247
Clinical Science (1987) 73, 247-252
Evidence for large intestinal control of potassium
homoeostasis in uraemic patients undergoing long-term
dialysis
G.1. SANDLE, E. GAIGER, S. TAPSTER
AND
T. H. J. GOODSHIP
Departments of Medicine, and Clinical Biochemistry and Metabolic Medicine, Royal Victoria Infirmary and University of
Newcastle upon Tyne, U.K.
(Received 23 July 1986/5 January 1987; accepted 11 March 1987)
SUMMARY
1. The role of the large intestine in the maintenance of
K + balance in uraemic patients established on long-term
dialysis was studied with a rectal dialysis technique in 14
normal subjects, ten normokalaemic patients undergoing
chronic ambulatory peritoneal dialysis (CAPD), and
seven patients undergoing haemodialysis. Dietary K +
intakes in the normal subjects, CAPD patients and
haemodialysis patients were 80-100 mmol/24 h, 70-80
mmol/24 hand 60-70 mmol/24 h, respectively.
2. At an initial intraluminal K + concentration of 45
mmol/l, rectal K + secretion in the CAPD patients
(204 ± 004 .umol hlcm") was greater than in normal subjects (1.2±0.2 .umol h- I cm ", P<0.02). Under similar
conditions, rectal K + secretion was also greater in the
haemodialysis patients than in normal subjects, both predialysis (3.7±004 zzmol h' cm", P<O.OOI) and postdialysis (204±0.5 .umol h' em:", P< 0.05), even though
haemodialysis decreased plasma K + concentration from
5.3 ± 0.1 mmol/l to 3.5 ± 0.2 mmol/l (P< 0.001).
3. There were no significant differences in rectal Na +
absorption, rectal potential difference, plasma aldosterone concentration, or total body K + content
(measured by whole-body counting of 4°K), between the
normal subjects and either the CAPD or the haemodialy~~~ms.
. .
4. These results indicate that K + homoeostasis tS
maintained in uraemic patients undergoing long-term
dialysis by a combination of K + losses during dialysis, and
enhanced large intestinal K + excretion. The role of the
large intestine appears to be particularly important ~t
higher dietary K + intakes, and the K + secretory process tS
sensitive to changes in plasma K + concentration.
Correspondence: Dr G. I. Sandie, Department of Medicine,
Clinical Sciences Building, Hope Hospital, Eccles Old Road,
Salford M6 8HD, UK
Key words: dialysis, large intestine, potassium transport,
uraemia.
Abbreviations: CAPD, chronic ambulatory peritoneal
dialysis; FFM, fat-free mass; TBK, total body potassium.
INTRODUCTION
The concept of 'K + tolerance' was first proposed by
Thatcher & Radike, who demonstrated that rats fed on a
K +-enriched diet were able to survive acute oral K + loads
that were lethal in control animals [1]. This phenomenon
of 'K + tolerance' of 'K + adaptation' has since been shown
to involve changes in the K + transport properties of
epithelia lining the renal tubular and collecting duct
systems [2-5] and the large intestine [6-9], which enhance
their capacity for K + secretion [10].
Chronic renal insufficiency constitutes a second, and
clinically more important, example of 'K + adaptation' in
renal and large intestinal epithelia [10]. Studies in animal
models of renal insufficiency have shown that normal
plasma K + concentrations are maintained despite a constant dietary K + intake, owing to an increase in the rate of
K + secretion by surviving nephrons. This adaptive
response is associated with, and possibly dependent on, (i)
enhanced Na +,K +-ATPase activity in the renal cortex and
outer medulla [11], and (ii) an increase in the rate of delivery of K+ to the distal tubule [12]. Although renal K+
adaptation in chronic renal insufficiency is reasonably
well characterized, the effects of chronic uraemia and the
associated reduction in renal K + excretion on large intestinal K + transport are less clear. Increased faecal K +
excretion occurs in patients with chronic uraemia [13,14],
which suggests that the human large intestine adapts to
playa more prominent role in the control of ~ + h~~oeo­
stasis. Studies in an animal model of renal insufficiency
induced by 70% nephrectomy have shown a rise in the
K + secretory capacity of the large intestine, which is asso-
248
G. I. Sandie et aI.
ciated with increased mucosal Na +,K +-Al'Pase activity
[15]. Recent studies with a rectal dialysis technique have
demonstrated increased rectal K + secretion in patients
with moderately severe uraemia not requiring dialysis
who were normokalaemic, and this change in K + transport was not associated with increases in either the transmural electrical potential difference or plasma
aldosterone concentration [16]. These findings raise the
possibility that K + transport processes in the mucosa of
the rectum and the remainder of the large intestine 'sense'
and respond to transient increases in plasma K + concentration, which may occur after food and produce intermittent increases in the excretory load of K + circulating
to the mucosa. In the present study, this hypothesis was
tested in patients with end-stage renal failure in whom the
excretory load of K + applied to the large intestine was
reduced chronically by peritoneal dialysis, or acutely by
haernodialysis, and overall K + balance was assessed by
measuring total body K + content (TBK).
METHODS
Subjects
After obtaining informed written consent, 14 subjects
with normal renal function (four male, ten female, age
22-64 years), ten normotensive uraemic patients undergoing chronic ambulatory peritoneal dialysis (CAPO)
(eight male. two female, aged 48-65 years), and seven
uraemic patients undergoing haemodialysis (two male,
five female, age 17-58 years), were studied with a rectal
dialysis technique approved by the Hospital Ethical Committee. Subjects with normal renal function were patients
who had presented originally with mild gastrointestinal
symptoms which were considered to be functional after
extensive negative investigations. Dietary assessment of
the normal subjects revealed dietary K + intakes of
80-100 mmol/24 h. Patients undergoing CAPO and
haemodialysis were maintained on diets designed to
achieve dietary K + intakes of 70-80 mmol/24 hand
60- 70 mmol/24 h respectively, and dietary compliance
was checked by the dietician at 1-2 monthly intervals.
None of the normal subjects or uraemic patients was
receiving diuretics, corticosteroids or cation-exchange
resins.
Rectal dialysis technique
Rectal potential difference and net electrolyte and
water fluxes were measured by using a dialysis technique
[17], modified as previously described [18]. Briefly, dialysis bags were constructed from 6-8 em lengths of Visking
tubing (1.43 ern diameter, Medicell International,
London) and sealed at both ends with silk thread and
epoxy resin, after incorporating a 4% agar-I 54 mrnol/l
sodium chloride bridge and a fine bore tube (Portex, internal diameter 1 mrn) to enable electrolyte solutions to be
introduced in the bag ill situ. The bag was placed in the
proximal rectum via a sigmoidoscope after cleaning the
mucosa, so that the lower end was 8 ern from the anus. A
subcutaneous cannula filled with 154 mmol/I sodium
chloride was sited on the lateral aspect of the thigh and
connected to a second bridge. Both bridges were attached
to a portable voltmeter via calomel half-cells in 3 mrnol/l
potassium chloride. Rectal potential difference was
lumen-negative and the electrical asymmetry in the
measuring system was < 1.5 m V.
Normal subjects and CAPO patients were studied in
the non-fasting state at 11.00 hours. CAPO patients were
undergoing four dialysis cycles each day, and were
studied at the start of a cycle with 2 Iitres of dialysate containing (mmol/l): Na+ 132, K+ 0.75, Ca"+ 1.75, CI- 102,
and lactate 35; Travenol Laboratories) in the peritoneal
cavity. Haemodialysis patients were undergoing dialysis
two to three times each week, and were studied in the
non-fasting state at 08.00 hours immediately before, and
at 13.30 hours immediately after, the dialysis session.
Haernodialysis fluid contained (in mmol/I): Na + 136, K +
1.54, Ca?" 1.55, Mg"+ 0.5, CI- 101, and acetate 40
(Macarthys Laboratories, code S/5(9). All rectal dialyses
were done over 30 min with an isotonic solution containing (mmol/I): Na ' 105, K+ 45, CI- 105 and HCG:; 45,
and polyethylene glycol 4000 (PEG; 5 g/I) was a nonabsorbable marker. Immediately afterwards, Na ", K +, CIand HCO; were measured by autoanalyser (Beckman,
Astra 8). and PEG was assayed turbidimetrically [19].
The volumes of solution in the dialysis bag at the start and
at the end of the rectal dialysis period were determined as
previously described [18]. Changes in content of water
and electrolytes were calculated from the changes in
volume and electrolyte concentrations that occurred
during the 30 min study period. The area of the bag was
assumed to be equal to the area of the mueosa over which
electrolyte and water movements occurred [17], and net
fluxes of electrolytes and water were therefore expressed
as ,umol h- I cm ? and,ul h- I cm ", respectively.
Determination oftotal body K + content (TBK)
Subjects were weighed in light indoor clothing and their
heights measured in stockinged feet. Measurements were
taken in CAPO patients after draining peritoneal effluent,
and in haemodialysis patients immediately after dialysis.
Skin-fold thickness was measured with Harpenden
calipers at the biceps and triceps, and at the subscapular
and suprailiac sites. Fat-free mass (FFM) was estimated
from body weight and the sum of the four skin-fold thicknesses by the method of Durnin & Womersely [20]. TBK
was estimated using a shadow shield whole-body counter
for detection of the natural radionuclide 4IJK [21], and was
expressed as mmol of K +/kg FFM.
Determination of plasma electrolyte and aldosterone concentrations
Immediately after each rectal dialysis period, 20 ml of
blood was drawn into plastic tubes containing anticoagulant, the plasma separated by centrifugation at 4°C, and
electrolytes were measured immediately by autoanalyser.
Bicarbonate concentrations on plasma and rectal dialys-
Large intestinal potassium transport in uraemia
ate were based on pH electrode measurements of total
carbon dioxide contents after acid displacement. As all
samples were analysed immediately after collection, total
carbon dioxide content was assumed accurately to reflect
bicarbonate concentration. The remainder of the plasma
was stored at - 20°C for subsequent determination of
aldosterone by radioimmunoassay as previously
described [16].
Statistical analysis
All results are expressed as means ± SEM, and statistical
comparisons were made by using a two-tailed Student's {test for paired or unpaired data as appropriate [22].
RESULTS
Plasma biochemistry
Plasma electrolytes and creatuune concentrations in
the normal subjects and in the two. groups of uraemic
patients undergoing dialysis, are shown in Table 1. The
main findings are that, compared with the mean plasma
K + concentration in the normal subjects (4.1 ± 0.1
mmol/l), plasma K + concentration was similar in the
CAPD patients (4.3 ± 0.3 mmol/l) but significantly raised
in the haemodialysis patients under pre-dialysis conditions
(5.3±0.1 mmol/l, P<O.OOl). Haemodialysis decreased
plasma K + concentration to 3.5 ± 0.2 mmol/l (P< 0.001),
the post-dialysis concentration being significantly lower
than in the normal subjects (P< 0.025).
249
preceding visits to the out-patient clinic. Haemodialysis
also resulted in a significant fall in weight (from 60.6 ± 4.6
kg to 58.7 ± 4.4 kg, P < 0.005).
Rectal electrolyte transport
Rectal electrolyte fluxes and transmural potential differences obtained in the normal subjects and the two
groups of uraemic patients are presented in Table 2. Compared with rectal K + secretion in normal subjects
(1.2 ± 0.2 ,umol h- I cm"), K + secretion was significantly
greater in the CAPD patients (2.4 ± 0.4 ,umol h- I cm",
P< 0.02), and in the haemodialysis patients under predialysis conditions (3.7 ±0.4 ,umol h- I crrr", P< 0.001).
Haemodialysis decreased rectal K + secretion from
3.7 ± 0.4 ,umol h' cm ? to 2.4 ± 0.5 ,umol h- I ern?
(P< 0.025), and the post-dialysis value remained greater
than in normal subjects (P< 0.05). Rectal absorption of
Na" , Cl- and water (data not shown), secretion of HC0:i,
and transmural potential difference, were similar in the
three groups.
Cardiovascular and weight measurements
Haemodialysis was associated with significant decreases in systolic blood pressure (from 149 ± 12 mmHg
to 120± 10 mmHg, P< 0.005) and diastolic blood pressure (from 79 ± 8 mmHg to 65 ± 7 mmHg, P < 0.05),
without a significant change in heart rate (from 89 ± 4
beats/min to 98 ± 8 beats/min, P> 0.1). In CAPD
patients, systolic and diastolic blood pressures were not
measured routinely before and after peritoneal dialysis,
but all of these patients were noted to be normotensive at
Anthropometric data and total body K + content
Table 3 shows the anthropometric measurements and
TBK obtained in nine normal subjects, nine patients
undergoing CAPD, and seven haemodialysis patients.
Owing to the predominance of men among the CAPD
patients, mean height in the CAPD group (1.72 ± 0.04 m)
was greater than in normal subjects (1.59 ± 0.3 m,
P < 0.02) and the haemodialysis patients (1.60 ± 0.1 m,
P< 0.02). There were no significant differences in body
weight between the three groups. In general, skin-fold
thicknesses were lower in the CAPD and haemodialysis
patients than in the normal subjects, but these differences
were significant only for the triceps and biceps folds in the
CAPD patients, and the triceps and suprailiac folds in the
haemodialysis patients. There were no significant differences in fat content, FFM and TBK between the three
groups, except that FFM in CAPD patients (52.8 ± 3.3
kg) was greater than in normal subjects (41.7 ± 2.7 kg
P < 0.05), which reflected the predominance of taller men
in the CAPD group. There were no differences in TBK
Table 1. Plasma electrolyte concentrations in normal subjects, and in patients undergoing
chronic ambulatory peritoneal dialysis (CAPD), or haemodialysis
Results are expressed as means ± SEM. ap< 0.001, »r-: 0.025 and cp< 0.05, compared with
normal subjects. Other differences between the three groups were not statistically significant.
dDifference between pre-dialysis and post-dialysis values.
Normal (n = 14)
CAPD(n=10)
Haemodialysis (n = 7)
Pre-dialysis
Post-dialysis
Sodium
(mmol/I)
Potassium
(rnrnol/l)
Chloride
Bicarbonate
(mmol/l)
(mmol/l)
Creatinine
(,umol/I)
141 ±2
139± I
4.1 ± 0.1
4.3±0.3
108± I
102 ± I"
24.8 ±0.7
24.8±0.7
68±4
1066 ± 113"
139± 1
140± 1
5.3±0.1"
3.5 ±0.2 h
<0.001
3.5-5.0
101 ± 1"
98 ± 1"
<0.02
96-106
22.3 ± 1.0e
26.5 ± 1.3
<0.05
22-29
1214 ± 148"
652 ± 103"
<0.001
53-124
[J<J
Normal range
134-147
250
G. l. Sandie et al.
Table 2. Rectal electrolyte fluxes and potential differences in normal subjects, and in patients
undergoing chronic ambulatory peritoneal dialysis (CAPD) or haemodialysis
Results are expressed as means ± SEM. Initial intraluminal electrolyte concentrations were (mmol/
I): Na ' 105, K+ 45, CI- 105 and HCO; 45. Potential difference was lumen-negative. "P< 0.001,
b P < 0.02 and c P < 0.05, compared with normal subjects. Other differences between the three
groups were not statistically significant. dDifference between pre-dialysis and post-dialysis values.
Net potassium
secretion
(,umol h' cm")
2.5 ± 0.4
4.0 ± 0.9
1.2±0.2
2.4 ± O.4b
3.6 ±0.5
4.9±0.6
2.8 ± 0.4
2.8 ±0.4
-46±3
-39±3
3.5 ±0.9
3.8± 1.1
3.7 ± 0.4"
2.4± 0.5'
<0.025
3.7±0.6
4.7 ± 0.7
2.9±0.6
2.6 ±0.6
-43±5
-47±3
Normal(n= 14)
CAPD(n= 10)
Haemodialysis (n = 7)
Pre-dialysis
Post-dialysis
[>.1
Net chloride
Net bicarbonate
secretion
absorption
(,umol lr' cm- Z) (,umol h- I cm")
Potential
difference
(mY)
Net sodium
absorption
(,umol h' cm- Z)
Table 3. Anthropometric measurements and total body K + contents (TBK) in nine normal subjects, nine patients undergoing chronic ambulatory peritoneal dialysis (CAPD), and seven
patients undergoing haemodialysis
Results are expressed as means ± SEM. "P < 0.05 or less compared with normal subjects. Other differences between the three groups were not statistically significant.
Male:female
Age (years)
Weight (kg)
Height (m)
Skin-fold thickness (mm)
Triceps
Biceps
Subscapular
Suprailiac
Fat content (%)
FFM (kg)
TBK (mmol of K +)
TBKjweight (mmol of K + jkg)
TBKjFFM (mmol of K + jkg)
Normal
CAPD
Haemodialysis
3:6
49.5 ± 3.9
61.3±2.1
1.59±O.03
7:2
56.1 ±2.1
71.1±5.0
1.72 ±0.04"
2:5
47.2 ±4.6
58.1 ±2.7
1.60 ± 0.01
18.6 ± 2.5
9.1 ± 1.4
21.2±3.2
17.7±2.7
32.2 ± 3.1
41.7±2.7
2423±215
39.5 ± 2.6
58.1 ± 1.3
between the three groups, whether expressed in terms of
body weight or FFM.
Plasma aldosterone concentrations
Plasma aldosterone concentrations were measured
because excessive aldosterone secretion has been
reported in patients with chronic renal insufficiency [23],
and it has been suggested that increased faecal K + excretion in chronic uraemia may at least partly reflect secondary hyperaldosteronism [14]. In the present study,
however, plasma aldosterone concentrations were similar
in the eleven normal subjects, nine CAPD patients, and
five haemodialysis patients, in whom measurements were
obtained (Fig. 1).
DISCUSSION
Recent studies have demonstrated increased rectal K +
secretion in patients with chronic uraemia who were
11.2 ± 1.4"
4.7 ±0.6"
16.1 ±3.2
15.7±3.5
25.2 ±2.8
52.8± 3.3"
2859±208
40.2 ±2.3
54.1 ±2.1
11.6 ±2.0"
5.5 ± 1.2
11.8±3.7
9.8 ± 2.2"
24.4 ±4.1
43.5 ± 1.7
2387 ± 179
41.1 ± 3.3
54.9 ± 2.8
normokalaemic and non-dialysed, even though maintained on a normal dietary K + intake of about 90 mmol/
day [16]. This finding, together with the results of other
studies [13, 14], suggests that the large intestine adapts in
chronic renal insufficiency to increase its capacity for K +
secretion. The present study was done to determine
whether this change in rectal K + transport persisted when
large amounts of K + were removed by CAPO or haemodialysis from uraemic patients who received 60-80% of
the normal dietary K + intake. The results indicate that
rectal K + secretion was greater than normal in the CAPD
patients and in the haemodialysis patients (under both
pre-dialysis and post-dialysis conditions), whereas rectal
Na + absorption and potential difference, and plasma
aldosterone concentrations, were normal in both dialysis
groups. These findings are similar to those obtained in
non-dialysed uraemic patients, in whom the addition of
1mmol/I amiloride (which inhibits aldosterone-sensitive,
electrogenic Na + transport) to the dialysis bag resulted in
decreases in rectal Na + absorption and potential differ-
Large intestinal potassium transport in uraemia
400
300
o
:::::..
"0
E
•
S
OJ
=
...0
s
'"
0
"0
8
200
t<l
""
E
'"
E:""
100
o
0
••
6b
•1.
0
0
0
0
Normal
••
CAPD
Pre-
<,
Post-
,/
Haemodialysis
Fig. 1. Plasma aldosterone concentrations in 11 normal
subjects, nine CAPD patients, and five haemodialysis
patients (pre-dialysis and post-dialysis).
ence which were similar to those observed in normal subjects [16]. The results of the present and previous study
[16] therefore suggest that enhanced rectal K + secretion
in the CAPD and haemodialysis patients did not reflect
secondary hyperaldosteronism, or an increase in the 'sensitivity' of the rectal mucosa to normal plasma concentrations of aldosterone.
Simple extrapolation of our data suggests total large
intestinal K + secretory fluxes of 54 mmol/day in normal
subjects and 108 mmol/day in the CAPD patients, assuming the large intestine to be 4 em in diameter and 150 em
in length. These values are clearly overestimates, and
probably reflect the initial concentration of K + (45 mmol/
I) present in the rectal dialysate. We have previously
demonstrated that although rectal K + secretion was greater in uraemic patients than in normal subjects over a
wide range of intraluminal K + concentrations (10-45
mmol/l), K + secretion in both groups decreased at
increasing intraluminal concentrations of K + [16]. We
would therefore expect K + secretory fluxes in the rectum
(and in other large intestinal segments) to be lower if
measured at intraluminal concentrations of K + which
were similar to those normally present in faecal water
(80-100 mmolfI). It should also be emphasized that the
rise in K + secretion in uraemic patients may be more
marked in the rectum and descending colon than in the
251
proximal large intestine, as studies in rat colon indicate
that the distal segment exhibits a larger K + secretory
response than the proximal segment during chronic
dietary K + loading [7, 24]. In our CAPD patients, peritoneal dialysis was performed with 2 litres of dialysate containing 0.75 mmol/l of K+, with a dwell-time of 6-8 h. As
K + moved passively from the plasma to the peritoneal
cavity to equilibrate at the prevailing plasma concentration, daily peritoneal losses were relatively constant at
about 30 mmoI. Consequently, CAPD patients with
dietary K + intakes of 70-80 mmol/day appear to maintain K + homo eostasis by increasing their total large intestinal K + excretion to 40-50 mmol/day, assuming
negligible urinary K + losses. Daily faecal K + outputs of
this magnitude exceed the value we have calculated (25
mmol of K+/day) from the results of Wilson et at. [14].
This difference, however, probably reflects the high K +
intake allowed in our patients, as daily faecal K + excretion varies directly with dietary K + intake in severe
uraemia [13].
The results obtained in the haemodialysis patients
indicate that K+ transport in the rectum (and presumably
throughout the large intestine) is at least partly dependent
on plasma K + concentration. Under pre-dialysis conditions, haemodialysis patients were hyperkalaemic compared with the normal subjects (Table 1), and rectal K+
secretion in the haemodialysis patients (3.7 ± 0.4 .umol h- I
crrr") was 200% greater than in the normal subjects
(1.2 ± 0.2 .umol h- I cm"; Table 2). This increase in rectal
K + secretion can be attributed equally to chronic adaptive changes in mucosal K + transport, and the effect of
pre-dialysis hyperkalaemia, as rectal K + secretion under
post-dialysis conditions (2.4 ± 0.5 .umol h- 1 crrr")
remained greater than normal (1.2 ± 0.2 .umol h' cm",
P< 0.05), whereas the decrease in rectal K+ secretion
(from 3.7 ± 0.4 .umol h- I cm ? to 2.4 ± 0.5 .umol h- I em:",
P< 0.025) induced by haemodialysis was associated with
a decrease in plasma K + concentration from 5.3 ± 0.1
mmol/I to 3.5 ±0.2 mrnol/l (P< 0.001). Conversely, these
results suggest that the colonic mucosa in uraemic
patients (which is already adapted for increased K + secretion), secretes even more K + as plasma K + concentration
gradually rises during the 48-72 h interdialysis period. In
this regard, it is interesting that in the rat, a 2 mmol/I rise
in portal vein K + concentration (produced by KCI infusion into the superior mesenteric artery) has been
shown to be associated with marked increases in colonic
K + secretion in normal animals and in animals maintained on a K +-enriched diet [24].
In the present study, total body K + content (TBK) was
similar in the normal subjects and in the CAPD patients,
although Goodship et al. [25] found TBK to be slightly
lower in 52 CAPD patients (54.4 ± 1.0 mmol of K+/kg
FFM) than in 52 normal subjects (59.7 ± 0.8 mmol of K+/
kg FFM, P < 0.001), who were better matched for sex,
age and body mass. We also found TBK to be normal in
the haemodialysis patients, in agreement with other
studies in which TBK was assessed by whole-body counting [26-28], or by measurement of intracellular K+ in
leucocytes [29] and skeletal muscle cells [30]. Our results
252
G. 1. Sandie et al.
suggest that enhanced large intestinal K + secretion in
uraemia is not dependent on an increase in TBK, but
rather that K + homoeostasis is maintained (as judged by
the normal TBK) by a combination of peritoneal or
haemodialysis, and increased K + secretion by the large
intestine. The level of large intestinal K + secretion in
dialysis patients appears to depend on the amount of K +
delivered to the mucosal sites of K + transport, and varies
with dietary K + intake and plasma K + concentration.
ACKNOWLEDGMENTS
We thank the Department of Medical Physics, Royal
Victoria Infirmary, for the total body potassium measurements; Miss Sarah Tisdall, for assessing dietary potassium
intakes; and Dr M. K. Ward for allowing us to study
patients under his care. G.I.S. holds a Medical Research
Council Senior Clinical Fellowship.
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