Vol. 45. Nro. 1
Printed in U.S.A.
T H E AMERICAN JOURNAL OF CLINICAL PATHOLOGY
Copyright © 1966 by The Williams & Wilkins Co.
GLOMERULAR BASEMENT MEMBRANE I N DIABETICS
PAUL K1MMELSTIEL, M.D., GENGO OSAWA, M.D., AND JOSEPH BERES, M.D.
Marquette University School of Medicine, and Milwaukee County General Hospital,
Milwaukee, Wisconsin 53226
Many authors believe that diabetic
glomerulosclerosis begins with thickening of
the peripheral basement membrane and
progresses to the formation of intercapillary
nodules. Bloodworth2 states that only
Kimmelstiel and associates9 take exception
to this concept. Primary thickening of
peripheral basement membranes is assumed
to precede the formation of nodules because
thickening is said to occur in diabetes without nodules, and has been described in
prediabetes. It is now generally agreed that
the diabetic nodule is derived from increased
deposition and fusion of mesangial bars
(basement membrane-like material); however, the relation of the mesangial change to
the deposition of PAS-positive, and of other
substances to the increased width in the
peripheral basement membrane, is not yet
clarified. The relations between diffuse or
nodular intercapillary sclerosis and changes
in the peripheral basement membrane are
not sequentially documented, and the
possibility that both lesions are related to
each other only by a common pathogenetic
factor, such as diabetes, cannot be dismissed.
Furthermore, most studies of glomerular
basement membranes in diabetes do not
adequately document the increased thickness. Most authors compare their measurements to the "normal" values published by
Bloom and associates,3 or to a few samples of
their own, but fail to give specific data
pertaining to the sites of measurements. In
addition, the number of measurements made
is either not recorded or too small to permit
definitive conclusions. Moreover, increased
thickness of basement membrane can only be
demonstrated if it exceeds twice the standard
deviation beyond the normal mean width.
For instance, taking the often quoted values
of Bloom and associates,3 a width of approximately 4400 A must be regarded as
being within normal limits at a confidence
level of 95 per cent. This rule has not always
been applied.12 The importance of excluding
portions of the basement membrane close to
or covering the mesangium must be emphasized. We found it difficult to measure this
area accurately because of the close approximation to or fusion with bars of the mesangial matrix and the frequency of tangential
planes of sections; therefore, a "normal"
mean of width in this area could not be established.
Our biopsy material was compared with a
series of previously reported13 normal glomeruli, using the same technic as described in
this publication.
Our study of normal glomeruli resulted in
values of mean width approximately 10 per
cent higher than those of Bloom and associates, but our standard deviation was nearly
twice as great as theirs. This may be due
to a somewhat more lenient definition of
"normal." We concluded that the maximal
mean width of peripheral basement membrane in the majority of normal glomeruli
o
was 4367 A, a value close to that of Bloom
and associates;3 however, in accordance with
our "normal" standards, the basement membrane may occasionally measure as much as
5323 A. These are the values with which the
width of peripheral basement membranes in
glomeruli of diabetics were compared.
MATERIAL
Renal biopsies of 30 patients and sections
from 2 autopsies were used for study; 45
glomeruli were examined. In IS cases (embedded in Araldite), only 1 glomerulus per
case was regarded as adequate for study;
in 14 cases (embedded in Vestopal), an
average of 2 glomeruli per case was
examined. Calculation of the mean width
and standard deviation was based on a total
of 7140 measurements.
In all of the instances the diagnosis of
Received, July 15, 1965.
Supported by United States Public Health
Grant AM 06866-03.
21
22
KIMMELSTIEL ET
overt diabetes was established. The duration
of diabetes was known in 22 cases. The
diagnosis of diabetes was established on the
basis of clinical and laboratory evidence;
namely, 2 fasting blood sugars of 150 mg. per
100 ml. or more, or a positive standard
glucose tolerance test. One case with several
fasting blood sugars of 130 to 140 mg. per 100
ml., and 1 above 150 mg. per 100 ml. with a
2-hr. postprandial blood sugar of 144 mg. per
100 ml. was omitted because the patient was
azotemic.
METHODS
The technic used in preparing the specimens for light and electron microscopy was
identical with that described in the study of
normal glomeruli.13 Selection of the areas
measured was as previously described. In
only 1 of the cases with inter capillary
nodules could more than 100 measurements
be made; however, this limited number of
measurements did not affect the interpretation, as the analysis of the results will
demonstrate. In 11 of 22 cases without
nodules, only 100 measurements per case
could be taken. As these glomeruli studied
constitute a homogeneous population, with
regard to their histology and the presence of
diabetes, the deficiency of the number of
measurements was balanced by the total
number of glomeruli studied. Furthermore,
only 3 glomeruli required more than 52
measurements because the standard deviation which indicates variability exceeded
726 A (Nos. 7, 10, and 12). Statistical
evaluation of the group was, therefore,
believed to be valid.
I t should be noted that one of us (G. O.)
worked independently on the measurements,
without comparing them with light microscopy or being able to evaluate his objective
data before final tabulation was completed.
RESULTS
The mean width of basement membranes
in the 33 cases ranged from 195S to 7723 A,
with standard deviation ranging from 504 to
20S0. The mean width of the 45 glomeruli
was 3540 A, ranging from 1791 to S7S0 A;
the mean standard deviation was 1570,
ranging from 504 to 2080 (Table 1).
Vol. 45
AL.
These mean values required correction
because the glomeruli of 7 cases revealed
nodules and were regarded as abnormal in
contrast to the other 25 cases. The mean
width of basement membranes of glomeruli
without nodules was 3293 A, with a standard
deviation of 1260. Glomeruli with nodules
o
had a mean width of 5373 A with a standard
deviation of 22S0 (Table 2).
DISCUSSION
As indicated in the previous paper,13 the
PAS-positive material in the mesangium was
regarded as being representative of the basement membrane bars in the matrix (as seen
by electron microscopy). This has also been
mentioned by Bloodworth.2 Inasmuch as no
method was found to quantitate the mesangial bars by electron microscopy, semiquantitation by light microscopy was used.
In 21 cases the PAS-positive material was
listed as 1 + . Because of the variability in
estimation, no subgrading less than 1 + was
attempted, and all of the glomeruli were
regarded as being within normal limits. PASpositive deposits, graded as 24- in 4 cases,
were believed to be at the upper limit of
normal.
Two of this group of 25 glomeruli without
nodules (Nos. 12 and 15) require special
consideration. In Case 12, only 4 glomeruli
were available for light microscopic analysis,
and the biopsy revealed a large scar with
lymphocytic infiltrate. In all of the other
cases, the quantitation of mesangial deposits was based on 10 or more glomeruli.
In Case 16, 1 of the 9 glomeruli had a
subcapsular deposit characteristic of diabetes. It has been our experience that further
search in such instances reveals nodular
lesions elsewhere.8 In view of these findings,
it is advisable to calculate the mean width of
the basement membranes of this group with
and without these 2 cases.
As in normal glomeruli, the thickness of
peripheral basement membranes increases as
the mesangial deposits increase. If we compare the glomeruli of diabetics, in the
absence of nodules, with controls, we find
that the mean width of their peripheral
capillaries falls within the limit of normal
(maximum 5323 A). Excluding Cases 12 and
TABLE 1
RESULTS
No.
Age
Sex
1
2
3
4
5
6
7
8
9
10
11
12*
60
24
59
48
44
58
40
32
21
48
38
33
M
P
M
M
M
F
13
14
15t
66
43
23
F
M
F
F
M
M
F
M
OF L I G H T
AND ELECTRON
Light
Mesang- Nod- MicroUrine
Duration Protein/Gm.
ium PAS ules scopy
Glo(+)
meruli
1 mo.
New
New
New
4 mo.
10 yr.
1 mo.
4 mo.
New
New
4 yr.
2 mo.
2.3-3.0
0.1
0
1.5-2.2
1.5-3.0
0.6
0.12
0.1
0.1
0.05
0.3
2.0-3.7
New
0
0
3 mo.
5-10 yr. 0.04
+
+
+
+
+
+
+
+
+
+
+
+
_
-
+
+
+
-
0
—
-
>10
>10
>10
>10
>10
>10
>10
9
>10
>10
4
4
MICROSCOPY'
Electron
Microscopy
Glomeruli
ct
C
c
c
c
c
c
c
c
c
c
4
a
b
c
d
10
>10
9
1
1
2
a
b
10
17
18
19
20
21
22
23
24
25
20
27
28f
29
30
31f
32
51
52
43
05
32
77
70
53
44
F
M
M
M
M
F
F
F
M
61
50
50
08
M
P
M
F
51
32
M
M
New
New
2 mo.
lyr.
1 yr.
2.8-3.2
1.2
+
+
0
0
0
New
3 yr.
20 yr.
16 yr.
20 yr.
3 yr.
7 yr.
15 yr.
13 yr.
25
12
0.4
2.1
3.2
9.0
1.5
1
2
a
b
>10
+
>10
+
10
+
>10
++
+++
+++
+++
++++
+++
++-M+++
* F o u r glomeruli—atrophic, large scar.
>10
>10
+
++
++
++
< 1 yr. 0.4
3yr.
0.06
2 mo.
0.23
-
3
a
b
c
3
a
b
c
2
a
b
2
a
b
—
-
>10
>10
>10
c
c
2
a
b
+
+
+
+
+
+
+
>10
>10
>10
>10
>10
>10
>10
>10
1
c
c
c
c
c
c2
a
b
| Capsular deposits.
STUDIES
No.
Measured
Mean
Width
Range
Standard
Deviation
100
100
200
200
100
100
100
50
100
100
100
720
60
210
300
150
250
250
380
180
200
140
440
210
230
490
130
190
170
350
140
120
90
500
250
250
500
250
250
200
100
520
300
220
250
100
100
100
100
100
100
200
100
100
195S
2360
2953
321S
1791
2071
2470
1964
3390
3263
3131
4666
7496
3713
4724
4753
2545
3164
5097
5025
5163
2414
3103
3342
2885
2434
2393
2388
2575
2985
3033
29S5
2909
30S2
313S
3027
2551
259S
2624
3551
3707
4190
1100-3500
1200-4000
1400-4700
1600-6100
1800-3200
1100-3200
1200-5000
1100-3200
1500-5700
1700-5100
1700-5900
1400-13300
4200-13300
1400-7000
2700-S600
2200-8600
1500-4000
1700-6000
2800-9200
2900-8000
2800-9200
1300-4000
1700-6300
1900-6300
1700-4900
1400-4900
1500-3700
1400-4100
1500-4900
1400-6900
1400-6900
1400-4600
1400-4900
1600-5600
1800-5600
1600-5000
1200-5000
1500-5000
1200-4800
1700-6000
2400-5300
2000-6900
2000-6400
2600-6900
1200-4500
1100-7900
2900-9100
2200-6700
1S00-9700
2700-9800
3800-10600
3500-14200
3600-14200
3500-9900
569
542
732
1130
509
534
771
504
1000
726
9S9
1940
2990
1250
943
779
509
1050
903
927
885
740
71S
S27
514
597
537
535
685
714
750
631
762
813
548
1010
620
605
639
S23
646
917
S21
750
521
1300
1600
1090
2070
1200
1420
2080
2060
1490
269S
2953
5302
4107
4523
5611
6041
7723
8780
6665
t C: Composite of several glomeruli.
24
Vol. 45
KIMMELSTIEL ET AL.
15, all 22 cases measured less than the mean
plus twice the standard deviation of the
majority of normal glomeruli (4367 A)
(Fig. 1).
The basement membrane of 5 of the
7 cases with nodular glomerulosclerosis
exceeded the maximal width of the majority
of normal glomeruli. Two of them (Nos. 26
and 2S) were within the limits of normal. In
this series thickening of peripheral basement
membranes in glomeruli of diabetics occurred only in glomeruli with nodular intercapillary glomerulosclerosis. Conversely,
nodular glomerulosclerosis occurred without
thickening of peripheral basement membrane (Figs. 2 and 3).
We shall attempt to explain why the
results of our study differed from that of
other observers who believe that the
thickening of peripheral basement membrane
is frequently or always present in glomeruli
of diabetics. Most observers assume that
thickening-precedes the intercapillary nodule.
Irvine and co-workers,6 in a frequently
quoted publication, stated that the earliest
change in diabetes is an irregular thickening
of the basement membrane which normally
is of uniform width. As the lesion progresses
"basement membrane-like material becomes
apparent in the endothelial cells." No details
are given, but it is likely that their observations included the mesangial area which was
not distinguished from peripheral endothelium. Furthermore, in our experience the
peripheral basement membrane in normal
glomeruli is not of uniform thickness.
Bergstrand and Bucht, 1 in 1959, noted focal
thickening of peripheral basement membrane
in 8 diabetic patients, but their report
was not documented with measurements.
Farquhar and associates,6 in 1959, studied 7
cases, of which only 3 did not have nodules.
The basement membrane thickness of 1 of
them was at the upper limits of normal; that
of the other 2 cases measured 2 to 3 and 5 to
7 times normal, respectively. The thickness
was described as variable, but measurements, particularly means of width and
standard deviations, were not given. In our
series, the greatest width, even in glomeruli
with nodules, did not exceed 3 times the
normal thickness; however, we cannot com-
pare our studies with those of Farquhar and
associates, because they did not clearly define the site of measurement, and a distinction between mesangium and peripheral
capillary was not made at that time. Therefore, the difference may be explained by
assuming that they included portions of
basement membrane covering the mesangium. Suzuki and co-workers, in 1963, u referred to thickening of basement membranes
as a well-known feature in early diabetes.
Dachs and colleagues4 found mild focal
thickening (4000 to 5000 A) in early cases,
but did not characterize the sites of measurement, means of width, and standard deviations. None of these reports indicate the
number of measurements made. A recent
report by Lannigan and associates11 also
concluded that thickening of basement
membrane and deposits in the axial portions
were present in all cases of diabetes, even the
earliest ones. The number of measurements
was given as "numerous." They were made
on the peripheral loop, but the proximity to
or distance from the mesangium was not
specified. These authors regarded 4500 A in
some loops as exceeding the limit of normal,
which o they stipulate is 3000 A. Although
3000 A may well be accepted as the mean
width, the upper limit of normal, however,
depends on standard deviation. The authors
emphasize the considerable variation in
thickness of the basement membrane of
TABLE 2
A L L C A S E S G R O U P E D IN ACCORDANCE WITH T H E
ESTIMATED
AMOUNT
OF
PAS-POSITIVE
MESANGIAL DEPOSITS*
No. of
Cases
Mesangium
II
in
21
4
7
+
++
+++
++++
Total
32
Group
i
StandNodules Mean Width ard Deviation
_
—
7
3210 A
3705 A
5373 A
1290
1010
2280
7
3540 A
1570
Omitting Cases 12 & 15
Total
30
3308 A
1490
* (I = + , I I = + + , I I I = + + + or more.)
Jan.
1966
GLOMERULAR BASEMENT MEMBRANE IN DIABETICS
25
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vX
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A.* A r
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^A«
-
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, ,,
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--**^
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'V
F I G . 1. Glomerulus without nodule. Reduced 30 per cent from X 10,900. Diabetes of 1 year's duration.
Mean width of basement membrane in this case was 2985 A. Thirty-five measurements were taken from
this electron micrograph at sites indicated by dots in accordance with the criteria set forth in the preceding paper. 13 No measurements were taken a t points indicated by X .
26
KIMMELSTIEL ET
normal glomeruli, which makes it difficult to
establish an upper limit of normal. We fully
agree with this statement.
Indeed, our study of normal glomeruli and
those of diabetic patients has convinced us
that the great variability in thickness
requires precise statistical evaluation if
comparable data are to be obtained. Three
requirements are necessary to achieve
reliable measurements of the peripheral
basement membrane: first, assurance that
mesangial portions are excluded; second,
tangential sections must be rigidly avoided;
third, an adequate number of measurements
must be taken. These criteria are discussed in
detail in the study of normal glomeruli.13
If the thickness of basement membranes is
expressed as the means of width, glomeruli of
diabetics without nodules have peripheral
basement membranes of normal width.
There is no method to quantitate focal
thickening in order to compare it with the
varied basement membrane thickness of
normal glomeruli; however, it would be
expected that a focally increased width of
significant magnitude would increase the
mean width, as occurs in glomeruli with
nodules, if a sufficient number of measurements are made. A great variation in
thickness is indicated by an increase of the
standard deviation, as is seen in glomeruli
without nodules from diabetics, where the
mean standard deviation is somewhat
higher than that of the majority of normals
(Table 3). The difference, however, is not
significant when compared with the mean of
the glomeruli with nodules.
The difference between the results of our
measurements and those of other investigators may be explained by restriction of basement membrane areas acceptable for precise
measurements, the number of measurements
made, and the calculation of means of
widths. Comparable results are obtainable
by this method, as we arrived at virtually the
same values obtained by Bloom and associates,3 who proceeded in a manner similar to
ours with approximately 150 measurements
per case.
The deposition of basement membrane
bars in the diabetic state, possibly induced
by mesangial cells in the matrix, merges with
AL\
Vol. 45
the basement membrane, producing thickening in this area. Irregular increase of its
width, extending into the adjacent junctional
areas toward the periphery, may give the
impression of "focal" thickening of the
peripheral basement membrane. We have
conscientiously excluded all of the areas from
measurement which were in close approximation to the mesangium, as did Bloom and
associates.3' 15
Another possible difference between the
results' of this study and that of others may
be related to the selection of cases. Our
series is composed of 7 patients with longstanding diabetes with nodular glomerulosclerosis, and 6 patients without nodular
glomerulosclerosis (omitting Case 15) known
to have had diabetes for 1 year or more. In S
patients, diabetes was first recognized between 1 and 12 months prior to the renal
biopsy, and in 9 cases diabetes was first
detected within a few days of the biopsy. If
the often repeated statement is true, namely,
that nodular glomerulosclerosis develops in
approximately 6 years after onset of the disease, the crucial prenodular period from 1 to
6 years is poorly represented in this series.
However, in 4 cases diabetes was known to
have existed from 1 to 10 years without the
formation of nodules and no thickening of
peripheral basement membrane was demonstrable. Prior to electron microscopy this
would not have been surprising, as glomerular
changes were found by means of light microscopy in only about 30 per cent of all cases.
It is now generally accepted that electron
microscopy reveals at least focal thickening
in the majority, if not all, diabetics even in
the prediabetic stage preceding demonstrable disturbances of carbohydrate metabolism. If this concept were correct, basement
membrane thickening would be expected in
all of our cases, including those in which no
nodules were found and which were of short
duration. This was not the case.
We have examined 1 well-studied case of
so-called prediabetes in which the glomeruli
failed to show any change in the basement
membrane. This case and several others
presently under investigation will be reported at a later date.
It must be concluded that this study of a
Jan.
1966
GLOMERULAR BASEMENT MEMBRANE IN DIABETICS
27
FIG. 2. Diabetic nodule. Reduced 30 per cent from X 3600. Peripheral portions of basement membrane
do not appear thickened. From all the electron micrographs relatively few areas meet the criteria necessary for accurate measurements. One of them may be seen in the square.
28
K1MMELSTIEL ET
limited number of glomeruli from diabetic
patients has failed to demonstrate an
increased incidence of significant thickening
of the basement membrane in the periphery
of capillaries when intercapillary nodules are
absent.
This study does not confirm the statement
that thickening of the peripheral capillary
precedes formation of nodules. Neither
Bloodworth's study 2 nor those of others
give evidence of such a relationship. Serial
biopsies in human or experimentally pro*
duced nodular glomerulosclerosis in animals
would be required to confirm a sequential
relationship.
It is of interest that in 3 of the 4 cases in
which mesangial PAS-positive deposits were
estimated to be at the upper limit of normal,
the peripheral basement membrane was
thicker than in all other non-nodular glomeruli, although still within the range of normal.
This observation, however, must not be
interpreted to mean a sequential relationship. The 2 phenomena may well be independently parallel, as previously stated.
Finally, this study has not confirmed our
own previous statement that peripheral
capillary thickening may in rare instances
exist in diabetes without mesangial thickening.7 The single case which prompted this
statement was re-examined, and when the
mean width was calculated it was found to be
within normal range. Random observation of
electron micrographs misled us.
We are currently inclined to assume that
thickening of peripheral basement membrane, if it occurs in diabetic patients, begins
at a time when there is also increased deposition of mesangial bars. This process does not
always occur in the same glomerulus.
Significant thickening of peripheral basement membrane was observed in this series
almost exclusively in conjunction with
nodular glomerulosclerosis. This may be
assumed to confirm the original concept10
that the mesangial process precedes peripheral thickening of basement membrane.
It does not, however, exclude the possibility
that both processes, peripheral thickening
and mesangial deposits, are independent
manifestations of a common pathogenetic
factor. It should be noted that nodular glo-
Vol. Ii5
AL.
merulosclerosis may occur without a significant thickening of the peripheral basement membrane (Cases 26 and 2S).
Arterio- and arteriolosclerosis. With very
few exceptions, semiquantitative grading
shows no significant difference between the
sclerosis of arterioles and that of interlobular
arteries. Grades from 0 to 4 + were listed;
half grades appear at the next higher step.
In 3 cases, so few vessels were seen that the
cases were eliminated from the tabulation,
and in some of the remaining 2S biopsies wewere not confident of the accuracy of the
grading. Because of this, only a brief list of
the extreme grades is made, comparing them
with the mesangial deposit and means of
width of the peripheral basement membrane.
Data in Table 4 indicate that there is no
consistent relation between arterio- and arteriolosclerosis and the glomerular changes.
The mesangial deposit of PAS-positive
material and nodules are found in 2 cases of
minimal and 5 cases of marked vascular
sclerosis. On the other hand, normal mesangium is found in 10 cases of mild and 4
cases of marked arterio- and arteriolosclerosis.
As in the study of normal glomeruli, no
clear relation can be established in diabetics
between vascular sclerosis, mesangial deposits, and the peripheral basement membrane
thickness.
SUMMARY AND CONCLUSIONS
1. In 30 needle renal biopsies and 2
autopsies of diabetic patients, light and
electron microscopy studies revealed that:
(a) the mean width of peripheral basement
membrane ranged from 1791 to 7723 A per
case, and the standard deviation ranged from
504 to 20S0; (b) the mean width of peripheral
basement membrane of all glomeruli, ranged
from 1791 to 87S0 A, based on 7140 measurements, and the standard deviation ranged
from 504 to 2990; (c) a separation of cases
with nodules from those without nodules
showed a mean width of basement membrane
o
of 5373 A in glomeruli with nodules, and
a standard deviation of 2280; the mean
width in glomeruli without nodules was
3293 A, the standard deviation 1260.
2. It was concluded that the mean width of
Jan. 1966
GLOMERULAR BASEMENT MEMBRANE IN DIABETICS
29
^M,
FIG. 3. Capillary wall within the square of Figure 2. Reduced 30 per cent from X 34,500. The width
of basement membrane varies from 1300 A to 2500 A. The total mean width of basement membrane is
within normal limits.
30
Vol. 45
KIMMELST1EL ET AL.
TABLE 3
COMPARISON
OF N O R M A L
GLOMERULI
G L O M E R U L I FROM D I A B E T I C S *
Group
Normal
Majority
All
Diabetic
I & II
III
Mean Width
Standard
Deviation
2909 A
3146 A
729
983
3293 A
5373 A
1260
2280
PAS-positive deposits roughly parallel peripheral basement membrane thickness in
glomeruli of diabetics. Arterio- and arteriolosclerosis can not be related to either mesangial deposits or basement membrane thickness.
REFERENCES
* All glomeruli of 3 + or more mesangial deposit also had nodules. (I = + , I I = + + , I I I =
+ + + or more.)
1. Bergstrand, A., and Bucht, H . : T h e glomerular
lesions of diabetes mellitus and their electron-microscope appearances. J. P a t h . &
Bact., 77: 231-242, 1959.
2. Bloodworth, J. M . B . , J r . : Experimental diabetic glomerulosclerosis. I I . T h e clog.
Arch. P a t h . , 79: 113-125, 1965.
3. Bloom, P . M., H a r t m a n n , J . F . , and Vernier,
R. L . : An electron microscopic evaluation of
TABLE 4
COMPARISON O F M I N I M A L AND M A R K E D D E G R E E O F A R T E R I O S C L E R O S I S WITH M E S A N G I A L D E P O S I T S AND
W I D T H OF P E R I P H E R A L BASEMENT MEMBRANE
No. Cases
Grade of Arteriosclerosis
» »
+ or less
H- or less
» !
+ H—h or more
Mesangial Deposit
Mean Width
Nodules
+
+++
1964-3390
4107-7723
+
+ in 4 cases
+ + in 1 case
1791-3707
+++
+ + + or more
the basement membranes of glomeruli in
diabetics was within the range of normal but
was abnormally thick in 5 of 7 cases with
nodules. In 2 cases with nodules, the peripheral basement membrane was within the
range of normal.
3. These data do not confirm the statements that all diabetics have thickened
glomerular peripheral basement membranes
or that thickening occurred prior to the
development of intercapillary nodules. The
generally accepted concept of invariable and
early thickening of peripheral basement
membrane is based upon observations of
irregular focal increase of width which can
not be quantitated and compared with the
normal variation of thickness.
4. Comparable values can be obtained
only if the measurements exclude portions of
basement membrane covering the mesangium and if a statistically significant
number of measurements is taken.
5. As in the normal glomeruli, mesangial
4.
5.
6.
7.
8.
9.
10.
11.
2953-6041
+
the width of normal glomerular basement
membrane in man a t various ages. A n a t .
R e c , 133: 251, 1959.
Dachs, S., Churg, J . , M a u t n e r , W., and
Grishman, E . : Diabetic n e p h r o p a t h y . Am.
J . P a t h . , U: 155-168, 1964.
F a r q u h a r , M. G., Hopper, J., J r . , and Moon,
H . D . : Diabetic glomerulosclerosis. Electron
and light microscopic studies. Am. J. P a t h . ,
35: 721-753, 1959.
Irvine, E., R i n e h a r t , J. F . , Mortimore, G. E . ,
and Hopper, J., J r . : T h e u l t r a s t r u c t u r e of
the renal glomerulus in intercapillary glomerulosclerosis. Am. J . P a t h . , 32: 647-64S,
1956.
Kimmelstiel, P . : Diabetic n e p h r o p a t h y . In
Smith, D . , and Mostofi, F . K . (Editors),
Pathological Physiology and Anatomy of the
Kidney. Baltimore: T h e Williams & Wilkins Co., 1966, in press.
Kimmelstiel, P . : Glomerulosclerosis. J . M t .
Sinai Hosp., S3: 657-662, 1956.
Kimmelstiel, P . , Kim, O. J., and Beres, J . :
Studies on renal biopsy specimens, with the
aid of the electron microscope. I. Glomeruli
in diabetes. Am. J . Clin. P a t h . , 38: 270279, 1962.
Kimmelstiel, P . , and Wilson, C : Intercapillary lesions in the glomeruli of the kidney.
Am. J. P a t h . , 12: 83-98, 1936.
Lannigan, R., Blainey, J . D . , and Brewer, D .
B . : Electron microscopy of the diffuse glo-
Jan. 1966
GLOMERULAR BASEMENT MEMBRANE IN DIABETICS
meiular lesion in diabetes mellitus with special reference to early changes. J. Path. &
Bact., 88: 255-261, 1964.
1.2. La/.arow, A.: In Siperstein, M. D., Colvvell, A.
R., Sr., and Meyer, K.: Small Blood Vessel
Involvement in Diabetes Mellitus. Washington: American Institute of Biological
Sciences, 1964, pp. 9-10.
31
13. Osawa, G., Kimmelstiel, P., and Seiling, V.:
Thickness of glomerular basement membranes. Am. J. Clin. Path., J,5: 7-20, 1966.
14. Suzuki, Y., Churg, J., Grishman, E., Mautner,
W., and Dachs, S.: The mesangium of the
renal glomerulus. Am. J. Path., 48: 555578, 1963.
15. Vernier, R.: Personal communication.