PLASMA V I T A M I N A L E V E L I N R E N A L DISEASES*
C A P T . H A N S P O P P E R , M . C , A . U . S . , | L T . COMDR. F R E D E R I C K STEIGMANN, M . C ,
U.S.N.R.J
AND H A T T I E A. D Y N I E W I C Z , P H . C
From the Hektoen Institute for Medical Research and the Department of Therapeutics, Cook County Hospital,
Chicago, Illinois
Various investigators 1-4 reported a high plasma
vitamin A level in some patients with renal disease
whereas others reported normal values 5 ' 6 or even
reduced ones. 7 The disturbance of the vitamin A
metabolism in renal disease is peculiar. The
liver depots as judged from the examination of
tissue obtained a t post mortem from patients
with renal disease, are very low. 1 ' 8-12 In many
renal diseases considerable amounts of vitamin A
are excreted in the urine, 1 ' 7 ' 13-15 and vitamin A
fluorescence is found in the tissues of diseased
kidneys. 16 I t is not possible to correlate this with
the increased blood level since, especially in cases
of pneumonia, an even more marked urinary
excretion13 is associated with a low to zero plasma
vitamin A level.11 The paradoxical situation
was explained by Lindquist, 10 by the fact that in
kidney disease abnormal metabolites, most probably of protein character appear in the blood and
pass in the urine—metabolites which carry along
vitamin A possibly increasing its solubility in
blood and urine.
Lawrie, et al.13 found vitamin A in the urine
associated with a non-heat coagulable protein
and assumed alterations in the relative power of
the liver, blood, kidney, and urine to dissolve or
absorb the vitamin A, as a cause of appearance of
vitamin A in the urine. They also considered
that an inefficiency of the kidney in chronic
nephritis may lead to the accumulation in the
blood of substances which increase the solubility
of vitamin A. Linneweh17 also suggested the
combination of vitamin A with a protein as cause
for its appearance in the urine in renal conditions.
The mentioned publications indicate, however,
* Supported by a grant from the Committee on
Scientific Research of the American Medical Association and the S. M. A. Corporation (Division Wyeth
Incorporated) Philadelphia, Pa.
f Director of Hektoen Institute for Medical Research and of Laboratories of Cook County Hospital,
on Leave of Absence.
| Director of Department of Therapeutics of Cook
County Hospital, on Leave of Absence.
that a high vitamin A value is not uniformly found
in the blood of patients with kidney diseases.
Thus perusal of Hedberg's and Lindquist's data
reveals that some relation exists between the high
plasma vitamin A level and the degree of kidney
damage as judged by hypertension of azotemia.
Actually of 18 cases with a non-protein nitrogen of up to 50 mg. per 100 cc. of serum 7 had
a plasma vitamin A level above 250 U. whereas
of 8 cases with a serum non-protein nitrogen
above 50 mg. per cent all but one showed an
increased plasma vitamin A (above 250 U.). The
relation to the blood pressure was less clear.
The patients with high plasma vitamin A level
excreted the largest amount of vitamin A in the
urine.
The hyperlipemia and hypercholesteremia found
in renal diseases affords a parallelism to the
hypervitaminemia A. I t is still unexplained and
found simultaneously with excretion of lipoids
in the urine and deposition of fats of different
kinds in the kidney.
In the past years much interest has been aroused
by the endogenous or conditioned disturbance of
the vitamin A metabolism 4 - 18-21 which was independent of the nutritional intake. In the explanation of the problems involved in endogenous
hypovitaminosis A and hypovitaminemia A the
plasma vitamin A level in renal diseases as an
example of endogenous hypervitaminemia A
deserves new interest and was therefore examined
from three points:
1. The plasma vitamin A level was correlated
with the clinical picture and course of renal
diseases.
2. The influence of the administration of a
standard dose of vitamin A upon the plasma
vitamin A level in renal diseases wras studied.
Previous investigations 2223 have shown that the
response of the plasma vitamin A level (tolerance
curve) depends, among other factors, also upon
intestinal absorption. If the substance which
carries vitamin A in the blood would be increased
in renal diseases, due to the presence of pathologic
272
PLASMA VITAMIN A IN RENAL DISEASE
metabolites, the possibility exists that more
vitamin A would be absorbed from the intestine
than in normals.
3. The plasma vitamin A level in renal diseases
was correlated with results of liver function tests.
The finding of a low vitamin A concentration in
the liver and a high one in the blood as has been
reported in renal diseases, could be explained on an
inability of a damaged liver to store vitamin A.
In human liver damage, however, impaired release
of vitamin A from the liver is the rule,24 and not
increased release or inability to hold vitamin A.
MATERIAL AND METHODS
Sixty-two patients with various pathologic conditions of the kidney or other parts of the urinary tract
273
modification24 of the method of Josephs2' or by the
spectrophotometer of Coleman. The results were
recorded in micrograms per 100 cc. of plasma. In
hospital controls from the same economic stratum as
the patients reported in this study the average plasma
vitamin A level was found to be on the average 32
micrograms per 100 cc. (maximum 95 and minimum
9 micrograms per 100 cc.)4.
RESULTS
A. Medical renal disease. In 45 cases of medical
renal disease (nephritis, nephrosis, nephrosclerosis
or combination of them) the plasma vitamin A
level was correlated with various clinical and
laboratory data (table 1). In more than half
of the cases a marked elevation of the plasma
vitamin A level was found.
TABLE 1
COMPARISON OF CLINICAL AND LABORATORY DATA WITH THE PLASMA VITAMIN A LEVEL IN MEDICAL
RENAL DISEASE
AVERAGE OF
NO. or
CASES
PLASMA
VITAMIN A
LEVEL IN
Serum
Blood
pressure
Edema
Plasma
Albuminuria cholesterol
micrograms
pa 100 cc.
4
7
7
15
12
10-20
21-40
41-60
61-100
101-210
131/85
147/94
173/107
172/110
202/120
+ + + + ++++
' + + + +++
+
+++
+
+++
+
+++
were examined clinically and by routine laboratory
methods. The plasma vitamin A level was determined in all of them once, and in 12 cases repeatedly
during the course of the disease. In 23 of them (patients with medical renal disease) the cholesterol/
cholesterol ester ratio and in 15 the cephalin cholesterol
flocculation reaction25 were determined to test the liver
function. In cases of medical renal disease 75,000
units of vitamin A in corn oil§ were given and the
plasma vitamin A level was determined before, and
3, 6, and 24 hours later (tolerance curve). The plasma
vitamin A was determined by the method of Kimble20
using either the photoelectric colorimeter of SheardSanford, or copper sulphate standard according to a
§ Distilled vitamin A concentrate (natural ester
form distilled from fish liver and vegetable oil) containing 200,000 USP XI units per gram, generously
supplied by Distillation Products, Inc., Rochester,
N. Y.
Xon
protein
nitrogen
Albumin
Globulin
Total
protein
mg. per
100 cc.
mg. per
100 cc.
grams per
100 cc.
grams per
100 cc.
grams per
100 cc.
289
339
349
292
318
41
62
113
62
108
1.8
2.0
4.1
3.5
3.3
2.5
1.7
2.4
2.2
1.6
4.3
3.7
6.5
5.7
4.9
The patients with low plasma vitamin A level
had as a rule a normal blood pressure, edema, and
a low serum non-protein nitrogen level, and a low
total serum protein concentration with a tendency
to reversal of the albumin/globulin ratio. The
patients with plasma vitamin A levels above the
normal had on the average a high blood pressure,
little edema and azotemia, with almost normal
blood protein level. There was a tendency toward
more marked albuminuria in the patients with low
plasma vitamin A levels. The blood cholesterol
and plasma-vitamin A level did not show any
relation.
A parallel increase of serum non-protein nitrogen and plasma vitamin A level in a patient with
chronic nephritis is shown in figure 1.
B. Renal insufficiency due lo surgical renal
disease. In 17 cases with prostatism which
274
HANS POPPER, FREDERICK STEIGMANN AND HATTIE A. DYND3WICZ
showed elevation of the serum non-protein nitrogen
level (above 50 milligrams) the plasma A level
was on the average 32 micrograms with a maximum
of 67 and a minimum of 10 micrograms. No
direct relation of the blood pressure or the serum
non-protein nitrogen level to the plasma vitamin
A concentration was noted (table 2).
C. Response to administration of high doses of
vitamin A. Following the administration of
in one case was the cholesterol ester percentage
below 60; i.e., indicative of liver damage. A
patient with a vitamin A level of 210 had a cholesterol/cholesterol ester ratio of 87 per cent.
The cephalin cholesterol flocculation test also
failed to show evidence of impairment of hepatic
function.
2.8Z
260
RENAL DISEASES
•
2,3 cases
^B
260
220
c'l
/'
cj>200
/ 5erum non-protein
nitrogen
H
240
. 2 Q.
220
£ o
o
8
£ 140
<
120
UIUI
March 15 16 17 \d 19 20 21 22 25 24 25 26
FIG. 1. Relation between the plasma vitamin A level
and the serum non-protein nitrogen in a case of
chronic nephritis.
8
140
level
§c 1g
micrograms per
O 200
160
2 IOO
HOSPITAL rONTDOLS
16 cases
^ ^ ^ H
>
TABLE 2
COMPARISON OF CLINICAL AND LABORATORY DATA
WITH THE PLASMA VITAMIN A LEVEL IN SURGICAL
RENAL DISEASE
PLASMA
VITAMIN A
LEVEL IN
MICROGRAMS
PER 100 CC.
Blood
pressure
10-20
21-40
41-60
60+
140/92
153/94
159/92
150/93
1 60
60
H
AVERACE OF
Non-protein
nitrogen
X
••
mg. per 100 cc.
7
5
7
2
70
84
73
60
75,000 units of vitamin A the plasma vitamin A
level rose much higher in patients with medical
renal disease than in the hospital controls. Not
only was their average maximal increase far
higher than that of hospital controls but, in
general, there was a more gradual return cf the
plasma vitamin A level to normal (fig. 2).
D. Liver function tests in patients with medical
renal disease. The cholesterol/cholesterol ester
ratio of patients with medical renal disease was
plotted against the plasma vitamin A level and no
apparent correlation was found (fig. 3). Only
Hours
Before 3 6 24
Before 3 6 24
FIG. 2. Comparison of the response of the plasma vitamin A level to the intake of 75,000 units of vitamin
A in hospital controls and in patients with medical
renal diseases.
DISCUSSION
The previously made observations as to the
common occurrence of hypervitaminemia A in
renal disease has been confirmed in this study.
One would expect the increased concentration of
the fat soluble vitamin A to be part of the nephrotic
syndrome because of the disturbance of the lipoid
metabolism in that condition. However, hypervitaminemia A was missed in the nephrotic form
but was almost always present in the nephritic
form characterized by hypertension and azotemia.
Hedberg and Lindquist 1 found similarly urinary
PLASMA VITAMIN A IN RENAL DISEASE
excretion of vitamin A in the severe cases of
chronic nephritis with elevated serum nonprotein nitrogen, retinitis, and hypertension,
but no clear relation to albuminuria. This is the
more remarkable since patients with nephritis
are severely sick and according to observations
20
40
60
SO
100
Cholesterol esters in percent
o f total blood cholesterol
FIG. 3. Plot between the plasma vitamin A level and
the cholesterol/cholesterol ester ratio in patients
with medical renal diseases.
on other types of severely sick patients a low
vitamin A level would be expected.4 When,
however, azotemia and hypertension were found
in a patient with surgical renal disease, the plasma
vitamin A level was not elevated. The absence
of vitamin A from the urine in similar conditions
has also been reported.15 One may thus assume
that the destruction of the renal parenchyma as
275
seen in medical renal diseases is the cause of the
hypervitaminemia A, especially if one considers
that the renal tubules influence the fat metabolism
as previously claimed.23
In which way may renal destruction influence
the plasma vitamin A level? An impairment of
the hepatic function secondary to the renal damage
could be considered. The fact that after the
intake of a standard dose of vitamin A, the plasma
vitamin A level in patients with renal diseases is
elevated more and for a longer time than in
hospital controls could be explained by an inability of the liver to take out vitamin A from the
blood, especially in view of the fact that in renal
damage low liver stores have been reported.
The present investigation, however, does not
reveal any evidence of impairment of hepatic
function in renal conditions with elevated plasma
vitamin A level. Furthermore, in previous
studies no evidence was found of a relationship
between the shape of the tolerance curve and the
hepatic vitamin A concentration.22
Other possibilities should therefore be considered as explanations for the elevated plasma vitamin A level, the elevated tolerance curve and also
for the presence of vitamin A in the urine. The
first may be a difference in the solubility of vitamin
A in the plasma as claimed repeatedly before.1'.1315.17 Indeed the constitution of the
plasma is markedly altered in the uremic conditions in which the plasma vitamin A level is
elevated. However, the disturbance in the lipid
metabolism which is chiefly found in the nephrotic
condition is not the link between hypervitaminemia
A and change in the solubility of the fat soluble
vitamin A. One may therefore consider another
possibility, namely, either retention of substances
protecting vitamin A in the blood, or an inhibition
of substances which destroy it. The recent work
on the influence of the antioxidant tocopherol
(vitamin E ) 2 9 - 3 3 or other substances acting as
co-vitamin34 upon the vitamin A stores and the
studies of the destruction of vitamin A by various
substances 30 has emphasized the significance of
destruction and protection in the vitamin A
metabolism. It seems conceivable that the
destruction of the renal parenchyma may be related
to such processes.
SUMMARY
1. Hypervitaminemia A was found in azotemic
medical renal diseases of the nephritic type. It
was missed in conditions with a nephrotic com-
276
HANS POPPER, FREDERICK STEIGMANN AND HATTIE A. DYNIEWICZ
ponent, a n d in urologic conditions with azotemia.
2. I n azotemic renal conditions of nephritic or
nephrosclerotic origin t h e response of t h e plasma
vitamin A level to t h e intake of a test dose of
vitamin A was far in excess of the normal.
3. N o evidence was found t h a t t h e elevated
vitamin A level m a y b e due t o liver damage a n d
consequent inability of t h e liver t o take u p
v i t a m i n A.
-' 4. T h e assumption is presented t h a t t h e destruction of kidney parenchyma causes retention of a
substance protective, or decreases t h e production
of one destructive for vitamin A.
REFERENCES
Krankheitszustanden.
76: 471, 1931.
2. CLAUSEN,
S. W., AND MCCOORD, A. B . : Caro-
tinoids and vitamin A of blood. J. Pediat., 13:
635, 1938.
3. WENDT, H.: Hypercholesterinamie und Vitamin
A. Deutsche med. Wchnschr., 62: 1213, 1936.
^
13. LAWRIE, N . R., MOORE, T., AND RAJAGOPAL, K. R.:
Excretion of vitamin A in urine.
35: 1825, 1941.
14. BOLLER,
R.,
BRUNNER,
Biochem. J.,
O., AND BRODOTY,
E.:
15. SCHNEIDER,
16.
17.
18.
19.
E., AND WEIGAND,
H.: Vitamin
A
Verlust und sekundare
Hypovitaminosen.
Ztschr. f. klin. Med., 132: 423, 1937.
POPPER, H . : Histologic distribution of vitamin A
in human organs under normal and under
pathologic conditions. Arch. Path., 31: 766,
1941.
LINNEWEH, F . : Zur Frage der klinischen Bedeutung der Vehikelfunktion der Harneiweisskorper.
Klin. Wchnschr., 18: 301, 1939.
MOORE, T.: Vitamin A. Postgrad. M. J., 17:
52, 1941.
THIELE, W.: fiber das endogen bedingte Vitamin
A Defizit. Klin. Wchnschr., 19: 1201, 1940.
20. SPECTOR, S., MCKHANN,
C. F., AND MESERVE,
E. R.: Effects of disease on nutrition; Absorption, storage and utilization of vitamin A in
presence of disease. Am. J. Dis. Child., 66:
4. POPPER, H., AND STEIGMANN, F . : Clinical signifi376, 1943.
cance of plasma vitamin A level. J. A. M. A.,
21. JOLIFFE, N.: Handbook of nutrition; Conditioned
123: 1108, 1943.
malnutrition. J. A. M. A., 122: 299, 1943.
5. CATEL, W.: Klinische und tierexperimentelle
22. POPPER, H., STEIGMANN, F., AND ZEVIN, S.: On
Studien iiber die normale und pathologische
variations of plasma vitamin A level after
Physiologie des A Vitamins. Klin. Wchnschr.,
administration of large dosages of vitamin A in
16: 574, 1938.
liver disease. J. Clin. Investigation, 22: 775,
6. CATEL, W.: Klinische und tierexperimen telle
1943.
Studien iiber die normale und pathologische
Physiologie des A Vitamins. Monatschr f.
Kinderh., 73: 316, 1938.
7. GRANT, F . : (Vienna) Der Vitamin A und Cholesterinspiegel in seiner Beziehung zur Vitamin A
Ausscheidung im Harn. Vitamin A Nachweis
in Ergtissen im Duodenalsaft und in den Faeces.
Ztschr. f. klin. Med., 133: 168, 1937.
8. WOLFF, L. K.: On Quantity of vitamin A present
in human liver. Lancet, 2: 617. 1932.
23. BREESE, B. B., AND MCCCORD, A. B . : Vitamin A
absorption in catarrhal jaundice.
16: 139, 1940.
J. Pediat.,
24. POPPER, H., STEIGMANN, F., MEYER, K. A., AND
25.
9. BREUSCH, F., AND SCALABRINO, R.: Die quanti-
tativen Verhaltnisse der Leberlipoide. Ztschr.
f. d. ges. exper. Med., 94: 569, 1934.
10. MOORE, T.: Vitamin A and Carotene; Vitamin A
reserve of adult human beings in health and
disease. Biochem. J., 31: 155, 1937.
11. LINDQUIST, T.: Studien iiber das Vitamin A beim
Menschen. Acta med. Scandinav., Supp., 97:
1-262, 1-52, 1938.
12. KERPOLA, \V.: Das Auftreten und die Bedeutung
' der durch antimontrichlorid erzeugten Farbenreaktion in Menschenorganen in verschiedenen
jH
fiber die Ausscheidung von Vitamin A im Harn.
Wien. Arch. f. inn. Med., 31: 1, 1937.
1. HEDBERG, V., AND LINDQUIST, T.: Untersuchungen
iiber das Vitamin A bei chronischen Nephriten.
Acta med. Scandinav., 90: 231, 1938.
Acta med. Scandinav.,
26.
27.
28.
ZEVIN, S.: Relation between hepatic and plasma
concentrations of vitamin A in human beings.
Arch. Int. Med., 72: 439, 1943.
HANGER, F. M.: Serological differentiation of obstructive from hepatogenous jaundice by flocculation of cephalin-chclesterol emulsions. J.
Clin. Investigation., 18: 261, 1939.
KIMBLE, M. S.: Photocolorimetric determination
of vitamin A and carotene in human plasma.
J. Lab. & Clin. Med., 24: 1055, 1939.
JOSEPHS, H. W.: Studies in vitamin A; relation of
vitamin A and carotene to serum lipids. Bull.
Johns Hopkins Hosp., 65: 112, 1939.
HEYMANN, W.: Renal hyperlipemia in dogs.
Science, 96: 163, 1942.
29. DAVIES, A. W., AND MOORE, T . : Interaction of
vitamins A and E. Nature, (London) 147:
794, 1941.
^
^[
PLASMA VITAMIN A I N RENAL DISEASE
30. HICKMAN, K.: Fat soluble vitamins. Ann. Rev.
Biochem., Stanford Univ. Press, 12: 353, 1943.
31. HICKMAN, K. C. D., KALEV, M. \V., AND HARRIS,
P. L.: Covitamin studies; Sparing action of
natural tocopherol concentrates on vitamin A.
J. Biol. Chem., 152: 303, 1944.
32. HARRIS, P.
L.,
KALEY, M.
W.,
AND HICKMAN,
K. C. D.: Covitamin studies; Sparing action of
tocopherol concentrates on carotene.
Chem., 152: 313, 1944.
33.
277
J. Biol.
POPPER, H., AND STEIGMANN,_F. : To be published.
34. HICKMAN, K. C. D., KALEY, M. W., AND HARRIS,
P. L.: Covitamin studies; Sparing equivalence
of tocopherols and mode of action, J. Biol.
Chem., 152: 321, 1944.