Effect of Paricalcitol on Left Ventricular Mass and Function in CKD—The OPERA Trial

Wang, Angela Yee-Moon; Fang, Fang; Chan, John; Wen, Yue Yi; Shang, Qing; Chan, Iris Hiu Shuen; Lo, Gladys; Lai, Kar Neng; Lo, Wai Kei; Lam, Christopher Wai Kei; Yu, Cheuk Man

doi:10.1681/asn.2013010103

Cited by 222 publications

(204 citation statements)

References 50 publications

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“…96 Small clinical studies in hemodialysis patients have demonstrated a role of vitamin D agonists in reducing left ventricular wall thickness and improving diastolic function parameters, although larger randomized trials in CKD have not. 97,98 These larger trials have suggested that activated forms of vitamin D reduce left atrial size and potentially episodes of heart failure, 97 which are interesting findings that warrant confirmation.…”

Section: Vitamin Dmentioning

confidence: 98%

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

2016

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Abstract-Patients with chronic kidney disease and end-stage renal disease are at 5-to 10-fold higher risk for developing cardiovascular disease (CVD) than age-matched controls. Clinically, CVD in this population manifests as coronary artery disease, arrhythmias, stroke, or congestive heart failure. Beyond the traditional risk factors (eg, diabetes mellitus and hypertension), uremia-specific factors that arise from accumulating toxins also contribute to the pathogenesis of CVD.In this review, we summarize the literature on the epidemiology of both traditional and uremia-related CVD and focus on postulated mechanisms of the latter. P. Jousset, MD, 1 describing common causes of death among patients with Bright disease C hronic kidney disease (CKD) is an increasingly urgent public health concern that is projected to grow worldwide at a rate of 8% annually, with the fastest growth expected in developing nations.2,3 It has long been known that patients with kidney failure are predisposed to cardiovascular disease (CVD) that manifests clinically in various forms, including coronary artery disease, atrial or ventricular arrhythmias, myocardial infarction, stroke, or congestive heart failure. Over the last 30 years, it has become clear that the risk of CVD increases early in the course of progressive kidney disease and that the epidemiology, pathophysiology, prevention, and treatment of CVD and CKD are closely related and interdependent. 4 In this review, we initially describe the epidemiology of CVD among people with CKD, noting the limitations of available research. We then discuss common risk factors for CVD (traditional and nontraditional) and key shared aspects of its pathophysiology with CKD. Next we describe emerging diagnostic tools and novel therapies that may help to delay or prevent end-stage renal disease (ESRD) and to curtail the escalating burden of cardiorenal disease. In the final section, we discuss the health services and health policy challenges that CKD and its inextricably linked CVD morbidities pose worldwide, particularly for low-and middle-income countries (LMICs). Phenotypes and Epidemiology of CVD in Patients With CKDPatients with CKD and some forms of CVD share a number of risk factors and underlying pathophysiological mechanisms that, by virtue of their similarities, offer opportunities to improve their management. The epidemiology of 4 of the commonest clinical phenotypes of CVD associated with CKD is discussed below. Coronary Artery DiseaseCoronary artery disease (CAD) is a leading cause of death among people with advanced CKD. Clinical syndromes compatible with CAD (including angina and myocardial infarction) are exceedingly common in patients with nondialysis-dependent CKD, and the incidence of myocardial

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Section: Vitamin Dmentioning

confidence: 98%

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

2016

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“…The long-term consequence of this increase with respect to cardiovascular risk has not been explored, but strong evidence relating higher FGF23 with worse outcome possibly cautions against excessive active vitamin D use. Indeed, although observational studies of hemodialysis patients suggest a survival advantage with active vitamin D therapy (111) (albeit attenuated at high doses) (112) and studies in non-CKD animal models attest to the protective properties of vitamin D receptor agonists (VDRAs) on cardiac hypertrophy (113,114), recent randomized controlled trials in CKD patients have failed to show any improvement in left ventricular structure or function with paracalcitol versus placebo (115,116). Thus, in the setting of CKD, the benefit of VDRAs on the heart seems uncertain.…”

Section: Vitamin Dmentioning

confidence: 99%

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Smith

2014

Clinical Journal of the American Society of Nephrology

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The emergence of fibroblast growth factor 23 as a potentially modifiable risk factor in CKD has led to growing interest in its measurement as a tool to assess patient risk and target therapy. This review discusses the analytical and clinical challenges faced in translating fibroblast growth factor 23 testing into routine practice. As for other bone mineral markers, agreement between commercial fibroblast growth factor 23 assays is poor, mainly because of differences in calibration, but also, these differences reflect the variable detection of hormone fragments. Direct comparison of readout from different assays is consequently limited and likely hampers setting uniform fibroblast growth factor 23-directed targets. Efforts are needed to standardize assay output to enhance clinical use. Fibroblast growth factor 23 is robustly associated with cardiovascular and renal outcomes in patients with CKD and adds value to risk assessments based on conventional risk factors. Compared with most other mineral markers, fibroblast growth factor 23 shows better intraindividual temporal stability, with minimal diurnal and week-to-week variability, but substantial interindividual variation, maximizing discriminative power for risk stratification. Conventional therapeutic interventions for the CKD-mineral bone disorder, such as dietary phosphate restriction and use of oral phosphate binders or calcimimetics, are associated with variable efficacy at modulating circulating fibroblast growth factor 23 concentrations, like they are for other mineral metabolites. Dual therapy with dietary phosphate restriction and noncalcium-based binder use achieves the most consistent fibroblast growth factor 23-lowering effect and seems best monitored using an intact assay. Additional studies are needed to evaluate whether strategies aimed at reducing levels or antagonizing its action have beneficial effects on clinical outcomes in CKD patients. Moreover, a better understanding of the mechanisms driving fibroblast growth factor 23 elevations in CKD is needed to inform the use of therapeutic interventions targeting fibroblast growth factor 23 excess. This evidence must be forthcoming to support the use of fibroblast growth factor 23 measurement and fibroblast growth factor 23-directed therapy in the clinic.

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“…Treatment with active vitamin D has been considered a key therapy for cardiovascular events in CKD,8 but controversy remains as beneficial effects on cardiac abnormalities as observed in animal models9 could not be confirmed in clinical trials 10, 11. Moreover, while in vitro studies suggested a protective role for vitamin D in ameliorating damaged endothelium,12, 13 experimental in vivo CKD studies have primarily focused on the prevention of vascular calcification of the medial layer and heart failure9, 14, 15 but paid little attention to structural endothelial damage.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

Cuenca

Ferrantelli

Meinster

et al. 2018

JAHA

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BackgroundDysfunctional endothelium may contribute to the development of cardiovascular complications in chronic kidney disease (CKD). Supplementation with active vitamin D has been proposed to have vasoprotective potential in CKD, not only by direct effects on the endothelium but also by an increment of α‐Klotho. Here, we explored the capacity of the active vitamin D analogue paricalcitol to protect against uremia‐induced endothelial damage and the extent to which this was dependent on increased α‐Klotho concentrations.Methods and ResultsIn a combined rat model of CKD with vitamin D deficiency, renal failure induced vascular permeability and endothelial‐gap formation in thoracic aorta irrespective of baseline vitamin D, and this was attenuated by paricalcitol. Downregulation of renal and serum α‐Klotho was found in the CKD model, which was not restored by paricalcitol. By measuring the real‐time changes of the human endothelial barrier function, we found that paricalcitol effectively improved the recovery of endothelial integrity following the addition of the pro‐permeability factor thrombin and the induction of a wound. Furthermore, immunofluorescence staining revealed that paricalcitol promoted vascular endothelial‐cadherin–based cell‐cell junctions and diminished F‐actin stress fiber organization, preventing the formation of endothelial intracellular gaps.ConclusionsOur results demonstrate that paricalcitol attenuates the CKD‐induced endothelial damage in the thoracic aorta and directly mediates endothelial stability in vitro by enforcing cell‐cell interactions.

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Effect of Paricalcitol on Left Ventricular Mass and Function in CKD—The OPERA Trial

Cited by 222 publications

References 50 publications

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

Epidemiology and Mechanisms of Uremia-Related Cardiovascular Disease

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Vitamin D Attenuates Endothelial Dysfunction in Uremic Rats and Maintains Human Endothelial Stability

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