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,
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Jones NE: The of renal biopsies.
Pearson electron
of electron
Berger
Gotoff
HJO, lesions
:
Petersen in light-
gbomerulonephritis.
Sect SP,
microscopy
Isaacs
A distinct
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pathologic
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lupus
tnt
Goodman
and
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Practical
basement “benign”
FO:
Pathologic
membranous
mem-
hematuria. differentiation
Kid-
gbomerulopathy.
in the development
Med
Scand
CC:
gbomerular,
Hum
1-80,
for the diagno-
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1975
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and interstitial
gbomer-
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Pathol
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brane
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in an appropriate then
Based
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10.
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mt 35:
Kidney
gbomerubonephritis
microscopic
centers
cannot
A, Qureshi
entity
if
to increase.
a small
could
9.
native
Fogo
nephropathy:
study.
of fibrillary
diagnostic
cost-conscious
biopsies.
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.
