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DISEASE OF THE MONTH |
University of Aberdeen, Department of Medicine and Therapeutics, Aberdeen, Scotland, United Kingdom.
Correspondence to Dr. David C. Kluth, University of Aberdeen, Department of Medicine and Therapeutics, Aberdeen, Scotland, United Kingdom AB25 2ZD. Phone: +44 12 2468 1818; Fax: +44 12 2427 3066; E-mail: d.c.kluth{at}abdn.ac.uk
Anti-glomerular basement membrane disease (anti-GBM) is a rare but
well-characterized cause of glomerulonephritis. It is defined by the presence
of autoantibodies directed at specific antigenic targets within the glomerular
and/or pulmonary basement membrane. These antibodies bind to the 
3
chain of type IV collagen found in these specialized basement membranes. Its
importance for the nephrologist lies in that it is a rare yet highly treatable
cause of glomerulonephritis, but one in which delay in institution of the
correct therapy can be fatal. This pattern of rapidly progressive
glomerulonephritis and lung hemorrhage is often referred to as Goodpasture's
syndrome and can be caused by a number of pathologies
(Table 1). Ernest Goodpasture
originally described autopsy findings in an 18 yr old with massive hemoptysis
and acute renal failure during the influenza epidemic of 1918
(1). Thus, anti-GBM disease is
a clearly defined cause of Goodpasture's syndrome; however, both pulmonary and
renal disease can occur in isolation at least at presentation. A more
extensive review of the condition has been published elsewhere
(2).
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Epidemiology
Anti-GBM disease has an estimated incidence of one case per 2 million per year in European Caucasoid populations (2). It is responsible for 1 to 5% of all types of glomerulonephritis (3) and is the cause in 10 to 20% of patients with crescentic glomerulonephritis (4,5). The disease occurs across all racial groups but is most common in European Caucasoids. All age groups are affected but the peak incidence is in the third decade in young men with a second peak in the sixth and seventh decades affecting men and women equally (2,6,7). Lung hemorrhage is more common in younger men, while isolated renal disease is more frequent in the elderly with near equal gender distribution.
Environmental factors are thought to play a role in triggering the disease. There are a number of case reports of clusters of patients with anti-GBM disease (8,9), which may implicate an infective agent; however, no clear viral association has been identified. Several anecdotal reports have linked anti-GBM disease to hydrocarbon exposure, with review of all cases suggesting a causal link (10,11). There have been case reports of anti-GBM disease following lithotripsy (12,13,14) and ureteric obstruction (15), suggesting that antigen released from a mechanically damaged kidney may initiate disease in susceptible individuals. Regardless of the role of environmental factors in initiating the autoimmune attack, the environment plays a critical role in determining whether anti-GBM antibodies cause lung injury. Pulmonary hemorrhage occurs in nearly all current cigarette smokers, while it is very rare in nonsmokers (16).
Disease Associations
A large number of diseases have been associated with Goodpasture's syndrome
on the basis of individual cases; however, the most consistently reported
associations are with membranous nephropathy
(16,17,18,19,20)
and anti-neutrophil cytoplasmic (ANCA)-associated vasculitis
(17,18,19,20).
Approximately 10% of patients with ANCA-positive vasculitis have anti-GBM
antibodies, most of whom exhibit a perinuclear pattern of ANCA and antibodies
against myeloperoxidase
(21,22,23,24).
Double-positive patients are notable because the disease behaves more like
vasculitis than anti-GBM disease with a better response to therapy
(23,25).
It is reasonable to speculate that for both membranous and ANCA-positive
vasculitis, damage to the kidney elicits an immune response against the GBM
leading to the production of antibodies, which may or may not contribute to
disease progression.
Genetic Susceptibility
Anti-GBM disease provides insight into the mechanisms of autoimmunity, in particular the role of human leukocyte antigens (HLA) in disease predisposition. HLA class II molecules, including DR, DP, and DQ, present antigen-derived peptides to T cells, thus initiating immune responses, including antibody production. Anti-GBM disease is associated with DR alleles (as opposed to DQ and DP) with strong positive associations with HLA-DR15 and HLA-DR4 alleles and negative associations with HLA DR-7 and HLA DR-1, both of which are dominantly protective (reviewed in reference 26). There are at least 18 DRß alleles, and HLA DR15 has been split into the alleles DRB1*1501-1505. Analysis of these subsets in anti-GBM disease has shown that the disease is associated with DRB1*1501 and 1502, but the other DR15 alleles are too rare in Caucasian populations to assess. Exactly how these DR subgroups predispose to development of disease remains uncertain. Clearly, other factors are involved in disease initiation as DR 15 is relatively common in the general population, whereas anti-GBM disease is rare. Nevertheless, the dominant naturally processed Goodpasture antigen-derived peptides have been identified, and shown to bind to DR15 alleles with lower affinity than to the "protective" DR7 and DR1 alleles. This raises the question whether protective alleles "steal" the pathogenic peptides from DR15 (27,28).
Pathogenesis
The Goodpasture Antigen
The GBM is a specialized basement membrane separating the glomerular
endothelial cells from visceral epithelial cells. It has contact with blood
due to the presence of fenestrae in the endothelium, which allows antibodies
direct access to the GBM for binding. Type IV collagens are found only in
basement membranes and there are six types: 1 through 6. The
major type IV collagens in most basement membranes are 1 and 2,
whereas 3, 4, and 5 predominate in the GBM. Each chain of
type IV collagen consists of a central long collagenous domain, a collagenous
N-terminus (called the 7S domain), and the noncollagenous C-terminal (NC1
domain). Three -chains self-assemble to form a monomer, and these
monomers are linked at their NC1 domains by disulfide bridges producing a
fixed hexamer. The monomers are also linked at the 7S domains, thus
stabilizing this complex meshwork. The autoantibodies in anti-GBM disease are
directed at the NC1 domain of the 3 chain of type IV collagen. Recent
work has shown that the antibodies bind principally to the amino-terminal
region of the NC1 domain
(29,30,31).
Although antibodies from patients may bind to other regions of the NC1 domain,
only binding to the amino terminal region correlated with prognosis as
assessed by dialysis dependency at 6 mo after antibody measurement
(31). This antigen, as well as
being located in the lung, is also found in a number of other specialized
basement membranes, including Bruch's membrane in the eye and the retinal
capillaries, cochlear, neuromuscular junction, and choroid plexus in the
brain.
Anti-GBM Antibodies
Experiments by Lerner et al.
(32) established that anti-GBM
antibodies are pathogenic
(33). They showed that
antibodies eluted from kidneys of patients with Goodpasture's disease could
bind to the GBM of squirrel monkeys when injected in vivo and elicit
a pattern of disease similar to anti-GBM disease. Anti-GBM antibodies in
kidney and blood have identical specificities
(34), and further evidence for
the pathogenicity of anti-GBM antibodies comes from the close correlation
between disease activity and antibody level
(35), and more recently by
association between antibody binding to specific regions of the NC1 domain and
renal prognosis (31). It
should be emphasized, however, that the relationship between anti-GBM antibody
level and glomerular injury is not straightforward: For example, intercurrent
infection greatly increases the severity of glomerular injury independent of
the anti-GBM antibody concentration. Cell-mediated mechanisms are important in
generating the antibody with patients' T cells proliferating in response to
exposure to Goodpasture antigen and are required to provide signals to enable
B cell proliferation and antibody production. T cells have been isolated from
patients with anti-GBM disease, which are reactive with autoantigens
recognized by anti-GBM antibodies
(36,37).
In addition, there is evidence of T cells infiltrating the renal cortex in
anti-GBM disease (38), and
macrophages and neutrophils are a prominent feature within inflamed glomeruli,
highlighting the importance of cell-mediated mechanisms in the effector phase
of disease.
Clinical Features
General malaise, weight loss, fever, or arthralgia may be the initial features of anti-GBM disease in a way similar to but much less prominent than in systemic vasculitis. Symptoms relating to anemia may also occur even in the absence of significant hemoptysis. The principal clinical features relate to development of renal failure due to rapidly progressive glomerulonephritis or pulmonary hemorrhage.
Pulmonary Hemorrhage
Historically, hemoptysis has been the most common presenting feature,
occurring in approximately 70% of reported cases and often preceding the onset
of renal disease by months or years
(3,39,40,41).
The frequency of pulmonary hemorrhage is probably much less now because of the
lower prevalence of cigarette smoking. The patients are frequently dyspneic
with a cough; however, the degree of hemoptysis bears no correlation to the
quantity of pulmonary hemorrhage, and the bleeding that occurs can lead to
anemia. As mentioned earlier, pulmonary hemorrhage occurs almost exclusively
in current smokers. In addition, it is known to be precipitated by
intercurrent infections and fluid overload. It can be episodic and in many
patients resolves spontaneously; in others, however, it can progress from
minor hemoptysis to profound hemorrhage leading to respiratory failure in a
matter of hours. Indeed, pulmonary hemorrhage is the primary cause of early
death in anti-GBM disease, making prompt diagnosis imperative.
Clinical signs in lung hemorrhage are variable, often with signs on physical examination. Inspiratory crackles and occasionally bronchial breathing may be heard. Diagnosis may be made by noting a sudden fall in the hemoglobin in someone with hemoptysis, which is usually accompanied by radiologic changes on chest x-ray. The classical appearance of pulmonary hemorrhage includes alveolar-type shadowing with sparing of the upper lung fields. Unlike infection, shadowing tends not to be limited by fissures, and can resolve over 48 h. However, the picture is often complicated by coexistent fluid overload or infection. The KCO, a measure of the diffusion capability of the lung corrected for lung volume, is a sensitive indicator of lung hemorrhage. Because hemoglobin avidly binds carbon monoxide, the KCO is markedly elevated in lung hemorrhage (42,43). In addition to its diagnostic value, it also can provide a serial assessment to follow resolution of disease.
Despite the potential seriousness of lung hemorrhage, when patients recover there is virtually no residual pulmonary deficit or fibrosis. We and others have reported minor reductions in KCO at long-term follow-up (28).
Renal Manifestations in Anti-GBM Disease
Renal disease can occur in isolation or in association with pulmonary
hemorrhage. In general, renal disease progresses rapidly once significant
injury has occurred and rarely resolves spontaneously. The urine sediment
shows microscopic hematuria with red cell cast formation as disease
progresses, and in severe disease macroscopic hematuria may occur often with
associated loin pain. Proteinuria is modest (<3 g/24 h), but can be heavier
when the disease has a more subacute course. Progressive renal failure usually
develops leading to oliguria, which is a poor prognostic sign, and under these
conditions fluid overload, super-added infection, and lung hemorrhage with
hypoxia all contribute to renal failure.
Diagnosis
Anti-GBM Antibodies
The diagnosis of Goodpasture's disease is dependent on the detection of
anti-GBM antibodies either in the circulation or in kidney tissue. These
antibodies are normally detected using an enzyme-linked immunosorbent assay
method, although where doubt exists a Western blot in a specialized center
will be required. The antibodies have not been reported to occur in the
absence of disease, and false negatives are rare when appropriate checks are
performed.
The antibodies can also be detected on renal biopsy specimens with characteristic linear staining for IgG and frequently C3 detected along the GBM; however, this pattern of staining has been reported in a number of other circumstances (Table 2) giving false positive results. The anti-GBM antibodies are nearly always IgG, however, there are case reports of both IgA and IgM antibodies causing disease (44).
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Renal Biopsy
A renal biopsy is essential in suspected anti-GBM disease, with renal
involvement allowing diagnostic confirmation and assessing renal prognosis.
The histologic pattern of disease starts with mesangial expansion and
hypercellularity and progresses to focal and segmental glomerulonephritis with
infiltration by leukocytes accompanied by segmental necrosis with prominent
breaks in the GBM. Later, glomeruli develop extensive crescent formation
composed of parietal epithelial cells and macrophages in association with
destruction of the GBM. Of particular note (and in contrast to other forms of
crescentic nephritis), the crescents are usually at the same stage of
evolution—again emphasizing the explosive nature of the disease.
Interstitial inflammation is usually present and may relate to the binding of
antibody to basement membrane of distal convoluted tubules. As the disease
progresses, the glomeruli show diffuse inflammation with segmental or total
necrosis and extensive crescent formation, which eventually leads to scarring
and the appearance of an end-stage kidney. Linear binding of IgG is
universally detected by direct immunofluorescence. Linear C3 is found in 60 to
70% of kidney biopsies but does not influence the severity of the renal
lesion.
Differential Diagnosis
The presentation with hemoptysis, lung hemorrhage, and rapidly progressive glomerulonephritis with anti-GBM antibodies makes Goodpasture's disease highly likely, with the main differential diagnosis being from vasculitis. There are a number of reports of patients with vasculitis having anti-GBM antibodies, and with the development of ANCA assays this most commonly occurs in association with myeloperoxidase antibodies (22). In general, they tend to have lower anti-GBM titers that are more readily suppressed by treatment (23,25,45) and can restore renal function even when presenting with severe renal failure unlike Goodpasture's disease. The other causes of pulmonary hemorrhage and renal disease are listed in Table 1 and can usually be distinguished by both clinical context and investigation.
Treatment
Without treatment, the prognosis for patients with anti-GBM disease is dismal. For example, 25 of 53 patients in Wilson and Dixon's series (3) died and only seven retained independent renal function. It appeared that neither steroids nor immunosuppressive drugs had an influence on the renal outcome. Certainly they have none on circulating anti-GBM antibody titers in the short term. The demonstration that anti-GBM antibodies were pathogenic provided a rationale for the current approach to treatment by therapeutic plasma exchange combined with immunosuppressive drugs. The regimen needs to be used intensively to be certain that circulating anti-GBM antibody concentrations will be reduced. Thus, daily whole volume exchanges have been advocated (Table 3). The effectiveness of this approach on improving renal function has been reported from a number of different centers (Table 4). Overall, renal function improves coincident with the introduction of plasma exchange in about 80% of patients with a serum creatinine <600 µmol/L, but in far fewer of those with higher levels or those who require dialysis. Improvement is usually evident within days of starting plasma exchange, which argues in favor of a direct effect. However, it should be emphasized that the regimen has never been properly assessed by a prospective randomized controlled trial because of the rarity and acuteness of the condition. The only reported randomized controlled trial was very small and used lower doses of both plasma exchange and cyclophosphamide than those used generally (46). Overall, plasma exchange is a relatively safe treatment and aids in a rapid reduction in anti-GBM antibodies before the longer-term immunosuppression reduces further antibody synthesis.
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However, the poor outcome of those patients presenting with a creatinine >600 µmol/L may suggest that in the absence of pulmonary hemorrhage, the benefits of treatment are outweighed by the risks (47). There are a number of anecdotal reports of recovery in such patients (16,48,49,50) who usually have a short history with rapidly declining renal function and a renal biopsy revealing the recent onset of disease with possibly extensive crescent formation without evidence of scarring. Thus, even in the presence of severe renal failure, aggressive treatment may sometimes be justified in particular cases. Pulmonary hemorrhage is usually responsive to treatment with this regimen and may even respond to injection of methylprednisolone (51). Despite aggressive therapy, pulmonary hemorrhage is still the most common cause of death, especially in patients with infections.
Careful monitoring of the full blood count is essential. Cyclophosphamide should be stopped if the white cell count falls below 3.5 x 109/L, while sudden drops in the hemoglobin may reflect recurrent lung hemorrhage. The prednisolone is reduced at weekly intervals to 45 mg, 30 mg, 25 mg, then 20 mg with a slower reduction in dose after this point. Recommendations for monitoring progress after initial treatment are outlined in Table 5. If the disease is under control with no evidence of relapse, then normally all treatment can be stopped within 3 to 4 mo. The disease can relapse after initial symptoms have been controlled but before the antibody titer has been fully suppressed. This usually occurs with a rebound of anti-GBM antibody titers after stopping plasma exchange or more commonly due to superadded infection or fluid overload. Regular surveillance for infections and reducing potential sources of sepsis such as intravascular lines or urinary catheters is essential.
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Disease Recurrence
Recurrence of disease with antibody production has been reported but is quite rare. Recurrences may occur many years after the initial presentation with or without evidence of either renal or pulmonary disease (52,53,54,55). These episodes may occur spontaneously or be precipitated by infection or exposure to a toxic agent. Because the diagnosis in recurrent disease can be made more rapidly, outcome is usually better than with the original presentation. Renal transplantation is well known to initiate antibody production with or without renal disease (2). This should not preclude renal transplantation in patients with Goodpasture's disease but careful assessment is required. Our own practice is to delay engraftment for 6 mo after the antibody has become undetectable, and this approach is borne out by the experience of others (56). All patients will need careful monitoring for disease recurrence (presence of microscopic hematuria, rising anti-GBM titers, rising serum creatinine) after transplant; however, the incidence or recurrence is low, occurring in 1 to 12% of transplant recipients (56).
Anti-GBM Disease after Transplantation in Patients with Alport's Disease
Alport's syndrome is an inherited form of glomerulonephritis that usually
progresses to end-stage renal failure. The primary abnormality is in the GBM,
and it has been appreciated for many years that autoantibodies from patients
with Goodpasture's disease did not bind to the GBM of these patients. In fact,
the GBM in patients with Alport's lacks the 3, 4, and 5
chains. In the more common X-linked form of the disease, this is due to
mutations in COL4A5, which encodes the 5 chain, whereas in the rare
autosomal recessive form the defect is in the COL4A3 gene. Thus, there is
absence of either 3, 4, or 5 chains in the GBM. It
follows that after renal transplantation, patients with these diseases are at
risk of developing anti-GBM antibodies directed at the normal chains
in the transplanted kidney. The transient appearance of low titers of these
antibodies is not uncommon
(57,58),
but the risk of developing severe nephritis is small and the overall outcome
for renal transplantation in patients with Alport's is good
(59).
Nevertheless, there are at least 29 cases of anti-GBM disease after transplantation in Alport's syndrome (53). The onset occurs at a variable time after a first transplant and causes crescentic nephritis indistinguishable from Goodpasture's syndrome. The disease recurs in subsequent grafts, where it usually appears in the immediate post-graft period, coincident with the reappearance of anti-GBM antibodies and linear binding of IgG to the GBM. Treatment should be the same as for Goodpasture's syndrome, but the outlook is very poor with rapid development of severe crescentic nephritis (Figure 1).
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An important practical point is that anti-GBM antibody titers may be low or
even negative in conventional immunoassays that have been optimized to detect
the 3(IV)NCI. This is because anti-GBM antibodies in this situation are
directed primarily against the 5 chain, except in the rare patients
with autosomal recessive disease
(60). In some published cases,
the target for alloantibodies appeared to be the 3 chain
(61,62);
however, reagents for specific detection of antibodies to the 5 chain
of type IV collagen have only become available recently
(60).
Conclusion
Anti-GBM disease is a rare cause of renal failure and lung hemorrhage, but a disease in which prompt diagnosis and initiation of correct therapy can produce a cure. It has also provided valuable insight into the mechanisms of human autoimmune disease, including an understanding of the presentation of autoantigens and the precise specificity of pathogenic antibodies. These approaches are being applied to other autoimmune diseases in an attempt to develop disease-specific therapies.
Footnotes
American Society of Nephrology
References
This article has been cited by other articles:
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  X.-j. Zhou, J.-c. LV, L. Yu, Z. Cui, J. Zhao, R. Yang, J. Han, P. Hou, M.-h. Zhao, and H. Zhang FCGR2B gene polymorphism rather than FCGR2A, FCGR3A and FCGR3B is associated with anti-GBM disease in Chinese Nephrol. Dial. Transplant., January 1, 2010; 25(1): 97 - 101. [Abstract] [Full Text] [PDF]
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M. A. Little, B. Hassan, S. Jacques, D. Game, E. Salisbury, A. E. Courtney, C. Brown, A. D. Salama, and L. Harper Renal transplantation in systemic vasculitis: when is it safe? Nephrol. Dial. Transplant., October 1, 2009; 24(10): 3219 - 3225. [Abstract] [Full Text] [PDF]
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U. Persson, J. M. Hertz, M. Carlsson, T. Hellmark, I. Juncker, J. Wieslander, and M. Segelmark Patients with Goodpasture's disease have two normal COL4A3 alleles encoding the NC1 domain of the type IV collagen {alpha}3 chain Nephrol. Dial. Transplant., August 1, 2004; 19(8): 2030 - 2035. [Abstract] [Full Text] [PDF]
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M. Le Hir Histopathology of humorally mediated anti-glomerular basement membrane (GBM) glomerulonephritis in mice Nephrol. Dial. Transplant., July 1, 2004; 19(7): 1875 - 1880. [Abstract] [Full Text] [PDF]
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