Anti-Glomerular Basement Membrane Disease

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Stephen P. McAdoo and Charles D. Pusey

Abstract
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Anti–glomerular basement membrane (anti-GBM) disease is a rare small vessel vasculitis that affects the capillary
beds of the kidneys and lungs. It is an archetypic autoimmune disease, caused by the development of directly
pathogenic autoantibodies targeting a well characterized autoantigen expressed in the basement membranes of
these organs, although the inciting events that induce the autoimmune response are not fully understood. The
Renal and Vascular
recent confirmation of spatial and temporal clustering of cases suggests that environmental factors, including Inflammation Section,
infection, may trigger disease in genetically susceptible individuals. The majority of patients develop widespread Department of
glomerular crescent formation, presenting with features of rapidly progressive GN, and 40%–60% will have Medicine, Imperial
concurrent alveolar hemorrhage. Treatment aims to rapidly remove pathogenic autoantibody, typically with the use College London,
London, United
of plasma exchange, along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and
Kingdom
tissue inflammation. Retrospective cohort studies suggest that when this combination of treatment is started early,
the majority of patients will have good renal outcome, although presentation with oligoanuria, a high proportion of Correspondence: Dr.
glomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis. Relapse and recurrent Stephen P. McAdoo,
disease after kidney transplantation are both uncommon, although de novo anti-GBM disease after transplantation Renal and Vascular
for Alport syndrome is a recognized phenomenon. Copresentation with other kidney diseases such as ANCA- Inflammation Section,
Department of
associated vasculitis and membranous nephropathy seems to occur at a higher frequency than would be expected by
Medicine, Imperial
chance alone, and in addition atypical presentations of anti-GBM disease are increasingly reported. These observations College London,
highlight the need for future work to further delineate the immunopathogenic mechanisms of anti-GBM disease, and Hammersmith
how to better refine and improve treatments, particularly for patients presenting with adverse prognostic factors. Hospital Campus, Du
Cane Road, London
Clin J Am Soc Nephrol 12: 1162–1172, 2017. doi: https://doi.org/10.2215/CJN.01380217
W12 0NN. Email:
s.mcadoo@imperial.
ac.uk

Nomenclature and History
Anti–glomerular basement membrane (anti-GBM)
disease is a rare small vessel vasculitis that affects
glomerular capillaries (where it may result in glo-
merular necrosis and crescent formation), pulmonary
capillaries (where it may cause alveolar hemorrhage),
or both. It is characterized by the presence of circu-
lating and deposited antibodies directed against
basement membrane antigens, and as such is classified
an immune-complex small vessel vasculitis in the
Revised International Chapel Hill Consensus Confer-
ence Nomenclature of Vasculitides (1). The Consensus
acknowledges the relative misnomer of anti-GBM
disease, given the frequent involvement of alveolar
basement membranes, although recognizes the widely
accepted use of anti-GBM disease to describe this
condition with or without lung involvement.
The eponymous term “Goodpasture disease” is also
used to describe this condition, first being used by
Australians Stanton and Tange in 1958 (2), in their
report describing nine cases of GN associated with
lung hemorrhage. They credited Ernest Goodpasture,
an American pathologist, with the first description of
the syndrome in his 1919 paper describing a fatal case
of GN and lung hemorrhage that was, at the time,
attributed to an atypic influenza infection (3). We do
not know, however, if any of these patients had anti-
GBM disease as we recognize it today, because it was
not until the development of immunofluorescence
techniques in the 1960s that it became possible to de-
tect anti-GBM antibodies in kidney tissue (4), and to
demonstrate their pathogenic potential upon elution
and transfer to nonhuman primates (5). The detection
of circulating anti-GBM antibodies in patients quickly
followed (6), and the first comprehensive clinical de-
scription of “anti-GBM antibody–induced GN” was by
Wilson and Dixon (7). It is of historical interest to note
that Goodpasture’s original description of lung and
kidney disease in association with intestinal and splenic
inflammation, after a subacute clinical presentation, was
perhaps more in keeping with a diagnosis of ANCA-
associated vasculitis (AAV) than anti-GBM disease, and
that Goodpasture himself is said to have rejected the
eponymous use of his name.
The term “Goodpasture disease” has persisted, how-
ever, being generally reserved for patients with demon-
strable anti-GBM antibodies, whereas “Goodpasture
syndrome” may be used to describe copresentation
with GN and pulmonary hemorrhage of any cause.
We will use the term “anti-GBM GN” when referring
specifically to the kidney involvement seen in this
condition, and “anti-GBM disease” when referring to
the broader spectrum of kidney and lung disease.
Epidemiology and Etiologic Associations
Given its rarity, definitive observations regarding
the incidence of anti-GBM disease are lacking. It is

1162 Copyright © 2017 by the American Society of Nephrology www.cjasn.org Vol 12 July, 2017
 Clin J Am Soc Nephrol 12: 1162–1172, July, 2017
often said to have an incidence of ,1 per million population/yr
in European populations, largely on the basis of single-center
biopsy- or serology-based series, although accurately defining
populations at risk in such studies is difficult. A recent study
from Ireland is notable for being the first to define a nationwide
disease incidence, by identifying all cases over a decade via
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reference immunology laboratories and a nationwide pathol-
ogy database (8). It reported a disease rate of 1.64 per million
population/yr, higher than previous estimates. The disease is
well recognized in other white and in Asian populations (9–12),
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although is thought to be rarer in African populations (13).
Anti-GBM GN accounts for 10%–15% of all cases of
crescentic GN in large biopsy series (14), although it ap-
pears to be a rare cause of ESRD (15). A common observation
from larger series of anti-GBM disease is that of a bimodal
age distribution, with peak incidences in the third decade,
where a slight male preponderance and presentation with
both kidney and lung disease is observed, and in the sixth to
seventh decades, where presentation with isolated kidney
disease is more common (16–18).
Some series have reported disease “outbreaks” and
seasonal variation in incidence (16,17), and the Irish study
identified spatial and temporal clustering of disease, sug-
gesting that environmental factors may be important
triggers for disease onset, although they are yet to be
accurately defined (8,19). Infectious associations, particu-
larly with influenza A, have been the subject of anecdotal
reports (20,21), and may account for the aforementioned
seasonal or geographic “clustering” of anti-GBM disease
cases, and a recent study described a high prevalence of
prodromal upper and lower respiratory tract infection in a
cohort of 140 Chinese patients (22). The causative nature
of these associations, however, is not proven and remains
speculative.
A more conclusive environmental association is that with
cigarette smoking and the development of lung hemor-
rhage in anti-GBM disease (23). Similarly, inhalation of
hydrocarbons has also been implicated in disease onset
(24). It is suggested that localized inflammation induced
by inhaled toxins may increase capillary permeability, or
potentially disrupt the quaternary structure of the alveolar
basement membrane, exposing usually sequestered anti-
gens and allowing access to pathogenic autoantibodies.
A more recently identified trigger for anti-GBM disease
is treatment with the anti-CD52 mAb, alemtuzumab, a
lymphocyte-depleting agent that is increasingly used in the
treatment of relapsing multiple sclerosis (25). It is thought
that loss of regulatory T cell subsets, or abnormal immune
cell repopulation after depletion, may account for the in-
creased incidence of many autoimmune diseases, including
anti-GBM disease, after exposure to this agent.
It is likely that these environmental triggers act in genet-
ically susceptible individuals to induce disease onset. Anti-
GBM disease has a strong HLA-gene association, with
approximately 80% of patients inheriting an HLA-DR2
haplotype. A hierarchy of associations with particular DRB1
alleles has been identified, some positively associated with
disease (DRB1*1501, DRB1*0401) and some conferring a
dominant-negative protective effect (DRB1*07), which
might be attributed to the higher affinity of the latter alleles
for binding peptides from the target autoantigen (26). The
DRB1*1501 association has been replicated in Asian
Anti-GBM disease, McAdoo et al. 1163
populations (27,28). It should be noted, however, that these
susceptibility alleles are common in most populations and
that they are also associated with other autoimmune
diseases (including multiple sclerosis, perhaps contributing
to the association with alemtuzumab treatment), highlight-
ing that other factors are necessary to incite anti-GBM
disease, and thus HLA-gene testing is not routinely used in
the clinical work-up of these patients.
Polymorphisms and copy number variation in non-HLA
genes have also been implicated in disease susceptibility,
such as the genes encoding Fcg-receptors (29,30), consis-
tent with the role of pathogenic autoantibodies in disease
onset. On the basis of a small study, polymorphisms in
COL4A3, the gene encoding the Goodpasture autoantigen,
are not thought to be involved in disease predisposition
(31). To the best of our knowledge, there has not been an
undirected genetic study in anti-GBM disease.
Immunopathogenesis
In its native form, the GBM consists of a network of type
IV collagen molecules, each made up of triple-helical
protomers of a3, a4, and a5 chains (Figure 1). The principal
target of the autoimmune response in anti-GBM disease
has been identified as the noncollagenous (NC1) domain
of the a3 chain of type IV collagen (a3[IV]NC1; the
“Goodpasture autoantigen”) (32,33). The clinical pattern of
reno-pulmonary disease reflects the restricted expression of
this antigen to the basement membranes of glomerular and
alveolar capillaries (and to a lesser extent, the retina, choroid
plexus, and cochlea, where it is generally not associated
with clinical disease [34]). Two principle autoantibody (B cell)
epitopes within the autoantigen have been identified, desig-
nated EA and EB (35), which in native GBM are usually
sequestered within the quaternary structure of the noncol-
lagenous domains of the triple helix of a3, 4, and 5 chains.
Sera from all patients with anti-GBM disease appear to
react to a3(IV)NC1, although a proportion will also have
antibodies directed against other collagen chains, including
a5 and a4, identified either in serum or upon elution from
kidney tissue, and thought to arise via a process of “epitope
spreading” after a primary response to the a3 chain (36).
The directly pathogenic potential of these antibodies was
clearly demonstrated by Lerner and colleagues in 1967,
when they administered antibodies eluted from the kid-
neys of patients with anti-GBM disease to nonhuman
primates, leading to the development of crescentic GN in
the recipients (5). The pathogenicity of these antibodies has
since been confirmed in a number of other species and
animal models.
Clinical observations support a pathogenic role for these
antibodies; antibody titer, subclass, and avidity have each
been correlated with disease outcome (37–40). In addition,
the rapid removal of circulating antibodies by plasma
exchange is associated with better outcome, and if kidney
transplantation is performed in the presence of circulating
antibodies, disease is likely to recur rapidly in the allograft
(7,41).
In addition to humoral responses, T cells also have a role
in disease pathogenesis. Data from animal models sug-
gest that T cells may contribute directly to cell-mediated
glomerular injury, which can occur in the absence of
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Figure 1. | Structure of the glomerular basement membrane. In its native form, the collagen IV network in the glomerular basement membrane
consists of triple-helical protomers of a3, a4, and a5 chains (shown individually in [A]). The carboxy-terminal domains of these a3 a4 a5
protomers form a trimeric “cap” (B), end-to-end association of which results in the formation of the hexameric NC1 domain (C). The quaternary
structure of this hexamer is stabilized by hydrophobic and hydrophilic interactions across the planar surfaces of opposing trimers, and reinforced
by sulfilimine bonds crosslinking opposing NC1 domains. Two key autoantibody epitopes within a3(IV)NC1 have been described, designated EA
(incorporating residues 17–31 toward the amino terminus) and EB (residues 127–141 toward the carboxy terminus), which in the native form are
sequestered at the junction with a4 and a5 chains within the triple helical structure. Binding through 7s domains (shown in orange) completes
the lattice-like structure of the type IV collagen network (D). Reprinted from reference 102.

significant humoral immunity (42,43), and glomerular T
lymphocytes may be observed in kidney biopsy samples
taken from patients with active disease (44,45). The strong
HLA association and the presence of high-affinity, class-
switched autoantibodies also indicate a necessity for T cell
help in the development of the autoimmune response.
Notably, mononuclear cells from patients proliferate in
response to a3(IV)NC1 at much higher frequency than do
cells from healthy controls, and the frequency of auto-
reactive T cells correlates with disease activity (46–48). The
pathogenic T cell epitopes in humans, however, have not
been consistently defined.
That these autoreactive T cells can be identified in
healthy individuals, along with low-level natural autoan-
tibodies (49), suggests that tolerance to the a3(IV)NC1
antigen is not fully achieved during immunologic develop-
ment. In addition, a rising titer of anti-GBM antibodies has
been shown to predate the onset of clinical disease by
several months (50), highlighting that several tolerance
mechanisms must be disrupted before disease occurs. One
such breach of “peripheral” tolerance is disruption of the
quaternary structure of the Goodpasture autoantigen, and
in particular disruption of the sulfilimine crosslinks that
stabilize the association of opposing NC1 domains on
individual collagen chains (Figure 1). This may result in
modification or exposure of usually hidden epitopes, which
is suggested to be a key event in the pathogenesis of disease
(36). This may account for the association with etiologic
factors that may disrupt alveolar (e.g., smoking, inhalation
of hydrocarbons) or GBM (such as lithotripsy [51,52], and
the other kidney pathologies discussed below).
The recovery phase of anti-GBM disease is associated
with a progressive fall in autoantibody titers (even in the
absence of immunosuppression) and a lower frequency of
T cells reactive to a3(IV)NC1. The emergence of a CD251
suppressor T cell subset that may inhibit responses to a3
(IV)NC1 has been described (53), suggesting that immu-
nologic tolerance to a3(IV)NC1 can be re-established. This
may explain the rarity of clinical relapses in anti-GBM
disease, and the association with lymphocyte-depleting
therapy with alemtuzumab.
Clinical Presentation and Diagnosis
The majority of patients (80%–90%) will present with
features of rapidly progressive GN. Forty percent to 60%
 Clin J Am Soc Nephrol 12: 1162–1172, July, 2017 Anti-GBM disease, McAdoo et al. 1165

will have concurrent lung hemorrhage, and a small mi-

nority of patients may present with isolated pulmonary
disease. “Atypical” presentations are well recognized, and
discussed in more detail below. Central to the diagnosis of
anti-GBM disease is the identification of anti-GBM anti-
bodies, either in serum or deposited in tissue, along with
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pathologic features of crescentic GN, with or without evi-

dence of alveolar hemorrhage.
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Serologic Testing
In current practice, circulating anti-GBM antibodies are
usually detected using commercially available enzyme
immunoassays or bead-based fluorescence assays, which
typically use purified or recombinant human or animal
GBM preparations as antigenic substrate. Western blotting,
using similar GBM preparations, may be a more sensitive
method for antibody detection, although it is not
widely available outside research laboratories. Indirect
immunofluorescence using normal kidney tissue is an
alternative method, although this requires additional
input from a kidney pathologist and is prone to giving
false negative results. A proportion of patients who
have demonstrable deposition of IgG on the GBM by
immunofluorescence, but who are negative for circu-
lating antibodies by these conventional techniques,
may be positive when tested by highly sensitive bio-
sensor assay (54). In anti-GBM disease, the pathogenic
antibodies are usually of the IgG class, with IgG1 and
IgG3 subclasses predominating (37,38), although rare
cases of IgA- and IgG4-mediated disease have been
described (55,56). These antibodies may not be detected
on routine assays.
Serologic testing for anti-GBM antibodies is, by defini-
tion, an urgent laboratory test, and we recommend that
results should be available within 24 hours for patients
presenting with RPGN, particularly when there are contra-
indications to kidney biopsy, because initiating treatment
before developing a need for RRT may have a significant
effect on outcome. It should be noted, however, that
approximately 10% of patients do not have identifiable
circulating antibodies with conventional assays, and so
serologic testing should not be the sole method of diagnosis
when kidney biopsy is available.
Deposited Antibody
Direct immunofluorescence for Ig on frozen kidney
tissue has high sensitivity for detecting deposited anti-
bodies, and is the gold-standard for diagnosis of anti-GBM
disease, typically showing a strong linear ribbon-like
appearance (Figure 2). An important caveat is that fluo-
rescence may be negative or unclear in cases with severe
glomerular inflammation, where the underlying architec-
ture is so disrupted that the linear pattern may not be
recognized. Other causes of linear fluorescence should be
considered (including diabetes, paraproteinemias, lupus
nephritis, and rarely fibrillary GN). Immunoperoxidase
techniques using paraffin-embedded tissue may also be
used, but may be less sensitive. Lung biopsy samples are
not routinely used in the diagnosis of anti-GBM disease,
and, in our experience, immunofluorescence on lung tissue
is rarely informative.
Figure 2. | Kidney biopsy sample immunofluorescence for IgG re-
vealing linear deposits along the glomerular basement membrane,
and weaker staining of Bowman’s capsule and tubular basement
membranes.
Conventional direct immunofluorescence techniques
will identify all IgG subclasses, although will not differ-
entiate the antigenic target of the kidney-bound antibody.
Noncollagen chain antigens, such as entactin, have been
identified in historical case series, although their signifi-
cance is not well characterized. In addition to detecting
deposited anti-GBM antibody, immunofluorescence may
demonstrate the presence of C components, in particular
C3 and C1q, along the GBM (17). A proportion of patients
may also demonstrate Igs or C deposition along tubular
basement membranes.
Renal Biopsy Findings
Crescent formation is the histopathologic hallmark of
anti-GBM disease (Figure 3). Large biopsy series suggest
that 95% of patients will have evidence of crescent
formation on kidney biopsy, and that in 80% of patients
.50% of glomeruli will be affected. The average proportion
of affected glomeruli is approximately 75% (14,57). The
proportion of crescents observed in the biopsy sample
correlates strongly with the degree of renal impairment at
presentation (17,18). These crescents will typically be of
uniform age (Figure 3F), in contrast to other causes of
RPGN, such as AAV, where a mixture of cellular, fibro-
cellular, and fibrous crescents may be seen. Crescentic
glomeruli are likely to have areas of fibrinoid necrosis in the
underlying glomerular tuft. Noncrescentic glomeruli may
similarly have segmental fibrinoid change (Figure 3A),
although often they may appear completely normal. In
early or mild disease, segmental proliferative change
may be seen, with infiltrating neutrophils or mononu-
clear lymphocytes. In severe disease, rupture of Bowman’s
capsule, peri-glomerular inflammation (Figure 3E), pro-
gressing to granuloma formation with multinucleate giant
cells, may be observed in a proportion. Given the acuity of
disease onset, interstitial fibrosis and tubular atrophy are
uncommon in anti-GBM disease (unless there is preexisting
kidney pathology) although interstitial inflammation may
be observed.
 1166 Clinical Journal of the American Society of Nephrology
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Figure 3. | Renal histopathology in anti–glomerular basement membrane (anti-GBM) GN. (A–C) Hematoxylin and eosin–stained sections
demonstrating (A) segmental fibrinoid necrotizing lesion in early anti-GBM GN; (B) small, circumscribed cellular crescent; and (C) large,
circumferential cellular crescent. (D–E) Demonstrate the use of Jones methylamine silver stain to delineate glomerular and tubular basement
membranes, clearly identifying a segmental area of extracapillary proliferation (D). (E) Demonstrates obliteration of the glomerular architecture
and rupture of Bowman’s capsule, with extravasation of red blood cells into the urinary space, and significant peri-glomerular inflammation.
(F) Adjacent glomeruli with synchronous cellular crescent formation typical of anti-GBM disease.

Electron microscopy is of limited additional value in the
diagnosis of anti-GBM disease, showing nonspecific fea-
tures of crescentic GN including rupture of the GBM and
extracapillary localization of fibrin and proliferating cells.
Electron-dense deposits are not seen in isolated anti-GBM
disease, although electron microscopy is necessary to ex-
clude concomitant glomerular pathologies, such as mem-
branous GN, and may identify other diseases that may
cause linear fluorescence (such as fibrillary GN and di-
abetic GBM thickening).
Diagnosis of Alveolar Hemorrhage
Diffuse alveolar hemorrhage may be evident clinically,
or identified by radiologic examination. Broncho-alveolar
lavage may identify hemosiderin-laden macrophages, a
characteristic feature of alveolar bleeding, and may also be
useful to exclude other pathologies, such as atypical in-
fection. In addition, pulmonary function testing, in partic-
ular the determination of the alveolar carbon monoxide
transfer factor (KCO) may assist with the differentiation
of alveolar hemorrhage from other causes of pulmonary
infiltration. The utility of both bronchoscopy and func-
tional testing, however, may be limited by the clinical
condition of the critically unwell patient.
Treatment
Standard treatment for anti-GBM disease includes plas-
mapheresis, to rapidly remove pathogenic autoantibody,
along with cyclophosphamide and corticosteroids, to in-
hibit further autoantibody production and to ameliorate
end-organ inflammation. The use of this combination of
therapies was first described in 1976 (58), and they remain
the core recommendation of the latest Kidney Disease
Improving Global Outcomes guideline for treating anti-
GBM GN (59). We have reproduced a recommended
treatment schedule in Table 1 (13).
The inclusion of plasmapheresis is supported by obser-
vational studies that suggest improved renal and patient
survival compared with historical cohorts treated with
immunosuppression alone (18,60). In addition, a large
contemporaneous Chinese study of 221 patients suggested
better outcomes in patients who received plasmapheresis
in addition to cytotoxic and corticosteroid therapy (61). To
date, there has only been one randomized trial in anti-GBM
disease, which compared the addition of plasma exchange
to cyclophosphamide and steroids. Although this study
was small (n517), the groups not ideally matched at
randomization, and its treatment regimens not represen-
tative of current practice, its findings supported the use of
plasma exchange in anti-GBM disease (62). In particular, it
demonstrated a much more rapid fall in circulating anti-
GBM antibodies and improved kidney function in patients
receiving plasmapheresis.
Immunoadsorption is an alternative form of extracor-
poreal therapy that may be more efficient than plasma
exchange for the removal of pathogenic autoantibody
(although conversely it may not remove proinflammatory
or procoagulant factors). In small series, it appears to have
comparable outcomes to plasma exchange therapy (63,64),
and we note that a prospective, open-label study is planned
to study the kinetics of anti-GBM antibody removal using
 Clin J Am Soc Nephrol 12: 1162–1172, July, 2017 Anti-GBM disease, McAdoo et al. 1167

Table 1. Initial Treatment of Anti-GBM Disease

Agent Details and Duration Cautions

Plasma exchange Daily 4 L exchange for 5% human Monitor and correct as required: platelet
albumin solution. Add fresh human count, aim .70 3 109/L; fibrinogen,
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plasma (300–600 ml) within 3 d of aim .1 g/L (may require

invasive procedure (e.g., kidney biopsy) cryoprecipitate supplementation to
or in patients with alveolar hemorrhage. support PEX); hemoglobin, aim for
Continue for 14 d or until antibody levels .90 g/L; corrected calcium, aim to
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are fully suppressed. Monitor antibody keep in normal range

levels regularly after cessation of
treatment because plasma exchange may
require reinstatement if antibody levels
rebound.
Cyclophosphamide 2–3 mg/kg per d given orally for 2–3 mo. Stop if leukocyte count falls to ,4 3 109/
Reduce dose to 2 mg/kg in L and restart at reduced dose when
patients.55 yr. recovered. Insufficient evidence to
recommend use of IV
cyclophosphamide.
Corticosteroids Prednisolone 1 mg/kg per d (maximum 60 There is no evidence to support the use
mg) given orally. Reduce dose weekly to of methylprednisolone, and it may
20 mg by 6 wk, then gradually taper until increase the risk of infection
complete discontinuation at 6–9 mo.
Prophylactic treatments Prophylaxis against oropharyngeal fungal H2 receptor antagonists in those who are
infection (e.g., nystatin, amphotericin, or intolerant of PPI. Cotrimoxazole may
fluconazole) while on high-dose steroids. contribute to leukopenia; monitor
Peptic ulcer prophylaxis (e.g., with PPI) leukocyte count. Alternatives include
while on high-dose steroid treatment. nebulized pentamidine.
Prophylaxis against PCP (e.g.,
cotrimoxazole) while receiving high-
dose corticosteroids and
cyclophosphamide. Consider acyclovir
for CMV prophylaxis. Consider
prophylaxis against HBV reactivation
(e.g., lamivudine) in patients who have
evidence of previous infection (HBV cAb
positive).

Modified from reference 13, with permission. GBM, glomerular basement membrane; PEX, plasma exchange; IV, intravenous; PPI,
proton pump inhibitor; PCP, Pneumocystis jiroveci pneumonia; CMV, cytomegalovirus; HBV, hepatitis B virus; cAb, core antibody.

this technique (NCT02765789), which may be considered an
alternative depending on local availability.
In AAV, the equivalence of daily oral and pulsed intra-
venous cyclophosphamide in induction therapy has been
established in a large randomized controlled trial (65).
Nearly all published experience in anti-GBM GN, however,
has used daily oral dosing, and so we recommend this as
the first-line approach in this disease. Because the risk of
relapse is very low, and approximately only 3 months of
cytotoxic therapy is usually required, concerns about total
cumulative dose of cyclophosphamide are less relevant
than in AAV. In our experience, high-dose intravenous gluco-
corticoids are not required in the treatment of anti-GBM
disease, provided the other components of therapy, in
particular plasma exchange, can be initiated promptly (18).
The use of other immunosuppressive therapies in anti-
GBM disease is less well described. There are several
reports of rituximab use, as either “add-on” to standard
therapy or as a substitute for cyclophosphamide in patients
who are intolerant (66). Similarly, the use of mycophenolate
mofetil and cyclosporine has been reported in individual
cases or small series (67–69). There is insufficient evidence,
at present, to recommend their use in first-line therapy,
although they may be considered in patients who have
contra-indication or intolerance to conventional treatment.
In addition to targeted immunotherapy, patients may
require immediate organ support; in larger series, approx-
imately half of patients require hemodialysis at the point of
initial presentation (18). There are limited data on how
frequently artificial ventilation is required, although one
small series estimated that this occurred in 11% of patients
with lung hemorrhage (70). There are case reports of
successful use of extracorporeal membrane oxygenation in
patients with very severe lung disease (71–73).
Outcome and Prognosis
Long-term follow-up of the largest cohort of patients
(n571) all treated with the combination of plasma ex-
change, cyclophosphamide, and corticosteroids, from the
Hammersmith Hospital, London, United Kingdom, sug-
gests that it is effective in treating lung hemorrhage in
 1168 Clinical Journal of the American Society of Nephrology
.90%, and in preserving independent kidney function in
the majority of patients, including those who present
with severe kidney dysfunction (18). In patients presenting
with creatinine values ,500 mmol/L, renal survival was
95% and 94% at 1 and 5 years, respectively. In patients
presenting with creatinine .500 mmol/L, but not requiring
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immediate dialysis, renal survival was 82% and 50% at
the same respective time-points. In patients presenting
with an initial requirement for dialysis, however, renal
recovery occurred in only 8% at 1 year. Other reports have
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described similarly low levels of renal recovery in patients
presenting with dialysis-dependent kidney failure, with the
highest rate of approximately 20% recovery in one series (66).
Predictors of poor renal outcome include severity of
renal dysfunction at presentation, the proportion of glomer-
uli affected by crescents, and oligoanuria at presenta-
tion (17,18,74). In the Hammersmith series, no patient who
required hemodialysis and had 100% crescents on kidney
biopsy recovered renal function, and so withholding treat-
ment (and its incumbent toxicity) is often considered in these
cases. An isolated case of renal recovery despite these
findings (75), however, highlights the need to consider all
cases for treatment, with specific attention to other features
that might predict renal recovery on biopsy (such as
concomitant acute tubular injury) and the ability of patients
to tolerate each component of therapy. A short trial of early
treatment may be considered, and rapidly tapered if there is
no evidence of renal recovery within 2–4 weeks. In addition,
the potential benefit of a period of immunosuppression to
expedite autoantibody clearance, thus allowing earlier kid-
ney transplantation, should be considered in suitable pa-
tients. We have used rituximab monotherapy, for example,
in patients with ESRD who have an identified live-donor
for transplantation, but remain anti-GBM antibody–positive,
although controlled evidence for this indication is lacking.
A recent retrospective study (an Australia and New
Zealand Dialysis and Transplant Registry [ANZDATA]
study) analyzed the long-term outcomes of 449 patients
with ESRD due to anti-GBM disease, and found that their
survival was comparable to patients with ESRD of other
causes, whether they remained on dialysis or underwent
kidney transplantation (15). Chronic respiratory sequelae
after alveolar hemorrhage are uncommon (70).
Relapse is rare in anti-GBM disease, occurring in ,3% of
patients in the Hammersmith series (18). It is usually as-
sociated with ongoing exposure to pulmonary irritants
such as cigarette smoke and hydrocarbons (76,77), and
avoidance of these precipitants is an essential part of
long-term management of these cases. We recommend
repeat kidney biopsy in cases of relapse with kidney
involvement, in order to secure an accurate diagnosis and
to exclude concomitant pathologies such as AAV and
membranous nephropathy (discussed below). In confirmed
cases, standard retreatment with cytotoxics and corticoste-
roids is usually indicated. In a patient with multiply
relapsing alveolar hemorrhage we have found treatment
with rituximab beneficial.
Kidney Transplantation after Anti-GBM Disease
Kidney transplantation performed in the presence of
anti-GBM antibodies results in a high likelihood of disease
recurrence in the allograft, at frequencies of up to 50%
in historical series (41). Most centers therefore recommend
a period of at least 6 months’ sustained seronegativ-
ity before undertaking transplantation in patients who
have reached ESRD due to anti-GBM disease (59). Under
these circumstances, and with current immunosuppres-
sive regimens, recurrent disease is rare; the ANZDATA
registry study found that 6 of 449 (2.7%) patients de-
veloped biopsy-proven recurrent anti-GBM disease,
which led to graft failure in two cases (15). The frequency
of other causes of graft failure was similar to patients
transplanted for ESRD of other causes, and overall patient
and renal survival in anti-GBM disease was similar to
other groups in this study. These findings were somewhat
in contrast to a previous European study that suggested
patient survival was favorable in patients transplanted for
anti-GBM disease compared with those transplanted for
other primary kidney diseases (although significant dif-
ferences in age at transplantation may account for this
apparent difference in patient survival) (78). The Euro-
pean study also reported a higher frequency of recurrent
disease (14%), although this may reflect differences in
immunosuppressive use during an earlier era, and the
study did not comment on anti-GBM titers and their
relationship to timing of transplantation. In the current
era, isolated case reports of recurrent disease still exist
(79).
Post-Transplant Anti-GBM Disease in Alport
Syndrome
Mutations in any of the genes which encode the a3, a4, or
a5 chains may result in a failure to produce the normal type
IV collagen network present in GBM, and thus lead to
progressive kidney disease in Alport Syndrome. Mutations
in the COL4A5 gene located on the X chromosome are most
common, giving rise to typical X-linked Alport syndrome,
although autosomal recessive and dominant disease are
recognized with COL4A3 and COL4A4 mutations. After
kidney transplantation, these patients may develop anti-
GBM antibodies as an alloimmune response to the neo-
antigens contained in “normal” a3, a4, or a5 chains in the
kidney allograft. In X-linked disease, these antibodies do
not recognize the individual EA and EB epitopes of the a3
chain recognized by sera from Goodpasture patients, but
rather a distinct, composite epitope on the a5 chain, that is
not sequestered within the native hexamer of the Goopas-
ture antigen (36). It should be noted that commercially
available anti-GBM assays, which are optimized to detect
reactivity to the a3(IV)NC1 antigen, may fail to detect
circulating antibodies in this setting. Anti-GBM anti-
bodies may be detected in 5%–10% of Alport patients
after transplantation, although the development of overt
GN in the allograft is less frequent (perhaps owing to the
effects of maintenance immunosuppression). When GN
develops, however, it usually occurs early and carries a high
risk of graft loss (80,81). Repeated transplantation in this
setting almost invariably leads to more aggressive disease
recurrence and rapid graft loss, and is undertaken at very
high risk (82). Individuals with large COL4A5 gene dele-
tions are at increased risk of post-transplant anti-GBM
disease, and recent guidelines encourage the use of genetic
 Clin J Am Soc Nephrol 12: 1162–1172, July, 2017
testing to inform discussions regarding the risk of de novo
anti-GBM disease after transplantation (83).
Other Variant Forms of Anti-GBM Disease
Double-Positive Anti-GBM and ANCA-Associated GN
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The concurrence of ANCA and anti-GBM antibodies is
recognized to occur at much higher frequency than ex-
pected by chance alone. In some series, almost half of
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patients with anti-GBM disease have detectable ANCA
(usually recognizing myeloperoxidase [MPO]), and up to
10% of patients with ANCA also have circulating anti-GBM
antibodies (84–86). The mechanism of this association is
unclear, although it has been shown that ANCA may be
detected before the onset of anti-GBM disease, suggesting
that ANCA-induced glomerular inflammation may be a
trigger for the development of an anti-GBM response,
perhaps by modifying or exposing usually sequestered
disease epitopes in GBM (50). Conversely, a recent study
found that up to 60% of anti-GBM cases also had anti-
bodies directed against linear epitopes of MPO, versus 24%
recognizing intact MPO. The authors hypothesize that
MPO-ANCA recognizing linear and conformational epi-
topes may arise sequentially, via a process of inter- and
intramolecular epitope spreading (87). We recently ana-
lyzed the outcomes of a large cohort of these “double-
positive” patients from four centers in Europe, and found
that they experience the early morbidity and mortality of
anti-GBM disease, with severe kidney and lung disease at
presentation, requiring aggressive immunosuppres-
sive therapy and plasma exchange (88). During long-term
follow-up, they relapsed at a frequency comparable to a
parallel cohort of patients with AAV, suggesting they
warrant more careful long-term follow-up and maintenance
immunosuppression, unlike patients with single-positive
anti-GBM disease.
Anti-GBM Disease Associated with Membranous
Nephropathy
There are several reports of anti-GBM disease associated
with membranous nephropathy, occurring as a preceding,
simultaneous, or succeeding diagnosis (89,90). As with
the ANCA association, it is postulated that disruption of
glomerular architecture by one disease reveals hidden
epitopes that allow the second process to occur. A rapid
decline in kidney function in a patient with known
membranous nephropathy should raise suspicion of the
development of superimposed crescentic nephritis or anti-
GBM disease, and rebiopsy is recommended. We suggest
that these cases are treated initially as for anti-GBM disease,
although how they should be managed in the long-term is
not clear. The authors of a recent case report suggest that
rituximab may be a useful agent to treat both pathologies
simultaneously (91).
“Atypical” Anti-GBM Disease
Unusual presentations of anti-GBM disease have been
recognized for as long as the disease itself. Wilson and
Dixon’s original 1973 report, for example, included the
case of a male 14-year-old who had the incidental finding
of linear IgG deposition on a kidney biopsy sample taken
Anti-GBM disease, McAdoo et al. 1169
during splenectomy for hypersplenism and a diag-
nostic workup for optic vasculitis, who was treated with
steroids only, and who had normal renal function after
1 year follow-up (7). There have been a number of series of
“atypical” cases published in recent years, often with less
severe renal involvement than is seen in the classic pre-
sentation of anti-GBM disease, although it not always clear
whether these represent distinct clinical subphenotypes or
heterogenous cases on a spectrum of disease severity (92–95).
The largest of these series, reported by Nasr and
colleagues, described 20 patients with mild and indolently
progressive renal impairment, who had linear Ig deposi-
tion on kidney biopsy, but without predominant features of
crescentic GN, and without overt lung hemorrhage (95).
Circulating anti-GBM antibodies were not detected using
conventional assays, and both patient and renal prognosis
were good, with 90% and 85% survival at 1 year, re-
spectively. They estimated that these atypical cases ac-
counted for approximately 10% of anti-GBM cases at their
center. Notably, half of the cases had light-chain restric-
tion on immunofluorescence, although the authors suggest
that the pathologic features were not in keeping with
proliferative GN with monoclonal Ig deposition. They
suggest that differences in the antigen specificity, Ig sub-
class, and/or the ability to fix C and recruit inflammatory
cells, of these atyptical compared with “classic” anti-GBM an-
tibodies, account for the less severe disease phenotype seen.
Another small but well characterized series with a
distinct clinical phenotype was recently described in
Sweden; it included four young females, who had severe
lung disease and minimal kidney involvement, who were
found to have IgG4 subclass anti-GBM antibodies that were
not detectable with conventional anti-GBM assays (56). That
two of these patients demonstrated higher signal in the anti-
GBM ELISA when using a nondenaturing buffer suggests
that differences in epitope specificity might also account for
the negative testing seen with the routine assays, and
supports the hypothesis that differences in clinical pre-
sentation might be related to differences in the subclass or
target of the anti-GBM antibody.
Future Directions
Despite being one of the better characterized autoim-
mune diseases, unanswered questions remain regarding
the pathogenesis of anti-GBM disease, which may have
important clinical implications. These include the need to
further characterize the variant forms of disease, and how
differences in antibody subclass or specificity might influ-
ence presentation, the appropriate use of treatment, and
outcomes. Better understanding of T cell functions, and in
particular the role of regulatory cells that may suppress
disease, may have therapeutic significance, both in anti-
GBM disease and other autoimmune conditions. The
induction of immunologic tolerance using mucosal admin-
istration of GBM antigen has been described in experimental
models (96), which may likewise have therapeutic potential.
Finally, the inciting events that cause autoimmunity to GBM
antigens remain unclear. Idiotype–anti-idiotype interactions
have been invoked in a recent study (97), and the role of
infectious triggers that might operate via a similar mechanism
in clinical disease induction could be explored further.
 1170 Clinical Journal of the American Society of Nephrology
As a rare disorder requiring immediate treatment, co-
ordinating large, prospective studies in anti-GBM disease is
challenging. In addition, the efficacy of current treatment
regimens, when started early enough, is widely accepted.
Future therapeutic studies, therefore, should perhaps focus on
identifying “add-on” treatments that might improve outcomes
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in severe disease. We have recently shown that treatment with
fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, effec-
tively reverses crescent formation in rodent models of anti-
GBM disease (98,99) (and that intraglomerular SYK can be
WnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 03/27/2023
detected in patient kidney biopsy samples [100]), so it would
be of interest to explore the use of this agent in advanced
clinical disease. Another interesting agent that has shown
efficacy in experimental models is IdeS (IgG-degrading en-
zyme of Streptococcus pyogenes), an enzyme that is able to
cleave both circulating and membrane-bound Ig (101). IdeS
was safe and tolerable in early-phase human studies, and a
clinical study in severe anti-GBM disease, where it may
promote rapid clearance of pathogenic IgG, has been proposed
(EudraCT number: 2016–004082–39). Finally, large multicenter
studies might aim to identify clinical and histopatho-
logic indicators that reliably predict failure to respond to
treatment, so that the toxicities associated with intensive
immunosuppression may be avoided in futile cases.
As an archetypal autoimmune disorder, such studies of
anti-GBM disease and its experimental correlates are likely
to provide fresh insights into the mechanisms of renal
autoimmunity. However, it is the alarming clinical pre-
sentation, and the need for emergency treatment, often in
critically unwell patients, that underscores the need for
clinicians to be mindful of this rare condition, the pitfalls
associated with its diagnosis, particularly in atypical and
variant presentations, and the early and appropriate use of
immunosuppressive and extracorporeal therapies, in order
to prevent morbidity and to improve survival.
Acknowledgments
We acknowledge support from the National Institute for Health
Research Imperial Biomedical Research Centre.
Disclosures
None.
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