Vascular calcification in chronic kidney disease: different bricks in the wall?
TL;DR: A nuanced view is presented concerning the pathophysiologic and therapeutic implications of the different types of calcification in patients with chronic kidney disease, including an overview of the many different pathways underlying the ultimate occurrence of VC.
About: This article is published in Kidney International.The article was published on 2017-04-01 and is currently open access. It has received 194 citations till now.
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TL;DR: The potential role of various antioxidants and pharmacological agents, which may represent potential therapeutic targets to reduce OS in both pediatric and adult CKD patients, are discussed.
Abstract: Oxidative stress (OS), defined as disturbances in the pro-/antioxidant balance, is harmful to cells due to the excessive generation of highly reactive oxygen (ROS) and nitrogen (RNS) species. When the balance is not disturbed, OS has a role in physiological adaptations and signal transduction. However, an excessive amount of ROS and RNS results in the oxidation of biological molecules such as lipids, proteins, and DNA. Oxidative stress has been reported in kidney disease, due to both antioxidant depletions as well as increased ROS production. The kidney is a highly metabolic organ, rich in oxidation reactions in mitochondria, which makes it vulnerable to damage caused by OS, and several studies have shown that OS can accelerate kidney disease progression. Also, in patients at advanced stages of chronic kidney disease (CKD), increased OS is associated with complications such as hypertension, atherosclerosis, inflammation, and anemia. In this review, we aim to describe OS and its influence on CKD progression and its complications. We also discuss the potential role of various antioxidants and pharmacological agents, which may represent potential therapeutic targets to reduce OS in both pediatric and adult CKD patients.
368 citations
TL;DR: This review focuses non-traditional CVD risk factors in HD patients, such as chronic volume overload, anaemia, inflammation, oxidative stress, chronic kidney disease–mineral bone disorder and other aspects of the ‘uraemic milieu’.
Abstract: Cardiovascular disease (CVD) is a highly common complication and the first cause of death in patients with end-stage renal disease (ESRD) on haemodialysis (HD). In this population, mortality due to CVD is 20 times higher than in the general population and the majority of maintenance HD patients have CVD. This is likely due to ventricular hypertrophy as well as non-traditional risk factors, such as chronic volume overload, anaemia, inflammation, oxidative stress, chronic kidney disease-mineral bone disorder and other aspects of the 'uraemic milieu'. Better understanding the impact of these numerous factors on CVD would be an important step for prevention and treatment. In this review we focus non-traditional CVD risk factors in HD patients.
275 citations
Cites background from "Vascular calcification in chronic k..."
...These cells down-regulate the production of specific genes and up-regulate the growth of osteochondrogenesis markers, losing their contractile competence and acquiring collagen matrix production and forming calcium–phosphorus-rich vesicles able to start the mineralization process of the vessel internal surface [34]....
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TL;DR: A general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology, and a rapidly increasing collection of drugs interfering at different levels of W NT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future.
Abstract: WNT signaling is an elaborate and complex collection of signal transduction pathways mediated by multiple signaling molecules. WNT signaling is critically important for developmental processes, including cell proliferation, differentiation and tissue patterning. Little WNT signaling activity is present in the cardiovascular system of healthy adults, but reactivation of the pathway is observed in many pathologies of heart and blood vessels. The high prevalence of these pathologies and their significant contribution to human disease burden has raised interest in WNT signaling as a potential target for therapeutic intervention. In this review, we first will focus on the constituents of the pathway and their regulation and the different signaling routes. Subsequently, the role of WNT signaling in cardiovascular development is addressed, followed by a detailed discussion of its involvement in vascular and cardiac disease. After highlighting the crosstalk between WNT, transforming growth factor-β and angiotensin II signaling, and the emerging role of WNT signaling in the regulation of stem cells, we provide an overview of drugs targeting the pathway at different levels. From the combined studies we conclude that, despite the sometimes conflicting experimental data, a general picture is emerging that excessive stimulation of WNT signaling adversely affects cardiovascular pathology. The rapidly increasing collection of drugs interfering at different levels of WNT signaling will allow the evaluation of therapeutic interventions in the pathway in relevant animal models of cardiovascular diseases and eventually in patients in the near future, translating the outcomes of the many preclinical studies into a clinically relevant context.
222 citations
Cites background from "Vascular calcification in chronic k..."
...B. Vascular Calcification Vascular calcification is a key process involved in the development of atherosclerosis as well as other cardiovascular pathologies such as congestive heart failure and chronic kidney disease (Demer and Tintut, 2008; Vervloet and Cozzolino, 2017)....
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TL;DR: The issues surrounding CKD-MBD, cardiovascular disease and approaches to treatment are discussed, with Vitamin D compounds remain the first-line therapy for prevention and treatment of SHPT in CKD.
122 citations
TL;DR: The discovery of therapeutic interventions that can either lower FGF23 concentrations or block its effects should prompt the design of clinical trials that aim to establish whether targeting FGF 23 can reduce clinically relevant outcomes.
Abstract: Fibroblast growth factor 23 (FGF23) is a hormone with a central role in the regulation of phosphate homeostasis. This regulation is accomplished by the coordinated modulation of renal phosphate handling, vitamin D metabolism and parathyroid hormone secretion. Patients with kidney disease have increased circulating levels of FGF23 and in other patient populations and in healthy individuals, FGF23 levels also rise following an increase in dietary phosphate intake. Maladaptive increases in FGF23 have a detrimental effect on several organs and tissues and, importantly, these pathological changes most likely contribute to increased morbidity and mortality. For example, in the context of heart disease, FGF23 is involved in the development of pathological hypertrophy that can lead to congestive heart failure. Increased FGF23 concentrations can also lead to microcirculatory changes, in particular reduced vasodilatory capacity, and collectively these cardiovascular changes can compromise tissue perfusion. In addition, FGF23 is associated with inflammation and an increased risk of infection; other potentially detrimental effects of FGF23 are likely to emerge in the future. Most importantly, recent insights demonstrate that FGF23 can be therapeutically targeted, which holds promise for the treatment of many patients in a variety of clinical settings.
114 citations
References
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TL;DR: In this article, the authors used ultrafast computed tomography (UCT) to detect and quantify coronary artery calcium levels in 584 subjects (mean age 48 +/- 10 years) with and without clinical coronary artery disease.
6,545 citations
3,791 citations
University of California, Irvine1, Saint Francis University2, Wake Forest University3, National Institutes of Health4, University of Minnesota5, Northwestern University6, Columbia University7, Johns Hopkins University8, Carney Hospital9, University of Vermont10, University of California, Los Angeles11, University of Washington12
TL;DR: The coronary calcium score is a strong predictor of incident coronary heart disease and provides predictive information beyond that provided by standard risk factors in four major racial and ethnic groups in the United States.
Abstract: BACKGROUND In white populations, computed tomographic measurements of coronary-artery calcium predict coronary heart disease independently of traditional coronary risk factors. However, it is not known whether coronary-artery calcium predicts coronary heart disease in other racial or ethnic groups. METHODS We collected data on risk factors and performed scanning for coronary calcium in a population-based sample of 6722 men and women, of whom 38.6% were white, 27.6% were black, 21.9% were Hispanic, and 11.9% were Chinese. The study subjects had no clinical cardiovascular disease at entry and were followed for a median of 3.8 years. RESULTS There were 162 coronary events, of which 89 were major events (myocardial infarction or death from coronary heart disease). In comparison with participants with no coronary calcium, the adjusted risk of a coronary event was increased by a factor of 7.73 among participants with coronary calcium scores between 101 and 300 and by a factor of 9.67 among participants with scores above 300 (P<0.001 for both comparisons). Among the four racial and ethnic groups, a doubling of the calcium score increased the risk of a major coronary event by 15 to 35% and the risk of any coronary event by 18 to 39%. The areas under the receiver-operating-characteristic curves for the prediction of both major coronary events and any coronary event were higher when the calcium score was added to the standard risk factors. CONCLUSIONS The coronary calcium score is a strong predictor of incident coronary heart disease and provides predictive information beyond that provided by standard risk factors in four major racial and ethnic groups in the United States. No major differences among racial and ethnic groups in the predictive value of calcium scores were detected.
2,547 citations
TL;DR: Mgp, a mineral-binding ECM protein3 synthesized by vascular smooth-muscle cells and chondrocytes, is the first inhibitor of calcification of arteries and cartilage to be characterized in vivo.
Abstract: Calcification of the extracellular matrix (ECM) can be physiological or pathological. Physiological calcification occurs in bone when the soft ECM is converted into a rigid material capable of sustaining mechanical force; pathological calcification can occur in arteries and cartilage and other soft tissues. No molecular determinant regulating ECM calcification has yet been identified. A candidate molecule is matrix GLA protein (Mgp), a mineral-binding ECM protein synthesized by vascular smooth-muscle cells and chondrocytes, two cell types that produce an uncalcified ECM. Mice that lack Mgp develop to term but die within two months as a result of arterial calcification which leads to blood-vessel rupture. Chondrocytes that elaborate a typical cartilage matrix can be seen in the affected arteries. Mgp-deficient mice additionally exhibit inappropriate calcification of various cartilages, including the growth plate, which eventually leads to short stature, osteopenia and fractures. These results indicate that ECM calcification must be actively inhibited in soft tissues. To our knowledge, Mgp is the first inhibitor of calcification of arteries and cartilage to be characterized in vivo.
2,030 citations
TL;DR: AMC is a strong prognostic marker of all-cause and CV mortality in HD patients, independently of classical atherogenic factors and the principal effect of AMC on arterial function is increased arterial stiffness.
Abstract: Background Cross-sectional and follow-up studies on end-stage renal disease patients showed that arterial calcifications are associated with cardiovascular (CV) morbidity and are an independent predictor of all-cause and CV mortality. However, these studies did not examine the impact on prognosis according to the type of calcification, i.e. intimal vs medial. Arterial media calcification (AMC), a non-occlusive condition, affects haemodynamics differently from arterial intima calcification (AIC), which occurs in atherosclerotic plaques. The aim of this study was to investigate the prognostic value of AMC in relationship to all-cause or CV mortality for stable haemodialysis (HD) patients. Methods We included 202 such patients in the present study. At baseline, soft-tissue native radiograms of the pelvis and the thigh were analysed for the presence and type (AMC vs AIC) of arterial calcifications. All patients underwent B-mode ultrasonography of the common carotid artery to determine the presence of atherosclerotic calcified plaques, measurement of aortic pulse wave velocity and echocardiography. Results AIC was usually observed in older patients with a clinical history of atherosclerosis before starting HD treatment and typical risk factors associated with atherosclerotic disease. AMC was observed in young and middle-aged patients without conventional atherosclerotic risk factors. AMC was closely associated with the duration of HD and calcium-phosphate disorders, including the oral dose of elemental calcium prescribed as phosphate binder (CaCO(3)). Compared to patients with AIC, patients with AMC had a longer survival, but in turn their survival was significantly shorter than that of patients without calcifications. Conclusions AMC is a strong prognostic marker of all-cause and CV mortality in HD patients, independently of classical atherogenic factors. The principal effect of AMC on arterial function is increased arterial stiffness.
1,709 citations