J Am Soc Nephrol 10: 2446 –2453, 1999
DISEASE OF THE MONTH
Anti-Glomerular Basement Membrane Disease
DAVID C. KLUTH and ANDREW J. REES
University of Aberdeen, Department of Medicine and Therapeutics, Aberdeen, Scotland, United Kingdom.
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 base-
ment membrane. These antibodies bind to the a3 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).
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 hem-
orrhage 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
Correspondence to Dr. David C. Kluth, University of Aberdeen, Department of
Medicine and Therapeutics, Aberdeen, Scotland, United Kingdom AB25 2ZD.
Phone: 144 12 2468 1818; Fax: 144 12 2427 3066; E-mail: d.c.kluth@
abdn.ac.uk
1046-6673/1011-2446
Journal of the American Society of Nephrology
Copyright © 1999 by the American Society of Nephrology
of anti-GBM disease following lithotripsy (12–14) and ureteric
obstruction (15), suggesting that antigen released from a me-
chanically 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 Good-
pasture’s syndrome on the basis of individual cases; however,
the most consistently reported associations are with membra-
nous nephropathy (16 –20) and anti-neutrophil cytoplasmic
(ANCA)-associated vasculitis (17–20). Approximately 10% of
patients with ANCA-positive vasculitis have anti-GBM anti-
bodies, most of whom exhibit a perinuclear pattern of ANCA
and antibodies against myeloperoxidase (21–24). Double-pos-
itive 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 anti-
gens (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 associa-
tions with HLA DR-7 and HLA DR-1, both of which are
dominantly protective (reviewed in reference 26). There are at
least 18 DRb 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 un-
certain. 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
J Am Soc Nephrol 10: 2446 –2453, 1999
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 base-
ment membranes and there are six types: a1 through a6. The
major type IV collagens in most basement membranes are a1
and a2, whereas a3, a4, and a5 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 a-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 a3 chain of type IV collagen. Recent work has
shown that the antibodies bind principally to the amino-termi-
nal region of the NC1 domain (29 –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 special-
ized basement membranes, including Bruch’s membrane in the
eye and the retinal capillaries, cochlear, neuromuscular junc-
tion, 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 spec-
ificities (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 empha-
sized, however, that the relationship between anti-GBM anti-
body level and glomerular injury is not straightforward: For
example, intercurrent infection greatly increases the severity of
glomerular injury independent of the anti-GBM antibody con-
centration. Cell-mediated mechanisms are important in gener-
ating the antibody with patients’ T cells proliferating in re-
sponse 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 rec-
ognized by anti-GBM antibodies (36,37). In addition, there is
Anti-GBM Disease 2447
Table 1. Cause of rapidly progressive glomerulonephritis/
renal failure and lung hemorrhagea
Anti-GBM disease
Systemic vasculitis
Wegener’s granulomatosis
microscopic polyarteritis
systemic lupus erythematosus
Churg-Strauss syndrome
Other vasculitides
rheumatoid vasculitis
Behcets disease
cryoglobulinemia
drugs: penicillamine, hydralazine
Other causes of renal failure and lung hemorrhage
pulmonary edema with acute renal failure
severe pneumonia (in particular Legionella)
paraquat poisoning
renal vein thrombosis with pulmonary emboli
a
GBM, glomerular basement membrane.
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 glo-
merulonephritis or pulmonary hemorrhage.
Pulmonary Hemorrhage
Historically, hemoptysis has been the most common present-
ing feature, occurring in approximately 70% of reported cases
and often preceding the onset of renal disease by months or
years (3,39 – 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 infec-
tions 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 lead-
ing to respiratory failure in a matter of hours. Indeed, pulmo-
nary 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 occa-
sionally bronchial breathing may be heard. Diagnosis may be
2448 Journal of the American Society of Nephrology
Table 2. Causes of linear staining on direct immunofluorescence
microscopy of kidney tissue
Anti-GBM disease
Alport’s syndrome after renal transplantation
Diabetes mellitus
Severe nephrotic syndrome
Systemic lupus erythematosus
Transplant biopsies
Normal autopsy kidneys
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 hema-
turia 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 appro-
priate checks are performed.
The antibodies can also be detected on renal biopsy speci-
mens with characteristic linear staining for IgG and frequently
C3 detected along the GBM; however, this pattern of staining
J Am Soc Nephrol 10: 2446 –2453, 1999
Table 3. Treatment of anti-GBM diseasea
Treatment Description
Plasma exchange 4-L exchanges daily with human
albumin as replacement
solution. Where there is risk
of hemorrhage FFP should be
given at the end of the
procedure.
Corticosteroids Prednisolone 1 mg/kg for first
week then reduce at weekly
intervals to 45, 30, 25, 20, 15,
10, and 5 mg.
Cytotoxic drugs Cyclophosphamide 3 mg/kg
rounded down to nearest 50
mg. In patients over 55 yr of
age, use 2 mg/kg rounded
down to nearest 25 mg.
a
FFP, fresh frozen plasma.
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).
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 glo-
meruli 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 immu-
nofluorescence. 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 anti-
bodies 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
J Am Soc Nephrol 10: 2446 –2453, 1999 Anti-GBM Disease 2449

Table 4. Results of studies assessing the effect of treatment on mortality and renal survivala
Dialysis- Renal
No. of Mortality Dependent or
Category Survival Treatment and Comments
Patients (%) Transplanted (%)
(%)

No treatment
Benoit et al. (1963) (63) 52 96 NA 2
Immunosuppression
Wilson and Dixon 53 47 39 13 75% received some form
(1973) (3) of oral
immunosuppression
Beirne et al. 1977 (10) 29 58 24 17 7 received no therapy
and 6 of these died;
remainder received
prednisolone 6
azathioprine or
nitrogen mustard
Briggs et al. (1979) (41) 18 16 61 22 No treatment in 7, 5
given renal
transplants; remainder
given steroids 1
cyclophosphamide or
azathioprine
Immunosuppression 1
plasma exchange
Walker et al. (1985) (48) 22 41 14 45 Treated with
prednisolone 1
cyclophosphamide and
plasma exchange
Savage et al. (1986) (35) 108 21 47 31
Johnson et al. (1986) (a) 9 (a) 11 (a) 55 (a) 22 (a) received prednisolone
(46) and low dose
cyclophosphamide
(b) 8 (b) 0 (b) 25 (b) 75 (b) treated as (a) plus
plasma exchange
Herody et al. (1993) (39) 29 7 52 41 Most received steroids
and plasma exchange
6 azathioprine
Merkel et al. (1994) (7) 35 11 60 29 Treated with
prednisolone 1
cyclophosphamide 1
plasma exchange
Turner et al. (1998) (2) 38 25 33 42
a
The series show that treatment regimens with plasma exchange and immunosuppression appear to have a better outcome.

antibodies, and with the development of ANCA assays this Treatment

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.
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 immuno-
suppressive 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
2450 Journal of the American Society of Nephrology
approach to treatment by therapeutic plasma exchange com-
bined with immunosuppressive drugs. The regimen needs to be
used intensively to be certain that circulating anti-GBM anti-
body 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 mmol/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.
However, the poor outcome of those patients presenting with
a creatinine .600 mmol/L may suggest that in the absence of
pulmonary hemorrhage, the benefits of treatment are out-
weighed by the risks (47). There are a number of anecdotal
reports of recovery in such patients (16,48 –50) who usually
have a short history with rapidly declining renal function and
a renal biopsy revealing the recent onset of disease with pos-
sibly extensive crescent formation without evidence of scar-
ring. Thus, even in the presence of severe renal failure, aggres-
sive 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 methylpred-
nisolone (51). Despite aggressive therapy, pulmonary hemor-
rhage 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 3 109/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. Recom-
mendations 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 symp-
toms 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.
Disease Recurrence
Recurrence of disease with antibody production has been
reported but is quite rare. Recurrences may occur many years
J Am Soc Nephrol 10: 2446 –2453, 1999
Table 5. Monitoring treatment of anti-GBM diseasea
Monitor disease activity
serum creatinine to monitor renal function
hemoglobin measurement because a fall may indicate lung
hemorrhage
anti-GBM antibody titres that should fall with effective
therapy
serial chest radiographs
pulmonary function KCO to monitor lung hemorrhage
Monitor for side effects of treatment
white cell count because leukopenia can occur with
cyclophosphamide
platelet count because plasma exchange can lead to
consumption of platelets
continued surveillance for infections
a
KCO, a measure of the diffusion capability of the lung
corrected for lung volume.
after the initial presentation with or without evidence of either
renal or pulmonary disease (52–55). 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 anti-
body 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 glomerulonephri-
tis that usually progresses to end-stage renal failure. The pri-
mary abnormality is in the GBM, and it has been appreciated
for many years that autoantibodies from patients with Good-
pasture’s disease did not bind to the GBM of these patients. In
fact, the GBM in patients with Alport’s lacks the a3, a4, and
a5 chains. In the more common X-linked form of the disease,
this is due to mutations in COL4A5, which encodes the a5
chain, whereas in the rare autosomal recessive form the defect
is in the COL4A3 gene. Thus, there is absence of either a3, a4,
or a5 chains in the GBM. It follows that after renal transplan-
tation, patients with these diseases are at risk of developing
anti-GBM antibodies directed at the normal a 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
J Am Soc Nephrol 10: 2446 –2453, 1999
Figure 1. Progression of anti-glomerular basement membrane (anti-
GBM) disease in an Alport’s syndrome patient renal transplant. (A)
Day 2 after renal transplant with normal histologic appearance in the
glomerulus. (B) At day 7 after transplant, there is marked focal
proliferation within the glomeruli, which progresses to destruction of
the glomeruli and loss of architecture by day 12, as shown in Panel C.
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 syn-
drome. The disease recurs in subsequent grafts, where it usu-
ally 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 Good-
pasture’s syndrome, but the outlook is very poor with rapid
development of severe crescentic nephritis (Figure 1).
Anti-GBM Disease 2451
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 a3(IV)NCI. This is
because anti-GBM antibodies in this situation are directed
primarily against the a5 chain, except in the rare patients with
autosomal recessive disease (60). In some published cases, the
target for alloantibodies appeared to be the a3 chain (61,62);
however, reagents for specific detection of antibodies to the a5
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 au-
toimmune disease, including an understanding of the presen-
tation of autoantigens and the precise specificity of pathogenic
antibodies. These approaches are being applied to other auto-
immune diseases in an attempt to develop disease-specific
therapies.
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