goodpasture syndrome involving overlap with wegener’s...
TRANSCRIPT
Goodpasture Syndrome Involving Overlap with
Wegener’s Granulomatosis and Anti-Glomerular Basement
Membrane Disease
RAGHU KALLURI,* KEVIN MEYERS,t ANDRAS MOGYOROSI,*
MICHAEL P. MADAIO,* and ERIC 0. NEILSON**penn Center for Molecular Studies of Kidney Diseases, Renal-Electrolyte and Hypertension Division, and
�Division of Pediatric Nephrology, Departments of Medicine and Pediatrics, University of Pennsylvania,
Philadelphia, Pennsylvania.
Abstract. A 68-year-old Caucasian woman presented to the
hospital with nodular pulmonary infiltrates and acute renal
failure. Wegener’s granubomatosis was initially considered tobe most likely because of the presence of increased serumlevels of c-anti-neutrophil cytoplasmic antibodies (c-ANCA).
A consultation through the Internet after a renal biopsy dem-
onstrated crescentic, necrotizing glomerulonephritis and linear
deposits of immunoglobulin G (IgG) and complement C3,
typical of anti-glomerular basement membrane (GBM) disease.
Hemodialysis was instituted; however, the patient suddenly
developed a massive cerebral hemorrhage and died before full
therapy could take effect. Postmortem analysis of the patient’s
sera revealed high titers of IgG against the a3 NCI domain of
type IV collagen. Serologic evidence of both p-ANCA and
anti-GBM antibodies are becoming more frequently recog-
nized in the setting of rapidly progressive glomerubonephritis.
The patient reported here had the unusual combination of
c-ANCA antibodies with anti-GBM disease, and this association
raises complex questions regarding the pathogenesis of this typeof renal injury. (J Am Soc Nephrol 8: 1 795-1 800, 1997)
Basement membranes provide supportive underlayment for
epithelium in organ tissues. These basal laminae form as a
lattice of type IV collagen, laminin, entactin, and proteogly-
cans. Goodpasture syndrome, a form of anti-glomerular base-
ment membrane (GBM) disease, is characterized by rapidly
progressive glomerulonephntis and pulmonary hemorrhage as-
sociated with autoantibodies directed to the globular NC1
domains of a3(IV) collagen in selected basement membranes
( 1 ,2). Circulating and tissue-bound anti-a3(IV) NC 1 antibodies
from kidney and lung recognize similar pathogenic epitopes
(3,4), and two interaction sites have been identified at each end
of the domain (3,4). The presence of these antibodies reflects
one pathophysiologic component of the disease (1 ,5-7). The
other important immunologic element in anti-GBM disease is
the T cell immune response driven by susceptibility genes
responsive to the a3(IV) NC1 domain (8,9). Recently, anti-
GBM antibodies have been found in the sera of some p-
ANCA-positive patients with Wegener’s granulomatosis.
Herein, we report this overlap syndrome in a patient with
c-ANCA reactivity.
Received September 24, 1996. Accepted January 17, 1997.
Correspondence to Dr. Raghu Kalluri, Nephrology Division/Department of
Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School,
330 Brookline Avenue, Boston, MA 02215.
1046-6673/0801 1-1795$03.00/0
Journal of the American Society of Nephrology
Copyright © 1997 by the American Society of Nephrology
Case HistoryA 68-year-old female retired schoolteacher presented to an
outside hospital with nodular pulmonary infiltrates and rapidly
progressive renal failure. Her previous history was remarkable
for heavy smoking and chronic obstructive airway disease; 23
years before admission, she underwent upper lobectomy of the
right lung for a bacterial infection. Six months before admis-
sion, she complained of diffuse but unexplained arthralgias.
One month before admission, she developed a new cough and
fever. A chest x-ray at that time revealed bilateral pulmonary
infiltrates, and Mycobacterium avium was isolated by fine-
needle lung aspiration. Her blood urea nitrogen (BUN) and
creatinine levels remained normal, her symptoms improved,
and the pulmonary infiltrates resolved after treatment with
ethambutol and chlor-erythromycin. Three weeks later, the
cough and fever recurred in association with increasing short-
ness of breath and pleuritic chest pain. Her bronchial symp-
toms worsened despite oral antibiotics, and she was admitted to
intensive care at her local hospital with respiratory failure.
Her past medical history included mild chronic sinusitis,
right-sided sensory neural hearing loss, supraventricular tachy-
arrhythmias, mild hypercalcemia, and Schatzki’s ring. All were
longstanding and inactive. A review of her symptoms and
family history were not informative, although she was said to
be allergic to penicillin. There was no known toxin exposure.
On physical examination, she appeared chronically ill,
weighing 48. 1 kg with a temperature of 99#{176}F,and a blood
pressure of 135/55 mmHg. The skin was normal, and there
were no mucosab ulcerations. The sinuses were not tender, and
her conjunctiva, sclera, and funduscopic examinations were
1796 Journal of the American Society of Nephrology
normal. Mild, diffuse crackles and wheeze were auscultated
throughout both lung fields. The left ventricle was not dis-
placed, the cardiac rhythm was regular, and there were no
murmurs, gallops, or rubs. Pulses were present and full in all
extremities. The abdomen was without organomegaly, masses,
or tenderness; there were no bruits, and the bowel sounds were
audible and normal. There was no evidence of arthritis, and the
neurobogic examination was within normal limits.
Initial laboratory findings included the following values:
hemoglobin, 9.3 g/dl; hematocrit, 28.5%; platelets, 710,000/pA;
white blood cell count, 19,100/pA (73% neutrophils, 20% lym-
phocytes, 5% monocytes, and I % eosinophils); a BUN of 90
mg/dl; creatinine, 13.6 mg/dl; sodium, 143 meq/l; chloride, 109
meq/l; carbon dioxide, 10 mmolIl; potassium, 6.4 meq/l; phos-
phate, 9 mg/dl; calcium, 8.2 mg/dl; lactate dehydrogenase, 223
U/I; serum aspartate transaminase, 79 U/l; serum alanine
transaminase, 89 U/I; albumin, 2.8 g/dl; total bilirubin, 1.2
mg/dl. Red blood cells too numerous to count, 500 mg/db of
protein, and many fine granular casts were found on urinalysis.
Chest x-ray and computed axial tomography (CAT) scans
revealed new nodular infiltrates in the anterior segment of the
left upper lobe, chronic obstructive airway disease. and calci-fled mediastinal and hilar lymph nodes. A CAT scan of the
sinuses was normal. Ultrasound evaluation of the kidneys,
liver, and pancreas were unremarkable. Anti-proteinase 3 (c-
ANCA) antibody titers were positive at 1 1 units, whereas
anti-myeloperoxidase (p-ANCA) antibody titers were negative.
The ANA and hepatitis serologies (A, B, and C) were alsonegative.
Wegener’s granulomatosis was considered to be the most
likely clinical diagnosis, and the patient was treated with
oxygen, antibiotics, steroids, and hemodialysis. An open renal
biopsy revealed extensive necrotizing glomerulonephritis with
fibrocellular crescents involving 100% of glomeruli; this was
associated with disruption of the gbomerular basement mem-
brane and Bowman’s capsule (Figure 1A). Large infiltrates of
mononuclear cells were present within the interstitium, focal
degenerative and atrophic changes were present in the tubular
epithelium, and there was evidence of mild arteriosclerosis.
Immunofluorescence studies demonstrated intense, diffuse lin-
ear staining of IgG along glomerular basement membranes
(Figure 1B); there were also occasional, focal, granular gb-
merular deposits of 1gM, C3, and fibrin. When examined by
electron microscopy, there was focal collapse of glomerular
basement membranes and loss of cells. Extensive effacement
of the visceral epithelial foot processes was present. Electron-
dense deposits were not visualized. The biopsy findings were
consistent with crescentic glomerulonephritis from anti-GBM
Figure 1. Pathology. (A) Periodic acid-Shiff-stained 5-�sM section of the kidney biopsy tissue obtained from the patient. Magnification, X250.
Crescentic glomerulonephritis with interstitial infiltrates is observed in this section. (B) Linear deposits of IgG on the gbomerular basement
membrane of the patient by direct immunofluorescence, using mouse antihuman IgG antibodies. Occasional tubular basement membrane IgG
deposits are also observed. Magnification. X 250.
Goodpasture Syndrome 1797
Table 1. Autoantibodies to gbomerubar basement membrane and neutrophil cytoplasm in rapidly progressive
glomerubonephritisa
No. ofPatients
Anti-GBM-Positive
Anti-GBM-Positive Only
Anti-GBM-andANCA-Positive
. .ANCA-Positive
ANCA-Positive withAnti-GBM Antibodies
Reference
889 67 47 20 266 20 15 (Jayne et al.)
RPGN (7.5%) (70%) (30%) (30%) (7.5%)
23 23 1 6 7 1 6 (Weber et al.)
GPS (100%) (70%) (30%)
1550 160 126 34 1390 34 17 (Short et al.)
GN (10%) (79%) (21%) (90%) (2.5%)
a RPGN, rapidly progressive glomerulonephritis; GPS, Goodpasture syndrome; GN, glomerulonephritis.
disease. Dialytic therapy was initiated and immunosuppressive
therapy was contemplated, but the patient suffered a massive
intracerebral hemorrhage and died shortly after her renal bi-
opsy. Several days later, the serum complement bevels were
reported to be normal, with an anti-GBM antibody titer from an
outside laboratory registering 892 units (positive > 20).
Our attention to this patient was first drawn from Internet
contact through the Goodpasture home page (http:llreh-
d.med.upenn.edu: 1025/), resulting in further consultation with
the family and attending physicians at her outside hospital. A
serum sample from the patient was subsequently tested by
enzyme-linked immunosorbent assay (ELISA) and Western
blot in our laboratory against a3(IV) NCI collagen extracted
from tissue or isolated as recombinant molecule. The assay
here was positive for anti-GBM antibodies (Figure 2).
DiscussionIn addition to anti-GBM disease, several other systemic
illnesses may present with Goodpasture syndrome, including
Wegener’ s granulomatosis, systemic lupus erythematosus, ne-
crotizing vasculitis, and Henoch-Sch#{246}nlein purpura (10,1 1).
Pneumonia with postinfectious gbomerulonephritis may some-
times masquerade as a systemic disease and confound the
diagnosis (10,1 1). In most cases, the serologies and serum
complement levels are very helpful in distinguishing these
entities ( 12). Low serum complement levels suggest systemic
lupus or postinfectious gbomerulonephritis, although patients
with right-sided endocarditis may occasionally present with
pulmonary infiltrates, hypocomplementemia, and glomerulo-
nephritis (10,1 1,13). Systemic vasculitis or anti-GBM disease
are the most common causes of the normocomplementemic
syndrome and, therefore, determination of ANCA and anti-
GBM antibody levels are particularly helpful ( 13). There re-
mains a subgroup of the latter patients that have circulating
levels of both ANCA and anti-GBM antibodies (1,14-17). As
was the situation in the present case, both the immunofluores-
cence evaluation of the kidney biopsy and determination of the
specificity of the circulating autoantibodies assisted us in ar-
riving at a diagnosis.
Type IV collagen is the major protein in basement mem-
branes such as the GBM (2,18,19). Type IV collagen is com-
posed of six genetically distinct chains termed al through a6
(2). The al and cw2 chains of type IV collagen are present
ubiquitously in all basement membranes (2), whereas the cr3,
cr4, cr5 and cr6 chains have a much more restricted distribution
(2). In the kidney, these later chains predominate along the
GBM and Bowman’s capsule. The cr-chains of type IV cobba-
gen can be divided into three domains: the non-colbagenous
N-terminal 75 domain of variable length, a middle triple heli-
cal domain of approximately 1400 amino acid with a charac-
teristic Gly-X-Y motif, and a C-terminal noncollagenous glob-
ular domain of approximately 230 amino acids (2,6,20).
Type IV collagen monomer is a triple helical molecule
composed of three polypeptide a-chains. With six cr-chains of
type IV collagen, there are 56 possible combinations of type IV
collagen monomer (2,6,20-22). Although some tumors secrete
type IV collagen monomers in a 2: 1 ratio of cr1 and cr2 (23,24),
firm data regarding the monomer composition for type IV
collagen is not available for native human basement mem-
branes. The cr3 chain of type IV collagen, the Goodpasture
autoantigen, is most abundant in the glomerulus and seminif-
erous tubule (2,21,25) but is also present in basement mem-
brane from the lung, eye, choroid plexus, and inner ear (6).
Basement membranes of placenta, amnion, liver, and skin
contain very little cr3(IV) (2,26,27).
The use of purified antigen from tissue or recombinant
a3(IV)NC1 domain in diagnostic assays is essential for an
accurate diagnosis of anti-GBM disease (1). Crude basement
membrane preparations used in many commercial screening as-
says can result either in misdiagnosis (28) or in a lower sensitivity
in patients who do not have robust titers (5). Detailed biochemical
and immunologic studies have identified the globular NC1 do-
main of type N collagen as the region of cr3 chain that binds
Goodpasture autoantibodies (1,2,5,26,27,29,30). In a recent study
with serum from 58 patients with anti-GBM disease, the primary
target for all patients was identified as the cr3(IV)NC1 domain (I).
Additional antibodies to crl(IV)NC1 and cr4(IV)NCI were
present in 15% and 4% of patients, respectively (1). These batter
specificities may represent cross-reactive antibodies or antibodies
generated in parallel with the cr3(IV)NC 1 antibodies ( I ). Most
recently, two immunologically privileged peptide regions within
the cr3(IV)NC1 domain have been identified as epitopes for these
autoantibodies (3), and a candidate T-cebl epitope has been iden-
rifled at the N-terminal region of the cr3(IV)NCI domain (8.9).
2
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Bovine Kidney
o;l cr2 a3 cr4 a5 a6 patients with Goodpasture syndrome demonstrated anti-my-eloperoxidase (the major category of p-ANCA) antibodies,
whereas only one of 23 (4%) showed a positive serum protein-
ase (c-ANCA) reactivity. None of the patients with established
Wegener’s granubomatosis (28 of them c-ANCA positive, two
p-ANCA positive, and one double-positive) tested positive for
anti-GBM antibodies. In a larger prospective study, 160 pa-
tients with anti-GBM antibody and 1 390 patients with ANCA-
positivity were serobogically evaluated ( 1 7) (Table 1 ). Thirty-
four patients had both antibodies, which represented
approximately 2 1 % of the anti-GBM population and less than
3% of the ANCA-positive patients. Based on the results of
these studies, we estimate that approximately 20% to 30% of
patients with anti-GBM disease will test positive for either
c-ANCA or p-ANCA, and up to 8% of ANCA-positive patients
will have anti-GBM antibodies. Approximately 74% of pa-
tients with both ANCA and anti-GBM antibodies are p-ANCA-
a2 a3 ct4 cc5 ct6 positive. Our double-positive patient belonged to a smaller
group of patients who have c-ANCA and anti-GBM antibodies.
The reason for concurrent ANCA and anti-GBM antibody
production in selected patients is not known. It is possible that
ANCA-related proteases damage or expose the nephritogenic
epitopes in cr3(IV) collagen in GBM, and this in turn leads to
anti-GBM antibody production. It is unlikely that the cross-
reactivity between p-ANCA and anti-GBM antibodies is de-
rived from the same autoantibody repertoire, because there
does not appear to be a structural relationship between c-
ANCA and a3(IV) NC I collagen ( 17). It is currently unclear
whether there is any structural cross-reactivity between c-
ANCA and anti-GBM antibodies.
Rapid and correct diagnosis of the underlying tissue lesion is
essential when both antibody reactivities are present in serum,
because, in addition to treatment with high-dose steroids and
cyclophosphamide, patients with anti-GBM antibody disease
usually require daily plasmapheresis to remove circulating
autoantibodies (7). Plasmapheresis should be continued until
anti-GBM antibody bevels are undetectable, and the usual
course is 2 to 4 wk. Immunosuppressive therapy should be
administered for approximately 8 wk, and the antibody titers
are usually undetectable at this time. If administered early in
the disease, this approach has been successful in attenuating
progression to end-stage renal failure in as many as 40% of
patients (31).
By contrast, plasmapheresis is not considered beneficial in
ANCA-positive patients, although anecdotal success has been
reported (32). Furthermore, these patients may require a longer
course of steroids and cycbophosphamide. This approach is
especially applicable to individuals with Wegener’s granulo-
matosis, other organ system involvement, and a relapsing
course. Trimethaprim sulfamethoxazole has been shown to be
beneficial in preventing relapses in these patients.
Whether ANCA influences the outcome of patients with
anti-GBM disease is uncertain. Bosch et a!. (33) reported that
patients with anti-GBM disease and anti-myeboperoxidase an-
tibodies (p-ANCA) had a more favorable outcome than pa-
tients with anti-GBM antibodies alone, although this finding
requires confirmation. In patients with Wegener’s granuboma-
1798 Journal of the American Society of Nephrology
Recombinant Human
Type IV Collagen NCI Domains
Figure 2. Serological analysis for anti-glomerular basement mem-
brane (GBM) antibodies. The patients’ antisera were analyzed for
antibodies to NC1 domain of a3 chain of type IV collagen, using
bovine kidney-isolated, type IV collagen NCI domains (24) and
recombinant human type IV collagen NC I domains ( 1,3) by direct
enzyme-linked immunosorbent assay (ELISA) and immunoblotting.
The patient antibodies are shown as solid black bars, reference Good-
pasture antibodies (LL) (24) are shown as striped bars, and control
antibodies are shown as white bars. By direct ELISA, the patient
antibodies bind to n3 chain of type IV collagen specifically, with
minimal binding to other NC 1 domains. Control antibodies do not
reveal any significant binding to the NCI domains of type IV colba-gen. Immunoblotting with the patient antibodies, using all six recom-
binant type IV collagen NCI domains, is shown in the inset. Again, as
observed with direct ELISA. immunobbotting shows specific binding
to the recombinant human cr3 NC I type IV collagen. All antisera were
used at a 1:25 dilution in the direct ELISA and immunobbotting
experiments. For direct ELISA. the antigen was coated at 50 ng for
bovine kidney NC1 domains and 200 ng for recombinant NCI do-
mains. For immunoblotting, 500 ng of each of the recombinant NC1
domains was used.
That anti-neutrophil cytoplasmic antibodies may be present
in patients with anti-GBM disease has been known since 1989
(14). Since then, numerous reports have dealt with the notion
of concurrent reactivity. In 889 consecutive patients with the
clinical diagnosis of rapidly progressive gbomerulonephritis,
5% were positive for anti-GBM antibodies alone, 28% were
positive for ANCA alone, and 2% had both antibodies (65% of
the patients had no antibodies at all). Thirty percent of the
patients with anti-GBM antibodies had ANCA positivity, and
approximately 8% of patients with ANCA had concurrent
anti-GBM antibodies (15), although the study did not differ-
entiate between c-ANCA and p-ANCA reactivity.
In a study by Weber and others (I 6), seven of 23 (30%)
Godpasture Syndrome 1799
tosis, the presence of anti-proteinase antibodies (c-ANCA, the
major category) has been associated with a worse renal out-
come (34); however, it is uncertain whether a similar relation-
ship applies to patients with coexistent anti-GBM antibodies.
AcknowledgmentsWe thank Drs. Betty Phon-Yie Yeh, Gary G. Bluemink at the
Chesapeake General Hospital in Chesapeake, and Virginia and J.
Charles Jennette at the University of North Carolina for their assis-
tance in providing the case history of the patient and histological
slides of the kidney. We also thank Dr. Billy G. Hudson for providing
the reference Goodpasture antibodies (LL). This work was supportedin part by Grants DK-46282, DK-07006, DK-30280, DK53088, and
DK-45 191 from National Institutes of Health, the DCI RED fund, and
a National Kidney Foundation fellowship to Dr. Kevin Meyers.
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Renal-Electrolyte and Hypertension Division at the University of Pennsylvania
The University of Pennsylvania School of Medicine was the first medical school in the I 3 colonies and the first
to have a teaching hospital in the United States. Its Renal-Electrolyte and Hypertension Division was formed in 1936
as the Renal Section and was enhanced in I 947 for the purpose of training academic nephrobogists. One hundred
ninety-three fellows have passed through the program since its inception. Most fellows remain in training for at least
three years.
Clinical training in support of this effort includes active inpatient consultation at the Hospital of the University of
Pennsylvania and at the Veterans Administration Medical Center, outpatient dialysis, transplantation, and pediatrics.
We currently admit over 850 patients to the hospital each year, see 1250 new consults, make 8650 bedside visits,
perform 4800 dialyses in the hospital, care for 295 dialysis patients in our outpatient units, and care for I 30 new renal
transplants each year. We also have active subspecialty outpatient programs in immune nephritis, transplantation,
nephrobithiasis, diabetic nephropathy, renal nutrition, and complex hypertension.
At the present time, there are 3 1 faculty members serving the educational mission of the Division and its extended
research training program. Eight faculty members are oriented toward clinical teaching and patient care and serve as
a bridge between the laboratory and the bedside. Four faculty are senior administrators in the medical school, and
19 additional faculty have active research programs with interests in the field of nephrology and serve as research
trainers for the 20 to 25 postdoctoral fellows now in our research laboratories. All of our research faculty are
encouraged to join graduate groups and interdisciplinary centers that broaden their investigative capacity, and we
offer tuition support to assist our fellows toward the attainment of advanced second degrees in their research areas
of interest.
Our faculty research programs are built around an institutional training grant from the National Institutes of Health.
These research programs focus on integrative biology applied to the structure or function of the kidney in health or
disease and utilize the tools of basic molecular genetics, cellular biology, immunology, biochemistry, physiology,
electrophysiology, and clinical epidemiology. This research activity is supported by the National Institutes of Health
through the George M. O’Brien Kidney Center’s Program (NIDDK-45191), the Renal Research Training Program
(NIDDK-07006), a program project (NIDDK-492l0), and numerous individual grants from many extramural
agencies.
Applications for renal fellowship can be obtained by writing to Eric G. Neilson, M.D., Chief, Renal-Electrolyte
and Hypertension Division, 700 Clinical Research Building, 415 Curie Boulevard, University of Pennsylvania,
Philadelphia, PA 19104-6144, or by downloading an application from the Division’s web site at http:/IREH-
D.med.upenn.edu/.