Investigation of a targeted panel of gut microbiome–derived toxins in children with chronic kidney disease

Pediatric Nephrology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 16, 2025

Язык: Английский

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Inflammation in Children with CKD Linked to Gut Dysbiosis and Metabolite Imbalance

Journal of the American Society of Nephrology, Год журнала: 2022, Номер 33(12), С. 2259 - 2275

Опубликована: Авг. 19, 2022

CKD is characterized by a sustained proinflammatory response of the immune system, promoting hypertension and cardiovascular disease. The underlying mechanisms are incompletely understood but may be linked to gut dysbiosis. Dysbiosis has been described in adults with CKD; however, comorbidities limit CKD-specific conclusions.We analyzed fecal microbiome, metabolites, phenotypes 48 children (with normal kidney function, stage G3-G4, G5 treated hemodialysis [HD], or transplantation) mean±SD age 10.6±3.8 years.Serum TNF-α sCD14 were stage-dependently elevated, indicating inflammation, barrier dysfunction, endotoxemia. We observed compositional functional alterations including diminished production short-chain fatty acids. Plasma metabolite analysis revealed stage-dependent increase tryptophan metabolites bacterial origin. Serum from patients on HD activated aryl hydrocarbon receptor stimulated monocytes, corresponding shift classic nonclassic intermediate monocytes. Unsupervised T cells loss mucosa-associated invariant (MAIT) regulatory cell subtypes HD.Gut dysfunction microbial imbalance apparently mediate phenotype, thereby driving susceptibility data highlight importance microbiota-immune axis CKD, irrespective confounding comorbidities.

Язык: Английский

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Faecal Microbiota Transplantation and Chronic Kidney Disease

Nutrients, Год журнала: 2022, Номер 14(12), С. 2528 - 2528

Опубликована: Июнь 17, 2022

Faecal microbiota transplantation (FMT) has attracted increasing attention as an intervention in many clinical conditions, including autoimmune, enteroendocrine, gastroenterological, and neurological diseases. For years, FMT been effective second-line treatment for Clostridium difficile infection (CDI) with beneficial outcomes. is also promising improving bowel diseases, such ulcerative colitis (UC). Pre-clinical studies suggest that this microbiota-based may influence the development progression of chronic kidney disease (CKD) via modifying a dysregulated gut–kidney axis. Despite high morbidity mortality due to CKD, there are limited options until end-stage occurs, which results death, dialysis, or transplantation. This imposes significant financial health burden on individual, their families careers, system. Recent have suggested strategies reverse gut dysbiosis using therapy CKD. review summarises preclinical evidence postulates potential therapeutic effect management

Язык: Английский

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Uremic Toxin Indoxyl Sulfate Promotes Macrophage-Associated Low-Grade Inflammation and Epithelial Cell Senescence

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(9), С. 8031 - 8031

Опубликована: Апрель 28, 2023

In this study, we investigated the impact of uremic toxin indoxyl sulfate on macrophages and tubular epithelial cells its role in modulating response to lipopolysaccharide (LPS). Indoxyl accumulates blood patients with chronic kidney disease (CKD) is a predictor overall cardiovascular morbidity/mortality. To simulate condition, primary were incubated at low concentrations as well found patients, both alone upon LPS challenge. The results showed that induced release reactive oxygen species low-grade inflammation macrophages. Moreover, combined (proinflammatory conditions), significantly increased TNF-α, CCL2, IL-10 but did not affect polarization Pre-treatment following challenge expression aryl hydrocarbon receptor (Ahr) NADPH oxidase 4 (Nox4) which generate (ROS). Further, experiments revealed might induce senescence parenchymal therefore participate progression inflammaging. conclusion, study provides evidence provokes inflammation, modulates macrophage function, enhances inflammatory associated LPS. Finally, signaling contributes during injury.

Язык: Английский

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New Insights into the Roles of Monocytes/Macrophages in Cardiovascular Calcification Associated with Chronic Kidney Disease

Toxins, Год журнала: 2019, Номер 11(9), С. 529 - 529

Опубликована: Сен. 12, 2019

Cardiovascular disease (CVD) is an important cause of death in patients with chronic kidney (CKD), and cardiovascular calcification (CVC) one the strongest predictors CVD this population. results from complex cellular interactions involving endothelium, vascular/valvular cells (i.e., vascular smooth muscle cells, valvular interstitial resident fibroblasts), monocyte-derived macrophages. Indeed, production pro-inflammatory cytokines oxidative stress by macrophages responsible for osteogenic transformation mineralization cells. However, monocytes/macrophages show ability to modify their phenotype, consequently functions, when facing environmental modifications. This plasticity complicates efforts understand pathogenesis CVC—particularly a CKD setting, where both uraemic toxins treatment may affect monocyte/macrophage functions thereby influence CVC. Here, we review (i) mechanisms which each subset either promotes or prevents CVC, (ii) how therapies might these functions.

Язык: Английский

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Interplay between gut microbiota, bone health and vascular calcification in chronic kidney disease

European Journal of Clinical Investigation, Год журнала: 2021, Номер 51(9)

Опубликована: Май 5, 2021

Abstract Deregulations in gut microbiota may play a role vascular and bone disease chronic kidney (CKD). As glomerular filtration rate declines, the colon becomes more important as site of excretion urea uric acid, an increased bacterial proteolytic fermentation alters microbial balance. A diet with limited amounts fibre, well certain medications (eg phosphate binders, iron supplementation, antibiotics) further contribute to changes composition among CKD patients. At same time, both calcification are common patients advanced disease. This narrative review describes emerging evidence on dysbiosis, calcification, demineralization their interrelationship termed ‘gut‐bone‐vascular axis’ progressive CKD. The diet, metabolites (ie indoxyl sulphate, p‐cresyl trimethylamine N‐oxide (TMAO) short‐chain fatty acids (SCFA)), vitamin K deficiency, inflammatory cytokines impact health discussed. framework open up novel preventive therapeutic approaches targeting microbiome attempt improve cardiovascular

Язык: Английский

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Serum indoxyl sulfate concentrations associate with progression of chronic kidney disease in children

PLoS ONE, Год журнала: 2020, Номер 15(10), С. e0240446 - e0240446

Опубликована: Окт. 27, 2020

The uremic toxins indoxyl sulfate (IS) and p-cresyl (pCS) accumulate in patients with chronic kidney disease (CKD) as a consequence of altered gut microbiota metabolism decline renal excretion. Despite solid experimental evidence for nephrotoxic effects, the impact on progression CKD has not been investigated representative patient cohorts. In this analysis, IS pCS serum concentrations were measured 604 pediatric participants (mean eGFR 27 ± 11 ml/min/1.73m2) at enrolment into prospective Cardiovascular Comorbidity Children study. Associations analyzed by Kaplan-Meier analyses Cox proportional hazard models. During median follow up time 2.2 years (IQR 4.3-0.8 years), composite survival endpoint, defined 50% loss eGFR, or <10ml/min/1.73m2 start replacement therapy, was reached 360 (60%). Median shorter levels highest versus lowest quartile both (1.5 years, 95%CI [1.1,2.0] 6.0 [5.0,8.4]) (1.8 [1.5,2.8] 4.4 [3.4,6.0]). Multivariable regression disclosed significant association IS, but pCS, survival, which independent other risk factors including baseline proteinuria blood pressure. exploratory analysis we provide first data showing children, known factors. absence comorbidities, interfere toxins, such diabetes, obesity metabolic syndrome, these results highlight important role accentuate unmet need effective elimination strategies to lower toxin burden abate CKD.

Язык: Английский

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Pathophysiology and consequences of arterial stiffness in children with chronic kidney disease

Pediatric Nephrology, Год журнала: 2020, Номер 36(7), С. 1683 - 1695

Опубликована: Сен. 7, 2020

Язык: Английский

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Circulating Extracellular Vesicles as Putative Mediators of Cardiovascular Disease in Paediatric Chronic Kidney Disease

Journal of Extracellular Vesicles, Год журнала: 2025, Номер 14(3)

Опубликована: Март 1, 2025

Cardiovascular disease (CVD) is the leading cause of mortality in chronic kidney (CKD). However, pathogenesis CVD CKD remains incompletely understood. Endothelial extracellular vesicles (EC-EVs) have previously been associated with CVD. We hypothesized that alters EV release and cargo, subsequently promoting vascular remodelling. recruited 94 children CKD, including patients after transplantation healthy donors, performed phenotyping functional analyses absence age-related comorbidities. Plasma EC-EVs were increased haemodialysis decreased transplantation. Thirty microRNAs less abundant total plasma EVs predicted importance angiogenesis smooth muscle cell proliferation. In vitro, induced transcriptomic changes pathways functionally impaired angiogenic properties, migration proliferation ECs. High shear stress, as generated by arterio-venous fistulas, uremic toxins considered potential drivers release, but only combination generation from venous The resulting recapitulated miRNA observed vivo. conclusion, results altered profiles anti-angiogenic which may mediate pathology CKD. their cargo represent future therapeutic targets to attenuate

Язык: Английский

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Uraemic extracellular vesicles augment osteogenic transdifferentiation of vascular smooth muscle cells via enhanced AKT signalling and PiT‐1 expression

Journal of Cellular and Molecular Medicine, Год журнала: 2021, Номер 25(12), С. 5602 - 5614

Опубликована: Май 7, 2021

Abstract Extracellular vesicles (EV) function as messengers between endothelial cells (EC) and vascular smooth muscle (VSMC). Since chronic kidney disease (CKD) increases the risk for calcifications, we investigated whether EV derived from uraemic milieu‐stimulated EC rats impact osteogenic transdifferentiation/calcification of VSMC. For that purpose, human were treated with urea indoxyl sulphate or left untreated. Experimental uraemia in was induced by adenine feeding. ‘Uraemic’ control (EV UR ; CTRL ) isolated supernatants plasma using an exosome isolation reagent. Rat VSMC a pro‐calcifying medium (CM) without supplementation. Gene expressions, miRNA contents protein expressions determined qPCR Western blots, respectively. Calcifications colorimetric assays. Delivery inhibitors/mimics to siRNA achieved via transfection. differed size contents. Contrary , EC‐ plasma‐derived significantly increased effects CM, including altered gene osterix, runx2, osteocalcin SM22α. Further, enhanced expression phosphate transporter PiT‐1 phosphorylation AKT ERK. Knock down individual inhibition ERK signalling blocked . Similar miR‐221/‐222 mimicking miR‐143/‐145 In conclusion, might represent additional puzzle piece complex pathophysiology calcifications CKD.

Язык: Английский

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