Intercapillary Glomerulosclerosis: A Clinical

and Pathologic Study

II. A Clinical Study of 100 Anatomically Proven Cases”

JOSEPH ROGERS, M.D., STANLEY L. ROBBINS, M.D. and HAROLD JEGHERS, M.D.

Boston, Massachusetts

I

N view of the conclusion presented in Part I of this paper, namely, that a clearly defined clinical syndrome could not be accurately

associated with the anatomic lesion of inter- capillary glomerulosclerosis, the clinical features of a series of 100 diabetic patients with proven

DlABETlCS WITHOUT lCGS

DIABETICS WITH ICGS

FIG. 1. Sex distribution.

intercapillary glomerulosclerosis were compared with a group of 176 diabetics without inter- capillary glomerulosclerosis. The clinical fea- tures compared included age, sex, duration of diabetes, severity of diabetes, hypertension, edema, albuminuria, azotemia and cardiac failure. The anatomic causes of death of this series of patients with intercapillary glomerulo- sclerosis were compared with a control group

Jl’ashin,gton, D.C.

of diabetic patients. It was reasoned that in a large series of patients with diabetes those having intercapillary glomerulosclerosis might as a group demonstrate certain clinical features having some differential worth. In the indi- vidual patient our experience has indicated that the antemortem diagnosis is inaccurate.

Sex and Age. Figure 1 shows no essential difference in sex distribution between those in- dividuals with intercapillary glomerulosclerosis and those without the lesion; 60.8 per cent of the diabetic patients without intercapillary glomerulosclerosis were females. It appears that intercapillary glomerulosclerosis is some- what more common in women. This obscrva- tion is in keeping with the well known greater frequency of diabetes in women beyond middle age.

The average age of the patients with intcr- capillary glomerulosclerosis is slightly higher than that of diabetics without intercapillar\ glomerulosclerosis. This difference is probably of no significance. (Table I.) In this series, which does not include child diabetics, inter- capillary glomerulosclerosis is rare under fifty years of age, is most common between the ages of fifty to seventy-nine and may occur after eighty. This age distribution agrees with the findings of most other workers. Mann, Gardnrr and Root2 however, hold that the syndrome is not found frequently in patients over forty y-ears of age. This discrepancy may well be a reflection that the latter authors are reporting from a specialized service and dealing with a large number of younger diabetics. It is perhaps significant that their seven cases autopsied had had diabetes for an average of nineteen years

* From the First, Third, Fifth and Sixth Medical Services, Boston City Hospital, Department of Medicine, Tufts College Medical School and the Mallory Institute of Pathology, Boston City Hospital, Boston, Mass.

692 AMERICAN JOURNAL OF MEDICINE

Intercapillary Glomerulosclerosis, II--Rogers et al. 693

capillary glomerulosclerosis with increasing duration of diabetes. When only 14 per cent of patients with diabetes of less than four years’ duration show intercapillary glomerulosclerosis, the incidence rises to 64 per cent in diabetics of

TABLE II

FREQIJENCY OF INTERCAPILLARY GLOMER”LOsCLEROsIs

AT POSTMORTEM EXAMINATION OF ROUTINE As WELL

As DIABETIC CASES

prior to death, suggesting that the diabetic age rather than the chronologic age is the important factor.

Frequency. The data concerning the fre- quency of intercapillary glomerulosclerosis from the Mallory Institute of Pathology are given in

TABLE I

AGE

I

Jumber

with Inter- capil-

lary Gl0-

nerulo- rlerosis

Diabetics without Diabetics with

Intercapillary Intercapillary

Glomerulosclerosis Glomerulosclerosis

Yc Dia- betics with

Inter- capil- lary Gl0-

merulo- sclerosis

.4gc

Group NO Per cent No.

O-9

10-19

20-29

30-39

40-49

50-59

60-69

70-79

80.-89

.6

.6

2.3

5.6

13.1

21.5

26.7

25

4.5

0

4

10

23

38

47

44

8

0 0

26

33

28

6

Total 176 1 100 , 100

Average age 59.9 64.1

Au- topsies

on Dia-

betics

No. 01 Au-

topsies Year

1934 1935 1736 1937 1938 1939 1940 1941 1942 1943 1944 1945 1946

‘L‘oral

Per cent

730 704 714 784 708 856

1063 869 766 686 591 618 735

R 4

12 4 9 6

11 6

1 68 51

1 27 70

.x4 69

I .96 1 02 1 .18

.95 6s

I 2R

’ 5,” 7

26

33

28

6

I 19 32 47 411 44 I9 19 26 24

36 14 I ::

15 7

2’1 1 34 I2 12

37 31

6 20 1 ‘I

__~_

23 ’ 21

l- 9824

I l1O2 100 287 ! ?6Yb

from ten to fourteen years’ duration. The apparent fall of incidence of intercapillary glomerulosclerosis in diabetes of fifteen to twenty years’ duration may be explained on the basis of increasing mortality in this group.

Severity of Diabetes. It is admittedly difficult and inaccurate to attempt to classify diabetes on the basis of insulin requirement alone. How- ever, in the absence of more reliable methods diabetes was considered to be mild when the insulin requirement was from 0 to 20 units, moderate from 20 to 40 units and severe when the requirement was 40 units or more. Applying these criteria to the diabetics with and without intercapillary glomerulosclerosis no significant difference was demonstrated in the distribution of degree of severity of diabetes between the two groups. (Fig. 3.) The majority of diabetics both with and without intercapillary glomerulo- sclerosis were using less than 20 units of insulin daily. One observation that is of considerable interest is an apparent significant discrepancy between the blood sugar levels and glycosuria. Forty-five or nearly half of the patients with intercapillary glomerulosclerosis showed mini-

Table II and include figures from each year from 1934 through 1946 as well as the grand total for this thirteen-year period. Intercapillary glomer- ulosclerosis was found from four to fifteen times each year and 100 times in 9,824 autopsies. The yearly percentage of diabetics demonstrating intercapillary glomerulosclerosis at postmortem examination varied from 15 to 39 per cent and averaged twenty-six per cent for the thirteen- year period. The consistency of these findings from year to year and the large size of this series indicate that the results are significant. In other words intercapillary glomerulosclerosis is found in about 1 per cent of routine autopsies and in about 26 per cent of autopsies on dia- betics. These percentages stress the importance of the subject.

Duration of Diabetes. Intercapillary glomer- ulosclerosis has been shown by previous workers usually to be associated with diabetes of long-standing and it is generally considered that with increasing diabetic years the incidence of intercapillary glomerulosclerosis rises. Figure 2 demonstrates the increasing incidence of inter-

JUNE, 1952

694 Intcrcapillary Glomerulosclerosis, II----Kuge~s et al.

ma1 amounts of glycosuria, yet at the same Hypertension. Figure 4 demonstrates a signifi- time the blood sugar in these forty-five patients cant increase in the incidence of hypertension ranged from normal to over 500 mg. per 100 cc. in diabetics with intercapillary glomerulo- In twenty-eight instances the blood sugar was sclerosis. Hypertension was divided into three 200 rng. or over at the time glycosuria was grades of severity as follows: minimal when the minimal. It is not uncommon in elderly dia- systolic pressure ranged from 140 to 170 mm.

60

r-l

m No. witl, KGS

tn 50 INo. wifhout KGS

c

70

0 None 60 m Minimal

r EBJ Moderate 2 m Severe 6 50

p4

DURATION of DIABETES FIG. 2. Reiationship of intercapillary giomerulosis to duration of diabetes.

FIG. 3. Severity of diabetes.

betics to find a high blood sugar without as much glycosuria as might be observed in a younger patient with diabetes.3 The mechanism in diabetics without renaI disease has been shown to bc an increased tubular resorptive capacity.4 In diabetics with renal disease the glomerular filtration rate is lowered and this has been shown to hold in intercapillary glomeruiosclerosis by Corcoran, Taylor and Page.5 There is insufficient information in the cases in this series to determine whether or not elevated blood sugar with minimal glycosuria is of significance in aiding the clinical diagnosis of intercapilIary glomeruloscIerosis.

DIABETICS DIABETICS WITHOUT ICGS WITH ICGS

FIG. 4. Hypertension.

and the diastolic was 90 mm.; moderate when the systolic pressure ranged from 140 to 190 mm. and the diastolic 90 to 115 mm.; and marked when the systolic pressure was 190 or higher and the diastolic 115 or higher. Sixty-four per cent of the diabetic patients without intercapillary glomerulosclerosis were normotensive whereas only 31 per cent of those with intercapillary glomerulosclerosis had normal pressures. Con- versely, the incidence of hypertension in inter- capillary glomerulosclerosis was 69 per cent, nearly twice the 36 per cent incidence of hypcr- tension in those with diabetes alone. This inci- dence of hypertension compares with that noted by other authors, yet in our expericncc the presence of hypertension in a diabetic was of little aid in arriving at a correct clinical diagnosis.

Albuminuria. Eighteen per cent of our dia- betics without intercapillary glomerulosclerosis showed 3 or 4 plus albuminuria in contrast to 55 per cent of diabetics with intercapillar) glomerulosclerosis. (Fig. 5.) Alhuminuria was absent in only 3 per cent of those with inter- capillary glomerulosclerosis whereas nearly 25 per cent of the diabetics showed no albumin in the urine. The difference in the figures is such to suggest that albuminuria is a significant

AMERICAN JOURNAL OF MEDICINE

Intercapillary Glomerulosclerosis, II-Rogers et al. 695

manifestation of inlercapillary glomerulosclero- sis and this has been the clinical expericncc of

most 0 bservers. AZotemia. There is a trend for azotemia to

be greater in diabetics with intercapillary glomerulosclerosis, yet this difference is not

FIG. 5. Albuminuria.

50

E g 40 OQ g 30

‘z 20

E L IO

0 Normoi

0 DIABETICS DIABETICS

WITHOUT ICGS WITH ICGS

FIG. 6. Azotemia.

striking. Other authors have reported similar observations.6,7 (Fig. 6.) The non-protein nitro- gen levels of the blood were below 40 in 41 per cent of the diabetic patients and in 26 per cent of those with intercapillary glomerulosclerosis. Eight per cent of the diabetics had non-protein nitrogen levels over 100 and 22 per cent of those with intercapillary glomerulosclerosis were in this range.

Edema and Cardiac Failure. Edema, dependent or generalized, was noted in 60 per cent of the diabetics with intercapillary glomerulosclerosis and in 24 per cent of those without intercapillary glomerulosclerosis. (Fig. 7.) In the majority of instances the edema was of dependent type and probably related to cardiac failure rather than to renal failure. This is borne out by Figure 8 which shows the difference in the incidence of

JUNE, 1952

cardiac failure which was prcscnt in nearly

GO I)cr ccnl of Lhr tlial)ctics with inlcrcapillar).

glomerulosclcrosis whcrcas only 36 per cent of those without intercapillary glomerulosclerosis were in congestive failure. Hendersoq6 Rifkin ct al.* and Lefebrr and Dxhard” have also

Frc.. 7. Rdema.

FIG. 8. Cardiac failure.

noted that in the majority of instances the edema appeared to be related to cardiac failure.

CAUSES OF DEATH

It is of interest to compare the causes of death, from the anatomic viewpoint, of the 100 patients with intercapillary glomerulosclerosis with a previously reported group of random diabetics.‘O Although the numbers of cases cited permit of

696 Intercapillary Glomerulosclerosis, II-Rogers et al.

110 grit stiitislic~;~l significanccs, certain rliffibr- ences merit attention. (TatlIe III.)

Cardiac decompensation appears somewhat more frequently in the intercapillary glomerulo- sclerotic group of patients, being present in 19 per cent as compared with the control group

/

I Diabetics Diabetics I wlthout with

Inter- Inter- capillary capillary

Glomerulo- Glomerulo- sclerosis sclerosis

’ No. cFt No.

Coma. I Cardiac decompensation .1 Myocardial infarction. .I Cerebral accident. Pulmonary infections includ-

22 35 31 15

l- 7.2 4

11.4 19 10.0 ’ 12

4.9 12

ing tuberculosis. 73

7 19 12 12

17 23.8 12 .I Infections other than pulmon-

ary., _. ( 42 ( 13.7 ) 16 1 16

Per cent

Renal decompensation with 1 uremia 25

Other causes including un- known. 44

incidence of 11.4 per cent. This difference is almost entirely due to an increased frequent) of hypertensive heart disease in patients with intercapillary glomerulosclerosis, a finding that agrees well with the clinical significance of hyper- tension in this group. Although myocardial infarction appeared to be equally prevalent in the control and intercapillary glomerulo- sclerotic group, cerebral accidents were dis- tinctly more common in the patients with inter- capillary glomerulosclerosis. This finding may perhaps reflect the result of both the vascular degenerative disease common to both the heart and brain with the additional factor of intra- cerebral hemorrhage secondary to hypertension causing the increased frequency of cerebral acci- dent in the experimental group of cases. Uremia as a cause of death is considerably more common in patients with intercapillary glomerulosclerosis (15 per cent) than in the diabetic population at large (8.2 per cent). Although seemingly at variance with the clinical evaluation that azo- temia is not significantly more prominent in a

group of patients with intercapillary glomerulo- sclerosis, this observation may only indicate that although it is not more common once present it is of grave significance, leading usually to progressive renal failure and death. This sequence of events is not at all unfamiliar to the clinician dealing with advanced diabetes. ‘The incidence of uremia in this series of 15 per cent is somewhat lower than that reported I)) Kifkin et aL8 (nine of twenty-two patients). This difference is very likely due to the fact that their cases were all instances of clinically recog- nizable intercapillary glomerulosclerosis and were in all probability patients with well ad- vanced disease. The variations in the incidence of infections permit of no ready explanation save that since the patient with intercapillary glo- merulosclerosis suffers as the result of the in- creased hazards of hypertension and renal involvement he dies less frequently of other causes, notably pulmonary infections.

CLINICAL COMPARISON OF FOUR GRADES OF

INTERCAPILLARY GLOMERULOSCLEROSIS

The cases with intercapillary glomerulo- sclerosis were further classified according to the severity of pathologic renal changes in groups I to IV, the latter being the most severely involved. The four categories of severity of involvement of intercapillary glomerulosclerosis could then be compared with each other with respect to the clinical features previously cited. The size of the groups was too small to permit comparisons of statistical significance but cer- tain trends became apparent and seem worthy of comment. When the four classes of intercapil- lary glomerulosclerosis were compared as to the duration of diabetes, no significant differ- ences between the groups were noted. The trend, however, was for those with grade IV

lesions to have been diabetic for longer periods of time than those with grade I intercapillar) glomerulosclerosis. This trend can best be illus- trated by observing the severity of the anatomic lesion in patients having diabetes for less than fifteen years and in those with diabetes of over fifteen years’ duration. In the former group most patients had 1 to 2 plus intercapillary glomerulo- sclerosis with only eight of forty-nine patients showing the severe 4 plus lesion. In the latter group, that is the long term diabetics with a known history of over fifteen years’ duration, most patients had 3 to 4 plus lesions, ten of eighteen having the most severe form of involve-

Intercapillary Glomerulosclerosis, II-Rogers et al. 697 ment. This distribution leaves little doubt but that there is a definite relationship between duration of diabetes and severity of intercapil- lary glomerulosclerosis.

Severe hypertension was present in signifi- cantly greater incidence in grade IV cases than grade I. Fifty-five per cent of those with grade IV intercapillary glomerulosclerosis had severe hypertension in contrast to 9 per cent of those with grade I lesions. The severity of albuminuria correlated clearly with the degree of intercapil- lary glomerulosclerosis. Twenty-four per cent of those with grade I had 3 or 4 plus albuminuria whereas 76 per cent of those with grade IV inter- capillary glomerulosclerosis had this amount of albumin in the urine. There was a tendency for azotemia to be more severe as the lesion of intercapillary glomerulosclerosis increased. It was also noted that in those with grade I lesions edema was less frequent than in those with grade IV lesions, the increase in incidence being from 44 to 84 per cent. Although cardiac failure was a prominent feature of intercapillary glo- merulosclerosis when taken as a group, there was no clear correlation between the frequency of cardiac failure and the severity of intercapil- lary glomerulosclerosis.

COMMENTS

The results of a comparison of the clinical features of a group of diabetics with intercapil- lary glomerulosclerosis and a control group of diabetics without intercapillary glomerulosclero- sis indicate differences suggesting that in the presence of this glomerular lesion certain clinical features are found in increased frequency.

Intercapillary glomerulosclerosis is more apt to occur in women but this is a reflection of the known increased incidence of diabetes in women over middle age. About one of every four dia- betics will show intercapillary glomerulosclerosis at autopsy. It is of interest that in the years under study, 1934 to 1946, no increase in frequency was noted. Since intercapillary glomerulo- sclerosis is correlated with the duration of diabetes, an increased incidence may be antici- pated in the future. The average age of a group of diabetics with intercapillary glomerulo- sclerosis is slightly greater than a similar group without intercapillary glomerulosclerosis. In the series reported the lesion was rare in patients under fifty years of age and was most common in those between the ages of fifty and seventy- nine, and is correlated with the duration of

JUNE, 1952

diabetes, being significantly increased in inci- dence in those patients with diabetes of over ten years’ duration.

The frequency of occurrence of intercapillary glomerulosclerosis does not seem to be corre- lated with the severity of the diabetes. Although it is true that most patients with intercapillar) glomerulosclerosis have mild diabetes, in all probability this is due to the fact that mild diabetes, as defined by insulin requirement, is more common than moderate or severe diabetes. In this series a discrepancy between the degree of elevation of blood sugar and the amount found in the urine was noted. Nearly half of the patients with intercapillary glomerulosclerosis had minimal amounts of sugar in the urine when their blood sugars were at such levels that one would expect large amounts of glucose to be present in the urine. Whether this phenome- non is more frequent in diabetics with inter- capillary glomerulosclerosis than in those with- out was not determined. This observation may, however, have some importance in shedding light on cases of intercapillary glomerulosclerosis found in non-diabetic patients since it is possible that the diabetes may have been missed by virtue of the absence of urinary sugar and consequent failure to do blood sugar determina- tions. In three instances recently observed by one of the authors (S. L. R.) intercapillary glomerulosclerosis was found at postmortem examination in the absence of known diabetes. On investigating the histories and previous hospital records evidence of diabetes in the past was brought to light. It is therefore not un- reasonable to postulate that in some of the reported instances of intercapillary glomerulo- sclerosis found in the absence of diabetes the clin- ical diagnosis of diabetes may have been over- looked due to transient or minimal glycosuria.

In diabetics with intercapillary glomerulo- sclerosis the incidence of hypertension was significantly increased. However, the most striking and most reliable criterion in the clinical estimation of intercapillary glomerulo- sclerosis appears to be the demonstration of 3 or 4 plus albuminuria. In general, when 3 to 4 plus albuminuria is found in a diabetic, inter- capillary glomerulosclerosis is apt to be present. With less than this amount of albuminuria the diagnosis becomes increasingly doubtful. Elec- trophoretic analysis of plasma and urinary proteins may prove to be of diagnostic aid.”

The degree of azotemia in intercapillary

Intercapillary Glomerulosclerosis, II-Rogers et al.

glomerulosclerosis was slightly greater. Edema and cardiac failure were likewise more frequent in this group and the edema was most frequently that which one would associate with cardiac failure.

The result of a comparison between a group

TABLE IV

Grade of No of No. with Classic Intercapillary ’

Cases Triad of Per cent

Glomerulosclerosis Symptoms

_~ _____~ ~._ ~

1 26 2 8 2 19 2 10 3 27 7 25 4 28 14 50

of diabetics with intercapillary glomerulo- sclerosis and a group without intercapillary glomerulosclerosis indicates that in diabetics with the renal lesion an increased incidence of severe hypertension, albuminuria, edema and cardiac failure can be demonstrated. The in- creased incidence of these clinical characteristics is of such a degree as to suggest that the etiologic factor related to these clinical stigmas is inter- capillary glomerulosclerosis. However, hyper- tension, edema, cardiac failure and albu- minuria occur with sufficient frequency in diabetes to make these findings of limited diagnostic value in distinguishing intercapil- lary glomerulosclerosis.

Of more importance than the incidence of the different individual clinical features is the frequency with which the edema, hypertension and albuminuria occur together in any one pa- tient producing the so-called symptom complex. Considering this classic symptom complex as comprising 3 to 4 plus albuminuria and some degree of hypertension and edema, analysis of the patients with typical glomerular lesions revealed the presence of this diagnostic triad in twenty-five of one hundred cases (significantly the control diabetics presented five instances of the “classic syndrome”).

A breakdown of these one hundred cases into the four grades of severity of the glomerular lesion demonstrated the presence of the so-called classic symptom complex in 8 per cent of the grade I cases, 10 per cent of the grade II cases, 25 per cent of the grade III and 50 per cent of the grade IV cases. (Table IV.) Although these correlations are of considerable interest, the

reverse relationship may be more important, namely, that the classic clinical features were not present in approximately 75 per cent of the proved cases of intercapillary glomerulosclerosis and were absent in over 50 per cent of the patients with more severe lesions. It is of equal significance that five of the control diabetics presented the “classic syndrome.” It is apparent that in any given instance the presence of the classic features does not necessarily indicate with certainty the presence of the glomerular lesion. It is equally clear that the anatomic lesion is often not associated with the diagnostic clinical triad of findings.

SUMMARY AND CONCLUSIONS

One hundred diabetics with proven inter- capillary glomerulosclerosis were compared clinically with 176 diabetics not having this glomerular lesion. It was thus hoped that certain clinical differences might be revealed that would be of help in establishing the diagnosis of intercapillary glomerulosclerosis in any individual patient. The following points of interest were found:

With increasing duration of the diabetes there was a definite increase in the incidence of inter- capillary glomerulosclerosis. Whereas only 14 per cent of the patients with diabetes of less than four years’ duration had this renal lesion, the incidence rose to 64 per cent in patients with diabetes of ten to fourteen years’ duration. No significant difference was found in the severity of the diabetes between the group of patients with intercapillary glomerulosclerosis and the control group. In passing it was noted that the patients with this specific glomerular lesion tended to show less glycosuria than was expected from the associated levels of hyper- glycemia. The significance of this observation is discussed. Hypertension, albuminuria, azotemia and cardiac failure all were more frequent and more severe in the patients with intercapillary glomerulosclerosis. The causes of death of this group of 100 patients were likewise compared with those of a control group of diabetics. It became evident that uremia, cardiac decom- pensation and cerebrovascular accidents were significantly more prevalent among these pa- tients than in the control group.

When the patients with intercapillary glo- merulosclerosis were divided into four categories on the basis of the severity of involvement of the kidneys, certain differences were observed.

AMERICAN Jo”RNAL OF MEDICINE

Intercapillary Glomerulosclerosis, II -Rogers et al. 699 Patients with the most extensive grade IV lesion tended to have more severe edema, hyper- tension, albuminuria and cardiac failure than the less severely involved grade I group. More- over, the grade IV patients were, on the whole, diabetics of longer duration than the other patients.

sclerosis in diabrtcs mellitns. .lr/r. ,7. .Zlrd., 7: 3, 1943.

Perhaps of greatest importance is the problem of how often these various features occur to- gether in any individual patient to produce a clinically recognizable syndrome. This occurred in twenty-five of the one hundred patients with intercapillary glomerulosclerosis. It also oc- curred in five of the control group of diabetics, The conclusion was clear: Many if not most cases of intercapillary glomerulosclerosis do not present the classic triad of clinical findings; moreover, the classic pattern may occasionally be found in diabetic patients not having inter- capillary glomerulosclerosis. As was said before, the entity is more often missed clinically than misdiagnosed.

REFERENCES

1. ROGERS, J. and ROBBINS, S. L. Part I. 2. MANN, G. V., GARDNER, C. and ROOT, H. F. Clin-

ical manifestations of intercapillary glomerulo-

3. MIRSKY, .\. and NBI.SON, N. Signihcancc of glyco- suria. Arci2. Int. Med.. 71 : 827. 1943.

4. FARBER, S. J., BERG& E. Y.’ and EARLE, D. P. Effect of diabetes and insulin on the maximum capacity of the renal tubules to reabsorb glucose. J. Clin. Investigation, 30: 125, 1951.

5. CORCORAN, A. C., TAYLOR, R. D. and PAGE, I. H. Functional patterns in renal disease. .4n12. ht. Med., 28: 560, 1948.

6. HENDERSON, L. L., SPRAGUE, R. G. and WAGENF.R, H. P. Intercapillary glomerulosclerosis. Am. 3. Med., 3: 131, 1947.

7. LAIPPLY, F. C., EITZEN, 0. and DUTRA, F. R. Inter- capillary glomerulosclerosis. Arch. Znt. Med., 74: 354, 1944.

8. RIFKIN, H., PARKER, J. G., POLIN, E. B., BERKMAN, J. I. and SPIRO, D. Diabetic glomerulosclerosis. Medicine, 27: 429, 1948.

9. LEFEBER, E. J. and DECHARD, G. M., JR. Nephrotic edema in diabetes mellitus. Texas State J’. .tlpd.. 41: 506, 1946.

10. ROBBINS, S. L. and TUCKER, A. W., JR. l’he cause of death in diabetes. “vevew England 3. Med., 231: 865, 1944.

11. RIFKIN, H. and PETERMANN, M. L. Electrophoretic analysis of plasma and urinary proteins in dia- betic glomerulosclerosis (Kimmelstiel-Wilson syn- drome). Abstract of paper presented at Am. l:ed. for Clin. Research Meeting, May 1951.

JUNE, 1952