BLOOD AND BONE MARROW STUDIES IN RENAL DISEASE*
IRWIN R. CALLEN, M.D., AND LOUIS R. LIMARZI/M.D.
From the Department of Internal Medicine of the University of Illinois College of
Medicine, and the Research and Educational Hospitals, Chicago, Illinois
This study is based on a review of the literature pertaining to the peripheral
blood and bone marrow in renal diseases, and an analysis of our findings in 102
patients with renal disease.
The association of anemia with renal diseases has long been recognized,30' 3 2 ' 6 6 ' 7 9 and various causes for the anemia have been suggested. A
hemolytic process has been postulated by sortie, 30 ' 32, 6S but denied by
others. 8 ' 1 4 ' 3 1 , 6 4 Other factors which have been considered include the inhibitory
effect of urinary poisons,14 and protein deficiency related to proteinuria or dietary
inadequacy. 4 ' 27 Protein deficiency as a cause is not accepted by certain authors; 10
and it has been pointed out that in pure lipoid nephrosis, in which proteinuria
is prominent, anemia is rare unless renal insufficiency supervenes6 •80 as a complication. Furthermore, the diets of patients with renal diseases are not usually
deficient in protein"unless the patients are too ill to eat. 6 ' 2 8
Brown and Roth 10 showed that there is no relationship between hematuria
and anemiar/They considered defective blood formation to be an important factor
in the production of anemia. It was felt that an unknown toxic substance was
responsible for the deficient red cell production. Ceconi,14 as well as others 27 ' 61
considered toxic injury to the bone marrow as the basis for the anemia. Whitby
1 and Britton 78 stated that when there is much edema in nephritis, the anemia
is often due to a disturbance of water balance. Nylander 61 discussed selective
damage to the bone marrow involving erythropoiesis, while leaving myelopoiesis
intact.
Widal, Abrami and Brule79 examined one case and found a very active bone
marrow they described as aplastic. Others 6 ' M also found the bone marrow replaced by fat tissue or revealing no evidence of increased marrow activity. These
studies have been criticized67 • 68 because of the autolysis that occurs to bone marrow tissue obtained at autopsy.
Nordenson60 used Arinkin's method 3 of staining the bone marrow. An "incipient aplasia" of the erythroid tissue with a myeioid-erythroid ratio of 8 to" 1
was described. Similar findings were described 15,3S except for the presence of a
normal cellular or hypercellular bone marrow. Contradictory results were reported by Giacchero and Belletti24 who found an increased number of normoblasts. Isaacs33 mentioned that the bone marrow at first suggested invasion by
lymphoblastoma cells. The peripheral blood demonstrated an alteration in the
red cell diameter prior to the onset of gross kidney dysfunction.
* This study was made possible by grants from the Hematology Research Foundation
and from Armour and Company, Chicago, Illinois.
Presented at the Twenty-Seventh Annual Meeting of the American Society of Clinical
Pathologists in Chicago, October 13, 1948.
Received for publication, May 24, 1949.
3
4
CALLEN AND LIMARZI
t " An increase in polychromatic and basophilic normoblasts with, however, a
' reduction of mature erythroblasts was found in 38 patients with "nephrogenic
^anemia". 2 Dameshek17 and others 8 3 , 6 2 , 1 8 suggested the bone marrow revealed a
Vdistinct hypoplasia of erythropoietic tissue. The etiology62 of this anemia was
tsaid to bear a direct relationship to the degree~of nitrogen retention, whatever
Jthe cause. This results in a depressed activity of the hemopoietic tissues.62
Others40 •71 noted decreased cellularity with an increased relative number of
normoblasts. Reduced erythropoietic tissue without hyperactivity of either
erythroid or myeloid cells has been described.53' 67,18 Vogel, Erf and Rosenthal77
and Falzoi20 noted a shift to the right in myelopoiesis of the bone marrow.
Gingold, Comsa and Roman-Crivat 25 found the bone marrow to be unable to
retain normoblasts and terminally to become aregenerative. As the kidney lesions
became progressively severe, erythropoietic aplasia became more pronounced.19 • 69
\Fieschi 21 and Biichmann and Stodtmeister 11 observed cases of chronic nephritis
.with uremia in which the bone marrow revealed hyperplasia of the granulocytic
(cells and marked reduction in the erythroblastic elements. Stem cell involvement
in the bone marrow was thought to be the cause.
\ Leitner,41 in 11 patients with nephrogenic anemia, found a decrease in normoblasts in the sternal marrow in all but three instances. The marrow findings in
Ithe latter cases were observed after improvement in the uremic state. In general,
there was an absence of the younger forms of the erythroblastic series and a decrease in the number of erythroid mitoses. In summary, Leitner states that the
fsternal marrow in nephrogenic anemia shows a hypoplasia and, occasionally,
| j m aplasia of erythropoiesis. The granulocytes were intact, aside from a slight
neutrophilic metamyelocyte and myelocyte shift to the left. The same was true
of the megakaryocyte series. In a few cases, eosinophils and plasma cells were
/ Jseen which might indicate an allergic reaction. With improvement in the kidney
^[lesion and decrease in nitrogen retention, the_anemia improved. This, according
to Leitner, indicates an aregenerative type of anemia and not an aplastic anemia.
In progressive chronic nephritis the sternal marrow shows progressive aplasia
of the erythroblastic picture. The response of the anemia to iron, liver and arsenic
is observed only after improvement of the kidney function. The sternal marrow,
therefore, permits the estimation of the tendency toward regeneration or aplasia.
i Rohr, 67 Kienle, 34 ' 3S Thaddea,74 and File,22 in their studies of chronic nephritis
[with anemia, found hypoplasia of the erythroblastic cells which may be due to a
fprimary toxin or a decrease of the primitive erythroblasts. Thaddea 74 and
Gottsegen26 noted that the neutrophilic metamyelocytes and mature granulocytes are always numerous, frequently with a hypersegmentation of the nucleus,
v whereas the lymphocytes are markedly decreased in the end-stage of uremia.
Because of the hypoplastic and aplastic character of the erythroblastic tissue,
there is no effect from treatment with iron and liver. Nephrogenic anemia
is considered to be a toxic aregenerative anemia in which the influence of the
toxic substance is either on formation or maturation of the erythroid tissue in
the bone marrow. Vaughan76 stated that the pathologic changes of hemopoietic
tissues in nephritis are not known in detail. But there is no evidence to suggest
(
BONE MARROW IN RENAL DISEASE
any great hyperplasia of erythropoietic tissue. Maggej^5 stated that anemia'
occurs regularly in cases of renal insufficiency and nitrogen retention, regardless!
of the nature of the renal lesion, and that the degree of anemia is usually propor-,
tional to the degree of impairment of excretory function of the kidney. Thisf
dyshemopoietic type of anemia is due to a deficient production of red blood
cells and not to excessive loss of red blood cells by hemorrhage or hemolysis. /
Alexeieff1 studied renal diseases in patients and experimental uremia in dogs.
He concluded that: fnj) Anemia of nephritic patients is a true anemia due to
intoxication of the bone marrow by nitrogenous products. The degree of this
anemia is found to correspond not to the azotemia of the blood but rather to
the duration of the disease. The study of the bone marrow reveals a feeble
regeneration of normoblastic type which characterizes anhemopoeitic anemias.
^2])The leukocytosis, which is observed in nepjiritic patients, just as in patients
poisoned by mercury bichloride, is due to a pronounced regeneration of the
myeloid tissue. (3) The number of blood platelets and of megakaryocytes in
the bone marrow do not show great modifications. Hemorrhagic symptoms
that are observed are not dependent on thrombopenia. (4) The bone marrow
cannot be considered as a depot of nonprotein nitrogenous products. (5) Fluctuations in the nonprotein nitrogen content of the blood and bone marrow are
roughly parallel.
Wintrobe81 drew attention to the similarity of the blood picture in the anerhias
of nephritis, aplasia of the marrow and the anemia which he found in various
inflammatory diseases. All were normocytic or microcj'tic but in none was there
a marked hypochromia.
Murphy, Grill and Moxon58 stated that in acute nephritis a red count below
3.5 millions per cu. mm. implies progressive breakdown of renal function.
MacArthur 54 noted that in chronic hemorrhagic nephritis there is often a severe
orthochromic normocytic anemia with a normal or slightly increased number
of reticulocytes and mild leukocytosis. The blood was not that of aplastic anemia.
Boyd9 stated that the anemia in glomerulonephritis seems to be due to interference with the building up of hemoglobin in the liver, rather than to lack of
formation of red cells in the bone marrow. An important factor is diminution or
absence of hydrochloric acid in the stomach which interferes with the proper
metabolism of ingested food and absorption of iron. Haden 29 took the viewpoint
that the anemia of kidney disease is due to a toxic action of retained metabolic!
products on the marrow. Fowler23 shared the opinion of others that the anemia!
of chronic nephritis is probably clue to a toxic depression of the bone marrow
as there are but slight evidences of blood regeneration.
Kugelmass39 noted that in children a normocytic anemia, proportional to the
severity of impaired kidney function, occurs only in chronic forms of the disease.
Bone marrow studies in chronic nephritis show a tendency for hematopoiesis
to be arrested in the erythroblastic stage; hence, the anemia is due to diminished
blood production. Castle and Minot,12 in discussing the anemia of chronic]
nitrogen retention, concluded that the anemia is due to diminished blood pro-,
duction since there are few signs of regeneration of the red blood cells. Theyi
6
CALLEN AND LIMARZI
, agreed with others that the anemia is due to depressed activity of the hemopoietic
tissues. The leukocytes are not always depressed and platelets usually are normal
tin number. With infection, the leukocytes show a shift toward immaturity of the
neutrophils. On the other hand, Schilling70 stated that there is no significant
alteration in uncomplicated cases of chronic nephritis. Sturgis72 accepted the
theory that the anemia results from a depressed hemopoietic activity of the
red blood cells, forming elements in the bone marrow which in some unknown
manner is secondary to severe impairment of renal function. Sturgis did not
favor the suggestion of Townsend, Massie and Lyons75 that the diminished
hydrochloric acid plays any major role in the production of the anemia, although
it may contribute to it.
MATERIALS AND METHODS
This study was made on 102 patients. Of_these 44 had azotemia and renal
disease other than glomerulonephritis. Patients with a nonprotein nitrogen above
40 nig. per 100 ml. blood, except for two with extra-renal uremia, were autoTABLE 1
DIAGNOSES IN 102 PATIENTS OF PRESENT STUDY
DIAGNOSIS
Azotemia
Chronic glomerulonephritis with azotemia..
Acute glomerulonephritis without azotemia
Hypertension
Miscellaneous kidney diseases
Extra-renal uremia
*?
NUMBER OF
PATIENTS
NUMBER OP
AUTOPSIES
44
22
6
20
8
2
102
21
5
0
0
1
0
27
matically included in this group. Twenty-one of the 44 with azotemia came to
autopsy. In addition there were 22 patients with chronic glomerulonephritis
five of whom were autopsied; six patients had acute glomerulonephritis, 20
essential hypertension, and eight miscellaneous kidney disorders. One patient of
the last group was autopsied (Table 1).
All the patients had a complete medical study, including history, physical
examination, complete blood count, urinalysis and Wassermann test. In most
instances special examinations included several kidney function determinations,
using urea clearance, phenosulphonphthalein test, and a modified urine concentration test. The blood chemical studies included tests of nonprotein nitrogen,
urea nitrogen, creatinine, sugar, carbon dioxide combining power, cholesterol
and proteins. In some instances x-ray examinations of the chest and kidneys
were made, the basal metabolic rate was determined, and analysis was made of
the gastric contents.
Complete hematologic studies were made in each case. These included a blood
count, photo-electric hemoglobin determination, hematocrit reading, sedimenta-
/r,
'
c
BONE MARROW IN RENAL DISEASE
7
tion rate (Wintrobe), reticulocyte count, platelet count and icterus index; and
determination of the mean corpuscular volume, hemoglobin and hemoglobin
concentration.
The bone marrow was studied in every patient. The method of sternal aspiration and preparations of marrow specimens with detailed description of the
apparatus and procedure has been described by Limarzi and associates,'12-45 • 40, M
and by Berman and Axelrod.7
RESULTS
Peripheral Blood Findings in Azotemia
The 44 patients with azotemia had an average nonprotein nitrogen value of
1_23 mg.; urea nitrogen, 86 mg.; uric acid, 7 mg.; and creatinine, 9.5 mg. (Table 2).
In 40 of these patients the erythrocyte counts were under 4.0 milli'on per cu.
mm., ranging from 1.2 to 3.9 millions per cu. mm.; the average was 2.9 millions
per cu. mm. The hemoglobin readings ranged from 3.25 to' 15.0' Gm. with an
average of 8.5 Gm. The hematocrit readings varied from 11 to 43 per cent with
an average reading of 26 per cent (Table 3). There was one patient with a normal
blood finding; this patient had a nonprotein nitrogen value of 57 mg. The mean
corpuscular volume ranged from 63 to 102 cubic microns and the average was
87.9 cubic microns. A normocytic normochromic anemia was observed in 34 of
the 44 patients with azotemia (81 per cent). Of the remaining 10 patients, two
showed a microcytic hypochromic anemia and__eight a macrocytic anemia; in
These patients the nonprotein nitrogen varied from 41 to 186 mg.
Further grouping of the 44 patients according to the level of nonprotein
nitrogen revealed some correlation of this value with the severity of the a n e m ^ .
I t will be noted in Table 4 that, as the nonprotein nitrogen increased, there
was a gradual decrease in the respective values of the hemoglobin, erythrocyte
count and hematocrit determination. For example, in 10 patients having nonprotein nitrogen levels from 40 to 49 mg., the average values were as follows:
hemoglobin, 10.5 Gm.; erythrocyte count, 3.3 millions per cu. mm.; and hematocrit reading, 30 per cent. On the other hand, in nine patients with nonprotein
nitrogen levels ranging from 200 to 340 mg., the average value of hemoglobin
was 6.6 Gm., erythrocyte count, 2.3 millions per cu. mm., and hematocrit reading, 20 per cent. There was no change in the mean corpuscular volume, mean
corpuscular hemoglobin or mean corpuscular hemoglobin concentration. There
was a .rather constant normocytic anemia, irrespective of the level of the nonprotein nitrogen in the blood.
The leukocyte count was slightly elevated, averaging 10,700 per cu. mm.
],n uncomplicated nephritis.with anemia,.tliere is little or no shift in.theJeuk.Qfiyies.
but with an infection with leukocytosis there may be a shift to the left. In general
there is a tendency for persistent polymorphonuclear leukocytosis as the nonprotein nitrogen increases.
The sedimentation rate in the 44 patients with azotemia averaged 57 mm.
in one hour, uncorrected, and 20 mm. in one hour, corrected. There was no corre-
TABLE 2
K i d n e y Function T e s t s
Urea clearance, cc./mm
Phenolsulphonphthalein, 15 min
Concentration (specific gravity)
N u m b e r of P a t i e n t s
Blood Chemical T e s t s
Values per 100 ml.
Nonprotein nitrogen, m g
Urea nitrogen, mg
Uric acid, mg
Creatinine, m g
Carbon dioxide
combining power
Sodium chloride, mg
Glucose, mg
Albumin, Gm
Globulin, Gm
Urinalysis
Specific gravity
Albumin
Microscopic
/"15.4 ^
5%
V
1-015'
26.1
14%
1.023
Various casts, red
cells
Various casts, red
cells
1.014
54.0
476.0
93.0
3.2
2.2
2+ to 3+
1.011
34.0
530.0
114.0
3.5
1.9
35.0
18%
1.023
1.015
2 + to 3 +
M a n y red cells
94.0
3.7
1.9
51.0
45.0
18%
1.019
1.018
52.5
514.0
85.0
4.2
3.0
32.0
12.1
3.1
1.3
32.0
16.1
4.2 '.
2.0
123.0
86.0
7.0
9.5
31.0
16.0
4.1
1.6
20
ESSENTIAL HYPERTENSIVE
22
:
44
3+
(
DISEASES
ACUTE GLOMERULONEPHRITIS
( N P N BELOW 40)
OF MISCELLANEOUS
CHRONIC GLOMERULONEPHRITIS
( N P N BELOW 40)
AND G R O U P
AZOTEMIA
(NP.M ABOVE 40)
HYPERTENSION
28%
1.018
3 +
a n d white
54.0
449.0
77.0
3.4
2.75
32.9
13.0
2.3
2.6
MISCELLANEOUS
DISEASES
ESSENTIAL
Red
cells
B L O O D C H E M I C A L V A L U E S , U R I N A L Y S I S AND K I D N E Y F U N C T I O N I N A Z O T E M I A , A C U T E AND C H R O N I C G L O M E R U L O N E P H R I T I S ,
/
TABLE 3
PERIPHERAL BLOOD F I N D I N G S IN A Z O T E M I A , A C U T E AND C H R O N I C G L O M E R U L O N E P H R I T I S ,
E S S E N T I A L H Y P E R T E N S I O N AND M I S C E L L A N E O U S D I S E A S E S *
CHRONIC
ACUTE
GLOMERU- GLOMERU- ESSENTIAL
LONEPHRI- LONEPHRI- HYPERTENABOVE 4 0 ) TIS ( N P N TIS ( N P N
SIVE
BELOW 4 0 ) BELOW 4 0 )
AZOTEMIA
(NPN
Number of Patients
Examinations Made
Hemoglobin (Cm.)
E r y t h r o c y t e s (millions)
Leukocytes (thousands)
Hematocrit (erythrocytes per cent)
Hematocrit (buffy, per cent)
Sedimentation rate (uncorr.) mm. in 1 h r . .
Sedimentation rate (corr.) mm. in 1 h r
Mean corpuscular volume ( C M . )
Mean corpuscular hemoglobin (jip).
Mean corpuscular hemoglobin concentration
(per cent)
Reticulocytes (per cent)
Icterus index (units)
Differential smear
Stab neutrophils
Segmented neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
MISCELLANEOUS
DISEASE
44
22
S.5
2.9
10.7
26.0
0.S
57.0
20.0
S7.9
30.3
12.7
4.3
10.S
3S.7
0.7
31.0
22.0
SS.7
29.0
13.9
4.412.6
40.0
1.0
29.0
23.0
SS.6
30.5
13.4
4.7
S.6
42.5
0.7
22.0
20.0
90.0
28.5
13.7
4.52
10.06
42.9
0.75
33.3
25.5
94.2
30.0
32.4
0.7
5.0
32.3
0.8
6.4
34.2
0.53
6.0
31.0
0.5
6.6
31.8
0.76
6.8
8.0
69.0
14.0
6.0
2.1
0.9
7.2
59.0
24.0
6.S
2.3
0.7
9.3
53.2
25.S
9.4
2.3
0.0
S.l
5S.0
25.0
6.3
2.3
0.3
4.9
64.5
22.4
5.5
2.5
0.2
6
20
* The platelet count was normal or increased in all instances studied.
TABLE 4
CORRELATION OF NONPROTEIN
N I T R O G E N AND S E L E C T E D B L O O D
F I N D I N G S IN C H R O N I C
G L O M E R U L O N E P H R I T I S WITH AZOTEMIA
VALUE OF NONPROTEIN NITROGEN (MG.)
40-49
Number of P a t i e n t s
Examinations Made
Hemoglobin (Gm.)
E r y t h r o c y t e s (millions)
Leukocytes (thousands)
Hematocrit, (erythrocytes per c e n t ) . . .
Mean corpuscular volume ( C M . ) . . . .
Mean corpuscular hemoglobin (fifi) . . .
Mean corpuscular hemoglobin concentration (per cent)
Stab neutrophils* (per cent)
Segmented neutrophils* (per cent) . . .
Nonprotein nitrogen (mg.) (average)..
Urea nitrogen (mg.) (average)
Uric acid (mg.) (average)
Creatinine (mg.) (average)
10
50-59
70-99
6
5
10.5
3.3
10.0
30.0
91.2
32.1
10.7
3.68
8.S
32.0
S7.3
29.0
9.7
3.40
11.7
31.0
S9.0
2S.0
35.3
6.1
65.5
44
24
2.9
2.6
33.0
S.2
62.2
54
2S
4.9
3.4
31.0
6.6
68.4
SO
46
7.0
5.1
100-149
10
6.4
2.32
10.0
19. S
87.9
28.0
31.0
4.3
75.1
127
99
7.3
9.2
150-199
4
6.5
2.34
15.7
21.5
S9.7
26.7
29.0
0.66
68.6
173
112
S.2
13.4
200-340
9
6.0
2.30
11.1
20.2
S7.9
2S.9
32.6
3.2
77.3
252
165
10.2
1S.S
* N o t e : For t h e sake of brevity only t h e s t a b and segmented neutrophils have been
included in the table.
9
10
CALLEN AND LIMARZI
lation between the corrected sedimentation rate, the severity of the anemia and
the level of the nonprotein nitrogen of the blood. The icterus index and in most
j instances the reticulocyte count were within normal limits.
Peripheral Blood Findings in Chronic Glomerulonephritis
/
/
.
,.;
1
'
'
S
!'
.'
There were 22 patients having the clinical and laboratory requirements for
the diagnosis of chronic glomerulonephritis. The average urea clearance was
abnormal, 26.1 ml. of urea being cleared per minute, in contrast to the average
clearance in the group with azotemia with a value of only 15.4 ml. per minute.
In most instances, the urinalysis revealed 2 to 3 plus albumin, many white and
red blood cells and hyaline and granular casts. The average blood chemical
values in patients with chronic glomerulonephritis were: nonprotein nitrogen,
32 mg.; urea nitrogen, 16.1 mg.; uric acid, 4.2 mg.; and creatinine, 2.0 mg. per
100 ml. (Table 2). The average carbon dioxide combining power was 54 volumes
per cent, in contrast to the average value of 34 volumes per cent in patients with
azotemia.
The average value of hemoglobin in the 22 patients with chronic glomerulonephritis was 12.7 Gm., of the erythrocyte count 4.3 millions per cu. mm. and of
the hematocrit determination 38.7 per cent. The anemia was of normochromic
type, similar to that observed in most of the cases of azotemia.
The patients with azotemia were separated somewhat arbitrarily from those
with chronic glomerulonephritis. All patients with a nonprotein nitrogen of 40
mg. and over were included in the azotemic group, whereas those with chronic
renal damage and a nonprotein nitrogen value below 40 mg. were included in the
group of chronic glomerulonephritis without azotemia. By thus separating cases
of chronic glomerulonephritis with azotemia from those without azotemia, some
mild instances of anemia were included in the latter category. Thus, in 10
patients with chronic glomerulonephritis with a nonprotein nitrogen below 40
mg., the hemoglobin averaged 10.7 Gm., the erythrocyte count 3.73 millions per
cu. mm., and hematocrit reading 32.8 per cent. These patients represented mild
cases of anemia. The average findings of all the 22 patients included in this group
were hemoglobin 12.7 Gm., erythrocyte count 4.3 millions per cu. mm. and
hematocrit reading 38.7 per cent. Apparently these 10 patients showed anemia
as a result of early mild retention of nitrogenous waste products that was not
demonstrated by the nonprotein nitrogen alone. For instance, patient M. S.
showed a hemoglobin value of 9.0 Gm., an erythrocyte count of 3.65 millions
per cu. mm., a hematocrit reading of 33 per cent, nonprotein nitrogen 24 mg.,
and creatinine 1.2 mg. The blood urea nitrogen, however, was 18 mg., slightly
elevated above normal. In another patient, A. R., the hemoglobin was 11.5
Gm., the erythrocyte count 4.0 millions per cu. mm., and the hematocrit reading
33 per cent. His blood urea nitrogen value was 13.7 mg., uric acid 1.9 mg., and
creatinine 1.5 mg. The nonprotein nitrogen, however, was 37 mg., which was
slightly above normal (Kolmer37).
Eight of the patients with chronic glomerulonephritis clinically were in the
nephrotic phase. Six of these patients showed no anemia, while two with a mild
BONE MARROW IN RENAL DISEASE
11
anemia later had abnormal values for nitrogenous waste products. Nephrosis
with its albuminuria is not related to the anemia in cases of renal disease.
Three of the 22 patients with chronic glomerulonephritis had slight elevations
of their blood chemical findings but no anemia; all three, however, did develop
anemia later. The other peripheral blood findings in these 22 patients did not
show significant variation as compared to those with azotemia.
Peripheral Blood Findings in Acute Glomerulonephritis, Essential
and Miscellaneous Kidney Diseases
Hypertension
Tn_these groups only rarely were the findings in the peripheral blood abnormal
(Table 3). In the cases of acute glomerulonephritis the leukocyte count averaged
12,800 per cu. mm. with some increase in the relative percentage of stab neutrophils. Otherwise, variations were only slight. The blood chemical and urinary
findings were essentially the same. The cases of acute glomerulonephritis showed
persistent gross hematuria, but no other significant differences.
Extrarenal Azotemia
There were two instances of extrarenal azotemia with nonprotein nitrogen
values of 52 mg. and 86 mg. In one of these (V. R.), a complicating anemia was
due to bleeding hemorrhoids. Both patients had been vomiting and suffered
from severe dehydration from loss of fluids and electrolytes. The patient without
bleeding had no anemia and his bone marrow findings were normal.
PATHOLOGIC DATA
^ '"~"\
During the period of observation of the .102 patients, 26 died and came to
autopsy. In addition one patient had a nephrectomy. Of those that died, 21 had
been classified in the azotemic group (nonprotein nitrogen over 40 mg.). Twelve /
of these 21 had a final diagnosis of chronic glomerulonephritis, two clTronic
pyelonephritis, two benign nephrosclerosis (one of these had congenital cysts in
the right kidney), two congenital cystic kidneys and one acute hemorrhagic
nephritis associated with subacute bacterial endocarditis.
*•
In the group of chronic glomerulonephritis without azotemia (nonprotein
nitrogen under 40 mg.), there were four patients who came to autopsy and one
patient who had a nephrectomy. Two of these four patients who came to autopsy
had an anemia associated with a borderline azotemia: one had no anemia, but
slightly elevated nonprotein nitrogen; one showed no anemia or elevation of
nonprotein nitrogen until much later in the course of the disease; two of the
patients had chronic glomerulonephritis, one nephrosclerosis and one congenital
hypoplasia of the kidney. The patient who had a nephrectomy had anemia,
diabetes and intercapillary glomerulosclerosis. The only patient in the miscellaneous kidney group that died (B. G.) had old kidney infarcts and heart failure.
In this group was included one patient with cystitis, one each with orthostatic
albuminuria, hydronephrosis, and tuberculosis of the kidney. There was no
correlation between any specific pathologic lesion and anemia, but there was a
correlation between azotemia and anemia.
>
12
CALLEN AND LIMARZI
MISCELLANEOUS STUDIES
Other studies, including blood_Wassermann test, basal metabolic rate, and
gastric analysis for acidity, were noncontributory. Electrocardiographic studies
were made in about one-half of the patients and did not reveal any correlative
factors with the anemia. A majority of patients with azotemia, however, did
reveal patterns in the electrocardiogram usually associated with left ventricular
enlargement on x-ray examination. Intravenous pyelograms were made in about
25 per cent of all patients and, in general, showed abnormalities in those having
elevated levels of blood nitrogenous waste products.
DISCUSSION
Analysis of the Results of the Peripheral Blood
this study it was seen that the anemia increased as the nonprotein nitrogen
,'jirose. Besides the nonprotein nitrogen, uric acid, urea nitrogen and_ creatinine,
other chemical determinations in the blood such as chloride, carbon dioxide
combining power, glucose and albumin and globulin were completed in most of
the cases. Abnormalities in values of these other chemical substances could
not be correlated with the degree of anemia, n^»r could the degree of anemia be
correlated with the level of the nitrogenous waste products in the blood. In
addition, some patients had. determinations made of the blood cholesterol,
calcium and phosphorus. There was no constant correlation of these with the
nonprotein nitrogen values.
Nylander61 and Nordenson60 suggested the possibility that the intestinal
retention products, such as indican and other phenol derivatives, were possibly
responsible for these anemias. These substances were not examined in our
patients. It is believed that, in general, they have not been found to have greater
value than the other blood chemical substances more commonly examined. Some
factors that have been suggested as etiologic agents in these anemias have not
been found to be of any importance in this study.,Review of these patients'
histories failed to show that albuminuria, as stated by DaCosta, 16 or a deficient
' protein diet, as suggested by Grignani,27 had any effect on the anemias studied
in these patients. Hematuria was seen in many of the patients without anemia
and in some with anemia. There was no correlation between hematuria and
anemia. ~~~
~~~
r^j
On the other hand, it was noticed that of the 44 patients with anemia and
^ ^ a z o t e m i a , 81 per cent had a normocytic normochromic anemia, two a microcytic
1
hypochromic anemia, and eight (approximately 15 per cent) definite macrocytic anemia. In these eight there was no correlation between the anemia,
gastric acidity and hemopoiesis in the bone marrow. There was no evidence
of a depressed hemopoietic activity of the erythrocyte-forming elements in the
'^(_bpne marrow, even in cases with diminished hydrochloric acid.
/
A correlation between the severity of the anemia and the level of nonprotein
^ n i t r o g e n values is apparent from Table 4. Here, as the nonprotein nitrogen
V ^ rose above 100 mg., the blood count, hemoglobin and hematocrit values fell
BONE MARROW IN RENAL DISEASE
13
but the mean corpuscular volume and the mean corpuscular hemoglobin concentration remained unaltered.
An examination of the peripheral blood smears of patients with anemia due
to azotemia did hot reveal any significant abnormalities. Only rarely was a
normoblast found in these smears. No distinguishing characteristics were noted.
Though the erythrocytes were not measured in microns as Isaacs33 had done,
a comparison of the mean corpuscular volume and his studies did not reveal
comparable changes. He had found that 25 per cent of 114 patients with a known
nephropathy had a cell diameter of less than 7.5 microns, 50 per cent 7.5 microns,
25 per cent more than 7.5 microns. Our study revealed only 15 per cent with a
mean corpuscular volume over 92 cubic microns and only two cases with microcytic characteristics.
This study has shown that anemia is rarely present in cases of renal dis-s6 i
ease unless there is an associated elevation of the nitrogenous waste products"^ \
m the blood. There is, however, a generally accepted belief that a mild or moderate anemia is present in patients with chronic glomerulonephritis, who have
\]
impairment of kidney function but no evidence of azotemia, the implications
,\
being that the disturbed kidney function is a causative factor in producing the
anemia. Very recently it was stated 65 that "chronic nephritis or nephrosis
sufficient to produce a continuing profuse proteinuria would be almost certainly
associated with some anemia." This is not in keeping with the results seen in this
group of patients. Of 22 patients having chronic glomerulonephritis without
azotemia (azotemia being defined as a blood nonprotein nitrogen above 40 mg.),
10 had a mild anemia. Only two of the 10 had no elevation of other blood chemical values, but one of these two later developed an elevated nonprotein nitrogen.
In this group, then, there was only one instance of anemia in a patient with
clironic nephritis who had no elevation of the blood nitrogen values at the time
of the first study or in the subsequent three years of observation. The-etiology
of this anemia was not discovered in this period. It would seem safe then to say
that anemia is not related to proteinuria, is certainly not present in nephrosis
without azotemia and is not related to damaged kidney function per se.
Analysis of Results of Bone Marrow Studies
With respect to bone marrow findings, there has been wide disagreement
among various authors. As mentioned previously, relatively few bone marrow
studies were made prior to 1929 except on autopsy material. It must be remembered also that the bone marrow undergoes rapid postmortem autolysis.
The average myeloid-erythroid volume (volumetric reading) in the 44 patients
with azotemia was 8.0 per cent (Table 5). A further breakdown of these cases
in various degrees of azotemia (Table 6) revealed a somewhat gradual but
insignificant decrease in the myeloid-erythroid volume as azotemia increased.
Another interesting observation concerns the relationship between myeloiderythroid volume, myeloid-erythroid ratio and the nonprotein nitrogen. The
average myeloid-erythroid ratio for all 44 patients with chronic glomerulonephritis with azotemia (Table 5) was 2.5:1.0. I t was noticed that, as the non-
14
CALLEN AND LIMARZI
protein nitrogen became higher, there was a tendency for a decrease in the
myeloid-erythroid volume (Table 6); the myeloid-erythroid ratio was 2.0:1.0 in
the group of patients whose nonprotein nitrogen values ranged from 40 to 49
mg., and 4.0:1.0 in the group whose nonprotein nitrogen values ranged from 200
to 300 mg. With the progressive elevation of the nonprotein nitrogen, there was
little or no increase in the relative percentage of polychromatic normoblasts
TABLE 5
BONE
MARROW
FINDINGS
IN
AZOTEMIA,
CHRONIC
AND
ACUTE
GLOMERULONEPHRITIS,
E S S E N T I A L H Y P E R T E N S I O N AND M I S C E L L A N E O U S D I S E A S E S
CHRONIC
ACUTE
GLOMERULO- GLOMERULOAZOTEMIA
NEPHRITIS
NEPHRITIS
( N P N ABOVE
( N P N BELOW ( N P N BELOW
40)
40)
N u m b e r of P a t i e n t s
Q u a n t i t a t i v e studies
Myeloid erythroid volume (per
cent)
Red cell volume (per cent)
Plasma (per cent)
F a t volume (per c e n t ) . . . :
Megakarocytes
Qualitative studies (per cent)
Myeloid series
Myeloblasts
Leukoblasts
Promyelocytes
Neutrophilic myelocytes
Neutrophilic metamyelocytes.
..Segmented neutrophils. . . . . . .
Eosinophils
Basophils
E r y t h r o i d series
Pronormoblasts
Basophilic normoblasts
Polychromatic n o r m o b l a s t s . . .
Orthochromatic normoblasts..
Myeloid erythroid
per cent
ratio
44
22
8.0
•24.1
65.0
2.9
9.8
34.7
50.6
4.9
Normal
0.9
3.3
2.
19
37
30
"6.
"o.
• 0.3
3.5
3.4
17.0
43.0
26.8
5.6
0.4
40)
ESSENTIAL
HYPERTENSIVE
MISCELLANEOUS DISEASES
10
14.2
7.9
35.0
36.0
46.1
52.6
4.7
3.5
or increased
10.
37,
44.
7.3
0
3
1
19
44
27
4
0
0.2
3.4
2.2
23.1
4S.0
19.0
4.0
"0.1
0.1
4.0
2.2
23.9
39.5
23.9
6.1
0.3
1.8
6.0
88.6
3.6
3.3
7.2
85.8
3.7
2.9
5.5
S2.5
9.1
1.9
5.5
89.1
3.5
2.2
5.6
90.8
1.4
72:28
2.5:1
66:33
2:1
75:25
3:1
65:35
l.S:l
66:33
2:1
but there was a definite increase in the number of mature granulocytes in the
bone marrow as compared with the controls (hypertensive patients). Furthermore, there was a decrease in the number of basophilic normoblasts but the
number of orthochromatic (acidophilic) normoblasts remained about the same
(Table 6). It is of interest to note that in the bone marrow in chronic glomerulonephritis (Table 6) with marked elevations in the nonprotein nitrogen the
myeloid-erythroid volume (4.8 per cent) was only moderately decreased from
the controls (7.9 per cent).
BONE MARROW I N RENAL
.15
DISEASE
The myeloid-erythroid volume in the acute glomerulonephritis group was
14.2 per cent which is significantly higher than the other types (Table 5), including cases of azotemia and controls. This increase is due to increased numbers
of myeloid cells as expressed in a slightly higher myeloid-erythroid ratio of
3.0:1.0. However, the relative percentage of the various myeloid cells remained
close to the range seen in other groups (Table 5). There was little or no increase
in the number of polychromatic normoblasts in all groups.
TABLE 6
SELECTED CORRELATION S T U D I E S O P THE B O N E M A R R O W AND BLOOD CHEMISTRY IN CHKONIC
G L O M E R U L O N E P H R I T I S WITH AZOTEMIA
VALUE OF NONPROTEIN NITROGEN (MC.)
100-149
Number of patients
Examinations made
Myeloid erythroid volume (per
cent)
Neutrophilic
myelocytes
(per
cent)
Neutrophilic metamyelocytes (per
cent)
Polymorphonuclear
neutrophils
(per cent)
Basophilic
normoblasts
(per
cent)
Polychromatic normoblasts (per
cent)
Orthochromatic normoblasts (per
cent)
Myeloid erythroid per cent
ratio
Nonprotein nitrogen (mg. per 100
ml. blood)
Urea nitrogen (mg. per 100 ml.
blood)
Uric acid (mg. per 100 ml. blood)
Creatinine (mg. per 100 ml. blood).
10
10
10.4
8.0
10.2
7.0
4.S
5.4
20.3
26.2
25.0
20.1
20.0
10.4
42.8
3S.7
35.0
39.S
39.3
26.7
21.6
17.5
22.3
S7.9
31.6
54.S
S.5
8.0
6.3
4.6
3.6
S7.0
86.3
84.5
88.0
92.3
91.7
3.6
66:34
2:1
3.8
66:34
2:1
3.5
76:24
3:1
5.2
71:29
2.4:1
2.0
70:30
2.3:1
44
54
SO
127
173
252
24
2.9
2.6
2S
4.9
3.4
46
7.0
5.1
112
S.2
13.4
165
10.2
1S.S
7.13
99
7.3
9.2
3.0
SO: 20
4:1
f A normal cellularity or hypercellularity of the bone marrow was observed
[in most cases of nephritis, irrespective of the stage of the disease (Fig ].). In
I at least 80 per cent of patients with azotemia, the bone marrow was hyperIcellular. No patient showed an aplastic bone marrow. The relative percentages \
of the bone marrow elements were apparently normal except for those listed, in
Table 6 where the myeloid-erythroid ratio is seen to increase as the nonprotein
nitrogen rises. In extreme cases we obtained a ratio of 4:1 with a nonprotein ^
nitrogen varying from 200 mg. to 340 mg., but we never reached a ratio of 8:1,
as reported by Nordenson.60 In addition, the myeloid-erythroid volume was
16
CALLEN AND LIMARZI
found to decrease as the nonprotein nitrogen rose and, in view of the change in
the myeloid-erythroid ratio to 4 : 1 , the greatest reduction occurred in the erythroid tissue. Some reduction in the myeloid tissue, however, was also present.
. . Except in the group with nonprotein nitrogen of 200 to 340 mg. (Table 6),
the relative percentages of neutrophilic myelocytes, metamyelocytes and^polymorphonuclears remained about the same. This is in contrast to the findings
reported by Nordenson.
f A leukopenia or lymphocytosis of the peripheral blood was not observed in
__any of our patients with nephritis, irrespective of the stage of the disease. In
general, the bone marrow pattern consisted of a moderate to marked myeloid
activity with varying degree of granulocytic immaturity (Fig. 4). It was noted
that the increased number of granulocytic elements consisted mostly of neutrophilic myelocytes, metamyelocytes and eosinophils and less frequently, of
leukoblasts and neutrophilic promyelocytes. Immaturity of the myeloid tissue
was never carried to the stage of myeloblastic involvement. Frequent mitosis
of the granulocytic cells were associated with the myeloid activity and
immaturity. The development of a neutrophilic leukocytosis in the peripheral
blood was associated with a shift to the right in the granulocytic series to include
many segmented neutrophils. The morphologic pattern of the myeloid tissue
was similar to that observed in a number of other toxic conditions.51, 62 This
toxic bone marrow pattern with a varying degree of shift to the left also showed
an increased number of histiocytes and plasma cells, and frequently phagocytic
cells. The normoblastic reaction revealed frequent karyorrhexis of the normoblast nuclei.47 A rather common observation in the cases of acute and chronic
nephritis was the presence of frequent numbers of eosinophils in various stages
of maturation. In some cases they were moderately increased in number, and in
practically all instances eosinophilia of the bone marrow could not be correlated
with the peripheral blood eosinophilia. In a case of so-called nephrosis 25 per
cent of the myeloid elements of the marrow consisted of various types of eosinophils while the eosinophilia in the peripheral blood was only 13 per cent.
-'-•? The bone marrow in most patients with nephritis showed a normoblastic
\~"type of erythropoiesis (Fig. 3). Megaloblastic erythropoiesis did not occur in
nephritis even when the anemia was macrocytic. Regardless of the stage of the
disease or the severity of the anemia, the bone marrow was usually normal.
Patients with a hypercellular bone marrow showed a normal or increased erythrocytogenesis and megakaryocytogenesis as well as myeloid activity. Pronormoblastic erythropoiesis was an infrequent finding. Hypoplasia of the erythroid
tissue was an uncommon observation and aplasia of this tissue was never seen,
even in cases of terminal nephritis (uremia) with severe anemia. Polychromatic
normoblastic activity-\vas-the_mpst frequent type of erythrocytogeneiisT The
normoblastic reaction consisted of groups or clusters oi~erythroid-cHrlS_some of
which are in the phase of mitosis. Karyorrhexis of the normoblast nuclei was
one of the most constant findings in cases of nephritis. There was no correlatiori
between the stage of the nephritis and the number of karyorrhexic figures.
A tendency toward hypoplasia of the erythroid cells was noted in a few patients
F I G . 1. Bone marrow section (marrow particles) from a patient with chronic glomerulonephritis, showing cellular marrow. X 300.
F I G . 2. Bone marrow section taken a t autopsy from a, subject with chronic glomerulonephritis. Note the hypercellularity of the bone marrow with many megakaryocytes. X 300.
17
18
CALLEN AND LIMARZI
with chronic nephritis but aplasia of the erythroid tissue was never found. In
some instances the relative decrease in the number of normoblasts was in part
due to the marked admixture with blood. This was indicated by the low volumetric reading of the bone marrow, infrequent numbers of megakaryocytes and
myeloid cells, and the presence of increased numbers of segmented neutrophils.
f "Although the exact mechanism involved in the anemia of nephritis is unknown,
/there is some evidence that it is associated with toxic retention products in the
(\blood due to renal dysfunction. The varying degree of shift to the left in the
I piyeloid cells, karyorrhexis of the normoblastic tissue47 and the increased numbers
| | of reticulum and plasma cells are indicative of a toxic or irritative effect upon
y bone marrow hemopoiesis. In acute nephritis without azotemia the toxic agent
acting upon the bone marrow may be associated with the infection that precedes
the onset of acute glomerulonephritis in approximately 69 per cent of the cases.66
In chronic glomerulonephritis associated secondary infection may in part be
responsible for the bone marrow reaction but apparently this is not the sole or
important factor. I t is interesting that the bone marrow in patients with hypertension and without renal dysfunction or azotemia showed a normal cellularity
of the bone marrow. The megakaryocyte hyperplasia in nephritis was similar
to that seen in a number of toxic states. 46 •48 The cause of the bone marrow eosinophilia in glomerulonephritis is not clear. It may be clue to some allergic
phenomenon or sensitization related to factors causing the nephritis or to toxic
products associated with the disease.
Histologic studies of the bone marrow, provided by marrow particles obtained
at the time of sternal aspiration (Fig. 1) and autopsied material (Fig. 2), confirmed the normal cellularity and hypercellularity of the bone marrow. Marked
hypoplasia and aplasia of cells of erythrocytic series were not observed.
The anemia observed in chronic glomerulonephritis is often associated with a
neutrophilic leukocytosis and a normal or elevated platelet count in the peripheral
blood. Furthermore, although repeated blood transfusions may temporarily
improve the anemia in cases of chro^jgJiepKr-itis, the bone marrow remains
refractory to this or any_Qthei^t5!l5e^oi_tr_ea.tment. Anisocytosis, poikilocytosis,
and polychromatophilia of the erythrocytes and normoblasts are not commonly
observed in the peripheral blood. Rarely, and apparently transiently, the bone
marrow may undergo stimulation and be associated with a slight reticulocytosis
in the circulating blood.03 This is of interest because in most of these cases the
bone marrow is hypercellular and shows a normal type of erythrocytogenesis
in spite of the anemia in the peripheral blood.82 The discrepancy between the
anemia in the peripheral blood and the apparent adequacy of the erythroid
tissue in the bone marrow in many cases of chronic glomerulonephritis is difficult
to explain. Apparently the mechanism regulating the delivery of cells to the blood
stream is at fault, rather than the development (maturation) of the cells. This
mechanism is a selective one in chronic glomerulonephritis, inasmuch as there
is no interference with leukopoiesis and megakaryopoiesis. It emphasizes again
that cellularity of the marrow in itself does not constitute evidence of hemopoietic
activity.
FIG. 3. Bone marrow smear (concentration technic) from a patient with chronic glomerulonephritis, showing normoblastic activity at the polychromatic stage of erythropoiesis
and a number of neutrophilic myelocytes and metamyelocytes. X 1100.
FIG. 4. Bone marrow smear (concentration technic) from a patient with chronic glomerulonephritis. Note the myeloid cells in various stages of development and polychromatic
normoblasts. X 1100.
19
20
CALLEN AND LIMARZI
The bleeding state which is commonly observed in the terminal stage of
chronic nephritis or uremia is not due to injury of megakaryocytes in the bone
marrow since the platelets are adequate in the blood. The bleeding is probably
due to a combination of toxic capillary injury and prothrombin deficiency
resulting from the toxic retention products associated with the abnormal renal
condition.
It is interesting to note that quantitative and qualitative disturbances in the
bone marrow in chronic glomerulonephritis, particularly in the erythroid cells,
do not occur until the nonprotein nitrogen is above 150 mg. (Table 6). At that
level the myeloid-erythroid volume drops, the myeloid-erythroid ratio increases
and the basophilic normoblasts decrease in number. Andereggen and Nordenson
both noticed this change in nephritis. Generally, it is only after the nonprotein
| nitrogen is above 150 mg. that the bone marrow shows any quantitative evidence
I of a moderate hypoplasia. All the bone marrow elements show some hypoplasia
when the nonprotein nitrogen rises above 150 mg., but the erythroid tissue is
selectively affected more than the other cells. The aregenerative anemia of chronic
glomerulonephritis is the result of what one might call a chronic disease of
the erythroid tissue, due to some toxic inhibitory factor in this disease. This is
followed by a gradual quantitative reduction in the number of normoblasts in
the bone marrow, but an actual aplasia of these elements never results.
SUMMARY
The peripheral blood and bone marrow were studied in 102 patients with
nephritis, related diseases and hypertension. In 44 patients with renal disease
of sufficient severity to produce azotemia, the degree of anemia was definitely
/related to the level of retention of nitrogenous products in the blood. Autopsy
f of 21 of these 44 revealed a lack of correlation between autopsy findings and the
knemia'. The anemia was normocytic in type in 81 per cent of patients with
renal disease and azotemia.
( / The bone marrow was hypercellular in 80 per cent of patients with renal
disease and azotemia. Hypercellularity mainly involved the myeloid and
megakaryocytic cells. Erythropoiesis was normal.
Definite evidence of quantitative and qualitative hypoplasia of the erythroid
tissue in renal disease was observed only when the nonprotein nitrogen level of
the blood was over 150 mg. Aplasia of the normoblastic tissue was never observed in these marrows.
The suppression of the normoblastic elements in chronic glomerulonephritis
is a selective one, as there is no interference with leukopoiesis and megakaryopoiesis.
The finding of a cellular bone marrow in chronic glomerulonephritis is not in
itself evidence of hemopoietic activity nor does it have prognostic significance.
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