The Impact of CKD on Uremic Toxins and Gut Microbiota

Numerous studies have indicated that the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD) is strictly associated with the accumulation of toxic metabolites in blood and other metabolic compartments. This accumulation was suggested to be related to enhanced generation of toxins from the dysbiotic microbiome accompanied by their reduced elimination by impaired kidneys. Intestinal microbiota play a key role in the accumulation of uremic toxins due to the fact that numerous uremic solutes are generated in the process of protein fermentation by colonic microbiota. Some disease states, including CKD, are associated with the presence of dysbiosis, which can be defined as an “imbalanced intestinal microbial community with quantitative and qualitative changes in the composition and metabolic activities of the gut microbiota”. The results of studies have confirmed the altered composition and functions of gut microbial community in chronic kidney disease. In the course of CKD protein-bound uremic toxins, including indoxyl sulfate, p-cresyl glucuronide, p-cresyl sulfate and indole-3-acetic acid are progressively accumulated. The presence of chronic kidney disease may be accompanied by the development of intestinal inflammation and epithelial barrier impairment leading to hastened systemic translocation of bacterial-derived uremic toxins and consequent oxidative stress injury to the kidney, cardiovascular and endocrine systems. These findings offer new therapeutic possibilities for the management of uremia, inflammation and kidney disease progression and the prevention of adverse outcomes in CKD patients. It seems that dietary interventions comprising prebiotics, probiotics, and synbiotics could pose a promising strategy in the management of uremic toxins in CKD.

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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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The Impact of Uremia and Intestinal Dysbiosis on Hepatic Drug Metabolism in a Rat Model of Progressive Chronic Kidney Disease

10.1101/531939 ◽

2019 ◽

Author(s):

Emily D Hartjes ◽

Yong Jin Lim ◽

Thomas J Velenosi ◽

Kait F Al ◽

Jean M Macklaim ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Drug Metabolism ◽

Gut Microbiota ◽

Uremic Toxins ◽

Uremic Toxin ◽

Bacterial Microbiota ◽

Intestinal Dysbiosis ◽

Metabolite Profiles ◽

The Impact

AbstractNonrenal clearance pathways such as drug metabolism are decreased in chronic kidney disease (CKD). Although the mechanism remains elusive, uremic toxin retention and an altered gut microbiota are suspected to influence cytochrome P450s (CYPs) contributing to the unpredictable pharmacokinetics in patients with CKD. We characterized dysbiosis and uremia in CKD to elucidate associations between CYP expression and CKD progression. Rats fed control or CKD-inducing adenine diet were subsequently studied at five time points over 42 days. CYP expression and activity were compared to alterations in the 1) plasma and liver metabolome and 2) gut bacterial microbiota. CYP3A2 and CYP2C11 were downregulated in CKD by ≥76% (p<0.001) concurrently with or slightly prior to CKD onset as defined by serum creatinine. Metabolite profiles were altered prior to changes in the gut microbiota, and gut-derived uremic toxins including indoxyl sulfate, phenyl sulfate and 4-ethylphenyl sulfate correlated with CYP3A2 or CYP2C11 expression. Bacterial genera Turicibacter and Parabacteroides were identified as being characteristic of CKD. In conclusion, CYP3A2 and CYP2C11 are downregulated before dysbiosis and correlate with select uremic toxins.

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Association of Sarcopenia and Gut Microbiota Composition in Older Patients with Advanced Chronic Kidney Disease, Investigation of the Interactions with Uremic Toxins, Inflammation and Oxidative Stress

Toxins ◽

10.3390/toxins13070472 ◽

2021 ◽

Vol 13 (7) ◽

pp. 472

Author(s):

Elisabetta Margiotta ◽

Lara Caldiroli ◽

Maria Luisa Callegari ◽

Francesco Miragoli ◽

Francesca Zanoni ◽

...

Keyword(s):

Oxidative Stress ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Inflammatory Cytokines ◽

Interleukin 10 ◽

Uremic Toxins ◽

Interleukin 12 ◽

European Working ◽

And Oxidative Stress

Background: Sarcopenia is a prevalent condition in chronic kidney disease (CKD). We determined gut microbiota (gMB) composition in CKD patients with or without sarcopenia. Furthermore, we investigated whether in these patients, there was any association between gMB, uremic toxins, inflammation and oxidative stress. Methods: We analyzed gMB composition, uremic toxins (indoxyl sulphate and p-cresyl sulphate), inflammatory cytokines (interleukin 10, tumor necrosis factor α, interleukin 6, interleukin 17, interleukin 12 p70, monocyte chemoattractant protein-1 and fetuin-A) and oxidative stress (malondialdehyde) of 64 elderly CKD patients (10 < eGFR < 45 mL/min/1.73 m2, not on dialysis) categorized as sarcopenic and not-sarcopenic. Sarcopenia was defined according to European Working Group on Sarcopenia in Older People 2 criteria. Results: Sarcopenic patients had a greater abundance of the Micrococcaceae and Verrucomicrobiaceae families and of Megasphaera, Rothia, Veillonella, Akkermansia and Coprobacillus genera. They had a lower abundance of the Gemellaceae and Veillonellaceae families and of Acidaminococcus and Gemella genera. GMB was associated with uremic toxins, inflammatory cytokines and MDA. However, uremic toxins, inflammatory cytokines and MDA were not different in sarcopenic compared with not-sarcopenic individuals, except for interleukin 10, which was higher in not-sarcopenic patients. Conclusions: In older CKD patients, gMB was different in sarcopenic than in not-sarcopenic ones. Several bacterial families and genera were associated with uremic toxins and inflammatory cytokines, although none of these latter substantially different in sarcopenic versus not-sarcopenic patients.

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Rhubarb Enema Decreases Circulating Trimethylamine N-Oxide Level and Improves Renal Fibrosis Accompanied With Gut Microbiota Change in Chronic Kidney Disease Rats

Frontiers in Pharmacology ◽

10.3389/fphar.2021.780924 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chunlan Ji ◽

Yin Li ◽

Yenan Mo ◽

Zhaoyu Lu ◽

Fuhua Lu ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Intestinal Microbiota ◽

Renal Fibrosis ◽

Interstitial Fibrosis ◽

Underlying Mechanism ◽

Uremic Toxins ◽

16S Rrna Sequence ◽

Tubular Atrophy ◽

The Impact

Objectives: Trimethylamine N-oxide (TMAO), a metabolic product of gut flora, is increased in chronic kidney disease (CKD) subjects and is recognized as one type of uremic toxins which is associated with poor cardiovascular outcomes and kidney function loss. Previous studies have suggested that rhubarb enema could reduce circulating uremic toxins such as urea, creatinine, and indoxyl sulfate and also regulate the intestinal microbiota. However, whether rhubarb enema retards kidney dysfunction by reducing circulating TMAO and its underlying mechanism, are still unclear. The present study aims to investigate the impact of rhubarb enema on TMAO and its precursors, as well as on the intestinal microbiota in 5/6 nephrectomized (5/6Nx) CKD rats.Design: Rats in the treatment groups were given rhubarb enema after modeling. At the end of the study, blood, feces, and kidney tissues were collected and processed for biochemical analyses, histological and western blot analyses, 16S rRNA sequence and untargeted metabolomic analyses.Results: Rhubarb enema reduced serum TMAO and trimethylamine (TMA) levels, inhibited the expression of inflammatory markers (interleukin-6, tumor necrosis factor α and Interferon-γ) and alleviated tubular atrophy, monocyte infiltration and interstitial fibrosis in 5/6Nx CKD rats. Moreover, rhubarb enema significantly increased the abundance of some symbiotic bacteria and probiotics, while reduced the abundance of some potential pathogens at the genus level. In addition, Spearman’s correlation analysis revealed that lachnospiraceae and romboutsia were positively correlated with TMAO.Conclusion: Rhubarb enema decreases circulating TMAO level and improves renal fibrosis in 5/6Nx CKD rats, which may be related to the regulation of intestinal microbial community.

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Ketoacid Analogues Supplementation in Chronic Kidney Disease and Future Perspectives

Nutrients ◽

10.3390/nu11092071 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2071 ◽

Cited By ~ 14

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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The role of chronic kidney disease-associated dysbiosis in cardiovascular disease

Experimental Biology and Medicine ◽

10.1177/1535370219826526 ◽

2019 ◽

Vol 244 (6) ◽

pp. 514-525 ◽

Cited By ~ 6

Author(s):

Mark A Bryniarski ◽

Fares Hamarneh ◽

Rabi Yacoub

Keyword(s):

Cardiovascular Disease ◽

Chronic Kidney Disease ◽

Microbial Community ◽

Kidney Disease ◽

Cardiovascular Events ◽

Environmental Changes ◽

Intestinal Microbiome ◽

Intestinal Lumen ◽

Stage Renal Disease ◽

The Impact

Survival outcomes of patients with end stage renal disease are worse than those of many metastatic cancers. Kidney disease patients are often inflicted with higher rates of cardiovascular disease, in which nearly half of the mortalities are attributed to adverse cardiovascular events. Of the multifarious reasons for this detrimental impact, dysbiosis in the intestinal microbiome is surfacing as a potential participant. This is likely due to the numerous metabolic and inflammatory shifts found in chronic kidney disease, as well as environmental changes within the intestinal lumen. Studies are beginning to link microbiota alterations mediated by chronic kidney disease to negative cardiovascular outcomes. Here, recent findings connecting dysbiosis in chronic kidney disease and various cardiovascular insults are reviewed. Impact statement Negative alterations, or dysbiosis, in the intestinal microbial community balance in response to chronic kidney disease is emerging as a substantial and important factor in inducing and exacerbating multiple comorbid conditions. Patients with renal insufficiency experience a substantial increase in cardiovascular risk, and recent evidence is shedding light on the close interaction between microbiome dysbiosis and increased cardiovascular events in this population. Previous association and recent causality studies utilizing experimental animal models have enriched our understanding and confirmed the impact of microbial community imbalance on cardiac health in both the general population and in patients with renal impairment.

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Uremic Toxins, Oxidative Stress, Atherosclerosis in Chronic Kidney Disease, and Kidney Transplantation

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6651367 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15 ◽

Cited By ~ 1

Author(s):

Ewa Wojtaszek ◽

Urszula Oldakowska-Jedynak ◽

Marlena Kwiatkowska ◽

Tomasz Glogowski ◽

Jolanta Malyszko

Keyword(s):

Oxidative Stress ◽

Risk Factors ◽

Cardiovascular Disease ◽

Chronic Kidney Disease ◽

Kidney Transplantation ◽

Kidney Disease ◽

Uremic Toxins ◽

Transplant Recipients ◽

Risk Of Death ◽

The Impact

Patients with chronic kidney disease (CKD) are at a high risk for cardiovascular disease (CVD), and approximately half of all deaths among patients with CKD are a direct result of CVD. The premature cardiovascular disease extends from mild to moderate CKD stages, and the severity of CVD and the risk of death increase with a decline in kidney function. Successful kidney transplantation significantly decreases the risk of death relative to long-term dialysis treatment; nevertheless, the prevalence of CVD remains high and is responsible for approximately 20-35% of mortality in renal transplant recipients. The prevalence of traditional and nontraditional risk factors for CVD is higher in patients with CKD and transplant recipients compared with the general population; however, it can only partly explain the highly increased cardiovascular burden in CKD patients. Nontraditional risk factors, unique to CKD patients, include proteinuria, disturbed calcium, and phosphate metabolism, anemia, fluid overload, and accumulation of uremic toxins. This accumulation of uremic toxins is associated with systemic alterations including inflammation and oxidative stress which are considered crucial in CKD progression and CKD-related CVD. Kidney transplantation can mitigate the impact of some of these nontraditional factors, but they typically persist to some degree following transplantation. Taking into consideration the scarcity of data on uremic waste products, oxidative stress, and their relation to atherosclerosis in renal transplantation, in the review, we discussed the impact of uremic toxins on vascular dysfunction in CKD patients and kidney transplant recipients. Special attention was paid to the role of native and transplanted kidney function.

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MO550INDOXYL SULFATE AFFECTS ERYTHROPOIESIS DURING THE COURSE OF CHRONIC KIDNEY DISEASE: A MOLECULAR STUDY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab085.0013 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Eya Hamza ◽

Hakim Ouled-Haddou ◽

Nicolas Jankovsky ◽

Yohann Demont ◽

Benjamin Brigant ◽

...

Keyword(s):

Cell Cycle ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Cell Line ◽

Uremic Toxins ◽

Erythroid Cell ◽

Uremic Toxin ◽

Cd34 Cells ◽

Phase Cycle ◽

The Impact

Abstract Background and Aims Chronic kidney disease (CKD) is a global health condition characterized by a progressive deterioration of renal function due to high serum levels of uremic toxins. Anemia is a major trouble in CKD patients that contributes to a faster deterioration of renal failure, leading to cardiovascular disease and increasing morbimortality. Erythropoietin (EPO) is known to contribute to CKD-associated anemia. Thus, accumulation of uremic toxins in blood impairs EPO synthesis, leading to a subsequent impairment of erythropoiesis in the bone marrow. Very few molecular clues explain why erythropoiesis is affected in CKD or explain why erythropoiesis-stimulating agents (ESA) are not efficient in some patients with CKD. The current study aims to characterize the impact of one of the most representative uremic toxins, Indoxyl Sulfate (IS), in CKD-related anemia. IS is a protein-bound uremic toxin derived from the tryptophan dietary metabolism which is difficult to remove by dialysis. Our study demonstrates the molecular effects of IS on the growth and the differentiation of red blood cells in an erythroid cell line and in primary cell cultures CD34+. Method Firstly, we examined in vitro the time-courses of IS under clinically relevant concentrations of IS (250 µM -1 mM) in a human leukemic cell line in which proliferation is induced by EPO, the UT7/EPO cell line. Cell apoptosis, proliferation, differentiation and cell cycle analysis were assessed by the MACSQuant flow cytometry. Erythroid gene expression analysis was assessed by RT-qPCR (Quantstudio 7 flex). The ratio A260/280 assessed the quality of nucleic acids. Western blotting experiments were performed to study protein expression. Human primary CD34+ cells were obtained from mobilized peripheral blood mononuclear cells (MNC) of healthy subjects and were isolated by magnetic microbeads separation on MACS columns. Results IS at 250 µM and 1 mM increased apoptosis of UT7/EPO cell line at 48h compared to control condition. On the other hand, we found no significant effect of IS on the phenotype of UT7/EPO, when using CD235a (Glycophorin A), as a marker for the detection of the erythroid cell lineage. Ki67 cellular levels, a cell proliferation marker, was not altered between control and IS experiments. This indicated that IS did not affect proliferation in UT7/EPO. At 48h, at the clinically relevant concentration of IS (250 µM), we observed an increase of the cell phase cycle Sub-G1. The analysis of erythropoiesis related genes shows that HIF2α was deregulated with IS (250 µM). Finally, in the Epo-EpoR signalling pathway, we studied the activation of the Jak2/Stat5 proteins. Results in human primary CD34+ cells confirmed the apoptotic effect of IS observed in UT7/EPO. Conclusion Our findings suggest that IS, a representative protein-bound uremic toxin, could affect cell viability, apoptosis and the cell cycle. This study suggests clues to develop new therapies for CKD-associated anemia.

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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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