Pediatric Anti-GBM Disease (Goodpasture Syndrome) 

Updated: Mar 05, 2015
Author: Rudolph P Valentini, MD; Chief Editor: Michael R Bye, MD 

Overview

Background

Goodpasture syndrome (GS) is the clinical entity of acute glomerulonephritis and pulmonary alveolar hemorrhage, and the term Goodpasture syndrome is used interchangeably with pulmonary renal syndrome. This condition is rarely seen in children, has numerous underlying etiologies, and often occurs in the setting of a small vessel vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCAs); examples include Wegener granulomatosis and microscopic polyangiitis.

Goodpasture's name has been used in a more specific clinical condition known as Goodpasture disease, which is the pulmonary renal syndrome specifically associated with anti–glomerular basement membrane (anti-GBM) antibodies.[1] These anti-GBM antibodies produce a characteristic linear deposition along the GBM, one way in which Goodpasture syndrome is differentiated from Wegener granulomatosis.

Because pulmonary renal syndrome is discussed extensively elsewhere (see Wegener Granulomatosis), this article focuses on the specific form of this syndrome associated with anti-GBM antibodies. To avoid confusion between Goodpasture syndrome and Goodpasture disease, the term anti-GBM disease is used.

Anti-GBM disease is defined as the triad of glomerulonephritis (usually rapidly progressive or crescentic), pulmonary hemorrhage, and anti-GBM antibody formation. Despite this triad of clinical findings, patients with anti-GBM disease may present with a spectrum of conditions ranging from pulmonary hemorrhage with minimal or no renal involvement to full-blown renal failure with limited or no pulmonary involvement. Because of limited experience with the disease in children, much of the information presented in this article is derived from the literature pertaining to adults.

Go to Goodpasture Syndrome for complete information on this topic.

Historical information

In 1919, Ernest Goodpasture described an 18-year-old man with a fever and cough, followed by hemoptysis and renal failure. On the basis of this clinical report, Goodpasture's name is often linked to the pulmonary renal syndrome of alveolar hemorrhage and necrotizing and proliferative glomerulonephritis, although vasculitis and not anti-GBM disease is believed to be the cause of the pulmonary renal syndrome in Goodpasture's original patient. The discovery of the role of anti-GBM antibodies by Lerner et al in 1967 helped provide both a better understanding of the pathogenesis for this specific form of pulmonary renal syndrome and a more rational approach to treatment.[2]

See also the following:

  • Acute Renal Failure

  • Antiglomerular Basement Membrane Disease

  • Glomerulonephritis, Crescentic

  • Glomerulonephritis, Diffuse Proliferative

  • Glomerulonephritis, Rapidly Progressive

  • Goodpasture Syndrome

  • Management of Acute Complications of Acute Renal Failure

  • Wegener Granulomatosis

Pathophysiology

The pathogenesis of anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease) is linked to the presence of autoantibodies that react with the alveolus in the lung and the basement membrane of the glomerulus in the kidney. Anti-GBM autoantibodies that are present in the circulation of patients with anti-GBM disease cross the fenestrated endothelium in the glomerulus and bind with the underlying GBM, inducing renal injury.

Anti-GBM antibodies interact with the GBM glycoproteins, almost exclusively the epitope of the noncollagenous domain (NC1) of the α3 chain of type IV collagen. This interaction results in complement activation with glomerular infiltration of polymorphonuclear leukocytes (PMNs) and monocytes. Fibrinogen leaks through the damaged GBM into the Bowman space, and it is polymerized to fibrin through procoagulant factors from activated monocytes, resulting in crescent formation. These autoantibodies are believed to cross-react with the alveolar basement membrane and cause similar damage.

The degree of cross-linking of the α3NC1 hexamer subunits is approximately 3 times greater in the alveolar basement membrane than in the GBM. The Col 4α3NC1 epitope is thought to be less accessible for anti-GBM binding in the lung, and partial denaturation of NC1 domains may be required for full exposure of this sequestered epitope to the antibody. If true, this theory may explain why pulmonary hemorrhage is often associated with factors that increase pulmonary capillary permeability, such as active cigarette smoking, infections, recent hydrocarbon inhalation, and hyperoxia.

Etiology

Although anti–glomerular basement membrane (anti-GBM) antibodies cause this autoimmune disorder, usually when a genetically predisposed individual encounters a particular environmental insult (eg, exposure to cigarette smoke, inhaled hydrocarbons, or viral infections), the etiology of anti-GBM production is not yet well understood. Anti-GBM antibody has been described in identical twins, siblings, and first cousins.

Genetic predisposition

An animal model for anti-GBM disease (Goodpasture disease) has demonstrated that a 10 amino acid, nephritogenic, T-cell epitope of Col4alpha3NC1 was capable of inducing an anti-GBM glomerulonephritis in rats. The positive association of anti-GBM disease with human leukocyte antigen (HLA) DRB1*1501 is among the strongest reported for autoimmune diseases.

HLA-DR2 is expressed in 88% of patients with anti-GBM disease compared with 25-32% of a control group of blood donors. Simultaneous expression of HLA-B8 and HLA-DR2 is associated with a worse prognosis because of the tendency to form glomerular crescents. Anti-GBM antibody is strongly associated with HLA-DR15 and HLA-DR4 alleles. Anti-GBM disease is seen less often with HLA-DR1 and HLA-DR7; both have strong negative associations, and both are highly protective.

Environmental insults

Smoking is closely linked with hemoptysis. In a large case series, 47 of 51 adult patients with anti-GBM disease had a history of smoking.[3] In all, 37 of 37 smokers experienced pulmonary hemorrhage compared with 2 of 10 nonsmokers. Pulmonary hemorrhage is probably less common in adults than previously reported because of the decreasing prevalence of cigarette smoking.

Exposure to hydrocarbon solvents has been associated with anti-GBM disease. Gasoline fumes or industrial solvents are believed to induce chemical injury to the lung or kidney, stimulating antibody production. Anti-GBM disease was reported in a 16-year-old adolescent girl who engaged in heavy smoking and glue sniffing.[4]

Influenza type A2 has been associated with anti-GBM disease. Upper respiratory tract infection or flulike illness occurred before the onset of disease in 20-61% of adults with anti-GBM disease.

Epidemiology

Anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease) is rare in adults and children in the United States. According to the 2011 US Renal Data System (USRDS) Annual Data Report, from 2005-2009, Goodpasture disease was the underlying cause of end-stage renal disease (ESRD) in 28 pediatric patients younger than 20 years (0.4%).[5] These patients are predominantly white (89%) with a median age of 17 years. The mortality of this disease appears to be trending in a favorable direction from 3.4% from the period from 2000-2004 to 0% from 2005-2009.[6]

Presumably, the term Goodpasture syndrome referred to anti-GBM disease, because other causes for the pulmonary renal syndrome that contributed to ESRD (eg, systemic lupus erythematosus [SLE], Henoch-Schönlein purpura [HSP], Wegener granulomatosis) were all listed separately.

Among white Europeans, the annual incidence of pediatric anti-GBM disease is estimated to be 1 case per 2 million population. A retrospective study of ESRD in Dutch children from 1987-2001 listed Goodpasture syndrome as the primary cause of renal failure in 4 (1.1%) of 351 cases.[7]

Racial differences in incidence

Anti-GBM disease has been described in many racial groups, but white individuals are affected most often. According to the 2008 United States Renal Data System (USRDS) annual data report (2002-2006 data), 92% of the pediatric patients with ESRD whose primary diagnosis was Goodpasture syndrome were white.[5]

Sexual differences in incidence

The pediatric literature indicates no predilection in either sex. According to the 2008 USRDS Annual Data Report (2002-2006 data), 42% of young patients (< 20 y) who developed ESRD (termed Goodpasture syndrome by the USRDS) were male.[5]

In adults, reports indicate a male-to-female ratio of 2:1 to 9:1. The literature about adults has also shown that anti-GBM disease with pulmonary renal syndrome typically occurs in young men, whereas renal disease that occurs in isolation is more common in elderly women.

Age-related differences in incidence

In children, anti-GBM disease has been reported in all ages. An 11-month-old infant is the youngest reported patient.[8] The 2008 USRDS Annual Data Report (2002-2006 data) reported the median age of 17 years for patients with ESRD and the primary diagnosis of Goodpasture syndrome.[5]

In the few reported pediatric cases of anti-GBM disease, some children presented with limited renal disease, and others presented with pulmonary hemorrhage alone.[9, 10, 11] In one child, a diagnosis of pulmonary hemosiderosis was made 4 years before anti-GBM disease was seen. Anti-GBM–mediated renal disease resulted in ESRD in most children.

In adults, the mean age of onset is 20-30 years, with a peak incidence in young men aged 20-30 years. A second peak occurs in those aged 50-70 years, with men and women equally affected.

Prognosis

Prognosis in children with anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease) has greatly improved in the past 2 decades, because plasma exchange has been used more aggressively. Reports from the 1960s, before the advent of immunosuppressive therapy and plasma exchange, indicate a 96% mortality rate in adults; in the era of plasma exchange, the mortality rate in adults is 0-41%.

Pulmonary outcomes

The pulmonary prognosis is usually excellent. Some adult patients have had a low diffusion capacity of the lungs for carbon monoxide (DLCO), which suggests residual pulmonary fibrosis. If fulminant pulmonary hemorrhage occurs, it can lead to respiratory failure, which may result in death.

Renal outcomes

Data collected between 2002 and 2006 show the first year mortality for children in the United States with Goodpasture syndrome and ESRD was 4.2%.[5] Renal disease may be indolent, resulting in advanced and often irreversible disease at the time of presentation. Renal failure usually requires dialysis, and patients requiring dialysis at presentation usually develop end-stage renal disease (ESRD). Fewer than 25 cases of immunologically confirmed anti-GBM renal disease have been reported in children. Approximately 90% of patients developed ESRD, and 4 died.

The literature on adults suggests that patients presenting with oligoanuria and serum creatinine level of 6-7 mg/dL do not recover their renal function. Before the advent of plasma exchange, renal survival (with no need for dialysis or transplantation) was less than 25% in adults. According to the current literature about adults, the incidence of ESRD in anti-GBM disease is 25-69%. More recent reports indicate a better outcome with the aggressive use of plasma exchange.

A study looked to determine the clinicopathologic predictors of patient and renal outcomes in anti-GBM disease with or without anti-neutrophil cytoplasmic antibodies (ANCA). The study concluded that oligoanuria is the strongest predictor of patient and renal survival while percentage of glomerular crescents is the only pathologic parameter associated with poor renal outcome in anti-GBM disease. Kidney biopsy may not be necessary in oligoanuric patients without pulmonary hemorrhage.[12]

A single-center, retrospective study of 71 patients over 25 years reported excellent patient and renal survival for patients presenting with a serum creatinine level of less than 5.7 mg/dL.[13] Those who had a creatinine level greater than 5.7 mg/dL and were not dialysis-dependent at presentation had an 82% renal survival at 1 year and 69% at their last follow-up visit. Those who were dialysis-dependent at presentation had a 1-year renal survival of 8%, which fell to 5% at the last follow-up visit.[13] The authors concluded that aggressive use of immunosuppression and plasma exchange should be expeditiously instituted in patients with anti-GBM disease with severe renal involvement to attempt to optimize the chance of renal recovery.[13]

Patient Education

Because relapse can occur, patients with anti–glomerular membrane (anti-GBM) disease (Goodpasture disease) should be educated regarding the potential signs and symptoms of such a relapse. In addition, patients should minimize environmental risk factors associated with this disease (eg, cigarette smoking, hydrocarbon exposure).

Pulmonary relapse can result in a cough, dyspnea, or fatigue. If these symptoms arise, medical attention should be sought immediately because of the potential life-threatening nature of pulmonary hemorrhage.

For patient education information, see Wegener Granulomatosis, Acute Kidney Failure, Kidney Disease, Blood in the Urine, Cough, and Bronchoscopy.

 

Presentation

History and Physical Examination

Hemoptysis is the most common presenting symptom in anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease), followed by dyspnea, fatigue or weakness or both, and cough. In approximately two thirds of cases, hemoptysis precedes the onset of renal disease by 8-12 months. This interval can be as long as 12 years before nephritis develops.

Physical examination findings in patients with anti-GBM disease are those related to pulmonary hemorrhage, renal failure, and anemia and include pallor (the most common clinical sign), crackles and rhonchi, heart murmur, hepatomegaly, and edema.

Prompt diagnosis of pulmonary hemorrhage is imperative, because it is the principal cause of early death in patients with anti-GBM disease.

Go to Goodpasture Syndrome for complete information on this topic.

Renal assessment

Renal disease may be present; it can then be isolated or accompanied by pulmonary hemorrhage. When significant renal disease is present, it usually progresses rapidly. Signs and symptoms of disease can vary from hematuria and proteinuria with normal renal function to severe oligoanuric renal failure, such as the following:

  • Gross hematuria (10-41% of adults)

  • Edema (in as many as 25% of patients)

Hypertension can be present but is an uncommon manifestation of glomerulonephritis, reported in 4-17% of adult patients. Similarly, hypertension is unusual in children but has been reported.

Pulmonary assessment

Pulmonary hemorrhage can range from mild to life threatening, including the following:

  • Hemoptysis (82-90% of adults): This feature can vary from blood-tinged sputum to profound bleeding; mild hemoptysis may resolve spontaneously or progress to massive hemorrhage in a short period, resulting in fulminant respiratory failure

  • Cough (40-60% of adults)

  • Exertional dyspnea (57-72% of adults): This likely reflects both lung parenchymal involvement and anemia from pulmonary hemorrhage; in severe cases, clinical signs of pulmonary hemorrhage include tachypnea, inspiratory crackles and rhonchi, and cyanosis

  • Fatigue and weakness (38-66% of adults)

  • Fevers, chills, diaphoresis (15-24% of adults)

  • Tachypnea

  • Cyanosis

  • Inspiratory crackles

  • Bronchial breathing

Generalized vasculitis assessment

The general features listed below are more prominent in patients with systemic vasculitis than in others. The following can be the initial signs or symptoms in patients with anti-GBM disease:

  • Malaise

  • Weight loss

  • Arthralgias

  • Fever

  • Pallor: This is correlated with the degree of anemia present; approximately 51-90% of adults have pallor

Approximately 20-25% of patients have a functional heart murmur because of anemia.

Unlike patients with antineutrophil cytoplasmic autoantibodies (ANCA) disease, patients with anti-GBM disease typically lack symptoms of generalized vasculitis.

 

DDx

Diagnostic Considerations

It is essential to promptly diagnose pulmonary hemorrhage, because this the principal cause of early death in patients with in anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease).

When renal disease is present, it can then be isolated or accompanied by pulmonary hemorrhage. When significant renal disease is present, it usually progresses rapidly.

Essential mixed cryoglobulinemia should also be considered when evaluating a patient with suspected anti-GBM disease.

Differential Diagnoses

 

Workup

Approach Considerations

Approximately 20-30% of adults with anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease) have coexisting antineutrophil cytoplasmic autoantibodies (ANCA) in their circulation. The renal prognosis of these patients was originally thought to be better when both antibodies are present than when anti-GBM is present alone. However, this has been refuted by a report by Rutgers et al,[14] which showed a similarly poor renal prognosis in adult patients with either anti-GBM antibodies alone or those who were double-positive for myeloperoxidase (MPO)-ANCA and anti-GBM antibodies. Incidentally, those patients with MPO-ANCA antibodies alone had a significantly better renal prognosis than the groups associated with anti-GBM antibodies.

Azotemia occurs in 55-71% of adults with anti-GBM disease, and proteinuria occurs in 76-100% of adults. Nephrotic syndrome is unusual.

Recommended Laboratory Studies

All patients with anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease) require urinalysis; complete blood cell (CBC) count with differential; and assessments of blood urea nitrogen (BUN), creatinine, and electrolyte levels.

Microscopic hematuria, as defined by the presence of red blood cells (RBCs), occurs in 83-94% of adults with anti-GBM disease, and macroscopic hematuria is present in 10-40% of adults. RBC casts have been reported in 6-100% of adults with anti-GBM disease.

Anemia occurs out of proportion to hemoptysis or renal failure. A hemoglobin level less than 12 mg/dL is observed in 90-100% of adults. In one series involving adults, the mean hemoglobin level was 7.5 g/dL.

Leukocytosis may be present. Approximately 40-50% of adults have a white blood cell (WBC) count of greater than 10,000 cells/µL. A leftward shift is common.

The erythrocyte sedimentation rate (ESR) is usually only mildly elevated, unlike in patients with vasculitis.

It should be noted that very limited pediatric data exists, because very few cases are reported in the literature. As such, details regarding clinical features at presentation are sparse.[15] Recently, Williamson et al reported 4 cases over a 25-year period from a single center estimated to have performed 2000 renal biopsies in that period. The most consistent feature is crescentic glomerulonephritis with either circulating anti-GBM antibodies or linear staining of IgG on the immunofluorescence. Clinical features included severe renal dysfunction in all patients and pulmonary hemorrhage in half of them.[15]

Serologic Testing

Assessments of antinuclear antibody (ANA), C3, and C4 levels and of the Westergren sedimentation rate are recommended to eliminate other causes of rapidly progressive glomerulonephritis (RPGN). Test results for ANA and rheumatoid factor are usually negative.

Specific recommended serologic tests include the following:

  • Assessments of anti–glomerular basement membrane (anti-GBM) titers and antineutrophil cytoplasmic autoantibodies (ANCA) titers through indirect immunofluorescence testing

  • Enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA), to evaluate proteinase 3 and myeloperoxidase

Results from serologic studies such as antistreptolysin O (ASO) titers and complement studies are usually normal.

The presence of anti-GBM antibody formation can be determined in a number of ways. Linear immunoglobulin G (IgG) deposition along the glomerular capillary walls on the immunofluorescence portion of the renal biopsy is highly suggestive of the disease, especially in the setting of crescentic glomerulonephritis (see the following image).

This image of direct immunofluorescence shows smoo This image of direct immunofluorescence shows smooth linear staining of the basement membrane secondary to immunoglobulin G deposition. This confirms the diagnosis of anti-GBM disease (Goodpasture disease). Image courtesy of K. Orr, MD.

Circulating anti-GBM titers, which are typically of the IgG class, may be elevated in more than 90% of patients. These can be documented through indirect immunofluorescence or RIA techniques. Compared with indirect immunofluorescence, RIA is more sensitive (>90%) and almost as specific (>98%).

IgG can occasionally be eluted from lung or kidney biopsy tissue for analysis and characterization.

ANCA titers are elevated in 20-30% of patients with anti-GBM disease. The ANCA titer is usually perinuclear antineutrophil cytoplasmic autoantibody (p-ANCA) from antimyeloperoxidase antibody.

Pulmonary Studies

This section briefly discusses radiologic studies, pulmonary function testing (PFT), pulse oximetry, and bronchoscopy and bronchoalveolar lavage (BAL) in anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease).

Radiologic evaluation

Chest radiography is the most useful imaging test available to document the presence of pulmonary hemorrhage. The findings depict patchy or diffuse infiltrates with sparing of the upper lung fields. Unlike infection, pulmonary infiltrates from hemorrhage may resolve within a few days.[16]

Chest computed tomography (CT) scanning has a more limited role but may be helpful in identifying localized areas of pulmonary hemorrhage.

Pulmonary function testing

Pulmonary function testing can be used to assess pulmonary hemorrhage by demonstrating accelerated diffusion capacity of the lungs for carbon monoxide (DLCO). A progressive decline in vital capacity or total lung capacity suggests developing interstitial fibrosis.

Go to Pulmonary Function Testing for complete information on this topic.

Pulse oximetry

Pulse oximetry is indicated in all patients with suspected anti-GBM disease who may have hypoxemia from their parenchymal lung injury. However, in patients with severe anemia, oximeter readings may become less accurate.

Bronchoscopy and bronchoalveolar lavage

Bronchoscopy with transbronchial forceps biopsy (TBB) has a higher rate of false-negative results, but it is less invasive than collection through open lung biopsy. TBB is technically more difficult in younger children, and the small biopsy forceps used in them results in smaller tissue samples, with lower diagnostic yield.

Bronchoalveolar lavage can be used to detect hemosiderin-laden macrophages.

Renal and Pulmonary Biopsy and Histology

Renal biopsy is a superior diagnostic test relative to lung biopsy for anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease).

Renal biopsy in patients with anti-GBM disease (Goodpasture syndrome) can usually be performed without incident, even in a patient in relatively unstable condition. The biopsy allows assessment of the severity of the glomerulonephritis and examination for the characteristic linear immunoglobulin G (IgG) deposition along the GBM.

Renal histologic features include a diffuse glomerulonephritis with focal or complete necrosis of the glomerular tuft and segmental or circumferential cellular crescents surrounding some or all glomeruli. Linear IgG along the GBM can be observed with immunofluorescence testing. Linear C3 along the GBM is present in two thirds of biopsy samples. Other causes of linear staining on direct immunofluorescence analysis include systemic lupus erythematosus (SLE) and diabetes mellitus.

Lung biopsy is rarely indicated, but it may be helpful. Pulmonary histologic features include nonspecific findings of hemorrhage with variable degrees of inflammation and fibrosis. Samples obtained during lung biopsy may show IgG staining of the alveolar septum, which is diagnostic for anti-GBM disease.

 

Treatment

Approach Considerations

Treatment of anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease) requires a 2-pronged approach consisting of the removal of the pathogenic antibody and the prevention of new antibody production.

A comprehensive review by Knoll et al stated that patients with anti-GBM disease and end-stage renal disease (ESRD) should be candidates for a renal transplant if they have undetectable anti-GBM titers and are in clinical remission off alkylating agents for at least 6 months.[17]

Successful transplantation of 2 pediatric patients with ESRD and anti-GBM disease were recently described; they were transplanted at 9 months and 12 months after presentation, respectively.[15] Closely monitor patients by obtaining regular anti-GBM titers, serum creatinine levels, and chest radiographs to decide on the duration of various therapies.

Go to Goodpasture Syndrome for complete information on this topic.

Consultations

Patients with anti-GBM disease can present with renal or pulmonary symptoms and are often critically ill. Therefore, pulmonologists, nephrologists, and critical care specialists are commonly involved in the care of these patients.

Most treatments are aimed at both renal and pulmonary conditions. Effective cooperation and communication with regard to the timing and duration of these therapies is essential.

Transfer

A severely ill patient with anti-GBM disease may need to be transferred if the hospital has insufficient intensive care support.

Extracorporeal membrane oxygenation (ECMO) has been tried in pediatric patients with severe pulmonary involvement that is unresponsive to conventional ventilatory support. Transfer to a tertiary care center may be needed if such circumstances are impending.

Plasma Exchange

For anti–glomerular basement membrane (anti-GBM) antibody removal, literature about adults recommends plasma exchange every day for 14 days or every third day for a month. Each session consists of an exchange volume of 3-4 L and its replacement with albumin or fresh-frozen plasma.

Pediatric patients with anti-GBM disease (Goodpasture disease) have also been given plasma exchange in conjunction with corticosteroids and cyclophosphamide. The pediatric literature supports plasma exchange of a single or 1.5-times plasma volume on a daily basis for at least 5 days, followed by a change to alternate day for an additional 6-7 treatments. Replacement is usually with fresh-frozen plasma or 5% albumin. Anti-GBM titers should be monitored to demonstrate removal.[15, 18]

Patients must be monitored for leukopenia or thrombocytopenia, as well as regularly assessed for their blood pressure, renal function, and pulmonary function. It is also critical to prevent or treat opportunistic infections.

Other complications of plasma exchange include the following:

  • Anaphylactoid reactions, usually when fresh-frozen plasma is used

  • Metabolic alkalosis from solutions with high citrate and low chloride, especially when renal function is poor

  • Hemorrhage or thrombosis

  • Posttransfusion hepatitis

  • End-stage renal disease (ESRD)

Opportunistic infections can occur secondary to the patient's immunosuppressed state. Fungal, opportunistic bacterial, and catheter-related infections should be considered in these patients, especially if they are receiving triple therapy with corticosteroids, cyclophosphamide, and plasma exchange.

Although theoretically possible, relapse of anti-GBM disease is relatively uncommon. Recurrent pulmonary hemorrhage associated with infection or cigarette smoking has been reported in adults.

It should be noted that in the only randomized trial of plasma exchange in anti-GBM disease was performed in adults. While only 2 of 8 patients in the plasma exchange group were dialysis dependent versus 6 of 9 in the immunosuppression only group, the authors concluded that renal function and the degree of crescentic involvement on renal biopsy were better predictors of outcome than was the therapeutic intervention selected.[19]

Immunosuppression

Therapy with corticosteroids (eg, prednisone) and cyclophosphamide is aimed at eliminating ongoing antibody synthesis.

Adult patients who present with a serum creatinine level greater than 8 mg/dL have poor renal outcomes. Therefore, seriously consider whether to use this aggressive treatment regimen in patients presenting with limited pulmonary disease and marked renal impairment (serum creatinine >8 mg/dL). There does not appear to be a serum creatinine value that is predictive of renal outcome, as Williamson et al have reported a teenager with a creatinine level of 13.9 mg/dL and 100% crescents on renal biopsy at presentation who was treated with prednisone, cyclophosphamide, plasmapheresis, and peritoneal dialysis. One year later this patient was off dialysis with a creatinine value of 2.1 mg/dL.[15]

Isolated reports describe the use of rituximab, an anti-CD20 monoclonal antibody, in autoimmune disorders aimed at targeting B lymphocytes and their antibody production.

Arzoo et al reported the use of rituximab markedly improved the condition of a 73-year-old woman whose recurrent anti-GBM disease was refractory to treatment with steroids, plasmapheresis, and cyclophosphamide.[20] The marked improvement occurred after the second of 6 weekly prescribed doses of rituximab at 375 mg/m2/dose. This coincided with the disappearance of circulating anti-GBM antibodies.[20]

In pediatric patients, plasma exchange has been administered in conjunction with corticosteroids and cyclophosphamide. The duration of the immunosuppressive treatment varies but is typically 6 months for steroids and 3 months for cyclophosphamide. Rituximab has been used in pediatric autoimmune disorders, but no reports suggest its use for anti-GBM disease in the pediatric age group. This agent is a potent immunosuppressive and needs to be used with caution, weighing the risks and benefits (see Medication).

Dietary and Activity Considerations

Sodium restriction

Pediatric patients with anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease) who are taking corticosteroids are restricted to a sodium intake of 3 mEq/kg/d. The daily total should not exceed 2 g. On the basis of the molecular weight of sodium, 1 mEq is equal to 23 mg.

Fluid restriction

The recommended fluid intake largely depends on the patient's renal function and whether the patient is taking cyclophosphamide.

Patients with a good urine output and a stable blood pressure do not require fluid restriction. Moreover, if the same patients are taking cyclophosphamide, liberal fluid intake is encouraged to promote urine output and to prevent the risk of hemorrhagic cystitis.

Conversely, administration of cyclophosphamide to patients with oliguric renal failure can be challenging. Caregivers must weigh the benefits of this therapy against the risks of hemorrhagic cystitis, with a potential increased risk for bladder cancer in the future. One consideration in this setting would be intravenous cyclophosphamide (dose adjusted for renal dysfunction) accompanied by MESNA; in addition, instilling a urinary catheter for bladder irrigation can be considered if oligoanuria exists.

Activity

Once discharged from the hospital, recovering patients can resume their usual activities unless they have undergone renal biopsy. These patients should avoid running and jumping for 2 weeks, and they are restricted from contact sports for 1 month after the date of biopsy.

If significant anemia is present, the patient's tendency to become fatigued is likely to restrict his or her usual activity level.

Long-Term Monitoring

Continued inpatient treatment is necessary for the following potential complications of anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease):

  • Relapse of anti-GBM disease (ie, pulmonary hemorrhage, deterioration of renal function)

  • Need to initiate dialysis

  • Complications related to dialysis

  • Need for kidney transplantation

  • Opportunistic infections

Perform a weekly complete blood cell (CBC) count to monitor for leukopenia or thrombocytopenia while the patient is taking cyclophosphamide.

Outpatient clinic visits may be required to monitor the patient's blood pressure, renal function, and pulmonary function. Pulmonary function and hemorrhage can be monitored with pulmonary function testing and diffusion capacity of the lungs for carbon monoxide (DLCO) measurements.

Patients may receive peritoneal dialysis or hemodialysis. Peritoneal dialysis can be performed daily at home, whereas hemodialysis is typically performed 3 times per week at a dialysis center.

Pediatric patients needing plasma exchange may receive exchange volumes of 0.5-3.8 L, depending on their size. The treatments are typically given daily for approximately 10 days or until the anti-GBM titer has decreased to normal levels.

 

Medication

Medication Summary

Medications used to treat anti–glomerular basement membrane (anti-GBM) disease (Goodpasture disease) are immunosuppressive agents and prophylactic antibiotics, such as the following:

  • Medications include prednisone, cyclophosphamide, and trimethoprim-sulfamethoxazole

  • Antihypertensives may be required if hypertension occurs

  • Calcium channel blockers (eg, extended-release nifedipine) and diuretics are useful

  • Angiotensin-converting enzyme inhibitors should be used with caution, because these agents may increase serum potassium levels and decrease renal function

  • Avoid beta-blockers as well in light of the patient's pulmonary disease

  • Clindamycin lotion can be used topically to treat steroid-induced acne

Corticosteroids

Class Summary

Glucocorticoids have anti-inflammatory properties and cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.

Methylprednisolone (Solu-Medrol, A-Methapred, Depo-Medrol, Medrol)

Methylprednisolone is used to treat pulmonary hemorrhage and rapidly progressive glomerulonephritis (RPGN). This agent decreases anti-GBM antibody production as well as decreases inflammation by suppressing migration of polymorphonuclear leukocytes (PMNs) and reversing increased capillary permeability.

Prednisone

Prednisone is initially used after pulse methylprednisolone treatment is completed. This agent decreases anti-GBM antibody production.

Antineoplastics, Alkylating

Class Summary

Alkylating agents bind with DNA and interfere with cell growth and differentiation.

Cyclophosphamide

Cyclophosphamide is a potent immunosuppressant used as an adjunct to corticosteroids and plasma exchange. This agent interferes with the inflammatory response by decreasing bone marrow response through the interference of DNA cross-linking and decreases anti-GBM antibody production.

Monoclonal Antibodies

Class Summary

Monoclonal antibodies are used to bind to specific antigens, thereby stimulating the immune system to target these antigens.

Rituximab (Rituxan)

Rituximab is a genetically engineered, chimeric, murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. Thus, rituximab (anti-CD-20) monoclonal antibody binds to pre-B cells and mature B cells. This results in lymphocytotoxic effects to B cells, which should result in reduced autoantibody production.

Rituximab is an immunoglobulin G type 1 (IgG1) kappa immunoglobulin containing murine light-chain and heavy-chain variable region sequences and human constant region sequences. There have been isolated reports of rituximab being used for Goodpasture disease/anti-GBM disease in adults with disease refractory to corticosteroids, alkylating agents, and plasmapheresis.

Antibiotics

Class Summary

Antibiotics are used to prevent opportunistic infection with Pneumocystis carinii.

Trimethoprim and sulfamethoxazole (Bactrim DS, Septra DS)

Trimethoprim and sulfamethoxazole prevents or reduces incidence of P carinii pneumonia in immunosuppressed patients.

Clinamycin (Cleocin, Clindagel, Clindamax)

Clindamycin lotion can be used topically to treat steroid-induced acne. Treats serious skin and soft tissue staphylococcal infections. Also effective against aerobic and anaerobic streptococci (except enterococci). Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest. Commonly used topically, but can be given orally. Apply thin film twice daily except for the gel form. Apply gel form once daily.

Calcium Channel Blockers

Class Summary

The treatment of hypertension should be designed to reduce the blood pressure and other risk factors of coronary heart disease. Pharmacologic therapy should be individualized based on a patient’s age, race, known pathophysiologic variables, and concurrent conditions.

Nifedipine (Adalat, Procardia, Afeditab CR, Nifediac CC, Nifedical XL)

Nifedipine reduces systemic vascular resistance through relaxation of vascular smooth muscle, thereby reducing systemic blood pressure.

Amlodipine (Norvasc)

Amlodipine is generally regarded as a dihydropyridine, although experimental evidence suggests that it also may bind to nondihydropyridine binding sites. Amlodipine blocks the postexcitation release of calcium ions into cardiac and vascular smooth muscle, thereby inhibiting the action of adenosine triphosphatase (ATPase) on myofibril contraction.

The overall effect is reduced intracellular calcium levels in cardiac and smooth-muscle cells of the coronary and peripheral vasculature, resulting in dilatation of coronary and peripheral arteries. Amlodipine also increases myocardial oxygen delivery in patients with vasospastic angina, and it may potentiate ACE inhibitor effects.

During depolarization, amlodipine inhibits calcium ions from entering slow channels and voltage-sensitive areas of vascular smooth muscle and myocardium. It benefits nonpregnant patients with systolic dysfunction, hypertension, or arrhythmias. It has a substantially longer half-life than nifedipine and diltiazem and is administered once daily.

Isradipine (DynaCirc)

Isradipine is a dihydropyridine calcium-channel blocker. It inhibits calcium from entering select voltage-sensitive areas of vascular smooth muscle and myocardium during depolarization. This causes relaxation of coronary vascular smooth muscle, which results in coronary vasodilation. Vasodilation reduces systemic resistance and blood pressure, with a small increase in resting heart rate. Isradipine also has negative inotropic effects.

Diuretics, Thiazide

Class Summary

Thiazide diuretics inhibit the reabsorption of sodium in the distal tubules, increasing the excretion of sodium, water, and potassium and hydrogen ions. They have been effective in treating hypertension of various etiologies. Besides diminishing sodium reabsorption, they also appear to diminish the sensitivity of blood vessels to circulating vasopressor substances. In all patients treated with diuretics, electrolyte levels should be monitored. Examples of thiazide diuretics are hydrochlorothiazide and chlorthalidone.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as of potassium and hydrogen ions.

Chlorthalidone (Thalitone)

Chlorthalidone inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as of potassium and hydrogen ions.

Diuretics, Loop

Class Summary

Loop diuretics inhibit the reabsorption of sodium chloride in the thick ascending limb of the loop of Henle. They can be used to treat hypertension in patients with renal insufficiency; they are less effective than thiazide diuretics in patients who are hypertensive with normal renal function. Examples of loop diuretics are furosemide and bumetanide.

Furosemide (Lasix)

Furosemide is a loop diuretic that increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium and chloride reabsorption in the ascending loop of Henle and the distal renal tubule. It increases renal blood flow without increasing the filtration rate. The onset of action is generally within 1 hour. Furosemide increases potassium, sodium, calcium, and magnesium excretion.

The dose must be individualized to the patient. Depending on the response, administer furosemide at increments of 20-40 mg, no sooner than 6-8 hours after the previous dose, until the desired diuresis occurs. When treating infants, titrate with 1 mg/kg/dose increments until a satisfactory effect is achieved.

Diuretics have major clinical uses in managing disorders involving abnormal fluid retention (edema) and in treating hypertension; their diuretic action causes decreased blood volume.

Bumetanide (Bumex)

Bumetanide increases the excretion of water by interfering with the chloride-binding cotransport system, which, in turn, inhibits sodium, potassium, and chloride reabsorption in the ascending loop of Henle. These effects increase the urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Renal vasodilation occurs after administration, renal vascular resistance decreases, and renal blood flow is enhanced. In terms of effect, 1 mg of bumetanide is equivalent to approximately 40 mg of furosemide.