Pediatric Anti-GBM Disease (Goodpasture Syndrome)

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

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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.

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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.

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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]

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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.

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