Goodpasture Syndrome Involving Overlap with Wegener's ...

Goodpasture Wegener’s Membrane

Syndrome Granulomatosis Disease

RAGHU MICHAEL *penn

KALLURI,* KEVIN MEYERS,t P. MADAIO,* and ERIC 0.

Center

Division

for

Studies

of Kidney

Nephrology,

Diseases,

Departments

Caucasian

of c-anti-neutrophil

A consultation

woman

crescentic,

deposits

of

typical

the

presented

necrotizing

to the

was

Basement

membranes in organ

lattice

of type

cans.

Goodpasture

ment

membrane

progressive

provide

kidney

(3,4),

and

two

directed

to

sites

the

anti-a3(IV) similar have

proteogly-

GBM

a3(IV)

antibodies

have

ANCA-positive

patients

Herein,

we report

c-ANCA

reactivity.

this

NC1 been

domain found

with

overlap

in the

syndrome

complex

Case

Correspondence

to

24, 1996. Accepted Dr.

Raghu

Medicine, Beth Israel Deaconess 330 Brookline Avenue, Boston,

Kalluri,

January Nephrology

Medical Center MA 02215.

17,

asNC1

end

some

p-

granulomatosis.

with

1997.

1046-6673/0801 1-1795$03.00/0 Journal of the American Society of Nephrology Copyright © 1997 by the American Society of Nephrology

with

years

before

right

lung

for

sion,

she

complained

fever.

anti-

Medical

both

more

domain

of

p-ANCA

and

frequently

of

School,

progressive

recog-

glomerubonephritis.

the pathogenesis

Nephrol

female

hospital

8: 1 795-1

of

of this type 1997)

800,

Her

creatinine

underwent

Six but

was

time

avium

Her

remained

remarkable disease;

months

23 of the

before

unexplained

admis-

arthralgias.

a new cough

revealed

Mycobacterium

rapidly

lobectomy

she developed

at that

to an

and

airway upper

infection.

aspiration. levels

history

obstructive

admission,

x-ray

and lung

she

presented

infiltrates

previous

of diffuse

before

infiltrates,

schoolteacher pulmonary

chronic

a bacterial

A chest

needle

retired

nodular

admission,

One month

epitopes

Division/Department

of

History

and

Recently,

and Harvard

Soc

failure.

in a patient

the a3 NCI

becoming

regarding

(J Am

A 68-year-old

bilateral was

isolated

blood

urea

nitrogen

normal,

her

symptoms

and

pulmonary by

fine-

(BUN)

and

improved,

and the pulmonary infiltrates resolved after treatment with ethambutol and chlor-erythromycin. Three weeks later, the cough

and

fever

ness

of

toms

breath

worsened

intensive

recurred and

past

at her

medical

right-sided

sensory

arrhythmias,

mild

with

increasing

short-

chest

Her

bronchial

symp-

oral

hospital

history neural

not

included

pressure

were her

48. 1 kg of

135/55

no mucosab conjunctiva,

loss,

with

ulcerations. sclera,

The and

supraventricular

tachy-

of

of skin

sinuses

funduscopic

to

failure.

sinusitis,

was

All were symptoms and ring.

her

she

was no known she appeared The

admitted

chronic

although

a temperature

mmHg.

was

Schatzki’s

A review informative,

she

respiratory

mild

and

be allergic to penicillin. There On physical examination, weighing

and with

hearing

inactive.

were

pain.

antibiotics,

local

hypercalcemia,

and

history

in association

pleuritic

despite

care

Her

family September

questions

injury.

longstanding Received

are

renal

of

against evidence

of rapidly

smoking

at each

sera

antibodies

in the setting

for heavy

NC 1 antibodies

Wegener’s

of IgG

Serologic

progressive

membranes

(8,9).

titers

base-

globular

identified

high

collagen.

by rapidly

pathogenic

been

IV

outside

hemorrhage

basement

revealed

type

as a

of anti-glomerular

in selected

sera

of renal

(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 the

of Pennsylvania,

developed a massive cerebral hemorrhage and died before full therapy could take effect. Postmortem analysis of the patient’s

raises

for

form

and

and pulmonary

recognize

interaction

to

and

The patient reported here had the unusual combination c-ANCA antibodies with anti-GBM disease, and this association

C3,

of the domain

responsive

University

Division,

linear

suddenly

laminae

is characterized

and tissue-bound lung

Pediatrics,

Hypertension

nized

disease.

patient

entactin,

a form

collagen

and

and

and

dem-

underlayment

basal

disease,

autoantibodies

1 ,2). Circulating

from

and (GBM)

the

laminin,

glomerulonephntis with

biopsy

complement

membrane

These

syndrome,

of a3(IV)

and

supportive

tissues.

(GBM)

sociated

Renal-Electrolyte

anti-GBM

(c-ANCA).

a renal

however,

IV collagen,

domains

(IgG)

basement instituted;

epithelium

after

glomerulonephritis G

of anti-glomerular

antibodies

Internet

immunoglobulin

Hemodialysis

(

cytoplasmic

through

onstrated

MOGYOROSI,*

of Medicine

hospital with nodular pulmonary infiltrates and acute renal failure. Wegener’s granubomatosis was initially considered to be most likely because of the presence of increased serum levels

ANDRAS NEILSON*

Basement

Pennsylvania.

68-year-old

A

Molecular

of Pediatric

Philadelphia,

Abstract.

Involving Overlap with and Anti-Glomerular

was

said

to

toxin exposure. chronically ill,

99#{176}F,and normal,

were

a blood and

not tender,

examinations

there

and were

1796

Journal

normal.

of

Mild,

the

American

diffuse

Society

crackles

and

throughout both lung fields. placed, the cardiac rhythm murmurs,

gallops,

extremities.

or rubs.

The

or tenderness; there audible and normal. neurobogic

Initial

laboratory

phocytes,

were

5% creatinine,

was was

and

within

meq/l;

carbon

13.6

potassium,

8.2 mg/dl; transaminase,

lactate 79

transaminase,

albumin,

89

U/I;

Red blood and many

2.8

cells too numerous fine granular casts

fled

mediastinal

sinuses

Figure

Crescentic membrane deposits

lobe, was

chronic and

normal.

1. Pathology.

obstructive hilar

lymph

Ultrasound

(A) Periodic

total

observed.

airway

(CAT) segment

acid-Shiff-stained

X 250.

scan the

5-sM

hepatitis

Anti-proteinase

positive

at

antibody

serologies

3 (c-

1 1 units, titers

whereas

were

(A, B, and

biopsy

revealed

fibrocellular

scans of the of the

with

brane and mononuclear

Bowman’s cells

negative.

C) were

and

staining

and

also

gbomerular

with

this

was mem-

capsule (Figure 1A). Large infiltrates of were present within the interstitium, focal atrophic

there

changes was

IgG

there

present

of mild

demonstrated

along were

were

evidence glomerular

membranes

and

of the visceral

epithelial

dense

were

intense,

tissue

of cells. processes

not visualized.

obtained

The

the patient.

granular

gb-

examined by of glomerular

Extensive

effacement

present.

biopsy

lin-

membranes

focal,

was

glomerulonephritis

from

diffuse

basement

occasional,

loss foot

crescentic

in this section. (B) Linear antihuman IgG antibodies.

also

in the tubular arteriosclerosis.

deposits of 1gM, C3, and fibrin. When microscopy, there was focal collapse

biopsy

with

renal

basement

1B);

with

most

An open

of glomeruli;

merular electron

deposits

the

treated

glomerulonephritis

100%

(Figure

basement

be

was

hemodialysis.

of the

studies

of

to

patient

necrotizing

disruption

and

considered

the

involving

Immunofluorescence

of the kidney

is observed using mouse

extensive

crescents

consistent

kidneys,

and

steroids,

associated

ear

was

diagnosis,

antibiotics,

epithelium,

1.2

granulomatosis

clinical

degenerative

section

unremarkable. were

(p-ANCA)

and

Wegener’s likely

223 alanine

and calci-

A CAT of

ANA

phos-

500 mg/db of on urinalysis.

disease.

evaluation

Magnification.

109

bilirubin,

glomerulonephritis with interstitial infiltrates of the patient by direct immunofluorescence, are also

of 90

chloride,

6.4 meq/l;

to count, were found

nodes.

a BUN

dehydrogenase, U/l; serum

Chest x-ray and computed axial tomography revealed new nodular infiltrates in the anterior

left upper

values:

710,000/pA; 20% lym-

meq/l;

were titers

anti-myeloperoxidase

The

were

and the

following

g/dl;

pancreas antibody

oxygen,

platelets, neutrophils,

10 mmolIl;

and

ANCA)

negative.

limits.

the

143

in all

sounds

I % eosinophils); sodium,

full

masses,

bowel

normal 28.5%; (73%

and

and

liver,

not diswere no

of arthritis,

phate, 9 mg/dl; calcium, U/I; serum aspartate mg/dl. protein,

dioxide,

the

included

mg/dl;

auscultated

was there

organomegaly,

no evidence

findings

monocytes,

were

present

without

9.3 g/dl; hematocrit, cell count, 19,100/pA

mg/dl;

wheeze

no bruits,

There

examination

hemoglobin, white blood

was

were

Nephrology

The left ventricle was regular, and Pulses

abdomen

of

Electron-

findings from

Magnification,

were

anti-GBM

X250.

deposits of IgG on the gbomerular basement Occasional tubular basement membrane IgG

Goodpasture

Table

1. Autoantibodies

to gbomerubar

basement

membrane

and

neutrophil

cytoplasm

in rapidly

Syndrome

1797

progressive

glomerubonephritisa No.

of

Anti-GBM-

Patients

Positive

889

67 (7.5%)

RPGN 23

disease. therapy

266

20

(30%)

(7.5%)

intracerebral opsy.

(79%)

(21%)

reported

days

later,

to be normal,

outside

laboratory

Our

and

died

the

serum

with

to this

through

>

drawn

from

immunosorbent laboratory against or isolated positive

first home

patient

tissue

units

was

from

was

renal

bevels

titer

serum

from

her

antibody

resulting physicians

here

after

complement

(positive

1025/), attending

enzyme-linked blot in our

shortly

Goodpasture

the

Goodpasture

892

d.med.upenn.edu: the family and sample

GPS,

an anti-GBM

patient

the

1390

from

an

assay a3(IV)

tested

by

(ELISA) and Western NCI collagen extracted

as recombinant

molecule.

antibodies

The

(Figure

The

GBM

to

anti-GBM

present

Wegener’

s granulomatosis,

crotizing

vasculitis,

Pneumonia with times masquerade diagnosis

(10,1

complement lupus

assay

2).

levels

may

causes

therefore,

may and

serum these

suggest

systemic

although

patients

occasionally

present and

ular

or anti-GBM

of the

normocomplementemic of

domain

and

evaluation

specificity riving Type branes posed

of the kidney

of the

biopsy

circulating

and determination

autoantibodies

anti-

us in ar-

at a diagnosis. IV collagen such

is the

as the GBM

of six genetically

major

protein

(2,18,19).

Type

distinct

chains

in basement IV collagen termed

al

memis com-

through

IV

chains

capsule.

The

three

collagen

predominate

cr-chains

of variable

are

along

of type

the

length,

230

monomer

present

(2), whereas the cr3, restricted distribution

domains:

amino

the

IV cobba-

non-colbagenous

a middle

acids

is a triple

triple

heli-

a characglob-

(2,6,20).

helical

molecule

data

regarding is not

The

a6

the

monomer

available

cr3 chain

for

composition

native

of type abundant

erous

(2,21,25)

but

is also

eye, of

choroid placenta,

brane from the lung, Basement membranes contain The

domain

says

of

preparations

disease

used

in many

can result

either in misdiagnosis who do not have robust

immunologic

studies

have

seminif-

basement

tissue

assays

anti-GBM

Goodpasture and

in

IV

mem-

mem-

plexus, and inner ear (6). amnion, liver, and skin

in diagnostic

diagnosis

the

present

type

basement

in the glomerulus

very little cr3(IV) (2,26,27). use of purified antigen from

a3(IV)NC1

for

human

IV collagen,

is most

tubule

of IV

(2,6,20-22). Although some tumors secrete monomers in a 2: 1 ratio of cr1 and cr2 (23,24),

autoantigen,

and

of the

assisted

type

membranes a much more later

into

collagen

collagen monomer type IV collagen

in patients

GBM antibody levels are particularly helpful ( 13). There remains 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 immunofluorescence

of

of approximately

IV

membrane

with disease

ANCA

these

75 domain

Type

accurate

glomerulo-

vasculitis

determination

1).

somethe

confound

serologies

gbomerulonephritis,

common

(10,1

in distinguishing

complement

Systemic

ne-

purpura

kidney,

be divided

branes.

systemic including

erythematosus,

hypocomplementemia,

1,13).

and,

the

helpful

endocarditis

most

syndrome

cases,

very

serum

infiltrates,

the

lupus

Henoch-Sch#{246}nlein

most

are

Low

(10,1

nephritis

are

1). In

right-sided

pulmonary

other

syndrome,

postinfectious gbomerulonephritis as a systemic disease and

or postinfectious

with

several

Goodpasture systemic

and

levels

( 12).

entities

disease,

with

et al.)

cal domain of approximately 1400 amino acid with teristic Gly-X-Y motif, and a C-terminal noncollagenous

firm

may

(Weber

17 (Short et al.)

cw2 chains

and Bowman’s can

collagen

In addition

16

composed of three polypeptide a-chains. With six cr-chains type IV collagen, there are 56 possible combinations of type

Discussion illnesses

and

in all basement cr6 chains have

In the

(2).

et al.)

glomerulonephritis.

al

N-terminal

Internet

(http:llreh-

subsequently

GN,

ubiquitously cr4, cr5 and

gen

20).

in further consultation with at her outside hospital. A was

for anti-GBM

page

biwere

(Jayne

34

syndrome;

(2).

15

(2.5%)

(90%)

initiated and immunosuppressive but the patient suffered a massive

registering

attention

contact

34

glomerulonephritis;

hemorrhage

Several

Reference

7

(10%)

was

with

Antibodies

20

(30%)

Dialytic therapy was contemplated,

ANCA-Positive

Anti-GBM

(30%)

16

progressive

. .

47

(70%) 126

rapidly

ANCA-Positive

ANCA-Positive

(100%) 160

GN RPGN,

Anti-GBM-and

Only

(70%)

23

GPS 1550

a

Anti-GBM-

Positive

or

recombinant

is essential (1).

Crude

commercial

for

an

basement

screening

as-

(28) or in a lower sensitivity titers (5). Detailed biochemical 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

Additional antibodies to crl(IV)NC1 and present in 15% and 4% of patients, respectively specificities

generated recently,

may

the cr3(IV)NC1 autoantibodies rifled

represent

cross-reactive

in parallel with two immunologically domain

have

been

(3), and a candidate

at the N-terminal

antibodies

the cr3(IV)NC privileged

region

identified T-cebl

domain

cr4(IV)NCI (1). These

(I). were batter

or antibodies

1 antibodies ( I ). Most peptide regions within as epitopes epitope

of the cr3(IV)NCI

for these

has been domain

iden(8.9).

1798

Journal

of

the

American

2

Society

o;l

of

Nephrology

a3

cr2

cr4

a5

a6

patients with eloperoxidase whereas only

Goodpasture syndrome (the major category one of 23 (4%) showed

ase (c-ANCA) reactivity. Wegener’s granubomatosis p-ANCA

positive,

anti-GBM E

tients

C Lfl

1

None of the patients with established (28 of them c-ANCA positive, two

and one

antibodies.

with

were

double-positive)

In a larger

anti-GBM

positivity

demonstrated anti-myof p-ANCA) antibodies, a positive serum protein-

antibody

and

serobogically

tested

prospective 1 390

patients

( 1 7)

evaluated

0

four

patients

had

approximately 3%

of

these

ANCA-positive

studies,

we estimate

with

tients cx3

Bovine

ci4

a!

a3

a2

ct4

cc5

ct6

with

anti-GBM

group

Kidney Recombinant

both

positive.

Human

Type Figure

2. Serological

brane

(GBM)

IV Collagen analysis

antibodies.

for

The

NCI

Domains

anti-glomerular

patients’

antisera

were

antibodies to NC1 domain of a3 chain of type bovine kidney-isolated, type IV collagen NCI recombinant

human

enzyme-linked

type

IV collagen

immunosorbent

The patient

antibodies

are shown

(ELISA)

as solid

black

analyzed

reveal

bind binding

to n3 chain of type IV to other NC 1 domains.

any significant

binding

( 1,3)

with

observed

direct

to the recombinant used at a 1 :25 experiments. kidney

mains.

For

domains

bars,

reference

NC1

with

positive

entiate

of

positive for

200

ng for

binding were

immunobbotting

coated

recombinant

NCI

8% antibodies

In a study

anti-GBM and

c-ANCA

by Weber

patients (15),

doNC1

2%

and

with patients

had

alone,

both

with

antibodies

Thirty

percent

ANCA

positivity,

p-ANCA

others

the

the

study

were

(65%

had

ANCA

had did

of

of the and

seven

in GBM,

to

a smaller

antibodies. antibody

It is possible the this

that

nephritogenic in turn

leads

anti-GBM

when both in addition

antibody reactivities to treatment with

anti-GBM

2 to

administered

bevels

4 wk.

usually

are

at this

this approach to end-stage

has renal

tissue

anti-GBM

lesion

antibody

to should

disease

and

the

therapy

time.

and

the

antibody

early

in

been successful in attenuating failure in as many as 40%

If administered

of

Furthermore,

steroids applicable other

and

these

patients

may

cycbophosphamide. to individuals with

organ

system

require

involvement,

and

sulfamethoxazole

a longer

This approach is Wegener’s granulohas

been

a

relapsing

shown

in preventing relapses ANCA influences

in these patients. the outcome of patients

anti-GBM

disease

Bosch

not

tibodies

(p-ANCA)

requires

be

titers

plasmapheresis is not considered beneficial in patients, although anecdotal success has been

Trimethaprim

with

usual

should

beneficial Whether

tients

is

remove circulating be continued until

undetectable, 8 wk,

undetectable

(32).

course of especially

c-

are present in serum, high-dose steroids and

Immunosuppressive

for approximately

the disease, progression

course.

with

daily plasmapheresis (7). Plasmapheresis

antibody is

of the underlying

patients

usually require autoantibodies

between

antibodies. diagnosis

cyclophosphamide,

are

relationship

to

crossis dethere

( 17). It is currently unclear cross-reactivity between c-

and correct

essential because,

of

either

are p-ANCA-

anti-GBM

and

a structural

and

with

of 23 (30%)

collagen

and

or expose

ANCA

patients

differ-

for

and anti-GBM

damage

to be

concurrent

reactivity.

(I 6),

appear

of

to 30%

positive

is not known.

and a3(IV) NC I collagen there is any structural

matosis,

28%

at all). with

not

reported

1989

20%

belonged

ANCA

patients

ANCA whether

since

notion

concurrent

in cr3(IV)

be present the

c-ANCA

proteases

patients (31). By contrast, ANCA-positive

gbomerulonephritis,

antibodies

although and

known

dealt

consecutive

antibodies

of

been

have

progressive

no antibodies

anti-GBM

between

In 889

alone,

had

with

has

may

does

than

results

anti-GBM antibody production. It is unlikely that the reactivity between p-ANCA and anti-GBM antibodies rived from the same autoantibody repertoire, because

course

at 50 ng for

of the recombinant

antibodies

reports

rapidly

for

ANCA

approximately anti-GBM

and was

ng of each

disease

numerous

reactivity.

patients

patients

and 500

cytoplasmic

diagnosis were

the

domains

anti-GBM

then,

of concurrent 5%

ELISA

specific All antisera

used.

Since

clinical

in the

the antigen

with do not

of type IV colba-

shows

IV collagen.

epitopes

Rapid

using all six recomin the inset. Again, as

immunobbotting

ELISA.

anti-neutrophil

in patients

(14).

direct

domains

antibodies, is shown

direct

Good-

and control the patient

specifically, antibodies

cr3 NC I type

immunoblotting,

was

That

dilution

For

bovine

ELISA.

human

by direct

immunoblotting.

collagen Control

to the NCI

gen. Immunoblotting with the patient binant type IV collagen NCI domains,

for

and

pasture antibodies (LL) (24) are shown as striped bars, antibodies are shown as white bars. By direct ELISA, antibodies minimal

mem-

IV collagen, using domains (24) and

NC I domains

assay

for

less

the

antibodies

patient

have

in selected

ANCA-related

basement

and anti-GBM

who

reason

represented

on

test

ANCA-

and up to 8% of ANCA-positive patients antibodies. Approximately 74% of pa-

double-positive

of patients

The

will

pa-

1 ). Thirty-

and

approximately

disease

ANCA

Our

production

that

with

which Based

for

160

(Table

population

patients.

c-ANCA or p-ANCA, will have anti-GBM czl+a2

antibodies,

2 1% of the anti-GBM

the

patients

both

positive

study,

is uncertain.

anti-GBM anti-GBM

confirmation.

disease had

a more

and

et a!.

(33)

to be with

reported

that

anti-myeboperoxidase

favorable

antibodies

alone,

In patients

with

an-

outcome although

Wegener’s

than this

pa-

finding

granuboma-

Godpasture

tosis,

the

major

presence

of anti-proteinase

category)

come (34); ship applies

has

been

however,

antibodies

associated

with

it is uncertain

to patients

with

(c-ANCA,

a worse

whether

coexistent

the

renal

a similar

Madaio

MP,

acute 13.

relation-

anti-GBM

12.

out-

Harrington

antibodies.

JT: Current

gbomerubonephritis.

Lockwood

CM,

concepts:

N Engi

Bowman

Autoimmunity

and

Syndrome

C,

Bakes

The

309:

J Med D,

gbomerulonephritis.

1799

diagnosis

of

1299-1302.

Pressey Ath’

1983

A,

Dash

Nephrol

A:

I 6: 291-

306, 1987 14.

Acknowledgments

lardie

We thank Drs. Betty Phon-Yie Yeh, Gary Chesapeake General Hospital in Chesapeake, Charles

Jennette

at the

University

of North

tance

in providing

the case

history

slides

of the kidney.

We also

thank

the reference in

Goodpasture

by Grants

part

DK-45

a National

National

Kidney

Institutes

This work

fellowship

to Dr.

15.

and

RED

and

Kevin

cytoplasmic

ular

membrane

basement

Jayne

DRW,

16.

Meyers.

Kabburi Neilson

R, Wilson EG, Hudson IV collagen

membrane rol6: 2.

Hudson Structure,

common

Kalluri

Mi,

Weber

Structural

syndrome.

J An

and Alport syndromes 268: 26033-26036, BG,

Neilson

delineation

on a3(IV)

Ebner

KE, Noelken

ME,

EG:

of

chain

271: 9062-9068, 1996 R, Gunwar S, Reeders

Soc

Neph-

and 1993

The

two

19.

EG:

toantibodies

20.

Hudson

KC,

Mariyama

BG: Goodpasture

Specificity

WK,

M,

21.

syndrome:

Hudson

B, Kabburi S: Molecular

mt

Meyers

CM,

antibodies

K, Muller and

syndrome.

GA,

Proc

Assoc

R,

Gunwar

S, Noelken

characteristics

43: 135-139.

Kalluri

22.

au-

Am

M,

Phvs

Mariyama

of Goodpasture

Ross

CN, Analysis

23.

EG:

Anti-basement

syndrome.

In:

membrane

Immunologic

Lombardi

G, Mason

PD,

of T cell responses

syndrome

CB:

of type

251-255.

SJ, Lockwood

K,

CM:

in rapidly

37: 965-970,

Pullig

0.

Autoantiprogressive

1990

Koderisch

antibodies

and

J, Netzer

K:

antiglomerular

base-

Rees

WC, AJ.

New

recognize

patients

with

Lechler

IV collagen.

Kidney

NC 1 domain Ira 49:

1 127-1

coexisting rapidly

NA:

1971

Timpl

and

R: Structure

Hudson

Eur

BG,

from

a chains.

Bioc/ie,n

biological

Lab ME,

Identification Chem

Noelken

BG:

S. Noelken

domain

of the a3(IV)

chain,

the Goodpasture

basement

membrane

collagen:

Selective

Hudson

of their

domain.

BJJ, Gunwar collagen

BG:

triple

J Biol Che,n

lagenous Wisdom IV

266: 15318-15324,

of

the

of collagenous

antigen.

chains.

of

structure

Noelken

and

a(IV) noncol-

1991 ME.

Engelbreth-Holm-Swarm

of constituent

of lens

cleavage

14088-14094,

MD.

noncollag-

Goodpasture

1991

Properties

helical

266:

S. Hudson

AM,

basement

of the

IV and

J Bio/

retention

1989

Glomerular

Gunwar

Good-

of base-

J, Chonko

subunits

of collagen

ME,

ME:

61 : 256-269,

of dimeric

(hexamer)

mem-

and function

R, Timoneda

Hudson

Corn-

1989

BJJ,

Invest

Res

of basement

antigen.

with

in J Kid-

membranes

Biop/n’s

architecture

F, Kalluri

Noelken

basement

activities

J, Wisdom

antigen.

domain

A,n

180: 487-502,

Molecular

5, Ballester Si,

anti-

detectable

glomerulonephritis.

of collagen

Wieslander

membrane

autoreactivities

J Biochein

syndrome:

Gunwar

cyto-

membrane

1995

identical

proteins.

Anti-neutrophil

basement

progressive

Isolation

three

CM:

distinct

inun 45: 226-234,

Hudson tumor

(‘onneci

BG: matrix:

Res 27: 225-

Tissue

1992

Timpl

R. Wiedemann

ecules

in

Lockwood

anti-glomerular

Dis 26: 439-445,

Kefalides

A network

to the autoantigen

the N-terminal

24.

model

H, Van

Veldon

V. Furthmayr,

for the organization

in basement

membranes.

Ear

H, Kuhn

of type

IV collagen

J Biochern

I 20:

K: mol-

203-2

1 1,

J, Hudson

B:

1981

25.

Kahsai

1, Enders

Seminiferous IV

of 133.

G, Gunwar

S. Kalluri

basement

membrane:

tubule

collagen

Goodpasture

response edited

to immunological

by Brenner

gbomerular

B, Philadelphia.

injury.

W.B.

26.

Saun-

chains,

and

antigen

and

abundance Alport

R, Zhou

Composition of

the

alloantigen.

of type

a3(IV)ehain, J Bio/

Cheiii

the

1995,

CB: The

renal

response

by Brenner

1991, pp 1062-1181

Kashtan

CE,

genome

to bedside

Michael

AF:

Alport

[Reviewl.

Aii

syndrome:

J Kidney

From

bedside

to

Dis 22: 627-640.

I993

ders, 1996, pp 1253-1391 edited

Two

VLM, and

in press Renal

In: The Kidney,

Kidney,

bodies:

234,

disease. C/in Exp Im,nuno/ 100: 262-268, 1995 F, Kalluri R, Marx M, Enders U, Neilson EG, RamHG, Hudson BG, Weber M. Autoreactive 1-cells in

the cr3 chain 1995

I 1 . Wilson

mt

Kidney

Esnault

Identification

Renal

Goodpasture’s

Goodpasture

antibodies

Type

Ci,

CD:

M,

autoanti-

Deny

Merkel mensee

AK,

plasm

membrane:

1993

R, Neilson

in Goodpasture

Pusey

Short

chains

Chapt. 43, edited by Neibson EG, Couser Lippincott-Raven, I 996, pp 959-973

Wilson

32:

in Goodpasture’s syndrome and in J A,n Soc Nephro/ 2: 1227-1234.

enous

Strutz

tissue-bound

York,

Diseases,

10.

anti-glomer-

Nephro/

cytoplasm

granubomatosis.

Edwards

1991

Sattler

of circulating

in Goodpasture

gen. Kidney

9.

Jones

neutrophil

Andrassy

membrane

ment ST, Morrision

E, Rumpf

Reeders

RI,

Balwith

ment

pasture

J Biol

108: 134-139, 1996

8.

complicating

Cliii

W,

vasculitis

antibodies

brane

Goodpasture

IV collagen.

266: 24018-24024.

Che,n

R, Melendez

F, Neilson

7.

antibodies

PD,

and

MFA,

containing

diffuse

immunologically

of type

I 8.

of the epitope for the autoantibodies to the carboxregion of thea3(IV) chain of basement membrane J Biol

Kalluri

in anti-basement

Tryggvason K: Type IV collagen: and role in human diseases. Mo-

Chem Kalluri

collagen.

6.

Lawler

Antineutrophil-cytoplasmic

ne)

Hudson

epitopes

Localization yl-terminal

autoantigen

17.

1995

of Goodpasture J Bio/ Chem

R, Sun

Gunwar S. Chonko AM, of the a3(IV) chain of

and Goodpasture

BG, Reeders ST. gene organization,

privileged

5.

as the

disease

Autoantigen:

4.

CB, Weber M, BG: Identification

1178-1185,

lecular basis leiomyomatosis. 3.

PEC, of systemic

I992

References

type

Brenchley

disease.

Marshall

to GBM

Wegener’s

1.

CD,

development

gbomerubonephritis.

DK53088, fund,

Short

Sequential

anti-neutrophil

bodies

was supported

the DCI

Di,

FW:

1989

for providing

DK-30280,

of Health,

assis-

and histological

G. Hudson

(LL).

at the and J.

for their

of the patient

DK-07006,

Foundation

G. Bluemink and Virginia

Carolina

Dr. Billy

antibodies

DK-46282,

191 from

O’Donoghue

BM

to immunological Jr. Philadelphia,

injury. W.B.

In: The Saunders,

27.

Kleppel

MM,

Santi

PA,

Cameron

ID,

Wieslander

Human tissue distribution of novel basement gen. Am J Pat/to! 134: 813-825, 1989

I, Michael

membrane

AF:

colla-

18(X)

28.

Journal

Society

of Nephrology

Kalluri R, Pettrides S. Wilson CB, HI, Grippi MA, Madaio M, Neilson

Tomaszewski

autoantibodies

lung

adenocarcinoma

Ann

Intern

as the

of the

American

associated

Goodpasture

with

syndrome.

EG:

JE, Palevsky

Anti-a3(IV)

32.

presenting

Med

Madore

F, Lazarus

in renal

diseases.

Glassock

RJ:

3 1.

collagen

124:

bonephritis: 1992

651-653.

1996 29.

Saus

I, Wieslander

Identification collagen 30.

I, Langeveld

of Goodpasture IV. J Biol

Butkowski

Chem

son BG:

Localization

Quinones as the

JPM,

33.

of

epitope

to a novel 262:

34.

chain

X, Mirapeix implications

with

myeboperoxidase

mt

The

University

to have

Renal

Clinical

hospital

Section

ninety-three three years.

have

training

enhanced

passed

in support

dialyses

transplants each year. nephrobithiasis, diabetic At the present

time,

research

training

a bridge

between

19 additional

was

I 947

the

the program

effort

includes

for 295 dialysis subspecialty nutrition,

are 3 1 faculty faculty

laboratory have

and

active

offer

support

to assist

members

our

medical

the bedside. programs

Most

in the

the educational toward

faculty

are

senior

interests

B:

Differences

between

3-associated

renal

was

toward

the attainment

are built

around

an institutional

and

in training

Hospital

of the

nephritis,

administrators

for at least University

and

degrees

from

the National

renal

and its extended care

and

in the medical

second

of

and pediatrics. bedside visits, transplantation,

patient

of nephrology

hundred

for I 30 new

of the Division and

in 1936

One

remain

and care

teaching

of advanced

antidisease.

the first

formed

nephrobogists.

in our research laboratories. All of our centers that broaden their investigative

fellows

1 3, 1991

I 3 colonies

units,

in the field

basement

107-1

in immune

mission

clinical

R: Progantibodies

36:

Division

at the

programs hypertension.

270-275,

X, Rodriguez cytoplasmic

dialysis, transplantation, new consults, make 8650

in our outpatient

gbomeru-

20:

of Pennsylvania

fellows

consultation

patients

with

fellows now and interdisciplinary

1995

academic

outpatient see 1250

outpatient and complex

Four

193-199,

school

of training

inpatient

are oriented

Arends

anti-proteinase

University

its inception.

serving

members

research

the 20 to 25 postdoctoral to join graduate groups

purpose

active

RO,

Dis

in anti-gbomerular

and

and Hypertension

Medical Center, hospital each year,

care

Eight

the first

since

active renal

there

faculty

for

We also have nephropathy,

program. the

was

at the

Its Renal-Electrolyte

in the hospital,

trainers for encouraged tuition

in

through of this

Division

of Medicine States.

and at the Veterans Administration admit over 850 patients to the

4800

perform

School

in the United

and

fellows

Pennsylvania We currently

Hypertension

of Pennsylvania

a teaching

as the

and

Gans

47:

in crescentic

J Kidney

specificity

C/in Nephro/

myeloperoxidaseKidney

exchange

Am

help?

E, Font J, Borrellas of anti-neutrophil

disease. CF,

plasma

or no

Bosch nostic

Franssen

7874-7877,

I987

Renal-Electrolyte

Intensive Help

membrane

J, Hud-

I, Hamilton

J Bio/ Chem

collagen.

BG:

chain

1988

Wieslander

of the Goodpasture

membrane

5, Hudson cr3(IV)

263: 13374-13380,

RJ, Langeveld

of basement

JPM, antigen

iM, Brady HR: Therapeutic plasma exchange J Am Soc Nephro/ 7: 367-386, 1996

serve

school,

serve

as research

research faculty capacity, and in their

as and

research

are we areas

of interest. Our These

disease

faculty research

and

research

programs

programs

utilize

focus

the

tools

on

integrative

of basic

biology

molecular

genetics,

electrophysiology, through the George

and clinical M. O’Brien

epidemiology. This research Kidney Center’s Program

(NIDDK-07006),

a

project

program

training

applied

(NIDDK-492l0),

to the

cellular

grant

structure

biology,

or function

immunology,

of the

numerous

individual

kidney

biochemistry,

activity is supported by the National (NIDDK-45191), the Renal Research and

Institutes

grants

from

M.D.,

Chief,

of Health. in health

physiology,

Institutes Training many

of Health Program extramural

agencies. Applications

for

and Hypertension Philadelphia, PA D.med.upenn.edu/.

renal

fellowship

Division, 19104-6144,

700

can

be

obtained

Clinical Research or by downloading

by

writing

to Eric

Building, 415 an application

G.

Curie from

Neilson,

Boulevard, University the Division’s web

Renal-Electrolyte

site

of Pennsylvania, at http:/IREH-

or