Increased Risk of Cardiovascular Complications in Chronic Kidney Disease: Introduction to a Compendium.

HomeCirculation ResearchVol. 132, No. 8Increased Risk of Cardiovascular Complications in Chronic Kidney Disease: Introduction to a Compendium Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBIncreased Risk of Cardiovascular Complications in Chronic Kidney Disease: Introduction to a Compendium Heidi Noels and Joachim Jankowski Heidi NoelsHeidi Noels Correspondence to: Heidi Noels, PhD, Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany, Email E-mail Address: [email protected] https://orcid.org/0000-0003-3053-6984 Institute for Molecular Cardiovascular Research (IMCAR) (H.N., J.J.), University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Germany. Aachen-Maastricht Institute for Cardiorenal Disease (AMICARE) (H.N., J.J.), University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Germany. Department of Biochemistry (H.N.), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands. Search for more papers by this author and Joachim JankowskiJoachim Jankowski Joachim Jankowski, Prof. Dr. rer. nat., Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany, Email E-mail Address: [email protected] https://orcid.org/0000-0002-4528-2967 Institute for Molecular Cardiovascular Research (IMCAR) (H.N., J.J.), University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Germany. Aachen-Maastricht Institute for Cardiorenal Disease (AMICARE) (H.N., J.J.), University Hospital Rheinisch-Westfälische Technische Hochschule Aachen, Germany. Department of Pathology (J.J.), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands. Search for more papers by this author Originally published13 Apr 2023https://doi.org/10.1161/CIRCRESAHA.123.322806Circulation Research. 2023;132:899–901Chronic kidney disease (CKD) is defined by kidney damage or a reduced kidney filtration function with an estimated glomerular filtration rate <60 mL/(min·1.73m²) for >3 months. CKD is a highly prevalent condition affecting ≈13.4% of the population worldwide,1 has a progressive character, and has devastating effects on the patients’ health. At the end stage of kidney disease, patients depend for survival on dialysis or kidney transplantation to replace the failing kidney function. However, <1 % of patients with CKD will ultimately reach this end stage of CKD.1 Instead, most patients with moderate to advanced CKD will prematurely die, and this with cardiovascular disease (CVD) as the main cause of death.1 Of note, the cardiovascular risk increases with CKD progression, with 33.3% to 37.1% of patients with mild to moderate CKD and 39.9% of patients with moderate to severe CKD dying from CVD, compared to 21.7% to 26% of the general population.2 Also, patients in the end stage of kidney disease display an increased cardiovascular risk, with dialysis patients aged 25 with 34 years suffering from an annual cardiovascular mortality risk that is 500× to 1.000× higher compared to similarly aged persons with healthy kidneys.3 Overall, this highlights the extreme cardiovascular burden in patients with CKD.Compared with patients without CKD, traditional therapeutic strategies to reduce cardiovascular risk with lipid-lowering therapies proved to be less efficient in patients with progressing CKD.4 Furthermore, clinical studies revealed that CKD triggers alterations in the type of CVD that patients are presenting with. Myocardial infarction and cerebrovascular events—and thus atherosclerotic CVD types—are responsible for ≈75% of cardiovascular deaths in the general population. Although these CVD types stay highly important in advanced CKD (accounting for ≈58% of cardiovascular deaths in these patients), especially the proportions of sudden cardiac deaths and heart failure as cause of cardiovascular deaths are increasing in advanced CKD. In patients with CKD on dialysis, they account for 28% and 9% of cardiovascular deaths compared to 2% and 7% in the general population.5The revelation of this close interaction of CKD with cardiovascular complications, the altered CVD phenotype, and the reduced treatment response of patients with advanced CKD to traditional therapies have over the past decade highly increased the focus on unraveling the pathophysiological crosstalk of the chronically diseased kidney and the heart. As such, CKD is revealed as an independent risk factor for cardiovascular events, beyond traditional risk factors in the general population,6 and a progressively growing number of clinical and basic research studies have focused over the past years on discovering novel cellular and molecular mechanisms of increased cardiovascular risk in CKD.7–9Therefore, we are highly honored by the opportunity to serve as guest editors of this Compendium on “Increased Risk of Cardiovascular Complications in Chronic Kidney Disease.” Together with the expert scientists that contributed to this Compendium, we aim to provide readers of Circulation Research comprehensive insights into the epidemiology, pathophysiology, and therapy options for cardiovascular disease in CKD based on the current state of knowledge.In the first article in the Compendium, Schuett et al10 describe the actual clinical problem by providing insights into the epidemiology and clinical presentation of CVD in patients with CKD. This is followed by a discussion of currently available therapeutic options in relation to the most prevalent CVD types in this patient cohort, including coronary artery disease, heart failure, arrhythmias, and sudden cardiac death.In a second set of articles, this Compendium provides insights into the pathophysiological processes that underlie increased cardiovascular risk in patients with CKD, covering alterations in systemic inflammation, the vasculature as well as the heart:With patients with CKD presenting with a chronic, systemic low-grade inflammation, Zoccali and Mallamaci11 summarize changes in the innate immune system in patients with cardiovascular and CKD and discuss the potential of emerging, urgently needed anti-inflammatory therapies in reducing increased cardiovascular risk in the general population as well as in patients with CKD.Thakur et al12 provide an update on NETs (neutrophil extracellular traps) and immunothrombosis in chronic inflammation, discuss implications for cardiovascular risk, and shed light on therapeutic strategies targeting NETs-induced immunothrombosis. Since also patients with CKD are at increased risk of thrombosis, the focus is then extended to CKD conditions, and current knowledge on neutrophils and NET formation in patients with CKD is summarized.Next, Hobson et al13 elaborate on the concept of CKD being a state of advanced cardiovascular aging: they discuss novel insights into pathophysiological mechanisms that may contribute to early vascular aging in the uremic milieu, since such findings ultimately may trigger novel therapeutic interventions for patients with CKD, and potentially also for the elderly general population.Two of these pathophysiological mechanisms contributing to advanced vascular aging and cardiovascular risk are endothelial dysfunction and cardiovascular calcification, which form the topics of the next 2 articles. The characteristics of endothelial (cell) dysfunction and its contribution to cardiovascular risk are discussed by Baaten et al14 starting from observations in the general population and extending to a specific focus on patients with CKD. Therapeutic strategies aiming to improve endothelial health are also covered in this article. Hutcheson and Goettsch15 provide deeper insights into cardiovascular calcification in CKD, with a focus on its heterogeneity in presentation, and its clinical implications in terms of cardiovascular risk as well as considerations for therapy.On the side of pathophysiological mechanisms in the heart, Schreibing et al16 summarize current knowledge on fibrosis as a contributor to heart and kidney pathology. As special focus, they elaborate on how RNA-sequencing approaches, especially on single-cell level, provide unique opportunities facilitating the discovery of novel molecular contributors to disease and the identification of interesting novel drug targets. This is complemented by a contribution by Nguyen and Schulze,17 who comprehensively describe current knowledge of cardiac metabolism in heart failure, both in the general population as well as with a view on patients with CKD.In a third set of articles, the comorbid status of patients with CKD as well as a more extended pathophysiological organ crosstalk is taken into account in more detail. With a large majority of patients with CKD with hypertension, Burnier and Damianaki18 discuss existing evidence of hypertension as a cardiovascular risk factor in CKD. They also elaborate on different clinical phenotypes of hypertension in patients with CKD and provide an overview of clinical trials evaluating hypertension management in CKD. Analyzed from the perspective of the “Remote Sensing and Signaling Theory,” Glorieux et al19 focus on inter-organ communication of gut-heart-kidney through small molecules, with a focus on those mediators of intestinal origin. Starting from the observation that CKD is characterized by gut dysbiosis and uremic toxin accumulation, they discuss the role of the gut microbiome in pathophysiological crosstalk between gut, heart, and kidney in patients with CKD.Finally, triggered by the increasing appreciation of the importance of comorbidities and pathophysiological organ crosstalk, Wu et al20 touch upon the topic of computational ecosytems, which aim to integrate data, methods, processes, and interdisciplinary knowledge of multiorgan crosstalk. With a focus on kidney-heart crosstalk, they describe examples, methods, and opportunities of applying computational ecosystems with the aim to reveal novel insights into pathophysiological organ crosstalk.Reflecting a joint effort from all contributing scientists, this Compendium aims to provide the reader a comprehensive collection of reviews covering the current state of knowledge on increased cardiovascular risk in patients with CKD, from epidemiology and clinical presentation to pathophysiology and therapeutic strategies and developments. We hope that readers will enjoy this Compendium and that they will find it a valuable source of information supporting them on their own ways of research, clinics, and life.We are very grateful for the expertise and dedication of the contributors to this Compendium, without whom this Review collection would never have been. May this Compendium stimulate increased focus on pathophysiological kidney-heart crosstalk and on comorbidities and inter-organ crosstalk in general. Enjoy reading!Article InformationAcknowledgmentsThe authors are grateful to Dr Jane Freedman for giving them the opportunity and trust to organize this Compendium; to Gemma Bridges-Lyman—the managing editor of Circulation Research—for her great support and the perfect organization; and to all scientists who contributed to this Compendium. Also, we thank all members of the German research consortium SFB/TRR219 for sharing ideas and joint efforts in the past years to drive forward cardiorenal research, and to the German Research Foundation (DFG) for their financial support.Sources of FundingThis work was supported by the German Research Foundation (DFG) Project-ID 322900939–SFB/TRR219 (to H. Noels and J. Jankowski) and Project-ID 403224013 – SFB 1382 (to H. Noels and J. Jankowski); by the German Center for Cardiovascular Research (DZHK-B23 to H. Noels), the “Else Kröner-Fresenius-Stiftung” (Project 2020_EKEA.60 to H. Noels) and the Interdisciplinary Centre for Clinical Research within the faculty of Medicine at the Rheinisch-Westfälische Technische Hochschule Aachen University (to J. Jankowski; PTD 1-12 to H. Noels). Further funding was provided by the European Union’s Horizon 2020 research and innovation program European Union's Innovative Training Network INTRICARE (722609), CaReSyAn (764474), and the European Union-Cost PerMedik (CA21165).Disclosures H. Noels and J. Jankowski are founding shareholders of AMICARE Development GmbH.FootnotesFor Sources of Funding and Disclosures, see page 901.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Heidi Noels, PhD, Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany, Email [email protected].deJoachim Jankowski, Prof. Dr. rer. nat., Institute for Molecular Cardiovascular Research (IMCAR), University Hospital Aachen, Rheinisch-Westfälische Technische Hochschule Aachen University, Pauwelsstraße 30, 52074 Aachen, Germany, Email [email protected].deReferences1. Hill NR, Fatoba ST, Oke JL, Hirst JA, O-Callaghan CA, Lasserson DS, Hobbs FDR. 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Use of computation ecosystems to analyse the kidney-heart crosstalk.Circulation Research. 2023; 132: 1084–1100. doi: 10.1161/CIRCRESAHA.122.321765LinkGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. 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