RENAL FUNCTION*
M. HERBERT BARKER
From the Department of Medicine, Northwestern University and the Medical Ward,
Passavant Memorial Hospital, Chicago, III.
Every discussion of renal function must be limited by the
knowledge that some seventy-five per cent of renal substance
must be destroyed before any appreciable limitation may be
detected. The knowledge that only ten per cent of glomeruli
may be working at a time and that only three to five of the thirtythree to forty glomerular groups may be in operation, further
emphasizes the extent of the renal reserve. It is not surprising
that repeated objections to the present renal function tests are
voiced on the part of practitioners and by all of those desiring
information of renal efficiency. The continued research for
better methods of evaluation have brought about numerous
procedures, most of which have been discarded after periods of
clinical trial, so that only a few are generally used. It is my
purpose to discuss those tests which have been most helpful to
me in our cardio-renal-vascular clinic, and to further comment
upon some of the factors which must be considered when interpreting the results.
DILUTION AND CONCENTRATION TESTS
Most students of the problem of renal disease agree with Volhard1 and with Fishberg2 who believe that the most important
simple test of renal function is its ability to concentrate the urine.
This test is employed routinely in all of our patients in the clinic
and in the hospital wards in the following way:
The patient is given the usual evening meal but without added fluid such
as soup, water, or coffee. He is asked to void on retiring and preserve the
* Received for publication September 30, 1939.
Read before the Eighteenth Annual Meeting of The American Society of
Clinical Pathologists, St. Louis, May 12, 1939.
21
22
M. HERBERT BARKER
early rising specimen for examination. Urine collected, after such instruction,
should show a specific gravity above 1.025. In our experience, kidneys that
are able to produce such concentrated urine under such simple restrictions
have the capacity to do good work.
Certain exceptions must be made, the first being that polyuria
or nocturia will interfere with obtaining a concentrated specimen.
Examples are diabetes insipidus where large volumes of urine
are passed, and in congestive heart failure where the patient
voids little during the day and flushes out his dependent edema
at night after assuming the horizontal position. Obviously,
such hydrostatic interference creates errors in the tests if interpretations are based upon standard procedure. The ambulatory
cardiac sufferer may well be better tested for his ability to concentrate by fluid restriction in the forenoon and the collection of
the specimen in the afternoon. These warnings are found to be
helpful in instructing medical students and internes because so
many patients are hospitalized that ambulatory determinations
have been observed in but very few.
The normal kidney should be able to dilute the specific gravity
of the urine to 1.001-1.003. This test is employed in our clinic
in the following way:
The patient is asked to drink 1,500 cc. of water at room temperature between
the hours of seven and eight a.m. and he is to void at eight, nine, ten and eleven
a.m. The volume of the urine should rapidly rise so that approximately 400 cc.
is obtained at the end of the first hour and the specific gravity is found normally to be 1.001-1.003. There is a gradual decrease in the volume and a
gradual increase in the specific gravity so that at the end of the fourth hour the
urine volume is 100 cc. or less, and the specific gravity is 1.012 to 1.016.
This test is facilitated by making use of the normal diurnal
diuresis which begins in the early morning so that there is a
natural impetus to water clearance. It is also obvious that
it would be rather difficult to prolong the concentration test
through the period of natural morning diuresis. Interference
with the dilution test may be expected whenever the circulatory
mechanism is not delivering an adequate blood supply to the
kidney. It is not surprising, therefore, that it is difficult to get
an adequate dilution test in the cardiac with a congestive failure.
23
RENAL FUNCTION
Hydropigenous states, such as the nephrotic symdrome, the
salt and phosphorus retention of chronic nephritis, dehydration
and inanition, render useless the attempts at dilution evaluation.
My own experience with the dilution test causes me to use it
less frequently than the concentration test, but if it is used, and
found abnormal, important clues to pathologic physiology are
promptly raised. Of course, the dilution test should be withheld
DILUTION TEST. 1500 0. 0. OP WATER
Time
7
Sp. 0.
Vol.
1.024
400
1.022
375
1.020
350
8
9
325
1.016
300
1.014
275
11
12
j?
1
1.018
10
1
]
\
»
• Specific Gravity
t
0 Volume
/
s\
" §\
j
U -P \
© aj \
u
"3 s \\
1.012
250
O -P
1.010
225
O• OU
1.008
200
1500
• a
l.OOS
175
1.004
150
1.002
125
1.000
100
g
\
'
\\
i
1
\
A
x
/
/
\
>-*
\
\
i
\>
GRAPH 1
in the decompensated heart and only room temperature water
should be taken in this large volume.
P H E N O L S U L P H O N E P H T H A L E I N EXCRETION
Much debate as to the value of the excretion of this dye has
ensued following Rowntreeand Garaghty's 3 recommendation that
it be used for a renal instead of a liver function test. Some fifteen
24
M. HERBERT BARKER
years personal experience has more firmly established it as a
routine procedure in our cardio-renal clinic, but its limitations
and variations must be carefully considered in each case. Our
experience supports the observations of Freiburg4 and his coworkers, and their technic is used.
One cubic centimeter of the dye is given intravenously and fifteen minutes
later the patient is asked to void. Twenty-eight to thirty-three per cent of
the phenolsulphonephthalein should be excreted in this fifteen minute period.
Forty-five minutes later a second specimen is collected and twenty-five to
twenty-eight per cent additional dye may be expected. One hour later the
third specimen is collected and an additional ten per cent, making a total of
approximately sixty per cent of the phenolsulphonephthalein, will be returned
in two hours. Certain cautions regarding this test are to be observed. It is
important that the patient not void prior to starting the tests so that a volume
of urine in the bladder facilitates prompt voiding of an adequate fifteen minute
urine volume on which the prompt dye return evaluation is to be made. Two
hundred cubic centimeters of water should be taken as the test is started and
another 200 cc. may be taken at the end of the first hour to insure adequate
flushing. Smoking or the taking of coffee, or tea, should be withheld at least
two hours prior to, and during the test.
Variations from normal are striking in certain clinical conditions, the first being congestive heart failure where the blood
supply to the kidney may be reduced and where passive congestion of the kidneys and liver interfere with the normal movement
and distribution of the dye, resulting in a small return. In
cirrhosis of the liver the renal clearance of the dye is greatly
increased to as much as ninety or one-hundred per cent. In
the fibrosed liver the forty per cent pre-renal deviation of the dye
is prevented so that nearly all of the phenolsulphonephthalein
is passed through the kidney. It is not accurate therefore, to
report a "normal" phenolsulphonephthalein excretion when
ninety per cent of the dye has been recovered in the urine. In
our experience such an increase over the normal expected renal
clearance of phenolsulphonephthalein has been occasionally the
first clue to the diagnosis of cirrhosis of the liver. Hyperthyroidism and certain hypertension cases with a vigorous circulation will Ukewise show an abnormally high dye excretion, both
of which return to a normal level if the clinical problems may
RENAL FUNCTION
25
be alleviated. It is my feeling that the phenolsulphonephthalein
excretion by the kidney is a valuable test which should not be
limited to renal function alone but that it be interpreted in the
much broader diagnostic sense in the field of clinical medicine.
TJREA CLEARANCE
The urea clearance, as described by Van Slyke6 and his coworkers, is used routinely in our laboratory and it is our opinion
that it is the best clinical test for renal insufficiency.
The patient is asked to void and discard the urine and exactly two hours
later a second voiding is obtained and preserved. Ten cubic centimeters of
TABLE 1
Urea clearance
urine urea X Vvolume of urine
blood urea
Standard clearance
(if urine volume
under 2 cc. per
minute)
Average 54 cc.
Variation 30-65 cc.
urine urea X Volume
blood urea
Average 75 cc.
Variation 40-85 cc.
Maximum clearance =
blood are drawn midway during this two hour period. The urea nitrogen
is determined on both the urine and the blood and the ratio of the excretion
of the urine urea to the blood urea is determined.
Van Slyke and his co-workers believe that the normal kidney
should clear 54 cc. of blood of its urea per minute. This volume
of blood cleared is then regarded as 100 per cent efficiency. Certain precautions in doing the test are urged in that urinary tract
obstructions or bladder retention naturally give false readings,
as would the fact that the patient may not have emptied the
bladder prior to starting the tests, so that variable amounts of
nitrogen would be collected in the two hour period. The taking
of caffein (coffee) just prior to the test alters the glomerular
26
M. H E B B E B T BABKER
filtration as does hyperthyroidism and certain cases of very
high blood pressure where a hyperactive circulation is met.
Congestive heart failure reduces proportionately the urea clearance so that normalizing the circulation may be required before
the true status of renal function may be established by this
test. Just as with the phenolsulphonephthalein excretion it
is obvious that the clinician must be fully aware of all of the
factors entering into high and low returns before he may pass
judgment upon the kidney itself.
OTHEB BENAL FUNCTION TESTS
The non-protein nitrogen-urea ratio of Mosenthal 6 and the
creatinine clearance of Rehberg 7 have not supplied many clinicians with enough additional information to replace the three
tests just discussed. Inulin clearance bids fair to gain a place
in routine tests for renal efficiency. The technique as employed,
and the newer blood tests for the material, as developed by
Corcoran and Page 8 will soon clarify this situation. The sulphate
clearance as suggested by Wakefield, Power and Keith 9 apply to
a limited number of chronic nephritis patients who have a rather
specific type of mineral retention. For a detailed discussion
of these and other tests, references may be made to the many
books on laboratory procedure.
PACTOBS INFLUENCING BENAL FUNCTION
In addition to the factors of diurnal diuresis, congestive heart
failure, cirrhosis of the liver, the intake of fluid and stimulants,
all of which alter our interpretation of renal function tests, other
factors should be mentioned. The first is that deviation of acidbase equilibrium affect the kidneys' ability to do work. If a
patient is found to be in a high grade alkalosis or acidosis, a
depression of renal function may be met. Under such circumstances one would withhold his opinion of the existence and
extent of renal disease until acid-base equilibrium had been corrected. Renal function may be similarly greatly depressed
whenever the blood chlorides are reduced under 350 mgm. In
my experience this is especially true of the older person who has
27
RENAL FUNCTION
arteriosclerosis. The older person who may lose chlorides
through vomiting may present the picture of uremia until the
chlorides are replaced, after which renal compensation occurs.
In this connection the effect of sodium chloride in chronic glomerular nephritis may be striking in some instances10. A dramatic
depression of urea clearance, together with an elevation of both
EFFECT OP SODIUM CHLORIDE IN CHRONIC GLOMERULAR NEPHRITIS
UREA
B.P. OLR.
210
205
SYST0LIC-^_„ „
7>B.P.
0 DIASTOLIC^
•-UREA CLEARANCE
190
185
180
175
170
165
160
155
150
145
140
135
130
185
120
115
110
105
100
95
90
/
•
200
195
/
^m
*
\
/
/
\
30
29
28
27
26
25
24
23
22
21
20
19
18
17
16
15
14
13
12
11
10
•
/
V
J*.
\
JOT
A
J^
/
0
\ s \
V''
/
NACL - 15 ( M S . *
DAILY
•"'
\ _
_.-d
---ft-—"*"'
GRAPH 2
systolic and diastolic blood pressure, may be observed when
sodium chloride is being taken by those particular patients. Conversely, when sodium chloride is replaced by potassium chloride
there may be a prompt rise of the urea clearance and a fall in
the blood pressure. We have patients regularly attending our
clinic that will show gradual increases of pressure and a gradual
28
M. H E R B E R T BARKER
retention of waste products until they are thrown into a uremic
crisis, which may be corrected by the rigid restriction of sodium
chloride. Thus it may be seen that the interpretation of a urea
clearance, and the entire renal status may be greatly altered after
this type of patient has been hospitalized on a low sodium diet.
Further influences by specific ions have been noted with both
phosphates and sulphates. Patients with poor renal function
do not clear phosphorus readily, so that the retention of phos-
UREA AND CHOLESTEROL IN END - STAGE NEPHRITIS
BUN
0H0L
160
600
140
i
550
t
t
i
500
/>
\
V''
t
i
120
450
100
400
60
350
\
O— CHOLESTEROL
O— BLOOD UREA NITROOEN
^
\
/ \
\
1
V
/
-6
300
60
250
40
20
JO-—a'
,-A
"v
/
6
200
150
a'
GBAPH 3
phorus and associated acidosis depress renal efficiency. Conversely, this same group of patients usually clear the sulphate
ion readily. The administration of several grams of ammonium
sulphate daily has been associated with a diuresis, a decrease
in blood pressure, and an improvement in urea clearance in an
occasional patient suffering with a chronic glomerular nephritis.
My experience corroborates Page's observations that renal efficiency is not impaired by dropping an elevated blood pressure10.
Actually, when blood pressure is increased by the addition of
RENAL
FUNCTION
29
sodium chloride in the sodium sensitive patient, renal efficiency
is depressed. One cannot say that the depression of renal function is due to the sodium chloride alone, but it may be said that
increasing the blood pressure did not improve kidney function.
The determination of blood cholesterol has been of value in
a prognostic sense in our cases of chronic glomerular nephritis.
Earlier in the disease all of the patients attending our clinic at
Northwestern University Medical School have shown a high
normal to a greatly increased level of blood cholesterol. As renal
efficiency becomes impaired and as nitrogen retention increases,
the blood cholesterol gradually falls12. I t is my opinion that
the patient who appears with a high nitrogen retention, but
who has an elevated blood cholesterol, has a chance for clinical
improvement. However, the same degree of nitrogen retention
with the low blood cholesterol presents little hope for improvement.
SUMMARY
This rather superficial review of renal function is intended to
point out those tests which have been most helpful to me in
the evaluation of the renal status, certain cautions and pitfalls
which alter these tests and, finally, those adjustments of acidbase equilibrium and specific mineral concentrations in the body
which may greatly alter renal function.
REFERENCES
(1) VOLHAED: Ueber die Functionelle Unterscheidung der Schrumpfnieren,
Verhandl. deutch Kong. inn. Med. Wiesbaden, 27: 735, 1910.
(2) FISHBEBG: Hypertension and Nephritis. P . 55, 3rd Edition, Lea and
Febiger, 1934.
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
ROWNTEEE AND GERAGHTY: Arch. Int. Med., 9: 284, 1912.
FEIEDBEEG: J. A. M. A., 105: 1575, 1935.
MOELLEE, MCINTOSH AND VAN SLTKE: J. Clin. Invest., 6: 427, 1928.
MOSENTHAL: Med. Clin. N . Am., 4: 209, 1920.
REHBEEG: Jour. Biochem., 20: 448, 1926.
COBCOEAN AND PAGE: J. Biol. Chem., 127: 601, 1939.
WAKEFIELD, POWEE AND K E I T H : J. A. M. A., 97: 913, 1931.
BAEKEE: J. A. M. A., I l l : 1907, 1938.
(11) BAEKEE: Medical Papers Dedicated to Henry A. Christian, Feb. 1936.