Anti–glomerular basement membrane (anti-GBM) disease is a classic autoimmune disorder characterized by the presence of circulating pathogenic autoantibodies directed against proteins in the glomerular and alveolar basement membranes.[1, 2, 3] In the kidneys, binding of these autoantibodies with the GBM results in activation of the complement cascade and can lead to rapidly progressive glomerulonephritis. In Goodpasture syndrome, glomerulonephritis is accompanied by pulmonary hemorrhage due to anti-GBM antibodies acting on the alveolar basement membrane.[4]
An early and precise diagnosis of anti-GBM disease is extremely important for preventing death and preserving renal function.[5] Immunosuppression with high-dose steroids and oral cyclophosphamide, together with plasmapheresis, is used in the treatment of severe forms of this disease. Early diagnosis and aggressive treatment have substantially reduced overall mortality rates from 95% in earlier years to 10-20% in recent years. However, current therapy remains less than optimal, with many adverse effects and unacceptably high mortality rates. A better understanding of the pathogenic mechanisms should lead to the development of more specific treatment strategies.[6]
Go to Pediatric Anti-GBM Disease (Goodpasture Syndrome) for complete information on this topic.
In 1919, E.W. Goodpasture described a 19-year-old man with fatal lung hemorrhage and glomerulonephritis. The syndrome was subsequently shown to be caused by an antibody response against antigens present in the alveolar and glomerular basement membranes.[7] Immunofluorescent examination of affected kidneys demonstrated that these antibodies were localized in a continuous linear deposit along the GBM.
In 1958, Stanton and Tange introduced the term Goodpasture syndrome to describe patients with these conditions. In 1967, in a classic experiment, Lerner and colleagues transferred anti-GBM disease to monkeys by injecting them with kidney-bound antibodies from patients with anti-GBM nephritis.[8]
Over the years, tremendous gains have been made in knowledge of the pathogenic mechanisms underlying anti-GBM nephritis. The fact that the anti-GBM antibodies are directed against the noncollagenous globular domain (NC1 domain) of the alpha-3 chain of type IV GBM collagen is well known.
Anti-GBM antibodies are directed against an epitope located at the NC1 domain at the C-terminal of the alpha-3 chain of type IV collagen. The alpha-3 chain of type IV collagen has a limited distribution in the body; it is found only in a few specialized basement membranes, including the glomerular and alveolar basement membranes.
This distribution helps explains the specific organ involvement (ie, glomerulonephritis and pulmonary hemorrhage) in persons with anti-GBM nephritis. When bound to the specific antigens in the kidneys and lungs, the antibodies initiate an inflammatory destruction of tissues by complement activation and recruitment of proinflammatory cells, leading to rapidly proliferative glomerulonephritis, often accompanied by pulmonary hemorrhage. Antibodies reacting with the alpha-3 chain of type IV collagen can be detected in the serum and can be eluted from kidneys of patients with anti-GBM nephritis.
Because the antigenic epitope is hidden within the triple helix of the collagen, an environmental factor (eg, smoking, hydrocarbon exposure) presumably is required to unmask the cryptic antigen to the immune system.
Once the anti-GBM antibodies bind to the specific GBM antigen, complement is activated. Proinflammatory cells and CD4+ and CD8+ cells are recruited to the site, and, subsequently, proinflammatory cytokines, chemokines, and proteolytic enzymes are released. This leads to endothelial damage, endothelial cell detachment from the underlying GBM, and fibrin accumulation beneath the disrupted endothelial cells. Breaks develop in the GBM, plasma proteins and cells leak into the Bowman space, and, eventually, crescents develop.[9, 10]
In the United States the disease is rare, accounting for only 5% of human glomerulonephritides and approximately 10-20% of patients with rapidly progressive crescentic glomerulonephritides. Internationallly, the disease accounts for 10-20% of rapidly progressive glomerulonephritis.
Mortality/Morbidity
In the early years, the mortality rate was extremely high (approximately 90-95%). With the introduction of immunosuppression and plasmapheresis, patient and renal survival rates are approximately 85% and 60%, respectively.
Race-, sex-, and age-related demographics.
Whites are affected more often than blacks. With respect to sex and age, the incidence of anti-GBM nephritis is bimodal. The first, and larger, peak occurs in the second and third decades of life. In this age group, men are more susceptible than women. The second, and smaller, peak occurs in the sixth and seventh decades of life, and in this age group, women have a higher preponderance of the disease than men.
Patients with anti–glomeurlar basement membrane (anti-GBM) disease can present with glomerulonephritis alone or with accompanying pulmonary hemorrhage.[11] Although pulmonary hemorrhage may be minor, it is often severe and life threatening. Pulmonary hemorrhage occurs more frequently in young men, whereas anti-GBM nephritis without lung involvement tends to occur more frequently in women in their seventh decade of life.[12]
The disease may begin with either renal or pulmonary manifestations. Usually, both organs are involved more or less simultaneously.[13] However, in some cases, involvement of the second organ may not occur until as much as a year later.
Prodromal features are as follows:
In 25-30% of patients, a prodromal period of flulike illness occurs.
In approximately 5% of patients, arthralgia, myalgia, and arthritis are prominent features.
Pulmonary manifestations are as follows:
The onset of pulmonary hemorrhage may be insidious, with signs symptoms such as anemia, pallor, weakness, lethargy, dyspnea upon exertion, and, sometimes, dry cough.
In some cases, onset is acute and includes fever, massive hemoptysis, acute respiratory failure, asphyxia, and death; however, in many cases, the symptoms—including hemoptysis, dyspnea, cough, fever, tachycardia, and fatigue—may be present intermittently for weeks to months before the diagnosis is established.
Renal manifestations are as follows:
Patients usually present with abrupt onset of oliguria or anuria. Hematuria or the passage of tea-colored urine is usually observed.
Rarely, the renal involvement progresses more insidiously and the patient remains asymptomatic initially; the glomerulonephritis progresses slowly until the development of uremic symptoms.
Physical examination in the acute stage of the disease reveals respiratory distress, tachycardia, and cyanosis.
The patient usually appears pale because of anemia.
In severe cases, the patient may be in hemorrhagic shock and in respiratory failure, thus requiring volume resuscitation and ventilatory support, respectively.
Chest examination may reveal fine rales and dullness to percussion over the affected lung areas.
The disease is caused by autoantibodies directed against the NC1 domain of the alpha-3 chain of type IV collagen. Both genetic susceptibility and environmental features are typically involved.
Genetic susceptibility includes the following:
Anti-GBM disease shows a strong association with HLA-DR2.
Further molecular genetics studies of HLA-DR2 reveal that the association of anti-GBM nephritis is with HLA-DRB1 alleles (HLA-DRB1 1501 and 1502 alleles), HLA-DQA1 01 alleles, and HLA-DQB1 06 alleles.
Anti-GBM nephritis is major histocompatibility complex–restricted. HLA-DRB1*1501 and 1502 alleles increase the susceptibility, while HLA-DR1 and HLA-DR7 are protective.
Environmental factors include the following:
A number of studies suggest a strong association between pulmonary hemorrhage and smoking.
Pulmonary hemorrhage may also be associated with exposure to hydrocarbons or other agents (eg, respiratory pathogens).
The workup for anti–glomerular basement membrane (anti-GBM) disease includes the following laboratory studies:
Urinalysis and 24-hour urine collection
Complete blood cell count (CBC) and blood chemistry
Complement levels and serology
Urine studies
A urinary dipstick test and a 24-hour urine collection to test for protein and creatinine should be performed for detection of hematuria and proteinuria. Urinary sediment should be analyzed using microscopy to detect dysmorphic red blood cells and cellular casts. Typical findings are as follows:
Hematuria: Urinary sediment frequently reveals dysmorphic red blood cells and red blood cell casts.
Proteinuria: This is usually absent in patients in the early years of life. Proteinuria usually progresses with age and may be in the nephrotic range in up to 30% of patients.
CBC and blood chemistry
On the CBC, hemoglobin and hematocrit levels may be low, reflecting blood loss from pulmonary hemorrhage; serial analysis may be helpful for monitoring blood loss. Low hemoglobin levels can also be due to advanced renal failure. The platelet count is usually within reference ranges. A mild leukocytosis is often observed.
On blood chemistry studies, blood urea nitrogen and serum creatinine levels are usually elevated. Serum bicarbonate levels are usually low, and serum phosphate levels may be elevated because of renal failure.
Complement levels and serology
Complement: levels are usually within reference ranges. Antineutrophil cytoplasmic antibodies (ANCA):are usually absent. However, approximately 25-30% patients with anti-GBM disease have circulating ANCA. Of these patients, approximately 75% have perinuclear ANCA; the remaining 25% have cytoplasmic ANCA.
Circulating anti-GBM antibodies
More than 95% of patients with anti-GBM nephritis have circulating anti-GBM antibodies. The antibodies are usually of the immunoglobulin G (IgG) class, although immunoglobulin A or immunoglobulin M anti-GBM antibodies are occasionally observed.
Anti-GBM antibodies can be detected with indirect immunofluorescence assays, usually using monkey kidneys as the substrate, or by radioimmunoassay or enzyme-linked immunosorbent assay (ELISA), which use human recombinant GBM antigens.[14] Radioimmunoassay and ELISA are more sensitive and specific than indirect immunofluorescence assays. Currently, ELISA is most commonly used to detect circulating anti-GBM antibodies. ELISAs are highly sensitive, but their specificity varies depending upon the antigen used.[14]
Unless contraindicated, a renal biopsy should be promptly performed in every case. Rapid diagnosis is necessary to assess the degree of crescentic involvement and the extent of fibrosis and to exclude other disease processes. Furthermore, prompt diagnosis is essential in order to start specific treatment as early as possible to preserve renal function.
Light microscopy reveals the presence of crescents in more than 95% of patients (see the image below), and approximately 80% of patients show crescents involving more than 50% of the glomeruli. In early stages, the crescents are cellular and associated with necrotizing glomerular lesions. They gradually evolve into fibrotic crescents and glomerular sclerosis. Focal rupture of the GBM and fibrinoid necrosis of glomeruli are usually observed. In severe cases, rupture of the Bowman capsule ensues.
View Image
Light microscopy of kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing extensive crescent formation and the....
Tubulointerstitial changes, including interstitial edema and inflammation and tubular damage, are usually observed along with glomerular injury. If necrotizing inflammation is observed in arteries or arterioles, the possibility of concurrent ANCA-associated glomerulonephritis should be considered.
Immunofluorescent examination of the biopsy specimen reveals the characteristic linear deposition of IgG (rarely immunoglobulin A or immunoglobulin M) antibodies along the GBM (as demonstrated in the image below). Linear staining for IgG may also occur along the tubular basement membrane. Weak linear staining of the GBM is frequently observed in persons with diabetic nephropathy, but clinical data and light microscopic features can easily distinguish the 2 conditions.
View Image
Immunofluorescent examination of a kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing a linear deposition o....
Electron microscopy findings reflect those observed with light microscopy and include the presence of crescents, disruption of the GBM, and cellular infiltration at the sites of necrosis.
Antii–glomerular basement membrane (anti-GBM) nephritis is a rapidly progressive disease with a high mortality rate if not treated. Therefore, a prompt diagnosis and early treatment are of paramount importance in preventing death and preserving renal function.
The usual treatment for anti-GBM nephritis is with plasmapheresis in combination with intense immunosuppression consisting of corticosteroids and cyclophosphamide or azathioprine. Other therapeutic options include immunoadsorption using protein A affinity columns or treatment with cyclosporine.[15, 16, 17]
Plasmapheresis
Since the first successful treatment by Lockwood and colleagues in 1976, plasmapheresis has become the standard treatment of anti-GBM nephritis.[18] This therapy effectively removes circulating anti-GBM antibodies and consists of removal of 1 volume of plasma (usually 4 L) and replacement with an equal volume of 5% albumin.
Plasmapheresis is continued daily until anti-GBM antibodies are undetectable in the blood. Usually, 10-14 treatments are required.
In patients with pulmonary hemorrhage, replace clotting factors by administering fresh frozen plasma at the end of treatment.
An early series of studies suggested that oliguric patients and those on dialysis before treatment rarely improve with plasmapheresis. However, more recent reports suggest that patients with advanced renal disease occasionally do respond, particularly if they are not anuric or if the biopsy specimen reveals a low proportion of sclerosed glomeruli.
Protein A immunoadsorption
Several investigators have reported the successful use of immunoadsorption with protein A in patients with anti-GBM nephritis who do not respond to plasmapheresis.
Protein A, isolated from the cell wall of the Staphylococcus aureus Cowan I strain, binds to the Fc portions of IgG. Thus, separated plasma from the patient is pumped through a protein A-Sepharose column to enable anti-GBM antibodies to bind, and the plasma is then returned to the patient. This prevents depletion of coagulation factors and other essential plasma proteins and obviates the need for large-volume replacement of fluids.
Immunosuppression
Immunosuppression usually includes high doses of steroids and cyclophosphamide. Cyclophosphamide is administered at a dose of 2-2.5 mg/kg/d. Adjust the dose of cyclophosphamide according to the degree of renal impairment. Administer cyclophosphamide for at least 1 year after remission, and then taper in 25-mg decrements every 2-3 months until discontinuation or disease recurrence.
Monitor the total leukocyte count frequently, and maintain it between 3000-5000/µL. High-dose steroids are also administered along with cyclophosphamide.
The role of pulse steroids is not clear in persons with anti-GBM nephritis, but some centers usually administer pulse steroids in patients with fulminant disease. Typically, methylprednisolone is given in dosages of 7-17 mg/kg/d for 3 consecutive days. Thereafter, oral prednisolone is started at a dosage of 1 mg/kg/d for 4 weeks and tapered slowly to 20 mg on alternate days by week 52 and withdrawn, as tolerated, thereafter (see Medication).
Consultation with pulmonary and critical care specialists is needed in patients presenting with hypoxia due to severe pulmonary hemorrhage. These patients may require intubation and mechanical ventilation. Furthermore, they may present with hemorrhagic shock and require hemodynamic monitoring in an intensive care unit.
The standard treatment of antii–glomerular basement membrane (anti-GBM) nephritis consists of plasmapheresis in combination with intense immunosuppression. The latter involves high-dose corticosteroids in combination with cyclophosphamide. Rarely, azathioprine or cyclosporine may be used in patients who cannot tolerate cyclophosphamide.
Clinical Context:
Synthetic glucocorticoid for parenteral use. Extremely potent anti-inflammatory activity, ie, greater than that of prednisolone. Has less salt-retaining activity compared with prednisolone. Administered in high doses for the first 3 d in the treatment of anti-GBM nephritis.
Clinical Context:
Synthetic glucocorticoid with potent anti-inflammatory properties. Readily absorbed from GI tract. Constitutes important component of immunosuppressive regimen in treatment of anti-GBM nephritis. Administration begins on day 4, after patient has received 3 doses of IV methylprednisolone.
Anti-GBM nephritis is a rapidly progressive disease associated with a high mortality rate if not treated. However, early diagnosis and prompt treatment can prevent progression, preserve renal function, and reduce mortality. High doses of corticosteroids constitute an important component of the intense immunosuppression for anti-GBM nephritis.
Clinical Context:
Synthetic alkylating agent chemically related to nitrogen mustards. Biotransformed in liver to active metabolites. Well absorbed after PO administration (>75% bioavailability). Approximately 5-25% is excreted unchanged in urine. One of its metabolites, acrolein, is thought to be responsible for urinary bladder toxicity.
Clinical Context:
Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.
Clinical Context:
Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease for a variety of organs.
After discharge from the hospital, patients need a detailed follow-up visit with a nephrologist. Renal function should be closely monitored for progression or recurrence of renal disease. Patients should also have their blood cell counts checked frequently while they are taking cyclophosphamide
Patients presenting with respiratory failure may require intubation and mechanical ventilation. Furthermore, patients may present with hemorrhagic shock and require blood transfusion and hemodynamic monitoring. Patients presenting with advanced renal failure may require short- or long-term dialysis.
While in the hospital, patients should also receive supportive care, cindluing the following:
Adequate nutrition
Prophylaxis for deep vein thrombosis and stress ulcers
Methylprednisolone at 7-17 mg/kg/d intravenously for 3 days should be administered to patients with fulminant disease.
The starting dose of prednisolone is 1 mg/kg/d. In patients receiving intravenous methylprednisolone, oral prednisolone should be started on the fourth day. Administration should be continued after discharge in tapering doses for one year.
Cyclophosphamide should be administered orally at 1 mg/kg/d. This agent should be started once the diagnosis is confirmed and should be continued in an outpatient setting for a total of one year.
Calcium carbonate at 500 mg orally 2-3 times/d should be administered for osteoporosis prevention.
Double-strength trimethoprim-sulfamethoxazole or equivalent should be administered at a dose of one tablet every other day for prophylaxis of Pneumocystis jiroveci infection.
Omeprazole at 20 mg or an equivalent proton pump inhibitor should be administered once or twice a day for prophylaxis of stress ulcers.
Anti-GBM nephritis is a rare disease with a fulminant course if left untreated. The patient should be transferred to a well-equipped tertiary care center for prompt diagnosis and treatment.
Patients with severe pulmonary hemorrhage may present with profound hypoxia and respiratory failure. They usually require admission to an intensive care unit for intubation and ventilation support. Furthermore, patients may present with hemorrhagic shock and may require blood transfusion and hemodynamic monitoring.
Patients presenting with advanced renal failure may require short- or long-term dialysis.
Hemorrhagic shock
In addition to respiratory failure, patients with severe pulmonary hemorrhage may present with hemorrhagic shock. They may require blood transfusion and hemodynamic monitoring. They also may require transfusion of other blood products, such as fresh frozen plasma and platelets, to replenish clotting factors and to prevent further bleeding.
Because many of these patients are young and are potential candidates for kidney transplantation, every attempt should be made to use leukocyte-poor blood to prevent allosensitization.
Renal failure
Patients with anti-GBM nephritis usually present with rapidly progressive renal failure. Those with an advanced degree of renal failure may require short- or long-term dialysis.
Anti-GBM disease is an aggressive disease with a rapidly progressive course. In the early years, the mortality rate was extremely high (90-95%). With the introduction of immunosuppression and plasmapheresis, the prognosis has improved considerably, with patient and renal survival rates of approximately 85% and 60%, respectively.
Both renal survival and patient survival depend on the severity of the disease at the time of presentation. The following reported survival rates underscore the importance of rapid diagnosis and prompt institution of aggressive immunosuppression therapy for patients with Goodpasture syndrome and severe renal failure:
Patients who present with a serum creatinine level of less than 500 µmol/L (5.7 mg/dL) have 1-year patient and renal survival rates of 100% and 95%, respectively.
Patients who present with a serum creatinine level of more than 500 µmol/L (5.7 mg/dL) but do not require dialysis have 1-year patient and renal survival rates of 83% and 82%, respectively.
Patients who present with dialysis-dependent renal failure have 1-year patient and renal survival rates of 65% and 8%, respectively.
Importantly, patients with advanced renal disease at the time of presentation (ie, oliguric or dialysis dependent) do not usually respond to plasmapheresis, methylprednisolone, or other immunosuppressive therapy.
Other poor prognostic factors include the following:
Extensive crescent formation (>50%)
Significant tubular atrophy
Interstitial fibrosis or glomerulosclerosis
Oliguria or anuria
Serum creatinine level of more than 6 mg/dL
HLA-DR W2 and HLA-B7
Nasr and colleagues reported 20 cases of "atypical anti-GBM disease," characterized by bright, linear GBM immunoglobulin deposition but without a diffuse crescentic phenotype, pulmonary involvement, or detectable circulating α3NC1 antibodies. The 1-year patient and renal survival rates were 93% and 85%, respectively, indicating an indolent course for this rare variant.[19]
Patient education should cover the following risks:
Bladder cancer
Osteoporosis
Opportunistic infections
Risk of bladder cancer
Patients with anti-GBM nephritis receive large doses of cyclophosphamide for a prolonged period. This makes them high-risk candidates for the development of hemorrhagic cystitis and bladder cancer. They should drink large quantities of water to ensure urine output of at least 2 L/d and should avoid becoming dehydrated.
They should also watch for gross hematuria and report it promptly to their physician. Patients should have regular urinalyses to screen for nonglomerular hematuria.
Cigarette smoking has been shown to increase the risk of bladder cancer in patients receiving cyclophosphamide. Therefore, patients should be encouraged to quit smoking.
Risk of osteoporosis
Patients are at a high risk for developing steroid-induced osteoporosis. They should be encouraged to take adequate calcium in their diets and to take additional calcium supplements. Postmenopausal women should also receive estrogen.
Risk of opportunistic infections
Intense immunosuppression can make patients susceptible to opportunistic infections. Therefore, patients should be advised to avoid close contact with ill people.
They should receive prophylaxis against certain infections (eg, Pneumocystis jiroveci, yeast) and should contact their physician if they develop fever, sore throat, cough with expectoration, or any other signs of infection.
Patient education information sources
For patient education information, see Blood in the Urine, Kidney Transplant, and Mayo Clinic - Kidney Transplant Information.
Ramesh Saxena, MD, PhD, Professor, Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center
Disclosure: Received honoraria from e-medicine for authoring review articles.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Christie P Thomas, MBBS, FRCP, FASN, FAHA, Professor, Department of Internal Medicine, Division of Nephrology, Departments of Pediatrics and Obstetrics and Gynecology, Medical Director, Kidney and Kidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics
Disclosure: Nothing to disclose.
Chief Editor
Vecihi Batuman, MD, FASN, Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System
Disclosure: Nothing to disclose.
Additional Contributors
Chike Magnus Nzerue, MD, FACP, Professor of Medicine, Associate Dean for Clinical Affairs, Meharry Medical College
Light microscopy of kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing extensive crescent formation and the collapse of glomerular tuft.
Immunofluorescent examination of a kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing a linear deposition of immunoglobulin G along the glomerular basement membrane.
Light microscopy of kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing extensive crescent formation and the collapse of glomerular tuft.
Immunofluorescent examination of a kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing a linear deposition of immunoglobulin G along the glomerular basement membrane.
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