phosphate binders in ckd

Current evidence does not support the general prescription of phosphate binders to CKD patients. 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. has received honoraria from Keryx Biopharmaceuticals over the past 12 months. 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. . Lanthanum carbonate, a noncalcium phosphate binder, does not appear to improve outcomes in CKD patients who are not yet on dialysis; trial is … Animal models provide further evidence linking phosphate overload with medial arterial calcification in kidney failure. High serum phosphate usually requires dietary measures, adequate dialysis prescription and/or phosphate binders. Therefore, at present, the prolonged use of aluminium-containing phosphate binders in patients with CKD is strongly discouraged, in accordance with recent clinical practice guidelines. On the other hand, Mehrotra et al. Noordzij M, Korevaar JC, Bos WJ et al. CLINCAL INFORMATION See Phosphate Binders Prescribing Information Sheet AREAS OF RESPONSIBILITY Specialist’s Roles and Responsibilities 1. Clipboard, Search History, and several other advanced features are temporarily unavailable. . Dhingra R, Sullivan LM, Fox CS et al. Alexandra Voinescu, Kevin J. Martin, in Nutritional Management of Renal Disease, 2013. Moe et al. In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. However, certain aspects of experimental models temper direct application to human calcification. In patients with CKD stage 5D, we suggest lowering elevated phosphorus levels toward the normal range (2C)." Am J Kidney Dis. These include guidance on the use of oral phosphate binders, activated vitamin D compounds and analogues and calcimimetics. . -, Circ Res. Adeney KL, Siscovick DS, Ix JH et al. . A link between end-stage renal disease and cardiovascular disease? Nephrol Dial Transplant 2016; 31: 196–199.). CKD-MBD, defined by disturbances in mineral metabolism hormones and associated bone disease, is one of the most common recognized metabolic complications of CKD [36]. The Phosphate Normalization Trial randomized 148 CKD patients (estimated GFR 20–45 mL/min/1.73 m2) to one of three phosphate binders (calcium acetate, sevelamer or lanthanum) versus matching placebos [39]. Kestenbaum B, Sampson JN, Rudser KD 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 [46]. Differences in demographics, CKD etiologies, comorbidity assessment and the timing of serum phosphate measurements, which may vary by as much as 1.0 mg/dL throughout the day [19], may have contributed to heterogeneous associations. If you can't take calcium acetate for any reason, they should talk to you about taking a different binder called calcium carbonate. 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]. Smith DH, Johnson ES, Thorp ML et al. . This problem may be attenuated by newer phosphate binders such as sevelamer hydrochloride and lanthanum carbonate. Wang S, Alfieri T, Ramakrishnan K et al. . 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. Similarly, for any of the available drugs, gastrointestinal adverse effects are a possible limitation and may promote non-adherence to medication. Menon V, Greene T, Pereira AA et al. This topic is beyond the scope this review. 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]. Finally, Seifert 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. 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. The addition of exogenous phosphate to cultured vascular smooth muscle cells and isolated aortic rings causes loss of the smooth muscle phenotype, expression of bone-specific markers and mineralization of the extracellular matrix [30–32]. Many interventions that targeted biochemical pathways suggested by association studies and suspected biological importance have yielded null or harmful results. 2015 Oct;30(10):1843-52. doi: 10.1007/s00467-015-3125-3. 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. Pediatr Nephrol. 2000 Sep 29;87(7):E10-7 Although dietary management may be adequate to control plasma phosphate in its early stages, most patients develop hyperphosphataemia by CKD stages 3−4 and require the addition of a phosphate binder. J Am Soc Nephrol. containing phosphate binders versus calcium-free phosphate binders: study characteristics Table S20. Some, but not all, head-to-head comparison studies have suggested greater calcification potential for calcium-based phosphate binders [55, 56]. Sinha MD, Turner C, Booth CJ, Waller S, Rasmussen P, Goldsmith DJ, Simpson JM. Stevens LA, Djurdjev O, Cardew S et al. Interventions that correct these metabolic disturbances are typically more complex than initially understood. 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 demise of calcium-based phosphate binders-is this appropriate for children? 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. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. Goodman WG, Goldin J, Kuizon BD et al. . Pragmatic clinical trials of phosphate binders are conspicuously lacking from the current pool of evidence and represent an optimal approach for evaluating the clinical risks and benefits of these medications in CKD populations. Roman-Garcia P, Carrillo-Lopez N, Fernandez-Martin JL et al. No intervention to lower serum phosphate concentrations in CKD should be approved without evidence that the intervention provides at least some clinical benefit, is generally acceptable to patients and is relatively safe over long-term use. Reynolds JL, Joannides AJ, Skepper JN et al. 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. 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. 2. There are many different kinds of phosphate binders. Epub 2015 May 15. Such trials typically avoid hypervigilant procedures for ensuring compliance with treatment, which are clinically unrealistic, may utilize a no-treatment group in place of a formal placebo and can be completed at relatively lower costs. [ 6, 7] With … For example, Isakova et al. . 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. Adherence to phosphate binders is variable across patients and decreases in association with a greater number of prescribed pills [62]. . 2009 Mar;35 Suppl 1:65-70. doi: 10.1111/j.1755-6686.2009.00052.x. 2012 Feb;5(Suppl 1):i62-i70. 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. Phosphate binders are ubiquitously prescribed to chronic dialysis patients and sporadically prescribed to patients who have chronic kidney disease (CKD). Phosphate Binders Aluminum Salts. Drugs. 2020 Oct;35(10):1915-1923. doi: 10.1007/s00467-020-04571-x. Although phosphate binders reduce serum phosphate in these patients, it remains uncertain whether they improve clinical outcomes. 1 ... To help lower serum phosphorus levels and reduce the relative risk of mortality, phosphate binders are utilized. Epub 2009 Aug 18. Treatment of hyperphosphatemia in CKD essentially relies on two measures: restricting dietary phosphate intake; and use of oral phosphate binders. This condition is characterized by high phosphate levels and requires phosphate-lowering agents—phosphate binders. Because of the improved removal of phosphate from the Several studies have found relatively lower risks of mortality comparing chronic dialysis patients treated with phosphate binders to similar untreated patients [46–49]. doi: 10.1093/ndtplus/sfr168. 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. Reliable data regarding the risks and benefits of phosphate binders must derive from studies that specifically focus on these medications, not serum phosphate concentrations or phosphate metabolism. . Jamison RL, Hartigan P, Kaufman JS et al. Null effects of phosphate binders on these hormones may reflect insufficient blockade of gastrointestinal phosphate absorption, in part due to compensatory up-regulation of sodium–phosphate channels in the gut [41]. Which phosphate binder in which CKD patient? . Phosphate binders are ubiquitously prescribed to chronic dialysis patients and sporadically prescribed to patients who have chronic kidney disease (CKD). Calcium Carbonate and Calcium Acetate. Are propensity scores really superior to standard multivariable analysis? Greater total pill burden in this study was associated with lower physical component scores on the Kidney Disease Quality of Life (KDQOL) instrument. Moreover, current knowledge is insufficient to support guidelines regarding ‘optimal’ serum phosphate concentrations in CKD. Such concentrations are far lower than those used to induce calcification in experimental models, precluding a plausible mechanism for observed associations. 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. Chue CD, Townend JN, Moody WE et al. The guidelines also suggest that long-term use of aluminum-containing phosphate binders be avoided in patients with CKD stages 3 through 5D. Craver L, Marco MP, Martinez I et al. This site needs JavaScript to work properly. Raggi P, Boulay A, Chasan-Taber S et al. Young EW, Albert JM, Satayathum S et al. COVID-19 is an emerging, rapidly evolving situation. Seifert ME, de las Fuentes L, Rothstein M et al. . Animal models and cell culture data suggest direct calcifying effects of phosphate on vascular smooth muscle tissue. Qunibi W, Moustafa M, Muenz LR et al. Navaneethan SD, Palmer SC, Craig JC, Elder GJ, Strippoli GF. . . If you have stage 5 CKD (and are on dialysis) For adults, your healthcare professional should offer a phosphate binder called calcium acetate first. Null findings from these studies should not discourage subsequent trials using clinical endpoints. B.K. Please enable it to take advantage of the complete set of features! In this regard, phosphate binders are considered the prime option; however, dietary phosphate restriction and intensified dialysis are also valuable supportive tools. , it is clearly affirmed that all of the available phosphate binders are effective in lowering serum phosphate. The rationales for prescribing phosphate binders to CKD patients derive from studies of serum phosphate concentrations and phosphate metabolism, not phosphate binders. Epub 2014 Dec 28. Epub 2020 May 8. Recent advancements have been made in phosphate-binder treatment. Modification of Diet in Renal Disease Study Group, Effects of phosphate binder therapy on vascular stiffness in early-stage chronic kidney disease, Phosphorus binders and survival on hemodialysis, Comparative effectiveness of calcium-containing phosphate binders in incident U.S. dialysis patients, Phosphate binder use and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study (DOPPS): evaluation of possible confounding by nutritional status, Use of phosphate-binding agents is associated with a lower risk of mortality, Outcomes associated with phosphorus binders in men with non-dialysis-dependent CKD, Practice patterns of phosphate binder use and their associations with mortality in chronic kidney disease, In defense of pharmacoepidemiology—embracing the yin and yang of drug research, Propensity score methods gave similar results to traditional regression modeling in observational studies: a systematic review. There is a misconception that complex methodologies (propensity scores, inverse probability weighting and instrumental variables) are mandatory for this purpose; however, standard adjustment methods yield similar validity in most situations and produce results that are easier to interpret and have greater generalizability [53, 54]. In this review, the role of phosphate as a uraemic toxin and the advantages and disadvantages of the currently available phosphate binders are discussed. However, knowledge pertaining to serum phosphate concentrations and phosphate metabolism cannot substitute for information regarding the clinical risks and benefits of interventions that are used to reduce phosphate. 2007 Dec;23(12):3167-75. doi: 10.1185/030079907X242719. -, Circulation. [33] directly demonstrated a 44% prevalence of medial arterial calcification, an otherwise rare finding, in inferior epigastric arteries removed from ESRD patients undergoing renal transplantation. NLM . . 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. Staging pregnancy-related acute kidney injury according to Kidney Disease: Improving Global Outcomes guidelines: what are the barriers? Chronic kidney disease (CKD) is frequently accompanied by hyperphosphatemia. Summary table of randomized controlled trials examining the treatment of CKD-MBD with calcium- containing phosphate binders versus calcium-free phosphate binders: study population characteristics Table S21. Nephrol Dial Transplant 2016; 31: 184–188; See related article by Zoccali and Mallamaci. (See related article by Bellasi. 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]. Second, disturbances in FGF-23, PTH, 1,25(OH)2D and klotho are detectable at the earliest stages of CKD, when filtration is theoretically sufficient to excrete the daily phosphate load without compensation [42, 43]. 2009 Oct;54(4):619-37. doi: 10.1053/j.ajkd.2009.06.004. Click below to view dosing and additional information on each type of binder. Three recent studies compared the impact of phosphate binders versus placebo on serum phosphate concentrations, mineral metabolism hormones and subclinical cardiovascular disease measurements. 2015 Dec;30(12):2061-71. doi: 10.1007/s00467-014-3017-y. . Phosphate binders are prescribed to chronic kidney disease (CKD) patients based on associations of serum phosphate concentrations with mortality and calcification, experimental evidence for direct calcifying effects of phosphate on vascular smooth muscle tissue and the central importance of phosphate retention in CKD-mineral and bone disorder (CKD-MBD). patients with CKD (attached). Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. It is reasonable that the choice of phosphate binder takes into account CKD stage, presence of other components of CKD-MBD, concomitant therapies, and side-effect profile (not graded). 20. Calcium-based phosphate binders are often used for CKD stages 3 to 5; they are inexpensive, but have a potential to cause hypercalcemia. First, reduction of gastrointestinal phosphate absorption using phosphate binders failed to meaningfully change PTH, FGF-23 or 1,25(OH)2D among stage III–IV CKD patients [39, 40]. Published by Oxford University Press on behalf of ERA-EDTA. Oral phosphate binders for the management of serum phosphate levels in dialysis patients. They are frequently used in people with chronic kidney failure (CKF), who are less able to excrete phosphate, resulting in an elevated serum phosphate. 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). HHS Cannata-Andia JB, Fernandez-Martin JL, Locatelli F et al. 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. Isakova T, Gutierrez OM, Chang Y et al. Block et al. Epub 2013 Oct 9. A novel polymeric phosphate binder, AMG 223 was being developed by Amgen after its June 2007 acquisition of Ilypsa. USA.gov. Kempson SA, Lotscher M, Kaissling B et al. . Moderator's view: Phosphate binders in chronic kidney disease patients: a clear ‘No’ at the moment, but stay tuned. For example, Foley 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]. 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. (See related article by Bellasi.  |  See related article by Zoccali and Mallamaci. Phosphate binders are taken with meals to stop the body from absorbing some of the phosphorus in your food. To achieve this objective, such studies must first account for potential differences in characteristics between treated and untreated individuals. There are no definitive clinical trials that compare phosphate binders versus no treatment on clinically relevant outcomes. . . For full access to this pdf, sign in to an existing account, or purchase an annual subscription. 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. Epub 2019 Oct 30. Your kidney doctor may order a medicine called a phosphate binder for you to take with meals and snacks. Plasma phosphate levels are important in the evolution of hyperparathyroidism and ectopic calcification in chronic kidney disease (CKD). 2008 Oct 21;118(17):1748-57 Phosphate binders are medications used to reduce the absorption of dietary phosphate; they are taken along with meals and snacks. . All rights reserved. Investigating new treatment opportunities for patients with chronic kidney disease in type 2 diabetes: the role of finerenone, Cytomegalovirus after kidney transplantation in 2020: moving towards personalized prevention, Influence of a low-dose tacrolimus protocol on the appearance of, Fibrosis and cancer: shared features and mechanisms suggest common targeted therapeutic approaches. [16] found no adjusted association of serum phosphate concentrations with all-cause mortality or ESRD among 10 672 individuals who had CKD in the community-based Kidney Early Evaluation Program (KEEP) [16]. . 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). Background Chronic kidney disease-mineral and bone disorder (CKD-MBD) has been linked to poor health outcomes, including diminished quality and length of life. Block GA, Hulbert-Shearon TE, Levin NW et al. Dietary calcium intake does not meet the nutritional requirements of children with chronic kidney disease and on dialysis. Gutierrez O, Isakova T, Rhee E et al. tain adequate nutrition (Polzin and Churchill 2016). . . Where diet alone is not sufficient, the use of intestinal phosphate binders is recommended (Sparkes et al. . 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. Current evidence supports clinical trials of phosphate binders on clinically relevant endpoints as the next appropriate scientific step. Block GA, Wheeler DC, Persky MS et al. 2013 May;73(7):673-88. doi: 10.1007/s40265-013-0054-y. 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