Fermentable Carbohydrate

Supplementation Alters Nitrogen Excretion

in Chronic Renal Failure
Hassan Younes, PhD,* Nadine Egret, MD,* Mohamed Hadj-Abdelkader, MD,*
Christian Rmsy, PhD, Christian Demign, PhD, Claudine Gueret, MD,*
Patrice Deteix, MD, PhD,* and Jean-Claude Alphonse, MD*
Background: Considerable attention has been given to the impact of nutrition on kidney disease. Most dietary
attempts to treat chronic renal failure (CRF) and to decrease uremia use a protein restriction. An alternative dietetic
approach based on fermentable carbohydrate (FC) supplementation of the diet could lead to the same urealowering effect by increasing urea nitrogen (N) excretion in stool, with a concomitant decrease of the total N quantity
excreted in urine.
Methods: In the present prospective study, the impact of FC (40 g/d) on uremia and on N excretion routes was
investigated during 5 weeks in nine CRF patients in the presence of a moderated restrictive protein diet (0.8 g/kg/d).
Patients were their own controls and were treated by the cross-over method after randomization (5 weeks with FC
versus 5 weeks without FC).
Results: Feeding FC significantly increased the quantity of N excreted in stool from 2.1 0.8 to 3.2 1.1 g/d
(51%) (P .01) and decreased, in parallel, the urinary N excretion from 9.4 1.7 to 8.3 1.4 g/d (12%) (P
.01). The total N quantities excreted by the two routes were unchanged by the FC, which shows that the FC was
efficient to shift N excretion from the urinary route toward the digestive route. As a result of the increase of urea
transfer into the colon, the plasma urea concentration was significantly decreased from 26.1 8.7 to 20.2
8.2 mmol/L (23%) (P .05).
Conclusions: These results show the same beneficial effects in CRF as those obtained with a restrictive protein
diet without its nutritional drawbacks. This should be confirmed by other prospective works over a longer duration
and a larger number of patients to study the effects of FC on CRF progression and on CRF terminal stage tolerance.
2006 by the National Kidney Foundation, Inc.

URING THE LAST decades, several

works have reported a beneficial effect of
restrictive protein diets in patients suffering from
chronic renal failure (CRF).1 6 Interventions that
restrict protein intake lower the plasma urea concentration, alleviate adverse clinical symptoms,
*Department of Nephrology, Hemodialysis Unit, Hotel Dieu,
CHU Clermont-Ferrand, France.
Human Nutrition Research Center, Metabolic Diseases and
Micronutrients Unit, INRA, Saint-Genes Champanelle, France.
Presented at the 12th International Congress on Nutrition and
Metabolism in Renal Disease, Abano Terme (Padova-Venice), June
19 22, 2004.
Supported by a grant from Bellco France, 9, rue Georges Besse,
92160 Antony, France.
Address reprint requests to Hassan Younes, PhD, CHU Clermont-Ferrand, Department of Nephrology, Hemodialysis Unit,
Hotel Dieu, Bd. Lon Malfreyt, 63003 Clermont-Ferrand,
France. E-mail: hyounes@chu-clermontferrand.fr
2006 by the National Kidney Foundation, Inc.
1051-2276/06/1601-0011$32.00/0
doi:10.1053/j.jrn.2005.10.007

Journal of Renal Nutrition, Vol 16, No 1 ( January), 2006: pp 67-74

and may slow the progression of CRF. Although

these studies provide a logical explanation for a
relationship between a low-protein diet and delaying the progression of functional renal deterioration, this treatment is not easy in practice and
is often accompanied by muscle wasting and
malnutrition.7,8
More recently, the question arose of whether
the effect of a moderate dietary protein restriction
could be reinforced by enrichment of the diet
with fermentable carbohydrates (FC), because
these carbohydrates may influence the nitrogen
(N) metabolism by stimulating the extrarenal
route of N excretion, namely the digestive
route.9 16 Indeed, we have shown in previous
works11,12 that compared with fiber-free conditions, the consumption of FC results in a greater
rate of urea transfer from blood to the cecal
lumen of uremic rats and therefore in a higher
fecal N excretion coupled with a lowering of
67

68

YOUNES ET AL

urinary N excretion. In parallel to this transfer,

the plasma urea concentration was significantly
decreased. We have also shown a synergistic action between the FC supplement and the protein
restriction, particularly on the decrease of uremia.17,18
How are these results explained? In fact, FCs
are poorly digested in the small bowel and will
reach the colon, where they are potentially available to microflora and fermentation. This last
phenomenon increases the N requirements in the
colon to ensure bacterial growth. Generally, N
reaching the large intestine is mainly of endogenous origin: protein coming from the small intestine (pancreatic enzymes and sloughed mucosal
cells) or urea coming either directly from the
blood or from the ileum. Also, it may come from
undigested dietary proteins, but this represents a
small quantity. However, when the intake of FC
increases, the quantity of N present in the colon
may limit maximal bacterial growth. In such
conditions, several investigations have shown that
the blood urea constitutes the major and the most
available source of N for bacterial protein synthesis (see Younes et al19).
It has been shown that the breakdown of FC in
the rat large intestine leads to (1) a cecal hypertrophy with an enlargement of the cecal absorptive mucosa via the production of short-chain
fatty acids (the major end products of the FC
breakdown), (2) a high cecal blood flow, and (3)
a stimulation of ureolytic microflora activity.20 22
All of these parameters act synergistically to create
and to maintain a concentration gradient favorable to a net uptake of blood urea by the large
intestine. Ammonia generated by urease-positive
bacteria is used for bacterial protein synthesis,
promoting irreversible loss of N in the feces at the
expense of renal excretion.11,12
The extrarenal N excretion via the digestive
route may be clinically relevant in patients with
impaired renal function. In those patients, the
question of the efficiency of a moderate protein
restriction has rarely been considered together
with FC supplementation. Consequently, it was
necessary to carry out a clinical prospective trial
(1) to study the influence of a diet enriched in FC
in the presence of a moderate protein restriction
on N excretion pathways in patients suffering
from CRF, and (2) to see whether with this diet
we could obtain the same beneficial effects on

uremia as those obtained with low-protein diets

but without their nutritional drawbacks.

Methods
Patients
The study protocol was carried out during 5
weeks in nine CRF patients, six women and
three men with an average age of 67.7 11.5
years (range, 28 to 82). Etiologies of CRF included glomerulonephritis (five patients), congenital hypoplasia (two patients), and polycystic
kidney (one patient). The patients mean ( standard error of the mean) plasma urea concentration
and clearance of creatinine at baseline were 25 5
mmol/L and 25 5 mL/min, respectively.
The study protocol and its constraints were
explained to each of the nine patients during a
meeting with a physician and a dietician. A consent form was given to them after the meeting,
with a reflection delay before signing it. The
study and its consent form were approved by the
ethical committee for the use of human subjects
in research at the Auvergne University.
Diets
Every patient was placed on a diet with 0.8 g/
kg/d of protein; 40 g/d of FC were supplied per day
in two forms (bread and fiber powder) so that they
could be evenly distributed in each meal and to
optimize their consumption. It must be noted that
bread is a staple food widely consumed and easily
accepted by the patients. However, it was difficult
to introduce the totality of the daily supplement of
fibers in the bread without making it compact and
unpalatable, hence the addition of a fiber powder as
a seasoning. The whole-meal bread provided 25 g
fiber per day (taking into account some patients
saltless diets). The remaining 15 g were supplied
through a powdered mixture providing 4.5 g inulin
(a source of oligosaccharide) and 10.5 g crude potato starch (a source of resistant starch). The N
intake from fiber-enriched bread was 1.29 g/d
(taken into account in the daily total protein intake);
that from powder was negligible (0.003 g/d).
The choice of carbohydrates used was based on
their high fermentability and their well-established beneficial effects on N metabolism in animals with CRF.12,17,18 The choice of the quantity of fiber (40 g/d) took into account (1) the
quantities already used in previous studies on humans,9,15 (2) the present recommendation concern-

FERMENTABLE CARBOHYDRATE SUPPLEMENTATION

ing the quantity of fiber intake (from 30 to 35

g/d),23 and (3) the possibility that the effective
ingestion would be less than the quantities given to
patients. The fiber supply was progressively increased during the first 3 weeks of the study to
adapt the large intestine microflora to the high
supply of FC.

Study Design
This was a prospective study concerning a
group of CRF patients. All patients took part in
the two periods of the study, which each lasted 5
weeks: a control period without any modification
of the diet during which 0.8 g/kg/d of protein
intake was recommended, and a treatment period
with the same diet but enriched with 40 g FC per
day for each patient.
After inclusion, the patients were randomized
to the control or treatment group. Afterward,
groups were inverted according to the cross-over
design; in this way each patient was his or her
own control. The results obtained during both
the control and the treatment periods were compared for each patient.
Each period was composed of two phases: (1) a
3-week adaptation phase, during which the patients
continued the same diet with the usual recommendations about the protein intake (0.8 g/kg/d), and
(2) a 2-week measuring phase, during which the
patients daily received at home two meals with
individual portions. For the same patient, meals
were isoproteic and isoenergetic for both periods.
The Measuring Criteria
Checking Patient Compliance It was
possible to calculate the effective intake of fiber
and protein by directly measuring the daily consumed quantities. For fiber: supplied quantity (40
g/d) remaining quantity in bread and powder;
and for protein: (measured N intake in the meals
evaluated N intake in the probable breakfast
and snacks) (measured N quantity in the remaining of meals).
Checking Nutritional Status Weight
was noted during the patients medical visits. The
anthropometric parameters (the midarm muscle
circumference, the biceps skinfold thickness, and
the triceps skinfold thickness) were measured
with a skinfold compass during the medical visits
by the same physician.
The N balance was calculated by the difference
between the consumed N quantities per day

69

(calculated as previously described) N quantities eliminated in the stool and urine per day. The
24-hour stools were individually collected at the
patients homes in identified, dated, and weighed
plastic pots. Those collected materials were immediately stocked in deep-freeze (at 80C).
Then, the total quantity of stool of the same
patient, collected at the same period, was defrosted and mixed before being diluted with water (1/2) and ground; then two samples of ground
stool were dried. The N quantity in the stool
powder was determined according to the DUMAS method.
The 24-hour urine collection was also done
individually at the patients homes before being
removed, as for the stool, when the meals were
distributed to the patients. The diuresis was measured by the nurses in the hemodialysis unit and
noted in the study file. Then, two samples were
taken and identified. One of those samples was
used to measure creatinuria to calculate creatinine
clearance. The other, for N measurement, was
treated with chlorhydric acid 0.5 M (1 mL/L
urine) to prevent any bacterial development and
then frozen at 20C until analyzed. The measurement was performed according to the pyrochemiluminescent technique.
Plasma Parameters Urea (mmol/L),
creatinine (mol/L), albumin (g/L), and prealbumin (g/L) were measured in the hospital biochemistry laboratory according to standardized
methods.

Statistical Analysis
The data are presented as mean standard
error of the mean. A paired t-test was used to
compare mean values between the control and
treatment periods. Differences were considered
statistically significant at P .05.

Results
Compliance With the Study Protocol
There was no patient dropout nor any exclusion throughout the study. The actual FC intake
(Table 1) was 35.8 4.6 g/patient/d, 90% of the
theoretical quantity. The portion of FC actually
consumed by the patients as bread and powder mix
was 21.3 3.9 and 14.5 0.83 g/patient/d,
respectively. The effective protein intake (Table 1)
was 0.81 0.23 g/kg/d during the control period

70

YOUNES ET AL

and 0.89 0.25 g/kg/d during the treatment

period, hence a 10% increase (significant, P
.05). Energy intake (Table 1) was significantly
increased (P .01) from 22.1 6.1 kcal/kg/d
during the control period to 26.3 6.6 kcal/
kg/d during the treatment period (19%).

The Effects of FC on Plasma Urea and

Creatinine Concentrations and on
Creatinine Clearance
The present study shows a significant decrease
in the plasma urea concentration from 26.1 8.7
to 20.2 8.2 mmol/L (23%) (P .05) (Table
2). However, there was no alteration of plasma
creatinine concentration or creatinine clearance
(Table 2).
The Effects of FC on Stool Weight
Feeding FC diets significantly increases the total
weight of the stool in all patients, from 158 35 to
214 52 g/d/patient (P .05), essentially a
reflection of dry matter excretion, which was increased from 39.2 9.3 to 59.1 11.7 g/d/patient
(51%) (P .05).
The Effects of FC on the N Excretion
Routes
Figure 1 shows the effects of FC on the N
excretion in stool and urinary routes. When the
diet was enriched with FC, there was a significant
increase in the N stool excretion from 2.0 0.8
to 3.1 1.0 g/d (55%) (P .01). In parallel,
the N urinary excretion decreased significantly
from 9.4 1.7 to 8.3 1.38 g/d (12%) (P
.01) in the FC-enriched diet. In fact, the elimination of N was shifted from the stool to the
urinary route because the total N excretion by

Table 2. Effects of Fermentable Carbohydrate

(FC) on the Plasma Urea and Creatinine and on
the Clearance of Creatinine
Control
Period
Plasma urea (mmol/L)
Plasma creatinine
(mol/L)
Clearance of
creatinine (mL/min)

Treatment
Period

26.1 8.7
357 143

20.2 8.2*
339 146

22.6 12.2

24.2 13.9

*P .05 between the control and treatment periods.

both routes did not vary with FC. Its average was
11.4 2.3 g/d. The proportion of N excreted by
the stool route reached nearly one-third of the
total N excretion by both the urinary and stool
routes compared with FC-free conditions (from
18% to 28% with FC diet).

The Effects of FC on the Nutritional

Status
As shown in Table 3, a significant increase in
patient body weight was noted, from 72.1 12.7
to 72.7 11. 9 kg during the treatment period
(600 g) (P .05). The body mass index was
also slightly increased in the presence of FC, but
not significantly.
Regarding the anthropometric parameters, the
midarm muscle circumference, the biceps skinfold thickness, and the triceps skinfolds thickness,
no significant differences were noted in the presence of FC (Table 3). The biological parameters
(albuminemia and prealbuminemia) also did not
present any significant difference between the
control and treatment periods (Table 3).

Table 1. Effective Intake of Fermentable

Carbohydrate (FC), Proteins, and Calories
Control
Period
Total FC intake (g/
patient/d)
Bread fiber (g/d)
Powder fiber (g/d)
Protein intake (g/kg/d)
Energy intake (kcal/
kg/d)

0
0
0
0.81 0.23
22.1 6.1

Treatment
Period
35.8 4.6
21.3 3.9
14.5 0.8
0.89 0.25*
26.3 6.6

*P .05 between the control and treatment periods.

P .01 between the control and treatment periods.

Figure 1. Nitrogen (N) excretion routes (g/d/patient)

of chronic renal failure patients consuming a FCfree diet ( ) or an enriched-FC diet ( ). **P .01.

FERMENTABLE CARBOHYDRATE SUPPLEMENTATION

Table 3. Effects of Fermentable Carbohydrate
(FC) on the Clinical and Biological Characteristics
of Nutritional Status

Body weight (kg)

BMI
MMC (cm)
BSF thickness (cm)
TSF thickness (cm)
Albumin (g/L)
Prealbumin (g/L)

Control
Period

Treatment
Period

72.1 18.7
27.9 3.2
27.3 3.9
4.5 1.5
3.4 1.0
41.8 3.36
0.35 0.08

72.7 18.9*
28.2 3.8
27.1 3.5
4.6 1.4
3.4 0.9
40.3 4.6
0.34 0.09

Abbreviations: BMI, body mass index; BSF, biceps

skinfold; MMC, mid-arm muscle circumference; TSF, triceps skinfold.
*P .05 between the control and treatment periods.

The patients N balances (calculated by the

difference between the N intake and the total N
excretion) were negative. However, a small but
not significant improvement was observed during
the treatment period: from 2.54 2.18 g/d to
1.63 1.81g/d with FC (Fig. 2).

Discussion
Urea is not the only toxic substance in CRF,
but the experimental studies indicate that it can
be responsible for nausea, vomiting, anorexia,
somnolence, and the slowing down of intellectual
function.24 26 Our work on both normal and
uremic animals11,12,17,18 has shown, like the studies using low-protein diets,1 6 that the FC-enriched diets could decrease the concentration of
plasma urea. This FC effect was obtained by
stimulating the urea transfer from blood into the
colon, and consequently its elimination in stool.
To check these results in CRF patients, we performed the present study on a small number of
patients and during a short period.
The constraints inherent to this trial were not
excessive; patients were not requested to complete more medical and dietetic consultations
than usual, and only two additional blood samples
were done. The real constraint was identified as
patient collection of the 24-h urine and stool.
However, this difficulty was overcome by daily
home visits, during which the controlled meals
were given, the urine and stool were recovered,
and the study protocol was re-explained.
Few untoward effects have been noted during
the whole period of the trial. In general, patients
have reported a beneficial effect from their FC

71

intake, especially on their intestinal transit. Only

one patient complained about digestive troubles,
essentially in the form of flatulence.
The effective intake of FC has satisfied the
objectives fixed at 30 to 35 g/d. Contrary to our
expectations, there was a better compliance for
FC powder intake than for FC bread intake. We
suppose that bread exerted a marked satiating
effect, and thus limited its own consumption.
Alternatively, the powdered fiber mix was similar
to a medicine, and its prescription was more
strictly observed by the patients.
As for the protein intake, the instructions were
generally followed: 0.85 g/kg/d on average. This
intake was a slightly higher during the FC-enriched period (10%), which reflects a general
increase in the food consumed during that period.
Accordingly, the average energy intake was also
higher (19%), although the dietetic recommendations given to the patients were not different
and the meals were isoenergetic and isoproteic
during the both the control and the treatment
periods for the same patient. This increase in
energy and N intake can be explained by several
factors: (1) as shown in the presence of a proteinrestricted diet,24 26 the FC-enriched diet in uremic patients could have a beneficial effect on the
appetite through a decrease of the plasma urea
concentration; (2) the FC could have decreased,
as was shown in the rat (in another study in our
laboratory), the plasma leptin concentration being responsible for the CRF patients appetite
troubles (results not published).

Figure 2. Nitrogen (N) balance ( N intake total

N excretion) (g/d/patient) of chronic renal failure
patients consuming a FC-free diet ( ) or an enriched-FC diet ( ).

72

YOUNES ET AL

The patients had a significant decrease in

plasma urea concentration after 5 weeks of FC
consumption. This decrease reached about 23%,
which was similar to the results reported by
Aparicio et al, who have obtained,6 with a verylow-protein diet (0.3 g/kg/d essential amino
acids and ketoanalogs), a 26% decrease in the
plasma urea. In the same view, a significant decrease in urinary N excretion (12%) and a
significant increase in N in the stool (51%) was
observed during the period with FC. Similar
results have been reported by other investigators
using diets enriched with different FCs, such as
gum arabic15 and ispaghula (hemicellulose).9
These investigators reported a plasma urea decrease of 12% or 19% and a stool N increase of
39% or 41% in the presence of gum arabic or
ispaghula, respectively. However, they have not
reported any significant effect on the urinary N
excretion. In contrast, the present work shows,
for the first time in CRF patients, a significant
decrease in the urinary N excretion as a consequence of shifting N excretion toward the digestive route. A similar result has been reported in
cirrhotic patients receiving a vegetable diet rich in
fiber.27
Several hypotheses previously have been proposed concerning how FC leads to that effect. (1)
The fecal N could stem from structural proteins
of plant cell walls containing fiber, which could
decrease the digestibility of dietary protein in the
small intestine.28 In our trial, purified FC has
been supplied daily in powder and bread, providing a modest quantity of N that was taken into
account in the daily total protein intake. In addition, a recent study has shown in humans that
the presence of FC (such as guar gum) in the diet
should not reduce the digestibility and the availability of dietary protein in the small intestine.29
(2) The fiber could adsorb the N metabolic waste
in the intestinal content and thus could serve as a
vehicle for their elimination in stool.30 This
seems unlikely because the fiber used in the above
study is extensively fermented by colonic bacteria31 and would thus constitute a poorly effective
sorbent. On the other hand, Bliss et al15 have not
reported a significant N increase in the fraction of
stool containing undigested fiber, but rather in
the fraction containing bacteria, showing that the
increase of N excretion in the stool was chiefly
attributable to the changes in colonic bacterial
protein metabolism.

How do fermentation and changes in bacterial

mass affect N metabolism in CRF patients? The
results of the present study are reminiscent of the
physiological modifications observed in uremic
rats.12,18 Those modifications are the result of the
development of colonic bacteria in response to
FC intake, which is depolymerized and fermented in the colon, leading to a considerable
enlargement of the colonic contents and a hypertrophy of the cecal wall.11,17,20 This can be ascribed to high concentrations of short-chain fatty
acids, especially butyrate, which is considered a
particularly potent trophic factor.32,33 In this
view, the resistant starch used in our study could
exert a trophic effect on colonic mucosa.34 As a
result of the colonic wall hypertrophy, there is an
enlargement of the exchange surface area between blood and colonic lumen, together with an
increase in colonic blood flow.11,12,35 In such
conditions, the N necessary to promote optimal
bacterial growth increases and will be provided
by the blood urea through an osmotic effect. This
is all the more possible because the colonic bacterial has a high ureasic activity.36 Urea is hydrolyzed into ammonia, a part of which will be used
for the bacterial protein synthesis in the colon,
bacteria being finally eliminated in stool.19,37,38
In humans, noninvasive techniques to measure
the urea flux to the colon are not available.
Nevertheless, Bliss et al15 have treated the stool
according to the technique of Stephen and Cummings,39 enabling separation of different parts of
stool. They showed that the increase of the stool
weight mostly concerned the bacteria mass,
which was multiplied by 1.5 with a gum arabic
enriched diet.15 In our study, this measurement
could not be performed, but it seems likely that
the increase of our patients stool weight, especially the dry weight, was also connected with the
increase of colonic bacterial mass. In fact, because
bacteria make up 55% of the dry stool weight in
humans on a western diet,39 and because bacteria
are composed of 7% to 8% N (dry weight),40 any
proliferation in the colon will increase the stool
mass and thus the N excretion. Consequently, the
FC effects on uremia and on N routes observed in
our patients are essentially related to the bacterial
flora and the fermentation processes.
On the other hand, this increase of bacterial
mass can also be particularly interesting in CRF
patients because it directly or indirectly exerts a
bulking effect, hence a reduction of the transit

FERMENTABLE CARBOHYDRATE SUPPLEMENTATION

time in the large intestine, and prevents constipation.41

The present study, like others,9,10,15 has not
put forward a significant difference in the renal
function estimated by the plasma creatinine and
the creatinine clearance. A previous study in CRF
patients42 has shown a blunting of the plasma urea
and creatinine increase and an improvement in the
creatinine clearance after a 30-week rhubarb-enriched diet without modification of the nutritional
state. The effects observed in this study could be
attributable to the diarrhea phenomenon, which
was attempted in the past under the name of intestinal dialysis to reduce the ammoniac recycling toward the liver.43
The increase of the stool N excretion provoked by the consumption of FC had no undesirable consequences on nutritional status. This
can be explained by the energy provided by FC as
well as by the fact that the fiber used did not alter
protein digestibility as reported in some previous
studies.44,45 In fact, the results of Mariotti et al29
are in keeping with our observations: they did
not observe any negative effect of the consumption of guar gum on the digestion and the availability of dietary proteins in humans.
Our patients N balance, even if still negative,
seemed to improve when FC was added to the
diet. Their weight also increased significantly
(600 g). Those results were attributable to the
increase in patients energy and protein consumption. It is well known that a deficient energy
intake compromises protein metabolism and contributes to malnutrition.46 In our study, like in
most others dealing with the same subject, the
energy intake failed to satisfy the usual recommendations (35 kcal/kg/d) because it was only
22.2 kcal/kg/d during the control period and
26.4 kcal/kg/d during the treatment period. The
increase in the patients energy and N intakes,
without any increase in either the total N excretion or the plasma urea, is promising and suggests
that in the long term, a significant improvement
in N balance could be achieved. These elements
must be confirmed in future works.
In conclusion, the need for CRF patients
protein restriction has been known for half a
century, whereas that of FC is more recent. The
results obtained in the present work with FC are all
the more interesting because they are nearly equivalent to those obtained with protein-restricted diets,
without drastic changes in the patients nutritional

73

habits. Conceivably, FC administration might seem

as effective as protein restrictions, particularly on
uremia, but with limited nutritional drawbacks.
This should be investigated by other long-term
studies on a larger number of patients to study the
effect of FC on the renal function itself.

Acknowledgments
The authors acknowledge the dietitian Mme. J. Richard
and the care staff of the hemodialysis unit, Department of
Nephrology, CHU of Clermont-Ferrand, for their technical
help. We also acknowledge the CHU central catering unit
for providing meals, and the patients for their participation in
this study.

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