescents on biopsy	Almost never recovers

The window is measured in days - delay is the commonest reason for a lost kidney

After treatment

Monophasic - relapse is rare (<5%), so maintenance immunosuppression is usually not needed
- *Exception: ANCA double-positive patients relapse like ANCA vasculitis - maintain and monitor*
Recurrent pulmonary haemorrhage in the absence of rising antibody -> look for infection or a fresh smoking/hydrocarbon exposure
Monitor anti-GBM titre until undetectable; then periodically in double-positive disease
Deaths are mostly from pulmonary haemorrhage early and infection later (treatment-related)

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