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Special Issue "Uremia and Cardiovascular Disease"

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

Deadline for manuscript submissions: 31 August 2018

Special Issue Editor

Guest Editor
Prof. Dr. Ziad A. Massy

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
Website 1 | Website 2 | E-Mail
Interests: uremic toxins; cardiovascular; bone; cerebral disease

Special Issue Information

Dear Colleagues,

Chronic Kidney Disease (CKD) is common affecting 10–12% of the adult population, and 30% or more over 70 years of age. Cardiovascular disease (CVD) is the leading cause of death in CKD patients with a steadily increased risk as kidney function declines up to 10–20 times more in end-stage renal disease (ESRD) than in the general population. CKD is mainly associated with two types of CVD: Accelerated atherosclerosis and specific CKD-related CVD, including arteriosclerosis and cardiac abnormalities (i.e., left ventricular hypertrophy and diastolic dysfunction). CVD risk is associated with traditional risk factors (e.g., diabetes, hypertension, dyslipidemia, and smoking), and with additional CKD-related factors called uremic toxins. Uremic toxins are classified by molecular weight into three groups: Low-molecular-weight toxins (e.g., urea and phosphate), middle molecule toxins (e.g., Beta 2 mcroglobulin, fibroblast growth factor (FGF) 23), and protein-bound toxins (e.g., indoxyl sulfate and p-cresyl sulfate). Cardiovascular toxicity has been demonstrated extensively in in vitro, in vivo (animal) and clinical studies for several uremic toxins, such as phosphate, FGF23, indoxyl sulfate and p-cresyl sulfate. Uremic toxicity can alter different portions of the cardiovascular system, including the endothelium, cardiomyoctes, and cerebral vascular circulation.

CKD is associated with both extensive vascular calcification and abnormal bone remodelling. Vascular calcification has been recently recognized as an active cell-mediated process, similar to skeletal mineralization. Moreover, growing evidence points towards a close relationship between bone and vessel. What is the role of different uremic toxins in this cross-talk between bone and vessel? And how may contribute to the development of both vascular and bone remodelling derangements in CKD patients? These questions are currently under investigation.

The focus of this Special Issue of Toxins will be on the kidney–cardiovascular– bone axis, in all its aspects: Individual toxicity, organ toxicity, possible interventions trying to decrease generation of toxins and this with the aim to decrease CVD and to improve the outcome of CKD patients.

Prof. Dr. Ziad A. Massy
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 papers will be 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 1500 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
  • endothelium
  • smooth muscle cells
  • cardiomyocytes
  • cerebral circulation
  • bone
  • CKD

Published Papers (8 papers)

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Research

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Open AccessArticle Impact of the Oral Adsorbent AST-120 on Organ-Specific Accumulation of Uremic Toxins: LC-MS/MS and MS Imaging Techniques
Received: 31 October 2017 / Revised: 14 December 2017 / Accepted: 26 December 2017 / Published: 28 December 2017
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Abstract
Elevated circulating uremic toxins are associated with a variety of symptoms and organ dysfunction observed in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are representative uremic toxins that exert various harmful effects. We recently showed that
[...] Read more.
Elevated circulating uremic toxins are associated with a variety of symptoms and organ dysfunction observed in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are representative uremic toxins that exert various harmful effects. We recently showed that IS induces metabolic alteration in skeletal muscle and causes sarcopenia in mice. However, whether organ-specific accumulation of IS and PCS is associated with tissue dysfunction is still unclear. We investigated the accumulation of IS and PCS using liquid chromatography/tandem mass spectrometry in various tissues from mice with adenine-induced CKD. IS and PCS accumulated in all 15 organs analyzed, including kidney, skeletal muscle, and brain. We also visualized the tissue accumulation of IS and PCS with immunohistochemistry and mass spectrometry imaging techniques. The oral adsorbent AST-120 prevented some tissue accumulation of IS and PCS. In skeletal muscle, reduced accumulation following AST-120 treatment resulted in the amelioration of renal failure-associated muscle atrophy. We conclude that uremic toxins can accumulate in various organs and that AST-120 may be useful in treating or preventing organ dysfunction in CKD, possibly by reducing tissue accumulation of uremic toxins. Full article
(This article belongs to the Special Issue Uremia and Cardiovascular Disease)
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Review

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Open AccessReview The Impact of Uremic Toxins on Cerebrovascular and Cognitive Disorders
Toxins 2018, 10(7), 303; https://doi.org/10.3390/toxins10070303 (registering DOI)
Received: 20 June 2018 / Revised: 17 July 2018 / Accepted: 19 July 2018 / Published: 22 July 2018
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Abstract
Individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing cognitive disorders and dementia. Stroke is also highly prevalent in this population and is associated with a higher risk of neurological deterioration, in-hospital mortality, and poor functional outcomes.
[...] Read more.
Individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing cognitive disorders and dementia. Stroke is also highly prevalent in this population and is associated with a higher risk of neurological deterioration, in-hospital mortality, and poor functional outcomes. Evidence from in vitro studies and in vivo animal experiments suggests that accumulation of uremic toxins may contribute to the pathogenesis of stroke and amplify vascular damage, leading to cognitive disorders and dementia. This review summarizes current evidence on the mechanisms by which uremic toxins may favour the occurrence of cerebrovascular diseases and neurological complications in CKD. Full article
(This article belongs to the Special Issue Uremia and Cardiovascular Disease)
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Graphical abstract

Open AccessFeature PaperReview Gut Microbiota and Cardiovascular Uremic Toxicities
Received: 4 June 2018 / Revised: 5 July 2018 / Accepted: 6 July 2018 / Published: 11 July 2018
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Abstract
Cardiovascular disease (CVD) remains a major cause of high morbidity and mortality in patients with chronic kidney disease (CKD). Numerous CVD risk factors in CKD patients have been described, but these do not fully explain the high pervasiveness of CVD or increased mortality
[...] Read more.
Cardiovascular disease (CVD) remains a major cause of high morbidity and mortality in patients with chronic kidney disease (CKD). Numerous CVD risk factors in CKD patients have been described, but these do not fully explain the high pervasiveness of CVD or increased mortality rates in CKD patients. In CKD the loss of urinary excretory function results in the retention of various substances referred to as “uremic retention solutes”. Many of these molecules have been found to exert toxicity on virtually all organ systems of the human body, leading to the clinical syndrome of uremia. In recent years, an increasing body of evidence has been accumulated that suggests that uremic toxins may contribute to an increased cardiovascular disease (CVD) burden associated with CKD. This review examined the evidence from several clinical and experimental studies showing an association between uremic toxins and CVD. Special emphasis is addressed on emerging data linking gut microbiota with the production of uremic toxins and the development of CKD and CVD. The biological toxicity of some uremic toxins on the myocardium and the vasculature and their possible contribution to cardiovascular injury in uremia are also discussed. Finally, various therapeutic interventions that have been applied to effectively reduce uremic toxins in patients with CKD, including dietary modifications, use of prebiotics and/or probiotics, an oral intestinal sorbent that adsorbs uremic toxins and precursors, and innovative dialysis therapies targeting the protein-bound uremic toxins are also highlighted. Future studies are needed to determine whether these novel therapies to reduce or remove uremic toxins will reduce CVD and related cardiovascular events in the long-term in patients with chronic renal failure. Full article
(This article belongs to the Special Issue Uremia and Cardiovascular Disease)
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Open AccessFeature PaperReview Deleting Death and Dialysis: Conservative Care of Cardio-Vascular Risk and Kidney Function Loss in Chronic Kidney Disease (CKD)
Received: 2 May 2018 / Accepted: 11 May 2018 / Published: 12 June 2018
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Abstract
The uremic syndrome, which is the clinical expression of chronic kidney disease (CKD), is a complex amalgam of accelerated aging and organ dysfunctions, whereby cardio-vascular disease plays a capital role. In this narrative review, we offer a summary of the current conservative (medical)
[...] Read more.
The uremic syndrome, which is the clinical expression of chronic kidney disease (CKD), is a complex amalgam of accelerated aging and organ dysfunctions, whereby cardio-vascular disease plays a capital role. In this narrative review, we offer a summary of the current conservative (medical) treatment options for cardio-vascular and overall morbidity and mortality risk in CKD. Since the progression of CKD is also associated with a higher cardio-vascular risk, we summarize the interventions that may prevent the progression of CKD as well. We pay attention to established therapies, as well as to novel promising options. Approaches that have been considered are not limited to pharmacological approaches but take into account lifestyle measures and diet as well. We took as many randomized controlled hard endpoint outcome trials as possible into account, although observational studies and post hoc analyses were included where appropriate. We also considered health economic aspects. Based on this information, we constructed comprehensive tables summarizing the available therapeutic options and the number and kind of studies (controlled or not, contradictory outcomes or not) with regard to each approach. Our review underscores the scarcity of well-designed large controlled trials in CKD. Nevertheless, based on the controlled and observational data, a therapeutic algorithm can be developed for this complex and multifactorial condition. It is likely that interventions should be aimed at targeting several modifiable factors simultaneously. Full article
(This article belongs to the Special Issue Uremia and Cardiovascular Disease)
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Open AccessFeature PaperReview Uremic Toxins and Clinical Outcomes: The Impact of Kidney Transplantation
Received: 6 May 2018 / Revised: 31 May 2018 / Accepted: 1 June 2018 / Published: 5 June 2018
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Abstract
Non-transplanted and transplanted patients with chronic kidney disease (CKD) differ in terms of mortality and the risk of clinical events. This difference is probably due to the difference of both traditional and non-traditional risk factors. Uremic retention solutes may constitute important non-traditional risk
[...] Read more.
Non-transplanted and transplanted patients with chronic kidney disease (CKD) differ in terms of mortality and the risk of clinical events. This difference is probably due to the difference of both traditional and non-traditional risk factors. Uremic retention solutes may constitute important non-traditional risk factors in this population. In the present review, we selected a set of uremic toxins that have been associated with harmful effects, and are an appealing target for adjuvant therapy in CKD. For each toxin reviewed here, relevant studies were selected and the relationship with hard clinical outcomes of uremic toxins were compared between non-transplanted CKD patients and transplanted patients taking into account the level of glomerular filtration rate in these two situations. Full article
(This article belongs to the Special Issue Uremia and Cardiovascular Disease)
Open AccessFeature PaperReview Uremic Toxin Clearance and Cardiovascular Toxicities
Received: 10 April 2018 / Revised: 25 May 2018 / Accepted: 31 May 2018 / Published: 2 June 2018
PDF Full-text (261 KB) | HTML Full-text | XML Full-text
Abstract
Uremic solutes contribute to cardiovascular disease in renal insufficiency. In this review we describe the clearance of selected uremic solutes, which have been associated with cardiovascular disease. These solutes—indoxyl sulfate (IS), p-cresol sulfate (PCS), phenylacetylglutamine (PAG), trimethylamine-n-oxide (TMAO), and kynurenine—exemplify different mechanisms of
[...] Read more.
Uremic solutes contribute to cardiovascular disease in renal insufficiency. In this review we describe the clearance of selected uremic solutes, which have been associated with cardiovascular disease. These solutes—indoxyl sulfate (IS), p-cresol sulfate (PCS), phenylacetylglutamine (PAG), trimethylamine-n-oxide (TMAO), and kynurenine—exemplify different mechanisms of clearance. IS and PCS are protein-bound solutes efficiently cleared by the native kidney through tubular secretion. PAG and TMAO are not protein-bound but are also cleared by the native kidney through tubular secretion, while kynurenine is not normally cleared by the kidney. Increases in the plasma levels of the normally secreted solutes IS, PCS, TMAO, and PAG in chronic kidney disease (CKD) are attributable to a reduction in their renal clearances. Levels of each of these potential toxins are even higher in patients on dialysis than in those with advanced chronic kidney disease, which can be accounted for in part by a low ratio of dialytic to native kidney clearance. The rise in plasma kynurenine in CKD and dialysis patients, by contrast, remains to be explained. Our ability to detect lower levels of the potential uremic cardiovascular toxins with renal replacement therapy may be limited by the intermittency of treatment, by increases in solute production, and by the presence of non-renal clearance. Reduction in the levels of uremic cardiovascular toxins may in the future be achieved more effectively by inhibiting their production. Full article
(This article belongs to the Special Issue Uremia and Cardiovascular Disease)
Open AccessFeature PaperReview The Impact of Uremic Toxins on Vascular Smooth Muscle Cell Function
Received: 30 April 2018 / Revised: 26 May 2018 / Accepted: 27 May 2018 / Published: 29 May 2018
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Abstract
Chronic kidney disease (CKD) is associated with profound vascular remodeling, which accelerates the progression of cardiovascular disease. This remodeling is characterized by intimal hyperplasia, accelerated atherosclerosis, excessive vascular calcification, and vascular stiffness. Vascular smooth muscle cell (VSMC) dysfunction has a key role in
[...] Read more.
Chronic kidney disease (CKD) is associated with profound vascular remodeling, which accelerates the progression of cardiovascular disease. This remodeling is characterized by intimal hyperplasia, accelerated atherosclerosis, excessive vascular calcification, and vascular stiffness. Vascular smooth muscle cell (VSMC) dysfunction has a key role in the remodeling process. Under uremic conditions, VSMCs can switch from a contractile phenotype to a synthetic phenotype, and undergo abnormal proliferation, migration, senescence, apoptosis, and calcification. A growing body of data from experiments in vitro and animal models suggests that uremic toxins (such as inorganic phosphate, indoxyl sulfate and advanced-glycation end products) may directly impact the VSMCs’ physiological functions. Chronic, low-grade inflammation and oxidative stress—hallmarks of CKD—are also strong inducers of VSMC dysfunction. Here, we review current knowledge about the impact of uremic toxins on VSMC function in CKD, and the consequences for pathological vascular remodeling. Full article
(This article belongs to the Special Issue Uremia and Cardiovascular Disease)
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Open AccessReview Role of Uremic Toxins for Kidney, Cardiovascular, and Bone Dysfunction
Received: 27 March 2018 / Revised: 4 May 2018 / Accepted: 10 May 2018 / Published: 16 May 2018
PDF Full-text (944 KB) | HTML Full-text | XML Full-text
Abstract
With decreasing kidney function, cardiovascular disease (CVD) and mineral bone disorders frequently emerge in patients with chronic kidney disease (CKD). For these patients, in addition to the traditional risk factors, non-traditional CKD-specific risk factors are also associated with such diseases and conditions. One
[...] Read more.
With decreasing kidney function, cardiovascular disease (CVD) and mineral bone disorders frequently emerge in patients with chronic kidney disease (CKD). For these patients, in addition to the traditional risk factors, non-traditional CKD-specific risk factors are also associated with such diseases and conditions. One of these non-traditional risk factors is the accumulation of uremic toxins (UTs). In addition, the accumulation of UTs further deteriorates kidney function. Recently, a huge number of UTs have been identified. Although many experimental and clinical studies have reported associations between UTs and the progression of CKD, CVD, and bone disease, these relationships are very complex and have not been fully elucidated. Among the UTs, indoxyl sulfate, asymmetric dimethylarginine, and p-cresylsulfate have been of particular focus, up until now. In this review, we summarize the pathophysiological influences of these UTs on the kidney, cardiovascular system, and bone, and discuss the clinical data regarding the harmful effects of these UTs on diseases and conditions. Full article
(This article belongs to the Special Issue Uremia and Cardiovascular Disease)
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