Topic Editor: Robert Giles, MBBS, BPharm
Review Date: 12/14/2012
Definition
Anti-glomerular basement membrane (Anti-GBM) disease or Goodpasture's Syndrome (GS) is an autoimmune disorder characterized by rapidly progressive glomerulonephritis and quite frequently, pulmonary-alveolar hemorrhage. The underlying cause is the presence of auto-antibodies against glomerular and alveolar basement membranes.
Description
- Goodpasture's Syndrome (GS) is an autoimmune condition in which anti-glomerular basement membrane (Anti-GBM) antibodies bind to renal and often pulmonary basement membranes with resulting renal (glomerulonephritis) and pulmonary (diffuse pulmonary-alveolar hemorrhage with clinical presentation being hemoptysis) complications
- GS accounts for 20% of cases of pulmonary-renal syndrome (Wegeners Granulomatosis is the most common cause)
- This condition appears due to autoantibodies directed against the noncollagenous (NC-1) domain of the alpha-3 chain of type IV collagen largely found in the alveolar and glomerular basement membranes
- GS has been also strongly linked to the major histocompatibility complex. Human leukocyte antigen (HLA) DR15, DR5 and DRW2 increases susceptibility for this syndrome
- For GS (Anti-GBM disease) to be diagnosed one of the following must be demonstrated:
- Anti-glomerular basement membrane antibodies in serum
- Linear binding of IgG on direct immunofluorescence to the glomerular basement membrane on renal biopsy
- Treatment includes early plasmapheresis, and immunosuppression utilizing both corticosteroids and cyclophosphamide
- Some patients require hemodialysis on initial presentation due to acute renal failure
Epidemiology
Incidence/Prevalence
- GS is a rare disease with an incidence of 0.5-1.8 cases/million persons/year
- GS accounts for up to 20% of patients with renal-pulmonary syndrome (diffuse alveolar hemorrhage and acute renal failure secondary to glomerulonephritis)
Age- Age at onset ranges from 10 to 90 years
- There is bimodal age distribution with disease onset peaking at 20-30 years (predominantly male) and 50-70 years (predominantly female)
- One 2012 study had a age range from 12-74 years with a median of 45 years
Gender
- The incidence of GS is some studies is slightly higher in men than women, however, others have shown no such predominance
Race
- It is more common in Caucasians than Blacks
- Although some sources indicate it is more common in New Zealand Maori's, a 2012 found this to be incorrect
Genetics
- Approximately 80% of patients inherit HLA class II genes carrying the HLA-DR2 haplotype
- HLA-DRB1*1501 and DRB1*04 alleles increase susceptibility; DRB1*03 is neutral, whereas DRB1*07 is protective in nature
- GS has been also strongly linked to the major histocompatibility complex. Human leukocyte antigen (HLA) DR15, DR5 and DRW2 increases susceptibility for this syndrome
Risk factors
- Patients with human leukocyte antigen (HLA) class II genes have a higher susceptibility and worse prognosis
- In one recent study of 23 cases, 11 were regular smokers and 8 were ex-smokers
- Genetic susceptibility and environmental exposure to
- Cigarette smoke
- Hydrocarbon solvent inhalation
- Pneumonia
- Sensitivity to pollen
- Viral respiratory tract infections
Etiology
- GS depends on numerous immunologic, humoral, and environmental factors in genetically susceptible individuals
- In GS, antibodies attack the noncollagenous (NC1) domain of the alpha3 chain of type IV collagen [alpha3 (IV) NC1] located in the basement membrane, especially those in the lung, kidneys, choroid plexus, uveal tract, thymus, and cochlea
- Autoantibodies recognize multiple cryptic epitopes on the alpha3 (IV) NC1 domain in the glomerular and alveolar basement membrane because of its high accessibility
- Infection or exposure to organic solvents also enhances the probability of autoantibodies encountering the pathogenic epitope
- Immunoglobulin antibodies, largely IgG1, and IgG4 become localized in the basement membrane rupturing the collagen. Thereafter, the basement membrane loses integrity
- Binding of antibody activates complement and proteases, thereby augmenting the process of renal injury
- CD4+ and CD8+ T cells also play a significant role in the inflammatory process by inducing the movement of macrophages and neutrophils
History
- Patients usually have non-specific symptoms such as malaise, arthralgia, mild shortness of breath, and/or dry cough. Because the early symptoms are non-specific, late presentations for care is common
- Hemoptysis is the most common pulmonary symptom, occurring in approximately 70% of cases, along with cough and dyspnea
- Historical items due to renal failure such as hematuria, edema, tachypnea, decreased urinary outputconfusion (from uremia) may also be present in later presenters
- History of, or current smokers are more likely to have pulmonary hemorrhage
- Symptoms of anemia, such as decreased exercise tolerance, pallor, breathlessness can occur in patients with pulmonary hemorrhage
Physical findings on examination
The most common observations on physical examination of the patient with GS are:
- Crackles and rhonchi on chest examination
- Cyanosis
- Heart murmur
- Hepatomegaly
- Hypertension
- Lower extremity edema
- Pallor
- Skin rash
- Tachycardia
- Tachypnea
General treatment items
- Early intensive treatment is essential to minimize morbidity and mortality
- Further, it is essential to limit the patient's exposure to other risk factors
- Standard treatment includes all 3 of following:
- Plasmapheresis: To remove antibodies, thus stopping the immediate autoimmune destruction of organs
- Corticosteroids: As an anti-inflammatory and immunosuppressant to decrease production of antibodies
- Cyclophosphamide: As an immunosuppressant to decrease production of antibodies
- Details of therapy
- Plasmapheresis
- This is an extracorporeal method performed at the beginning of the treatment to remove circulating pathogenic autoantibodies from plasma
- 50 mL/kg (Max 4000 mL) of plasma, exchanged for 5% human albumin daily (less commonly every other day) for the first 14 days or until anti-GBM antibodies are no longer detectable. In some cases, replacement may need to be with fresh frozen plasma rather than 5% albumin to prevent bleeding
- Plasma exchange, in combination with immunosuppressive agents, may increase the likelihood of patient survival and recovery of renal function in patients with severe renal failure
- Imunosuppressive agents
- Oral or intravenous (IV) cyclophosphamide is usually administered as a cytotoxic agent
- Oral cyclophosphamide is generally started at 3 mg/kg/day in most patients. In patients with life threatening pulmonary hemorrhage, IV dosing is recommended
- Therapy should be discontinued if the white blood cell count decreases below 3,500/mm3 or the platelets drop below 100,000 mm3
- Azathioprine oral or IV may be used in patients intolerant to cyclophosphamide
- Patients with resistant disease may benefit from rituximab or mycophenolate mofetil (case reports)
- Corticosteroids
- Traditionally prednisone or prednisolone at 1 mg/kg/day orally has been used to decrease the antibody-mediated glomerular inflammatory responses
- In cases of life threatening pulmonary infiltrates, IV pulse methylprednisolone has been used to initiate the therapy (1 gram/day for 3 days then gradual taper); however, this increases risk of infection which may give rise to further complications. Following completion of pulse therapy, patients should be switched to oral steroids prednisolone, prednisone, or methylprednisolone
- Renal transplantation is advised only after 6 months, when all the serum autoantibodies are eliminated in case of severe renal failure. This waiting period reduces GS recurrence rate to 5-15%
Medications indicated with specific doses
Corticosteroids
- Methylprednisolone [Injectable]
- Methylprednisolone [Oral]
- Prednisone
Immunosupressants- Azathioprine [Oral]
- Azathioprine [IV]
- Cyclophosphamide [Oral]
- Cyclophosphamide [IV]
Diet or Activity restrictions
- Patients on corticosteroid therapy should be advised to restrict their total salt intake to about 2 grams/day
- Patients with deteriorated renal function and experiencing oliguria are may need to limit fluid intake
- Patients should be advised to partake in limited physical activity as they are likely to suffer some degree of fatigue
Disposition
Admission criteria
- Suspected or definite diagnosis of Goodpasture's Syndrome, as therapy required (plasmapheresis, initiation of immunosuppressant therapy, careful monitoring) should generally, at least initially, be performed as an inpatient
- Hemoptysis
- Patients presenting with significant hemorrhage should be admitted to the ICU, preferably with pulmonary/critical care available
- Patients with limited pulmonary reserve or respiratory compromise should be considered for immediate hospitalization
- Patients with respiratory compromise may require ventilatory support
- Glomerulonephritis
- Patients with evidence of acute renal failure, oliguria, anuria, uremia, electrolyte imbalance, hypertensive crisis, or unstable vital signs require hospital admission
Discharge criteria- All hospital intensive management is complete and patient is on stable oral therapy
- Hemoptysis
- Hemodynamically stable patients with negligible hemoptysis may be discharged following appropriate assessment and treatment
- Glomerulonephritis
- Patients with normal vitals and stabilized renal function may be discharged with appropriate follow-up
Prevention
- GS may be prevented by limiting exposure to offending agents like cigarette smoke and hydrocarbons
Prognosis
- Overall one year survival is 75%, with renal survival at 90% in patients who present early and are treated with appropriate therapy. Deaths are generally related to pulmonary hemorrhage or complications (such as infection) related to immunosuppressive treatments
- Late detection or delayed diagnosis of the disease is associated with a poor prognosis
- In the absence of treatment, patients are at high risk for dialysis-dependence and mortality due to rapidly progressive loss of renal function
- Patients with a serum creatinine >5 mg/dL (440 µmol/L) and 50-100% crescents on renal biopsy have an increased likelihood of requiring long term hemodialysis
- Patients who require dialysis from the start of treatment have a 90% chance of requiring long term hemodialysis (or transplant)
- Patients without evidence of advanced disease often recover with immunosuppressive treatment and 8-10 sessions of plasma exchange
- Plasma exchange improves renal function in ~80% to 95% of patients with serum creatinine levels of
5.7-6.8 mg/dL (500-600 µmol/L) - One 2012 review of 23 cases showed the following outcomes
- 5 deaths (22% mortality rate)
- Of the 18 who survived:
- 8 with end-stage renal disease
- 2 with chronic kidney disease
- 8 with normal renal function
- Patients rarely experience relapse, though it may be higher risk in patients with continued exposure to cigarette smoking or hydrocarbons
Associated conditions
- Antineutrophil cytoplasmic-associated vasculitis
- Membranous nephropathy
Pregnancy/Pediatric affects on condition
- Pregnant women with GS may develop hypertension and associated deteriorating fetal growth, leading to premature delivery
Synonyms/Abbreviations
Synonyms
- Antiglomerular basement membrane disease
- Goodpasture's syndrome
- Anti GBM disease
ICD-9-CM
- 446.21 Goodpasture's syndrome
ICD-10-CM
- M31.0 Hypersensitivity angiitis
