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

EC

Lfl 10

czl+a2 cx3 ci4 a!

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/.