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      Strategies for Phosphate Control in Patients With CKD

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          Abstract

          Hyperphosphatemia is a common complication in patients with chronic kidney disease (CKD), particularly in those requiring renal replacement therapy. The importance of controlling serum phosphate has long been recognized based on observational epidemiological studies that linked increased phosphate levels to adverse outcomes and higher mortality risk. Experimental data further supported the role of phosphate in the development of bone and cardiovascular diseases. Recent advances in our understanding of the mechanisms involved in phosphate homeostasis have made it clear that the serum phosphate concentration depends on a complex interplay among the kidneys, intestinal tract, and bone, and is tightly regulated by a complex endocrine system. Moreover, the source of dietary phosphate and the use of phosphate-based additives in industrialized foods are additional factors that are of particular importance in CKD. Not surprisingly, the management of hyperphosphatemia is difficult, and, despite a multifaceted approach, it remains unsuccessful in many patients. An additional issue is the fact that the supposedly beneficial effect of phosphate lowering on hard clinical outcomes in interventional trials is a matter of ongoing debate. In this review, we discuss currently available treatment approaches for controlling hyperphosphatemia, including dietary phosphate restriction, reduction of intestinal phosphate absorption, phosphate removal by dialysis, and management of renal osteodystrophy, with particular focus on practical challenges and limitations, and on potential benefits and harms.

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          Most cited references113

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          Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.

          Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100 RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.
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            Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

            Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism. Copyright 2004 Massachusetts Medical Society
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              Relation between serum phosphate level and cardiovascular event rate in people with coronary disease.

              Higher levels of serum phosphate are associated with adverse cardiovascular outcomes, especially in the setting of overt hyperphosphatemia. Given the biological importance of phosphorus, it is plausible that higher levels of serum phosphate within the normal range may also be associated with adverse outcomes. We performed a post hoc analysis of data from the Cholesterol And Recurrent Events (CARE) study. Baseline serum phosphate levels were measured in 4127 fasting participants who were randomized to receive pravastatin 40 mg daily or placebo and followed up for a median of 59.7 months. We used Cox proportional-hazards models to examine the association between serum phosphate and adverse clinical outcomes after adjustment for potential confounders. During nearly 60 months of follow-up, 375 participants died. A significant association was noted between baseline serum phosphate level and the age-, race-, and sex-adjusted risk of all-cause death (hazard ratio per 1 mg/dL, 1.27; 95% confidence interval, 1.02 to 1.58). After categorization based on baseline phosphate level ( or =4 mg/dL) and further adjustment, a graded independent relation between phosphate and death was observed (P for trend=0.03). For instance, participants with serum phosphate > or =3.5 mg/dL had an adjusted hazard ratio for death of 1.27 (95% confidence interval, 1.02 to 1.59) compared with those with serum phosphate of <3.5 mg/dL. Higher levels of serum phosphate were also associated with increased risk of new heart failure, myocardial infarction, and the composite of coronary death or nonfatal myocardial infarction, but not the risk of stroke. We found a graded independent relation between higher levels of serum phosphate and the risk of death and cardiovascular events in people with prior myocardial infarction, most of whom had serum phosphate levels within the normal range. Given the ready availability and low cost of serum phosphate assays, this finding may prove clinically useful.
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                Author and article information

                Contributors
                Journal
                Kidney Int Rep
                Kidney Int Rep
                Kidney International Reports
                Elsevier
                2468-0249
                20 June 2019
                August 2019
                20 June 2019
                : 4
                : 8
                : 1043-1056
                Affiliations
                [1 ]Service of Nephrology, Department of Internal Medicine, Federal University of Paraná, Curitiba, Paraná, Brazil
                [2 ]Institut National de la Santé et de la Recherche Médicale U-1018, Team 5, Centre de Recherche en Epidémiologie et Santé des Populations, Versailles Saint-Quentin-en-Yvelines University (Paris-Ile-de-France-Ouest University), Paris-Sud University and Paris Saclay University, Villejuif, France
                [3 ]Division of Nephrology, Ambroise Paré Hospital, Assistance Publique-Hôpitaux de Paris, Boulogne Billancourt/Paris, France
                Author notes
                [] Correspondence: Fellype C. Barreto. Serviço de Nefrologia, Hospital de Clínicas – Universidade Federal do Paraná, Rua General Carneiro, 181; 12 o. andar, 80060-900, Curitiba, Brasil. fellype.barreto@ 123456ufpr.br
                Article
                S2468-0249(19)31360-9
                10.1016/j.ekir.2019.06.002
                6698320
                31440695
                196f9ca6-2b20-45b2-9088-2135f9d19bec
                © 2019 International Society of Nephrology. Published by Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 11 April 2019
                : 27 May 2019
                : 3 June 2019
                Categories
                Review

                chronic kidney disease,dialysis,diet,hyperphosphatemia,phosphate binders,renal osteodysthrophy

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