Contribution of Gut Microbiota-Derived Uremic Toxins to the Cardiovascular System Mineralization

Chronic kidney disease (CKD) affects more than 10% of the world population and leads to excess morbidity and mortality (with cardiovascular disease as a leading cause of death). Vascular calcification (VC) is a phenomenon of disseminated deposition of mineral content within the media layer of arteries preceded by phenotypic changes in vascular smooth muscle cells (VSMC) and/or accumulation of mineral content within the atherosclerotic lesions. Medial VC results in vascular stiffness and significantly contributes to increased cardio-vascular (CV) morbidity, whereas VC of plaques may rather increase their stability. Mineral and bone disorders of CKD (CKD-MBD) contribute to VC, which is further aggravated by accumulation of uremic toxins. Both CKD-MBD and uremic toxin accumulation affect not only patients with advanced CKD (glomerular filtration rate (GFR) less than 15 mL/min./1.72 m2, end-stage kidney disease) but also those on earlier stages of a disease. The key uremic toxins that contribute to VC, i.e., p-cresyl sulphate (PCS), indoxyl sulphate (IS) and trimethylamine-N-oxide (TMAO) originate from bacterial metabolism of gut microbiota. All mentioned toxins promote VC by several mechanisms, including: Transdifferentiation and apoptosis of VSMC, dysfunction of endothelial cells, oxidative stress, interaction with local renin–angiotensin–aldosterone system or miRNA profile modification. Several attractive methods of gut microbiota manipulations have been proposed in order to modify their metabolism and to limit vascular damage (and VC) triggered by uremic toxins. Unfortunately, to date no such method was demonstrated to be effective at the level of “hard” patient-oriented or even clinically relevant surrogate endpoints.

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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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Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression

Toxins ◽

10.3390/toxins10070300 ◽

2018 ◽

Vol 10 (7) ◽

pp. 300 ◽

Cited By ~ 33

Author(s):

Esmeralda Castillo-Rodriguez ◽

Raul Fernandez-Prado ◽

Raquel Esteras ◽

Maria Perez-Gomez ◽

Carolina Gracia-Iguacel ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Gut Microbiota ◽

Molecular Mechanisms ◽

Kidney Diseases ◽

Toxin Production ◽

Uremic Toxins ◽

Uremic Toxin ◽

Ckd Progression ◽

Increased Risk

In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of CKD progression. Some uremic toxins result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves, such as trimethylamine N-Oxide (TMAO), p-cresyl sulphate, indoxyl sulphate and indole-3 acetic acid. Increased intake of some nutrients may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of CKD progression. This offers the opportunity for therapeutic intervention by either modifying the diet, modifying the microbiota, decreasing uremic toxin production by microbiota, increasing toxin excretion or targeting specific uremic toxins. We now review the link between nutrients, microbiota and uremic toxin with CKD progression. Specific focus will be placed on the generation specific uremic toxins with nephrotoxic potential, the decreased availability of bacteria-derived metabolites with nephroprotective potential, such as vitamin K and butyrate and the cellular and molecular mechanisms linking these toxins and protective factors to kidney diseases. This information provides a conceptual framework that allows the development of novel therapeutic approaches.

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MO137DIFFERENCES IN GUT MICROBIOTA PROFILES AND FUNCTIONS BETWEEN END-STAGE KIDNEY DISEASE AND HEALTHY POPULATIONS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab092.0015 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Ping-Hsun Wu ◽

Ting-Yun Lin ◽

Hsiu J Ho ◽

Ching-Hung Tseng ◽

Yi-Ting Lin ◽

...

Keyword(s):

Kidney Disease ◽

Gut Microbiota ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Validation Cohort ◽

Uremic Toxins ◽

End Stage Kidney Disease ◽

Discovery Cohort ◽

Α Diversity ◽

End Stage

Abstract Background and Aims Patients with end-stage kidney disease (ESKD) are characterized by altered gut microbiota, impaired intestinal barrier function, and experienced gut microbiota-derived metabolites related to systemic complications. However, limited studies evaluated the microbial diversity and function in ESKD patients previously. Method Compared to age- and gender-matched subjects without kidney disease, 82 ESKD patients in the discovery cohort and 58 ESKD patients in the validation cohort were investigated for the microbial richness, biodiversity, gut dysbiosis, microbial composition differences, and the functional changes by gut metabolic module analysis. Bacterial derived free form protein-bound uremic toxins were analyzed by mass spectrometry and their association with microbial richness in ESKD patients was determined. Results Compared to controls, an increased α-diversity and distinct β-diversity were found in ESKD (Figure). The increase in α-diversity was correlated with protein-bound uremic toxins, particularly hippuric acid. A higher microbial dysbiosis index (MDI) was found in ESKD patients with the following enriched genera: Facealibacterium, Ruminococcus, Fusobacterium, Dorea, Anaerovorax, Sarcina, Akkermansia, Streptococcus, and Dysgonomonas. MDI at the genus level successfully differentiated between ESKD and controls in the discovery cohort (area under the curve [AUC] of 81.9%) and the validation cohort (AUC of 83.2%). Regarding functional enrichment analysis with gut metabolic modules, ESKD subjects presented with gut microbial function of increased saccharide and amino acid metabolism compared with matched controls. Conclusion An enriched but dysbiotic gut microbiota was presented in ESKD patients, in which the bacteria that were present increase amino acid metabolism linked to the production of protein-bound uremic toxins.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22126270 ◽

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.

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Protection of Residual Renal Function and Nutritional Treatment: First Step Strategy for Reduction of Uremic Toxins in End-Stage Kidney Disease Patients

Toxins ◽

10.3390/toxins13040289 ◽

2021 ◽

Vol 13 (4) ◽

pp. 289

Author(s):

Adamasco Cupisti ◽

Piergiorgio Bolasco ◽

Claudia D’Alessandro ◽

Domenico Giannese ◽

Alice Sabatino ◽

...

Keyword(s):

Kidney Disease ◽

Residual Renal Function ◽

The Body ◽

Uremic Toxins ◽

End Stage Kidney Disease ◽

Waste Products ◽

Hemodialysis Treatment ◽

Life Saving ◽

Kidney Replacement Therapy ◽

End Stage

The retention of uremic toxins and their pathological effects occurs in the advanced phases of chronic kidney disease (CKD), mainly in stage 5, when the implementation of conventional thrice-weekly hemodialysis is the prevalent and life-saving treatment. However, the start of hemodialysis is associated with both an acceleration of the loss of residual kidney function (RKF) and the shift to an increased intake of proteins, which are precursors of uremic toxins. In this phase, hemodialysis treatment is the only way to remove toxins from the body, but it can be largely inefficient in the case of high molecular weight and/or protein-bound molecules. Instead, even very low levels of RKF are crucial for uremic toxins excretion, which in most cases are protein-derived waste products generated by the intestinal microbiota. Protection of RKF can be obtained even in patients with end-stage kidney disease (ESKD) by a gradual and soft shift to kidney replacement therapy (KRT), for example by combining a once-a-week hemodialysis program with a low or very low-protein diet on the extra-dialysis days. This approach could represent a tailored strategy aimed at limiting the retention of both inorganic and organic toxins. In this paper, we discuss the combination of upstream (i.e., reduced production) and downstream (i.e., increased removal) strategies to reduce the concentration of uremic toxins in patients with ESKD during the transition phase from pure conservative management to full hemodialysis treatment.

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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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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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Abstract 17220: Effects of the Oral Adsorbent of AST-120 in Patients with both Chronic Heart Failure and Chronic Kidney Disease

Circulation ◽

10.1161/circ.130.suppl_2.17220 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Miki Imazu ◽

Masanori Asakura ◽

Takuya Hasegawa ◽

Hiroshi Asanuma ◽

Shin Ito ◽

...

Keyword(s):

Heart Failure ◽

Chronic Kidney Disease ◽

Chronic Heart Failure ◽

Kidney Disease ◽

Diastolic Dysfunction ◽

Uremic Toxins ◽

Control Group ◽

Blood Levels ◽

Uremic Toxin ◽

Oral Adsorbent

Background: One of uremic toxins, indoxyl sulfate (IS) is related to the progression of chronic kidney disease (CKD) and the worse cardiovascular outcomes. We have previously reported the relationship between IS levels and the severity of chronic heart failure (CHF), but the question arises as to whether the treatment of uremic toxin is beneficial in patients with CHF. This study aimed to elucidate whether the treatment with the oral adsorbent which reduces uremic toxin improved the cardiac function of the patients with CHF. Methods: First of all, we retrospectively enrolled 49 patients with both CHF and stage ≤3 CKD in our institute compared with the healthy subjects without CHF or CKD in the resident cohort study of Arita. Secondly, we retrospectively enrolled 16 CHF outpatients with stage 3-5 CKD. They were treated with and without the oral adsorbent of AST-120 for one year termed as the treatment and control groups, respectively. We underwent both blood test and echocardiography before and after the treatment. Results: First of all, among 49 patients in CHF patients, plasma IS levels increased to 1.38 ± 0.84 μg/ml from the value of 0.08 ± 0.06 μg/ml in Arita-cho as a community-living matched with gender and eGFR of CHF patients. We found both fractional shortening (FS) and E/e’, an index of diastolic function were decreased (25.0 ± 12.7%) and increased (13.7 ± 7.5), respectively in CHF patients compared with the value of FS and E/e’ in Arita-cho (FS: 41.8 ± 8.3%, E/e’: 8.8 ± 2.1). Secondly, in the treatment group, the plasma IS levels and the serum creatinine and brain natriuretic peptide levels decreased (1.40 ± 0.17 to 0.92 ± 0.15 μg/ml; p<0.05, 1.91 ± 0.16 to 1.67 ± 0.12 mg/dl; p<0.05, 352 ± 57 to 244 ± 49 pg/ml; p<0.05, respectively) and both FS and E/e’ were improved following the treatment with AST-120 (28.8 ± 2.8 to 32.9 ± 2.6%; p<0.05, 18.0 ± 2.0 to 11.8 ± 1.0; p<0.05). However, these parameters did not change in the control group. Conclusions: The treatment to decrease the blood levels of uremic toxins improved not only renal dysfunction but cardiac systolic and diastolic dysfunction in patients with chronic heart failure. Oral adsorbents might be a new treatment of heart failure especially with diastolic dysfunction.

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MO448MICRORNAS IMPLICATED IN CHRONIC KIDNEY DISEASE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab090.0010 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Laurent Metzinger

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Clinical Outcomes ◽

Molecular Mechanisms ◽

Neointimal Hyperplasia ◽

Uremic Toxins ◽

University Hospital ◽

Transcriptional Level ◽

Uremic Toxin ◽

Ckd Stage

Abstract Background and Aims The gene program is controlled at the post-transcriptional level by the action of small non-coding RNAs known as microRNAs (miRNAs), short, single-stranded molecules that control mRNA stability or translational repression via base pairing with regions in the 3' untranslated region of their target mRNAs. Recently, considerable progress has been made to elucidate the roles of miRNAs in vascular pathogenesis and develop the use of miRNAs as biomarkers, and innovative drugs. We demonstrated during the last decade that miRNAs miR-126 and miR-223 are implicated in the course of chronic kidney disease (CKD) and cardiovascular damage. miR-223 expression is enhanced in vascular smooth muscle cells (VSMCs) subjected to an uremic toxin and also in aortas of a murine model of CKD. As restenosis is a common complication of angioplasty, in which neointimal hyperplasia results from migration of VSMCs into the vessel lumen we measured the effect of miR-223 modulation on restenosis in a rat model of carotid artery after balloon injury. We over-expressed and inhibited miR-223 expression using adenoviral vectors, coding a pre-miR-223 sequence or a sponge sequence, used to trap endogenous microRNA, respectively. We demonstrated that inhibiting miR-223 function significantly reduced neointimal hyperplasia by almost half in carotids. Thus down-regulating miR-223 could be a potential therapeutic approach to prevent restenosis after angioplasty. We also correlated miR-126 and miR-223 expression with clinical outcomes in a large cohort of CKD patients, in collaboration with the University Hospital of Ghent (Belgium) and Ambroise Paré Hospital, France. We evaluated both miRNA’s link with all-cause mortality and cardiovascular and renal events over a 6-year follow-up period. The serum levels of miR-126 and miR-223 were decreased as CKD stage advanced, and patients with higher levels of miR-126 and miR-223 had a higher survival rate. Similar results were observed for cardiovascular and renal events. In conclusion, CKD is associated with a decrease in circulating miR-126 and miR-223 levels in CKD patients. We will also present links between several uremic toxin concentrations and miRNA concentration in the patients of this cohort. Finally, anemia is a common feature of CKD that is associated with cardiovascular disease and poor clinical outcomes. A mixture of uremic toxins accumulates in the blood of CKD patients during the course of the disease, and there is good evidence that they modulate erythropoiesis, explaining at least partly anemia. The exact molecular mechanisms implicated are however poorly understood, although recent progresses have been made to identify key components in the CKD process. We will present results on the effect of uremic toxins on erythropoiesis, having an impact on cell metabolism during this process. Taken together, our findings could be of interest to both researchers and clinicians working in the field since they might shed new light on the molecular mechanisms involved in the CKD process. MicroRNAs implicated in Chronic Kidney Disease Pr. Laurent Metzinger, UR-UPJV 4666 HEMATIM, CURS, Université de Picardie Jules Verne, CHU Amiens Sud, Avenue René Laënnec, Salouel, F-80054, Amiens, France. Tel: (+33) 22 82 53 56, Email: [email protected]

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