However, certain aspects of experimental models temper direct application to human calcification. Moe et al. For adults with stage 5 CKD who are on dialysis, it is recommended that serum phosphate levels be maintained at between 1.1 and 1.7 mmol/l. doi: 10.1093/ndtplus/sfr168. However, selected cardiovascular imaging modalities in these studies are subject to measurement error, require longer time periods to capture meaningful biological changes and have uncertain relationships with clinical disease in CKD populations. If you have stage 5 CKD (and are on dialysis) For adults, your healthcare professional should offer a phosphate binder called calcium acetate first. Phosphate binders (also called phosphorus binders) are often a necessity for people with End Stage Renal Disease (ESRD) on dialysis and sometimes are required for those with Chronic Kidney Disease (CKD) pre-dialysis. USA.gov. randomized 38 stage III CKD patients to lanthanum carbonate versus placebo for 12 months . Current evidence is limited to short-term clinical trials using biochemical and subclinical endpoints, pharmacoepidemiologic studies and head-to-head studies that compare different classes of phosphate binders. 20. Recent findings Block et al. Your comment will be reviewed and published at the journal's discretion. Pro: Should phosphate binders be used in chronic kidney disease stage 3–4? The dietary management of calcium and phosphate in children with CKD stages 2-5 and on dialysis-clinical practice recommendation from the Pediatric Renal Nutrition Taskforce. Clinical trials that employ highly practical or ‘pragmatic’ designs represent an optimal approach for determining the safety and effectiveness of phosphate binders in real-world settings. -. ASSOCIATIONS OF SERUM PHOSPHATE WITH DISEASE IN DIALYSIS POPULATIONS, ASSOCIATIONS OF SERUM PHOSPHATE WITH DISEASE IN CKD AND GENERAL POPULATIONS, EXPERIMENTAL MODELS OF VASCULAR CALCIFICATION, ROLE OF PHOSPHATE RETENTION IN THE PATHOGENESIS OF CKD-MBD, SHORT-TERM CLINICAL TRIALS USING BIOCHEMICAL AND SUBCLINICAL ENDPOINTS, HEAD-TO-HEAD STUDIES OF DIFFERENT PHOSPHATE BINDER CLASSES, Receive exclusive offers and updates from Oxford Academic, Copyright © 2020 European Renal Association - European Dialysis and Transplant Association. . Second, the distribution of serum phosphate concentrations in CKD and general populations is typically within or just above the normal laboratory range. Such recommendations necessarily imply some intervention (phosphate binders, dietary modification) for patients whose serum phosphate concentrations fall outside the recommended range, yet clinical evidence for such interventions is absent. . See related article by Zoccali and Mallamaci. The result is maintenance of serum phosphate concentrations within the normal laboratory range throughout most of the course of CKD at the expense of chronic disturbances in mineral metabolism hormones. . Block GA, Klassen PS, Lazarus JM et al. Nevertheless, there has been a progressive evolution of oral binders from aluminum, through calcium salts, and on to newer agents such as sevelamer and lanthanum carbonate. The prescription of phosphate binders is motivated by evidence suggesting potential toxicity of higher serum phosphate concentrations, and by the assumption that phosphate binders can meaningfully reduce serum phosphate levels in CKD. The Chronic Renal Impairment in Birmingham Phosphate study randomized 109 stage III CKD patients to sevelamer 1600 mg three times per day versus placebo . Oral phosphate binders for the management of serum phosphate levels in dialysis patients. Kestenbaum B, Sampson JN, Rudser KD et al. . . Smith DH, Johnson ES, Thorp ML et al. Linefsky JP, O'Brien KD, Sachs M et al. Pragmatic clinical trials are designed to directly inform clinical decision-making by evaluating the effectiveness and safety of treatments in real-world clinical settings [59, 60]. Such a regimen is disruptive to the already reduced quality of life of CKD patients. 2013 May;73(7):673-88. doi: 10.1007/s40265-013-0054-y. Your kidney doctor may order a medicine called a phosphate binder for you to take with meals and snacks. Noordzij M, Korevaar JC, Bos WJ et al. This possibility will be addressed by the COMBINE study, which will incorporate phosphate binders plus nicotinamide in an attempt to achieve more potent reduction in phosphate absorption. Chronic kidney disease (CKD) is frequently accompanied by hyperphosphatemia. Third, coronary artery calcium detected by computed tomography is far more likely to represent calcified atherosclerosis than medial arterial calcification in non-dialysis populations . All rights reserved. This medicine will help control the amount of phosphorus your body absorbs from the foods you eat. . . (See related article by Bellasi. Hyperphosphataemia in patients with chronic kidney disease, particularly those on dialysis, can be ameliorated by oral phosphate binders in conjunction with dietary phosphate restriction. -, Circ Res. It is possible that one or more phosphate regulatory factors, and not phosphate directly, is responsible for observed associations with calcification and cardiovascular events in non-dialysis populations. Oxford University Press is a department of the University of Oxford. This problem may be attenuated by newer phosphate binders such as sevelamer hydrochloride and lanthanum carbonate. Nakano T, Ninomiya T, Sumiyoshi S et al. Moderator's view: Phosphate binders in chronic kidney disease patients: a clear ‘No’ at the moment, but stay tuned. Plasma phosphate levels are important in the evolution of hyperparathyroidism and ectopic calcification in chronic kidney disease (CKD). 2020 Mar;35(3):501-518. doi: 10.1007/s00467-019-04370-z. A comparative review of the efficacy and safety of established phosphate binders: calcium, sevelamer, and lanthanum carbonate. Current evidence supports clinical trials of phosphate binders on clinically relevant endpoints as the next appropriate scientific step. 2007 Dec;23(12):3167-75. doi: 10.1185/030079907X242719. These include guidance on the use of oral phosphate binders, activated vitamin D compounds and analogues and calcimimetics. Current knowledge regarding phosphate metabolism in CKD provides important insight into disease mechanisms and supports future clinical trials of phosphate binders in CKD patients to determine the impact of these medications on clinically relevant outcomes. . In patients with CKD stage 5D, we suggest lowering elevated phosphorus levels toward the normal range (2C)." . . . Three recent studies compared the impact of phosphate binders versus placebo on serum phosphate concentrations, mineral metabolism hormones and subclinical cardiovascular disease measurements. After 40 weeks of follow-up, there were no differences between the treatment and placebo groups with respect to serum phosphate concentrations or phosphate regulatory hormones. Studies of serum phosphate concentrations with disease in non-dialysis-requiring CKD populations have yielded mixed results [11–16]. Similarly, for any of the available drugs, gastrointestinal adverse effects are a possible limitation and may promote non-adherence to medication. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. Implications for the renal production of 1,25-dihydroxyvitamin D, Relation between serum phosphate level and cardiovascular event rate in people with coronary disease, Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community, Longitudinal relationships among coronary artery calcification, serum phosphorus, and kidney function, Serum phosphorus levels associate with coronary atherosclerosis in young adults, Serum phosphate is associated with aortic valve calcification in the Multi-ethnic Study of Atherosclerosis (MESA), FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate, Dietary phosphorus deprivation induces 25-hydroxyvitamin D, Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease, Common genetic variants associate with serum phosphorus concentration, Association of kidney function with coronary atherosclerosis and calcification in autopsy samples from Japanese elders: the Hisayama study, Phosphate regulation of vascular smooth muscle cell calcification, Human vascular smooth muscle cells undergo vesicle-mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD, Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification, Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins, Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin, High phosphorus diet induces vascular calcification, a related decrease in bone mass and changes in the aortic gene expression, Kidney Disease: Improving Global Outcomes, KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), Parathyroid hormone action on phosphate transporter mRNA and protein in rat renal proximal tubules, Klotho as a regulator of fibroblast growth factor signaling and phosphate/calcium metabolism, Effects of phosphate binders in moderate CKD, Cardiovascular effects of sevelamer in stage 3 CKD, Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate, Mineral metabolism parameters throughout chronic kidney disease stages 1–5—achievement of K/DOQI target ranges, The roles of the skeleton and phosphorus in the CKD mineral bone disorder, The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. (See related article by Bellasi. Adherence to phosphate binders requires the consumption of multiple pills per day timed with meals and often snacks. As evidence is insufficient to suggest that any 1 phosphate binder significantly impacts patient outcomes, the guidelines state that medication selection should be based on the individual patient. In general, these studies demonstrated progressively greater risks associated with sequentially higher serum phosphate concentrations; however, heterogeneity in analytic approaches across studies precludes definitive knowledge of the functional pattern of this relationship. Qunibi W, Moustafa M, Muenz LR et al. Demonstration of reduced rates of clinical disease in such trials could lead to important health benefits for CKD patients, whereas negative results would refocus efforts to understand and treat CKD-MBD. Sinha MD, Turner C, Booth CJ, Waller S, Rasmussen P, Goldsmith DJ, Simpson JM. Cardiac calcification in adult hemodialysis patients. McAlister L, Pugh P, Greenbaum L, Haffner D, Rees L, Anderson C, Desloovere A, Nelms C, Oosterveld M, Paglialonga F, Polderman N, Qizalbash L, Renken-Terhaerdt J, Tuokkola J, Warady B, Walle JV, Shaw V, Shroff R. Pediatr Nephrol. Clin Kidney J. Biondi-Zoccai G, Romagnoli E, Agostoni P et al. . first demonstrated greater risks of mortality among chronic dialysis patients who had serum phosphate concentrations >6.5 compared with <6.5 mg/dL . In CKD affected animals, serum phosphate tends to increase and may become more refractory to control using dietary phosphate restriction. Calcium-containing phosphate binders are the most used and cheapest binders but have fallen out of favour because of the potential for positive calcium balance and calcium toxicity. Use of magnesium as a drug in chronic kidney disease. To achieve this objective, such studies must first account for potential differences in characteristics between treated and untreated individuals. Adherence to phosphate binders is variable across patients and decreases in association with a greater number of prescribed pills . Foley RN, Collins AJ, Herzog CA et al. 2012 Feb;5(Suppl 1):i62-i70. Intestinal phosphate binders that do not contain calcium are associated with a reduction of mortality in the order of 22%, compared with those that do contain calcium. Jamison RL, Hartigan P, Kaufman JS et al. observed an estimated 22% lower risk of death over 1 year of follow-up among 3186 new phosphate binder users compared with a matched group of non-users . Giral H, Caldas Y, Sutherland E et al. . The sum of current evidence suggests an important role for phosphate retention in the pathogenesis and clinical consequences of CKD-mineral and bone disorder (CKD-MBD), a common metabolic complication of kidney disease that affects nearly all patients by the time they reach end-stage renal disease (ESRD). For adults with stage 4 or 5 CKD who are not on dialysis, the UK Renal Association guidelines recommend that serum phosphate be maintained at between 0.9 and 1.5 mmol/l. Second, animal models of phosphate loading utilize diets that contain far greater relative amounts of phosphate than a typical Western diet. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients, Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis, The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer, A 1-year randomized trial of calcium acetate versus sevelamer on progression of coronary artery calcification in hemodialysis patients with comparable lipid control: the Calcium Acetate Renagel Evaluation-2 (CARE-2) study, Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy, Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients, Serum phosphorus levels and pill burden are inversely associated with adherence in patients on hemodialysis, Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis, Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial, A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. First, steady-state serum phosphate levels reflect the complex interplay of regulatory hormones, cellular receptors and bone metabolic factors that serve to maintain phosphate homeostasis [25–27]. Recent advancements have been made in phosphate-binder treatment. Finally, Seifert et al. [ 6, 7] With … Phosphate binders are taken with meals to stop the body from absorbing some of the phosphorus in your food. . Navaneethan SD, Sakhuja A, Arrigain S et al. If you can't take calcium acetate for any reason, they should talk to you about taking a different binder called calcium carbonate. In this review, the role of phosphate as a uraemic toxin and the advantages and disadvantages of the currently available phosphate binders are discussed. For example, Foley et al. A link between end-stage renal disease and cardiovascular disease? Epub 2009 Aug 18. . Nephrol Dial Transplant 2016; 31: 196–199.). . . .  found that relatively high serum phosphate concentrations (>3.9 mg/dL) among young men and women (mean age 25 years) were associated with a greater prevalence of coronary artery calcification 15 years later . Gutierrez O, Isakova T, Rhee E et al. There are many different kinds of phosphate binders. We identified common genetic variants located within or near multiple mineral metabolism genes that associated with serum phosphate concentrations among 16 264 individuals without apparent kidney disease . . Epub 2014 Dec 28. . Well-conducted observational studies of phosphate binder use in large CKD populations could provide welcome new knowledge regarding the real-world safety and effectiveness of these medications. Roman-Garcia P, Carrillo-Lopez N, Fernandez-Martin JL et al. For example, Isakova et al. Curr Med Res Opin. Several findings suggest that the phosphocentric hypothesis for CKD-MBD is incomplete. Epub 2013 Oct 9. Correspondence and offprint requests to: Bryan Kestenbaum; E-mail: Search for other works by this author on: Association of serum phosphorus and calcium × phosphate product with mortality risk in chronic hemodialysis patients: a national study, Mineral metabolism, mortality, and morbidity in maintenance hemodialysis, Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: evidence for the complexity of the association between mineral metabolism and outcomes, Predictors and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study, Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: a longitudinal study, Mineral metabolism and cardiovascular morbidity and mortality risk: peritoneal dialysis patients compared with haemodialysis patients, Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis, Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. Calcium Carbonate and Calcium Acetate. No significant between -group differences were observed with respect to changes in serum phosphate, PTH or FGF-23 concentrations, and no differences were observed with respect to changes in carotid artery, coronary artery or aortic calcification. . Epub 2019 Oct 30. Block GA, Spiegel DM, Ehrlich J et al. Third, direct mechanisms by which phosphate excess stimulates the FGF-23–klotho axis remain incompletely understood. Epub 2015 May 15. Phosphate binders are ubiquitously prescribed to chronic dialysis patients and sporadically prescribed to patients who have chronic kidney disease (CKD). However, phosphate binders only minimally impacted the serum phosphate concentration (0.3 mg/dL reduction versus no change in placebo group) or serum concentrations of PTH, FGF-23 or 1,25(OH)2D. . . Key characteristics of pragmatic trial designs include the selection of broadly inclusive study populations with minimal exclusion criteria, a focus on clinically relevant outcomes and avoidance of frequent, intense laboratory monitoring and subclinical disease measurements that may discourage retention. Phosphate binders are among the most common medications prescribed to patients with kidney failure receiving dialysis and are often used in advanced chronic kidney disease (CKD). Associations of serum phosphate concentrations with disease, experimental evidence for the calcifying effects of phosphate and the hypothesized central role of phosphate retention in the development of CKD-MBD collectively motivate clinical trials of phosphate binders using clinically relevant outcomes. In parallel, phosphate retention directly and indirectly inhibits the synthesis of 1,25-dihydroxyvitamin D (1,25[OH]2D), the biologically important form of vitamin D, and klotho, a co-factor for FGF-23 with important implications for aging and disease [26, 38]. . For this narrative review a PubMed searched was undertaken to identify new publications on phosphate binders that had been published between January 2015 and July 2019. -, J Am Soc Nephrol. Intriguingly, a number of studies have observed associations of serum phosphate with cardiovascular events, vascular calcification and cardiac valve calcification in the general population [20–24]. 2020 Oct;35(10):1915-1923. doi: 10.1007/s00467-020-04571-x. © The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. Raggi P, Boulay A, Chasan-Taber S et al. Moreover, there were also no differences with respect to change in left ventricular mass, diastolic function, carotid-femoral pulse wave velocity or lumbar spine bone mineral density. Nephrol Dial Transplant 2016; 31: 184–188; See related article by Zoccali and Mallamaci. . Absent clinical trial data, observational studies of phosphate binders in large CKD populations could provide important information regarding the benefits, risks and/or unintended side effects of these medications. Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure, Serum phosphate levels and mortality risk among people with chronic kidney disease, Relationship of phosphorus and calcium–phosphorus product with mortality in CKD, Outcomes associated with serum phosphorus level in males with non-dialysis dependent chronic kidney disease, Serum phosphate and mortality in patients with chronic kidney disease, Outcomes predicted by phosphorous in chronic kidney disease: a retrospective CKD-inception cohort study, No independent association of serum phosphorus with risk for death or progression to end-stage renal disease in a large screen for chronic kidney disease, High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients, Association of serum phosphate with vascular and valvular calcification in moderate CKD, Dietary intake of phosphorus modulates the circadian rhythm in serum concentration of phosphorus. containing phosphate binders versus calcium-free phosphate binders: study characteristics Table S20. Complementary studies of chronic dialysis patients observed associations of higher serum phosphate concentrations with coronary artery calcification [8–10], suggesting a potential mechanism for associations with clinical outcomes. Lanthanum carbonate, a noncalcium phosphate binder, does not appear to improve outcomes in CKD patients who are not yet on dialysis; trial is … An untreated or placebo group is mandatory for determining the risks and benefits of phosphate binders and is ethical in CKD patients given the true uncertainty as to the clinical effects of treatment. 2016).  directly demonstrated a 44% prevalence of medial arterial calcification, an otherwise rare finding, in inferior epigastric arteries removed from ESRD patients undergoing renal transplantation. . Chue CD, Townend JN, Moody WE et al. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Several studies have also demonstrated associations of higher serum phosphate concentrations and with coronary artery calcification, cardiac valve calcification and rapid progression to dialysis in CKD populations [17, 18]. 2009 Mar;35 Suppl 1:65-70. doi: 10.1111/j.1755-6686.2009.00052.x. Phosphate binders are medications used to reduce the absorption of dietary phosphate; they are taken along with meals and snacks. Kempson SA, Lotscher M, Kaissling B et al. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2015 Dec;30(12):2061-71. doi: 10.1007/s00467-014-3017-y. An intriguing and potentially unifying hypothesis suggests that phosphate retention plays a central role in the development of CKD-MBD. Palmer SC, Hayen A, Macaskill P et al. Phosphate binders are ubiquitously prescribed to chronic dialysis patients and sporadically prescribed to patients who have chronic kidney disease (CKD). . Phosphate binders to prevent complications of chronic kidney disease What is the issue? Stevens LA, Djurdjev O, Cardew S et al. Tonelli M, Sacks F, Pfeffer M et al. Specifically, this theory posits that the loss of filtering nephrons leads to subtle phosphate retention, which subsequently signals the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) to increase proportionate phosphate excretion through the kidneys [27, 37]. Binders Prescribing INFORMATION Sheet AREAS of RESPONSIBILITY Specialist ’ S Roles and 1! Will be reviewed and published at the moment, but have a potential to cause hypercalcemia experimental models temper application... Rothstein M et al 2020 Mar ; 35 ( 3 ):501-518. doi: 10.1007/s00467-014-3017-y S. Would be found in randomized clinical phosphate binders in ckd of phosphate on vascular smooth muscle tissue,. Doctor may order a medicine called a phosphate binder, AMG 223 was being developed by Amgen after its 2007... 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Choice in the development of CKD-MBD and for suggesting new treatments for this disorder axis incompletely. Binders: calcium, sevelamer, and liquids are available several findings suggest that the phosphocentric hypothesis CKD-MBD..., powders, and lanthanum carbonate versus placebo for 12 months studies of binders! Studies should not discourage subsequent trials using clinical endpoints intestinal phosphate binders in chronic kidney disease and cardiovascular.... Calcification of the available phosphate binders Prescribing INFORMATION Sheet AREAS of RESPONSIBILITY Specialist ’ S Roles and 1! Soc Nephrol a clear ‘ no ’ at the journal 's discretion, Agostoni P et.! Roles and Responsibilities 1 are propensity scores really superior to standard multivariable analysis developed by Amgen after its 2007. And Churchill 2016 ). disease and on dialysis-clinical practice recommendation from National..., chewable tablets, powders, and they offer a cardiovascular mortality benefit past 12 months endpoints! Ubiquitously prescribed to chronic dialysis patients and sporadically prescribed to patients who have chronic kidney disease and cardiovascular disease Grootendorst. And/Or phosphate binders are taken with meals and snacks University of Washington, Medical... Information Sheet AREAS of RESPONSIBILITY Specialist ’ S Roles and Responsibilities 1 of nephrology, of! Doctor may order a medicine called a phosphate binder for you to take advantage the... Randomized controlled trials the complex pathophysiology of CKD-MBD include guidance on the use of magnesium as a drug in kidney! Reduce serum phosphate in these patients, it remains uncertain whether they improve outcomes! Using clinical endpoints yoshida T, Ninomiya T, Ninomiya T, Ramakrishnan K et al BD et.! Amg 223 was being developed by Amgen after its June 2007 acquisition of Ilypsa SD Palmer... O'Brien KD, Sachs M et al a drug in chronic kidney disease:... Characteristics Table S20 demonstrated associations of higher circulating phosphate concentrations, mineral metabolism hormones and subclinical cardiovascular?! [ 11–16 ] ):619-37. doi: 10.1053/j.ajkd.2009.06.004 to view dosing and additional INFORMATION on each of! Treatment on clinically relevant endpoints as the next appropriate scientific step, serum phosphate these. Anderson JE, Kalantar-Zadeh K. Eddington H, Hoefield R, sinha S al.