Clinical Science (1970) 38,439-449.
OBSERVATIONS O F RENAL FUNCTION I N PATIENTS
U N D E R G O I N G THERAPEUTIC DIURESIS
WITH FRUSEMIDE
R. F. JEWKES, N. B U R K I
AND
A. GUZ
Department of Medicine, Charing Cross Hospital Medical School, London
(Received25 August 1969)
SUMMARY
1. Changes in extracellular water, plasma volume, blood urea and glomerular
filtration rate were recorded over intervals of up to 28 days in ten patients requiring
diuretic therapy, eight of whom were oedematous and none of whom had obvious
renal disease.
2. Diuresis with frusemide was invariably associated with a fall in extracellular
water and, in all but one instance, with a fall in plasma volume. It was also associated
in every case with a rise in blood urea and fall in glomerular filtration rate.
3. The fall in glomerular filtration rate was observed when the extracellular water
and the plasma volume of each patient was still within the 'normal' range predicted
on the basis of dry weight.
4. Cessation of treatment was followed by a return to initial levels of the plasma
volume and extracellular water, blood urea and glomerular filtration rate.
5. When body weight became stable during the administration of frusemide,
there was a partial re-expansion of the plasma volume and a tendency for the glomerular filtration rate to rise.
6. The mechanism whereby these changes in renal function are brought about is
unknown.
The use of diuretics may be associated with a deterioration of renal function as shown by a
rise in blood urea and a fall in glomerular filtration rate (Corcoran et al., 1959; Heidland
et al., 1964a). Renal function may return to normal with the passage of time but always does
so if treatment is reduced or terminated. These changes are seen more frequently since the
advent of frusemide but similar changes have been observed with thiazide diuretics (Corcoran
et al., 1959). Though there is little quantitative information available it seems likely that any
difference merely reflects the greater potency of frusemide. This study was intended to document some changes in renal function encountered using frusemide and to show the extent
Correspondence: Dr R. F. Jewkes, Department of Medicine, Charing Cross Hospital Medical School,
Fulham Hospital, London, W.6.
439
R. F. Jewkes, N . Burki and A . Guz
440
to which they reflect the effectiveness of diuresis, as judged by changes in body weight, extracellular water or plasma volume.
MATERIALS A N D METHODS
Patients
Five men and five women between 51 and 82 years of age were studied (Table 1). Two
subjects were in heart failure, one from rheumatic valvular disease and the other from myocardial infarction. Six subjects had respiratory failure from chronic bronchitis and emphysema.
The two remaining subjects (both women) had oedema of long duration for which no cause
was found. This group reflects the type of patient seen in the unit most concerned in this work.
There was no selection of cases. The study was partly retrospective and partly prospective.
TABLE
1. Patient data
Patient Age Sex
C.A.
A.C.
A.D.
E.H.
F.N.
H.N.
E.R.
W.S.
C.S.
L.W.
42
76
67
51
76
66
82
, 65
62
53
F
M
M
F
F
M
F
M
M
F
Diagnosis
Idiopathic oedema; obesity
Myocardial infarction; acute LV failure
Respiratory failure; acute on chronic bronchitis
Mitral stenosis; congestive cardiac failure
Respiratory failure; acute on chronic bronchitis
Respiratory failure; chronic bronchitis
Respiratory failure; acute on chronic bronchitis
Respiratory failure; chronic bronchitis
Respiratory failure; chronic bronchitis; carcinoma of the larynx
Idiopathic oedema
Oedema
(Oto
+++)
+
++
+++
+++
0
+++
+
+
+
0
Diuretic
F
F+A
F
F+A
F+ A
F+A
F+A
F
F
F
Diuretics: F = Frusemide, A = Aldactone A.
All subjects were normotensive. In eight subjects there was no evidence of renal disease as
shown by the initial level of blood urea, the creatinine clearance and chemical and microscopic
examination of the urine. Three of these (E.R., L.W. and A.D.) later came to post-mortem
examination and the kidneys were shown to be anatomically normal. In one case (F.N.)
there was evidence of renal disease as shown by persistently raised urinary white cell excretion
and a reduced glomerular filtration rate, though the blood urea was usually within normal
limits. In one patient (E.H.) with severe heart failure, the blood urea was consistently raised
and the glomerular atration rate reduced, though no renal cause was found on gross or
microscopic examination of the kidneys post mortem.
Methods
The patients were weighed daily, and blood pressure measurements were made several
times each day by the nursing staff. A mean of these measurements was taken as the average
blood pressure for a particular day. Plasma urea and electrolytes were estimated frequently,
usually daily. Glomerular filtration rate was estimated by the 24 hr creatinine clearance using
standard AutoAnalyser N-Methodology. In three cases the validity of the changes of creatinine
Renal function after frusemide
441
clearance was checked by the estimation of renal clearance of [51Cr]EDTA (Favre & Wing,
1968). Plasma volume was measured by dilution of [13’1] human serum albumin. Extracellular
water was measured by 82Br dilution after equilibration for 16-24 hr. Total body water was
measured by dilution of tritiated water. Predictions of normal body composition were made
from the data of Moore et al. (1963). Circulatory studies were performed on one patient (C.A.)
during diuresis. Cardiac output was measured repeatedly with the aid of an indwelling pulmonary artery catheter using the Fick principle. All patients received the general ward diet.
The diuretic used was frusemide with supplements of potassium chloride (50-150 mEq/day).
Five cases indicated in the patient data table also received spironolactone (Aldactone A 25 mg
four times daily) throughout the study. In all cases diuresis was regulated by manipulating
the dosage of frusemide, the pattern of administration being dictated by therapeutic requirements.
RESULTS
When diuretics were first given, the body weight fell steadily for a few days before levelling
out into a flat ‘plateau’ or a period when the weight fluctuated. Further fall in weight could be
brought about by increasing the dose of the diuretic. If diuretics were stopped, weight was
regained spontaneously.
The results have been considered in relation to ‘acute change’ periods and ‘plateau’periods.
The ‘acute change’ periods were periods of between 3 and 28 days when body weight fell,
and include four periods after diuretics were discontinued when body weight rose. The ‘plateau’
periods were periods of 3-14 days following initial diuresis when body weight remained steady
while diuretics were continued.
Not all variables were documented in every case and data could sometimes not be used when
measurements were subsequently shown to have been mistimed in relation to a patient’s
change of weight. As a result, eighteen ‘acute change’ periods were available for the variable,
blood urea; however, changes in extracellularwater were measured in only ten of these periods.
Periods in which body weight fluctuated irregularly were considered uninterpretable and are
not reported here.
Detailed results on all patients are shown in Clinical Science, Table 38/14, deposited with
the Librarian, The Royal Society of Medicine, London, W.l. from whom copies may be
obtained.
‘Acute change’ periods
Eighteen such periods of between 3 and 28 days in length were observed in the ten patients.
Fourteen periods were during diuresis and four were periods of ,spontaneous weight gain after
diuretics had been stopped.
Weight change and blood urea (Fig. 1). The blood urea rose when the body weight fell, and
conversely fell if the body weight was allowed to rise again.
Weight change and glomerular filtration rate (Fig. 2). The relationship between the fall in
glomerular liltration rate (GFR) and the weight loss was recorded in eleven periods. In each
period as the weight fell, the GFR fell or, conversely, if the weight rose, the GFR also rose.
The GFR fell during diuresis to 50-70% of its initial value and the extent of the fall was
not related to the initial level of the GFR.
442
R. F. Jewkes, N . Burki and A. Guz
FIG.1. Weight change and change in blood urea in eighteen ‘acute change’ periods.
n
LL
W
4
41
4
2
Weight gain ( k g )
0
2
4
6
Weight loss ( k g )
8
FIG.2. Weight change and change in glomerular filtration rate in eleven ‘acute change’ periods.
Each period is represented by an arrow joining the initial GFR value to the final GFR value.
Renal function after frusemide
443
Weight change and changes of body composition. Weight change was related to change in
plasma volume in thirteen periods (Fig. 3), and to the total extracellular fluid volume (ECW)
in ten periods (Fig. 4).
I
Weight gain (kg)
Weight loss (kg)
FIG.3. Weight change and change in plasma volume in thirteen ‘acute change’ periods.
1:.
L
8 ”
FIG.4.Weight change and change in extracellular water in ten ‘acute change’ periods.
The changes in body weight and plasma volume were in the same direction with one exception. This patient (C.S.) was in respiratory failure and the only patient in this series in whom
oedema was associated with a low plasma volume (two standard deviations below the predicted
mean value for age and weight). In this case, diuresis was associated with fall in weight, in
extracellular water and in GFR, but plasma volume rose.
D
R. F. Jewkes, N . Burki and A. Guz
444
The changes in ECW were always in the same direction as the changes in body weight. The
proportion of the weight change represented by change in ECW averaged 80%.
Fig. 5 illustrates the effect of diuresis on the plasma volume and ECW of these patients
relative to normal values predicted for each patient on the basis of estimated dry weight. With
one exception the lowest plasma volume recorded in each case still fell within the normal
limits, though the values as a whole cluster in the lower part of the range. Again with one
exception, the lowest ECW recorded is within the normal range or above.
(males)
200
'
(females)
0
"f
x
140
P
6o
I
FIG.5. The lowest value recorded in each patient of plasma volume and extracellular water,
expressed as a percentage of the mean predicted value for that patient at dry weight. The uppermost and lowest lines represent the 95% confidence limits of prediction according to the
data of Moore et ul. (1963).
The relation between changes in the plasma volume and the ECW, and the corresponding
change in the GFR is illustrated in Fig. 6. The correlation coefficient for percentage change
in plasma volume against percentage change in GFR is 0.75 (PcO-05). The correlation coefficientforthe percentagechange in ECW against percentage change in GFRis 0.88 (P <0*01).
Blood pressure changes. Diuresis was usually associated with a fall in blood pressure of the
order of 10%.
Weight change and change in cardiac output. This was documented in one case (C.A.) who
had had a catheter introduced into the pulmonary artery for another study. This permitted
daily resting cardiac output estimations and the findings are recorded in Fig. 7 . There was no
significant fall in cardiac output or blood pressure over a period of 7 days during which time
the GFR fell by half.
Plasma electrolyte changes. During the fourteen 'acute change' periods, the plasma sodium
stayed constant or rose slightly in five and fell slightly in nine. In only one case did the plasma
sodium fall below 130 mEq/l.
Renal function after frusemide
I
60
I
1
30
0
% GFR rise
0
445
1
60
30
% GFR fail
e
0
-s
z20-
.%
0
'C
FIG. 6. The relation between changes in plasma volume and extracellular water and the
accompanying changes in GFR. Changes in plasma volume indicated by closed circles and extracellular water by open circles.
Dote
20
21
22
23
24
25
26
Weight (kg)
91.2
89.5
88.5
87.9
88.2
87.7
87.9
\<\\\\\\\Ledimesu<fv\\\\\\\\\h
I.
Cardiac
0
Heart rate
80
72
70
76
70
74
74
Ozcon5umPtion
(ml/min)
236
218
251
271
256
237
235
Arterio-venous
O2dif ference
(VOlS 70)
5.4
4.5
4.9
5.3
6.2
5.2
4.9
GFR (ml/min)
101
47
FIG.7. Daily measurements of cardiac output during diuresis in subject C.A. The dotted line
indicates the mean value for cardiac output during the 7 day period.
446
R. F. Jewkes, N. Burlzi and A. Guz
‘Plateau’periods
Data on ten ‘plateau’ periods are presented in Fig. 8. Their duration was between 3 and
14 days and the limits of weight change were -0.6 kg and 1.2 kg-the largest weight gain
occurring over the longest time interval. The tendency for the blood urea to fall was proportional to the elevation produced by the preceding diuresis. The greater fall in blood urea
+
GFR
14-30
Py
(% rise)
19
21
43-69
58-65
17
Nil
47-44
70-67
9
FIG.8. Change in blood urea during ten ‘plateau’ periods. Each period is indicated by a line
joining the initial value to the final value. The columns on the right list additional information
concerning coincident changes in GFR and plasma volume.
was associated with correspondingly greater proportionate improvements in GFR and reexpansion of the plasma volume. In those cases where the blood urea had not risen outside
the normal range, there was little tendency for a return to the original levels while diuretics
were continued.
During the ten ‘plateau’ periods, the plasma sodium stayed constant or rose slightly in six
and fell slightly in three, in two of which it fell below 130 mEq/l. In one ‘plateau’ period the
plasma sodium remained steady below 130 mEq/l.
DISCUSSION
This study demonstrated a consistent fall in glomerular filtration rate during therapeutic
diuresis which was closely associated with a fall in extracellular water and rather less closely
with a fall in plasma volume. This effect of diuretics has not hitherto been clearly demonstrated
in oedematous patients undergoing routine treatment. Heidland et al. (1964a) reported a
study of hypertensive patients and oedematous patients with valvular heart disease treated with
cyclopenthiazide. They showed a fall of glomerular filtration rate when the patients were
Renal function after frusemide
447
restudied after 14-21 days. Corcoran et al. (1959) and Dustan et al. (1959) studied normal and
hypertensive subjects on chlorothiazide and showed a fall in plasma volume, cardiac output,
glomerular filtration rate and renal plasma flow over periods of treatment of 3-14 days. None
of their subjects was oedematous.
In contrast, many studies have reported the acute effects of diuretics. These have been carried
out on normal subjects or non-oedematous ambulant hypertensive subjects. They indicate that
the effects of frusemide and chlorothiazide are not identical under these circumstances. Single
doses of chlorothiazidein man cause a fall in cardiac output, renal plasma flow and glomerular
filtration rate (Crosley et al., 1960; Villareal et al., 1962). Similar studies with frusemide have
shown a rise in renal blood flow and glomerular filtration rate (Buchborn & Anastasakis, 1964;
Schirmeister & Willman, 1964; Heidland et al., 1964b; Vorburger, 1964; Jahnecke, Konietzko
& Kruck, 1964). These findings have been questioned as the clearance techniques for measuring glomerular filtration rate and renal plasma flow are prone to large errors in situations of
rapidly changing urine flow rates. Hook et al. (1966), and Ludens et al. (1968) using flowmeter
techniques, however, have shown an increase in renal blood flow during frusemide diuresis
in the dog, and contrasted this with a reduction in renal blood flow produced by chlorothiazide
and chlormerodrin. This effect of frusemide on the renal circulation appears to be unique
among saliuretic diuretics. The changes in glomerular filtration rate we have demonstrated
over longer time intervals, however, appear to be common to both thiazide diuretics and
frusemide.
The fall in glomerular filtration rate here reported could be due to a fall in blood pressure
or cardiac output, in spite of any renal vasodilation produced by frusemide. However, in our
patients falls in blood pressure were slight, of the order commonly seen in patients on no
specific treatment in the first few days after hospital admission. We made detailed observations
of cardiac output in one patient (C.A.) with a stable blood pressure who had a catheter in the
pulmonary artery for several days as part of a separate investigation. Resting cardiac output
was measured daily and did not fall significantly over 7 days of diuretic therapy during which
time the glomerular filtration rate fell by half. Clearly in this patient there was no question of a
haemodynamic change initiated by diuresis which was outside the range of normal daily
variation. Falls in blood pressure or cardiac output do not account for our findings.
The possibility has to be considered that the fall in glomerular filtration rate was a direct
effect of the diuretic on the kidney. However, comparable changes in glomerular filtration
rate, extracellular water and plasma volume to those we have observed have been described in
sodium depletion brought about without diuretics. This was first shown by McCance (1936,
1938) in normal man after sodium depletion by sweating. Chasis et al. (1950), Murphy (1950),
Watkin et al. (1950) and Weston et al. (1950) documented this more completely in hypertensive
subjects treated with the Kempner rice diet. Also the acute studies of diuretic action referred to
earlier show that the direct effectsof frusemide and chlorothiazide on the kidney are different,
the former increasing and the latter reducing renal blood flow. But the changes in glomerular
filtration rate we have recorded over longer time intervals suggest an effect common to both
thiazides and frusemide. The evidence therefore favours a common extrarenal factor initiating
renal vasoconstriction when sodium depletion is maintained over a period of days. The
correlation with fall in extracellularwater and plasma volumes is striking though we are unable
to confirm that this is causative rather than coincidental.
Other facets of therapeutic diuresis concerning which we have data support the suggestion
448
R. F. Jewkes, N . Burki and A . Guz
that the common extrarenal factor initiating renal vasoconstriction is the fall in intravascular
or total extracellular fluid volume. In four periods we recorded the restoration of glomerular
filtration rate during rehydration, at the same time as the extracellularwater and plasma volume
returned to previous levels. Glomerular filtration rate also tended to increase during the
‘plateau’ periods when weight was relatively constant and the administration of diuretics
continued. The improvement in each ‘plateau’ was roughly comparable in magnitude to the
impairment produced by the preceding acute change periods, but was incomplete over the
intervals of up to 14 days which our observation covered. The plasma and interstitial compartments partially refilled during the ‘plateaux’ and it seems likely that this accounts for the
improvement of renal function observed.
Salt depletion causes an increase in plasma renin and angiotensin levels (Brown et al., 1964)
but it is unlikely that this would account for the changes we have observed. Indeed, Bohr &
Uchida (1967) have suggested that the afferent arteriolar musculature is unresponsive to
circulating angiotensin. Renal vasoconstriction might be due to increased sympathetic activity
with a generalized increase in vascular tone similar to that occurring after haemorrhage.
However, renal vasoconstriction in response to a fall in circulating fluid volume can occur
normally in man after sympathectomy (Wilkins et al., 1953). Pharmacological blockade of the
sympathetic system did not reverse renal vasoconstriction following salt depletion (Weston
et al., 1950). But neither of these studies is conclusive and this possibility has not been fully
explored.
It is concluded that at present the mechanism of this fall in glomerular filtration rate is
unknown.
ACKNOWLEDGMENTS
The authors wish to express their gratitude to Professor H. E. de Wardener for his valuable
guidance and encouragement during this work. Hoechst Pharmaceuticals are thanked for their
generous support throughout this study.
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