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Role of Carbohydrates in Chronic Kidney Disease: History
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Contributor:
Mara Lauriola
, Ricard Farré , Pieter Evenepoel , Saskia Adriana Overbeek , Björn Meijers

Patients with chronic kidney disease (CKD) have a higher cardiovascular risk compared to the average population, and this is partially due to the plasma accumulation of solutes known as uremic toxins. The binding of some solutes to plasma proteins complicates their removal via conventional therapies, e.g., hemodialysis. Protein-bound uremic toxins originate either from endogenous production, diet, microbial metabolism, or the environment. Although the impact of diet on uremic toxicity in CKD is difficult to quantify, nutrient intake plays an important role. Dietary carbohydrates can be classified according to their degree of polymerization into sugars, including monosaccharides, disaccharides, polyols, oligosaccharides, and polysaccharides. Due to their role in CKD, especially reducing sugars, i.e., sugars that, because of their aldehyde or ketone group, act as reducing agents in basic solutions. 

  • uremic toxins
  • chronic kidney disease
  • metabolism

1. Carbohydrates

Dietary carbohydrates can be classified according to their degree of polymerization into sugars, including monosaccharides, disaccharides, polyols, oligosaccharides, and polysaccharides [1]. Due to their role in chronic kidney disease (CKD), especially reducing sugars, i.e., sugars that, because of their aldehyde or ketone group, act as reducing agents in basic solutions.  Glucose, fructose, galactose, lactose, and maltose are reducing sugars and can be considered the precursors of some protein-bound uremic toxins (PBUTs).. In fact, they participate in the so-called Maillard reactions, i.e., chemical reactions between reducing sugars and amino acids that occur when cooking/baking/roasting food at high temperatures. These reactions confer browned food its distinctive flavor (cookies, biscuits, bread, fried dumplings, and toasted marshmallow) [2]. Products of Maillard reactions considered as uremic toxins include both intermediate glycation products (IGPs), i.e., fructoselysine, 3-deoxyglucosone, glyoxal, and methylglyoxal, and the more stable advanced glycation end-products (AGEs), i.e., Nε-carboxymethyllysine (CML), Nε-carboxyethyllysine (CEL), and and pentosidine [3].
Precautions can be taken to lower the amount of reducing sugars in foods. For instance, storing potatoes at temperatures above 8 °C helps to decrease the content of reducing sugars [1]. Using other cooking methods, such as steaming or boiling, and applying soaking or blanching before cooking can also diminish reducing sugars and, thereby, the formation of Maillard reaction products.

2. Maillard Reaction Products

Maillard reactions start with the formation of an unstable Schiff base that undergoes spontaneous rearrangement to form ketoamines, also known as Amadori products [2]. From the degradation of Amadori products, furfurals, reductones, and fragmentation products are generated. When the reaction goes further, these compounds start to condense without the need for other amino groups. Ultimately, reactions between these intermediate products with amino compounds lead to the formation of advanced glycation end-products (AGEs), also called melanoidins in food science. In general, Maillard reactions, also called non-enzymatic browning, can take place both in foods and within the human body. Indeed, glycation of body proteins, i.e., the reaction between glucose or its derived products with amines, amino acids, peptides, and proteins, can be seen as the first step of this series of reactions. While a low percentage of glycated proteins within the human body is considered physiological, several studies have confirmed that conditions of diabetes and uremia present higher plasma levels of IGPs and AGEs [2][4][5].
The mechanisms promoting the accumulation of these products are not yet fully elucidated. It is clear that despite a great contribution to the endogenous formation of these compounds, diet-derived IGPs and AGEs play an important role in CKD progression [4][6][7][8][9], especially outside of diabetes [10]. Uribarri et al. found a correlation between serum levels of AGEs with dietary AGE intake based on a 3-day food diary or dietary questionnaires in a cohort of 189 patients on dialysis [4]. The same authors found that nondiabetic CKD patients on peritoneal dialysis who were asked to follow a high-AGE diet for four weeks showed a higher plasma retention of IGPs and AGEs compared to those on a low-AGE diet [8]. Interestingly, a study in rats showed that the administration of a thermolyzed diet led to a sustained increased plasma level of Maillard reaction products during the intervention [9].

2.1. Intermediate Glycation Products

Fructoselysine

Fructoselysine (FL), also called Nε -fructosyl-lysine, is the Amadori product of the amino acid lysine when the reducing sugar is glucose. FL is one of the most common Maillard reaction products present in processed foods, such as pasteurized milk, pasta, chocolate, cereals, and carbonated soft drinks [11]. Importantly, the absorption of FL in the gastrointestinal tract seems to depend upon the free or bound form of this compound [12]. When free FL was administered to rats and humans, around 60% was found in urine. Contrarily, when FL was administered in the bound form, the excretion was estimated between 3 and 10% [12][13][14][15]. Only 1–3% was excreted via feces [13]. This low excretion was reported to be due to the high microbial fermentation of this compound, which contributed to its reduced absorption [11][15][16].

3-deoxyglucosone

3-deoxyglucosone(3-DG), which derives from the dehydration and rearrangement of Amadori products, presents highly reactive carbonyl groups [17]. It is found in high amounts in carbohydrate-rich processed products, e.g., syrups and honey [18]. Elevated plasma levels of 3-DG in CKD have been attributed to the loss of the reductase enzyme responsible for the catabolism of 3-DG, which is located in the kidneys [17]. However, diet might contribute to a further rise in its plasma level. This is suggested by a study by Rückriemen et al., who demonstrated that urinary excretion of 3-DG endogenous metabolites (3-deoxyfructose and 2-keto-3-deoxygluconic acid) was increased after meal consumption in healthy humans [19].

Glyoxal and Methylglyoxal

Glyoxal and methylglyoxal (MG) can derive from sugar fragmentation or lipid degradation [2][20]. Many food products, e.g. bread, boiled potatoes, honey, heated fats, and many beverages (beer, cola, and roasted coffee), as well as cigarette and air pollution, are the sources of these compounds [20][21]. MG has also been identified as a microbial-derived compound and is, therefore, present in fermented products, including alcoholic drinks and dairy products [20]. Studies pointing out the effect of diet content on the plasma levels of glyoxal and MG are controversial. In a study by Nakayama et al., the consumption of glucose-carbonated soda drinks rich in glucose and MG raised the plasma levels in the short term in healthy volunteers [22]. However, it is not clear whether this increase in the plasma levels was due to the content of MG per se or due to the glucose drink content. The latter option seems to be the most plausible one according to another study, where the administration of a test meal rich in carbohydrates led to higher levels of MG and 3-DG, probably due to the host metabolism [23]. In addition, an in vitro digestion study showed that MG is highly reactive toward lysine and arginine residues that are present in digestive enzymes/proteins along the gastrointestinal tract [24]. This property, together with the putative capacity of intestinal epithelial cells to degrade MG via the glyoxalase system, could be the reason why MG quantity absorbed in such a way may not be relevant [24]. This is in line with the finding of the same authors that rich-in-MG honey supplementation did not lead to an increase in urinary MG and its metabolite D-lactate [24]. Nonetheless, no longitudinal or metabolic studies have been conducted on CKD patients. Therefore, no conclusions can be reached regarding the potential effect of a diet enriched in glyoxal and MG on the plasma retention of patients with reduced kidney excretion capacity.

2.2. Advanced Glycation End-Products: Pentosidine, Nε-carboxymethyllysine, and Nε-carboxyethyllysine

Pentosidine, Nε-carboxymethyllysine (CML), and Nε-carboxyethyllysine (CEL) belong to the class of compounds generated during the advanced stages of Maillard reactions. While pentosidine is solely generated as an advanced glycation product, CML and CEL are also derived from lipid peroxidation and ascorbate autoxidation.
Foods rich in AGEs include meat, especially when cooked under dry heat, higher-fat aged cheese, and high-fat spreads (butter, cream cheese, margarine, and mayonnaise) [25]. Of note, the type of lipid added in the processing determines the final AGE content of a certain food. For instance, scrambled eggs cooked using cooking spray, margarine, or oil had up to 75% fewer AGEs than if prepared with butter [25]. Foods with lower AGEs include grains, legumes, bread, vegetables, fruits, and milk, when not prepared with added fats [25].
Like most of the other Maillard reaction products, pentosidine can derive from endogenous sources and diet [26]. Förster et al. demonstrated in healthy volunteers that a diet low in AGEs leads to a decrease in pentosidine urinary levels. The authors hypothesized that pentosidine in its free form, such as that present in coffee, is absorbed more easily compared to the protein-bound form, which is present mostly in bakery products [26].
Nε-carboxymethyllysine (CML) and Nε-carboxyethyllysine (CEL) are among the most recognized AGEs. Studies concerning the metabolism and kinetics of CML and CEL have been carried out mostly in rodents and highlighted the accumulation of these compounds in specific organs, such as the kidney [27][28][29], suggesting the potentially detrimental effect of dietary AGEs in a uremic condition. Controversial results regarding the role of dietary AGEs on their plasma concentration were found by different authors when CML or CEL was administered to rodents [29][30][31][32]. However, none of these studies have been performed in CKD animal models. A study in human infants found that formula-fed babies had a 60% higher plasma concentration of CML, confirming the putative importance of dietary AGEs in humans [33].

This entry is adapted from the peer-reviewed paper 10.3390/toxins15020116

References

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