Approach Considerations
The three principles of therapy in anti–glomerular basement membrane (anti-GBM) disease are as follows:
- Rapidly remove circulating antibody, primarily by plasmapheresis
- Stop further production of antibodies using immunosuppression with medications
- Remove offending agents that may have initiated the antibody production
The rapid institution of appropriate therapy depends on distinguishing anti-GBM disease from other pulmonary renal syndromes with similar presentations. Beginning therapy despite a pending or preliminary negative test result for serum anti-GBM antibodies may be necessary; a delay in this setting can be associated with adverse clinical outcomes.
Patients who develop massive hemoptysis or acute respiratory failure should be cared for in an intensive care unit (ICU). Transfer to a hospital where plasmapheresis and/or hemodialysis is available may be necessary. Standard indications for dialysis are followed.
After hospital discharge, patients require long-term regular visits for monitoring of kidney function and immunosuppressive therapy. If kidney function does not return, dialysis is continued indefinitely and the patient should be referred for kidney transplantation.
Patients receiving kidney transplants must be informed that anti-GBM disease can recur in the transplanted kidney, although graft loss due to this is very rare.
Go to Pediatric Anti-GBM Disease (Goodpasture Syndrome) for complete information on this topic.
Plasmapheresis
In published case series and one randomized trial, plasmapheresis has been shown to be beneficial in the treatment of Goodpasture syndrome by removal of anti-GBM antibodies. [35, 36, 37] Plasmapheresis is generally instituted after the diagnosis of Goodpasture syndrome is established either by kidney biopsy or by detection of anti-GBM antibodies.
When a patient presents with life-threatening pulmonary hemorrhage, however, plasmapheresis may be initiated if the diagnosis appears very likely, even though confirmation is not available immediately.
The extent and duration of plasmapheresis is not known, but 4-liter plasma exchanges daily or every other day is usually performed. Plasmapheresis is continued for 2-3 weeks or until the patient's clinical course has improved and serum anti-GBM antibodies are not detected.
A study by Zhang and colleagues in 28 patients with anti-GBM nephritis found that double filtration plasmapheresis cleared anti-GBM antibody about as effectively as immunoadsorption therapy (59.0% vs. 71.2% efficacy, respectively; P = 1.00). However, significantly fewer patients in the plasmapheresis group experienced reduced IgG (62.7% vs. 83.5%), and the plasmapheresis group also experienced fewer plasma-associated side effects. Patient survival and renal survival were similar in the two groups. [38]
Immunosuppressive Therapy
Immunosuppressive therapy is required to inhibit antibody production and rebound hypersynthesis, which may occur following discontinuation of plasma exchange. [2, 35, 36]
Initial therapy includes cyclophosphamide at 2 mg/kg orally, adjusted to maintain a white blood cell count of approximately 5000, and corticosteroids (eg, prednisone at 1-1.5 mg/kg). Treatment of acute life-threatening alveolar hemorrhage in patients with Goodpasture syndrome is with pulse methylprednisolone at 1 g/day for 3 days, followed by a gradual corticosteroid taper. Intravenous cyclophosphamide is begun concomitantly at 1 g/m2 and repeated 3-4 weeks later, depending on the recovery of bone marrow.
The duration of immunosuppressive therapy is not well established. Anti-GBM antibody levels must be monitored at regular intervals. In patients who achieve a prompt remission, immunosuppression with cyclophosphamide is continued for 2-3 months and steroids for 6 months. Patients with clinically or serologically active disease at 3-4 months need longer immunosuppression (6-9 mo). Azathioprine may be substituted for cyclophosphamide to reduce adverse effects, especially in patients needing prolonged immunosuppression.
Rituximab, a chimeric monoclonal antibody, effectively depletes CD20-positive B cells over 6-9 months and has been used in several case reports as an alternative approach in the treatment of anti-GBM antibody disease. In these reports, rituximab was used as either an initial or a second-line agent in patients in whom cyclophosphamide failed or yielded adverse effects. The anti-GBM antibodies became undetectable in all these patients, but they had variable renal outcomes. [39, 40]
Pneumocystis jiroveci pneumonia has an annual incidence of 1% but is a potentially deadly complication of immunosuppressive therapy in patients with Goodpasture syndrome. Prophylaxis with trimethoprim-sulfamethoxazole (160 mg trimethoprim and 800 mg sulfamethoxazole 3 times per week) may be a cost-effective method of prolonging life in these patients.
Relapse
The circulating antibodies clear within 8 weeks, but an early relapse (ie, within the first 2 mo) may occur when circulating antibodies are still present. This typically manifests as alveolar hemorrhage. The risk factors for relapse include infection, volume overload, and cigarette smoking. Late relapse has been documented only rarely.
Kidney Transplantation
Kidney transplantation has been used for end-stage renal disease secondary to Goodpasture syndrome. It is optimal to delay kidney transplantation until anti-GBM antibodies are undetectable in the serum for 12 months and the disease has been in remission for at least 6 months without the use of cytotoxic agents.
Many patients develop linear deposits of IgG along glomeruli of the renal allograft. However, this development does not cause histologic or functional damage to the transplanted kidney.
Interestingly anti-GBM disease can occur in approximately 3-5% of male patients with hereditary nephritis (Alport syndrome) who undergo kidney transplantation, known as de novo anti-GBM disease. [41] In Alport syndrome (an X-linked disorder), the antibodies are directed against the alpha5 (IV) chain and, in patients who develop posttransplant anti-GBM disease, the antibody is directed against the alpha3 (IV) chain. Anti-GBM disease occurs most commonly in this subset of patients within the first year, and up to 75% patients have serum anti-GBM antibodies.
The diagnosis is achieved with a kidney biopsy, with the characteristic findings of linear deposition of IgG along the capillaries and sometimes the distal tubules. Treatment consists of plasmapheresis and cyclophosphamide, but this appears to be limited. Retransplantation of patients with posttransplant anti-GBM nephritis has a very poor prognosis owing to recurrent disease.
Consultations
Consult a nephrologist for evaluation of the patient in regard to the differential diagnosis of the renal disease, indication for kidney biopsy, requirement for hemodialysis or plasmapheresis, and therapeutic input.
Consult a pulmonologist for patients with significant hemoptysis or respiratory compromise because these patients may deteriorate very rapidly and require bronchoscopy and/or intubation.
A consultation with a vascular surgeon may be required for establishment of vascular access for hemodialysis or plasmapheresis.
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Goodpasture syndrome. A 45-year-old man was admitted to the intensive care unit with respiratory failure secondary to massive hemoptysis and acute renal failure. The antiglomerular basement membrane antibodies were strongly positive. The autopsy showed consolidated lung from extensive bleeding, which led to asphyxiation.
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Goodpasture syndrome. Close-up view of gross pathology in a 45-year-old man admitted to the intensive care unit with respiratory failure secondary to massive hemoptysis and acute renal failure. The antiglomerular basement membrane antibodies were strongly positive. The autopsy showed consolidated lung from extensive bleeding, which led to asphyxiation.
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Cytoplasmic antineutrophilic cytoplasmic antibodies (c-ANCA), which can appear in Goodpasture syndrome, are also commonly observed in Wegener granulomatosis and other vasculitides.
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Perinuclear antineutrophilic cytoplasmic antibodies (p-ANCA), which can appear in Goodpasture syndrome, are also observed in Churg-Strauss vasculitis and occasionally in Wegener granulomatosis.
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This is a renal biopsy slide of a patient who presented with hemoptysis and hematuria. The renal biopsy revealed crescentic glomerulonephritis, which may be caused by systemic lupus erythematosus, vasculitis, or Goodpasture syndrome.
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Goodpasture syndrome. A 35-year-old man who previously smoked cigarettes heavily, developed massive hemoptysis. The blood work showed positive anti–glomerular basement membrane antibodies.
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Immunofluorescence staining for immunoglobulin (IgG) reveals diffuse, high-intensity, linear staining of the glomerular basement membrane in a patient with anti–glomerular basement membrane (GBM) disease. Courtesy of Glen Markowitz, MD, Department of Pathology, Columbia University.
