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      Effect of nutritional calcium and phosphate loading on calciprotein particle kinetics in adults with normal and impaired kidney function

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          Abstract

          Plasma approaches metastability with respect to its calcium and phosphate content, with only minor perturbations in ionic activity needed to sustain crystal growth once nucleated. Physiologically, calcium and phosphate are intermittently absorbed from the diet each day, yet plasma concentrations of these ions deviate minimally post-prandially. This implies the existence of a blood-borne mineral buffer system to sequester calcium phosphates and minimise the risk of deposition in the soft tissues. Calciprotein particles (CPP), endogenous mineral-protein colloids containing the plasma protein fetuin-A, may fulfill this function but definitive evidence linking dietary mineral loading with their formation is lacking. Here we demonstrate that CPP are formed as a normal physiological response to feeding in healthy adults and that this occurs despite minimal change in conventional serum mineral markers. Further, in individuals with Chronic Kidney Disease (CKD), in whom mineral handling is impaired, we show that both fasting and post-prandial levels of CPP precursors are markedly augmented and strongly inversely correlated with kidney function. This study highlights the important, but often neglected, contribution of colloidal biochemistry to mineral homeostasis and provides novel insight into the dysregulation of mineral metabolism in CKD.

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          Estimation of Relationships for Limited Dependent Variables

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            The serum protein alpha 2-Heremans-Schmid glycoprotein/fetuin-A is a systemically acting inhibitor of ectopic calcification.

            Ectopic calcification is a frequent complication of many degenerative diseases. Here we identify the serum protein alpha2-Heremans-Schmid glycoprotein (Ahsg, also known as fetuin-A) as an important inhibitor of ectopic calcification acting on the systemic level. Ahsg-deficient mice are phenotypically normal, but develop severe calcification of various organs on a mineral and vitamin D-rich diet and on a normal diet when the deficiency is combined with a DBA/2 genetic background. This phenotype is not associated with apparent changes in calcium and phosphate homeostasis, but with a decreased inhibitory activity of the Ahsg-deficient extracellular fluid on mineral formation. The same underlying principle may contribute to many calcifying disorders including calciphylaxis, a syndrome of severe systemic calcification in patients with chronic renal failure. Taken together, our data demonstrate a critical role of Ahsg as an inhibitor of unwanted mineralization and provide a novel therapeutic concept to prevent ectopic calcification accompanying various diseases.
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              Coronary Artery Calcification and Risk of Cardiovascular Disease and Death Among Patients With Chronic Kidney Disease

              Question Does coronary artery calcification (CAC) predict cardiovascular disease risk among patients with chronic kidney disease (CKD)? Findings In this prospective cohort study, 1 SD log higher in CAC score was significantly associated with a 40% higher risk of cardiovascular disease, a 44% higher risk of myocardial infarction, and a 39% higher risk of heart failure after adjusting for important risk factors. Inclusion of CAC score led to a significant increase in the C statistic for predicting cardiovascular disease over use of established and novel risk factors among patients with CKD. Meaning Use of the CAC score improves risk prediction for cardiovascular disease, myocardial infarction, and heart failure over use of established and novel risk factors among patients with CKD. Importance Coronary artery calcification (CAC) is highly prevalent in dialysis-naive patients with chronic kidney disease (CKD). However, there are sparse data on the association of CAC with subsequent risk of cardiovascular disease and all-cause mortality in this population. Objective To study the prospective association of CAC with risk of cardiovascular disease and all-cause mortality among dialysis-naive patients with CKD. Design, Setting, and Participants The prospective Chronic Renal Insufficiency Cohort study recruited adults with an estimated glomerular filtration rate of 20 to 70 mL/min/1.73 m 2 from 7 clinical centers in the United States. There were 1541 participants without cardiovascular disease at baseline who had CAC scores. Exposures Coronary artery calcification was assessed using electron-beam or multidetector computed tomography. Main Outcomes and Measures Incidence of cardiovascular disease (including myocardial infarction, heart failure, and stroke) and all-cause mortality were reported every 6 months and confirmed by medical record adjudication. Results During an average follow-up of 5.9 years in 1541 participants aged 21 to 74 years, there were 188 cardiovascular disease events (60 cases of myocardial infarction, 120 heart failures, and 27 strokes; patients may have had >1 event) and 137 all-cause deaths. In Cox proportional hazards models adjusted for age, sex, race, clinical site, education level, physical activity, total cholesterol level, high-density lipoprotein cholesterol level, systolic blood pressure, use of antihypertensive treatment, current cigarette smoking, diabetes status, body mass index, C-reactive protein level, hemoglobin A 1c level, phosphorus level, troponin T level, log N-terminal pro–B-type natriuretic peptide level, fibroblast growth factor 23 level, estimated glomerular filtration rate, and proteinuria, the hazard ratios associated with per 1 SD log of CAC were 1.40 (95% CI, 1.16-1.69; P  < .001) for cardiovascular disease, 1.44 (95% CI, 1.02-2.02; P  = .04) for myocardial infarction, 1.39 (95% CI, 1.10-1.76; P  = .006) for heart failure, and 1.19 (95% CI, 0.94-1.51; P  = .15) for all-cause mortality. In addition, inclusion of CAC score led to an increase in the C statistic of 0.02 (95% CI, 0-0.09; P  < .001) for predicting cardiovascular disease over use of all the above-mentioned established and novel cardiovascular disease risk factors. Conclusions and Relevance Coronary artery calcification is independently and significantly related to the risks of cardiovascular disease, myocardial infarction, and heart failure in patients with CKD. In addition, CAC improves risk prediction for cardiovascular disease, myocardial infarction, and heart failure over use of established and novel cardiovascular disease risk factors among patients with CKD; however, the changes in the C statistic are small. This cohort study assesses the prospective association of coronary artery calcification with risk of cardiovascular disease and all-cause mortality among dialysis-naive adult patients with chronic kidney disease from 7 US clinical centers.
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                Author and article information

                Contributors
                mark.tiong@mh.org.au
                edward.smith@mh.org.au
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                5 May 2022
                5 May 2022
                2022
                : 12
                : 7358
                Affiliations
                [1 ]GRID grid.416153.4, ISNI 0000 0004 0624 1200, Department of Nephrology, , The Royal Melbourne Hospital, ; Grattan Street, Parkville, VIC 3052 Australia
                [2 ]GRID grid.1008.9, ISNI 0000 0001 2179 088X, Department of Medicine (RMH), , University of Melbourne, ; Parkville, Australia
                [3 ]Calciscon AG, Biel, Switzerland
                [4 ]GRID grid.415941.c, ISNI 0000 0004 0509 4333, Lindenhofspital Bern, ; Bern, Switzerland
                [5 ]GRID grid.9970.7, ISNI 0000 0001 1941 5140, Department of Physiology and Pathophysiology, , Johannes Kepler University, ; Linz, Austria
                Article
                11065
                10.1038/s41598-022-11065-3
                9072391
                35513558
                b0de5430-fd06-4df0-8b5f-648d7a96eead
                © The Author(s) 2022

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 23 February 2022
                : 31 March 2022
                Funding
                Funded by: Royal Melbourne Hospital Research Funding Program Grant in Aid
                Award ID: Grant number 2018.036
                Categories
                Article
                Custom metadata
                © The Author(s) 2022

                Uncategorized
                chronic kidney disease,phosphorus metabolism disorders
                Uncategorized
                chronic kidney disease, phosphorus metabolism disorders

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