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      Intradialytic Calcium Kinetics and Cardiovascular Disease in Chronic Hemodialysis Patients

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          Abstract

          Background/Objective: Calcium loading has been associated with cardiovascular risk in hemodialysis (HD) patients. However, it remains to be elucidated whether alterations of intradialytic calcium buffering add to the increased cardiovascular disease burden in this high-risk population. Methods: Intradialytic calcium kinetics was evaluated in a cross-sectional observational study by measuring dialysate-sided ionized calcium mass balance (iCa<sub>MB</sub>), calcium buffer capacity, and change in serum calcium levels in 40 chronic HD patients during a routine HD session. A dialysate calcium of 3.5 mEq/L was used to adequately challenge calcium buffer mechanisms. Aortic pulse wave velocity and serum osteocalcin levels were measured prior to the HD session. Presence of cardiovascular disease and diabetes was assessed. Results: The mean dialysate-sided iCa<sub>MB</sub>, extracellular fluid ionized calcium mass gain, and buffered ionized calcium mass were 469 (±154), 111 (±49), and 358 (±145) mg/HD, respectively. The mean ionized serum calcium increase (∆iCa) was 0.42 (±0.14) mEq/L per HD. The mean intradialytic calcium buffer capacity was 73 (±18)%. Multivariate regression analysis revealed significant independent association of (1) iCa<sub>MB</sub> with the dialysate-to-blood calcium gradient at HD start and (2) intradialytic calcium buffer capacity with undercarboxylated osteocalcin. The presence of coronary heart disease was associated with higher ∆iCa but not iCa<sub>MB</sub> in the multivariate model. Conclusions: In line with our proof-of-concept study, we provide clinical evidence for a rapidly accessible and exchangeable calcium pool involved in intradialytic calcium regulation and for the role of osteocalcin as a potential biomarker. Our findings argue for evaluating the prognostic potential of intradialytic calcium kinetics in prospective clinical trials.

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          Most cited references 44

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          Ambulatory Pulse Wave Velocity Is a Stronger Predictor of Cardiovascular Events and All-Cause Mortality Than Office and Ambulatory Blood Pressure in Hemodialysis Patients.

          Arterial stiffness and augmentation of aortic blood pressure (BP) measured in office are known cardiovascular risk factors in hemodialysis patients. This study examines the prognostic significance of ambulatory brachial BP, central BP, pulse wave velocity (PWV), and heart rate-adjusted augmentation index [AIx(75)] in this population. A total of 170 hemodialysis patients underwent 48-hour ambulatory monitoring with Mobil-O-Graph-NG during a standard interdialytic interval and followed-up for 28.1±11.2 months. The primary end point was a combination of all-cause death, nonfatal myocardial infarction, and nonfatal stroke. Secondary end points included: (1) all-cause mortality; (2) cardiovascular mortality; and (3) a combination of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, coronary revascularization, or hospitalization for heart failure. During follow-up, 37(21.8%) patients died and 46(27.1%) had cardiovascular events. Cumulative freedom from primary end point was similar for quartiles of predialysis-systolic BP (SBP), 48-hour peripheral-SBP, and central-SBP, but was progressively longer for increasing quartiles for 48-hour peripheral-diastolic BP and central-diastolic BP and shorter for increasing quartiles of 48-hour central pulse pressure (83.7%, 71.4%, 69.0%, 62.8% [log-rank P=0.024]), PWV (93.0%, 81.0%, 57.1%, 55.8% [log-rank P<0.001]), and AIx(75) (88.4%, 66.7%, 69.0%, 62.8% [log-rank P=0.014]). The hazard ratios for all-cause mortality, cardiovascular mortality, and the combined outcome were similar for quartiles of predialysis-SBP, 48-hour peripheral-SBP, and central-SBP, but were increasing with higher ambulatory PWV and AIx(75). In multivariate analysis, 48-hour PWV was the only vascular parameter independently associated with the primary end point (hazard ratios, 1.579; 95% confidence intervals, 1.187-2.102). Ambulatory PWV, AIx(75), and central pulse pressure are associated with increased risk of cardiovascular events and mortality, whereas office and ambulatory SBP are not. These findings further support that arterial stiffness is the prominent cardiovascular risk factor in hemodialysis.
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            Increased bone formation in osteocalcin-deficient mice.

            Vertebrates constantly remodel bone. The resorption of preexisting bone by osteoclasts and the formation of new bone by osteoblasts is strictly coordinated to maintain bone mass within defined limits. A few molecular determinants of bone remodelling that affect osteoclast activity have been characterized, but the molecular determinants of osteoblast activity are unknown. To investigate the role of osteocalcin, the most abundant osteoblast-specific non-collagenous protein, we have generated osteocalcin-deficient mice. These mice develop a phenotype marked by higher bone mass and bones of improved functional quality. Histomorphometric studies done before and after ovariectomy showed that the absence of osteocalcin leads to an increase in bone formation without impairing bone resorption. To our knowledge, this study provides the first evidence that osteocalcin is a determinant of bone formation.
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              Relationship between serum osteocalcin levels and carotid intima-media thickness in Chinese postmenopausal women.

              Serum osteocalcin has been shown to be closely related to metabolic risk factors. Therefore, the aim of our study was to evaluate the association between serum osteocalcin levels and subclinical atherosclerosis in Chinese postmenopausal women. A total of 1,319 postmenopausal women (age range, 41-78 y) without any history of cardiovascular disease or carotid plaque were analyzed. Electrochemiluminescence immunoassay was used to measure total serum osteocalcin levels. B-mode ultrasound measurement of carotid intima-media thickness (C-IMT) was used to evaluate subclinical atherosclerosis. Participants within the upper quartile of C-IMT measurements (≥0.65 mm) were classified as having increased C-IMT in the present study. C-IMT association with metabolic parameters was assessed by Spearman correlation analysis, whereas that with serum osteocalcin was assessed by multiple stepwise regression adjusted for potential confounders. The overall median (interquartile range) level of osteocalcin was 20.51 (16.71-24.98) ng/mL, and that of C-IMT was 0.60 (0.55-0.65) mm. Four hundred sixteen (31.5%) participants had increased C-IMT. Participants with increased C-IMT had significantly lower serum osteocalcin levels than those who had C-IMT lower than 0.65 mm (19.77 [16.17-24.52] vs 20.84 [16.92-25.39] ng/mL, P = 0.01). Serum osteocalcin level was significantly and negatively correlated with C-IMT (r = -0.107, P < 0.01) and was identified as an independent factor that significantly influenced C-IMT (standardized β = -0.117, P < 0.01). Serum osteocalcin level is negatively associated with subclinical atherosclerosis in Chinese postmenopausal women.
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                Author and article information

                Journal
                BPU
                Blood Purif
                10.1159/issn.0253-5068
                Blood Purification
                S. Karger AG
                0253-5068
                1421-9735
                2020
                November 2020
                24 July 2020
                : 49
                : 6
                : 723-732
                Affiliations
                aDepartment of Internal Medicine IV – Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria
                bDepartment of Cardiac, Vascular and Thoracic Surgery, Kepler University Hospital, Linz, Austria
                Author notes
                *Dr. Markus Pirklbauer, Medical University Innsbruck, Department of Internal Medicine IV - Nephrology and Hypertension, Anichstrasse 35, AT–6020 Innsbruck (Austria), markus.pirklbauer@i-med.ac.at
                Article
                508060 Blood Purif 2020;49:723–732
                10.1159/000508060
                32712610
                The Author(s). Published by S. Karger AG, Basel

                This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Tables: 6, Pages: 10
                Categories
                Research Article

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