Changes in Plasma Renin Activity in Cirrhosis:
A Reappraisal Based on Studies in 67 Patients
and "Low-Renin" Cirrhosis
S. P. WILKINSON, M.D.,
I. K. SMITH, PH.D., AND ROGER WILLIAMS, M.D.
SUMMARY The generally held views that plasma renin activity (PRA) is increased in cirrhosis and that this
is secondary to reductions in the "effective" blood or extracellular fluid (ECF) volumes, consequent on the
effects of portal hypertension, were re-examined in the present study. Measurements of PRA in 67 patients
representing different clinical stages of cirrhosis showed that the mean value in 15 patients'without ascites was
significantly reduced. In 21 of 35 with ascites, PRA was either reduced or within the normal range. A low
plasma renin substrate concentration was not the cause for the low PRA. These findings are not in keeping
with the concepts of reduced "effective" blood or ECF volumes at least for the majority of patients at these
stages of cirrhosis under the conditions of the present study. The only group showing a significantly increased
PRA had evidence of renal impairment. In these 17 patients the underlying reduction in renal perfusion may
have been the stimulus to the kidney that led to an increase in renin secretion.
(Hypertension 1: 125-129,1979)
KEY WORDS • plasma renin activity * cirrhosis • extracellular fluid volume • renin •
renal impairment • blood volume • portal hypertension • ascites • renin substrate
A
hepatic synthesis of substrate may be impaired911 the
effect of which may limit the full activity of the renin
secreted by the kidney.
In the present study we have determined PRA in 67
patients with cirrhosis at different stages of hepatic
decompensation. The plasma concentration of renin
substrate has also been determined.
NUMBER of studies have reported plasma
renin activity (PRA) to be increased in
cirrhosis.1"8 This has usually been attributed
to an increased renal release secondary to a deficit in
either the "effective" blood volume (from splanchnic
pooling consequent on portal hypertension) or "effective" extracellular fluid (ECF) volume (because of loss
of the ECF into the peritoneal compartment as
ascites), even though total blood, plasma and ECF
volumes are usually increased.68 However, most of
the above studies have been confined to patients with
relatively advanced liver disease with ascites and/or
renal failure and it has not always been clear whether
they were being treated with diuretics, which are
known to be a potent stimulus to renin secretion.
Furthermore, little attention has been given to the
values in patients with well-compensated disease.
Another important factor in the analysis of the
renin-angiotensin system is the plasma concentration
of the renin substrate, since PRA is a function of both
this and its enzyme renin. In advanced liver disease,
Patients and Methods
The 67 patients in our series had histologically
proven cirrhosis attributable to alcohol (44 cases),
chronic active hepatitis (eight cases,fivebeing Hb8Ag
positive), primary biliary cirrhosis (six cases). Nine
cases were cryptogenic. Ages ranged from 33 to 68
years and 52 patients were men. They were divided
into the following three groups:
Group A (Well-compensated). None of these 15
patients had ever had ascites, peripheral edema or
hepatic encephalopathy. Radiological evidence of esophageal varices was present in 11. On the day of the
investigation the glomerular filtration rate, as determined by inulin clearance, ranged from 80 to 254
ml/min. (Abnormally high values for glomerular
filtration rate are well described in cirrhosis.12)
From the Liver Unit and Department of Biochemical Pharmacology, King's College Hospital and Medical School, London,
SE5, England.
Address for reprints: Dr. Roger Williams, King's College
Hospital Medical School, University of London, Denmark Hill,
London, SE 5 8RX, England.
125
126
HYPERTENSION
Group B (Increasing ascites). These 35 patients
were all in positive sodium balance with increasing
body weight and ascites. None had enccphalopathy.
Esophageal varices were present in 34 of the 35 cases.
The inulin clearance ranged from 40 to 249 ml/min.
Group C (Severe hepatic decompensation with
renal failure). This group of 17 patients had evidence
of more severe hepatic decompensation. In addition to
the presence of esophageal varices and ascites all had
renal failure, and all but two had encephalopathy,
seven being deeply comatose. The values for inulin
clearance (or in some cases creatinine clearance)
varied between < 1 and 24 ml/min. Based on the
biochemical findings in the urine, 13 of the 17 patients
had "functional renal failure" (sodium concentration
< 12 mmoles/liter, urine:plasma osmolality ratio
> 1:10), whereas in the others the features were indicative of "acute tubular necrosis" (sodium concentration > 20 mmoles/liter urine: plasma osmolality
ratio < 1:10).
The distribution of age, sex and cause of cirrhosis
was similar in the three groups. None of the 67
patients had had a recent gastrointestinal hemorrhage. Diuretics, which had previously been administered to some of the patients in Groups B and C,
were discontinued at least 2 weeks before the investigation. No patient was receiving corticosteroids
or any other drug known to interfere with renal function or the renin-angiotensin system. All of the
patients in Groups A and B received a controlled
sodium intake of 40-50 mmoles/day for 5 days. In 11
of the Group C patients it was not possible to control
the sodium intake for more than 2 days before study.
The other six patients received the same intake as
those of Groups A and B.
Plasma Renin Activity and Renin Substrate
The blood sample was taken on the morning of the
final day of controlled dietary sodium intake after the
patient had been supine for at least 1 hour. Both PRA
and renin substrate were determined by radioimmunoassay for angiotensin I generation, with excess renin added for the substrate measurements as
previously described.18 Normal values established for
healthy control subjects under identical conditions of
sodium intake and posture were 0.92 to 2.96
nmoles/liter/hr (mean 1.82 ± SD 0.57, n = 20), and
0.57 to 0.94 ^moles/liter (mean 0.78 ± SD 0.10,
n = 13), respectively.
Statistical Methods
Renin substrate values were compared using
Student's / test. The distributions of points for PRA
were non-parametric for Groups B and C and
therefore Wilcoxon's rank sum test for unpaired data
was used for group comparisons.
VOL 1, No 2, MARCH-APRIL
1979
Results
With one exception, PRA was either in the normal
range or reduced in the group of patients without
ascites (fig. 1). The mean value was approximately
one half of that for the control subjects (0.91
nmoles/liter/hr, 1.82 nmoles/liter/hr, respectively,
p < 0.01). The low values were not due to substrate
depletion since measurements for this were almost
identical to the control values (means of 0.83
^moles/liter ± SD 0.20, and 0.78 ^moles/liter ± SD
0.10, respectively, p not significant; fig. 2).
In the Group B patients with increasing ascites, the
mean value for PRA was approximately twice that for
the controls, but the difference did not achieve
statistical significance (3.99 nmoles/liter/hr and 1.82
nmoles/liter/hr, respectively). In five of the 35
patients it was reduced, in 16 it was within the normal
range, and increased up to 17.92 nmoles/liter/hr in
the others. Renin substrate was determined in 17
patients of this group, and although the mean value
was significantly lower than for the control subjects
(0.64 /imoles/liter ± SD 0.27 and 0.78 ^moles/liter
± 0.10, respectively, p < 0.05), substrate depletion
could not account for the low values of PRA found in
four patients with a reduced PRA in whom substrate
was determined; a low value for the latter was found in
only one case. Of the patients with a normal PRA,
substrate was normal or increased in four of eight
cases, but was reduced in four offivecases with an increased PRA.
In the Group C patients with the most severe
hepatic decompensation and renal failure, PRA was
significantly increased compared with control subjects (means of 9.50 nmoles/liter/hr and 1.82
nmoles/liter/hr, respectively, p < 0.01), the highest
value being 21.77 nmoles/liter/hr. Two of the 17
patients had a normal PRA and there was no
difference in the values between those with functional
renal failure and the smaller group with acute tubular
necrosis (means of 9.80 nmoles/liter/hr and 9.50
nmoles/liter/hr, respectively). Renin substrate concentration was significantly lower than for controls
(means of 0.48 ftmoles/liter ± SD o .l5 and 0.78
^moles/liter ± SD 0.10, respectively, p < 0.001), but
was not determined in the two patients with a normal
PRA.
Discussion
The high values for PRA and the reduced renin substrate concentration in the patients with the most
severe hepatocellular impairment (Group C) arc in
agreement with the results reported in other studies.
Although normal values for PRA and plasma renin
concentration have been reported in some patients
with ascites,14- " the abnormally low values, as found
in our patients without ascites (Group A) and in some
of those accumulating ascites (Group B), have not
been reported. Hepatic synthesis of renin substrate is
often presumed to be reduced in cirrhosis and might
127
RENIN IN CIRRHOSIS/Wilkinson et al.
• 21.77
20
18
•
•
16
:
W
•
12
#
10
.
•
8
6
i
•
— H
»A»
0
FIGURE
1.
•
ft
—
WELL
ACCUMULATING
SEVERE DECOMPENSATION
COMPENSATED
ASCITES
WITH RENAL FAILURE
Plasma renin activity in the three patient groups (shaded area indicates normal range).
1.1
1.2
1.0
ui 0-8
| 0.6
CO
| 0.4
0.2
0
WELL
COMPENSATED
FIGURE 2.
ACCUMULATING
ASCITES
SEVERE DECOMPENSATION
WITH RENAL FAILURE
Renin substrate values in the three patient groups (shaded area indicates normal range).
128
HYPERTENSION
therefore be expected to result in abnormally low
values for PRA. However, in the present study of 11
patients with a low PRA in whom substrate was determined (seven from Group A, four from Group B), an
abnormally low value for the latter was found in only
one instance. Clearly, factors other than a reduced
substrate must have been responsible for the low
PRA. Also, because of reduced substrate, PRA might
have been inappropriately low in those patients with a
normal PRA, but of 11 such patients with substrate
determinations (three in Group A, eight in Group B)
low values for the latter were found in only five. In
fact, in the complete series there was a statistically
significant inverse relationship between PRA and substrate (r = -0.51, p < 0.01), suggesting that consumption of substrate, secondary to an increased
plasma renin concentration, is an important factor
determining substrate levels in cirrhosis, in addition to
any presumed reduction in hepatic synthesis.
Major determinants of PRA are known to be the
"effective" blood and ECF volumes,1* the components
of these volumes available to volume receptors.
Because of splanchnic pooling of blood consequent to
portal hypertension, and loss of the ECF into the
peritoneal compartment as ascites, the "effective"
blood and ECF volumes are often thought to be
reduced in cirrhosis. The present finding of a reduced
PRA for Group A patients does not support this concept, at least under the conditions of the present study,
since most of these patients had esophageal varices
and, by inference, portal hypertension. Similarly, the
finding that PRA was normal or reduced in more than
half of the patients comprising Group B would also
argue against deficits in either the "effective" blood or
ECF volumes. These findings suggest that the
measured increases in total blood, plasma and ECF
volumes reported by others" are, at least in those
patients with a reduced PRA, "effective" and not
merely a reflection of sequestered pools in the
splanchnic circulation and peritoneal compartment.
In support of this interpretation the non-splanchnic
component of the total blood volume has been found
to be increased in dogs with dimethylnitrosamineinduced cirrhosis, whether or not ascites is present.17
A number of other factors are also known to result
in a reduced PRA including hyperkalemia, hypernatremia, an increased renal perfusion pressure and a
decreased renal sympathetic nervous activity.18 The
first two of these factors could be excluded in the present cases and no patient had hypertension to account
for an increased renal perfusion pressure. There is evidence for a reduced activity of the sympathetic nervous system in cirrhosis,1"1 m but we have found no
differences for the renal excretion of the metabolite of
catecholamines, vanillylmandelic acid (VMA), among
patients with low, normal or high PRA (unpublished
data), although we have no evidence that VMA excretion specifically relates to renal sympathetic activity.
Increasing age is also associated with a reduced PRA,"
but in the present series no relationship between age
and PRA was found (r = -0.05).
VOL 1, No 2, MARCH-APRIL
1979
The present findings are in keeping with a
mechanism proposed by Lieberman et al.M in which
the renal retention of sodium and water is a primary
abnormality. This results in an expansion of the blood
and ECF volumes and would be expected to suppress
PRA. Retained fluid "overflows" to the peritoneal
compartment as ascites if localizing physical factors
(portal hypertension, reduced plasma oncotic pressure
and impaired hepatic lymph drainage) favor this. Such
a mechanism would explain why a reduction in PRA
may be found in patients who have not yet developed
ascites. In those with ascites, PRA would be expected
to be normal if the amount of fluid that had
"overflowed" as ascites balanced the amount retained
by the kidney, or reduced if the latter exceeded the
former. The mechanism for the primary renal retention of sodium is uncertain but an increased renal
tubular sensitivity to aldosterone has been proposed.18
Some of the patients forming ascites in the present
series (Group B), however, did have strikingly high
values for PRA. Although a reduction in "effective"
blood or ECF volumes could be one reason for this,
there are other possibilities. Thus, an increased PRA
in cirrhosis has been shown to correlate with both
hyponatremia and a redistribution of plasma flow
within the kidney from the renin secreting outer cortical to juxtamedullary nephrons,18 both potent stimuli
to renin release. In the present study, 11 patients in
Group B had hyponatremia (plasma sodium concentration 119 to 129 mmoles/liter) and PRA was higher
for these patients than for the 24 with a normal
plasma sodium concentration (mean values of 8.26
nmoles/liter/hr and 2.03 nmoles/liter/hr, respectively, p < 0.001).
The increased PRA in the patients with renal failure
(Group C) may be largely a consequence of the
reduced renal perfusion responsible for the development of the renal failure. In keeping with this, Barnardo et al.8 found that increasing renal blood flow with
dopamine was followed by a reduction in a raised
PRA. However, the plasma angiotensin II concentra;
on correlates closely with PRA in cirrhosis,16 and it
has been suggested that the high circulating levels of
angiotensin II could be the cause for the renal failure
since it is a powerful renal vasoconstrictor." If this
were so, other mechanisms (such as reduced "effective" ECF volume and hyponatremia) would have to
be responsible for the initial stimulation of the reninangiotensin system. It must also be emphasized that
many patients with cirrhosis are refractory to the
renal vasconstrictor effects of angiotensin II.*8- ** A
further possible mechanism for an increased PRA is
reduced hepatic inactivation.*7
Acknowledgments
We are grateful to Mrs. J. Richardson for technical assistance, to
Dr. S. Lader of Wellcome Reagents for supplying the angiotensin I
antibody, and to Linda Rimmer for editorial assistance.
RENIN IN CIRRHOSIS/Wilkinson et al.
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