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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. 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