Introduction
Goodpasture's syndrome is a rare autoimmune disease where antibodies attack the alpha-3 subunit of type IV collagen found in the basement membrane of the lungs and kidneys. This anti-glomerular basement membrane (anti-GBM) disease leads to small vessel vasculitis in the kidneys and lungs causing bleeding in the lungs and renal failure. This results in permanent damage to both organs and leads to death if left untreated. In treated individuals, the five-year survival rate is over 80%.
Epidemiology
- Incidence: 0.10 cases per 100,000 person-years
- Peak incidence: 30-40 years
- Sex ratio: more common in males 2:1
| Condition | Relative incidence |
|---|---|
| Granulomatosis with polyangiitis | 10.00 |
| Post-streptococcal glomerulonephritis | 3.00 |
| Eosinophilic granulomatosis with polyangiitis | 2.00 |
| Goodpasture's syndrome | 1 |
| <1 | 1-5 | 6+ | 16+ | 30+ | 40+ | 50+ | 60+ | 70+ | 80+ |
Aetiology
Goodpasture's syndrome is more common in caucasian people. It has a bimodal age distribution at 20-30 years and 60-70 years. Chances of recurrence are low and patients may undergo transplant due to end-stage renal disease provided anti-GBM antibodies are undetectable. There are no known specific triggers of Goodpasture's syndrome however it is suspected that similarly to other autoimmune conditions, anti-GBM disease is caused by the combination of genetic and environmental factors.
- Genetic component:
- People with the human leukocyte antigen (HLA) serotype of HLA-DR15 and -DR4 are more likely to develop anti-GBM disease.
- Environmental factors:
- Cigarette smoke
- Organic solvents, hydrocarbons and metal dust
- Following infection (especially viruses like influenza)
Pathophysiology
The glomerular injury in Goodpasture's syndrome is due to the autoimmunity against the alpha-3 chain of type IV collagen in basement membranes. Type IV collagen is in all basement membranes but the alpha-3 chain is found primarily in the basement membranes of alveoli and glomeruli. There are three main mechanisms:
- Anti-GBM antibodies
- These attack the basement membranes of alveoli and glomeruli by binding to them and activating the complement cascade, leading to their death.
- Auto-reactive T cells
- These contribute to anti-GBM disease. Circulating T cells that are specific to epitopes in the alpha-3 chain of type IV collagen contribute to the formation of crescent formation.
- Genetic component
- There have also been rare cases of familial anti-GBM disease where patients with HLA-DR15 and -DR4 are at increased risk.
Clinical features
The classic clinical presentation of Goodpasture's syndrome is a patient with no history of lung or renal dysfunction who presents after noticing an abrupt onset of haemoptysis, cough, shortness of breath, peripheral oedema, dark urine and oliguria.
Symptoms:
Signs:
Risk factors:
- The majority of patients (90%) present with rapidly progressing glomerulonephritis with accompanying alveolar haemorrhage (25-60%).
- Very few patients present with isolated lung findings (10%).
Symptoms:
- Haemoptysis (65%)
- Cough (30%)
- Shortness of breath (30%)
- Nausea and vomiting (20%)
- Chest pain (20%)
- Decreased urine output (15%)
- Fatigue and malaise
- Haematuria (5%)
Signs:
- Lung crackles (45%)
- Fever (30%)
- Lower extremity oedema (15%)
Risk factors:
- Men to women ratio 3:2
- Bimodal age distribution (at 20-30 years and 60-70 years)
Investigations
There are no NICE guidelines on Goodpasture's syndrome and all BMJ recommendations are based on the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guidelines which recommend the following investigations:
- Renal biopsy - should be performed for definitive diagnosis
- Crescentic glomerulonephritis
- Linear IgG staining on immunofluorescence
- Bloods
- Anti-GBM antibody titre - useful confirmatory diagnostic test in addition to the renal biopsy.
- Anti-neutrophil cytoplasmic antibodies (ANCA) - positive in up to 30% of patients with anti-GBM disease.
- Urea & electrolytes - high urea and creatinine
- Urinalysis - proteinuria, hematuria and casts
- Chest imaging
- X-ray may show diffuse opacities
- CT characteristically shows ground glass or consolidative opacities in a diffuse and bilateral distribution
Differential diagnosis
- ANCA vasculitides. Main examples include granulomatosis with polyangiitis (Wegener’s), microscopic polyangiitis and Churg-Strauss syndrome.
- Similarities: blood tests may show positive ANCA
- Differences: renal biopsy shows no immune complex deposition.
- Post-streptococcal glomerulonephritis
- Similarities: presents only with glomerulonephritis
- Differences: renal biopsy shows immune complex deposition in a granular pattern but no immune complex deposition.
Management
A typical patient would be managed in a secondary setting using plasmapheresis, oral prednisolone and cyclophosphamide. If they develop respiratory failure or massive haemoptysis they may be moved to an intensive care unit.
There are no NICE guidelines on Goodpasture's syndrome and all BMJ recommendations are based on the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guidelines which recommend the following management of Goodpasture's syndrome:
Acute management:
Long term management
There are no NICE guidelines on Goodpasture's syndrome and all BMJ recommendations are based on the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guidelines which recommend the following management of Goodpasture's syndrome:
Acute management:
- Intensive plasmapheresis
- Removes the pathogenic antibody and inflammatory mediators
- 4 litres per day for 10-14 days, or until anti-GBM is undetectable
- Prednisone
- The dose is tapered over the course of 3 months
- Cyclophosphamide
- Suppresses the immune system
Long term management
- Optimal duration of treatment is unknown but the cessation of autoantibody formation can take at least 6 to 9 months.
- Maintenance therapy should include less toxic drugs such as azathioprine and low dose prednisolone.
- Smoking cessation as this causes glomerular and alveolar damage leading to the release of increased amounts of auto-antigen.
Complications
Short term
Long term
- Pulmonary haemorrhage
- High likelihood in smokers.
- Plasmapheresis related bleeding
- This removes clotting factors from the blood which may need to be replaced with fresh frozen plasma.
- Cyclophosphamide-related neutropenia
- This drug can cause dose-related leukopenia, therefore should be stopped and recommenced at a lower dose.
- Immunosuppression related infection
- May need antibiotic prophylaxis for Pneumocystis jirovecii pneumonia infection
Long term
- Chronic kidney disease requiring dialysis
- Most patients are left with a degree of renal impairment which may need dialysis.
- Long term prednisolone complications
- Requires prophylactic proton pump inhibitor for prevention of gastric ulcers
- Requires prophylactic bisphosphonates for prevention of osteoporosis
- Cyclophosphamide complications
- Can cause sterility if used for over 2-3 months. Gamete preservation should be considered.
- At high doses cyclophosphamide increases the risk of bladder cancer or haemorrhagic cystitis.
Prognosis
- Early treatment is associated with good chances of recovery with a five-year survival rate of over 80%.
- With aggressive treatment, out of the patients with mild to moderate kidney failure who do not need dialysis at arrival, 82-95% do not require dialysis at one year.
- In patients with more severe disease, the chance of renal recovery is 8%.
- Patients with end-stage renal disease and undetectable anti-GBM may undergo transplantation.
- Reports of recurrence is low.