MO460ASSOCIATION BETWEEN CARBAMYLATED ALBUMIN, GUT MICROBIOTA AND THEIR DERIVED METABOLITES IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney disease (CKD) is characterized by gut dysbiosis. We recently demonstrated a decrease of short-chain fatty acid (SCFA) producing bacterial species with the progression of CKD. Besides, levels of protein-bound uremic toxins (PBUTs) and post-translational modifications of protein are increased in CKD, both are risk factors for accelerated cardiovascular morbidity and mortality. The link between the gut-kidney axis and protein carbamylation is unclear. The aim of the study was to explore the relation between carbamylated albumin, estimated by the albumin symmetry factor, and plasma levels of PBUTs, fecal levels of SCFAs (ongoing), and the abundance of related gut microbiota in different stages of CKD (1-5). Method The study cohort includes 103 non-dialyzed CKD patients (stages 1-5). Serum proteins were detected by capillary electrophoresis and UV absorbance at 214 nm with the symmetry factor as a marker of albumin carbamylation [the lower the symmetry factor, the more carbamylated albumin]. The quantification of PBUTs and SCFAs in plasma and fecal samples, respectively, using validated UPLC methods. Results The Pearson correlation coefficient (r) shows a positive correlation between the albumin symmetry factor and the estimated glomerular filtration rate (eGFR) (r=0.3025; p=0.0019). The albumin symmetry factor correlates positively with the abundance of Butyricicoccus spp. (r= 0.3211; p=0.0009), Faecalibacterium prausnitzii (r=0.2765; p=0.0047) and Roseburia spp. (r=0.2527; p=0.0100) and negatively with the PBUTs, p-cresyl sulfate (pCS) (r=-0.2819; p=0.0039), p-cresyl glucuronide (pCG) (r=-0.2819; p=0.0039) and indoxyl sulfate (IxS) (r=-0.2650; p=0.0068). Conclusion The decreased abundance of SCFA producing gut bacteria with the progression of CKD can evoke unfavorable conditions in the gut. This can contribute to increased plasma levels of PBUTs potentially (indirectly) playing a role in albumin carbamylation. It will be further explored whether fecal levels of SCFAs are affected in parallel and could be potential targets to restore gut dysbiosis and uremia.

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Gut Microbiota and Their Derived Metabolites, a Search for Potential Targets to Limit Accumulation of Protein-Bound Uremic Toxins in Chronic Kidney Disease

Toxins ◽

10.3390/toxins13110809 ◽

2021 ◽

Vol 13 (11) ◽

pp. 809

Author(s):

Mieke Steenbeke ◽

Sophie Valkenburg ◽

Tessa Gryp ◽

Wim Van Biesen ◽

Joris R. Delanghe ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Plasma Levels ◽

Plasma Concentrations ◽

Intestinal Barrier ◽

Uremic Toxins ◽

Intestinal Barrier Function ◽

Post Translational Modifications ◽

Gut Dysbiosis ◽

Cardiovascular Morbidity And Mortality

Chronic kidney disease (CKD) is characterized by gut dysbiosis with a decrease in short-chain fatty acid (SCFA)-producing bacteria. Levels of protein-bound uremic toxins (PBUTs) and post-translational modifications (PTMs) of albumin increase with CKD, both risk factors for cardiovascular morbidity and mortality. The relationship between fecal metabolites and plasma concentrations of PBUTs in different stages of CKD (n = 103) was explored. Estimated GFR tends to correlate with fecal butyric acid (BA) concentrations (rs = 0.212; p = 032), which, in its turn, correlates with the abundance of SCFA-producing bacteria. Specific SCFAs correlate with concentrations of PBUT precursors in feces. Fecal levels of p-cresol correlate with its derived plasma UTs (p-cresyl sulfate: rs = 0.342, p < 0.001; p-cresyl glucuronide: rs = 0.268, p = 0.006), whereas an association was found between fecal and plasma levels of indole acetic acid (rs = 0.306; p = 0.002). Finally, the albumin symmetry factor correlates positively with eGFR (rs = 0.274; p = 0.005). The decreased abundance of SCFA-producing gut bacteria in parallel with the fecal concentration of BA and indole could compromise the intestinal barrier function in CKD. It is currently not known if this contributes to increased plasma levels of PBUTs, potentially playing a role in the PTMs of albumin. Further evaluation of SCFA-producing bacteria and SCFAs as potential targets to restore both gut dysbiosis and uremia in needed.

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Synbiotics Alleviate the Gut Indole Load and Dysbiosis in Chronic Kidney Disease

Cells ◽

10.3390/cells10010114 ◽

2021 ◽

Vol 10 (1) ◽

pp. 114

Author(s):

Chih-Yu Yang ◽

Ting-Wen Chen ◽

Wan-Lun Lu ◽

Shih-Shin Liang ◽

Hsien-Da Huang ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Statistical Significance ◽

Additional Treatment ◽

Indoxyl Sulfate ◽

Uremic Toxin ◽

Healthy Controls ◽

Gut Dysbiosis ◽

Novel Concept

Chronic kidney disease (CKD) has long been known to cause significant digestive tract pathology. Of note, indoxyl sulfate is a gut microbe-derived uremic toxin that accumulates in CKD patients. Nevertheless, the relationship between gut microbiota, fecal indole content, and blood indoxyl sulfate level remains unknown. In our study, we established an adenine-induced CKD rat model, which recapitulates human CKD-related gut dysbiosis. Synbiotic treatment in CKD rats showed a significant reduction in both the indole-producing bacterium Clostridium and fecal indole amount. Furthermore, gut microbiota diversity was reduced in CKD rats but was restored after synbiotic treatment. Intriguingly, in our end-stage kidney disease (ESKD) patients, the abundance of indole-producing bacteria, Bacteroides, Prevotella, and Clostridium, is similar to that of healthy controls. Consistently, the fecal indole tends to be higher in the ESKD patients, but the difference did not achieve statistical significance. However, the blood level of indoxyl sulfate was significantly higher than that of healthy controls, implicating that under an equivalent indole production rate, the impaired renal excretion contributes to the accumulation of this notorious uremic toxin. On the other hand, we did identify two short-chain fatty acid-producing bacteria, Faecalibacterium and Roseburia, were reduced in ESKD patients as compared to the healthy controls. This may contribute to gut dysbiosis. We also identified that three genera Fusobacterium, Shewanella, and Erwinia, in the ESKD patients but not in the healthy controls. Building up gut symbiosis to treat CKD is a novel concept, but once proved effective, it will provide an additional treatment strategy for CKD patients.

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Chronic Kidney Disease, Gut Dysbiosis, and Constipation: A Burdensome Triplet

Microorganisms ◽

10.3390/microorganisms8121862 ◽

2020 ◽

Vol 8 (12) ◽

pp. 1862

Author(s):

Ryota Ikee ◽

Naomi Sasaki ◽

Takuji Yasuda ◽

Sawako Fukazawa

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Inflammatory Responses ◽

Bacterial Species ◽

Short Chain Fatty Acids ◽

Uremic Toxins ◽

Fermentation Products ◽

Bacterial Fermentation ◽

Gut Dysbiosis ◽

Multiple Drugs

Gut dysbiosis has been implicated in the progression of chronic kidney disease (CKD). Alterations in the gut environment induced by uremic toxins, the dietary restriction of fiber-rich foods, and multiple drugs may be involved in CKD-related gut dysbiosis. CKD-related gut dysbiosis is considered to be characterized by the expansion of bacterial species producing precursors of harmful uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, and the contraction of species generating beneficial short-chain fatty acids, such as butyrate. Gut-derived uremic toxins cause oxidative stress and pro-inflammatory responses, whereas butyrate exerts anti-inflammatory effects and contributes to gut epithelial integrity. Gut dysbiosis is associated with the disruption of the gut epithelial barrier, which leads to the translocation of endotoxins. Research on CKD-related gut dysbiosis has mainly focused on chronic inflammation and consequent cardiovascular and renal damage. The pathogenic relationship between CKD-related gut dysbiosis and constipation has not yet been investigated in detail. Constipation is highly prevalent in CKD and affects the quality of life of these patients. Under the pathophysiological state of gut dysbiosis, altered bacterial fermentation products may play a prominent role in intestinal dysmotility. In this review, we outline the factors contributing to constipation, such as the gut microbiota and bacterial fermentation; introduce recent findings on the pathogenic link between CKD-related gut dysbiosis and constipation; and discuss potential interventions. This pathogenic link needs to be elucidated in more detail and may contribute to the development of novel treatment options not only for constipation, but also cardiovascular disease in CKD.

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Impact of Gut Dysbiosis on Neurohormonal Pathways in Chronic Kidney Disease

Diseases ◽

10.3390/diseases7010021 ◽

2019 ◽

Vol 7 (1) ◽

pp. 21 ◽

Cited By ~ 17

Author(s):

Nima Jazani ◽

Javad Savoj ◽

Michael Lustgarten ◽

Wei Lau ◽

Nosratola Vaziri

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Major Health Problem ◽

Beneficial Effects ◽

Gut Dysbiosis ◽

Glucosidase Inhibitors ◽

Obesity And Diabetes ◽

Traditional Risk Factors ◽

The Impact

Chronic kidney disease (CKD) is a worldwide major health problem. Traditional risk factors for CKD are hypertension, obesity, and diabetes mellitus. Recent studies have identified gut dysbiosis as a novel risk factor for the progression CKD and its complications. Dysbiosis can worsen systemic inflammation, which plays an important role in the progression of CKD and its complications such as cardiovascular diseases. In this review, we discuss the beneficial effects of the normal gut microbiota, and then elaborate on how alterations in the biochemical environment of the gastrointestinal tract in CKD can affect gut microbiota. External factors such as dietary restrictions, medications, and dialysis further promote dysbiosis. We discuss the impact of an altered gut microbiota on neuroendocrine pathways such as the hypothalamus–pituitary–adrenal axis, the production of neurotransmitters and neuroactive compounds, tryptophan metabolism, and the cholinergic anti-inflammatory pathway. Finally, therapeutic strategies including diet modification, intestinal alpha-glucosidase inhibitors, prebiotics, probiotics and synbiotics are reviewed.

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Isolation and Quantification of Uremic Toxin Precursor-Generating Gut Bacteria in Chronic Kidney Disease Patients

International Journal of Molecular Sciences ◽

10.3390/ijms21061986 ◽

2020 ◽

Vol 21 (6) ◽

pp. 1986 ◽

Cited By ~ 7

Author(s):

Tessa Gryp ◽

Geert R.B. Huys ◽

Marie Joossens ◽

Wim Van Biesen ◽

Griet Glorieux ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Kidney Function ◽

Bacterial Species ◽

Uremic Toxins ◽

Bacterial Number ◽

Uremic Toxin ◽

Microbial Composition ◽

Indolic Compounds ◽

Cardiovascular Morbidity And Mortality

In chronic kidney disease (CKD), impaired kidney function results in accumulation of uremic toxins, which exert deleterious biological effects and contribute to inflammation and cardiovascular morbidity and mortality. Protein-bound uremic toxins (PBUTs), such as p-cresyl sulfate, indoxyl sulfate and indole-3-acetic acid, originate from phenolic and indolic compounds, which are end products of gut bacterial metabolization of aromatic amino acids (AAA). This study investigates gut microbial composition at different CKD stages by isolating, identifying and quantifying PBUT precursor-generating bacteria. Fecal DNA extracts from 14 controls and 138 CKD patients were used to quantify total bacterial number and 11 bacterial taxa with qPCR. Moreover, isolated bacteria from CKD 1 and CKD 5 fecal samples were cultured in broth medium supplemented with AAA under aerobic and anaerobic conditions, and classified as PBUT precursor-generators based on their generation capacity of phenolic and indolic compounds, measured with U(H)PLC. In total, 148 different fecal bacterial species were isolated, of which 92 were PBUT precursor-generators. These bacterial species can be a potential target for reducing PBUT plasma levels in CKD. qPCR indicated lower abundance of short chain fatty acid-generating bacteria, Bifidobacterium spp. and Streptococcus spp., and higher Enterobacteriaceae and E. coli with impaired kidney function, confirming an altered gut microbial composition in CKD.

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Correlation of Plasma Klotho Levels and Carotid Intima- Media Thickness in CKD Patients on Regular Hemodialysis

Indonesian Journal of Kidney and Hypertension ◽

10.32867/inakidney.v2i3.32 ◽

2019 ◽

Vol 2 (3) ◽

Keyword(s):

Risk Factors ◽

Chronic Kidney Disease ◽

Logistic Regression ◽

Kidney Disease ◽

Carotid Artery ◽

Vascular Calcification ◽

Plasma Levels ◽

Pearson Correlation ◽

Intima Media Thickness ◽

Regular Hemodialysis

Background: The incidence of heart death is 5-10 times more in patients with chronic kidney disease (CKD) with regular hemodialysis compared to the general population. Vascular calcification is a risk factor. In CKD patients there is a decrease in the distal renal cell cells which are the main producer of Klotho in the body. The functions of Klotho are maintaining integrity, endothelial permeability and endogenous inhibitors of vascular calcification. Previous studies reported an association between vascular calcification and Klotho plasma levels. Vascular calcification for heart disease can be determined by the thickness Intima Media (TIM) Carotid Artery. Objective: To determine the correlation of plasma Klotho levels with the Intima Media thickness of the Carotid Artery in CKD patients with regular hemodialysis. Methode: This cross-sectional study was conducted at the Rasyida Kidney General Hospital in Medan from April to July 2018. Patients with CKD who have undergone routine hemodialysis are examined for plasma levels of Klotho and real time ultrasound examinations to determine the thickness of arterial intima media carotid. Data are analyzed with Mann Whitney test, binominal logistic regression and Pearson correlation. Results: Seventy patients with CKD showed an average plasma Klotho level of 281.43 + 298.63 pg / ml with an average TIM of the carotid artery of 0.22 + 0.09 cm. Patients were divided into 2 groups, namely the calcification group (n = 39) and the noncalcified group (n = 31). Mann-Whitney test was performed with the results that there were differences in plasma Klotho levels between the calcification group and the noncalcified carotid artery group which were statistically significant (p = 0.001). The binominal logistic regression analysis test was performed on risk factors associated with the incidence of vascular calcification and the results of Klotho serum levels, Diabetes Mellitus and Hypertension were found to be significant risk factors for calcification (p <0.05). With the Pearson correlation test, the negative correlation of plasma Klotho levels with the thickening of Intima Carotid Arterial Media was statistically significant with moderate correlation strength (p = 0.002; r = -0.368). Conclusion: Patients with chronic kidney disease with low plasma Klotho levels have thickening of the intima media of carotid artery.

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Gut-Derived Protein-Bound Uremic Toxins

Toxins ◽

10.3390/toxins12090590 ◽

2020 ◽

Vol 12 (9) ◽

pp. 590 ◽

Cited By ~ 1

Author(s):

Amanda L. Graboski ◽

Matthew R. Redinbo

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Filtration Rate ◽

Therapeutic Strategies ◽

Uremic Toxins ◽

Uremic Toxin ◽

Risk Of Death ◽

Gut Dysbiosis ◽

Causes Of Mortality

Chronic kidney disease (CKD) afflicts more than 500 million people worldwide and is one of the fastest growing global causes of mortality. When glomerular filtration rate begins to fall, uremic toxins accumulate in the serum and significantly increase the risk of death from cardiovascular disease and other causes. Several of the most harmful uremic toxins are produced by the gut microbiota. Furthermore, many such toxins are protein-bound and are therefore recalcitrant to removal by dialysis. We review the derivation and pathological mechanisms of gut-derived, protein-bound uremic toxins (PBUTs). We further outline the emerging relationship between kidney disease and gut dysbiosis, including the bacterial taxa altered, the regulation of microbial uremic toxin-producing genes, and their downstream physiological and neurological consequences. Finally, we discuss gut-targeted therapeutic strategies employed to reduce PBUTs. We conclude that targeting the gut microbiota is a promising approach for the treatment of CKD by blocking the serum accumulation of PBUTs that cannot be eliminated by dialysis.

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Constipation in chronic kidney disease: it is time to reconsider

Renal Replacement Therapy ◽

10.1186/s41100-019-0246-3 ◽

2019 ◽

Vol 5 (1) ◽

Cited By ~ 1

Author(s):

Ryota Ikee ◽

Kazuhiro Yano ◽

Tomomi Tsuru

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Intestinal Motility ◽

Intestinal Inflammation ◽

Colonic Transit ◽

Uremic Toxins ◽

Phosphate Binders ◽

Limited Information ◽

Gut Dysbiosis

AbstractConstipation is highly prevalent in patients with chronic kidney disease (CKD) and is primarily characterized by decreased intestinal motility. This chronic disorder affects the quality of life of patients. However, nephrologist and dialysis clinicians have long had a disproportionately limited understanding of constipation. Accumulating evidence has revealed a relationship between constipation and cardiovascular disease and CKD. The pathogenesis of constipation in CKD patients is multifactorial: decreased physical activity, comorbidities affecting bowel movement, such as diabetes mellitus, cerebrovascular disease, and hyperparathyroidism, a restricted dietary intake of plant-based fiber-rich foods, and multiple medications, including phosphate binders and potassium-binding resins, have all been implicated. CKD is associated with alterations in the composition and function of the gut microbiota, so-called gut dysbiosis. Recent studies showed that CKD-related gut dysbiosis decreased intestinal motility via intestinal inflammation or the increased generation of gut-derived uremic toxins, such as indoxyl sulfate and p-cresyl sulfate. Furthermore, the gastrointestinal secretion of mucin was found to be decreased in CKD animal models, which may delay colonic transit by diminished lubrication in the alimentary tract. Thus, CKD-related gut dysbiosis may play a role in constipation, but limited information is currently available. Since constipation is often intractable, particularly in CKD patients, every available means needs to be employed in its treatment. The effects of probiotics, prebiotics, and synbiotics on the composition of the gut microbiota and gut-derived uremic toxins have been increasingly reported. However, their effects on stool consistency or frequency in CKD patients remain unclear. Some laxatives may be beneficial for improving not only bowel habits but also gut dysbiosis. Further studies are required to elucidate the CKD-specific pathogenesis of constipation and develop novel effective treatment options.

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Dietary intake of tyrosine and phenylalanine, and p-cresyl sulfate plasma levels in non-dialyzed patients with chronic kidney disease

Brazilian Journal of Nephrology ◽

10.1590/2175-8239-jbn-2018-0214 ◽

2020 ◽

Vol 42 (3) ◽

pp. 307-314

Author(s):

Andressa Louzada Frauche Fernandes ◽

Natalia A. Borges ◽

Ana Paula Black ◽

Juliana dos Anjos ◽

Greicielle Santos da Silva ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Dietary Intake ◽

Plasma Levels ◽

Protein Intake ◽

Uremic Toxins ◽

Food Record ◽

Protein Nitrogen ◽

Bacterial Fermentation

ABSTRACT Background: Patients with chronic kidney disease (CKD) present an imbalance of the gut microbiota composition, leading to increased production of uremic toxins like p-cresyl sulfate (PCS), product from bacterial fermentation of the amino acids tyrosine (Tyr) and phenylalanine (Phe) from the diet. Thus, diet may be a determinant in the uremic toxins levels produced by the gut microbiota. The aim of this study was to evaluate the possible relationship between Tyr and Phe intake and PCS plasma levels in non-dialysis CKD patients. Methods: Twenty-seven non-dialysis CKD patients (stages 3 and 4) without previous nutritional intervention were evaluated. The dietary intake was evaluated using a 24-hour recall, 3-day food record and protein intake was also estimated by Protein Nitrogen Appearance (PNA). The plasma levels of PCS were measured using reverse phase high performance liquid chromatography. Results: The evaluated patients (GRF, 34.8 ± 12.4 mL/min, 54.2 ± 14.3 years, BMI, 29.3 ± 6.1 kg/m2) presented mean protein intake of 1.1 ± 0.5 g/kg/day), Tyr of 4.5 ± 2.4 g/day and Phe of 4.6 ± 2.5 g/day. PCS plasma levels (20.4 ± 15.5 mg/L) were elevated and positively associated with both, Tyr (r = 0.58, p = 0.002) and Phe intake (r = 0.53, p = 0.005), even after adjustments for eGFR and age. Conclusion: This study suggests that the diet is an important modulator of the uremic toxins plasma levels produced by the gut microbiota, in non-dialysis CKD patients.

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