What is the treatment approach for a patient diagnosed with Goodpasture syndrome, a rare autoimmune disease characterized by the presence of anti-glomerular basement membrane (anti-GBM) antibodies?

Treatment of Goodpasture Syndrome

Immediate Triple Therapy is Mandatory

Initiate aggressive triple therapy immediately with plasmapheresis, high-dose glucocorticoids, and cyclophosphamide without waiting for confirmatory testing in all patients with suspected Goodpasture syndrome, except those who are dialysis-dependent at presentation with >50% global glomerulosclerosis or 100% crescents on biopsy AND no pulmonary hemorrhage. 1, 2

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Diagnostic Approach

Urgent Serologic Testing

• Send anti-GBM antibodies, ANCA, and ANA immediately upon suspicion of rapidly progressive glomerulonephritis 1, 2
• Do not delay treatment while awaiting serologic confirmation if clinical presentation is consistent with Goodpasture syndrome 1, 2
• Anti-GBM antibodies are falsely negative in approximately 10% of cases, making kidney biopsy essential when safe and feasible 1, 2

Kidney Biopsy Findings

• Necrotizing and crescentic glomerulonephritis with linear IgG immunofluorescent staining on the glomerular basement membrane is diagnostic 3, 4
• Biopsy provides critical prognostic information regarding percentage of crescents, degree of tubular atrophy/interstitial fibrosis, and acute tubular necrosis 2

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First-Line Treatment Protocol

Plasmapheresis

• Start daily plasmapheresis immediately upon clinical suspicion without waiting for antibody confirmation 2, 5, 6
• Continue daily sessions until anti-GBM antibodies are undetectable on two consecutive tests 2
• Typical course involves 7-10 total treatments, transitioning to every-other-day once bleeding stops (if pulmonary hemorrhage present) 5
• Use 60 mL/kg volume replacement with fresh frozen plasma if active alveolar hemorrhage is present 5

High-Dose Glucocorticoids

• Initiate pulse methylprednisolone 500-1000 mg IV daily for 3 days immediately 2, 5
• Transition to oral prednisone with gradual taper over approximately 6 months 2, 5

Cyclophosphamide

• Administer oral cyclophosphamide 2-3 mg/kg daily for 2-3 months once infection is ruled out 2, 5
• Adjust dose for reduced GFR or older age 2
• Continue for full 2-3 month course even if clinical improvement occurs earlier 2

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Critical Exception: Pulmonary Hemorrhage Overrides All Renal Considerations

The presence of pulmonary hemorrhage mandates aggressive triple therapy regardless of dialysis status, percentage of crescents, or degree of glomerulosclerosis. 1, 5

• Pulmonary hemorrhage carries significant mortality risk if untreated and can be successfully controlled with aggressive therapy in most cases 5
• The standard exception for dialysis-dependent patients does not apply when active lung disease is present 5
• Heavy lung crepitations with significant weight loss strongly suggests active alveolar hemorrhage requiring immediate treatment 5

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When NOT to Treat Aggressively

Dialysis-Dependent Patients WITHOUT Pulmonary Hemorrhage

• Patients presenting on dialysis with 100% crescents or >50% global glomerulosclerosis on adequate biopsy AND no pulmonary hemorrhage have extremely poor renal prognosis 1
• Long-term outcome shows >90% remain on dialysis at 1 year with 35% mortality rate 1
• Consider aggressive treatment only if presentation is acute, non-oliguric, or biopsy shows features of acuity 2

Assessment of Renal Viability

• Clinical factors: dialysis requirement at presentation, oliguria vs non-oliguria 2
• Pathologic factors: percentage of crescents (100% is poor prognosis), degree of global glomerulosclerosis (>50% is poor prognosis) 1
• Patient factors: age, frailty, infection risk, and tolerability of aggressive immunosuppression 1

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Essential Supportive Care

Infection Prophylaxis

• Initiate trimethoprim-sulfamethoxazole for Pneumocystis jirovecii prophylaxis 5
• Continue until cyclophosphamide is complete AND prednisone dose is <20 mg daily 5

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Maintenance Therapy

Isolated Anti-GBM Disease

• No maintenance immunosuppression is necessary after completing the initial 6-month treatment course 2, 5
• Relapse rate is <5% in isolated anti-GBM disease 2, 5
• Monitor anti-GBM antibodies for at least 2 years as rare relapses have been reported 2

Dual-Positive Patients (Anti-GBM + ANCA)

• Patients with both anti-GBM and ANCA antibodies require maintenance immunosuppression as for ANCA-associated vasculitis due to higher relapse rates 1, 2

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Kidney Transplantation

• Defer kidney transplantation until anti-GBM antibodies remain undetectable for ≥6 months 3, 2, 5
• Patients with Alport syndrome may develop anti-GBM antibodies to the foreign collagen chain in the transplanted kidney in approximately 2-3% of cases 2

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Prognosis and Predictive Factors

Overall Survival

• One-year survival is approximately 87% with aggressive triple therapy 6
• Age <60 years and higher number of plasmapheresis sessions correlate with improved overall survival 6
• Severe infection is a major cause of death (7/16 deaths in one cohort) 6

Renal Survival

• Serum creatinine <500 μmol/L at presentation predicts renal survival in patients alive at 1 year 6
• Dialysis-dependent patients at presentation have only 8-10% chance of renal recovery 5

Untreated Disease

• Mortality rate is up to 96% in untreated patients, making prompt recognition and early treatment absolutely critical 1

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Novel Therapies

Imlifidase

• IgG-degrading enzyme from Streptococcus pyogenes has shown promise in phase 2 studies 2
• Achieves rapid antibody decline within 6 hours with 67% dialysis-free survival at 6 months 2

Eculizumab

• Complement blockade may halt life-threatening organ damage in severe cases with ARDS refractory to standard therapy 7
• Consider in pre-final stage patients with severe pulmonary involvement not responding to plasmapheresis and steroids 7

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Critical Pitfalls to Avoid

• Never delay treatment while awaiting biopsy or serologic confirmation in patients with suspected rapidly progressive glomerulonephritis and pulmonary-renal syndrome 1, 2
• Do not stop plasmapheresis prematurely—continue until antibodies are undetectable, not just reduced 2
• Do not undertreate based on initial dialysis dependence if pulmonary hemorrhage is present—lung involvement mandates aggressive therapy regardless of renal prognosis 5
• Remember that anti-GBM antibodies can be falsely negative—proceed with kidney biopsy when clinically suspected despite negative serology 1, 2, 4