Reviews

The Phosphate Binder Equivalent Dose

John T. Daugirdas,* William F. Finn, Michael Emmett, Glenn M. Chertow, and the Frequent Hemodialysis Network Trial Group1
*University of Illinois at Chicago, Chicago, Illinois, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, Baylor University Medical Center, Dallas, Texas, and Stanford University School of Medicine, Palo Alto, California

ABSTRACT Phosphate binders include calcium acetate or carbonate, sevelamer hydrochloride or carbonate, magnesium and lanthanum carbonate, and aluminum carbonate or hydroxide. Their relative phosphate-binding capacity has been assessed in human, in vivo studies that have measured phosphate recovery from stool and or changes in urinary phosphate excretion or that have compared pairs of different binders where dose of binder in each group was titrated to a target level of serum phosphate. The relative phosphate-binding coefcient (RPBC) based on weight of each binder can be estimated relative to calcium carbonate, the latter being set to 1.0. A systematic review of these studies gave the following estimated RPBC: for elemental lanthanum, 2.0, for sevelamer hydrochloride or carbonate 0.75, for calcium acetate 1.0, for anhydrous magnesium carbonate 1.7, and for heavy or hydrated, magnesium carbonate 1.3. Estimated RPBC for aluminum-containing binders were 1.5 for aluminum hydroxide and 1.9 for aluminum carbonate. The phosphate-binding equivalent dose was then dened as the dose of each binder in g its RPBC, which would be the binding ability of an equivalent weight of calcium carbonate. The phosphate-binding equivalent dose may be useful in comparing changes in phosphate binder prescription over time when multiple binders are being prescribed, when estimating an initial binder prescription, and also in phosphate kinetic modeling.

Several commercially available phosphate binders (calcium acetate, calcium carbonate, lanthanum carbonate, sevelamer carbonate and or hydrochloride, and magnesium- or aluminum-containing products) are used alone and in combination to help control hyperphosphatemia in patients on dialysis. While clinical trials have compared pairs of alternative binders head-tohead, understanding the relative phosphate-binding capacities of all binders is important and necessary to optimally control hyperphosphatemia in clinical practiceparticularly where multiple binders are often used in combination. In the Frequent Hemodialysis Network (FHN) (1) trial, we faced the issue of needing to determine the effects of more frequent hemodialysis on the control of hyperphosphatemia in a situation where patients often were taking multiple binders, and where the doses of multiple binders were changed between randomization and follow-up, or where binders were substituted between randomization and follow-up. To decide whether the total phosphate-binder load was reduced, we needed to determine the relative potency of multidrug phosphate-binder prescriptions at different time points. To do this, we reviewed the literature and attempted to
Address correspondence to: John T. Daugirdas, MD, University of Illinois at Chicago, 820 South Wood Street, Chicago, IL 60612, or e-mail: jtdaugir@uic.edu. 1 FHN Investigators (full list in Ref. 1). Seminars in DialysisVol 24, No 1 (JanuaryFebruary) 2011 pp. 4149 DOI: 10.1111/j.1525-139X.2011.00849.x 2011 Wiley Periodicals, Inc. 41

establish an equivalent phosphate-binding dose for each commercially available phosphate binder. Stool Phosphate Recovery Studies One way to determine phosphate binding in vivo is to measure stool phosphate after a test meal and then, at either a preceding or subsequent time, give the same meal in conjunction with a phosphate binder. The difference in stool phosphate collected after meals given with and without the phosphate binder will reect the amount of phosphate bound. A number of such studies have been carried out. Calcium Carbonate and Calcium Acetate Four studies (25) were carried out by the group at Baylor University Medical Center (BUMC-Dallas), two in healthy volunteers, and two in patients on hemodialysis (Table 1). All had the same basic design. First, the bowel was cleansed with an intestinal lavage. Then, in random fashion, subjects ingested a meal (usually steak, cheese, and potatoes, containing 300350 mg of phosphate) with placebo, the identical meal with a phosphate binder, or subjects were fasted except for water. After 10 hours, a second lavage was performed and the stool collected and analyzed. Complete collection was assessed by measurement of a tracer dose of ingested polyethylene glycol. Phosphate binders used in these four studies included calcium carbonate, calcium

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Daugirdas et al.
TABLE 1. Phosphate-binder studies using single-meal stool recovery technique Healthy volunteers Sheikh (1989) n = 10 50 mEq (3.95 g Ca acetate or 2.5 g CaCO3) Schiller (1989) n=5 Pratt (2010) n = 31 2.4 g sevelamer carbonate or 1.0 g elemental lanthanum (as lanthanum carbonate) Phosphate-binding mg phosphate g binder 44 45 41 135a 26.3 15 27 19 Ramirez (1986) n=5 CKD5D Mai (1989) n=6 50 mEq (3.95 g Ca acetate or 2.5 g CaCO3)

Dose of each binder Units Ca acetate CaCO3 (tabs) CaCO3 (powder) Lanthanum carbonate Sevelamer carbonate
a

50 mEq (2.5 g CaCO3)

75 mEq (3.75 g CaCO3)

g binder calculated as elemental lanthanum, not lanthanum carbonate.

acetate, and several aluminum-containing preparations. Binder doses used contained either 50 or 75 mEq of cation. In healthy volunteers (2,3), the phosphate-binding potencies of calcium acetate and calcium carbonate were similar, about 45 mg phosphate bound per g of salt (Table 1). However, because, by weight, calcium acetate is only 25% calcium, whereas calcium carbonate is 40% calcium, the binding per unit of elemental calcium was higher for acetate than carbonate. When identical experiments were carried out in patients on dialysis (4,5), phosphate binding by all studied agents was lower. Phosphate binding by calcium carbonate was 1519 mg g (4,5) and by calcium acetate was 27 mg g. In terms of a relative phosphate-binding coefcient, we arbitrarily set the phosphate-binding efciency of calcium carbonate, based on how many mg phosphate are bound per g calcium carbonate, to 1.0 as a reference standard. Then we dened a relative phosphate-binding coefcient (RPBC) for calcium acetate by calculating the phosphate bound per g of calcium acetate relative to amount bound per g of carbonate. In the BUMC-Dallas stool recovery studies, the RPBC for calcium acetate would be 1.0 in healthy volunteers, because phosphate binding was 44 mg phosphate per g of calcium acetate compared with 45 mg phosphate bound per g of calcium carbonate, and 44 45 = 1.0. In patients on dialysis, the RPBC of calcium acetate was higher, 27 mg phosphate bound per g of calcium acetate compared with 19 mg phosphate bound per g of calcium carbonate in the Mai et al. study where the same patients were exposed to both binders, for a ratio of 27 19 = 1.4. Sevelamer Carbonate and Lanthanum Carbonate Using a similar design to the BUMC studies, Pratt et al. (6) gave meals containing 380 mg of phosphate to 31 healthy volunteers along with placebo or either lanthanum carbonate (1.0 g elemental lanthanum) or 2.4 g of sevelamer carbonate. With lanthanum, fecal phosphate recovery was decreased by 135 mg, or 135 mg g

of elemental lanthanum. With sevelamer, the reduction was 26 mg g of sevelamer carbonate. If we consider the single-meal stool recovery studies in aggregate, we nd that 1 g of calcium acetate or carbonate in healthy volunteers binds about 45 mg of phosphate, 1 g of lanthanum binds 135 mg, and 1 g of sevelamer binds 26 mg. The RPBC values can then be estimated as 1.0 for calcium acetate, 0.58 for sevelamer carbonate, and 2.9 for elemental lanthanum (44 45, 26 45, and 135 45, respectively). Some caution must be used when interpreting the RPBC values for sevelamer and lanthanum, as calcium carbonate binders were not tested in the Pratt et al. study (6). Studies of Urinary Phosphate Excretion A number of studies have examined the phosphatebinding capacity of various agents by looking at urinary phosphate excretion with and without phosphate binders. The difference in excretion is presumed to be a consequence of phosphate binding in the gut, with reduced phosphate absorption leading to decreased urinary excretion. Calcium Carbonate In a study of patients with chronic kidney disease (CKD) (mean GFR 26 ml minutes), 2.0 g calcium carbonate reduced urinary phosphate excretion from 496 to 413 mg per 24 hours or by 41.5 mg g of calcium carbonate (7). In a group of 12 healthy volunteers, 4.0 g of calcium carbonate reduced urinary phosphate excretion from 968 to 862 mg or 26.5 mg g (8). These binding values are similar to, although somewhat less than, those obtained on the basis of changes in fecal excretion (2). Sevelamer Hydrochloride Burke et al. (9) evaluated the phosphate-binding capacity of sevelamer hydrochloride in 24 normal volunteers separated into four groups of six each. For 18 days,

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the subjects were fed a 1200-mg phosphate diet. During days 5 through 9, subjects were given either a placebo or sevelamer hydrochloride in divided doses of 3.0, 7.5, or 15 g day, respectively. Urinary phosphorus excretion was measured throughout while fecal phosphorus excretion was measured only in the placebo group and in the group receiving the highest dose of sevelamer hydrochloride. In the placebo-treated subjects, the average amount of phosphate recovered in the stool was 342 mg. At the same time, the average urinary phosphate excretion was 870 mg. Thus, the combined urinary and fecal phosphate excretion was nearly identical to the amount of phosphate in the diet and suggested that 70% of the dietary phosphate was absorbed. In the subjects given 15 g of sevelamer per day, the urinary phosphate excretion was reduced by 530 mg while fecal phosphate increased by 611 mg. The combined urinary and fecal phosphate excretion was within 5% of the phosphate in the diet and suggested that intestinal phosphate absorption had been reduced to 50%. The close approximation of the net phosphate recovery from urine and stool with the dietary phosphate supports the notion that a change in urinary phosphate excretion by itself is a suitable estimate of changes in intestinal phosphate absorption. Using the decrease in urine phosphate excretion with the 15 g dose, the binding capacity of sevelamer hydrochloride at that dose was 23 mg g. Burke et al. also studied lower doses of sevelamer. With 3.0 g sevelamer per day, the urinary phosphate excretion was 108 mg less than control or 36 mg g, and with 7.5 g day sevelamer, urinary phosphate excretion was 246 mg less than control, or 33 mg g. Thus, phosphate binding per g of sevelamer was inversely related to sevelamer dose. Russo et al. (10) did a study with an even lower dose of sevelamer, 1.6 g day, and found phosphate binding to be 50 mg g, while Heinrich et al. (8), using 6.4 g day sevelamer, measured phosphate binding of 32 mg g. Lanthanum Carbonate The phosphate-binding capacity of lanthanum carbonate was assessed by Sprague et al. (11) by measuring changes in urinary phosphate excretion. This study was not carried out in healthy volunteers but in 121 patients with CKD stages 3 and 4 (estimated glomerular ltration rate 1559 ml minutes 1.73 m2. Subjects were randomized to receive either lanthanum carbonate or placebo. Doses of lanthanum or placebo were titrated up to 3.0 g day over an 8-week period to achieve the desired level of control in serum phosphate. At week 4, the average lanthanum dose (as elemental lanthanum) was 1.93 g day, and at 8 weeks, it was 2.65 g day. As shown in the Appendix, the phosphate-binding ability of lanthanum at these two dose levels was 96 and 75 mg phosphate per g of elemental lanthanum. In an abstract presented at the ASN 2008 Renal Week, Finn and Kingman (12) summarized experience with reduction in urinary lanthanum excretion in 325 healthy volunteers with presumed normal renal function and in 41 patients with CKD stages 3 and 4. Subjects were tested taking either 3.0 g day (healthy volunteers) or 2.3 g day (patients

with CKD) of lanthanum. In the healthy volunteers, who took the higher dose of lanthanum, the average reduction in phosphate excretion was 95 mg g of lanthanum, and in the patients with CKD, who took the 2.3 g day dose, phosphate binding was slightly higher, 114 mg g of lanthanum. Combining Results of Stool and Urine Recovery Studies If one attempts to analyze the results from stool recovery and urinary phosphate studies in combination, the data do seem to agree reasonably well. For sevelamer, in the study by Burke et al. (9), the middle sevelamer dose range of 7.5 g day corresponds roughly to the 2.4 g meal given in the stool recovery study by Pratt et al. (described in Table 1). From urinary recovery, at this 7.5 g day sevelamer dose, phosphate binding was 33 mg g sevelamer, a value similar to the 26 mg g in the Pratt stool recovery study. The RPBC of sevelamer hydrochloride can be approximated by comparison with the Ca carbonate phosphate-binding value of 45 mg g found in Sheikh et al. (2). Thus, at a moderate, midrange dose, the RPBC for sevelamer would be 33 45 = 0.73 based on the Burke et al. study (9) and 26 45 = 0.58 from the Pratt et al. study (6). With respect to lanthanum, one can average the data from Sprague (75 mg phosphate bound per g when 2.65 g day were given) and Finn (95 mg phosphate bound per g at a dose of 3.0 g day) to get an average value of 85 mg phosphate bound per g of lanthanum (11,12), somewhat lower than the 135 mg phosphate bound per g of lanthanum in the single-meal stool recovery studies (2). Relative Phosphate Binding in Parallel-Group Trials A third set of studies can be used to conrm the RPBC estimates derived from stool and urinary collection studies. These are parallel group trials where two or more binders were studied and where the dose of each binder was titrated to achieve a given target level of serum phosphate. This last group of trials, performed in actual dialysis patients in a clinical setting should be the most generalizable, and RPBC values from such trials were weighted heavily in our analysis. A recent review (13) has compiled a large number of such trials; unfortunately, in some, the binder dose was not completely specied, and in others, the binder doses were not titrated to closely similar serum phosphate levels. However, if we analyze the main trials in which detailed binder data was given, a picture of the RPBC of different binders begins to emerge. Calcium Acetate vs. Calcium Carbonate Stool recovery studies in healthy subjects (2) suggest that the RPBC of calcium acetate relative to carbonate is close to 1.0. Do parallel dose studies in dialysis patients

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Daugirdas et al. of calcium acetate. In the subsequent CARE-2 study (21), sevelamer hydrochloride and calcium acetate were titrated to achieve a similar target serum phosphate concentration. The dose of calcium acetate at the end of the study was 5.5 g vs. 7.3 g for sevelamer, a dose ratio of 0.75. Thus, CARE-2 would support a RPBC for sevelamer of 0.75. In the large DCOR study (22), in which 2103 patients were randomized to sevelamer vs. calcium acetate or carbonate, serum phosphate control after titration was similar between the two groups (very slightly lower in the calcium arm), and the nal doses of binders averaged 5.3 g day for calcium acetate (70% of patients in the calcium arm took acetate), 4.9 g day for calcium carbonate, vs. 6.9 g for sevelamer. The weighted average for calcium binders would be 5.2 g day, yielding an RPBC for sevelamer of 0.75. Evenepoel et al. (23) randomized 143 peritoneal dialysis patients to sevelamer hydrochloride or calcium acetate, and patients wound up taking either 5.8 g day of sevelamer of 4.5 g day of calcium acetate to achieve a similar level of serum phosphate control. The results suggested an RPBC of 4.5 5.8 = 0.78. Similarly, Ferreira et al. (24) randomized 91 patients to receive sevelamer or calcium-based binders. Serum phosphate control seemed to be somewhat less good with sevelamer, at a time when the nal doses for sevelamer and calciumbased binders averaged 4.0 and 5.0 g day, respectively, suggesting that the RPBC for sevelamer should be less than 0.80. A trial by Asmus et al. (25) randomized 72 patients between sevelamer and calcium carbonate for 2 years. After a 1-year-dose-titration period, achieving similar levels of serum phosphate, the doses of sevelamer and calcium carbonate were 6.9 and 4.3 g day, respectively, giving an RPBC for sevelamer of 0.62. A number of additional randomized trials have been carried out comparing sevelamer with calcium-containing binders (13), and in some of these, the RPBC for sevelamer is as high as 0.85 to 0.95. However, in the largest trials, cited above, the RPBC for sevelamer seems to be close to 0.75. Lanthanum Studies In Hutchison et al. (26), 800 hemodialysis patients were randomly allocated to receive either lanthanum or CaCO3. At week 22, the patient groups had almost identical levels of serum phosphate control and were receiving an average of either 4.0 g day of CaCO3 or 2.0 g of elemental lanthanum. This result supports an RPBC for lanthanum of 2.0, similar to the value derived from stool and urinary recovery experiments. A similar study was carried out by DHaese et al. (27), who randomized 98 patients to receive either lanthanum carbonate or CaCO3. At the conclusion of the study, the median dose of calcium carbonate was 2.0 g day vs. 1.25 g day for lanthanum, suggesting a lower RPBC of 1.6. Sprague et al. (28) compared lanthanum carbonate and sevelamer hydrochloride in a parallel group trial.

support this notion? dAlmeida et al. (14) compared serum phosphate in patients given either 5.6 g day of calcium acetate or 6.2 g day of calcium carbonate in a randomized, crossover design. Twenty-three patients completed the study. The change in serum phosphate was similar, although the decrease in serum phosphate tended to be greater in the calcium carbonate treatment period, consistent with the 10% higher dose (as weight of salt) of calcium carbonate used in the study; the dAlmeida study thus supports an RPBC of 1.0 for calcium acetate. In a similarly designed, albeit small study, Almirall et al. (15) gave an average of 4.0 g day of acetate or carbonate to 10 dialysis patients and found equivalent control of serum phosphate. Wallot et al. (16) found similar results in an adolescent population. Naghibi et al. (17) found that a 10% lower dose of calcium acetate controlled serum phosphate better than calcium carbonate, suggesting that the RPBC for calcium acetate might be somewhat greater than 1.0. A number of other parallel group comparisons of calcium acetate vs. carbonate have been made, but the doses of acetate given were considerably lower than those of carbonate, making it difcult to interpret those results in terms of an RPBC for calcium acetate. Sevelamer vs. Calcium Carbonate/Calcium Acetate Studies A number of randomized trials have compared the phosphate-binding capacity of sevelamer (hydrochloride or carbonate) with either calcium carbonate or calcium acetate. If we assume RPBC values of 1.0 for calcium acetate and 0.70 for sevelamer, we can compute phosphate binder equivalent dose (PBED) values for each of these trials, to see how well each trial might validate these candidate RPBC values. In a study by Bleyer et al. (18), 83 patients were randomized to receive either calcium acetate or sevelamer hydrochloride, and the dose of each binder was titrated to achieve more or less equal serum phosphate levels. The nal mean doses of calcium acetate and sevelamer after titration were similar, 5.0 and 4.9 g day respectively, suggesting that an RPBC of 0.70 for sevelamer was an underestimate, and that the value should be close to 1.0. The Treat-to-Goal study (19) compared serum phosphate control with 6.5 g of sevelamer hydrochloride vs. 4.6 g of calcium acetate in the US or 3.9 g of calcium carbonate in Europe. Averaging the US and European doses (4.3 g day) and assuming an RPBC of 1.0 for calcium acetate, the average PBED for the calcium binder arm of the TTG study would be 4.3 g day. The Treatto-Goal study results are consistent with a RPBC value for sevelamer hydrochloride of slightly less than 0.70, about 0.66. The CARE study (20) compared serum phosphate control with 6.0 g day of sevelamer hydrochloride vs. 6.0 g day of calcium acetate. Serum phosphate control with sevelamer hydrochloride was moderately and signicantly poorer than with calcium acetate, supporting the notion that the RPBC of sevelamer is lower than that

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Following a washout period, 182 patients on hemodialysis were randomized to receive either 2.253.0 g day lanthanum carbonate (as elemental lanthanum), or 4.86.4 g day of sevelamer hydrochloride for 4 weeks. After a 2-week washout, subjects were switched to the alternative binder. At the end of the study, patients were receiving 3.0 g day lanthanum or 6.4 g day sevelamer. If one assumes an RPBC of 2.0 for lanthanum, then the PBED used would be 2.0 3.0 = 6 g day, vs. 0.75 6.4 = 4.8 g day, higher for the lanthanum group. In fact, the serum P control was slightly better in the lanthanum group. Magnesium Most phosphate-binding equivalence data comes from parallel or sequential studies where part of a calcium carbonate or calcium acetate regimen was replaced by magnesium and the dose of magnesium titrated to a given target serum phosphate level. One such report was by Delmez et al. (29), who in a 2-year study attempted to replace approximately half of a calcium carbonate-based phosphate-binding regimen with magnesium. As detailed in the Appendix, the RPBC of MgCO3, in this study (when expressed in terms of weight of anhydrous MgCO3 was 2.6. However, the Delmez et al. study may have been confounded by the differing amounts of calcitriol given to the two groups and its sequential (as opposed to parallel-dose) design. The RPBC value for anhydrous MgCO3 derived from the Delmez et al. study must therefore be considered with caution. In a randomized (2:1) parallel group study, Spiegel et al. (30) compared serum phosphate control with calcium acetate vs. Magnebind, a combination of magnesium and calcium carbonate containing 86 mg of elemental Mg and 101 mg of elemental Ca per pill. As detailed in the Appendix, the level of serum phosphate control in this study suggests that the RPBC of MgCO3 (anhydrous weight) is around 1.7, considerably less than the 2.6 value in the Delmez et al. study. In the CALMAG study, de Francisco et al. (31) compared serum phosphate control between a mixture of calcium acetate and hydrated (heavy) magnesium carbonate (Osvaren) with sevelamer hydrochloride. This was a randomized study in 326 patients on hemodialysis. The level of serum phosphate control was not statistically different, but did appear to be slightly better in the Osvaren-treated arm of the trial compared to the sevelamer arm. If the assumption is made that the RPBC for calcium acetate is 1.0 and RPBC for sevelamer is 0.75, and that the phosphate-binding capacity of the Osvarentreated arm was 10% higher than the sevelamer arm, then the RPBC of hydrated magnesium carbonate could be calculated to be 1.3 (see Appendix). This is somewhat lower than the RPBC of 1.7 computed for anhydrous MgCO3 in the study by Spiegel et al. (30) using Magnebind. Some, but not all of the difference may be because of the different formula weights of the anhydrous MgCO3 in Magnebind (84 Da) vs. the higher formula weight of the heavy magnesium carbonate in CALMAG (96 Da).

To compare the RPBC values for magnesium carbonate in the Spiegel et al. and de Francisco et al. (31) trials, one would need to multiply the RPBC of the hydrated magnesium (1.30) by 1.13 to adjust for the difference in formula weight. This would yield a value of 1.30 1.13 = 1.44; this 1.44 value is then similar to the RPBC of 1.7 for anhydrous magnesium carbonate suggested by Spiegel et al. (30). Another difculty in estimating a RPBC for magnesium in the de Francisco et al. study is the fact that the level of serum phosphate control was not quite the same in the two arms of the trial, and the calculations depend markedly on the assumed RPBC for calcium acetate and sevelamer, as detailed in the Appendix. Aluminum Aluminum-based binders are no longer commonly used because of risks of aluminum loading and toxicity. When aluminum salts are used, aluminum carbonate, Al2(CO3)2, and aluminum hydroxide, Al(OH)3, in either gel or tablet form are the products generally utilized. A number of stool and or urine recovery studies were carried out in the 1970s, in both healthy volunteers and patients with CKD (7,32,33) using aluminum hydroxide. Cam et al. (32) gave 100 ml (6.1 g) of Al(OH)3 to ve normal volunteers and two ESRD patients and measured the change in stool and urine recovery. The increase in stool P content and decrease in urinary P content were similar, averaging 465 mg, or 75 mg g Al(OH)3. Spencer et al. (33) gave a number of different aluminum and aluminum magnesium compounds to volunteers, including a similar dose (about 105 ml or 6.4 g) of Al(OH)3 to healthy volunteers, and found a reduction in urinary P excretion of about 390 mg day, and an increase in stool P of 520 mg day, or an average P change of 455 mg per 6.4 g binder, or 72 mg g Al(OH)3, very similar to the Cam et al. (32) data. Clarkson et al. (34) studied eight patients with stage 45 CKD and gave them 4.69.1 g day of Al(OH)3. In the ve patients given 6.1 g day, the difference in stool or urine P recovery was about 320 mg day, or 52 mg g of Al(OH)3. Normal subjects and patients on dialysis were also studied by the BUMC-Dallas group. In the BUMC-Dallas study of normal volunteers [Sheikh et al. (2)], aluminum carbonate bound 89 mg of phosphate per g of aluminum salt. In the BUMC study by Ramirez et al. (4), carried out in dialysis patients, the phosphate-binding potencies of 75 mEq of aluminum as aluminum carbonate tablets, aluminum carbonate suspension, or aluminum hydroxide tablets were compared with calcium carbonate (4). There was no statistical difference in phosphate binding. (Note the aluminum content of these compounds was directly measured). In that study, the amount of phosphate bound by 2.5 g of aluminum hydroxide or 2.0 g of aluminum carbonate was similar to that bound by 3.75 g. of calcium carbonate. Thus, in the Ramirez et al. study (4), the RPBC of aluminum hydroxide was 3.75 2.5 = 1.5, and for aluminum carbonate it was 3.75 2.0 = 1.9.

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TABLE 2. RPBC for various phosphate binders RPBC by g of compound listed in available product 1.0 1.0 1.7 1.3 1.5 1.9 0.75 2.0a

Data from the Cam (32) and Spencer (33) studies suggested that for aluminum hydroxide, about 75 mg phosphate were bound per g in normal volunteers, and a slightly lesser amount, 52 mg g, was bound in CKD patients (7). If one compares this to the Sheikh data of about 45 mg g for calcium carbonate in normals and 30 mg g in dialysis patients, the RPBC ratios are similar to the 1.5 value found in Ramirez et al. (4) (75 45 = 1.67, 52 30 = 1.73). The best comparison of relative phosphate binding ability of aluminum vs. calcium would be in a parallel group design studies. Most of the parallel group trials that compared aluminum-containing phosphate binders with other phosphate binders compared aluminum hydroxide with calcium carbonate. One such trial was by Slatopolsky et al. (35), where equivalent serum phosphorus control was achieved with 8.5 g day of calcium carbonate and 5.6 g day of aluminum hydroxide. The RPBC of aluminum hydroxide from this study would be 8.5 5.6 = 1.52, almost identical to the RPBC inferred from the stool recovery data in the Ramirez et al. paper (4). Initial Estimated Relative Phosphate-Binding Coefcients Although a degree of uncertainty about the RPBC of different binders remains, we can use the data reviewed here to obtain the approximate RPBC shown in Table 2. Utilitarian Nature of the Relative PhosphateBinding Coefcient We elected to set up the RPBC using the dose measure of phosphate binder as listed on the medication product information form. Thus, lanthanum was expressed as mg phosphate bound per g elemental lanthanum, whereas calcium carbonate, calcium acetate, magnesium carbonate, sevelamer carbonate or hydrochloride, aluminum carbonate, and aluminum hydroxide are all expressed per mg of binder compound. Some of these binders are polymers, and hydrated magnesium carbonate is in a compound with 4 Mg atoms. Because the RPBC is determined on the basis of how the binder dose is described in the product label and how the medication is generally prescribed, this coefcient must be evaluated as a relative measure that in no way compares the true chemical potency of these compounds on a molar basis. For example, the RPBC of elemental lanthanum relative to calcium carbonate is 2.0, and this is calculated in terms of g of elemental lanthanum, because the pills and wafers made by Shire Pharmaceutical are sold in doses expressed as elemental lanthanum. However, if one were to compute the RPBC based on weight of lanthanum carbonate the adjusted RPBC would be 1.2, because 1.67 g anhydrous lanthanum carbonate is required to provide 1 g of elemental lanthanum. One clinical point pertains to the equivalent RPBC for calcium acetate and calcium carbonate. This does not imply an equivalent calcium load for the two bind-

Phosphate binder Calcium carbonate (index value) Calcium acetate Magnesium carbonate (anhydrous weight, Magnebind) Heavy magnesium carbonate (hydrated weight, OsvaRen) Aluminum hydroxide Aluminum carbonate Sevelamer (carbonate or hydrochloride) Lanthanum carbonate

RPBC, relative phosphate-binding coefcient. a Lanthanum carbonate tablet or wafer sizes are marketed as mg of elemental lanthanum. If based on mg of lanthanum carbonate the RPBC (relative to mg of CaCO3 would be 1.2 instead of 2.0.

ers; calcium acetate is only 25% calcium, while calcium carbonate is 40% calcium. A 4 g daily dose of calcium carbonate contains 1.6 g of calcium [higher than the maximum value of 1.5 g day calcium recommended by the KDOQI guidelines (36)], whereas 4 g of calcium acetate provides a substantially lower amount of calcium, i.e., 1.0 g day. Thus, on the basis of ingested calcium load, calcium acetate is a more potent phosphate binder than calcium carbonate. In Table 3, the RPBC are used in combination with commonly available preparation sizes for phosphate binders, to calculate a PBED (as g of CaCO3). Implications for Phosphate Balance and Phosphate-Binder Dosing Once the PBED of a given regimen is known, the actual amount of phosphate bound by any phosphatebinder prescription can be estimated, and this can be put into the context of what we know about phosphate balance. In healthy subjects following an unrestricted diet, phosphate intake averages 1500 mg in men and 1200 mg in womenwith considerable individual variation depending on protein intake and other dietary sources of phosphorus. Depending on vitamin D status, 6080% of ingested phosphorus is absorbed (36). In patients on dialysis, adequate protein intake is required to abrogate negative nitrogen balance; the recommended daily protein intake is 1.0 g kg or higher of the adjusted body weight (ABW) (37). The phosphorus load of most conventional diets is 15 mg of phosphorus per g of protein (3739). Consequently, with a dietary protein intake of 1.0 g kg ABW, a 60-kg ABW patient will ingest 900 mg day of phosphorus, while an 80-kg ABW patient may typically consume 1200 mg day. At these levels of phosphorus intake and with intestinal phosphorus absorption of 70%, the absorbable phosphorus burden can be expected to range from 630 mg to 840 mg day or 4410 mg to 5880 mg week. On average, about 8001000 mg of phosphorus is removed by a conventional dialysis session (40) which

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TABLE 3. PBED values for commonly used phosphate-binder tablets, capsules, or wafers Tablet capsule gel size (mg) 750 667 800 500 300 MgCO3 250 CaCO3 400 MgCO3 200 CaCO3 435 CaAcetate 235 Mg carbonate heavy 500 400 per 5 ml 500 Phosphate-binder equivalent dose (to g of CaCO3) per tablet 0.75 0.67 0.60 1.0 0.75 0.90 0.75 0.95 0.75 0.75

Binder Calcium carbonate Calcium acetate Sevelamer carbonate Lanthanum carbonate Magnebind 300a Magnebind 400a Osvaren Aluminum carbonate (Basaljel capsules) Aluminum carbonate (Basaljel suspension) Aluminum hydroxide (Dialume capsules)

Weight units used in tablet capsule gel Calcium carbonate Calcium acetate Sevelamer carbonate Elemental lanthanum Anhydrous magnesium carbonate, calcium carbonate Anhydrous magnesium carbonate, calcium carbonate Calcium acetate hydrated (Heavy magnesium carbonate Mg5(CO3)4(OH)25H2O) Aluminum carbonate Aluminum carbonate Aluminum hydroxide

PBED, phosphate binder equivalent dose. Except for calcium acetate, values are rounded to nearest 0.05. a Magnebind tablets are denominated according to anhydrous weight, which is about 13% lower than the hydrated weight found in Osvaren.

translates into a removal of 24003000 mg week. The absolute amount of phosphorus removed depends on the pre-dialysis serum phosphorus concentration and the length and intensity of treatment. With a tendency of reducing dialysis time to <4.0 hours on the basis of urea kinetics (i.e., Kt Vurea) rather than phosphorus kinetics, and the goal of maintaining a lower predialysis serum phosphate concentration, the lower dialytic removal number of 800 mg treatment is likely to be more accurate. On a weekly basis, if one then subtracts this rate of dialytic phosphorus removal (2400 mg week) from the absorbable phosphorus burden (44105880 mg week), one nds that, in the absence of residual renal function, 20103480 mg week of phosphate absorption needs to be prevented by binding (40). Dividing by 7, this translates to a daily phosphate binding need of 290 or 500 mg day for these hypothetical 60- and 80-kg ABW patients with protein intake of 1.0 g kg ABW. Considering the data cited earlier from both stool and urinary recovery studies, one can estimate that the amount of P bound per g of PBED is about 45 mg phosphate per g PBED. With a number of binders, especially sevelamer and lanthanum, the amount of phosphate bound decreases markedly at higher binder dose, and this probably occurs for the calcium-based binders as well. If one assumes that the need for phosphate binding will be in the range of 290500 mg day for most patients, and an average mg phosphate bound per g PBED of 45 mg, then our analysis predicts that 290 45 = 6.4 g day to 500 45 = 11 g day of PBED will be required for anuric patients with ABW of 60 and 80 kg, respectively, who are being dialyzed using a conventional thrice weekly treatment schedule. This analysis does not quite agree with clinical experience, since, as detailed earlier, the typical mean PBED found in studies of dialysis patients is in the range of 47 g day. Thus, one must postulate that perhaps heavier patients are not ingesting phosphate in direct

proportion to their ABW, that absorption is <70% under clinical conditions which exist in outpatient dialysis populations, or that positive phosphate balance persists despite apparent adequate control of serum phosphate concentrations. The PBED required would be less if there were substantial residual renal function (41), or if extracorporeal removal of phosphate were increased using hemodialtration (42), longer dialysis sessions, or more frequent dialysis (43). Also, attention to dietary phosphate restriction, and especially, avoidance of food containing phosphate supplements (44), should be of benet. A highlighted by Schiller et al. (3), proper dosing and timing of phosphate binders relative to food intake is of critical importance. Conclusions Although the exact amounts of phosphate bound by phosphate binders are difcult to establish, relative phosphate-binding capacity of calcium carbonate, acetate, sevelamer, and lanthanum carbonate can be derived by integrating data spanning three decades and multiple methodologies. The RPBC may be a useful tool for adjusting therapy when a change from one phosphate binder to another is required, and for assessing changes in the total phosphate-binding capacity of a prescription when doses of multiple phosphate binders given simultaneously are titrated over time.
Acknowledgment The FHN Trials are supported by grants from the National Institutes of Health and the National Institutes of Diabetes and Kidney Disease (NIDDK). The help of Dr. John Fordtran from Baylor University Medical Center, is gratefully acknowledged.

48 Appendix (Calculations)

Daugirdas et al.
of the Osvaren arm exceeded that of the sevelamer arm. If the Osvaren regimen were 1.2 times as potent, instead of 1.1 times in the above calculation, then the RPBC for heavy magnesium carbonate would turn out to be substantially higher: PBED_ acetate + PBED_hmgcarb = 1.2 PBED (sevelamer) 3.17 + PBED_hmgcarb = 1.2 6.48 0.75 = 5.832 PBED_hmgcarb = 5.8323.17 = 2.66 Because 1.71 g of heavy magnesium carbonate was given, we can compute the RPBC for this binder. RPBC_hmgcarb = 2.66 1.71 = 1.56 In contrast, if the RPBC of sevelamer was <0.75, and or the RPBC of calcium acetate was >1.0, then the RPBC for heavy magnesium carbonate would be lower.

Sprague et al. study (9) (urinary excretion of phosphate with lanthanum): Change in urinary phosphate was measured at the 4- and 8-week time points. At week 4, urinary phosphate had fallen by 45 mg day in the placebo group and by 220 mg in the lanthanum group. Thus, at 4 weeks, at the 1.9 g day lanthanum dose, change in urinary phosphate excretion vs. placebo was (22045) = 185 1.93 = 96 mg g lanthanum. At week 8, at the mean 2.645 g day dose, change in urinary phosphate excretion vs. placebo was (28080) = 200 mg day. So 200 2.645 = 75 mg phosphate per g lanthanum. Delmez et al. study (30) (Magnebind vs. CaCO3): In this sequential, as opposed to parallel-dose, study, a similar level of serum phosphate control was achieved, despite an increase in calcitriol dosage with a Ca + Mg regimen (Magnebind) compared to a CaCO3-based regimen. In the magnesium-binder phase, 0.465 g of elemental magnesium (as MgCO3) allowed dose reduction of elemental calcium from 2.9 to 1.2 g day. When one converts these numbers to calcium and magnesium carbonate, 0.465 3.469 = 1.613 g of MgCO3 was able to replace 2.91.2 = 1.7 2.5 = 4.25 g of CaCO3. Thus, the RPBC of MgCO3 relative to CaCO3 was suggested to be 4.25 1.613 = 2.63. Spiegel et al. study (31) (Magnebind vs. calcium acetate): The calcium acetate prescription on average contained 1743 mg of elemental calcium, or 6.88 g of calcium acetate. With Magnebind, equivalent phosphate control was achieved with a regimen containing 908 mg of elemental calcium and 773 mg of magnesium, or 908 2.5 = 2.27 g of CaCO3 and 773 3.469 = 2.682 g of MgCO3. If we assume that CaCO3 and calcium acetate have the same RPBC of 1.0, then the 2.27 g of CaCO3 can be subtracted from 6.88 to get 4.61 g of calcium acetate being comparable to 2.682 g of MgCO3. This would suggest that the RPBC of MgCO3 is 4.61 2.682, or 1.72. CALMAG Study of de Francisco et al. (32) (Osvaren vs. sevelamer): In the CALMAG study, Osvaren was evaluated against sevelamer hydrochloride. Osvaren contains a hydrated form of magnesium carbonate, so-called magnesium carbonate heavy, which has an approximate formula weight of: 4MgCO3Mg(OH)25H2O = 485.6 Da, of which 5 24.3 = 121.5 Da is magnesium. Each pill contains 235 mg of heavy MgCO3 of which 58.7 mg is elemental Mg, plus 435 mg of calcium acetate of which 110 mg is elemental calcium. Patients were randomly allocated to receive either sevelamer (hydrochloride) or the Ca + Mg pill. The reduction in serum phosphate tended to be a bit greater with the Ca + Mg pill than with sevelamer (p = NS). At the end-study serum phosphate titration point, 7.3 tablets of Ca + Mg were being given vs. 8.1 of sevelamer. So 3.17 g of calcium acetate plus 1.71 g of heavy magnesium carbonate were equivalent to 6.48 g of sevelamer. From the serum phosphate traces, if we make the assumption that the CALMAG arm of the study had about a 10% higher phosphate P-binding ability than the sevelamer arm, we can calculate the PBED for heavy magnesium carbonate (heavy mgcarb) in the CALMAG study as follows: PBED_acetate + PBED_hmgcarb = 1.1 PBED_sevelamer 3.17 + PBED_hmgcarb = 1.1 6.48 0.75 = 5.346 PBED_hmgcarb = 5.346 3.17 = 2.176 Because 1.71 g of heavy magnesium carbonate was given, we can compute the RPBC for this binder. RPBC (heavy mgcarb) = 2.176 1.71 = 1.27 However, the RPBC for heavy magnesium carbonate depends on the extent to which the phosphate-binding ability

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