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Uremia and Cardiovascular Disease

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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 August 2018) | Viewed by 92087

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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 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

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Keywords

uremic toxins
endothelium
smooth muscle cells
cardiomyocytes
cerebral circulation
bone
CKD

Published Papers (14 papers)

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Research

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13 pages, 2038 KiB

Open AccessArticle

Association between Protein-Bound Uremic Toxins and Asymptomatic Cardiac Dysfunction in Patients with Chronic Kidney Disease

by Shanmugakumar Chinnappa, Yu-Kang Tu, Yi Chun Yeh, Griet Glorieux, Raymond Vanholder and Andrew Mooney

Toxins 2018, 10(12), 520; https://doi.org/10.3390/toxins10120520 - 05 Dec 2018

Cited by 23 | Viewed by 3573

Abstract

Although the relationship between protein-bound uremic toxins (PBUTs) and cardiac structure and cardiac mortality in chronic kidney disease (CKD) has been studied in the past, the association between cardiac dysfunction and PBUTs has not yet been studied. We therefore evaluated the association between impaired peak cardiac performance and the serum free and total concentrations of potentially cardiotoxic PBUTs. In a cross-sectional study of 56 male CKD patients (stages 2–5 (pre-dialysis)) who were asymptomatic with no known cardiac diseases or diabetes we measured peak cardiac power (CPO_max), aerobic exercise capacity (VO_2max), and echocardiographic parameters of cardiac morphology and evaluated their association with PBUTs. The serum total and free concentrations of indoxyl sulfate (IXS), p-cresyl sulfate (PCS), p-cresyl glucuronide, indole acetic acid, and hippuric acid showed significant negative correlation with CPO_max and VO_2max. IXS and PCS were independently associated with CPO_max and VO_2max even after controlling for eGFR. No correlation between left ventricular mass index (LVMI) and PBUTs was seen. The present study for the first time has demonstrated the association between subclinical cardiac dysfunction in CKD and serum levels of a panel of PBUTs. Further studies are required to evaluate the mechanism of cardiotoxicity of the individual uremic toxins. Full article

(This article belongs to the Special Issue Uremia and Cardiovascular Disease)

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15 pages, 5422 KiB

Open AccessArticle

Urea Memory: Transient Cell Exposure to Urea Causes Persistent Mitochondrial ROS Production and Endothelial Dysfunction

by Maria D’Apolito, Anna Laura Colia, Enrica Manca, Massimo Pettoello-Mantovani, Michele Sacco, Angela Bruna Maffione, Michael Brownlee and Ida Giardino

Toxins 2018, 10(10), 410; https://doi.org/10.3390/toxins10100410 - 11 Oct 2018

Cited by 11 | Viewed by 3060

Abstract

Urea at post-dialysis levels induces increased ROS in a number of cell types. The aim of this study was to determine whether urea-induced production of ROS remains elevated after urea is no longer present, and, if it does, to characterize its origin and effects. Human arterial endothelial cells were incubated with 20 mM urea for two days, and then cells were incubated for an additional two days in medium alone. Maximal ROS levels induced by initial urea continued at the same level despite urea being absent. These effects were prevented by either MnSOD expression or by Nox1/4 inhibition with GKT13781. Sustained urea-induced ROS caused a persistent reduction in mtDNA copy number and electron transport chain transcripts, a reduction in transcription of mitochondrial fusion proteins, an increase in mitochondrial fission proteins, and persistent expression of endothelial inflammatory markers. The SOD-catalase mimetic MnTBAP reversed each of these. These results suggest that persistent increases in ROS after cells are no long exposed to urea may play a major role in continued kidney damage and functional decline despite reduction of urea levels after dialysis. Full article

(This article belongs to the Special Issue Uremia and Cardiovascular Disease)

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22 pages, 4294 KiB

Open AccessArticle

Uremia Impacts VE-Cadherin and ZO-1 Expression in Human Endothelial Cell-to-Cell Junctions

by Rayana A. P. Maciel, Regiane S. Cunha, Valentina Busato, Célia R. C. Franco, Paulo C. Gregório, Carla J. R. Dolenga, Lia S. Nakao, Ziad A. Massy, Agnès Boullier, Roberto Pecoits-Filho and Andréa E. M. Stinghen

Toxins 2018, 10(10), 404; https://doi.org/10.3390/toxins10100404 - 07 Oct 2018

Cited by 30 | Viewed by 5084

Abstract

Endothelial dysfunction in uremia can result in cell-to-cell junction loss and increased permeability, contributing to cardiovascular diseases (CVD) development. This study evaluated the impact of the uremic milieu on endothelial morphology and cell junction’s proteins. We evaluated (i) serum levels of inflammatory biomarkers in a cohort of chronic kidney disease (CKD) patients and the expression of VE-cadherin and Zonula Occludens-1 (ZO-1) junction proteins on endothelial cells (ECs) of arteries removed from CKD patients during renal transplant; (ii) ECs morphology in vitro under different uremic conditions, and (iii) the impact of uremic toxins p-cresyl sulfate (PCS), indoxyl sulfate (IS), and inorganic phosphate (Pi) as well as of total uremic serum on VE-cadherin and ZO-1 gene and protein expression in cultured ECs. We found that the uremic arteries had lost their intact and continuous endothelial morphology, with a reduction in VE-cadherin and ZO-1 expression. In cultured ECs, both VE-cadherin and ZO-1 protein expression decreased, mainly after exposure to Pi and uremic serum groups. VE-cadherin mRNA expression was reduced while ZO-1 was increased after exposure to PCS, IS, Pi, and uremic serum. Our findings show that uremia alters cell-to-cell junctions leading to an increased endothelial damage. This gives a new perspective regarding the pathophysiological role of uremia in intercellular junctions and opens new avenues to improve cardiovascular outcomes in CKD patients. Full article

(This article belongs to the Special Issue Uremia and Cardiovascular Disease)

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17 pages, 2891 KiB

Open AccessArticle

The Impact of Uremic Toxicity Induced Inflammatory Response on the Cardiovascular Burden in Chronic Kidney Disease

by Ligia Maria Claro, Andrea N. Moreno-Amaral, Ana Carolina Gadotti, Carla J. Dolenga, Lia S. Nakao, Marina L.V. Azevedo, Lucia De Noronha, Marcia Olandoski, Thyago P. De Moraes, Andréa E. M. Stinghen and Roberto Pécoits-Filho

Toxins 2018, 10(10), 384; https://doi.org/10.3390/toxins10100384 - 23 Sep 2018

Cited by 38 | Viewed by 4852

Abstract

Uremic toxin (UT) retention in chronic kidney disease (CKD) affects biological systems. We aimed to identify the associations between UT, inflammatory biomarkers and biomarkers of the uremic cardiovascular response (BUCVR) and their impact on cardiovascular status as well as their roles as predictors of outcome in CKD patients. CKD patients stages 3, 4 and 5 (n = 67) were recruited and UT (indoxyl sulfate/IS, p-cresil sulfate/pCS and indole-3-acetic acid/IAA); inflammatory biomarkers [Interleukin-6 (IL-6), high sensitivity C reactive protein (hsCRP), monocyte chemoattractant protein-1 (MCP-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble Fas (sFas)] and BUCVRs [soluble CD36 (sCD36), soluble receptor for advanced glycation end products (sRAGE), fractalkine] was measured. Patients were followed for 5.2 years and all causes of death was used as the primary outcome. Artery segments collected at the moment of transplantation were used for the immunohistochemistry analysis in a separate cohort. Estimated glomerular filtration rate (eGFR), circulating UT, plasma biomarkers of systemic and vascular inflammation and BUCVR were strongly interrelated. Patients with plaque presented higher signs of UT-induced inflammation and arteries from CKD patients presented higher fractalkine receptor (CX3CR1) tissue expression. Circulating IS (p = 0.03), pCS (p = 0.007), IL-6 (p = 0.026), sFas (p = 0.001), sCD36 (p = 0.01) and fractalkine (p = 0.02) were independent predictors of total mortality risk in CKD patients. Our results reinforce the important role of uremic toxicity in the pathogenesis of cardiovascular disease (CVD) in CKD patients through an inflammatory pathway. Full article

(This article belongs to the Special Issue Uremia and Cardiovascular Disease)

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3054 KiB

Open AccessArticle

Impact of the Oral Adsorbent AST-120 on Organ-Specific Accumulation of Uremic Toxins: LC-MS/MS and MS Imaging Techniques

by Emiko Sato, Daisuke Saigusa, Eikan Mishima, Taeko Uchida, Daisuke Miura, Tomomi Morikawa-Ichinose, Kiyomi Kisu, Akiyo Sekimoto, Ritsumi Saito, Yuji Oe, Yotaro Matsumoto, Yoshihisa Tomioka, Takefumi Mori, Nobuyuki Takahashi, Hiroshi Sato, Takaaki Abe, Toshimitsu Niwa and Sadayoshi Ito

Toxins 2018, 10(1), 19; https://doi.org/10.3390/toxins10010019 - 28 Dec 2017

Cited by 63 | Viewed by 7985

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 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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11 pages, 499 KiB

Open AccessFeature PaperReview

Tryptophan-Derived Uremic Toxins and Thrombosis in Chronic Kidney Disease

by Tawfik Addi, Laetitia Dou and Stéphane Burtey

Toxins 2018, 10(10), 412; https://doi.org/10.3390/toxins10100412 - 12 Oct 2018

Cited by 61 | Viewed by 8932

Abstract

Patients with chronic kidney disease (CKD) display an elevated risk of thrombosis. Thrombosis occurs in cardiovascular events, such as venous thromboembolism, stroke, and acute coronary syndrome, and is a cause of hemodialysis vascular access dysfunction. CKD leads to the accumulation of uremic toxins, which exerts toxic effects on blood and the vessel wall. Some uremic toxins result from tryptophan metabolization in the gut through the indolic and the kynurenine pathways. An increasing number of studies are highlighting the link between such uremic toxins and thrombosis in CKD. In this review, we describe the thrombotic mechanisms induced by tryptophan-derived uremic toxins (TDUT). These mechanisms include an increase in plasma levels of procoagulant factors, induction of platelet hyperactivity, induction of endothelial dysfunction/ impairment of endothelial healing, decrease in nitric oxide (NO) bioavailability, and production of procoagulant microparticles. We focus on one important prothrombotic mechanism: The induction of tissue factor (TF), the initiator of the extrinsic pathway of the blood coagulation. This induction occurs via a new pathway, dependent on the transcription factor Aryl hydrocarbon receptor (AhR), the receptor of TDUT in cells. A better understanding of the prothrombotic mechanisms of uremic toxins could help to find novel therapeutic targets to prevent thrombosis in CKD. Full article

(This article belongs to the Special Issue Uremia and Cardiovascular Disease)

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29 pages, 352 KiB

Open AccessReview

Cardiotoxicity of Uremic Toxins: A Driver of Cardiorenal Syndrome

by Suree Lekawanvijit

Toxins 2018, 10(9), 352; https://doi.org/10.3390/toxins10090352 - 01 Sep 2018

Cited by 79 | Viewed by 6256

Abstract

Cardiovascular disease (CVD) is highly prevalent in the setting of chronic kidney disease (CKD). Such coexistence of CVD and CKD—the so-called “cardiorenal or renocardiac syndrome”—contributes to exponentially increased risk of cardiovascular (CV) mortality. Uremic cardiomyopathy is a characteristic cardiac pathology commonly found in CKD. CKD patients are also predisposed to heart rhythm disorders especially atrial fibrillation. Traditional CV risk factors as well as known CKD-associated CV risk factors such as anemia are insufficient to explain CV complications in the CKD population. Accumulation of uremic retention solutes is a hallmark of impaired renal excretory function. Many of them have been considered inert solutes until their biological toxicity is unraveled and they become accepted as “uremic toxins”. Direct cardiotoxicity of uremic toxins has been increasingly demonstrated in recent years. This review offers a mechanistic insight into the pathological cardiac remodeling and dysfunction contributed by uremic toxins with a main focus on fibroblastic growth factor-23, an emerging toxin playing a central role in the chronic kidney disease–mineral bone disorder, and the two most investigated non-dialyzable protein-bound uremic toxins, indoxyl sulfate and p-cresyl sulfate. Potential therapeutic strategies that could address these toxins and their relevant mediated pathways since pre-dialysis stages are also discussed. Full article

(This article belongs to the Special Issue Uremia and Cardiovascular Disease)

25 pages, 1039 KiB

Open AccessReview

The Impact of Uremic Toxins on Cerebrovascular and Cognitive Disorders

by Maryam Assem, Mathilde Lando, Maria Grissi, Saïd Kamel, Ziad A. Massy, Jean-Marc Chillon and Lucie Hénaut

Toxins 2018, 10(7), 303; https://doi.org/10.3390/toxins10070303 - 22 Jul 2018

Cited by 54 | Viewed by 8835

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. 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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18 pages, 461 KiB

Open AccessFeature PaperReview

Gut Microbiota and Cardiovascular Uremic Toxicities

by Manuel T. Velasquez, Patricia Centron, Ian Barrows, Rama Dwivedi and Dominic S. Raj

Toxins 2018, 10(7), 287; https://doi.org/10.3390/toxins10070287 - 11 Jul 2018

Cited by 54 | Viewed by 12543

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 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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71 pages, 1529 KiB

Open AccessFeature PaperReview

Deleting Death and Dialysis: Conservative Care of Cardio-Vascular Risk and Kidney Function Loss in Chronic Kidney Disease (CKD)

by Raymond Vanholder, Steven Van Laecke, Griet Glorieux, Francis Verbeke, Esmeralda Castillo-Rodriguez and Alberto Ortiz

Toxins 2018, 10(6), 237; https://doi.org/10.3390/toxins10060237 - 12 Jun 2018

Cited by 27 | Viewed by 7215

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) 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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18 pages, 288 KiB

Open AccessFeature PaperReview

Uremic Toxins and Clinical Outcomes: The Impact of Kidney Transplantation

by Sophie Liabeuf, Lynda Cheddani and Ziad A. Massy

Toxins 2018, 10(6), 229; https://doi.org/10.3390/toxins10060229 - 05 Jun 2018

Cited by 27 | Viewed by 3512

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 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)

16 pages, 261 KiB

Open AccessFeature PaperReview

Uremic Toxin Clearance and Cardiovascular Toxicities

by Robert D. Mair, Tammy L. Sirich and Timothy W. Meyer

Toxins 2018, 10(6), 226; https://doi.org/10.3390/toxins10060226 - 02 Jun 2018

Cited by 62 | Viewed by 5401

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 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)

21 pages, 789 KiB

Open AccessFeature PaperReview

The Impact of Uremic Toxins on Vascular Smooth Muscle Cell Function

by Lucie Hénaut, Aurélien Mary, Jean-Marc Chillon, Saïd Kamel and Ziad A. Massy

Toxins 2018, 10(6), 218; https://doi.org/10.3390/toxins10060218 - 29 May 2018

Cited by 80 | Viewed by 6675

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 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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18 pages, 944 KiB

Open AccessReview

Role of Uremic Toxins for Kidney, Cardiovascular, and Bone Dysfunction

by Hideki Fujii, Shunsuke Goto and Masafumi Fukagawa

Toxins 2018, 10(5), 202; https://doi.org/10.3390/toxins10050202 - 16 May 2018

Cited by 85 | Viewed by 6293

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 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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