Comorbidities in Chronic Kidney Disease (CKD) Printed Edition of the Special Issue Published in Toxins www.mdpi.com/journal/toxins Joachim Jankowski and Heidi Noels Edited by Comorbidities in Chronic Kidney Disease (CKD) Comorbidities in Chronic Kidney Disease (CKD) Special Issue Editors Joachim Jankowski Heidi Noels MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Heidi Noels Institute of Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, RWTH Aachen University, Germany Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands Special Issue Editors Joachim Jankowski Institute of Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, RWTH Aachen University, Germany Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands Editorial O ffice MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal Toxins (ISSN 2072-6651) in 2020 (available at: https://www.mdpi.com/journal/toxins/special issues/ Kidney Comorbidities). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year , Article Number , Page Range. ISBN 978-3-03936-668-2 (Pbk) ISBN 978-3-03936-669-9 (PDF) c © Cover image courtesy of Joachim Jankowski. 202 1 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Heidi Noels and Joachim Jankowski Editorial on the Special Issue “Comorbidities in Chronic Kidney Disease” Reprinted from: Toxins 2020 , 12 , 384, doi:10.3390/toxins12060384 . . . . . . . . . . . . . . . . . . 1 Nadine Kaesler, Anne Babler, J ̈ urgen Floege and Rafael Kramann Cardiac Remodeling in Chronic Kidney Disease Reprinted from: Toxins 2020 , 12 , 161, doi:10.3390/toxins12030161 . . . . . . . . . . . . . . . . . . 6 Thomas Ebert, Sven-Christian Pawelzik, Anna Witasp, Samsul Arefin, Sam Hobson, Karolina Kublickiene, Paul G. Shiels, Magnus B ̈ ack and Peter Stenvinkel Inflammation and Premature Ageing in Chronic Kidney Disease Reprinted from: Toxins 2020 , 12 , 227, doi:10.3390/toxins12040227 . . . . . . . . . . . . . . . . . . 22 Britt Opdebeeck, Patrick C. D’Haese and Anja Verhulst Molecular and Cellular Mechanisms that Induce Arterial Calcification by Indoxyl Sulfate and P-Cresyl Sulfate Reprinted from: Toxins 2020 , 12 , 58, doi:10.3390/toxins12010058 . . . . . . . . . . . . . . . . . . . 43 Yu-Hsien Lai, Chih-Hsien Wang, Chiu-Huang Kuo, Yu-Li Lin, Jen-Pi Tsai and Bang-Gee Hsu Serum P -Cresyl Sulfate Is a Predictor of Central Arterial Stiffness in Patients on Maintenance Hemodialysis Reprinted from: Toxins 2020 , 12 , 10, doi:10.3390/toxins12010010 . . . . . . . . . . . . . . . . . . . 55 Anika Himmelsbach, Carina Ciliox and Claudia Goettsch Cardiovascular Calcification in Chronic Kidney Disease—Therapeutic Opportunities Reprinted from: Toxins 2020 , 12 , 181, doi:10.3390/toxins12030181 . . . . . . . . . . . . . . . . . . 64 Merita Rroji, Andreja Figurek and Goce Spasovski Should We Consider the Cardiovascular System While Evaluating CKD-MBD? Reprinted from: Toxins 2020 , 12 , 140, doi:10.3390/toxins12030140 . . . . . . . . . . . . . . . . . . 82 Juan Rafael Mu ̃ noz-Casta ̃ neda, Cristian Rodelo-Haad, Maria Victoria Pendon-Ruiz de Mier, Alejandro Martin-Malo, Rafael Santamaria and Mariano Rodriguez Klotho/FGF23 and Wnt Signaling as Important Players in the Comorbidities Associated with Chronic Kidney Disease Reprinted from: Toxins 2020 , 12 , 185, doi:10.3390/toxins12030185 . . . . . . . . . . . . . . . . . . 105 Eduardo J. Duque, Rosilene M. Elias and Rosa M. A. Moys ́ es Parathyroid Hormone: A Uremic Toxin Reprinted from: Toxins 2020 , 12 , 189, doi:10.3390/toxins12030189 . . . . . . . . . . . . . . . . . . 122 Pieter Evenepoel, Sander Dejongh, Kristin Verbeke and Bjorn Meijers The Role of Gut Dysbiosis in the Bone–Vascular Axis in Chronic Kidney Disease Reprinted from: Toxins 2020 , 12 , 285, doi:10.3390/toxins12050285 . . . . . . . . . . . . . . . . . . 138 Sol Carriazo, Adri ́ an M Ramos, Ana B Sanz, Maria Dolores Sanchez-Ni ̃ no, Mehmet Kanbay and Alberto Ortiz Chronodisruption: A Poorly Recognized Feature of CKD Reprinted from: Toxins 2020 , 12 , 151, doi:10.3390/toxins12030151 . . . . . . . . . . . . . . . . . . 156 v About the Special Issue Editors Joachim Jankowski is Director of the Institute of Molecular Cardiovascular Research (IMCAR) at the University Hospital Aachen and RWTH Aachen University, Germany. This institute strives for scientific excellence in the field of cardiovascular diseases with a particular focus on patients with chronic renal insufficiency. Research is performed in close collaboration with the Cardiovascular Research Institute of the partner University of Maastricht (CARIM) in the Netherlands. Prof. Dr. Jankowski is the Speaker of the Transregional Collaborative Research Consortium SFB/TRR219 funded by the German Research Foundation (2018–2021). He is the Coordinator of the Marie Skłodowska-Curie International Training Network “CaReSyAn” (2018–2021). Heidi Noels is leading the research group “Experimental Cardiovascular Pathophysiology” in the Institute of Molecular Cardiovascular Research (IMCAR) at the RWTH Aachen University, Germany. Her group is focusing on the identification and characterization of pathological mechanisms and mediators underlying cardiovascular and cardiorenal disease. Dr. Noels is Managing Director of the Transregional Collaborative Research Consortium SFB/TRR219 funded by the German Research Foundation (2018–2021) and Program Manager of the Marie Skłodowska-Curie International Training Network “CaReSyAn” (2018–2021). vii This Special Issue was created in the context of the SFB/TRR219 Research Consortium funded by the German Research Foundation (Project-ID 322900939) and the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 764474 (CaReSyAn). toxins Editorial Editorial on the Special Issue “Comorbidities in Chronic Kidney Disease” Heidi Noels 1, * and Joachim Jankowski 1,2, * 1 Institute of Molecular Cardiovascular Research (IMCAR), RWTH Aachen, University Hospital Aachen, 52074 Aachen, Germany 2 Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, 6200 Maastricht, The Netherlands * Correspondence: hnoels@ukaachen.de (H.N.); jjankowski@ukaachen.de (J.J.) Received: 8 June 2020; Accepted: 9 June 2020; Published: 11 June 2020 Keywords: chronic kidney disease; cardiovascular; CKD–MBD; comorbidity; inflammation; fibrosis; calcification; senescence; uremic toxin With a mean worldwide prevalence of 13.4% [ 1 ], chronic kidney disease (CKD) imposes a massive health burden on our society. In addition to a reduced kidney function, patients with CKD su ff er increasingly from cardiovascular disease (CVD) [ 2 – 4 ], with CVD accounting for around half of the deaths of patients in CKD stages 4–5 [ 3 ]. In fact, CKD has been identified as an independent risk factor for CVD [ 5 ], but therapeutic options are highly inadequate. In addition to traditional cardiovascular risk factors, CKD-specific pathological mechanisms are expected to contribute to increased cardiovascular risk in this patient group, especially with progressing CKD [ 6 – 8 ]. However, detailed insights into the underlying pathophysiology of CKD-driven CVD largely remain to be unveiled [9,10]. Inflammation and fibrosis are increased in CKD patients [ 11 – 13 ], and the Chronic Renal Insu ffi ciency Cohort (CRIC) study recently revealed that inflammation biomarkers are independently associated with atherosclerotic cardiovascular events and death in CKD patients [ 14 ]. Moreover, vascular calcification is highly prevalent in CKD patients, increases with declining kidney function [ 15 ] and is associated with increased risk of cardiovascular events and death in CKD [ 16 – 19 ]. As one aspect, uremic retention solutes , also referred to as uremic toxins, accumulate in the circulation of CKD patients due to a failing kidney filtration function [ 20 ]. Many of these solutes have been associated with pathophysiological e ff ects, including inflammation, oxidative stress and calcification. As a consequence, they are expected to contribute to increased cardiovascular risk in CKD patients [ 21 ]. Furthermore, patients with CKD often present with enhanced bone demineralization along with extraosseous calcification, a condition clinically referred to as CKD-mineral and bone disorder (CKD–MBD). CKD–MBD highly coincides with increased vascular calcification and correlates with cardiovascular events, underlining the importance of identifying and characterizing CKD–MBD biomarkers as well as mediators of this pathological bone–vascular axis [ 22 ]. Moreover, patients with CKD present disturbances of gut microbiota [ 23 ], which too are expected to contribute to both reduced bone and cardiovascular health in CKD patients. This Special Issue aims to provide insights into comorbidities in CKD patients with a main focus on increased cardiovascular risk and summarizes the current knowledge of underlying pathophysiological mechanisms. 1. Increased Cardiovascular Risk in CKD Patients with CKD have an increased risk of atherosclerosis-related cardiovascular events, such as myocardial infarction and stroke [ 3 , 24 ]. However, with declining renal function, CKD patients are also becoming more prone to non-atherosclerotic cardiovascular events. Underlying cardiac remodeling involves left-ventricular hypertrophy, fibrosis and capillary rarefaction, and is often Toxins 2020 , 12 , 384; doi:10.3390 / toxins12060384 www.mdpi.com / journal / toxins 1 Toxins 2020 , 12 , 384 referred to as uremic cardiomyopathy. In this Special Issue, Kaesler et al. [ 25 ] provide detailed insights into cardiac remodeling in CKD and provide an update on the current knowledge of the cellular and molecular mechanisms of pathophysiological kidney–heart crosstalk in CKD patients. This includes alterations in relation to phosphate homeostasis, uremic toxins, growth factors, metabolic and oxidative stress, inflammation as well as fibrosis. Moreover, an overview of current mouse models to study cardiac remodeling in CKD is provided and potential therapeutic targets are being discussed in the context of current knowledge. This underlines the urgent need to further invest in closely studying the pathological crosstalk between kidney and heart in order to guide the development of e ff ective therapies. 2. Inflammation and Vascular Calcification in CKD Impact on Cardiovascular Health Chronic low-grade inflammation is a hallmark of CKD and is closely associated with cellular senescence and accelerated ageing. In this Special Issue, Ebert et al. [ 26 ] elaborate on this so-called “inflammageing” in CKD. They address the phenotype of inflammation and premature ageing in CKD patients as well as their mutual activation. Underlying cellular and molecular mechanisms are summarized with a focus on cellular senescence, uremic toxins, the phosphate–FGF23–Klotho axis and the CKD-mediated downregulation of NRF2 as a key transcription factor protecting from mitochondrial dysfunction and oxidative stress. Promising therapeutic candidates to reduce inflammageing in CKD are discussed. Uremia and uremic toxins not only trigger inflammation, but also accelerate vascular calcification in CKD. This was recently shown for the protein-bound uremic toxins indoxyl sulfate and p-cresyl sulfate, with underlying cellular and molecular mechanisms discussed in detail in this Special Issue by Opdebeeck et al. [ 27 ]. Along this line, Lai. et al. [ 28 ] reveals within this Special Issue that p-cresyl sulfate is a predictor of arterial sti ff ness in patients on hemodialysis, with arterial sti ff ness known to be associated with increased cardiovascular risk and mortality in CKD patients [29,30]. Although vascular calcification has been associated with increased cardiovascular risk, there are currently no therapies available that adequately tackle this pathological axis. This is being discussed by Himmelsbach et al. [ 31 ]: a detailed overview of new potential therapeutic strategies to reduce cardiovascular calcification in CKD is provided, covering findings from in vitro molecular studies and animal models to observational and interventional studies in CKD patients. 3. CKD–MBD as a Major Complication in CKD A ff ects Cardiovascular Health Vascular calcification and bone demineralization often coincide in CKD patients, which is often referred to as the bone–vascular axis or “calcification paradox”. In this Special Issue, Rroji et al. [32] discuss the pathophysiology of CKD–MBD and its association with increased cardiovascular risk. Insights are provided for how vitamin D deficiency, secondary hyperparathyroidism and hyperphosphatemia, as classical CKD-MBD biomarkers, could impact cardiac remodeling in uremic cardiomyopathy. Furthermore, accumulating data supporting a role for FGF23, Klotho-deficiency and sclerostin as new CKD-MBD biomarkers in early cardiovascular risk assessment are discussed in detail, and a role beyond biomarker function and as mediators of cardiovascular risk in CKD is being elaborated on. Muñoz-Castañeda et al. [ 33 ] further elaborate on the FGF23–Klotho axis, its regulation by the Wnt / β -catenin signaling pathway and vice versa. Starting from their deregulation in CKD, the impact of these axes on pathophysiological processes underlying CKD progression as well as cardiovascular disease and bone disorders are being discussed in detail. Duque et al. [ 34 ] specifically focused on secondary hyperparathyroidism as a complication of CKD, with its causes as well as its impact on the bone–vascular axis being discussed. In extension, current literature in relation to a potential impact of secondary hyperparathyroidism on CKD progression, cardiac remodeling, muscle weakness as well as glucose metabolism is summarized. 2 Toxins 2020 , 12 , 384 Furthermore, with CKD patients presenting with gut dysbiosis, Evenepoel et al. [ 35 ] provide detailed insights into the increasing evidence that CKD-associated gut dysbiosis contributes to the pathophysiology of the bone-vascular axis. This may include pathophysiological processes such as increased exposure to protein fermentation metabolites, decreased systemic levels of specific short-chain fatty acids by reduced carbohydrate fermentation, vitamin K deficiency as well as a leaky gut triggering a pro-inflammatory environment in CKD. 4. Chronodisruption in CKD: Implications for Kidney and Cardiac Health? Finally, the concept of chronodisruption as a chronic disturbance of circadian rhythms with a negative impact on health is being discussed in the context of CKD. Carriazo et al . [ 36 ] review current evidence for chronodisruption in CKD as well as its potential impact on kidney and cardiac pathology. Among others, diet, inflammatory factors and uremic toxins are being discussed as potential chronodisrupters in CKD, and the main challenges and open questions regarding the underlying mechanisms, implications for kidney–cardiac health, as well as therapeutic opportunities are summarized. 5. Conclusions Altogether, this Special Issue summarizes current knowledge on the pathophysiological mechanisms underlying the development of comorbidities in CKD, with a main focus on CVD. This reveals the urgent need to further invest e ff orts in uncovering CKD-specific cardiovascular pathological mechanisms and mediators of disease in order to pave the way for new therapeutic strategies, tailored specifically to the CKD patient. Author Contributions: All authors listed have made substantial, direct and intellectual contribution to the work, and approved it for publication. All authors have read and agreed to the published version of the manuscript. Funding: This work and associated APC were funded by the German Research Foundation (DFG) SFB / TRR219 (S-03, C-04, M-05), Project-ID 403224013-SFB 1382 (A-04), by the CORONA foundation, the Interreg V-A EMR program (EURLIPIDS, EMR23) and by a grant from the Interdisciplinary Centre for Clinical Research within the faculty of Medicine at the RWTH Aachen University (project E8-3). In addition, this work has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 764474 (CaReSyAn). Acknowledgments: We thank all scientists who contributed to this Special Issue. Conflicts of Interest: The authors declare that this work was conducted in the absence of any commercial or financial relationships that could present a potential conflict of interest. References 1. Hill, N.R.; Fatoba, S.T.; Oke, J.L.; Hirst, J.A.; O’Callaghan, C.A.; Lasserson, D.S.; Hobbs, F.R. Global prevalence of chronic kidney disease—A systematic review and meta-analysis. PLoS ONE 2016 , 11 , e0158765. [CrossRef] [PubMed] 2. Gansevoort, R.; Correa-Rotter, R.; Hemmelgarn, B.; Jafar, T.H.; Heerspink, H.J.L.; Mann, J.F.; Matsushita, K.; Wen, C.P. Chronic kidney disease and cardiovascular risk: Epidemiology, mechanisms, and prevention. Lancet (Lond. Engl.) 2013 , 382 , 339–352. [CrossRef] 3. 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This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http: // creativecommons.org / licenses / by / 4.0 / ). 5 toxins Review Cardiac Remodeling in Chronic Kidney Disease Nadine Kaesler 1, † , Anne Babler 1, † , Jürgen Floege 1 and Rafael Kramann 1,2, * 1 Clinic for Renal and Hypertensive Disorders, Rheumatological and Immunological Disease, University Hospital of the RWTH Aachen, 52074 Aachen, Germany; nkaesler@ukaachen.de (N.K.); ababler@ukaachen.de (A.B.); jfloege@ukaachen.de (J.F.) 2 Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands * Correspondence: rkramann@gmx.net † These authors contributed equally. Received: 17 February 2020; Accepted: 3 March 2020; Published: 5 March 2020 Abstract: Cardiac remodeling occurs frequently in chronic kidney disease patients and a ff ects quality of life and survival. Current treatment options are highly inadequate. As kidney function declines, numerous metabolic pathways are disturbed. Kidney and heart functions are highly connected by organ crosstalk. Among others, altered volume and pressure status, ischemia, accelerated atherosclerosis and arteriosclerosis, disturbed mineral metabolism, renal anemia, activation of the renin-angiotensin system, uremic toxins, oxidative stress and upregulation of cytokines stress the sensitive interplay between di ff erent cardiac cell types. The fatal consequences are left-ventricular hypertrophy, fibrosis and capillary rarefaction, which lead to systolic and / or diastolic left-ventricular failure. Furthermore, fibrosis triggers electric instability and sudden cardiac death. This review focuses on established and potential pathophysiological cardiorenal crosstalk mechanisms that drive uremia-induced senescence and disease progression, including potential known targets and animal models that might help us to better understand the disease and to identify novel therapeutics. Keywords: uremia; uremic cardiomyopathy; organ crosstalk; cardiorenal syndrome; chronic kidney disease; left-ventricular hypertrophy; heart failure; cardiac fibrosis Key Contribution: Here, we provide a most recent overview on the proposed mechanisms in organ crosstalk from kidney disease to myocardium, underlying cellular mechanisms and available mouse models. We thereby aim to o ff er potential therapeutic target sites in this understudied disease condition. 1. Chronic Kidney Disease Chronic kidney disease (CKD) a ff ects an increasing number of patients worldwide and is associated with dramatically increased morbidity and mortality [ 1 , 2 ]. Recent data suggest that CKD currently a ff ects more than 10% of the population in the developed world [3,4]. Diabetes mellitus and high blood pressure are among the most prevalent risk factors for the development of CKD and are responsible for the majority of cases. Other conditions that a ff ect the kidneys are glomerulonephritis, the third most common type of kidney disease, inherited diseases, such as polycystic kidney disease, and loss of renal tissue due to infections, malformations or urinary tract obstruction. Repeated episodes of acute kidney injury and certain therapeutics, such as non-steroidal anti-inflammatory drugs (NSAIDs) can also contribute to CKD [2]. In end-stage renal failure, dialysis and subsequent kidney transplantation are the only available treatment options apart from palliative care. However, not all patients qualify for kidney transplantation and transplant waiting times are often long. Thus, patients usually undergo many years of dialysis treatment. Longstanding uremia in turn promotes cardiovascular disease. Consequently, the leading Toxins 2020 , 12 , 161; doi:10.3390 / toxins12030161 www.mdpi.com / journal / toxins 6 Toxins 2020 , 12 , 161 causes of death in dialysis patients are sudden cardiac death and recurrent heart failure due to cardiac and vascular remodeling [5]. Cellular Crosstalk in the Heart The mammalian heart is a highly interactive complex of cardiac muscle cells, extracellular matrix (ECM) and vessels. Other essential cell types include endothelial cells, fibroblasts, vascular smooth muscle cells and perivascular cells [ 6 , 7 ]. Studies, using state-of-the-art methods such as single-cell transcriptomics, suggest that all cardiac cell types communicate vigorously with one another in homeostasis and disease [ 8 – 10 ]. Each cardiomyocyte is in physical contact with at least one capillary, allowing mechanical and paracrine crosstalk between at least four key cell types, namely, cardiomyocytes, endothelial cells, vascular smooth muscle cells (VSMCs) and pericytes / fibroblasts [ 11 ]. Cardiomyocytes crosstalk with endothelial cells and fibroblasts by secreting various specific growth factors [ 7 ]. Various lines of evidence suggest that endothelial cells crosstalk with cardiomyocytes and are key players in angiogenesis and vasomotor tone control by secreting angiocrine factors such as nitric oxide or endothelin-1 [ 12 ]. One example of paracrine intercellular crosstalk inside the myocardium is vasomotion. Endothelial cells are directly exposed to shear stress, contrary to VSMCs. To facilitate vasomotion, endothelial cells release nitric oxide in response to shear stress, thus signaling to the VSMCs to dilate. The cardiac morphology and function can be a ff ected by further external and internal stimuli. 2. Pathology and Pathophysiology of the Cardiorenal Syndrome Kidney and cardiac health are highly linked to each other, with diseases of either organ a ff ecting the other organ. In the following, we aim to give an overview of the mechanisms and relevant factors that have been reported to be involved in cardiac remodeling due to kidney injury, i.e., cardiorenal syndrome. The presence of CKD and end-stage renal disease (ESRD) leads to cardiac remodeling with hypertrophy, fibrosis and capillary loss [ 13 ]. Uremic cardiomyopathy a ff ects about 80% of hemodialysis patients [ 14 ] and is the main cause of death in this cohort. A similar prevalence has even been reported in pediatric uremic patients [ 15 ] who presumably lack traditional atherosclerotic risk factors. The comorbidities in CKD patients that contribute to cardiovascular remodeling are atherosclerosis, hyperlipidemia, diabetes and / or hypertension, but also include a plethora of so-called non-traditional cardiovascular risk factors such as those discussed below and summarized in Table 1. These stimuli exacerbate the pathophysiological cardiac changes, including left-ventricular hypertrophy (LVH), di ff use interstitial fibrosis and capillary rarefaction leading to systolic and diastolic dysfunction. In this review, we consider these cardiac abnormalities that frequently occur in patients with CKD as uremic cardiomyopathy. 2.1. Left-Ventricular Hypertrophy in CKD LVH is an independent predictor of cardiac death in dialysis patients. LVH can occur early in the course of CKD, even when the glomerular filtration rate (GFR) is still normal [ 16 ]. Once GFR is reduced, myocytes enlarge and cardiomyocytes expand, leading to LVH [ 17 ]. Cardiomyocytes are the major cell type, comprising about 70–85% of the total volume. They generate contractility by cyclic calcium fluxes [ 17 , 18 ]. Fibroblasts secrete collagen precursors and matrix metalloproteinases (MMPs) and thereby actively remodel the ECM [ 17 – 19 ]. The ECM embeds the myocytes and non-myocytes. Collagen is the most abundant protein here [ 19 ]. These structural changes are closely related to a functional impairment of the left ventricle causing diastolic dysfunction [ 20 ] while systolic function may, at least initially, remain normal [ 21 ]. LVH can be a consequence of increased preload due to hypervolemia or increased afterload due to increased peripheral resistance or hypertension, which are both very common in CKD. Further factors involved in the pathogenesis of LVH might be high cardiac output due to anemia or large arteriovenous fistulas for dialysis access [18,21]. 7 Toxins 2020 , 12 , 161 2.2. Cardiac Fibrosis In CKD patients, myocardial fibrosis is a pathologic process that occurs together with LVH. One hallmark of myocardial fibrosis is a marked increase in the production of extracellular matrix, especially collagens, which impair diastolic filling due to increased sti ff ness of the left ventricle, but they may also a ff ect systolic function since functional myocytes are replaced by fibrotic scar tissue [22,23]. The main causes of myocardial fibrosis are hemodynamic alterations and disturbed secretion of various systemic soluble factors. A primary factor leading to myocardial fibrosis in CKD patients is hypertension, which is mainly associated with pressure overload. Factors related to hemodynamic alterations in CKD patients like senescence, ischemia, catecholamines, angiotensin II and aldosterone further promote the development of cardiac fibrosis [ 21 ]. Arterial sti ff ening is accelerated in the presence of CKD and is caused by a loss of elastic fibers and vascular calcification [ 24 ]. Increased vascular sti ff ness leads to increased cardiac afterload, which promotes cardiac hypertrophy and fibrosis [21,25]. However, during CKD progression, left ventricular remodeling has been found to occur even earlier than changes in large arteries [ 26 ]. This might be explained by a range of factors and mechanisms including uremic toxins, TGF- β and other growth factors. In addition to the role of hemodynamic changes in the development of cardiac fibrosis, non-hemodynamic factors related to the uremic milieu, such as overactivity of the renin-angiotensin-aldosterone system, FGF-23, parathyroid hormone, endothelin, increased sympathetic nerve discharge and increased plasma catecholamines might also play an important role [21,27]. Perivascular mesenchymal cells surround the VSMC layer in the so-called adventitia of larger arteries but are also present as pericytes around the vasa vasorum and in direct contact with endothelial cells of both the large arteries and micro-vessels. They play a role in vasomotion, homeostasis and permeability of the vasculature [ 11 ]. The heterogeneity of perivascular cells has been unclear for many years, but recent single-cell RNA-sequencing data suggest that various, previously unknown, perivascular mesenchymal populations exist [ 28 , 29 ]. We have reported that Gli1 marks a specific perivascular cell type that drives cardiac fibrosis and vascular calcification [ 30 , 31 ]. Gli1 + cells are a subset of cardiac interstitial PDGFR β + cells, but are mostly distinct from cardiac NG2 + pericytes [ 31 ]. However, the complex system of the cardiac perivascular cell types remains unclear, and single-cell experiments are needed to shed light on their heterogeneity and the role they play in homeostasis and disease. 2.3. Capillary Rarefaction Endothelial cells line blood or lymphatic vessels and are the most abundant cells of the non-myocyte fraction in murine hearts [ 6 , 7 ]. The medial layer of small and large vessels consists of vascular smooth muscle cells (VSMCs). Endothelial dysfunction is frequent in CKD [ 32 ] and can be considered an early manifestation of coronary vascular disease [ 33 ]. Endothelial dysfunction leads to disturbed microcirculation and is considered an independent risk factor for cardiovascular events [ 33 , 34 ]. CKD-induced microangiopathy has been shown to lead to tissue hypoxia and dysfunctional angiogenesis [33]. 2.4. Oxidative Stress Oxidative stress in CKD results from an imbalance in reactive oxygen species production and impaired antioxidant defense [35]. Various oxidation products have been shown to be overabundant in CKD. Increased ROS production has been reported to contribute to myocardial hypertrophy and fibrosis by lipid peroxidation, proinflammatory cytokines and DNA damage [ 35 , 36 ]. A marker of oxidative stress, 8-isoprostane, increases as CKD progresses [ 37 ]. Furthermore, NADPH oxidase generates reactive oxygen species, and this in turn leads to endothelial dysfunction [ 38 ]. Another e ff ect of elevated oxidative stress is the oxidation of plasma proteins, which causes activation of phagocytes 8 Toxins 2020 , 12 , 161 and increases inflammation [ 39 ]. Advanced oxidation protein products promote cardiomyocyte apoptosis. This process is mediated by upregulation of c-Jun N-terminal kinase (JNK) signaling and enhanced endoplasmic reticulum stress [40]. 2.5. Inflammation CKD can be seen as a state of increased systemic inflammation with various cytokines being among the recognized uremic toxins. The Chronic Renal Insu ffi ciency Cohort Study (CRIC) study found that elevated plasma levels of high-sensitivity C-reactive protein (hs-CRP) and IL-6 were associated with LVH and systolic dysfunction in CKD patients [ 41 ]. Freise et al. stated that, amongst others, inflammatory processes involving tumor necrosis factor (TNF) and IL-10 impact pathobiological responses in arteries from children with CKD, and are thus associated with tissue remodeling and cardiovascular disease [ 42 ]. Furthermore, CKD patients develop endotoxemia, characterized by elevated levels of endotoxin, IL-6, CRP and lipopolysaccharide-binding protein (LBP), which contributes to chronic inflammation and has been associated with higher left-ventricular mass index (LVMI) and subsequently left-ventricular dysfunction [ 43 ]. Most of the soluble factors mentioned here are described as being secreted by cells of the heart (cardiomyocytes, endothelial cells, fibroblasts, VSMCs and pericytes) but also resident immune cells (e.g., macrophages, dendritic cells) and / or circulating cells might contribute to th