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Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction

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

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 40264

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Special Issue Editors

Prof. Dr. Sophie Liabeuf

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Guest Editor

Division of Clinical Pharmacology, Amiens University Medical Center, Amiens, France and EA7517 Unit— MP3CV, UPJV University, Amiens, France
Interests: uremic toxins; pharmaco-epidemiology, cardiovascular; vascular calcification
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Ziad A. Massy

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Division of Nephrology, Ambroise Paré Hospital, APHP, Paris-Ile-de-France-West Versailles-Saint-Quentin-en-Yvelines University (UVSQ), 9 avenue Charles de Gaulle, 92104 Boulogne Billancourt/Paris and Inserm U1018 Team5, CESP, UVSQ, University Paris Saclay, Villejuif, France
Interests: uremic toxins; cardiovascular; bone; vascular calcification; endothelium
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic kidney disease (CKD) is a global public health problem that is associated with major adverse health events, including kidney failure, cardiovascular disease and death. Due to the low life expectancy and high prevalence of comorbidities in patients with CKD, research in this field is focusing on the identification of modifiable risk factors. Uremic retention solutes may constitute important non-traditional risk factors in this population. The members of this large group of solutes (referred to as “uremic toxins” when they perturb normal biological functions) differ in their water solubility, protein-binding capacity, molecular weight, pattern of removal by dialysis, biological properties and ability to produce clinical symptoms. Three subgroups of uremic toxins have been suggested: small molecules (e.g., urea and phosphate), mid-sized molecules (e.g., fibroblast growth factor 23 (FGF23)) and protein-bound uremic toxins (e.g., p-cresylsulfate (PCS) and indoxylsulfate (IS)).

CKD is associated with extensive vascular calcification, vascular disease and abnormal bone remodelling. Moreover, growing evidence points towards a close relationship between bone and vessel. Some evidence has suggested that uremic toxins could impact the kidney–cardiovascular–bone axis.

The focus of this Special Issue of Toxins will include original research articles and reviews on the role of Uremic Toxins in Vascular Calcification, Vascular disease and Bone Dysfunction in these different aspects.

Prof. Sophie Liabeuf
Prof. Ziad Massy
Guest Editors

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

uremic toxins
vascular calcification
vascular stiffness
endothelium
bone dysfunction
chronic kidney disease
bone mineral disorder

Published Papers (10 papers)

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Research

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18 pages, 1469 KiB

Open AccessArticle

Association between Uremic Toxin Concentrations and Bone Mineral Density after Kidney Transplantation

by Benjamin Batteux, Sandra Bodeau, Camille André, Anne-Sophie Hurtel-Lemaire, Valérie Gras-Champel, Isabelle Desailly-Henry, Kamel Masmoudi, Youssef Bennis, Ziad A. Massy, Saïd Kamel, Gabriel Choukroun and Sophie Liabeuf

Toxins 2020, 12(11), 715; https://doi.org/10.3390/toxins12110715 - 13 Nov 2020

Cited by 2 | Viewed by 2186

Abstract

Although uremic osteoporosis is a component of mineral and bone disorder in chronic kidney disease, uremic toxin (UT) concentrations in patients with end-stage kidney disease and bone mineral density (BMD) changes after kidney transplantation have not previously been described. We hypothesized that elevated UT concentrations at the time of transplantation could have a negative impact on bone during the early post-transplantation period. Hence, we sought to determine whether concentrations of UTs (trimethylamine-N-oxide, indoxylsulfate, p-cresylsulfate, p-cresylglucuronide, indole-3-acetic acid, hippuric acid, and 3-carboxy-4-methyl-5-propyl-furanpropionic acid) upon transplantation are predictive markers for (i) osteoporosis one month after transplantation, and (ii) a BMD decrease and the occurrence of fractures 12 and 24 months after kidney transplantation. Between 2012 and 2018, 310 kidney transplant recipients were included, and dual-energy X-ray absorptiometry was performed 1, 12, and 24 months after transplantation. The UT concentrations upon transplantation were determined by reverse-phase high-performance liquid chromatography. Indoxylsulfate concentrations upon transplantation were positively correlated with BMD one month after transplantation for the femoral neck but were not associated with osteoporosis status upon transplantation. Concentrations of the other UTs upon transplantation were not associated with osteoporosis or BMD one month after transplantation. None of the UT concentrations were associated with BMD changes and the occurrence of osteoporotic fractures 12 and 24 months after transplantation. Hence, UT concentrations at the time of kidney transplantation were not predictive markers of osteoporosis or fractures. Full article

(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)

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11 pages, 883 KiB

Open AccessArticle

Indoxyl Sulfate and Incident Peripheral Artery Disease in Hemodialysis Patients

by Ting-Yun Lin, Hsin-Hua Chou, Hsuan-Li Huang and Szu-Chun Hung

Toxins 2020, 12(11), 696; https://doi.org/10.3390/toxins12110696 - 02 Nov 2020

Cited by 9 | Viewed by 2494

Abstract

Peripheral artery disease (PAD) is highly prevalent among patients with chronic kidney disease (CKD) and portends a very poor prognosis. Indoxyl sulfate has been shown to induce atherothrombosis and impaired neovascularization in uremic mice. However, there is no clinical evidence regarding the role of indoxyl sulfate in PAD associated with CKD. We examined associations between indoxyl sulfate and incident symptomatic lower extremity PAD events as well as major adverse cardiovascular events (MACE) and all-cause mortality using Cox proportional hazards models in a prospective cohort of 200 hemodialysis patients free of PAD at baseline. Patients were considered as having PAD if they developed PAD symptoms confirmed by an ankle-brachial index with waveforms, duplex ultrasound or angiography, and/or major adverse limb events including revascularization and amputation. During a median follow-up of 6.5 years, 37 patients (18.5%) experienced incident symptomatic PAD. MACE occurred in 52 patients, and a total of 85 patients died. After adjusting for traditional risk factors for PAD, including age, current smoking, diabetes, and cardiovascular disease, indoxyl sulfate was significantly associated with the risk of PAD (hazard ratio (HR), 1.19 for every 10-μg/mL increase in indoxyl sulfate; 95% confidence interval (CI), 1.05–1.35). However, indoxyl sulfate was not associated with risk of MACE (HR, 1.00; 95% CI, 0.90–1.12) or death from any cause (HR, 0.98; 95% CI, 0.90–1.07). Indoxyl sulfate was associated with incident symptomatic PAD but not with MACE or all-cause mortality, suggesting that indoxyl sulfate toxicity may be unique to PAD among hemodialysis patients. Full article

(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)

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14 pages, 2076 KiB

Open AccessArticle

Indoxyl Sulfate Contributes to Adipose Tissue Inflammation through the Activation of NADPH Oxidase

by Shoma Tanaka, Hiroshi Watanabe, Takehiro Nakano, Tadashi Imafuku, Hiromasa Kato, Kai Tokumaru, Nanaka Arimura, Yuki Enoki, Hitoshi Maeda, Motoko Tanaka, Kazutaka Matsushita, Masafumi Fukagawa and Toru Maruyama

Toxins 2020, 12(8), 502; https://doi.org/10.3390/toxins12080502 - 05 Aug 2020

Cited by 19 | Viewed by 3697

Abstract

Adipose tissue inflammation appears to be a risk factor for the progression of chronic kidney disease (CKD), but the effect of CKD on adipose tissue inflammation is poorly understood. The purpose of this study was to clarify the involvement of uremic toxins (indoxyl sulfate (IS), 3-indoleacetic acid, p-cresyl sulfate and kynurenic acid) on CKD-induced adipose tissue inflammation. IS induces monocyte chemoattractant protein-1 (MCP-1) expression and reactive oxygen species (ROS) production in the differentiated 3T3L-1 adipocyte. An organic anion transporter (OAT) inhibitor, an NADPH oxidase inhibitor or an antioxidant suppresses the IS-induced MCP-1 expression and ROS production, suggesting the OAT/NADPH oxidase/ROS pathway is involved in the action of IS. Co-culturing 3T3L-1 adipocytes and mouse macrophage cells showed incubating adipocytes with IS increased macrophage infiltration. An IS-overload in healthy mice increased IS levels, oxidative stress and MCP-1 expression in epididymal adipose tissue compared to unloaded mice. Using 5/6-nephrectomized mice, the administration of AST-120 suppressed oxidative stress and the expression of MCP-1, F4/80 and TNF-α in epididymal adipose tissue. These collective data suggest IS could be a therapeutic target for the CKD-related inflammatory response in adipose tissue, and that AST-120 could be useful for the treatment of IS-induced adipose tissue inflammation. Full article

(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)

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17 pages, 2757 KiB

Open AccessArticle

Scavenging Intracellular ROS Attenuates p-Cresyl Sulfate-Triggered Osteogenesis through MAPK Signaling Pathway and NF-κB Activation in Human Arterial Smooth Muscle Cells

by Jia-Feng Chang, Chih-Yu Hsieh, Jian-Chiun Liou, Shih-Hao Liu, Chi-Feng Hung, Kuo-Cheng Lu, Chih-Cheng Lin, Chang-Chin Wu, Shuk-Man Ka, Li-Li Wen, Mai-Szu Wu, Cai-Mei Zheng and Wen-Chin Ko

Toxins 2020, 12(8), 472; https://doi.org/10.3390/toxins12080472 - 24 Jul 2020

Cited by 14 | Viewed by 3713

Abstract

Osteogenesis in human arterial smooth muscle cell (HASMC) is a key feature of uremic vascular calcification (UVC). Concerning pro-oxidant properties of p-cresyl sulfate (PCS), the therapeutic effect of reactive oxygen species (ROS) scavenger on PCS triggered inflammatory signaling transduction in osteogenesis was investigated in this translational research. Based on severity level of chronic kidney disease (CKD), arterial specimens with immunohistochemistry stain were quantitatively analyzed for UVC, oxidative injury and osteogenesis along with PCS concentrations. To mimic human UVC, HASMC model was used to explore whether PCS-induced ROS could trigger mitogen-activated protein kinase (MAPK) pathways with nuclear factor-κB (NF-κB) translocation that drive context-specific gene/protein expression, including Runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP). In parallel with PCS accumulation, CKD arteries corresponded with UVC severity, oxidative DNA damage (8-hydroxy-2′-deoxyguanosine), Runx2 and ALP. PCS directly phosphorylated extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK)/P38 (pERK/pJNK/pP38) and modulated NF-κB translocation to promote expressions of Runx2 and ALP in HASMC. Notably, intracellular ROS scavenger attenuated pERK signaling cascade and downstream osteogenic differentiation. Collectively, our data demonstrate PCS induces osteogenesis through triggering intracellular ROS, pERK/pJNK/pP38 MAPK pathways and NF-κB translocation to drive Runx2 and ALP expressions, culminating in UVC. Beyond mineral dysregulation, osteocytic conversion in HASMC could be the stimulation of PCS. Thus PCS may act as a pro-osteogenic and pro-calcific toxin. From the perspective of translational medicine, PCS and intracellular ROS could serve as potential therapeutic targets for UVC in CKD patients. Full article

(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)

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Review

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23 pages, 1372 KiB

Open AccessReview

Role of Uremic Toxins in Early Vascular Ageing and Calcification

by Nikolaos C. Kyriakidis, Gabriela Cobo, Lu Dai, Bengt Lindholm and Peter Stenvinkel

Toxins 2021, 13(1), 26; https://doi.org/10.3390/toxins13010026 - 03 Jan 2021

Cited by 16 | Viewed by 4297

Abstract

In patients with advanced chronic kidney disease (CKD), the accumulation of uremic toxins, caused by a combination of decreased excretion secondary to reduced kidney function and increased generation secondary to aberrant expression of metabolite genes, interferes with different biological functions of cells and organs, contributing to a state of chronic inflammation and other adverse biologic effects that may cause tissue damage. Several uremic toxins have been implicated in severe vascular smooth muscle cells (VSMCs) changes and other alterations leading to vascular calcification (VC) and early vascular ageing (EVA). The above mentioned are predominant clinical features of patients with CKD, contributing to their exceptionally high cardiovascular mortality. Herein, we present an update on pathophysiological processes and mediators underlying VC and EVA induced by uremic toxins. Moreover, we discuss their clinical impact, and possible therapeutic targets aiming at preventing or ameliorating the harmful effects of uremic toxins on the vasculature. Full article

(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)

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16 pages, 1341 KiB

Open AccessReview

Uremic Vascular Calcification: The Pathogenic Roles and Gastrointestinal Decontamination of Uremic Toxins

by Chia-Ter Chao and Shih-Hua Lin

Toxins 2020, 12(12), 812; https://doi.org/10.3390/toxins12120812 - 21 Dec 2020

Cited by 17 | Viewed by 4298

Abstract

Uremic vascular calcification (VC) commonly occurs during advanced chronic kidney disease (CKD) and significantly increases cardiovascular morbidity and mortality. Uremic toxins are integral within VC pathogenesis, as they exhibit adverse vascular influences ranging from atherosclerosis, vascular inflammation, to VC. Experimental removal of these toxins, including small molecular (phosphate, trimethylamine-N-oxide), large molecular (fibroblast growth factor-23, cytokines), and protein-bound ones (indoxyl sulfate, p-cresyl sulfate), ameliorates VC. As most uremic toxins share a gut origin, interventions through gastrointestinal tract are expected to demonstrate particular efficacy. The “gastrointestinal decontamination” through the removal of toxin in situ or impediment of toxin absorption within the gastrointestinal tract is a practical and potential strategy to reduce uremic toxins. First and foremost, the modulation of gut microbiota through optimizing dietary composition, the use of prebiotics or probiotics, can be implemented. Other promising strategies such as reducing calcium load, minimizing intestinal phosphate absorption through the optimization of phosphate binders and the inhibition of gut luminal phosphate transporters, the administration of magnesium, and the use of oral toxin adsorbent for protein-bound uremic toxins may potentially counteract uremic VC. Novel agents such as tenapanor have been actively tested in clinical trials for their potential vascular benefits. Further advanced studies are still warranted to validate the beneficial effects of gastrointestinal decontamination in the retardation and treatment of uremic VC. Full article

(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)

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28 pages, 1799 KiB

Open AccessReview

Effects of Chronic Kidney Disease and Uremic Toxins on Extracellular Vesicle Biology

by Linda Yaker, Saïd Kamel, Jérôme Ausseil and Agnès Boullier

Toxins 2020, 12(12), 811; https://doi.org/10.3390/toxins12120811 - 21 Dec 2020

Cited by 9 | Viewed by 3604

Abstract

Vascular calcification (VC) is a cardiovascular complication associated with a high mortality rate, especially in patients with diabetes, atherosclerosis or chronic kidney disease (CKD). In CKD patients, VC is associated with the accumulation of uremic toxins, such as indoxyl sulphate or inorganic phosphate, which can have a major impact in vascular remodeling. During VC, vascular smooth muscle cells (VSMCs) undergo an osteogenic switch and secrete extracellular vesicles (EVs) that are heterogeneous in terms of their origin and composition. Under physiological conditions, EVs are involved in cell-cell communication and the maintenance of cellular homeostasis. They contain high levels of calcification inhibitors, such as fetuin-A and matrix Gla protein. Under pathological conditions (and particularly in the presence of uremic toxins), the secreted EVs acquire a pro-calcifying profile and thereby act as nucleating foci for the crystallization of hydroxyapatite and the propagation of calcification. Here, we review the most recent findings on the EVs’ pathophysiological role in VC, the impact of uremic toxins on EV biogenesis and functions, the use of EVs as diagnostic biomarkers and the EVs’ therapeutic potential in CKD. Full article

(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)

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29 pages, 1303 KiB

Open AccessReview

Uremic Toxins and Vascular Calcification–Missing the Forest for All the Trees

by Nikolas Rapp, Pieter Evenepoel, Peter Stenvinkel and Leon Schurgers

Toxins 2020, 12(10), 624; https://doi.org/10.3390/toxins12100624 - 29 Sep 2020

Cited by 13 | Viewed by 3501

Abstract

The cardiorenal syndrome relates to the detrimental interplay between the vascular system and the kidney. The uremic milieu induced by reduced kidney function alters the phenotype of vascular smooth muscle cells (VSMC) and promotes vascular calcification, a condition which is strongly linked to cardiovascular morbidity and mortality. Biological mechanisms involved include generation of reactive oxygen species, inflammation and accelerated senescence. A better understanding of the vasotoxic effects of uremic retention molecules may reveal novel avenues to reduce vascular calcification in CKD. The present review aims to present a state of the art on the role of uremic toxins in pathogenesis of vascular calcification. Evidence, so far, is fragmentary and limited with only a few uremic toxins being investigated, often by a single group of investigators. Experimental heterogeneity furthermore hampers comparison. There is a clear need for a concerted action harmonizing and standardizing experimental protocols and combining efforts of basic and clinical researchers to solve the complex puzzle of uremic vascular calcification. Full article

(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)

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24 pages, 1955 KiB

Open AccessEditor’s ChoiceReview

How do Uremic Toxins Affect the Endothelium?

by Regiane Stafim da Cunha, Andressa Flores Santos, Fellype Carvalho Barreto and Andréa Emilia Marques Stinghen

Toxins 2020, 12(6), 412; https://doi.org/10.3390/toxins12060412 - 20 Jun 2020

Cited by 34 | Viewed by 6348

Abstract

Uremic toxins can induce endothelial dysfunction in patients with chronic kidney disease (CKD). Indeed, the structure of the endothelial monolayer is damaged in CKD, and studies have shown that the uremic toxins contribute to the loss of cell–cell junctions, increasing permeability. Membrane proteins, such as transporters and receptors, can mediate the interaction between uremic toxins and endothelial cells. In these cells, uremic toxins induce oxidative stress and activation of signaling pathways, including the aryl hydrocarbon receptor (AhR), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways. The activation of these pathways leads to overexpression of proinflammatory (e.g., monocyte chemoattractant protein-1, E-selectin) and prothrombotic (e.g., tissue factor) proteins. Uremic toxins also induce the formation of endothelial microparticles (EMPs), which can lead to the activation and dysfunction of other cells, and modulate the expression of microRNAs that have an important role in the regulation of cellular processes. The resulting endothelial dysfunction contributes to the pathogenesis of cardiovascular diseases, such as atherosclerosis and thrombotic events. Therefore, uremic toxins as well as the pathways they modulated may be potential targets for therapies in order to improve treatment for patients with CKD. Full article

(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)

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Graphical abstract

27 pages, 960 KiB

Open AccessEditor’s ChoiceReview

Uremic Toxins and Vascular Dysfunction

by Isabelle Six, Nadia Flissi, Gaëlle Lenglet, Loïc Louvet, Said Kamel, Marlène Gallet, Ziad A. Massy and Sophie Liabeuf

Toxins 2020, 12(6), 404; https://doi.org/10.3390/toxins12060404 - 18 Jun 2020

Cited by 36 | Viewed by 5021

Abstract

Vascular dysfunction is an essential element found in many cardiovascular pathologies and in pathologies that have a cardiovascular impact such as chronic kidney disease (CKD). Alteration of vasomotricity is due to an imbalance between the production of relaxing and contracting factors. In addition to becoming a determining factor in pathophysiological alterations, vascular dysfunction constitutes the first step in the development of atherosclerosis plaques or vascular calcifications. In patients with CKD, alteration of vasomotricity tends to emerge as being a new, less conventional, risk factor. CKD is characterized by the accumulation of uremic toxins (UTs) such as phosphate, para-cresyl sulfate, indoxyl sulfate, and FGF23 and, consequently, the deleterious role of UTs on vascular dysfunction has been explored. This accumulation of UTs is associated with systemic alterations including inflammation, oxidative stress, and the decrease of nitric oxide production. The present review proposes to summarize our current knowledge of the mechanisms by which UTs induce vascular dysfunction. Full article

(This article belongs to the Special Issue Role of Uremic Toxins in Vascular Calcification, Vascular Disease and Bone Dysfunction)

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