Download Role of Fermentable Carbohydrate Supplements With a Low

EDITORIAL REVIEW
Role of Fermentable Carbohydrate Supplements With a Low-Protein
Diet in the Course of Chronic Renal Failure: Experimental Bases
Hassan Younes, PhD, Jean-Claude Alphonse, MD, Stephen R. Behr, PhD,
Christian Demigné, PhD, and Christian Rémésy, PhD
● During the past few years, considerable attention has been given to the impact of nutrition on kidney disease. The
question arises of whether the effect of a moderate dietary protein restriction could be reinforced by enrichment of
the diet with fermentable carbohydrates. Feeding fermentable carbohydrates may stimulate the extrarenal route of
nitrogen (N) excretion through the fecal route. Such an effect has been reported in several species, including
healthy humans and patients with chronic renal failure (CRF). Furthermore, studies of these subjects show that the
greater fecal N excretion during the fermentable carbohydrate supplementation period was accompanied by a
significant decrease in plasma urea concentration. In animal models of experimental renal failure, the consumption
of diets containing fermentable carbohydrates results in a greater rate of urea N transfer from blood to the cecal
lumen, where it is hydrolyzed by bacterial urease before subsequent microflora metabolism and proliferation.
Therefore, this results in a greater fecal N excretion, coupled with a reduction in urinary N excretion and plasma
urea concentration. Because elevated concentrations of serum urea N have been associated with adverse clinical
symptoms of CRF, these results suggest a possible usefulness of combining fermentable carbohydrates with a
low-protein diet to increase N excretion through the fecal route. Further investigations in this population of patients
of whether fermentable carbohydrates in the diet may be beneficial in delaying or treating the symptoms and
chronic complications of CRF will certainly emerge in the future. This should be realized without adversely affecting
nutritional status and, as far as possible, by optimizing protein intake for the patients without being detrimental to
renal function.
娀 1999 by the National Kidney Foundation, Inc.
INDEX WORDS: Fermentable carbohydrate; dietary protein; urea; nitrogen excretion; chronic renal failure.
D
URING THE PAST few years, considerable
attention has been given to the impact of
nutrition on kidney disease. Interventions that
restrict protein intake decrease plasma urea concentrations, alleviate adverse clinical symptoms,
and may slow the progression of chronic renal
failure (CRF).1-12 Although these studies provide
a logical explanation for the relationship between a low-protein diet and altering the progression of functional renal deterioration, this beneficial effect is often accompanied by some muscle
wasting and malnutrition.7,13,14 The question arises
of whether the effect of a moderate dietary protein restriction could be reinforced by enrichment of the diet with fermentable carbohydrates,
because these carbohydrates may stimulate the
extrarenal route of nitrogen (N) excretion through
the fecal route.15-21
Restriction of dietary protein is a way to limit
the symptoms linked to hyperuremia in patients
with CRF.1-4 This restriction helps prevent the
development of CRF and consequently delays
the start of dialysis.5-12 However, there is a risk
for protein malnutrition when the dietary restriction is excessive (⬍0.5 g/kg/d).22
At a physiological level, there are two routes
to eliminate N; urine and feces. Our results show
it is possible to increase the N fecal route excretion by reducing the protein supply and increasing fermentable carbohydrate availability.16,23,24
This additional dietary manipulation is very interesting in the case of renal deficiency.21,25 The
modification of urea N enterohepatic cycling by
fermentable carbohydrates is likely to promote
proliferation of the large-intestinal microflora,
which could be an interesting approach to deviate part of the N excretion to feces as a consequence of N utilization by bacteria.16,17,21 Conversely, a large proportion of the N released by
From the Laboratoire des Maladies Métaboliques et des
Micronutriments, INRA, Centre de Recherches en Nutrition
Humaine de Clermont-Ferrand/Theix, St-Genès-Champanelle; Service de Néphrologie, Hôtel-Dieu, ClermontFerrand, France; and Ross Products Division, Abbott Laboratories, Columbus, OH.
Received December 8, 1997; accepted in revised form
August 8, 1998.
Address reprint requests to Hassan Younes, PhD, Laboratoire des Maladies Métaboliques et des Micronutriments,
INRA de Clermont-Ferrand/Theix, 63122 Saint-GenèsChampanelle, France. E-mail: [email protected]
娀 1999 by the National Kidney Foundation, Inc.
0272-6386/99/3304-0002$3.00/0
American Journal of Kidney Diseases, Vol 33, No 4 (April), 1999: pp 633-646
633
634
urea hydrolysis in the digestive tract may be
recycled through the reabsorption of ammonia
and could thus contribute to a reduced need
of N.26-29
In the domain of preventive nutrition, the first
recognized effect of dietary fiber was to regularize digestive transit, especially in the case of
constipation.30,31 However, during the past decades, some other interesting effects have been
reported, especially lipid-reducing effects, improvement in blood glucose control, reduction of
colon cancer risk, and increase in availability of
some cations.32-41 In contrast, the efficacy of
dietary fiber in the treatment of CRF has been
less well investigated, although the availability
of dietary fiber should profoundly alter microflora metabolism and proliferation and, as a result, N metabolism.
The aim of this editorial is to review, for the
course of CRF, the capacity of an additional
dietary manipulation in increasing fermentable
carbohydrates that can stimulate the transfer of
urea into the large intestine and shift N excretion
from urine to the feces.
PRESENT DIETARY APPROACH TO TREAT
PATIENTS WITH CRF
Until now, research and dietetic propositions
for patients with CRF were based on the nephroprotection concept, making an attempt to maintain a satisfactory nutritional state. In other words,
the aim of the research and dietetic propositions
was to delay the progression of renal deterioration, reduce urea toxicity, and limit muscle wasting. Numerous studies have reported a reduction
in renal failure progression with a low-protein
diet. A link between glomerular hyperperfusion,
hyperfiltration, and structural change was suggested in studies involving dietary protein restriction.42
The relationship between dietary protein restriction and renal failure progression has been
known for a long time. Approximately 50 years
ago, Addis speculated that the severity of CRF
could be improved by reducing the dietary protein level.43 Since then, a considerable body of
evidence has accumulated suggesting the slowing or temporary halt of the progression of CRF.
In fact, a large number of diets have been proposed and more or less widely used during the
last decades. The overall strategy was to
YOUNES ET AL
reduce N intake by selecting foods of vegetable
origin and supplementing this basal diet with
small amounts of protein of high biological value
to satisfy the requirement for essential amino
acids (AAs). Another approach was to use a
supplement of essential AAs or keto acids
(KAs)44; however, the use of KAs was not particularly convincing.45
Studies of patients with CRF (randomized and
nonrandomized trials) reported that restricting
dietary protein and phosphate early in the course
of CRF had a considerable influence on the rate
of progression of this disease.1-12 In experimental
models, dietary protein restriction reduced the
load of N metabolism end products for excretion,
limited the adaptive changes in remnant nephrons, and slowed the tendency to renal disease
progression.6 Despite unambiguous support from
experimental studies, the conclusive results are
often regarded as unconvincing because they do
not meet strict statistical rules.46
More recently, from work performed within
the Modification of Diet in Renal Disease
(MDRD) study (a randomized, controlled trial),
it appears that protein restriction has only a slight
benefit for the patient with moderate renal failure.45 Moreover, when renal failure was at an
advanced stage, protein restriction, even when
severe and supplemented with KAs, did not
really reduce the progression of the disease.45 In
fact, there was an initial diet-induced decline in
glomerular filtration rate (GFR), followed by
long-term beneficial effects of dietary protein
restriction (after 4 months), with an improvement in functioning nephron conservation.12 This
initial rapid reduction in GFR, accompanied by a
reduction in protein excretion rate, is a functional
effect and does not reflect a further loss of
nephrons.47 In a second MDRD study, the investigators concluded that the addition of KAs did
not exert a beneficial effect,45 and, for patients
with a low GFR (⬍25 mL/min/1.73 m2), a dietary protein intake of 0.6 g/kg/d should be
prescribed.7
The question arises therefore on the degree of
protein restriction. For health maintenance, a
minimum daily supply of protein was defined by
the Food and Agriculture Organization (FAO) in
the range of 0.5 g/kg/d.22 In practice, in patients
who are predialysis and treated by a maintenance
method, a protein supply less than 0.6 g/kg/d has
FERMENTABLE CARBOHYDRATE AND FECAL N EXCRETION
been proposed in association with KA supplementation.13,14 However, the risk for protein malnutrition7,48,49 and the constraints inherent to this
supplementation led to a recommendation of a
moderate dietary protein supply of approximately 0.8 g/kg/d.22,45
In dialysis patients, the protein restriction question is more complex because there is an aggravated risk for protein-calorie undernutrition, with
increased morbidity and mortality (30% of the
dialysis patients).50,51 This leads to a rejection of
protein restriction with, as a result, a proposed
supply in the 1- to 1.2-g/kg/d range.52-59 However, it is still uncertain whether this policy is
enough to equilibrate the N balance in these
patients because there is a proportional relationship between protein supply and rate of N catabolism as estimated by the protein catabolic rate.60-62
The protein-calorie undernutrition observed in
dialysis patients is often linked to a deficient
supply,63,64 which is itself often linked to a depressed appetite.55,65 Moreover, dialysis sessions
constitute a protein catabolism stimulation by
means of an inflammatory response in contact
with the membrane, which induces the secretion
of such hypercatabolic factors as interleukins.66
The loss of glucose (25 g/session) and AAs (10
to 12 g/session) can also decrease the protein
anabolic capacity and thus lead to an increased
net proteolysis.67,68 In practice, and in certain
important undernutrition situations, it is necessary to provide a nutritional complement, especially AAs, which are injected intravenously
during the dialysis session. The dialysis fluid can
be used also as a nutritional vehicle for the
supplementation of N.69 The predialytic parenteral nutrition seems to yield good results to
preserve nutritional status70 and improve both
morbidity and mortality in retrospective data.71,72
Recent studies show that the catabolic rate of
AAs and net protein synthesis could be affected
by the speed of protein digestion.73 Thus, soluble
proteins of milk are more quickly oxidized and
lead to a less efficient protein synthesis than
casein. It is more helpful to have slowly digested
carbohydrates than rapid carbohydrates, and in
the same view, it also would be helpful to select
slowly degradated proteins (in particular, plant
proteins). This approach has not been sufficiently
investigated in comparison with the quantitative
approach.
635
In the elderly, the development of renal disease is frequently linked to such pathological
states as diabetes and/or cardiovascular diseases.74-77 Consequently, it is important to control the supply of both carbohydrates and lipids.
In this view, it has been shown that diets enriched
in fiber can improve blood glucose control and
reduce serum cholesterol levels in patients with
diabetes.78,79 It has been also shown that preservation of the remaining nephrons in nephrectomized rats is greatly dependent on the nature of
the carbohydrate ingested. Kidney preservation
thus could be improved by a supply of complex,
rather than simple, carbohydrates.80,81
Control of the lipid supply and the balance of
fatty acids is also important because patients
with CRF are frequently hyperlipidemic, with an
increase in the total amount of plasma cholesterol, triglycerides, phospholipids, low-density
lipoprotein, and very low-density lipoprotein and
a decrease in high-density lipoprotein levels.74,75
In some animal models of CRF,82,83 it has been
shown that low-fat diets have protective effects
on the progression of glomerular damage.
Furthermore, it is well known that diets for
patients with CRF must be restricted in phosphorus and potassium and provide a calcium supplement to help the fecal elimination of phosphate.84-86 Because of nutritional constraints
inherent to the renal deficiency, it is particularly
important to maintain the energetic balance of
patients and provide nutrition rich in protective
factors, in particular, antioxidants to limit the
severity of oxidative stress.
RELATIONSHIP BETWEEN FERMENTABLE
CARBOHYDRATE INTAKE AND SYMBIOTIC
FERMENTATION IN THE LARGE INTESTINE
Because digestive function is often disturbed
(constipation) in patients with CRF, it is important to consider dietary fiber for proper functioning of the colon, as well as for N elimination.
There is now substantial evidence that fermentative processes similar to those occurring in
nonruminant herbivorous and omnivorous species also take place in the human large intestine.87 In many animal species, the colon has an
important digestive role to recover energy from
unavailable dietary carbohydrates that are not
hydrolyzed and absorbed in the upper digestive
tract. Traditionally, the human large intestine has
636
YOUNES ET AL
Table 1. Classification of Fermentable Carbohydrates
Oligosaccharides and
Sugar Alcohols
Plant Cell Wall
Polysaccharides
Hydrocolloids
Fructooligosaccharide Nonsoluble
Pectins
Xylooligosaccharide
Cellulose
Gums
Galactooligosaccharide
Hemicelluloses
Exudate (arabic)
Xylitol
Soluble
Storage (guar)
Mannitol
Pectins
Bacteria synthesis (xanthane)
Sorbitol
␤-Glucans
Sea plant polysaccharides (carrageenans)
Hemicelluloses
been considered an organ that conserves minerals and water and controls the disposal of undigested products. In recent years, research has
also focused on the metabolic and digestive
effects of various dietary fibers. In humans, it has
been shown that the development of symbiotic
fermentation had beneficial effects through the
absorption and utilization of short-chain fatty
acids (SCFAs).88
The breakdown of nutrients transferred from
the ileum to the large intestine is performed by a
diverse population of bacteria. Bacteria are ubiquitous in the digestive tract, but are mainly
confined to the large intestine. In humans, there
are from 1011 to 1012 germs/g of content that are
divided into no less than 400 various species.
This represents 35% to 55% of the digestive
content weight.89,90 These flora, mainly anaerobic, establish symbiotic relationships with the
host. In addition, they probably fulfill a protective effect toward pathogenic species. The principal substrates for the bacteria are dietary fibers
(nonstarch polysaccharides, 10 to ⬎50 g/d), resistant starches (8 to 40 g/d), and oligosaccharides
(Table 1), as well as proteins. Concerning the
quantity of mucus (coming from the higher parts
of the digestive tract or secreted in situ) and the
sloughed epithelial cells, there is still uncertainty
about their quantitative contribution.
Resistant Starches
Cereal starch (amylomaize)
Crudo potato starch
Leguminous starch
Banana starch
Retrograded or modified starches
In humans, the major end products of carbohydrate breakdown are SCFAs (essentially acetate,
propionate, and butyrate)91 and the gases H2 and
CO2 (Fig 1).92 The total concentration of SCFAs
is relatively stable in the large intestine; in the
proximal part (cecum, proximal colon), they are
generally found in the range of 80 to 150 mmol/L
and, in the distal colon, they may be less (range,
50 to 100 mmol/L).88 The SCFAs are the main
anions in the large intestine. For osmotic reasons, it
is expected that they could not exceed 130 to 150
mmol/L. However, when the pH of fermentation is
very acidic (close to 5), the proportion of SCFAs
under protoned form becomes very important,
and then it is possible to find concentrations
greater than 150 mmol/L for SCFAs alone or,
more often, for SCFAs plus lactate.88
The availability of fermentable carbohydrates
influences the molar proportions of SCFAs in the
colon. Schematically, fermentation with a pH
greater than 6.5 is relatively slow and favors the
production of acetic acid. Fermentation close to a
pH of 6.0 to 6.5 is generally favorable to high
propionic acid fermentation, whereas acidic fermentation (close to 5.5) gives rise to the appearance of notable concentrations of lactate. Other
products of fermentation include branchedSCFAs from the deamination of branched-chain
AAs, ammonia, various carboxylic and phenolic
Fig 1. Conversion stages
of polysaccharides in SCFAs
and other fermentation products by microflora in the large
intestine.
FERMENTABLE CARBOHYDRATE AND FECAL N EXCRETION
acids, and amines.93 The branched-SCFAs (isobutyrate, isovalerate, 2-methylbutyrate) are very
low in quantity in the proximal part of the large
intestine (less than 10% of the total SCFA),
where a very active bacterial anabolism occurs.
In the distal part of the large intestine, the exhaustion of fermentable carbohydrate and the increase in luminal pH favor proteolysis that chiefly
affects bacterial protein, together with desaminations of AAs and production of the branchedSCFAs. In humans, the latter could be 35% to
40% of the total SCFA in the distal colon.88
Conversely, active fermentation stimulates bacterial growth and leads to considerable enlargement of the colonic contents and hypertrophy of
the cecal wall in the rat.16,17,94 These changes
result in enlargement of the exchange surface
area between blood and luminal fluid, together
with an increase in colonic blood flow.21,95,96
This in turn stimulates the exchange of urea and
ammonia N between blood and the digestive
lumen.17,21,96 The relative hypertrophy of the
cecal wall in rats fed fermentable carbohydrates
can be ascribed to high concentrations of SCFAs,
especially butyrate, which is considered a particularly potent trophic factor.97,98 In this view, it
must be noticed that resistant starch exerts a
marked trophic effect on colonic mucosa.99 Data
on the action of fiber on the colonic wall in
humans are lacking, but it is possible that fermentable carbohydrates exert similar trophic effects.
Dietary fiber contributes to reduced transit
time in the large intestine by exerting a bulk
effect directly or indirectly by the increase of
bacterial mass.100 There is a direct relationship
between an accelerated transit time, enhanced
fecal bacterial mass, and fecal N excretion.101
Furthermore, it has been shown that the increase
in fecal N excretion was compensated by a
decrease in urinary urea. The laxative effects of
fermentable carbohydrates are particularly interesting to prevent and treat constipation (frequent
in patients with CRF).102-104
RELATIONSHIP BETWEEN FERMENTABLE
CARBOHYDRATE INTAKE AND
ENTEROHEPATIC CYCLING OF UREA
AND AMMONIA
How do these changes in bacterial mass and
stool bulk affect N metabolism? Fermentation,
637
by stimulating microbial growth, increases the N
requirements of microorganisms. N reaching the
colon is mainly of endogenous origin, protein
coming from the small intestine, or urea coming
either directly from the blood or small intestine.
Indeed, with diets that provide a small quantity
of fermentable carbohydrates, only small amounts
of undigested dietary protein and endogenous
protein (pancreatic enzymes and sloughed mucosal cells) reach the large intestine. Here, they will
be hydrolyzed and used for microbial proliferation in the large bowel, but many of the end
products of protein fermentation are undesirable.
However, when the intake of fermentable carbohydrates increases, N transfer may not be enough
to promote an optimal bacterial growth. In such
conditions, several investigations16,17,105-107 have
shown that blood urea constitutes the largest and
the most available source of N for bacterial
protein synthesis. As a result, fecal N excretion is
significantly increased in comparison with fiberfree diets.16-21
During the past few years, several hypotheses
have been proposed for the manner in which
fermentable carbohydrate brings about this effect: (1) fecal N could originate from structural
proteins of plant cell walls,108 and (2) the fiber
could decrease the digestibility of dietary protein
in the small intestine.109,110 Although these N
sources may be significant, another source of N
is bacterial proliferation.111 Bacteria comprise
approximately 55% of the dry stool weight in
humans on a western diet,112 and because bacteria are composed of 7% to 8% N (dry weight),111
any increase in their colonic proliferation will
increase fecal mass and N excretion.
Urea disposal in the large intestine has been
shown in various species, including humans.26,27,105-107,113 In humans, it has been estimated that the urea hydrolyzed in the large
intestine could represent approximately one third
of the total urea produced by the liver.113 Various
factors control urea hydrolysis: the rate of urea
transfer to the site(s) of hydrolysis, activity of the
bacterial urease, demand of ammonia for bacterial protein synthesis, and availability of other N
sources.107 However, some studies suggest that
the human colon, unlike the colon of many
animals, is relatively impermeable to urea and, at
most, a passive flux might allow diffusion of
approximately 20% of the amount of urea de-
638
stroyed.114,115 These studies have entailed preliminary cleansing of the colon; however, the removal of digestive constituents (bacterial urease,
SCFAs, carbon dioxide) is known to affect gastrointestinal permeability to urea.116,117 Another study
has shown, by direct measurement of the contribution of endogenous urea to fecal ammonia,
that urea is a relatively minor source (8%) of
fecal ammonia in healthy subjects with intact
renal function.118 The intensity of urea contribution to colonic ammonia is certainly dependent
on fermentable carbohydrate availability for
maintaining highly active urease activity. Indeed,
the transfer of urea is proportional to the concentration gradient of urea across the colonic wall;
this explains the stimulatory effect of colonic
bacteria through their ureolytic activity to promote urea uptake by the colon. Consequently, in
the presence of fermentable carbohydrate (particularly oligosaccharides that exert osmotic effects and favor the ureolytic activity) and in the
case of hyperuremia, this transfer into the colon
may become considerable (Fig 2).17,21,96 Some
urea could be used in the distal ileum, which
presents a high permeability for this molecule.119
However, the bacterial population in the terminal
ileum is only one thousandth or so of that in the
colon. Although the permeability of the human
ileum to urea is greater than that of the colon, the
transfer of urea to the colon may be substantial
because the transit time in the colon is longer.
YOUNES ET AL
Part of the ammonia produced from urea will
be used for bacterial protein synthesis, which
will be eliminated in the stool, and therefore
fecal N excretion is increased.17,20,21 Another part
of the ammonia will be absorbed and converted
in the liver to urea or recycled by different ways
for nonessential AA synthesis, such as glutamate
and glutamine.29 Moreover, some AAs coming
from bacterial metabolism could be recovered by
the host, but the importance of this is still poorly
documented.28 In fact, the incorporation of ammonia into bacterial protein mainly leads to an
irreversible loss of N through the fecal route, and
it is more significant when the quantity of fermentable carbohydrates is high.120
Our results support the view that there is a
close relationship between the net flux of urea N
toward the large intestine and fecal N excretion,
hence, a decrease in plasma urea level (Fig 3).25
A high rate of urea transfer into the cecum is
favored by an enlarged surface area of exchange
between blood and the luminal fluid and by an
accelerated blood flow in the cecum.21,96 All
these parameters are enhanced by feeding various fermentable carbohydrates. In turn, a large
supply of urea elevates the cecal pool of ammonia and elicits a substantial absorption of ammonia despite a marked acidification of cecal contents (Fig 3A).25 In fact, ammonia and SCFAs are
generally considered to be transported across
biological membranes as uncharged molecules.121
Fig 2. Effects of fermentable carbohydrate (fructooligosaccharide; FOS) intake on urea N transferred from blood
into the cecum in normal (N) or nephrectomized (U) rats. Fluxes (␮g/min) ⴝ arteriovenous differences across the
cecum (␮g/g) ⴛ cecal blood flow (mL/min). Each value is the mean ⴞ standard error of the mean; n ⴝ 10. Statistical
evaluation of data by ANOVA. *Significant difference (P F 0.05) between groups of rats fed fiber-free (FF) and FOS
diets. †Significant difference (P F 0.05) between groups of normal and nephrectomized rats. §Significant difference
(P F 0.05) between groups of rats fed the low-protein level and those fed the slightly surfiet protein level (results not
published).
FERMENTABLE CARBOHYDRATE AND FECAL N EXCRETION
639
Fig 3. Relationship between cecal N fluxes, fecal N
excretion, and plasma urea
concentration in nephrectomized rats fed fiber-free (FF)
or oligosaccharide/fiber blend
(O/F) diets and those fed a normal (14% casein) or a lowprotein (8% casein) diet. Fluxes
(␮mol/min) ⴝ arteriovenous
differences across the cecum
(mmol/L) ⴛ cecal blood flow
(mL/min). Each value is the
mean ⴞ standard error of the
mean; n ⴝ 10. Statistical evaluation of data by ANOVA. *Significant difference (P F 0.05)
between groups of rats fed FF
and O/F diets. †Significant difference (P F 0.05) between
groups of rats fed the 8% and
14% casein level.
In colonocytes (intracellular pH of 7.0 to 7.1),
SCFAs and ammonia will be dissociated again,
and it is conceivable that protons required for
NH4⫹ formation arise from SCFA dissociation.
Thus, the enterohepatic cycle of urea and ammonia N observed in numerous works26-28,96,112 and
represented in Fig 4 suggests that this process is
not necessarily a futile cycle. It participates in
both the elimination of urea N by the fecal route
and in N salvage, particularly with a low-protein
diet enriched with fermentable carbohydrates.
ROLE OF FERMENTABLE CARBOHYDRATES
IN THE DIET OF CRF: EXPERIMENTAL
BASES AND DISCUSSION
There are synergistic actions between high–
fermentable carbohydrate diets and low-protein
diets, particularly as to their plasma urea–
640
YOUNES ET AL
Fig 4. Impact of fermentable carbohydrate intake on
N enterohepatic cycle.
reducing effects and, hence, progression of CRF.
Although the primary determinant of plasma
urea concentration is dietary protein level, feeding fermentable carbohydrates also has an important effect on this parameter.16,17,20,21,23,24 Consequently, it is interesting to promote low-protein
diets rich in various unavailable carbohydrates.
This can be obtained by consuming a diet rich in
plant products (cereal products, legumes, vegetables, and fruits; Table 2). However, these diets
are also particularly rich in potassium. Thus, to
deal with this drawback, it is necessary to select
foods rich in fermentable carbohydrates (resistant starch and oligosaccharides) to restrict the
potassium supply.
Extrarenal urea excretion through the enteral
route may be clinically relevant in patients with
impaired renal function. In patients with CRF,
the question of the efficiency of dietary protein
restriction has seldom been considered according to the availability of fermentable carbohydrates. Consequently, it is necessary to perform
experiments to confirm this hypothesis and to
determine the optimal fermentable carbohydrate
and protein supply for the protection of renal
function.
The selection of diets rich in slowly digested
carbohydrates is particularly important to reduce
N catabolism because part of the AAs are metabolized for glucose production if the supply of
carbohydrates is not optimal. In dialysis patients,
catabolism is accelerated, which theoretically
increases N demand. However, any increase in
dietary N is expected to increase in parallel N
catabolism and consequently precludes any significant improvement in N balance. For this
Table 2. Fiber Content of Some Plant Diet Sources
Total Fibers
Cereals and leguminous
Beans
Peas
Wheat bran
Corn
Oat
White wheat
Rice
Vegetables
Cabbage
Carrot
Salad (lettuce)
Onion
Tomato
Potato
Fruits
Apple
Orange
Apricot
Plum
Pineapple
Banana
Fresh
Weight
(g/100 g)
Dry
Weight
(g/100 g)
Soluble
Fibers (%)
17
19
37
10.5
9
3.1
3.1
19
21
42
12
10
3.5
3.5
47
29
14
22
30
40
43
2.9
2.4
1.5
2.5
1.1
1.6
31
19
24
19
18
7.2
45
58
46
53
40
55
1.7
2.1
2.1
1.6
1.4
1.3
12
15
14
10
9.1
4.9
40
65
57
63
61
59
Data from references 128 and 129.
FERMENTABLE CARBOHYDRATE AND FECAL N EXCRETION
reason, it is important to increase the supply of
slowly digested carbohydrates in the diet of these
patients, which can help decrease the hepatic
gluconeogenesis from AAs. Therefore, in dialysis patients, it is important that fermentable carbohydrates be provided, together with a substantial decrease in dietary protein. This is possible
because the increase in complex carbohydrates
leads to better utilization of dietary N. It would
also be important, in the future, to explore the
interest of slowly digested proteins.
The efficiency of fermentable carbohydrates
to reinforce the urea-reducing effect of a lowprotein diet has been shown by experimental
work in the rat.16,23,24 It appears possible, using a
diet rich in fermentable carbohydrates and low in
protein, to drastically reduce the concentration of
plasma urea to 0.75 mmol/L.24 This urea-reducing effect of fermentable carbohydrates also has
been observed in rat models of experimental
renal failure21,25 and in patients with CRF.15,20 In
nephrectomized rats, we have shown that feeding fermentable carbohydrates decreased the concentration of plasma urea from 2.6 to 1.8 mmol/L,
a 30% decrease. When, in addition, the dietary
protein level was reduced from 14% to 8%, the
plasma urea level was reduced from 5.9 to 1.8
mmol/L, a 70% decrease (Fig 3C).25
Moreover, our results obtained in nephrectomized rats showed that fermentable carbohydrates were all the more efficient to shift N
excretion from the urinary route toward the fecal
route because the protein level was low. Thus,
we have shown that with a normal protein level
(14% casein diet), fecal N represented 23% of
the total N excretion in rats fed fermentable
carbohydrate diets versus only 12% in rats in
fiber-free conditions, whereas, with a lower protein level (8% casein diet), fecal N represented
46% of the total N excretion (Fig 3B).25 As a
result of this increase in fecal N excretion, the net
effect of feeding fermentable carbohydrates with
a dietary protein restriction was to decrease urinary N excretion from approximately 250 mg/d
(14% casein, fiber-free diet) to approximately 60
mg/d (8% casein, fermentable carbohydrate diet).
This represents a 75% decrease of urinary N (Fig
5).25 In patients with CRF, supplementation with
gum arabic or ispaghula (hemicellulose) has been
shown to reduce serum urea N levels by 12% and
19%, respectively.15,20 Wizemann et al122 re-
641
Fig 5. Effects of dietary conditions on urinary and
fecal N excretion in nephrectomized rats fed fiber-free
(FF) or oligosaccharide/fiber blend (O/F) diet and those
fed a normal (14% casein) or a low-protein (8% casein)
diet. Each value is the mean of 10 rats.
ported also that lactulose increased fecal N in
uremic patients, together with a 25% decrease in
plasma urea concentration. In parallel, the total
fecal N excretion and particularly the bacteria
fraction was significantly increased with fermentable carbohydrates and accounted for 59% of the
total increase in stool N contents.18,20 This suggests that the large intestine can partially compensate for renal failure, provided that an appropriate supply of fermentable carbohydrates and
protein is allowed.
The question arises as to whether fermentable
carbohydrates have the same effects on N metabolism in healthy men as in those with CRF. To our
knowledge, this point has not been well documented. We compared the effects of fermentable
carbohydrate intake in normal and nephrectomized rats. The data indicate that the hypertrophy of the remaining kidney (40% to 50%) was
effective in ensuring a relatively high rate of urea
excretion, but it was not sufficient to counteract
increased blood urea levels. Elevated blood urea
levels had a minute influence on urea cycling and
ammonia absorption in the large intestine in rats
fed a fiber-free diet. In contrast, a large increase
in N fluxes through the large intestine was observed in nephrectomized rats fed fermentable
carbohydrates (Fig 6).21 In these animals, a large
part of the urea taken up was reabsorbed as
ammonia. This accelerated transfer of N in the
large intestine resulted in a slightly greater fecal
excretion in nephrectomized rats compared with
normal rats. In turn, this led to a significant
decrease in plasma urea levels, less pronounced
in nephrectomized rats fed a fermentable carbo-
642
YOUNES ET AL
CONCLUSION
In CRF, the plasma concentration of the end
products of protein catabolism, especially urea,
is increased. Although most of the dietary attempts to treat this disease and decrease the
serum urea N level involve a reduction of N
Fig 6. Comparison of the effects of fermentable
carbohydrate intake on cecal N flux in normal (䊐) and
nephrectomized (e) rats. Fluxes (␮mol/min) ⴝ arteriovenous differences across the cecum (mmol/L) ⴛ cecal blood flow (mL/min). Each value is the mean ⴞ
standard error of the mean; n ⴝ 10. Statistical evaluation of data by ANOVA. *Significant difference (P F
0.05) between groups of rats fed fiber-free and inulin
or resistant starch diets. †Significant difference (P F
0.05) between groups of normal and nephrectomized
rats.
hydrate diet (⫺32%) than in normal rats (⫺43%).
The urinary N excretion was also more effectively reduced by fermentable carbohydrate in
normal rats (⫺31%) than in nephrectomized rats
(⫺19%; Fig 7).21
Besides the decrease in urea N concentration,
several other processes participate in N elimination from the body. For example, creatinine and
uric acid contribute to fecal N excretion, but they
represent only a minor part (⬍ 10%) of the total
N excretion by the kidneys.123 However, feeding
fermentable carbohydrates did not influence the
concentration of plasma creatinine or creatinine
clearance.77
Fig 7. Comparison of the effects of fermentable
carbohydrate intake on urinary and fecal N excretion
and on plasma urea concentration in normal (䊐) and
nephrectomized (e) rats. Each value is the mean ⴞ
standard error of the mean; n ⴝ 10. Statistical evaluation of data by ANOVA. *Significant difference (P F
0.05) between groups of rats fed fiber-free and inulin
or resistant starch diets. †Significant difference (P F
0.05) between groups of normal and nephrectomized
rats.
FERMENTABLE CARBOHYDRATE AND FECAL N EXCRETION
intake, an additional dietary manipulation would
be to add fermentable carbohydrates, which can
increase N excretion in the feces. Our works and
those of others have shown that a low-protein
diet remains beneficial, and the combination of
these two dietary changes brings about the greatest fecal urea excretion, together with a reduced
urinary excretion. Thus, the consequences of
renal failure should be substantially alleviated if
the colon could take over the renal function to
ensure an increasing capacity of N excretion. Of
course, the colon could not substitute completely
for renal function. Reciprocally, when the digestive elimination route is disturbed, the consequences of renal failure are amplified.
In practice, it is recommended to increase fiber
gradually by using a large variety of vegetable
products to provide 35 to 40 g of fiber daily (24 g
from cereal products, leguminous seeds, and
other starchy foods; 8 g from vegetables; 2 to 4 g
from fruits; 4 g from resistant starches, oligosaccharides, and various hydrocolloids). Nevertheless, because intolerance seems to exist toward
certain foods, it is necessary to ensure that the
recommended products are well tolerated by
considering the supply of potassium present in
fruits. However, because of social and family
environments, it is difficult to change human
dietary habits; thus, it is sometimes necessary to
recommend preparations enriched with fermentable carbohydrates.
Finally, it is also important to indicate that
food rich in complex plant products could help
facilitate the elimination of cholesterol and, hence,
prevent the vascular complications caused by
CRF.75,124 Moreover, plant products rich in antioxidant micronutrients are very important to prevent lipid peroxidation and the production of free
radicals, which are exaggerated in patients with
CRF.125-127
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