P0922A LOW AROMATIC AMINO-ACID DIET IMPROVES RENAL FUNCTION AND PREVENTS KIDNEY FIBROSIS IN MICE WITH CHRONIC KIDNEY DISEASE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Christophe Barba ◽  
Christophe Soulage ◽  
Griet Glorieux ◽  
Cecile PICARD ◽  
Denis Fouque ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Amino Acid ◽  
Kidney Disease ◽  
Aromatic Amino Acid ◽  
Uremic Toxins ◽  
Kidney Fibrosis ◽  
Acid Diet ◽  
Low Protein ◽  
Amino Acid Diet

Abstract Background and Aims Despite decades of use of low protein diets (LPD) in the management of chronic kidney disease (CKD), the mechanisms through which it delays the progression to end-stage renal disease (ESRD) remain controversial. A reduced production of uremic toxins could contribute to the benefits of the LPD. Aromatic amino-acids are precursors of major uremic toxins such as p-cresyl sulfate (PCS), indoxyl sulfate (IS), indole-3-acetic acid or phenol. We investigated the hypothesis that a low aromatic amino acid diet (LAA, namely low intake of tyrosine, tryptophan and phenylalanine) while being normoproteic, could be as effective as a LPD, through the specific diminution of uremic toxins production. Method Renal failure was chemically induced in mice with a diet containing 0.25% (w/w) of adenine. Thereafter, they received 3 different diets for 6 weeks: normoproteic diet (NPD: 14.7% proteins, aromatics 0.019%), LPD (5% proteins, aromatics 0.007%) and LAA (14% proteins, aromatics 0.007%). Results LAA and LPD had no significant effect on body weight. Plasma creatinine was significantly lower in LPD and LAA groups compared to NPD group (72 ± 4 and 73 ± 4 µmol/L vs 127 ± 6 µmol/L, p<0.0001), as well as proteinuria (1.3 ± 0.3 and 1.2 ± 0.1 mg/24h vs 3.8 ± 0.9 mg/24h, p<0.05). Kidney fibrosis was more severe in NPD group vs LPD and LAA groups (17 ± 1% vs 10 ± 1 % and 13 ± 2 %, p<0.0001 and p=0.01). Kidney inflammation was also reduced with LPD and LAA. Free PCS and IS were lower in LPD and LAA groups compared to NPD group. Conclusion These results suggest that LAA confers similar benefits as compared with those of LPD to delay the progression of CKD through reduction of uremic toxins production, with lower risk of malnutrition. Renal function and urinary protein excretion in control and CKD mice Serum creatinine (A), blood urea nitrogen (B) and urinary proteins (C) in control and CKD mice fed with normoproteic diet (NPD), low protein diet (LPD) or low aromatic amino-acid diet (LAA). Data are expressed as mean ± SEM for n = 5-11 animals in each group. *p < 0.05, **p < 0.01, ***p < 0.001 vs CKD-NPD; (two-way ANOVA and Dunnett post hoc test).

scholarly journals A low aromatic amino-acid diet improves renal function and prevent kidney fibrosis in mice with chronic kidney disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christophe Barba ◽  
Bérengère Benoit ◽  
Emilie Bres ◽  
Stéphanie Chanon ◽  
Aurélie Vieille-Marchiset ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Amino Acid ◽  
Kidney Disease ◽  
Aromatic Amino Acid ◽  
Aromatic Amino Acids ◽  
Uremic Toxins ◽  
Kidney Fibrosis ◽  
Acid Diet ◽  
Chemically Induced ◽  
Amino Acid Diet

AbstractDespite decades of use of low protein diets (LPD) in the management of chronic kidney disease (CKD), their mechanisms of action are unclear. A reduced production of uremic toxins could contribute to the benefits of LPDs. Aromatic amino-acids (AA) are precursors of major uremic toxins such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS). We hypothesize that a low aromatic amino acid diet (LA-AAD, namely a low intake of tyrosine, tryptophan and phenylalanine) while being normoproteic, could be as effective as a LPD, through the decreased production of uremic toxins. Kidney failure was chemically induced in mice with a diet containing 0.25% (w/w) of adenine. Mice received three different diets for six weeks: normoproteic diet (NPD: 14.7% proteins, aromatic AAs 0.019%), LPD (5% proteins, aromatic AAs 0.007%) and LA-AAD (14% proteins, aromatic AAs 0.007%). Both LPD and LA-AAD significantly reduced proteinuria, kidney fibrosis and inflammation. While LPD only slightly decreased plasma free PCS and free IS compared to NPD; free fractions of both compounds were significantly decreased by LA-AAD. These results suggest that a LA-AAD confers similar benefits of a LPD in delaying the progression of CKD through a reduction in some key uremic toxins production (such as PCS and IS), with a lower risk of malnutrition.

scholarly journals A Low Aromatic Amino-Acid Diet Improves Renal Function and Prevent Kidney Fibrosis in Mice with Chronic Kidney Disease

2021 ◽  
Author(s):  
Christophe Barba ◽  
Bérengère Benoit ◽  
Bres Emilie ◽  
Stéphanie Chanon ◽  
Aurélie Vieille-Marchiset ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Amino Acid ◽  
Kidney Disease ◽  
Aromatic Amino Acid ◽  
Aromatic Amino Acids ◽  
Uremic Toxins ◽  
Kidney Fibrosis ◽  
Acid Diet ◽  
Chemically Induced ◽  
Amino Acid Diet

Abstract Despite decades of use of low protein diets (LPD) in the management of chronic kidney disease (CKD), their mechanisms of action are unclear. A reduced production of uremic toxins could contribute to the benefits of LPDs. Aromatic amino-acids (AA) are precursors of major uremic toxins such as p-cresyl sulfate (PCS) and indoxyl sulfate (IS). We hypothesize that a low aromatic amino acid diet (LA-AAD, namely a low intake of tyrosine, tryptophan and phenylalanine) while being normoproteic, could be as effective as a LPD, through the decreased production of uremic toxins. Kidney failure was chemically induced in mice with a diet containing 0.25% (w/w) of adenine. Mice received three different diets for six weeks: normoproteic diet (NPD: 14.7% proteins, aromatic AAs 0.019%), LPD (5% proteins, aromatic AAs 0.007%) and LA-AAD (14% proteins, aromatic AAs 0.007%). Both LPD and LA-AAD significantly reduced proteinuria, kidney fibrosis and inflammation. While LPD only slightly decreased plasma free PCS and free IS compared to NPD; free fractions of both compounds were significantly decreased by LA-AAD. These results suggest that a LA-AAD confers similar benefits of a LPD in delaying the progression of CKD through a reduction in uremic toxins production, with a lower risk of malnutrition.

scholarly journals Uremic Toxins and Frailty in Patients with Chronic Kidney Disease: A Molecular Insight

2021 ◽  
Vol 22 (12) ◽  
pp. 6270
Author(s):  
Chia-Ter Chao ◽  
Shih-Hua Lin
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Uremic Toxins ◽  
Heme Oxygenase 1 ◽  
Signal Pathways ◽  
Uremic Toxin ◽  
Nuclear Factor ◽  
Cognitive Frailty ◽  
Renal Function Decline

The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia/muscle wasting, cognitive impairment/cognitive frailty, osteoporosis/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients’ outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.

scholarly journals High Protein Food with Similar Phosphorus Content as Lower Protein Foods Increases Levels of Uremic Toxins

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 683-683
Author(s):  
Eden Ephraim ◽  
Dennis Jewell
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Treatment Period ◽  
Uremic Toxins ◽  
High Protein ◽  
Phosphorus Concentration ◽  
Urine Ph ◽  
Protein Food ◽  
Protein Levels ◽  
Low Protein

Abstract Objectives The aim of this study was to determine the effect of feeding cats with reduced renal function a high protein food while maintaining phosphorus concentration across foods containing varying protein levels. Methods The study was conducted using 23 cats of 5–13 years of age with chronic kidney disease. After a 1 month washout period, cats were randomly assigned to one of the 6 groups of approximately 4 cats to receive 3 treatment foods, each for 111 days, in a sequence following the William's Latin Square design. The treatment foods contained on a dry matter basis, low (25.94%), medium (31.91%) or high (36.77%) protein and had similar other nutrient levels including Phosphorus. Average body weights were determined after each treatment period. Blood and urine samples were collected at the end of each treatment period to compare changes in levels of metabolites associated with progression of kidney disease. Results The consumption of the foods with different protein levels did not have an effect on body weight. Urine pH was significantly higher after cats were fed high protein food (P = 0.0003). Blood chemistry results showed that cats had significantly increased level of blood urea nitrogen (BUN) after the consumption of the high protein food compared with the low protein food (P = 0.005). Increased urea levels were also confirmed from results of plasma metabolomics. Levels of microbial uremic toxins such as 3-indoxyl sulfate, 5-hydroxyindole sulfate, 6-hydroxyindole sulfate and 3-hydroxyindoline-one sulfate were significantly elevated after cats were fed high protein compared to both medium and low protein foods (P < 0.05). The glycine conjugate of butyric acid (butyrylglycine) was significantly lower in the plasma of cats fed the high protein compared to low protein food (P = 0.004). Levels of betaine were lower after feeding high protein compared to low (P = 0.001) and medium protein (P = 0.046) foods. Furthermore, cats had the lowest level of gamma-tocopherol/beta-tocopherol with high protein food compared to medium and low protein foods (P < 0.001). Conclusions Feeding high protein food to cats with chronic kidney disease leads to higher concentrations of uremic toxins in the blood. Funding Sources The study was funded by Hill's Pet Nutrition, Topeka, Kansas, USA.

scholarly journals Low-arginine and low-protein diets induce hepatic lipid accumulation through different mechanisms in growing rats

2020 ◽  
Author(s):  
Lila Otani ◽  
Hiroki Nishi ◽  
Ayaka Koyama ◽  
Yuta Akasaka ◽  
Yusuke Taguchi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Fatty Liver ◽  
Insulin Signaling ◽  
Acid Group ◽  
De Novo Lipogenesis ◽  
Total Amino Acid ◽  
Amino Acid Group ◽  
Acid Diet ◽  
Low Protein ◽  
Amino Acid Diet

Abstract Background Dietary protein deficiency and amino acid uimbalance cause hepatic fat accumulation. We previously demonstrated that only arginine deficiency as well as total amino acid deficiency in a diet caused significant hepatic triglyceride (TG) accumulation in young Wistar rats. In this study, we explored the mechanisms of this fatty liver formation using these two models. Methods A low-total-amino acid diet (equivalent to 5% protein) and a low-arginine diet (solely the arginine content alone is as low as the low-total-amino acid diet) to the rats for 2 weeks. Results There was substantially greater hepatic TG accumulation in the low-arginine group than in the low-total-amino acid group. The low-total-amino-acid diet potentiated insulin signals in the liver and enhanced de novo lipogenesis. By contrast, the low-arginine diet inhibited hepatic very-low-density lipoprotein secretion, without affecting hepatic insulin signaling and lipogenesis. Conclusions We conclude that, although the arginine intake of the low-arginine group was as low as that of the low-total-amino-acid group, these two diets developed a fatty liver via completely different mechanisms. The potentiation of insulin signaling and resultant increases in fatty acid synthesis seem to drive the effects of a low-protein diet, whereas lower VLDL secretion may be the main causes of low-arginine diet-induced TG accumulation in the liver.

scholarly journals Low-arginine and low-protein diets induce hepatic lipid accumulation through different mechanisms in growing rats

2020 ◽  
Author(s):  
Lila Otani ◽  
Hiroki Nishi ◽  
Ayaka Koyama ◽  
Yuta Akasaka ◽  
Yusuke Taguchi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Fatty Liver ◽  
Wistar Rats ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Total Amino Acid ◽  
Acid Diet ◽  
Low Protein ◽  
Lipoprotein Secretion ◽  
Amino Acid Diet

Abstract Background: Dietary protein deficiency and amino acid imbalance cause hepatic fat accumulation. We previously demonstrated that only arginine deficiency or total amino acid deficiency in a diet caused significant hepatic triglyceride (TG) accumulation in young Wistar rats. In this study, we explored the mechanisms of fatty liver formation in these models.Methods: We fed 6-week-old male Wistar rats a control diet (containing an amino acid mixture equivalent to 15% protein), a low-total-amino acid diet (equivalent to 5% protein; 5PAA), and a low-arginine diet (only the arginine content is as low as that of the 5PAA diet) for 2 weeks.Results: Much greater hepatic TG accumulation was observed in the low-arginine group than in the low-total-amino acid group. The lipid consumption rate and fatty acid uptake in the liver did not significantly differ between the groups. In contrast, the low-total-amino acid diet potentiated insulin sensitivity and related signaling in the liver and enhanced de novo lipogenesis. The low-arginine diet also inhibited hepatic very-low-density lipoprotein secretion without affecting hepatic insulin signaling and lipogenesis.Conclusions: Although the arginine content of the low-arginine diet was as low as that of the low-total-amino acid diet, the two diets caused fatty liver via completely different mechanisms. Enhanced lipogenesis was the primary cause of a low-protein diet-induced fatty liver, whereas lower very-low-density lipoprotein secretion caused low-arginine diet-induced fatty liver.

scholarly journals Ketoacid Analogues Supplementation in Chronic Kidney Disease and Future Perspectives

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2071 ◽  
Author(s):  
Laetitia Koppe ◽  
Mariana Cassani de Oliveira ◽  
Denis Fouque
Keyword(s):  
Chronic Kidney Disease ◽  
Glomerular Filtration Rate ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Filtration Rate ◽  
Uremic Toxins ◽  
Protein Diet ◽  
Current Evidence ◽  
Low Protein ◽  
The Impact

Diet is a key component of care during chronic kidney disease (CKD). Nutritional interventions, and, specifically, a restricted protein diet has been under debate for decades. In order to reduce the risk of nutritional disorders in very-low protein diets (VLDP), supplementation by nitrogen-free ketoacid analogues (KAs) have been proposed. The aim of this review is to summarize the potential effects of this dietary therapy on renal function, uremic toxins levels, and nutritional and metabolic parameters and propose future directions. The purpose of this paper is also to select all experimental and randomized clinical studies (RCTs) that have compared VLDP + KA to normal diet or/and low protein diet (LPD). We reviewed the SCOPUS, WEB of SCIENCES, CENTRAL, and PUBMED databases from their inception to 1 January, 2019. Following duplicate removal and application of exclusion criteria, 23 RCTs and 12 experimental studies were included. LPD/VLPD + KAs appear nutritionally safe even if how muscle protein metabolism adapts to an LPD/VLPD + KAs is still largely unknown. VLPD + KAs seem to reduce uremic toxins production but the impact on intestinal microbiota remains unexplored. All studies observed a reduction of acidosis, phosphorus, and possibly sodium intake, while still providing adequate calcium intake. The impact of this diet on carbohydrate and bone parameters are only preliminary and need to be confirmed with RCTs. The Modification of Diet in Renal Disease study, the largest RCTs, failed to demonstrate a benefit in the primary outcome of the decline rate for the glomerular filtration rate. However, the design of this study was challenged and data were subsequently reanalyzed. However, when adherent patients were selected, with a rapid rate of progression and a long-term follow up, more recent meta-analysis and RCTs suggest that these diets can reduce the loss of the glomerular filtration rate in addition to the beneficial effects of renin-angiotensin-aldosterone system (RAAS) inhibitors. The current evidence suggests that KAs supplemented LPD diets should be included as part of the clinical recommendations for both the nutritional prevention and metabolic management of CKD. More research is needed to examine the effectiveness of KAs especially on uremic toxins. A reflection about the dose and composition of the KAs supplement, the cost-effective features, and their indication to reduce the frequency of dialysis needs to be completed.

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