# Anti-GBM Disease (Goodpasture Syndrome)

## Epidemiology & Pathophysiology

Anti-GBM disease represents **5–10% of RPGN cases** and 1–2% of all GN. Annual incidence approximately 0.5–2 per million.

### Target & Mechanism

- **Target antigen:** NC1 domain of α3 chain of type IV collagen (α3(IV)NC1)
- Located in GBM, alveolar basement membrane, and Descemet membrane
- IgG anti-GBM antibodies circulate and deposit along GBM in a **linear pattern**
- Classical pathway complement activation → neutrophil infiltration → crescent formation → rapid loss of renal function

**⚠️ Critical:** Anti-GBM disease is rapidly progressive and requires urgent diagnosis and treatment. **Linear IgG on immunofluorescence** with serum anti-GBM antibodies confirms diagnosis. Pulmonary involvement (hemoptysis + alveolar infiltrates) occurs in ~50% and signifies life-threatening disease.

### Goodpasture Syndrome (~50% of patients)

Identical anti-GBM antibodies target alveolar basement membrane causing diffuse alveolar hemorrhage, hemoptysis, and pulmonary infiltrates. Can be life-threatening; often precedes renal manifestations.

### Triggering Factors

- Respiratory infection (viral URI; may expose cryptic epitope)
- **Smoking** (induces alveolar permeability; increases pulmonary hemorrhage risk)
- Hydrocarbon exposure
- Genetic predisposition (HLA-DR2, HLA-DQ2)

## Clinical Presentation

### Renal-Limited Disease (50%)

- Sudden onset hematuria + proteinuria
- Progressive rise in creatinine (doubling times 24–72 hours typical)
- Dysmorphic RBC + RBC casts on UA
- No systemic symptoms (distinguishes from systemic vasculitis)

### Pulmonary-Renal Syndrome

- **Hemoptysis** (blood-tinged sputum to life-threatening hemorrhage)
- Dyspnea, chest pain
- Diffuse alveolar infiltrates on CXR
- Anemia from ongoing hemorrhage

### Laboratory Features

- Creatinine often markedly elevated (1.5–10+ mg/dL)
- **Normal C3, C4** (distinguishes from immune-complex RPGN)
- **Negative ANA, ANCA, cryoglobulins** (seronegative RPGN pattern)
- **Positive serum anti-GBM antibodies** in \>90% (may be transiently negative in fulminant cases)

## Treatment: Triple Therapy (Urgent Initiation Required)

**⚠️ Critical Principle:** Anti-GBM disease progresses rapidly to ESRD. Treatment must begin within **days** of diagnosis. Delay \>4 weeks is associated with poor renal outcomes.

### 1. High-Dose Corticosteroids

- IV methylprednisolone 500 mg–1 g daily for 3–5 days, then oral prednisone 1 mg/kg/day
- Slow taper over 8–12 weeks

### 2. Cyclophosphamide

- 2 mg/kg/day oral (dose-reduced if elderly or low WBC) OR pulsed IV 1 g/m² x 3 monthly
- Duration: 8–12 weeks oral; monitor CBC weekly (target WBC 4,000–8,000)

### 3. Plasmapheresis

- Especially critical when Cr \>5.8 mg/dL, oliguria/anuria, or fulminant pulmonary hemorrhage
- 40–60 mL/kg daily for 7–14 days or until anti-GBM antibodies undetectable
- Removes pre-formed antibodies; cyclophosphamide prevents new antibody synthesis

**📚 Key Point:** Dialysis requirement alone does not settle treatment. KDIGO identifies a poor-recovery exception when dialysis at presentation coexists with 100% crescents or \>50% global glomerulosclerosis in an adequate biopsy and no pulmonary hemorrhage. Pulmonary hemorrhage and dual ANCA positivity change the decision. Isolated anti-GBM relapse is uncommon; dual-positive disease needs ANCA-informed follow-up.

## Prognosis

### Renal Outcomes by Creatinine at Diagnosis

| Creatinine at Diagnosis | Avoid Dialysis |
|-------------------------|----------------|
| \<2.8 mg/dL             | 85–90%         |
| 2.8–5.8 mg/dL           | 50%            |
| \>5.8 mg/dL             | 10%            |
| Oliguria/anuria         | \<5%           |

**Biopsy:** \>80% crescents = poor prognosis; \<50% crescents = better prognosis.

**Timing:** Initiation within 2 weeks of symptom onset yields much better outcomes. Initiation \>4 weeks: most become ESRD.

## RPGN Classification: Key Differentiating Features

| Feature | Anti-GBM | ANCA-RPGN | Immune-Complex RPGN |
|----|----|----|----|
| **Serology** | Anti-GBM+ | ANCA+ (MPO/PR3) | ANA+, anti-dsDNA+ |
| **Complement** | Normal | Normal | LOW C3, C4 |
| **IF Pattern** | LINEAR IgG | Pauci-immune | Granular |
| **Pulmonary** | Alveolar hemorrhage | Upper respiratory | Rare |
| **Plasmapheresis** | Essential in severe | Limited role | Optional |

## Clinical Pearls

1.  **Linear IgG on IF is virtually pathognomonic**
2.  Serum anti-GBM antibodies may be **transiently negative** in fulminant disease; negative serology does not exclude diagnosis
3.  **Time to treatment is the most modifiable predictor of outcome**
4.  Plasmapheresis should NOT be delayed waiting for biopsy if clinical suspicion is high
5.  Anti-GBM disease does **NOT recur** after antibodies clear
6.  Dialysis initiation is not a contraindication to therapy — late renal recovery possible years later
7.  **Smoking cessation essential** in Goodpasture syndrome

## References

1.  McAdoo SP, Pusey CD. Anti-GBM disease. *CJASN*. 2017;12(7):1162-1172. [PubMed](https://pubmed.ncbi.nlm.nih.gov/28515156/)
2.  Levy JB, Turner AN, Rees AJ, et al. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med. 2001;134(11):1033-1042. [PubMed](https://pubmed.ncbi.nlm.nih.gov/11388816/)
3.  . Chapter 14: Anti-glomerular basement membrane antibody glomerulonephritis. Kidney Int Suppl (2011). 2012;2(2):240-242. [PubMed](https://pubmed.ncbi.nlm.nih.gov/25018939/)
4.  Hellmark T, Johansson C, Wieslander J. Characterization of anti-GBM antibodies involved in Goodpasture's syndrome. Kidney Int. 1994;46(3):823-9. [PubMed](https://pubmed.ncbi.nlm.nih.gov/7527877/)

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