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An Update on Phosphate Binders: A Dietitian's Perspective
J Ren Nutr. 2016;26(4):209-218.
Control of serum phosphorus (PO4) has been long recognized as a goal in the nutritional and medical management of the patients with chronic kidney disease. Phosphate-binding compounds were introduced in the 1970s for the treatment of hyperphosphatemia in patients on dialysis after it was observed that oral administration of aluminum hydroxide as an antacid also reduced serum PO4 levels. Forty years later, aluminum is very seldom used as a phosphate binder as many other safer compounds are now available. This article is a comprehensive review, geared to the renal dietitian, of the most common binder categories. It will discuss pharmacokinetics, side effects, initial and optimal doses, phosphate affinity, and controversies of use. It will also review two novel approaches to serum PO4 management in chronic kidney disease patients receiving dialysis and provide a new calculation by which binders can be compared.
Control of serum phosphorus (PO4) has been long recognized as a goal in the nutritional and medical management of the patients with chronic kidney disease (CKD). The negative sequelae of hyperphosphatemia in the CKD population have been well established.1, 2, 3, and 4 Current therapies for management include providing renal replacement therapy, limiting dietary PO4, and prescribing phosphate-binding compounds.
Management of serum PO4 is a primary responsibility of the renal dietitian by providing the dialysis patient with continual, ongoing education of dietary PO4 sources, and the use of phosphate binders. This education has become more challenging over the past decade as we have learned that the bioavailability of PO4 differs between organic and inorganic sources. The understanding of bioavailability challenges some of the previous education about which foods are highest in PO4. Another challenge is keeping up with the development and approval of new phosphate-binding compounds and identifying the most appropriate binder for individual patients. The number of Food and Drug Administration (FDA) approved phosphate-binding compounds continues to grow, each having advantages and disadvantages for use. The renal dietitian must understand the use, dosage, and adverse events of phosphate binders and navigate the world of medication insurance before making a binder recommendation.
Phosphate-binding compounds were introduced in the 1970s for the treatment of hyperphosphatemia in patients on dialysis after it was observed that oral administration of aluminum hydroxide as an antacid also reduced serum PO4 levels.5 Forty years later, aluminum is almost never used as a phosphate binder as many other safer compounds are now available. Calcium-based binders (calcium bicarbonate and calcium acetate) became the binder of choice in the 1980s and 1990s. They were effective and did not lead to the encephalopathy and bone disease seen with aluminum compounds; however, in more recent years, their use has been linked to the development of cardiac and metastatic calcification.4, 6, 7, 8, 9, and 10 In 2001, the first nonmetal, nonabsorbable anion exchange binder, sevelamer hydrochloride (SH) was launched.11 and 12 SH has the advantage of reducing a patient's exposure to calcium. However, in the ion exchange, hydrochloride (HCl) was released increasing a patient's acid load and contributing to metabolic acidosis. In 2004, lanthanum carbonate was launched as the first chewable non–calcium-based binder (now also available in powder form).12 and 13 Between 2007 and 2015, Phoslyra® (calcium acetate), the first prescription liquid-based binder, and Renvela® (sevelamer carbonate) became available.14 and 15 Bixalomer another nonmetal, nonabsorbable is available in Japan.16 and 17 Velphoro® (sucroferric oxyhydroxide), a chewable, iron-based binder with no significant change on iron parameters,18 and Auryxia® (ferric citrate) an iron-based binder with clinically and statistically significant increases in iron parameters.19 Additionally, studies have looked into once daily dosing of sevelamer, the use of niacin/nicotinamide, and the use of a salivary phosphate-binding chewing gum to improve serum PO4 levels.15, 20, and 21Table 1 shows the various FDA-approved compounds to demonstrate comparable efficacy.
Comparison of Phosphate-Binding Agents
|Agent||Common Name||How Supplied||Starting Dose||Estimated PO4-Binding Capacity||Advantages||Potential Side Effects/Disadvantages||References|
|Calcium carbonate||Tums, Oscal, Calcichew, Caltrate||Varies||∼39 mg/g||Inexpensive, wide variety of products, easily available, no prescription required||Not covered by insurance, hypercalcemia, hypoparathyroid, metastatic calcification, GI side effects, constipation||6, 8, 9, and 27|
|Calcium acetate||Phoslo Phoslyra||Tablet: 667 mg; Gelcap: 667 mg; Liquid: 667 mg per 5 mL||2 tablets per meal; 2 gelcaps per meal; 10 mL per meal||∼45 mg/g||Less Ca absorption than calcium carbonate||Hypercalcemia, hypoparathyroid, metastatic calcification, GI side effects, constipation||6, 8, 9, 14, and 27|
|Sevelamer HCl||Renagel||Tablet: 400 mg, 800 mg; max dose: 13 g||2-4 400 mg per meal; 1-2 800 mg per meal||Varies ∼21 mg/g||Noncalcium nonmetal binder, not absorbed, reduces serum lipid levels||Contraindicated with pts who are at risk for small bowel obstruction, ↑S.Cl, ↓S.CO2||11, 15, 24, and 45|
|Sevelamer carbonate||Renvela||Tablet: 800 mg; Powder: 800 mg, 2,400 mg; max dose: 13 g||1-2 per meal; 0.8-1.6 g per meal||Varies ∼21 mg/g||Same as above||Contraindicated with pts who are at risk for small bowel obstruction, ↑S.CO2. Not available worldwide||11, 15, 24, and 45|
|Bixalomer||Kiklin (Japan)||Tablet||Not known||Noncalcium, nonmetal, reduced GI effects than Renagel, no effect on S. Cl, ↑S.CO2.||Less lipid lowering effects than Renagel. Not available worldwide.||16 and 17|
|Lanthanum carbonate (LaCO3)||Fosrenol||Chewable tablet: 500 mg, 750 mg, 1000 mg; Powder: 750 mg, 1000 mg||500 mg per meal; max dose: 4500 mg/day||Varies on reference 135 mg/g, 45 mg/500 mg||Reduced pill burden, high binding capacity, noncalcium, crushable||GI side effects may interfere with radiocontrast diagnostic results||13, 24, and 29|
|Sucroferric oxyhydroxide||Velphoro||Chewable tablet: 500 mg||500 mg per meal. Max dose: 3000 mg/day||130 mg/tab||Reduced pill burden, noncalcium, crushable||GI side effects||18 and 25|
|Ferric citrate||Auryxia Riona (Japan)||Tablet: 1 g||2 g per meal; max dose: 12 g/day||46 mg/gram||Noncalcium, increases iron parameters||GI side effects, contraindicated with patients who have iron overload syndromes such as hemochromatosis||19, 30, 46, and 51|
GI, gastrointestinal; HCl, hydrochloride.
This article is a comprehensive review, geared to the renal dietitian, of the most common binder categories. It will discuss pharmacokinetics, side effects, initial and optimal doses, phosphate affinity, and controversies of use. It will also review two novel approaches to serum PO4 management in CKD patients receiving dialysis and provide a new calculation by which binders can be compared. Aluminum and magnesium-based binders are not included in this discussion. Aluminum is rarely used due to its toxic effects on the body, and little is known about the long-term safety and efficacy of magnesium-based binders. Additionally, patients taking magnesium-based binders are at risk for hypermagnesemia.22
All phosphate-binding compounds work by reducing the absorption of dietary PO4 in the gastrointestinal (GI) tract. Compounds use the anionic nature of PO4 for ionic exchange with an active cation to form a nonabsorbable compound that is excreted in the feces.13, 14, 15, 16, 18, and 19 Calcium-, lanthanum-, and the newer iron-based salts exchange carbonate, acetate, oxyhydroxide, and citrate to bind with PO4. Sevelamer is a nonselective anion that will not only bind with PO4 but also binds with bile salts and other medications.15 and 23
To obtain FDA approval for use in the United States, all binders have shown that they are effective in reducing serum PO4 levels in patients with CKD undergoing dialysis. Some companies compared effectiveness with placebo, and others used FDA-approved PO4-binding compounds to compare to current standard of care.
Relative Phosphate-Binding Coefficient and the Phosphate Binder Equivalent Dose
Given the number of phosphate-binding agents, comparison between agents is challenging. Researchers in the Frequent Hemodialysis Network Trial faced this challenge when trying to interpret changes in serum PO4 levels. Their question was how much of the change was due to the increase in dialysis frequency and how much was due to the use of various phosphate binders? Daugirdas et al.24 reviewed stool and urinary in vivo phosphate-binding capacities (PBC) in subjects with non-CKD and CKD.
From here, they devised the “relative phosphate-binding coefficient” (RPBC) and the “phosphate binder equivalentdose” (PBED) to compare phosphate-binding capabilities in terms of milligrams of PO4 bound per gram of compound or per gram of active ingredient (lanthanum, sucroferric oxyhydroxide, and ferric citrate), arbitrarily choosing 1 g of calcium carbonate as the standard. Results from the Frequent Hemodialysis Network Trial suggest that patients with CKD and little urine output receiving conventional thrice weekly hemodialysis require approximately 6 g/day of a calcium carbonate to control serum PO4, and equivalent number of tablets required was established.24 and 25Table 2 shows the RPBC, PBED, and the number of tablets required to reach the 6 g/day dose.
Dosages of Selected Phosphorus Binders Required to Reach a Phosphorus Binder Equivalent Dose of 6.0 g/day
|Phosphorus Binder||Unit Dose Size (mg)||Phosphate Binder Equivalent Dose of One Tablet to 1 g Ca Carbonate||Dose of Binder Needed to Reach a PBED of 6 g/day||Approximate Number of Tablets to Reach PBED of 6 g/day||g of Calcium in a 6 g PBED Dose|
|Osvaren (Mg carbonate + Ca acetate)||435/235∗||0.75||—||8||0.5|
|Sucroferric oxyhydroxide (Velphoro)||500||1.6||1.5||3.75|
∗ Each tablet contains 435 mg Mg carbonate and 235 mg Ca acetate.
† Tablets are sold by weight of lanthanum and not of lanthanum carbonate.
The equivalent dose of PA21 is based on a single randomized controlled trial versus sevelamer (Floege, 2014), and thus, the equivalent dose is not as precise as for some of the other binders, where multiple studies were considered. Ferric citrate numbers were obtained from a single clinical randomized controlled trial versus sevelamer and calcium acetate (Lewis et al. 2014); Osvaren is not available in the United States.
Reproduced with permission from Wolter Kluwer.
The RPBC is a useful tool for practitioners switching between agents as a starting dose. Serum PO4 levels should be monitored, and dose titration was made per FDA package insert recommendations to reach optimal serum PO4 levels. For example, if a patient is prescribed six (6) 750-mg calcium carbonate tablets per day (4.5 g), the sevelamer equivalent dose would be ∼4 tablets per day.
Daugirdas et al. caution that the PBED is an estimate as the PBC studies showed an inverse relationship between PBC and binder dose. For example, urinary excretion studies using sevelamer revealed higher PBC with lower doses of sevelamer (1.6 gm/day sevelamer = 50 mg/g PBC) than with higher doses of sevelamer (7.5 gm/day sevelamer = 33 mg/g PBC), and urinary studies using lanthanum carbonate showed PBC of 96 mg/g with 1.93 g lanthanum versus 75 mg/g with 2.65 g lanthanum.24
The estimated RPBC and PBED described for all phosphate binders provide tools practitioners can use to compare binders and determine initial phosphate binder prescriptions. Please note that on-label indications provide starting doses for each compound and are included in each section.
Calcium-based–binding agents are the most commonly used medication for serum PO4 control despite multiple studies linking them to coronary and metastatic calcification.6, 8, 9, and 10 KDIGO and KDOQI guidelines recommend limiting or avoiding the use of calcium binders in patients who have elevated serum calcium levels, have low serum parathyroid levels, or have known calcification.22 and 26 Some studies have shown that many patients have calcification before dialysis is initiated calling into question the use calcium-based binders even in earlier stages of CKD.27 and 28 Despite the research, practitioners continue to use calcium-based binders to control serum PO4 and for its ability to lower parathyroid.29
Calcium carbonate is available over-the-counter without a prescription and is inexpensive. Various strengths are available; therefore, it is important to review with the patient the appropriate strength to use because approximately 20% to 30% of the elemental calcium will be absorbed.30
There are multiple studies comparing the effectiveness of calcium carbonate with calcium acetate as a phosphate binder.31, 32, and 33 In these cases, calcium acetate was equally effective or more effective in lowering serum PO4 levels when compared to calcium acetate. In all, exposure to calcium and the incidence of hypercalcemia were less in the calcium acetate arm.
The PBC of calcium carbonate is ∼39 mg PO4 per 1 g of calcium carbonate.26 Daugirdas et al.24 use the phosphate-binding efficiency of 1 g calcium carbonate as the reference standard. Therefore, the RPBC of calcium carbonate is 1.0. For dosing prescription, the strength of the calcium carbonate should be considered. For example, a 750-mg tablet of calcium carbonate would have a PBED of 0.75 (750 mg/1,000 mg) requiring 8 tablets to get an equivalent dose of 6 (1.0 g) tables of calcium carbonate.24
The calcium found in calcium acetate is less absorbable (21 ± 1% with meals, mean ± standard deviation [SD]) and has a slightly higher binding capacity of 45 mg per 1 g of calcium acetate.22 The RPBC is 1.0, meaning that the binding strength of calcium acetate is similar to the binding capacity of calcium carbonate. However, the PBED is 0.67 meaning that one 667-mg tablet of calcium acetate will bind less phosphate than 1 g of calcium carbonate requiring 9 tablets to get equivalent dose to 6 g of calcium carbonate.24
Adverse events associated with the use of calcium-based binders include constipation, hypercalcemia, and hypoparathyroidism. Additionally, there is evidence that overexposure to calcium can contribute to metastatic calcification.4, 5, 14, and 26
Sevelamer hydrochloride (Renagel®, Sanofi US, Bridgewater, NJ), and sevelamer carbonate (Renvela®, Sanofi US, Bridgewater, NJ) are the two products currently available in this class. Sevelamer is a nonabsorbable cross-linked polymer that exchanges HCl or carbonate (HCO3−) for PO4 in the GI tract.15 and 23 The HCl and HCO3− are absorbed into the body while the resulting PO4-laden polymer passes through the GI tract and is excreted.
In two pivotal studies examining the effectiveness of SH, serum PO4 levels improved during the course of the studies without increasing serum calcium levels.35 and 36 After a 2-week washout period in the first study, serum PO4 levels dropped from 9.1 ± 2.4 mg/dL to 6.6 ± 1.9 mg/dL in 144 patients with an average dose of 5.4 g of SH after 8 weeks.35 The second study was an open-label crossover study comparing the effectiveness of SH with calcium acetate in 84 patients. After a 2-week washout period, patients were randomized to receive either SH or calcium acetate for 8 weeks. After completion of this arm, patients underwent another 2-week washout period, then received the other phosphate binder. Effectiveness between both arms were similar (serum PO4 decline −2.0 ± 2.3 mg/dL with SH vs. −2.1 ± 1.9 mg/dL with calcium acetate); however, 22% of the participants experienced serum calcium levels greater than 11.0 mg/dL in the calcium acetate arm resulting in the discontinuation of the medication until serum calcium levels declined.36
In addition to PO4, the sevelamer complex also binds bile salts resulting in a 15% to 31% decline in serum mean total cholesterol and serum low-density lipoprotein cholesterol level.23 Because of its ability to bind bile salts, it may interfere with normal fat absorption and the absorption of fat soluble vitamins (A, D, E, and K). The FDA-approved package insert for SH and sevelamer carbonate encourages monitoring fat soluble vitamin and folic acid levels with the use of the product.
Sevelamer is contraindicated with patients who have a history of or are at risk of a bowel obstruction. Postmarketing experiences reveal esophageal tablet retention with patients who have dysphagia, bowel perforation, and fecal impaction requiring hospitalization and intervention. Less serious adverse events associated with sevelamer include vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain (9%), flatulence (8%), and constipation (8%).23
In concomitant drug therapy, sevelamer did not affect the bioavailability of digoxin, warfarin, enalapril, metoprolol, and ferrous sulfate. Sevelamer does decrease the bioavailability of ciprofloxacin by approximately 50%, and in postmarketing experience, reduced concentration of cyclosporine, mycophenolate mofetil, and tacrolimus have been reported. It is recommended that thyroid-stimulating hormone levels be monitored when the product is used with levothyroxine.15 and 23
The recommended starting dose for both SH and sevelamer carbonate ranges from 800 to 1,600 mg per meal, depending on serum PO4 levels.
PBC studies have been completed in healthy volunteers. One study compared the net absorption of PO4 from a standardized meal ingested with a typical clinical dose of phosphate binders. After undergoing gastric lavage, 31 healthy volunteers were given a meal consisting of ∼380 mg of phosphate and a single 2,400 mg dose of sevelamer carbonate. Stool samples were collected and analyzed for PO4 content showed. There was a 21% reduction in PO4 absorption which indicated an approximate 21 mg PBC for one sevelamer carbonate tablet or ∼26 mg PO4 per 1 g sevelamer carbonate.24 Other studies have evaluated the binding capacity of SH in 24 healthy volunteers. In one study, a diet of 1,200 mg PO4 was given to healthy individuals for 18 days. During days 5 through 9, subjects were given either placebo or SH in divided doses of 3, 7.5, or 15 g. The finding showed an inverse binding capacity with the dose of SH (36 mg/g; 33 mg/g; 23 mg/g, respectively). These findings are confirmed in two other studies that looked at the binding capacity of 1.6 g (50 mg/g) and 6.4 g (32 mg/g).24 Practitioners should be aware that an inverse relationship of dose and binding capacity has been shown in several studies.
The RPBC of sevelamer is 0.75 with a standard 800 mg dose having a PBED of 0.60 such that 9 tablets of sevelamer will be required to be equivalent to 6 tablets (1 g/tablet) of calcium carbonate.30
Bixalomer (Kiklin®, Astellas Pharma, Tokyo, Japan) is another nonabsorbable polymer that is currently only available in Japan.37 It is similar to sevelamer; however; it absorbs less water thus showing less swelling and higher fluidity than sevelamer.16 and 17
In phase 3 studies conducted in Japan, bixalomer was shown to be as effective as sevelamer for the management of serum PO4 levels with 72.2% of subjects achieving target PO4 levels, between 3.5 and 6.0 mg/dL as compared with the sevelamer group, which only had 68% achieve those levels. Additionally, the percentage of GI adverse events was significantly lower in the bixalomer group with 29.1% reporting events versus 47.3% in the sevelamer group.16 and 17 As sevelamer carbonate is not available in Japan, Kiklin® is a noncalcium, nonmetal binder option that does not contribute to acid load.
Lanthanum carbonate (Fosrenol®, Shire US Inc., Wayne, PA) is the first phosphate-binding compound to use the metal lanthanum to bind phosphate. Each chewable tablet contains lanthanum carbonate hydrate equal to 500, 750, or 1,000 mg of elemental lanthanum. In the GI track, lanthanum binds PO4 to form the nonabsorbable compound lanthanum phosphate. In vitro studies demonstrate that lanthanum binds phosphate at pH levels from 3 to 7. Most phosphate binding to lanthanum occurs at pH levels between 3 and 5 at 97%, whereas 67% binding occurs at pH 7.13
In phase 2 and 3 studies, lanthanum carbonate has been shown to reduce and maintain PO4 levels in goal range of 4.03 to 5.58 mg/dL. Additionally, when compared with calcium acetate and SH, lanthanum showed no superiority; however, the number of wafers required to maintain serum PO4 levels was much less with lanthanum.38, 39, and 40
The recommended starting dose is 1,500 mg, distributed equally at meals. Doses should be titrated every 2 to 3 weeks until target serum PO4 levels are reached, with a maximum dose of 4,500 mg.
In clinical trials, the most common adverse reactions were nausea (11%), vomiting (9%), and abdominal pain (5%). Postmarketing experience revealed additional adverse reactions including constipation, dyspepsia, allergic skin reaction, hypophosphatemia, and tooth injury while chewing the tablet.13
Serious GI complications have been seen with the use of lanthanum, and caution should be taken when prescribed to patients with altered GI anatomy. The product is contraindicated with patients who have a history of bowel obstruction. Some of those who have experienced severe cases of GI obstruction have required hospitalization and/or surgery. Additionally, as lanthanum is a heavy metal, it has radio-opaque properties that may alter images from abdominal X-ray procedures.13 and 41
The concomitant administration of lanthanum with other medications may decrease medication bioavailability or action of the second drug. Bioavailability of tetracyclines, fluoroquinolones, and quinolone is decreased when taken with lanthanum. The bioavailability of levothyroxine is decreased by approximately 40% when given in conjunction with lanthanum, thus should be spaced at least 2 hours before or 2 hours after lanthanum administration. Aluminum-, magnesium-, and calcium-based antacids should not be administered within 2 hours of lanthanum.13
A systematic review and meta-analysis of 16 randomized controlled trials involving 3,789 patients looked at the long-term efficiency and safety of lanthanum. Zhang et al. identified 10 studies that gathered data on lanthanum accumulation in bone and blood. Most results showed a slight increase in serum lanthanum levels; however, these increases did not indicate any statistical differences.37 Three significant bone histology studies followed 85 patients for 1 to 2 years, obtaining bone biopsies at baseline and then annually. Although lanthanum did accumulate within the bone, the accumulation was shown to be minor (<5.5 mcg/g), and the bone released the deposits once therapy was stopped.42, 43, and 44
In vivo phosphate absorption studies using lanthanum have been competed in healthy individuals. Thirty-one volunteers were given one 1,000 mg dose of lanthanum and a meal containing 375 mg phosphate. Stool recovery showed that lanthanum reduced phosphate absorption by 45% in contrast to ingesting the meal without a phosphate binder, thus estimating that 1,000 mg of lanthanum can bind 135.1 ± 12.3 mg of PO4 (mean ± SD).45 Daugirdas found that 500 mg of lanthanum has an RPBC of 2.0 with a PBED of 1.0 requiring 6 tablets to be equivalent to 6 tablets of calcium carbonate.24 and 30
Sucroferric oxyhydroxide (Velphoro®, Fresenius Medical Care North America) is the first iron-based phosphate binder introduced to North America. Each chewable tablet contains 500 mg of iron equivalent to 2,500 mg sucroferric oxyhydroxide. In the GI tract, phosphate binds to sucroferric oxyhydroxide to form an insoluble compound. The sucrose and starch components of the tablet are absorbed. In vitro studies show that the phosphate binding takes place between pH ranges of 1.2 to 7.5 with a PBC of 130 mg per tablet.18 and 46
Two phase 3 studies were conducted to show that sucroferric oxyhydroxide is effective in reducing serum PO4 levels in patients receiving dialysis. The first study was a 6-week, randomized, open-label, active control study to investigate optimal dose. Fifty clinical sites in Europe and the United States randomized 154 patients to receive either sucroferric oxyhydroxide or active control (SH). Those randomized to receive sucroferric oxyhydroxide were randomized to receive either 1.25, 5.0, 7.5, 10.0, or 12.5 g/day. All groups showed a significant decrease in serum PO4 with the exception of 1.25 g/day dose. Mean ± SD decreases in serum PO4 in the 5, 7.5, 10, and 12.5 g/day were −1.08 ± 2.12 mg/dL, −1.25 ± 1.21 mg/dL, −2.0 ± 1.71 mg/dL, and −1.69 ± 1.81 mg/dL, respectively.47
The second phase 3 study was a 55-week, multistage, randomized, open-label, active controlled study to investigate safety and efficacy.48 and 49 A total of 1,059 dialysis patients were randomized after a 2-week phosphate binder washout period to receive either sucroferric oxyhydroxide or sevelamer carbonate in the first stage of this study lasting 24 weeks. Starting doses for each were 1,000 mg and 4,800 mg, respectively, with titration to maintain serum phosphate levels <5.5 mg/dL. At the end of 24 weeks, those receiving sucroferric oxyhydroxide with controlled phosphate levels were then randomized into a 3 weeks second phase 2 of the study. Participants either maintained their current dose of sucroferric oxyhydroxide or received a lower dose of 250 mg/day.48 The final stage consisted of 658 dialysis patients who were treated for 28 weeks with either study drug or active control according to their original randomization.49
Serum PO4 levels declined 2.2 and 2.4 mg/dL for sucroferric oxyhydroxide and sevelamer carbonate, respectively, at the end of week 12 showing noninferiority of sucroferric oxyhydroxide to sevelamer carbonate. Efficacy was maintained through week 24 with patients requiring an average dose of 3 tablets per day sucroferric oxyhydroxide to maintain serum PO4 levels versus 8 tablets of sevelamer.48
Additionally, both studies revealed that there were no significant or clinical changes in iron parameters with sucroferric oxyhydroxide. After the 6-week study receiving various doses of sucroferric oxyhydroxide, serum ferritin and transferrin saturation levels remained stable (baseline ferritin levels range: 242.2 to 438.7 ng/mL, change from baseline at week 4 range: −10.5 to 21.0 ng/mL, baseline transferrin saturation levels: 21.2% to 26.2%, change from baseline at week 4: −0.1 to 3.1%).48 Similar results were seen in the 52-week study.49
Most common adverse reactions include diarrhea (24%), discolored feces (16%), and nausea (10%).18 Discolored feces is an expected adverse reaction due to the product's iron content. Other studies did not include patient with peritonitis, significant gastric or hepatic disorders, hemochromatosis, or other iron accumulation disorders. Patients taking doxycycline should take it at least 1 hour before taking sucroferric oxyhydroxide. Levothyroxine should not be administered to patients taking sucroferric oxyhydroxide.18
The recommended starting dose for is 500 mg at each meal with titration as often as weekly until serum phosphate levels are <5.5 mg/dL. The maximum dose studied was 3,000 mg/day.18
Daugirdas found that 500 mg of sucroferric oxyhydroxide to have a PBED of 1.6 requiring 3.75 tablets to be equivalent to 6 tablets of calcium carbonate.30
A second iron-based phosphate binder (Auryxia®, Keryx Biopharmaceuticals, New York, NY; Riona®, Japan Tobacco Inc, Tokyo, Japan, Nephoxil®, Panion BF Biotech Inc, Taiwan) was also recently approved and also clinically increases iron parameters. Each pill contains 210 mg of ferric iron, which is equivalent to 1 g ferric citrate. In the GI tract, ferric iron binds with phosphate to create ferric phosphate, which is insoluble and excreted.19
A phase 3 study demonstrated the efficacy, tolerability, and safety study enrolled 441 dialysis patients into a multicenter, sequential, randomized, open-label, 52-week active controlled, followed by a 4-week placebo controlled trial looking at the effectiveness of reaching and maintaining serum PO4 levels between 3.5 and 5.5 mg/dL.50 After completing a 2-week phosphate binder washout, eligible participants were randomized to receiving either ferric citrate or active control (calcium acetate and/or sevelamer carbonate). Patients receiving ferric citrate started on 6 g per day (2 pills at 3 meals) with weekly titration until serum PO4 levels reached the target range. At the end of 52 weeks, patients receiving ferric citrate were rerandomized to continue current dose therapy or receive placebo.
Mean baseline serum PO4 levels were 7.41 ± 0.10 mg/dL in the ferric arm and 7.56 ± 0.14 mg/dL in the active control arm (mean ± SD). Reduction in levels to the goal of 3.5 to 5.5 mg/dL was reached by week 12 in both arms and maintained through week 52 with final mean levels of 5.2 (4.4-6.1) mg/dL and 5.1 (4.4-6.2) mg/dL, respectively (mean [range]). Additionally, against placebo, ferric citrate reduced serum PO4 levels by 2.2 ± 0.2 mg/dL (P < .001).50
The study revealed that 8 tablets (8 g) of ferric citrate successfully treated and maintained serum PO4 levels between 3.5 and 5.5 mg/dL. This is a consistent pill dose required to reach and maintain the same goal in the active control arm: 7.7 tablets/day (5.14 g) for calcium acetate and 9.0 tablets/day (7.2 g) for sevelamer carbonate.51
Studies also demonstrated an increase iron parameters with ferric citrate administered as a phosphate binder. In the long-term study, serum ferritin levels improved from a mean baseline of 593 ± 18 ng/mL to 899 ± 31 ng/mL (mean ± SD) with ferric citrate, whereas those receiving active control had little change from baseline (609 ± 26 ng/mL) at week 52 (628 ± 31 ng/mL). Additionally, those in the ferric citrate arm received less intravenous elemental iron (median = 12.9 mg/week ferric citrate; 26.8 mg/week active control; P < .001) and less erythropoietin-stimulating agent (median epoetin-equivalent units per week: 5,303 units/week ferric citrate; 6,954 units/week active control; P = .04) than those in the active control arm by the end of week 52.52
The most common adverse events associated with ferric citrate were diarrhea (21%), nausea (11%), constipation (8%), vomiting (7%), and cough (6%). Discolored feces are common with ferric citrate use related to the iron content, but are not clinically relevant and do not affect laboratory testing for occult bleeding. Patients with inflammatory bowel disease or active, symptomatic GI bleeding were not included in studies. Medications most commonly taken by dialysis patients can be taken concomitantly with ferric citrate. Patients taking doxycycline should take doses at least 1 hour before and ciprofloxacin 2 hour before or after taking ferric citrate.19 Oral citrate has been known to increase GI absorption of aluminum. Serum aluminum levels were followed in the long-term 52-week study. For the 185 participants in the ferric citrate arm, the median aluminum level was 6.0 (5-24, range) μg/L at baseline and 7.0 (5-23, range) μ/L at week 52. For the active control arm, baseline levels were 6.0 (5-14) μ/L and 6.0 (5-15) μ/L at week 52. Researchers concluded that there were no meaningful changes in aluminum levels observed in the study between either group (P = .1).51
The recommended starting dose for ferric citrate is 2 tablets three times per day with each meal with titration every 1 to 2 weeks based on serum PO4 levels until target range is reached, up to a maximum dose of 12 tablets daily. Ferric citrate is contraindicated with patients who have iron overload syndromes such as hemochromatosis.19 Additionally, patients' iron statuses should be monitored so that adjustments can be made in IV iron therapy to keep levels in therapeutic ranges.19
In vitro PBC of ferric citrate showed the amount of bound PO4 and the reaction conditions of pH 2 to 7 was 46 ± 2 mg PO4/g of ferric citrate.52 Daugirdas lists the PBED for 1 tablet as 0.64 such that 9 tablets are required to get equivalent dose of 6 g calcium carbonate.30
Novel Approaches to Phosphate Control
Two novel ways to approach controlling serum PO4 levels used in the past few years are the use of niacin and the use of chitosan-containing chewing gum.
Niacin and nicotinamide reduce phosphate absorption by inhibiting intestinal sodium–phosphate cotransporter-2b. In an 8-week trial using nicotinamide in addition to the patient's PO4 binder, serum PO4 was lowered from 6.45 mg/dL to 5.28 mg/dL.20 Using these products in addition to PO4 binder therapy may be a benefit as it has been shown that both PO4 dietary restrictions and the use of PO4-binding agents can cause an upregulation of intestinal sodium–phosphate cotransporter-2b which may allow for high PO4 absorption when PO4 binder doses are either skipped or inappropriately low for the meal phosphate load.53
Binding salivary phosphate is a newer approach to improving serum phosphate levels in the CKD population.54 Chitin is a cellulose-like biopolymer found mainly in the exoskeleton of crustaceans that has been used in water purification plants to absorb greases, oils, metals, and toxic substances. Studies using chitosan chewing gum to bind salivary phosphate have shown mixed results in improving serum phosphate.17, 21, 55, and 56 Overall, chitosan is not an effective phosphate binder; it may improve fluid control by controlling thirst.
Improving serum PO4 levels continues to be a primary goal in the nutrition and medical management of the CKD patient on dialysis. Multiple strategies are used to control serum PO4 levels including phosphate-binding agents, dietary phosphate restrictions, and adequate dialysis therapy. The number of phosphate-binding agents has increased over the past 40 years giving practitioners a variety of agents and forms (powder, liquid, wafer, pills) to tailor binder regimens to the patient's preference, tolerance, phosphate load, comorbidities, and contraindications. Some binders provide additional benefits such as reducing serum cholesterol levels and increasing iron stores, whereas others require minimal dosing to be effective. Tools, such as the PBED and RPBC, allow the health care provider to determine equivalent doses for the many binder compounds. Barring lack of insurance coverage, we have a lot more weapons to battle hyperphosphatemia in our arsenal.
Over the last 2 decades, the number of FDA-approved phosphate-binding agents has increased. This article serves as a tool for practitioners to use when comparing potential phosphate binders. Additionally, the phosphate-binding equivalent dose (PBED) in conjunction with package insert dosing instructions can be used to guide dosing when therapies are changed.
The author thanks Dr. John Daugirdas for his review of the phosphate-binding capacity section. This article was researched and written with support from Keryx Biopharmaceuticals, Inc.
- 1 G.A. Block, P.S. Klassen, J.M. Lazarus, N. Ofsthun, E.G. Lowrie, G.M. Chertow. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15:2208-2218 Crossref
- 2 W.Y. Qunibi, C.A. Nolan, J.C. Ayus. Cardiovascular calcification in patients with end-stage renal disease: a century-old phenomenon. Kidney Int Suppl. 2002;62:S73-S80 Crossref
- 3 L.A. Stevens, O. Djurdjev, S. Cardew, E.C. Cameron, A. Levin. 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. J Am Soc Nephrol. 2004;15:770-779 Crossref
- 4 S.A. Jamal, B. Vandermeer, P. Raggi, et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet. 2013;382:1268-1277 Crossref
- 5 R.R. Bailey, J.B. Eastwood, E.M. Clarkson, et al. The effect of aluminium hydroxide on calcium, phosphorus and aluminium balances and the plasma parathyroid hormone in patients with chronic renal failure. Clin Sci. 1971;41:5P-6P
- 6 G.M. Chertow, S.K. Burke, P. Raggi, Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int. 2002;62:245-252 Crossref
- 7 G.A. Block, D.M. Spiegel, J. Ehrlich, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int. 2005;68:1815-1824 Crossref
- 8 G.A. Block, P. Raggi, A. Bellasi, L. Kooienga, D.M. Spiegel. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int. 2007;71:438-441 Crossref
- 9 D.M. Spiegel, P. Raggi, G. Smits, G.A. Block. Factors associated with mortality in patients new to haemodialysis. Nephrol Dial Transplant. 2007;22:3568-3572 Crossref
- 10 Q. Zhang, M. Li, Y. Lu, et al. Meta-analysis comparing sevelamer and calcium-based phosphate binders on cardiovascular calcification in hemodialysis patients. Nephron Clin Pract. 2010;115:c259-c267 Crossref
- 11 Genzyme Corporation. About Genzyme. Cambridge, MA. Available at: http://www.genzyme.com/Company/About-Genzyme.aspx Accessed April 1, 2015.
- 12 Drugs@FDA Approved Drug Products Database. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm Accessed April 1, 2015.
- 13 Fosrenol [Prescribing Information] (Shire US Inc., Wayne, PA, 2014)
- 14 Phoslyra [Prescribing Information] (Fresenius Medical Care North America, Waltham, MA, 2011)
- 15 Renvela [Prescribing Information] (Genzyme Corporation, Cambridge, MA, 2009)
- 16 T. Akizawa, H. Origasa, C. Kameoka, Y. Kaneko, S. Kawasaki, Bixalomer Study Group. Randomized controlled trial of bixalomer versus sevelamer hydrochloride in hemodialysis patients with hyperphosphatemia. Ther Apher Dial. 2014;18:122-131 Crossref
- 17 T. Akizawa, Y. Tsuruta, Y. Okada, et al. Effect of chitosan chewing gum on reducing serum phosphorus in hemodialysis patients: a multi-center, randomized, double-blind, placebo-controlled trial. BMC Nephrol. 2014;15:98 Crossref
- 18 Velphoro [Prescribing Information] (Fresenius Medical Care North America, Waltham, MA, 2013)
- 19 Auryxia [Prescribing Information] (Keryx Biopharmaceuticals, New York, NY, 2014)
- 20 S.C. Cheng, D.O. Young, Y. Huang, J.A. Delmez, D.W. Coyne. A randomized, double-blind, placebo-controlled trial of niacinamide for reduction of phosphorus in hemodialysis patients. Clin J Am Soc Nephrol. 2008;3:1131-1138 Crossref
- 21 G.A. Block, M.S. Persky, B.M. Shamblin, et al. Effect of salivary phosphate-binding chewing gum on serum phosphate in chronic kidney disease. Nephron Clin Pract. 2013;123:93-101 Crossref
- 22 National Kidney Foundation. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42:S1-S201
- 23 Renagel [Prescribing Information]. 2014. Cambridge, MA 02142: Genzyme Inc.
- 24 J.T. Daugirdas, W.F. Finn, M. Emmett, G.M. Chertow, Frequent Hemodialysis Network Trial Group. The phosphate binder equivalent dose. Semin Dial. 2011;24:41-49 Crossref
- 25 J.T. Daugirdas, G.M. Chertow, B. Larive, et al. Effects of frequent hemodialysis on measures of CKD mineral and bone disorder. J Am Soc Nephrol. 2012;23:727-738 Crossref
- 26 Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int. 2009;79:S1-S130
- 27 V. Savica, G. Bellinghieri, P. Monardo, U. Muraca, D. Santoro. An update on calcium metabolism alterations and cardiovascular risk in patients with chronic kidney disease: questions, myths and facts. J Nephrol. 2013;26:456-464 Crossref
- 28 D.M. Spiegel, G.A. Block. Should we be using calcium-containing phosphate binders in patients on dialysis?. Nat Clin Pract Nephrol. 2008;4:118-119 Crossref
- 29 G.M. Chertow, K.J. Martin. Current and future therapies for the medical management of secondary hyperparathyroidism. Semin Dial. 1998;11:267-270
- 30 J.T. Daugirdas, P. Blake, T. Ing. Bone disease. Wolters Kluwer Health. Philadelphia, PA Handbook of dialysis 5th ed. (Wolters Kluwer Health, Philadelphia, PA, 2015)
- 31 S. Pflanz, I.S. Henderson, N. McElduff, M.C. Jones. Calcium acetate versus calcium carbonate as phosphate-binding agents in chronic haemodialysis. Nephrol Dial Transplant. 1994;9:1121-1124 Crossref
- 32 B.Y. Choy, W.K. Lo, I.K.P. Cheng. Effectiveness of calcium acetate as a phosphate binder in patients undergoing continuous ambulatory peritoneal dialysis. Hong Kong Med J. 1998;4:23-26
- 33 I. Saif, A. Halim, A. Altaf, et al. Comparison of calcium acetate with calcium carbonate as phosphate binder in patients on maintenance haemodialysis. J Ayub Med Coll Abbottabad. 2007;19:26-28
- 34 Phoslo [Prescribing Information] (Fresenius Medical Care North America, Waltham MA, 2014)
- 35 E. Slatopolsky, S.K. Burke, M.A. Dillon. RenaGel, a nonabsorbed calcium- and aluminum-free phosphate binder lowers serum phosphorus and serum parathyroid hormone. The RenaGel Study Group. Kidney Int. 1999;55:299-307 Crossref
- 36 A.J. Bleyer, S.K. Burke, M. Dillon, et al. A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients. Am J Kidney Dis. 1999;33:694-701 Crossref
- 37 C. Zhang, J. Wen, Z. Li, J. Fan. Efficacy and safety of lanthanum carbonate on chronic kidney disease-mineral and bone disorder in dialysis patients: a systematic review. BMC Nephrol. 2013;14:226
- 38 A.J. Hutchison, M. Speake, F. Al-Baaj. Reducing high phosphate levels in patients with chronic renal failure undergoing dialysis: a 4-week, dose-finding, open-label study with lanthanum carbonate. Nephrol Dial Transplant. 2004;19:1902-1906 Crossref
- 39 W.F. Finn, M.S. Joy, G. Hladik, Lanthanum Study Group. Efficacy and safety of lanthanum carbonate for reduction of serum phosphorus in patients with chronic renal failure receiving hemodialysis. Clin Nephrol. 2004;62:193-201 Crossref
- 40 S.M. Sprague. A comparative review of the efficacy and safety of established phosphate binders: calcium, sevelamer, and lanthanum carbonate. Curr Med Res Opin. 2007;23:3167-3175 Crossref
- 41 J. Haratake, C. Yasunaga, A. Ootani, S. Shimajiri, A. Matsuyama, M. Hisaoka. Peculiar histiocytic lesions with massive lanthanum deposition in dialysis patients treated with lanthanum carbonate. Am J Surg Pathol. 2015;39:767-771 Crossref
- 42 P.C. D'Haese, G.B. Spasovski, A. Sikole, et al. A multicenter study on the effects of lanthanum carbonate (Fosrenol) and calcium carbonate on renal bone disease in dialysis patients. Kidney Int Suppl. 2003;63:S73-S78 Crossref
- 43 H.H. Malluche, G.A. Siami, C. Swanepoel, et al. Improvements in renal osteodystrophy in patients treated with lanthanum carbonate for two years. Clin Nephrol. 2008;70:284-295
- 44 G.B. Spasovski, A. Sikole, S. Gelev, et al. Evolution of bone and plasma concentration of lanthanum in dialysis patients before, during 1 year of treatment with lanthanum carbonate and after 2 years of follow-up. Nephrol Dial Transplant. 2006;21:2217-2224 Crossref
- 45 P. Martin, P. Wang, A. Robinson, et al. Comparison of dietary phosphate absorption after single doses of lanthanum carbonate and sevelamer carbonate in healthy volunteers: a balance study. Am J Kidney Dis. 2011;57:700-706 Crossref
- 46 M. Wilhelm, S. Gaillard, V. Rakov, F. Funk. The iron-based phosphate binder PA21 has potent phosphate binding capacity and minimal iron release across a physiological pH range in vitro. Clin Nephrol. 2014;81:251-258 Crossref
- 47 R.P. Wuthrich, M. Chonchol, A. Covic, S. Gaillard, E. Chong, J.A. Tumlin. Randomized clinical trial of the iron-based phosphate binder PA21 in hemodialysis patients. Clin J Am Soc Nephrol. 2013;8:280-289 Crossref
- 48 J. Floege, A.C. Covic, M. Ketteler, et al. A phase III study of the efficacy and safety of a novel iron-based phosphate binder in dialysis patients. Kidney Int. 2014;86:638-647 Crossref
- 49 J. Floege, A.C. Covic, M. Ketteler, et al. Long-term effects of iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients. Nephrol Dial Transplant. 2015;30:1037-1046 Crossref
- 50 J.P. Dwyer, M. Sika, G. Schulman, et al. Dose-response and efficacy of ferric citrate to treat hyperphosphatemia in hemodialysis patients: a short-term randomized trial. Am J Kidney Dis. 2013;61:759-766 Crossref
- 51 P.N. Van Buren, J.B. Lewis, J.P. Dwyer, et al. The phosphate binder ferric citrate and mineral metabolism and inflammatory markers in maintenance dialysis patients: results from prespecified analyses of a randomized clinical trial. Am J Kidney Dis. 2015;66:479-488 Crossref
- 52 J. Lewis, M. Sika, M. Koury, et al. Ferric citrate controls phosphorus and delivers iron in dialysis patients. J Am Soc Nephrol. 2015;26:493-503 Crossref
- 53 A. Lida, Y. Kemmochi, K. Kakimoto, et al. Ferric citrate hydrate, a new phosphate binder, prevents the complications of secondary hyperparathyroidism and vascular calcification. Am J Nephrol. 2013;37:346-358
- 54 H. Giral, Y. Caldas, E. Sutherland, et al. Regulation of rat intestinal Na-dependent phosphate transporters by dietary phosphate. Am J Physiol Renal Physiol. 2009;297:F1466-F1475 Crossref
- 55 V. Savica, L.A. Calo, D. Santoro, et al. Salivary glands: a new player in phosphorus metabolism. J Ren Nutr. 2011;21:39-42 Crossref
- 56 V. Savica, L.A. Calo, P. Monardo, et al. Salivary phosphate-binding chewing gum reduces hyperphosphatemia in dialysis patients. J Am Soc Nephrol. 2009;20:639-644 Crossref
Davita, Inc., Denver, CO, Keryx Biopharmaceuticals, New York, New York
∗ Address correspondence to Lisa Gutekunst, MSEd, RD, CSR, CDN, FNKF, 1542 Maple Road, Williamsville, New York 14221.
This article has an online CPE activity available at www.kidney.org/professionals/CRN/ceuMain.cfm
Support: See Acknowledgments on page 216.
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