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Toxins
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Study on the Uremic Toxin Targeting Mechanism
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Study on the Uremic Toxin Targeting Mechanism

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Uremic Toxins".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 21677

Special Issue Editor

Prof. Dariusz Pawlak

E-Mail Website
Guest Editor
Department of Pharmacodynamics, Medical University of Bialystok, 15-522 Bialystok, Poland
Interests: chronic kidney disease; uremic toxins; kynurenine pathway; osteoblastogenesis; renal osteodystrophy

Special Issue Information

Uremic toxins are biologically active compounds accumulated in the body in the course of chronic kidney disease (CKD). Their accumulation can lead to damage to multiple organ systems, raising the risk of death in patients with CKD. The mechanisms of uremic toxicity are multifactorial and still incompletely understood. Available treatment options for end-stage renal disease are principally limited to dialysis and organ transplantation, as other treatment alternatives have proven insufficient. Renal dysfunction is a complex biological process that is mediated by genetics, epigenetics, a dysregulated form of matrix mineral metabolism, hormones, and the activation of cellular signaling pathways.

This Special Issue is specifically focused on publishing original research articles, reviews, and short communications toward discovering and understanding novel mechanisms for interaction between uremic toxins and biological systems. A better understanding of the uremic toxin targeting mechanism can prevent/reduced uremic toxin accumulation and improve management of CKD patients.

Prof. Dariusz Pawlak
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • chronic kidney disease
  • uremic toxins
  • signaling and metabolic pathways

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Published Papers (5 papers)

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Research

Jump to: Review

12 pages, 4456 KiB  
Article
In Vitro and In Vivo Antifibrotic Effects of Fraxetin on Renal Interstitial Fibrosis via the ERK Signaling Pathway
by Yi-Hsien Hsieh, Tung-Wei Hung, Yong-Syuan Chen, Yi-Ning Huang, Hui-Ling Chiou, Chu-Che Lee and Jen-Pi Tsai
Toxins 2021, 13(7), 474; https://doi.org/10.3390/toxins13070474 - 9 Jul 2021
Cited by 11 | Viewed by 3244
Abstract
Fraxetin, a natural derivative of coumarin, is known to have anti-inflammatory, anti-oxidant, and hepatoprotective effects in multiple diseases and in liver fibrosis. Whether fraxetin exerts similar effects against renal fibrosis is unknown. In a Unilateral Ureteral Obstruction (UUO) mouse model of renal fibrosis, [...] Read more.
Fraxetin, a natural derivative of coumarin, is known to have anti-inflammatory, anti-oxidant, and hepatoprotective effects in multiple diseases and in liver fibrosis. Whether fraxetin exerts similar effects against renal fibrosis is unknown. In a Unilateral Ureteral Obstruction (UUO) mouse model of renal fibrosis, fraxetin decreased UUO-induced renal dysfunction with a marked reduction in renal interstitial collagen fibers as detected by Masson’s Trichrome staining. Fraxetin treatment also inhibited the expression of α-SMA, Collagen I, Collagen IV, fibronectin, N-cadherin, vimentin, phosphorylated-ERK, and increased the expression of E-cadherin in UUO mice, as shown by immunohistochemical staining and western blot analysis. In vitro studies showed that fraxetin and indoxyl sulfate had no cytotoxic effects on MES13 kidney cells, but that fraxetin significantly decreased IS-induced cell motility and decreased protein expression of α-SMA, N-cadherin, vimentin, and Collagen IV via the ERK-mediated signaling pathway. These findings provide insight into the mechanism underlying fraxetin-induced inhibition of fibrogenesis in renal tissue and suggest that fraxetin treatment may be beneficial for slowing CKD progression. Full article
(This article belongs to the Special Issue Study on the Uremic Toxin Targeting Mechanism)
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15 pages, 1280 KiB  
Article
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
by Elisabetta Margiotta, Lara Caldiroli, Maria Luisa Callegari, Francesco Miragoli, Francesca Zanoni, Silvia Armelloni, Vittoria Rizzo, Piergiorgio Messa and Simone Vettoretti
Toxins 2021, 13(7), 472; https://doi.org/10.3390/toxins13070472 - 8 Jul 2021
Cited by 35 | Viewed by 3931
Abstract
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. We [...] Read more.
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. 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. 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. 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. Full article
(This article belongs to the Special Issue Study on the Uremic Toxin Targeting Mechanism)
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12 pages, 1181 KiB  
Article
The Links between Microbiome and Uremic Toxins in Acute Kidney Injury: Beyond Gut Feeling—A Systematic Review
by Alicja Rydzewska-Rosołowska, Natalia Sroka, Katarzyna Kakareko, Mariusz Rosołowski, Edyta Zbroch and Tomasz Hryszko
Toxins 2020, 12(12), 788; https://doi.org/10.3390/toxins12120788 - 11 Dec 2020
Cited by 21 | Viewed by 3193
Abstract
The last years have brought an abundance of data on the existence of a gut-kidney axis and the importance of microbiome in kidney injury. Data on kidney-gut crosstalk suggest the possibility that microbiota alter renal inflammation; we therefore aimed to answer questions about [...] Read more.
The last years have brought an abundance of data on the existence of a gut-kidney axis and the importance of microbiome in kidney injury. Data on kidney-gut crosstalk suggest the possibility that microbiota alter renal inflammation; we therefore aimed to answer questions about the role of microbiome and gut-derived toxins in acute kidney injury. PubMed and Cochrane Library were searched from inception to October 10, 2020 for relevant studies with an additional search performed on ClinicalTrials.gov. We identified 33 eligible articles and one ongoing trial (21 original studies and 12 reviews/commentaries), which were included in this systematic review. Experimental studies prove the existence of a kidney-gut axis, focusing on the role of gut-derived uremic toxins and providing concepts that modification of the microbiota composition may result in better AKI outcomes. Small interventional studies in animal models and in humans show promising results, therefore, microbiome-targeted therapy for AKI treatment might be a promising possibility. Full article
(This article belongs to the Special Issue Study on the Uremic Toxin Targeting Mechanism)
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Review

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17 pages, 748 KiB  
Review
Contribution of Gut Microbiota-Derived Uremic Toxins to the Cardiovascular System Mineralization
by Iwona Filipska, Agata Winiarska, Monika Knysak and Tomasz Stompór
Toxins 2021, 13(4), 274; https://doi.org/10.3390/toxins13040274 - 10 Apr 2021
Cited by 23 | Viewed by 4943
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Study on the Uremic Toxin Targeting Mechanism)
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20 pages, 1510 KiB  
Review
Thrombolome and Its Emerging Role in Chronic Kidney Diseases
by Justyna Fryc and Beata Naumnik
Toxins 2021, 13(3), 223; https://doi.org/10.3390/toxins13030223 - 18 Mar 2021
Cited by 18 | Viewed by 5197
Abstract
Patients with chronic kidney disease (CKD) are at an increased risk of thromboembolic complications, including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. These complications lead to increased mortality. Evidence points to the key role of CKD-associated dysbiosis and its effect via [...] Read more.
Patients with chronic kidney disease (CKD) are at an increased risk of thromboembolic complications, including myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism. These complications lead to increased mortality. Evidence points to the key role of CKD-associated dysbiosis and its effect via the generation of gut microbial metabolites in inducing the prothrombotic phenotype. This phenomenon is known as thrombolome, a panel of intestinal bacteria-derived uremic toxins that enhance thrombosis via increased tissue factor expression, platelet hyperactivity, microparticles release, and endothelial dysfunction. This review discusses the role of uremic toxins derived from gut-microbiota metabolism of dietary tryptophan (indoxyl sulfate (IS), indole-3-acetic acid (IAA), kynurenine (KYN)), phenylalanine/tyrosine (p-cresol sulfate (PCS), p-cresol glucuronide (PCG), phenylacetylglutamine (PAGln)) and choline/phosphatidylcholine (trimethylamine N-oxide (TMAO)) in spontaneously induced thrombosis. The increase in the generation of gut microbial uremic toxins, the activation of aryl hydrocarbon (AhRs) and platelet adrenergic (ARs) receptors, and the nuclear factor kappa B (NF-κB) signaling pathway can serve as potential targets during the prevention of thromboembolic events. They can also help create a new therapeutic approach in the CKD population. Full article
(This article belongs to the Special Issue Study on the Uremic Toxin Targeting Mechanism)
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