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      Impact of post-dialysis calcium level on ex vivo rat aortic wall calcification

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          Abstract

          Objectives

          Vascular calcification is a frequent complication in chronic haemodialysis patients and is associated with adverse outcomes. Serum calcium and phosphate levels and imbalances in calcification regulators are thought to contribute to the process. In this regard, the dialysate calcium concentration is a modifiable tool for modulating the risk of vascular calcification. We explored pre- and post-dialysis phosphate and calcium concentrations in stable chronic haemodialysis patients treated by dialysis with the KDIGO-suggested 1.5 mmol/L calcium dialysate to investigate the effects on ex vivo calcification of rat aortic rings.

          Approach and results

          At the end of haemodialysis, mean serum calcium levels were increased in 88% of paired pre-/post-dialysis samples, while mean serum phosphate and parathyroid hormone levels were decreased. Rat aortic ring cultures grown at the same calcium and phosphate concentrations revealed that pre- and post-dialysis resulted in a similar degree of calcification. By contrast, haemodialysis with unchanged serum calcium resulted in a 5-fold reduction in calcium deposition.

          Conclusion

          Dialysis with the widely prescribed 1.5 mmol/L calcium dose results in persistent high serum calcification potential in a sizable proportion of patients, driven by increased post-dialysis calcium concentration. This could potentially be mitigated by individualising dialysate calcium dosage based on pre-dialysis serum calcium levels.

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          Most cited references15

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          The fallacy of the calcium-phosphorus product.

          Scattered through the practice of medicine are dogmas with little or no scientific basis. One of these is the product of the serum calcium and phosphorus concentrations, the so-called calcium-phosphorus product or Ca x P. The assumption that ectopic calcification will occur when the product of the serum calcium and phosphorus concentrations exceeds a particular threshold has become standard practice in nephrology even though there is little scientific basis. Experimental support is lacking, the chemistry underlying the use of the product is oversimplified and the concept that ectopic calcification is simply the result of supersaturation is biologically flawed. The evidence that the Ca x P is an independent risk factor for mortality and morbidity is also questionable. Although ectopic calcification can occur in many sites, this review will focus on vascular calcification, as it is the most common site and the site most likely to affect patient outcomes.
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            Reduction of Dialysate Calcium Level Reduces Progression of Coronary Artery Calcification and Improves Low Bone Turnover in Patients on Hemodialysis

            Exposure to high Ca concentrations may influence the development of low–turnover bone disease and coronary artery calcification (CAC) in patients on hemodialysis (HD). In this randomized, controlled study, we investigated the effects of lowering dialysate Ca level on progression of CAC and histologic bone abnormalities in patients on HD. Patients on HD with intact parathyroid hormone levels ≤300 pg/ml receiving dialysate containing 1.75 or 1.50 mmol/L Ca ( n =425) were randomized to the 1.25-mmol/L Ca (1.25 Ca; n =212) or the 1.75-mmol/L Ca (1.75 Ca; n =213) dialysate arm. Primary outcome was a change in CAC score measured by multislice computerized tomography; main secondary outcome was a change in bone histomorphometric parameters determined by analysis of bone biopsy specimens. CAC scores increased from 452±869 (mean±SD) in the 1.25 Ca group and 500±909 in the 1.75 Ca group ( P =0.68) at baseline to 616±1086 and 803±1412, respectively, at 24 months ( P =0.25). Progression rate was significantly lower in the 1.25 Ca group than in the 1.75 Ca group ( P =0.03). The prevalence of histologically diagnosed low bone turnover decreased from 85.0% to 41.8% in the 1.25 Ca group ( P =0.001) and did not change in the 1.75 Ca group. At 24 months, bone formation rate, trabecular thickness, and bone volume were higher in the 1.25 Ca group than in the 1.75 Ca group. Thus, lowering dialysate Ca levels slowed the progression of CAC and improved bone turnover in patients on HD with baseline intact parathyroid hormone levels ≤300 pg/ml.
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              Metabolic acidosis inhibits soft tissue calcification in uremic rats.

              Metabolic acidosis is common in patients with chronic kidney disease, which is known to affect bone metabolism. We examined the effect of metabolic acidosis on the development of vascular and other soft-tissue calcifications in uremic rats treated with calcitriol. Extraskeletal calcification was measured in vivo, in control rats and rats with a remnant kidney model of uremia with or without ammonium chloride-induced acidosis. Soft-tissue calcification was assessed histologically, by measurement of the expression of the sodium-dependent phosphate cotransporter Pit-1 and by quantification of tissue calcium and phosphorus. Calcitriol administration to uremic rats resulted in significant deposition of material positive for von Kossa stain in the aorta, stomach, and kidney, elevated aortic calcium and phosphorus, increased aortic Pit-1 expression, and high mortality. Calcitriol-treated uremic rats with acidosis did not develop aortic or soft-tissue calcification, did not increase aortic Pit-1 expression, and had significantly lower mortality. Additionally, an acidotic environment prevented calcification of vascular smooth muscle cells in vitro. Our study shows that metabolic acidosis inhibits extraskeletal calcification.
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                Author and article information

                Contributors
                Role: InvestigationRole: ValidationRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: ResourcesRole: Writing – original draftRole: Writing – review & editing
                Role: ResourcesRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                23 August 2017
                2017
                : 12
                : 8
                : e0183730
                Affiliations
                [001]Fundación Instituto de Investigación Sanitaria, Fundación Jiménez Díaz (FIIS-FJD), Madrid, Spain
                University Medical Center Utrecht, NETHERLANDS
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-1680-552X
                Article
                PONE-D-17-09692
                10.1371/journal.pone.0183730
                5568142
                28832652
                600b53af-3e16-408f-9b0f-3f3b89f7948a
                © 2017 Azpiazu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 March 2017
                : 9 August 2017
                Page count
                Figures: 3, Tables: 1, Pages: 9
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100003329, Ministerio de Economía y Competitividad;
                Award ID: SAF-2014-60699-JIN
                Award Recipient :
                Funded by: Foundation SENEFRO (Spanish Nephrology Society)
                This study was supported by grant SAF-2014-60699-JIN from the Spanish Ministerio de Economía y Competitividad (MINECO) to RVB and grant from Foundation SENEFRO (Spanish Nephrology Society). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Physical Sciences
                Chemistry
                Chemical Compounds
                Phosphates
                Medicine and Health Sciences
                Nephrology
                Medical Dialysis
                Biology and Life Sciences
                Physiology
                Physiological Processes
                Calcification
                Medicine and Health Sciences
                Physiology
                Physiological Processes
                Calcification
                Biology and Life Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Anatomy
                Body Fluids
                Blood
                Blood Plasma
                Biology and Life Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Medicine and Health Sciences
                Physiology
                Body Fluids
                Blood
                Blood Plasma
                Physical Sciences
                Materials Science
                Materials by Structure
                Crystals
                Biology and Life Sciences
                Biochemistry
                Hormones
                Parathyroid Hormone
                People and Places
                Demography
                Death Rates
                Physical sciences
                Chemistry
                Chemical compounds
                Organic compounds
                Vitamins
                Vitamin D
                Physical sciences
                Chemistry
                Organic chemistry
                Organic compounds
                Vitamins
                Vitamin D
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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