A Reevaluation of Routine Electron Microscopy in the Examination of ...

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of electron microscopy in native renal biopsies also examined by immunofluorescence and routine light microscopy was re- evaluated. From. January. 1996.
A Reevaluation

of Routine Electron Microscopy of Native Renal Biopsies

Examination MARK

HAAS

Departments

Electron

Abstract.

centers

in

the

studies,

primarily

justification largest found

of Pathology

microscopy evaluation its

the

use.

and

native

renal

l960s

and

Conducted

in

mation

I 1 %, as

well

in another

were

conducted

biopsy

36%.

widespread

electron

Several

two of these

l970s, et

and

variants

were

by immunofluorescence

pathologist. study,

and

From January were received, Of

which

and

those,

were

233

5

and

including globally toxylin and eosin, orescence-for

firmatory

data,

and in eight

was

supported

scarred periodic

within

recorded

formed,

and

In most

major

performed

a final

centers

performed as part of routine light microscopy for

the

1gM,

made.

where

renal

is

the biopsy evaluation, and immunofluorescence

routine

use

of electron

membrane

collapsing

electron

case

20

to

ies

1997)

are

tiating

with Jus-

in renal

indicated

a different

11 (13%)

of 91 renal

Tighe

electron

microscopy.

They

studies

the

electron

microscopy

indicated

sis

light

than

structural

microscopy

studies

provided

a substantially

and

that

important

in an

cases,

different additional

information

diagno36%

by

ultra-

substan-

nosis

Muehrcke were

ma! change

University

of Chicago,

5841

S. Maryland

Avenue,

Chicago,

l046-6673/0801-0070$03.00/() Journal of the American Society of Nephrology Copyright (C) 1997 by the American Society of Nephrology

MC6lOl, IL 60637.

The

The

to establish Neither

Olsen

confirmatory

(4)

diseases

that

ultrastructural cases

membranous

causing

that

or subclassifying

found

early

in

found

a correct diaget a!. (2) or

in distinguishing

from

alone

et a!. (3)

179

Jones

managemicroscopy

microscopy

necessary

helpful

reached

electron

of mini-

nephropathy

the nephrotic

syndrome,

by Pearson

et a!. (5) in a more

(5)

above

recent

88 cases.

all

without original

Hinglais

but

one

the

aid

description

(6),

localize lished

most

also

of

ducted

and

and/or

to patient

light

cases.

stud8: 70-76,

diagnosis,

that

If

on all such

Nephrol

Muehrcke

considered

glomerular

a conclusion

However, Received July 24, 1996. Accepted August 26, 1996. Correspondence to Dr. Mark Haas, Department of Pathology.

of

nephropathy

and other study

was (3)

than

useful

biopsies.

ultrastructural

relevant

et a!. (2) found

1 1 (6%)

et a!.

for

biopsies.

microscopy in only

renal

microscopic

diagnosis

nephritis, as was the

routinely Soc

directly

Olsen

pauci-im-

provides

of native

tissue

dif-

gbomerubo-

variant),

(J Am

the light

information

Similarly,

information.

in 1 1% of these

case.

of not

nephropathy,

segmental

be performed that

in each

or subclassifying

ment.

IgA

microscopy half

of oth-

usually

acute interstitial study confirms that,

electron

cannot

aside

diagnoses

focal

in nearly

it is recommended set

in providing

routinely

ago,

microscopy

be

(2 1 %),

yr

in cases

immunodeficiency of it in cases

gbomerulopathy

information

electron biopsies,

collapsing

30

diagnostic

then

per-

(not

Diag-

glomerubasement

thin

of this

included

nephritis,

unrelated

microscopy included diabetic nephropathy,

Common

lupus

electron

that

and

findings.

and human (or exclusion

microscopy

proliferative

biopsy evaluation has come from several studies, the majority of which were performed during the late l960s and early 1970s (1-5). In the largest of these studies, Siegel et a!. (I) evaluated a series of 213 consecutive renal biopsies using light and found

(or exclusion

mune crescentic glomerulonephritis, and amyloid nephropathy. This

Clq,

an additional,

electron early

hematuria), nephropathy

glomerulopathy).

requiring

diagnosis

microscopy

nephropathy

erwise unexplained virus-associated

sclerosis

together studies.

in

incorrect,

lupus nephritis, membranoproliferative postinfectious glomerulonephritis,

for

biopsies

microscopy

membranous lonephritis,

not

on

In 50 cases

native

electron

was

diagnosis;

was

ultrastructural

noses most frequently requiring minimal change nephropathy,

2

C3,

(3%),

the

fuse

evaluated

microscopy

was

evaluated,

IgA,

and a preliminary

Electron

diagnosis

medical

and

0,

the final

diagnosis

cases by

in this

microscopy,

needed-were

48 h of receipt,

if possible.

microscopy,

re-

renal same

Light microscopy (hemastains) and immunoflu-

(Ig) when

inclusion

electron

glomeruli. acid-Schiff

in renal several new In light of the routine use also examined

for

for light 1 for

kappa/lambda

;

studies

was

to make

Illinois.

a firm preliminary diagnosis could not be made. In the cases, the preliminary diagnosis was correct, but in 48 (2 1 %), ultrastructural study was felt to provide important con-

diagnosis

microscopy

Chicago,

other

infor-

additional

1996, 288 native evaluated by the

criteria

immunoglobulin

fibrinogen each biopsy

tification

met

needed

the preliminary

or

before

light

was

cases,

and diag-

described.

to June all were

gbomeruli

immunofluorescence,

was

routine

1996

microscopy

of Chicago,

in 48,

the

(1),

University

renal biopsies for a correct

this situation and the expense of the procedure, of electron microscopy in native renal biopsies evaluated. biopsies

provide

a!.

all of these

and

The

in most

the use of immunofluorescence

became

diseases

nearly

of Nephrology,

utilized

Siegel

confirmation

However,

before

diagnosis

gbomerular

as for

Section

biopsies.

early

by

study evaluated 2 1 3 consecutive that electron microscopy was needed

nosis

Medicine,

is routinely of

from

for

in the

who

1968,

and

of the

nephropathy

was

deposits not

until

were

by

Berger

to

and

to detect

and

was

pub-

later

that

in glomeruli, 5

con-

microscopy.

immunofluorescence

complex it

studies

immunofluorescence

of IgA

utilized

the immune in

of

10 yr

immunofluorescence complement evaluation

in

several

most

new

scribed, phropathy, establishing

In

immunogbobuhin

human

also been

hematuria,

In

of

of the fact that electron

procedure,

this study

was undertaken

of electron

microscopy

for native

immunofluorescence

and

light

that

these

are

to reevaluate

on and

use by

biopsies,

1996.

which

A single were

microscopy,

contained

glomeruhi

for

in this

for

studies,

light counting

the 233 biopsies

that met these

in-hospital,

205

and

were

in the midwestern transplant biopsies

copy was received cases, ultrastructural pathologist. sections and

per slide

weak

periodic

IgA,

1gM, C3, Clq,

within

stain)

and

In some

included

stained

history;

were

these

done

microscopy, studies, 233

were

were

cases,

two

evaluated

studies

a preliminary the

remaining

diagnosis

pathologist

be made

and

48 cases,

and/or

some

of these

cases,

ogist

but

firm

preliminary

one

could

if possible.

a firm

a differential

could

be made was

a long

clearly

not be sufficiently

IgG,

biopsy Red

diagnosis

of two

favored

in

to warrant

performed or major to one

diagnosis

on one final

was recorded,

or two

gbomeruli

from

diagnosis

was

recorded.

of the following

three

categories

the ultrastructural

findings

Required.

Electron

preliminary

diagnosis,

did not supply

final

contributed microscopy was

other

diagnosis.

not

clinically

to this resulted needed

ultrastructural

a

The

was

on the basis primary in no

to confirm

pertinent

biopsy

and

a

then

of how

diagnosis. change this

information

the

diagnosis, related

in which above

mation

noted

staining

by immunofluores-

with diagnosis

above with light

electron miof minimal

or specific immuof diabetic nephrop-

finding

of thickened

case

in this category

gbomerwould

in a patient

immunofluorescence

explaining

with

showed

and complement showed extensive

present.

the presence secondary

categories

cases,

only

components and resorption of the the

primary

microscopy

whereas diagnosis.

in the Results

of mesangial

deposits

membranous

lesion.

only

cases,

immunotluores-

additional was

diagnosis. crucial

in making

it was

not required

These

cases

are given

special

categories

was

inforof these

the

primary

to make

the

consideration

section. of biopsies

to the above

also on clinical

data.

and

For example.

capillaries of

a biopsy

by immunofluorescence.

minimal

change

from

contribution.”

but from and

a 50-yr-old, a creatinine

By contrast, mildly

a biopsy rate

but

child

with

that showed only mild trace linear IgO in gbwould

hypertensive

clearance

not only

findings.

a 7-yr-old

and typical

nephropathy

based

ultrastructurab

normal renal function and nephrotic syndrome mesangial matrix expansion histologically.

syndrome

In one

also

eight

primary

provided

seven,

immunofluorescence.

ings

of the

findings

in the other

on histological.

findings

ultrastructurally

to determination

ultrastructural

a distinct.

electron

diagnosis,

refer

In eight

supporting

‘important to

include

to that

gbomerubonephritis

in whom

deposits

a possible

diagnosis.

merular in

of SLE,

Assignment

stud-

the biopsy,

The final

or

immunofluoresExamples

similar

( I 3). Another

proliferative

complex

indicated

by the pathol-

excluded

history

SLE,

In the

and communicated;

by the ultrastructural membranes

or diffuse

immune

In 185 of the clinician.

and/or

cence findings. Finally, cases where ultra.structural findings suggested a possible disease etiology were categorized as “important contribution,” including three cases of membranous nephropathy. unrelated to

light

diagnosis

provide

and a biopsy from a diabetic patient with diffuse mesangial matrix expansion by light

weak staining for immunoglobuhins in whom electron microscopy

special

preliminary

to the appropriate

diagnosis

the preliminary

the primary

that

did

this primary diaginto the patient’s

insight

nephritis

the

the primary

tindings

without nodular gbomerulosclerosis findings, in whom the diagnosis

is confirmed

(for

provided,

nephritis,

did not alter

to making

diagnosis.

Clq

xl-

lupus

findings

findings,

or more)

showed but electron

V (12).

and negative immunofluorescence. confirming the strongly suspected

ular basement

diagnosis.

assigned

and

applicable)

than

variants

the other(s)

primary

Not

(where

was recorded

no better

diseases

ies were

and

thought

athy

three

studies

data

(2+

systemic

and tubulovesicular

ultrastructural

to the primary lupus

lesion; glomeruli

overt

of membranous Class

microscopic

related

microscopy nofluorescence

be a focal

ultrastructural

clinical

communicated

more

After

before

bight

ultraimmu-

membranous

not essential

the

of

zero to 4+), and electron

but without

confirming/strengthening clinically relevant

change nephropathy: proteinuria showing

chains, immubased on the and the chini-

on the

However.

prominent

microscopy croscopy

study.

(Congo

(‘hurnps”) where

normocellular

deposits

and were

of membranous

and eosin

on each

exudative

cence strongly suggesting this diagnosis; a case of a child nephrotic syndrome and a renal biopsy showing unremarkable

Of

to

hematoxyhin

additional

evaluated

Based

immunofluorescence,

cases,

could

also

on the biopsy.

for

in this

with

stain, immunofluorescence for kappa and lambda light nohistochemical stain for amyboid AA) were performed light microscopic and/or immunofluorescence findings cal

but with

hospitals,

immunofluorescence

and fibrinogen)

48 h of receipt.

gb-

28 were performed

slides,

diagnosis

data,

a case

acute

for IgA and Clq,

typical (WHO)

prehirncases

immunofluorescence

The ubtrastructural

diagnosis.

and

mesangial

Organization

findings

ANA

staining

inclusions)

Contribution.

cence

glomeruhi.

both

with

in whom

capillary

showed

Health

for

gbomerulus

30 outside

were

alternately

acid-Schiff

one

2

(SLE),

glomerular

historical

10% ofthese biopsies, and in these performed at the discretion of the

consecutive

slides

received

sclerotic over

of the

microscopy

criteria,

from

biopsies

(eight

was

a weakly

important information nosis and/or provided

States. Our laboratory also processed this period; tissue for electron micros-

transplant

and

least

inclusion

with fewer than studies were

microscopy

at

all

examination,

globally

received

United during

No renal

Light

if tissue

microscopic and

not

evaluated

and electron

immunofluorescence,

ultrastructural

most renal

study

immunofluorescence,

5

meruli

included

(M.H.)

a firm

the

an early

the

diagnosis

include

deposits nephropathy,

to exclude positive

with

ies (tububoreticular

of The University of Chicago renal biopsies during the first 6

pathologist

needed

erythematosus

World

to make

where

Examples beyond

in a patient

final

of

light

was

microscopy

the routine also examined

needed

in cases

made.

nephropathy

only

a costly

Methods

months

be

and a case of membranous lupus

in

microscopy.

Laboratory 288 native

not

71

the preliminary

showed modest ( I +, on a scale from linear bgG in the glomerular capillaries

preliminary

Renal Pathology Center received

diagnosis

could

Diagnosis

was

changing

gbomerubonephritis

microscopy

Important

The Medical

a differential

diagnosis

nofluorescence predominantly

, Alport’s

remains

biopsies

in

in diagnosis

microscopy

either

Biopsy

stage, identified by large subepithehial structurally; cases of minimal change

familial

aid

Electron

diagnosis,

postinfectious

useful correlations

developments

final

mary

C lq ne-

(e.g.

microscopy

renal

or resolving

yr.

(HIV)-assoand

diseases

nephritis)

25

de-

EM in Renal

Diagnosis.

primary

been

nephropathy/benign

bight

Crucialfor

and

biopsy

past

have

virus

glomerular

bupus

(10-12).

consideration

the

variants

findings Ultrastructural

membrane

membranous

biopsy

over

and

glomerubonephritis,

with other

basement

(Ig) of renal

immunodeficiency

fibrillary

made

thin

part

addition,

diseases

in which ultrastructural the diagnosis (7-9).

syndrome, renal

a routine

centers.

including

have

for

became

glomerular

nephropathy,

ciated

studies deposits

Routine

he

ultrastructurab categorized

showing patient

of 90

similar with

mL/min

as find-

nephrotic would

be

72

Journal

categorized ity that

of the American

as “crucial

Society

for diagnosis”

ultrastructural

findings

of Nephrobogy

because

might

yield

of the greater a different

possibib-

diagnosis

tice

(e.g.,

early membranous nephropathy or thickened glomerular basement membranes, suggesting early diabetic nephropathy). In most cases, the clinical

data

letter, where

used

was

provided

with

the biopsy

history sheet, and/or summary the clinical data was considered

pretation,

the

studies

appropriate

were

clinician

in the form

of a cover

of laboratory data. In cases inadequate for biopsy inter-

was

called

before

ultrastructural

performed.

has

changed

tic tests. procedure;

Diagnostic electron at our institution,

copy

are

approximately

copy

plus

was

not

late

l960s

microscopy

biopsies

was

meeting

thought

the

necessary

study for

criteria,

making

electron the

primary

final diagnosis (Crucial for Diagnosis category) in 50 (2 1%), including the 48 for which a firm preliminary diagnosis could not be reached based on the light microscopic and immunofluorescence findings. sulted in a change from involved

a woman

light

microscopy

tion

appeared

ever,

and

lupus

WHO

for

in the

and fibrinogen of membranous

microscopy dense

IgG

fairly

on two

category,

ultrastructural

portant

tion

related

and/or

to the

category) in another Cases) summarizes of electron

of

primary

the

total finding

additional

diagnosis

these

2 lists cases,

involved

adult

both

cases,

use l970s

unrelated with

and

interrupted

lin-

with

glomeruli

showed

trace

diagnosis

was

in the

Crucial

were

thought

Diagnosis

to provide

clinically

relevant

(Important

im-

informa-

line of Table 1 (All 1 also examines the of individual

studies strongly

to the

primary

additional

revealed

suggestive

final

diagnoses

the ultrastructural

an of

finding

an

diagnosis. for each

of

supporting

justification

for

evaluation

changes

in the practice

of renal

pathology

routine renal

article,

Siegel

and

for us to reevalin native renal of medical prac-

correla-

and

biopsy.

1983

(1-4),

provided

electron

and,

gb-

on renal

(1),

of

yr.

ultrastructural

1969

use

25

long-recognized

a!.

biopsies

and

important

microscopy

most

likely,

in

played

an

this practice, which remains in medical centers. In their 1973

reported

et a!. (1)

biopsy in 48%

that

ultrastructural

findings

contributed to diagnosis and/or patient of cases also studied by light microscopy

on

managebut not

immunofluorescence.

Perhaps

somewhat

remarkably

surprisingly,

similar

tural

studies

tant

confirmatory

to those

providing

is that

microscopy

merular

diseases,

by those

require

well

as by

diagnosis

of

that

diagnosis

an addi-

for

2 (see

studies

following

gb-

been since

of

offset 1973

diagnosis, that

aid

as in the

glomerular

diseases.

As

the

section),

we

Results

were

diseases

for

influence

described definitive

correlations

1 and

need

common the

to have

and variants

to

the

of several

long-recognized

ultrastructural

negated

appears

ultrastructural

of the

impor-

support

However,

microscopy

other

are

of immunofluorescence

below.

diseases

in Tables

that

essentially

on diagnosis

newer

summarized

has

in the diagnosis

electron

ultrastruc-

information,

findings

the addition

as detailed

glomerular

that

study

with

(45%) of 233 native renal biopsies six months of 1996. What makes this

procedure

electron

of our

et a!. (I),

diagnostic

and/or

on 105 the first

surprising diagnostic

the results

of Siegel

required

data,

most

helpful

or classes

in the

of diseases.

Glomerular Basement Membrane Abnormalities, Including Thin Basement Membrane Nephropathy, Alport ‘5 Syndrome, and Diabetic Nephropathy Without Nodular Glomerulosclerosis noted

in the

with

note

to Table

unexplained

markabbe and negative ultrastructural studies major

et

past

in properly

diagnosis

between

Siegel

im-

glomerular

useful,

several

in their

important role in dictating effect today in most major

patients

of medicine in general have provided impetus uate the routine use of electron microscopy biopsy diagnosis. First, the economic climate

newer

with

the

of native

on na-

localize

in the

and

of

routinely new

made

of

by con-

several described

the use

detail;

Third,

these,

published that

routine

and

or at least

aiding

studies

notably

As

diagnosis.

Discussion Three

Several most

performed

been

microsduring

of

in greatest

is needed,

been

diseases,

found

the categories defined in the Discussion section). In eight or

merular

of

also

diagnosis issue

to detect

have

immunofluorescence

Contribution

diagnosis

many

have

our

segmental

for

variants

identifying

result

glomerular

focal

microscopy

a costly micros-

bight

centers

deposits.

tionab diagnosis evaluated during

no electron-

in the

and

for

with

diagnos-

immunofluorescence

the

considered

in most

Electron

those

biopsy

when

is now

biopsies

diseases

tions

to

for renal

was

complex

by

10 Im-

early

decade,

remains electron

for

Second,

and

past

of high-cost

microscopy the charges

equivalent

in widespread

mune

in the

number

immunofluorescence.

renal

renal ment

recent

showed in two.

),

+

no

pattern. A preliminary was made, yet electron

ultrastructural

indicative

together

the additional

(2

in the by the

with

microscopy sclerosis

48 (21%). The final these results. Table

primary

male

capillaries,

diagnosis

microscopy

unexpected

Table

case

other

renal diseases, as assessed Methods section (also see (3%)

III. The second

irregularities

studies

confirmatory

value

with

strong

basement membranes. The final gbomerubosclerosis (FSGS). In addition to the 50 cases

How-

glomeruli probifer-

glomerular

or significant

V.

only,

in a similar nephropathy

performed

deposits

focal

focal

young

showed

with

was

diagnosis

Class

two

deposits

By

in ques-

Class

on

nephrotic syndrome; light glomeruli with segmental

staining C3,

WHO

mesangial final

normotensive,

munofluorescence

diagnosis

the lesion

(GN),

and

syndrome.

nephritis

performed

The

nephritis,

onset of the normocellular

the nephrotic lupus

studies

deposits.

a nondiabetic,

electron microscopy rediagnosis. One of these

immunofluorescence,

subendothelial

1gM,

and

glomerulonephritis

subepithelial

ear

SLE

membranous

ultrastructural

showed ative

with

to be

proliferative

In two cases, the preliminary

the

immunofluorescence

tive 233

to reduce

microscopy

trast, the

Of

even

pressure

electron

Results

dramatically

increasing

1,

hematuria

two

biopsies

were

performed

histologically

by immunofluorescence; were needed to exclude

on unre-

in these cases, thin basement

membrane nephropathy. Notably, seven of the eight cases where ultrastructural findings supported an additional diagnosis distinct

increased

from

the

glomerular

primary

basement

diagnosis

(Table

membrane

2) showed

(GBM)

either

thickness

Routine

Table

Value

1.

of electron

microscopy

in renal

biopsy

diagnosis

of individual

EM in Renal

-

Primary

Focal

Segmental

IgA

and

(includes

GN

(with

No. of cases

.

diagnosis

Henoch-Sch#{246}nlein

Diabetic Nephropathy Pauci-Immune Crescentic Membranous

final

Gbomerulosclerosis

Nephropathy

.

collapsing

glomerubopathy)

Nephritis

or without

vasculitis)

73

(%)

of cases

in eac h category .

Not required

Crucial for diagnosis

Important contribution

34 28

25 (74) 25 (89)

4 ( 12) 1 (4)

5

20 20

10 (50) 18 (90)

6 (30) 0

4 (20) 2 (10)

I8

1 1 (6 1 )

0

7 (39)

16

4 (25)

8 (50)

4 (25)

Nephropathy

Nephritis,

WHO

Class

V (includes

Lupus

Nephritis,

WHO

Class

IV

16

12 (75)

1 (6)

3 (19)

Lupus

Nephritis,

WHO

Class

III

7

2 (29)

3 (43)

2 (29)

Lupus

Nephritis,

WHO

Class

II

5

1 (20)

1 (20)

0

9 (75)

3 (60) 3 (25)

Change

Hypertensive

Acute

Vd)

15)

(

2 (7)

Lupus

Minimal

V, and

Diagnosis

diseases” No.

.

Biopsy

Nephropathy

12

Nephrosclerosis

Interstitial

10

Nephritis

and

Acute

Membranoproliferative

GN

(includes

Amyboid

(types

AA

Nephropathy

Post-Infectious

Pyelonephritis types

and

1, II, and

III)

AL)

GN

Clq Nephropathy Thin

Basement

Acute

Membrane

Tubular

Nephropathy

Necrosis

5 (50)

2 (20)

3 (30)

9

9 ( 100)

0

0

6 5

0 5 ( 100)

3 (50) 0

3 (50) 0

4

0

3 (75)

1 (25)

3

0

0

3 (boO)

3

0

3 (100)

0

3

3 ( 100)

0

0

Anti-GBM Nephritis HIV-Associated Nephropathy Light Chain Cast Nephropathy

2 2

2 (100)

0

0

0

2 ( 100)

0

2

1 (50)

0

No

Pathologic

2

0

2

All

Other

6

2 (33)

2 (33)

Diagnosis

Diagnoses

(see

Notes)

considers

only

the role

AllCases a

This

of ubtrastructural

findings

findings also supported an additional, unrelated diagnosis. with unexplained hematuria and normal bight microscopic

excluded a diagnosis of thin basement membrane (not required), findings consistent with Bartter’s complex ON contribution). Organization.

suggestive

thin

(crucial for diagnosis), ON, gbomerubonephritis;

of probable

basement

the primary

Change

As noted

disease basement

(important membrane;

(1 3) or concurrent

is useful

in the

distinguishing

that and

diagnosis them

(1,4,5,14),

possible

do not show capillary may lack convincing

be

early

loop thickening immunofluorescence

The

presence

bodies

electron

microscopy

of these

lesions,

membranous

and

acute

phase.

were

at least

some

lesions

by light microscopy findings.

of

means

(WHO

Class This

means

no strong

clinical

nephritis)

and/or

of V)

deposits

inclusions) distinguishing

from history when

and

needed

tubulovesicular

ultrastructurabby

Three

is of particular

of SLE

lupus

membranous (e.g.,

immunofluorescence

latent

the

when

there

C I q is weak.

of

each

old

by clinical by

light

Electron

beyond

history

and

the

showed and

light

microscopy,

the was

permits even

mi-

diagnosed

ultrastructurally

microscopy from

light

microscopy,

lesions,

is apparent

GN

by

lesions

“humps”

clinical

postinfectious other

postinfectious

membranoproliferative and

(important World Health

particularly

subepithebial

of MPGN

immune-

GN and

from

chronicity

for the diagnosis.

chronic

Postinfectious

four

weeks

of of

HIV-Associated

nephritis

membranous for

where

proper when

the

immu-

data.

a

nephropathy value

cases

nephropathy virus; WHO,

(MPGN)

distinguish of the

several

nofluorescence,

remains

membranous

idiopathic

of distinction

and ON

evidence

diagnosis

mesangial

for diagnosis).

immunofluorescence,

demonstration

Nephritis

(tubuloreticubar

primary (12).

Lupus

(crucial

to

and

subtyping

Membranous

48(21)

2 considers

and hemobytic-urernic immunodeficiency

difficult

croscopy

or confirmation from

syndrome

contribution), HIV, human

Membranoproliferative

Nephropathv studies

50(21) Table

Meinbranoproliferative

nephropathy.

in previous

diagnosis:

2 (33)

no pathologic diagnosis both involved patients findings: in these cases, electron microscopy included (N = I for each case): sarcoid nephropathy

nephropathy. “Other” diagnoses syndrome (not required), Alport’s

nephropathy

final

0

The two cases listed as having and negative immunofluorescence

light chain deposition GBM, gbomerubar

diabetic

membrane

in making

may

Minimal

135(58)

233

table

1 (50)

( 100)

lupus

is

Ultrastructural endothebiab cell

Nephropathv demonstration of tububovesicular bodies in cytoplasm is important for this diagnosis (e.g.,

References 7 and 15). It is also important to demonstrate the absence of these structures in cases of the collapsing glomeru-

74

Table

2.

Journal

of the American

Cases

in which .

Society

electron

.

Pnmary

of Nephrobogy

microscopic

findings

supported

.

.

diagnosis

.

.

Additional

diagnosis

an additional

diagnosis’

.

Ultrastructural

findings supporting diagnosis

additional

Focal Segmental (two cases)

Gbomerubosclerosis

Thin basement nephropathy

membrane

Diffusely thin gbomerular basement with attenuated but intact lamina

Focal

Gbomeruboscberosis

Probable

diabetic

Thickened

Segmental

early

nephropathy Diabetic Nephropathy Pauci-Immune Crescentic

Membranous ON

nephropathy

Probable

early

diabetic

Nephritis,

WHO

Class

V

gbomerular

without

Thin basement nephropathy

membrane

basement

deposits electron-dense

Thickened

nephropathy Lupus

glomerular

without Subepithelial

membranes densa membranes

deposits basement

membranes

deposits

Diffusely thin gbomerular basement with attenuated but intact lamina subepithebial

deposits

extended

into

present

membranes densa; the

barely

the gbomerular

basement

membranes Minimal

Change

Nephropathy

Thin

basement

membrane

Diffusely

nephropathy Acute

Interstitial

Nephritis

Probable

early

diabetic

The ultrastructural

findings

listed

are only those

the additional

diagnosis.

basement

but

intact

glomerular

without

supporting

gbomerular

attenuated

Thickened

nephropathy a

thin

with

membranes

lamina

basement

densa membranes

deposits

In seven

of the eight

cases

listed,

the

ultrastructural findings did not contribute to the primary diagnosis (not required), whereas in one (minimal change nephropathy), electron microscopy was needed to establish the primary diagnosis (crucial for diagnosis). Each of the four patients diagnosed with thin basement membrane nephropathy had microscopic hematuria on a urinalysis before the renal biopsy. None of the three patients with probable early diabetic nephropathy was noted diabetic in the clinical history provided with the renal biopsy, although subsequent discussions with the

appropriate

clinicians

revealed

respectively. The patient g/24 h; immunofluorescence

membranes,

considered

bopathy ated

variant

that two of these

with

consistent

of FSGS,

nephropathy

which

vant rized

often

resembles

with

or without

20 patients

diagnosed

microscopy

of the

agnosis,

cases HIV

showed

an absence

of

diagnoses most

Among

electron

often

these

added

little

diagnoses

are

microscopy

was

clinically

rebe-

those

summa-

Diseases

diseases

include

and

acute

neutrophil

acute

interstitial

tubular

nephritis,

acute

py-

rized

as Not

dense

deposits

angiab

areas.

In three was

very

deposits

cases weak,

was

Glomerulonephritis

of Henoch-

of the

IgA

staining

demonstration

considered

of

showed

deposits

helpful

diagnostically.

to immune

Clinical fluorescence

and

Crescentic

Glomerulonephritis

serologic data, light microscopy, were typically sufficient to make

and

IgA,

Anti-

and immunothe former di-

deposits staining

or

Clq.

and/or

1gM

were

likewise

ANCA-positive. and

C3

deposits

ultrastructurally

both

were

IgA,

also

Falk

( 1 7)-and do

two

in

considered

for

showing

four cases or

cases, helpful

of pauci-immune as Important

all

focal,

staining cases

all of these

two

by cres-

showed

C3, without

in

not

identifiable

of pauci-immune

noted

In these

their

deposits

of the latter

mesangial) was

to mes-

previously-e.g.,

immunofluorescence

was

three. catego-

of electron-

complexes cases

ultrastructurally;

or Clq.

diagnosis

categorized

and

ultrastructurally,

Two

(mainly

IgO,

the preliminary

C3

not seen

without

noted

for 1gM and/or However,

in

limited

electron-dense

Of the four

deposits 1gM

Pauci-Immune GBM Nephritis

been

the

I +

electron-dense

have

the

ANCA

and

number

anti-

with

pending

case

by Jennette

with

and

to

reported

performed;

a small

reported

ON

ON,

were

in each

unclear;

to correspond

I 6 of the

ANCA-positive

significance

is

were

case

(all

ultrastructurally,

1 + gbomerular

by immunofluorescence mesangial

(ANCA)

one

cases

and

In

or in discussions

studies in

20

biopsy,

crescentic

of biopsy

Required) Such

on the nephntis.

pauci-immune

in 19% of cases

IgO,

in which

present

autoantibodies

negative

four

centic

and

duration,

had proteinuria of 3.5 in tubular basement

anti-GBM

ultrastructural

reported

Notably,

appear

necrosis.

with

at the time

before

were

from

immunofluorescence.

IgA Nephropathy Sch#{246}nlein Purpura

and five years’

nephropathy capillaries and

vasculitis

cases

cytoplasmic

to be positive clinician

for several

Tubulointerstitial

Two

HIV-associ-

as Crucial for Diagnosis in Table 1 were glomerulopathy in patients of unknown

and

(7,16).

of three

nephropathy.

these

needed

ebonephritis,

diabetes and membranous in gbomerular

distinguish

information. below.

These

non-insulin-dependent

cases

contrast, not

had known

four

status, for which electron tububovesicular bodies. By

patients

nephropathy (with nodular gbomerulosclerosis) showed relatively weak ( 1 + ) and linear staining

with diabetic

histologically

of FSGS listed of collapsing

usually

diabetic for IgO

showed most

were 1-2+

gbomeruli,

the absence

of

in confirming

crescentic

Contribution.

where

cases

ON,

and

Routine

Diabetic

Nephropathy

Congo chemistry deposition

Red stain, immunofluorescence, could be used to exclude disease where appropriate.

with

Nodular

Amyloid

Nephropathy

ultrastructurally lesion was

Glomeruloscierosis

and

immunohistoand light chain

arnyboid

deposits

SLE

negative

Congo

Red

chemistry

guish

stain,

were

AA

immunofluorescence,

sufficient

and

AL

to make

amyboid

and

this

immunohistoand to distin-

diagnosis

in all five

cases

Proliferative

In

most

history

by

Lupus

cases,

light

a “full

house”

and

posits

Electron

cases

of

lesion

was

chronic;

pattern

membranous

nephritis

mild

and

in such

often less prominent deposits

focal

cases,

Classes

In WHO cellularity,

considered

plant

II and

in confirming

that

in

were

the

lesion

classified as WHO Class II. Three cases were also diagnosed; in all three, the

patients

or young

or clinical

children

evidence

of SLE.

angial proliferative munofluorescence; (and

absence

ally was relatively

considered uncommon

Focal Segmental the Collapsing nearly

was

15%

has

noted

practice

of our

native

similar

renal

biopsy in

in New

certain

FSGS than in other in every

ultrastructur-

York

case

City.

may be seen nephropathy

Histologic in other

ultrastructural

of FSOS)

for

(16)

renal

biopsy

lesions

resem-

findings,

such

as separation

cells from the underlying to occur more frequently

glomerular

of

glomerular diseases, IgA nephropathy (19).

and

diseases

(although

and may

reflect

disease

severity

serologies,

of membranous lesions and immunofluorescence;

histology

of normocellular

of IgA and (particularly) cence, membranous lupus confidence.

In membranous

its,

of

absence

mesangial

could

be diagnosed with negative

gbomeruli,

and

by SLE

absence

Clq deposits by immunofluoresnephritis could be excluded with lesions deposits

showing and

have

Our making

study found the primary

et a!.

(5)

is in good

weak

tububovesicular

Clq

deposbodies

termined

less

cases,

discretion

ultra-

of the

pa-

agreement

renal

was

necessary

found

with that

that

were

the

48%

et a!.

of Pearson

also

and

microscopy

studied

found

by light

that

electron

in 22 (25%). studies

Pearson

were

helpful

in

exceeds the 24% (adding the plus those cases in which

supported

Most

than

of electron

ultrastructural

findings

by our study.

renal

important

higher

for diagnosis

that

of native

contributed

role

biopsies

in

microscopy was crucial to on 21 % of renal biopsies.

the diagnostic immunofluorescence,

an to

microscopy

fraction

been

of their cases, which Contribution category

53%

trans-

immunowith

latter

of electron the

electron diagnosis

and

also

for

received

these

studies

actually

that final

examined

microscopy

be-

Renal

tissue

at the

questionable,

on 88 consecutive

biopsies. was

for

ultrastructural

study.

an

additional

diagnosis)

of this difference,

de-

however,

can be

accounted for by two diagnoses: IgA nephropathy and pauciimmune crescentic ON. Pearson et a!. (5) considered electron microscopy helpful but not necessary in the diagnosis of all nine

of their

cases

IgA

nephropathy

of “crescentic

or

ON”

of

cases

(not

IgA

was

and

otherwise

pauci-immune).

microscopy

By and

in eight

of their

specified;

contrast,

not needed

nephropathy

immune crescentic “crescentic ON”

88,

of

Nephropathy

The majority light microscopy

from

membranous

we

thought

for diagnosis

in

1 8 of

20

or

34%

of

10

presumably

that

in 25 of 28

cases

of

pauci-

ON. If the 17 cases of IgA nephropathy and from the study of Pearson et a!. (5) are shifted

from the Helpful to the Not Needed category, their results (electron microscopy helpful but not necessary

entity.

Membranous

remains

finding

and

As the value

may

who

renal because

performed

by that

cases

appropriate light micro-

scopic lesions of FSOS, together with negative or nonspecific immunofluorescence findings, are sufficient for diagnosis

positive

biopsies

the study of Siegel et a!. (1) included of renal allograft biopsies performed

indicated

electron

are not

were

to which

idiopathic

basement in primary they

and pathogenesis (20-22). Still, in cases with clinical and serologic findings, the characteristic

this

regard

biopsies

another Important

D’Agati

active

with

two

three

microscopy

rejection.

microscopy

accounting

diagnoses. her

acute

ultrastructural

diagnosis,

experience

this

(5),

Not

on

neg-

Contribution.

native

biopsies,

studies

This

(FSGS),

and

B-related

a patient

latter

included

electron

By contrast, number

exclude

only

of these

thologist. unspecified

a mes-

Variant

frequent

of gbomerular epithelial membrane, are reported present

showed

from

of the

not

structural

deposits by imelectron-dense

bodies)

Glomerulosclerosis Glomerulopathy

bling primary FSOS including membranous In addition,

no serologic

helpful in confirming the diagnosis of this and recently described disease (9,18).

most

based

with

microscopy

of tubulovesicubar

our

a

Light

females

ON with mesangial Clq demonstration of mesangial

deposits

FSGS

adult

and

10%

information

was, in fact, properly of C lq nephropathy were

were

than

Class II lesions with more exclusion of subendothelial

helpful

included

fluorescence

or very

findings

that the mesangial

hepatitis

findings

as Important

study

de-

useful

III),

biopsy

Each

categorized

biopsies

this

glomerular

the immunofluorescence

convincing. mesangial was

(WHO

more

proliferative

in confirming presence of

a possible

Similar

lesion.

was

Our

to make

to be

the

IV clinical

complement

sufficient

tended

where

Class

appropriate

of Ig and were

microscopy

lupus

WHO an

on one

75

patients with unknown serobogies (except negative ANA) led to the suggestion of a possible secondary (but not SLE-related)

received.

Nephritis,

microscopy,

immunofluorescence

diagnosis.

lesion

Diagnosis

immunofluorescence

suggested

B serologies.

sions

Diffuse

C 1 q by

serobogies)

membranous hepatitis

Biopsy

was considered helpful related to SLE. The

not

(with

ative

EM in Renal

cases)

become

fairly

similar

to

revised in 30 of

those

of

this

study. Our findings suggest that routine use of electron to evaluate native renal biopsies is not wasteful

microscopy or frivolous,

even

We

same this nosis

in the

current

conclusion was

not

tested

of certain

is extremely

of others Receiving

diseases

anti-GBM helpful

,

economic to

climate.

(e.g.

is required

,

IgA

the

nephritis,

in the diagnosis

for

diag-

nephropathy/Henoch-

Clq

nephropathy)

and/or

classification

lupus nephritis, light chain-related unfixed tissue for immunofluorescence

(e.g.

feel

immunofluorescence-although

systematically-which renal

Sch#{246}nlein nephritis, and

medical applies

diseases). studies also

Journal

76

affords

the

maining

of the American

pathologist

tissue

(although

for

with

a single

the

albeit

the past extensive,

may

needed

procedures

as electron

economic

on

the

be

restraints

findings

recommend cortical

on

electron discretion

to justify

native

microscopy, which of the pathologist.

costly

8.

study that

be

we

fixative

performed

I 2.

for

to Dr.

Haas

from

Heart

Associ-

sies.

3.

4. 5.

NJ, Spargo

BH,

electron

Nephron

M, Hayslett

10: 209-215,

Biava

microscopically

defined

of

linmunol

RC,

Mandal

types Scand AK,

The clinical

value

intern Med

124: 170-176,

Tighe JR, microscopy

Jones NE: The of renal biopsies.

Pearson electron

of electron

Berger

Gotoff

HJO, lesions

:

Petersen in light-

gbomerulonephritis.

Sect SP,

microscopy

Isaacs

A distinct

syndrome:

pathologic

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tnt

Goodman

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Practical

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Pathologic

membranous

mem-

hematuria. differentiation

Kid-

gbomerulopathy.

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Med

Scand

CC:

gbomerular,

Hum

1-80,

for the diagno-

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A, Qureshi

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if

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a small

could

9.

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Fogo

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study.

of fibrillary

diagnostic

cost-conscious

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be saved

>2000

HIV-associated

comparative

immunofluorescence

studies

renal

should

such

and for

read

hope that this investigation

continue

care

if ultrastructurab

all

tissue

10 yr. We multicenter

study,

of

re-

microscopy

or ultrastructurab

has

health

of our

that

performed

who

microscopy on

any

electron

prove inadequate. An obviit represents the judgment of

one

renal biopsies over encourages a more

or

in histologic

the latter specimens of this study is that

ultimately

to reprocess

light

reduction

pathologist,

of Nephrobogy

opportunity

additional

some

detail) should ous limitation

Society

SM:

Primary

histological

Dis 22: 874-883,

focal variants,

1993

segmental and

gbomerulopathogenesis.