Effect of MCI-196 (colestilan) as a phosphate binder on hyperphosphataemia in haemodialysis patients: a double-blind, placebo-controlled, short-term trial

Satoshi Kurihara1, Yoshinari Tsuruta2 and Tadao Akizawa3

1 Kasukabe Naika Clinic, Kasukabe, Saitama, 2 Meiyo Clinic Hemodialysis Center, Toyohashi, Aichi and 3 Wakayama Medical University, Center of Blood Purification Therapy, Wakayama, Wakayama, Japan

Correspondence and offprint requests to: Satoshi Kurihara, MD, PhD, Kasukabe Naika Clinic, 1-22-32 Bingo Higashi, Kasukabe, Saitama 344-0032, Japan. Email: kurihara{at}k-naika-cl.jp



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusion
 References
 
Background. MCI-196 (colestilan), an anion exchange resin, is widely used as an anti-hypercholesterolaemic drug in Japan. To evaluate the efficacy and safety of MCI-196 as a phosphate binder, a double-blind, randomized, placebo-controlled prospective trial was conducted in Japanese end-stage renal disease patients with hyperphosphataemia on intermittent haemodialysis treatment.

Methods. Phosphate binders were discontinued during a 2-week washout period. Subsequently, patients whose serum phosphorus levels were ≥6.5 mg/dl, but <10 mg/dl were eligible to enter the treatment protocol. Patients were randomized to either MCI-196 6 g/day or placebo for 2 weeks. The efficacy and safety of MCI-196 were assessed in 33 and 46 patients, respectively.

Results. Serum phosphorus in the placebo group increased by 0.84±0.95 mg/dl (mean±SD), while serum phosphorus in the MCI-196 group decreased by 0.55±1.23 mg/dl. The difference between the two groups was statistically significant (P = 0.002). A reduction of ≥1 mg/dl in serum phosphorus was observed in 43% in the MCI-196 group and 0% of patients in the placebo group (P = 0.0122). Calcium–phosphorus (Ca x P) product, intact parathyroid hormone (iPTH) and low-density lipoprotein (LDL)-cholesterol in the MCI-196 group also decreased significantly compared with the placebo group, while serum calcium was unchanged. Adverse reactions were observed in 51.7% of the MCI-196 group and 29.4% of the placebo group (P = 0.2186). The most frequent adverse reactions in the MCI-196 group were gastrointestinal symptoms and signs, including constipation.

Conclusions. The present findings suggest that the short-term administration of MCI-196 is effective in decreasing serum phosphorus in haemodialysis patients. Its long-term efficacy needs to be evaluated.

Keywords: cholesterol; colestilan; hyperphosphataemia; phosphate binder



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusion
 References
 
Hyperphosphataemia is common in chronic haemodialysis patients. It is associated with severe complications, including metastatic calcification and secondary hyperparathyroidism with osteitis fibrosa [1]. Reduction of intestinal phosphorus absorption is crucial in the treatment of hyperphosphataemia [2]. Although calcium-based agents are generally used as phosphate binders, they induce hypercalcaemia, accelerating metastatic calcification [3–5].

MCI-196 (colestilan), a non-absorbed anion exchange resin, decreases cholesterol levels by bile acid adsorption through the gastrointestinal tract [6], and is widely used as an anti-hypercholesterolaemic drug in Japan (Figure 1). It has been reported that 1 g of MCI-196 binds 2.52 mmol of phosphate at 2–4 mM phosphate concentration and pH 7.2 in vitro, and MCI-196 decreases urinary phosphorus excretion in rats (European Patent No. 793960). In a previous clinical trial, MCI-196 increased fecal phosphorus excretion in healthy volunteers (unpublished data). Moreover, Date et al. have reported that MCI-196 reduces serum phosphorus in combination therapy with calcium carbonate in end-stage renal disease (ESRD) patients receiving haemodialysis [7]. These results suggest that MCI-196 may be useful in terms of phosphate binding. To evaluate the efficacy and safety of MCI-196 as a phosphate binder, a double-blind, randomized, placebo-controlled short-term trial was conducted in Japanese ESRD patients with hyperphosphataemia who were undergoing intermittent haemodialysis treatment.



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Fig. 1. The structure of MCI-196. MCI-196 is represented by formula [I] of a fundamental structure, which consists of randomized and complicated structures partially shown in formula [II]. Non-proprietary names are colestilan (INN) and colestimide (JAN). Chemical names are 2-methylimidazole polymer with 1-chloro-2, 3-epoxypropane (INN) and 2-methylimidazole-epichlorohydrin copolymer (JAN).

 


   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusion
 References
 
Patients
Regular haemodialysis patients with ESRD 20 years of age or older who were on haemodialysis therapy three times a week continuously for ≥3 months were eligible for the study. Inclusion criteria required a dialysate calcium concentration of 3.0 mEq/l, and stable dosage of calcium carbonate as a phosphate binder for ≥1 month. If patients used vitamin D derivatives, the dosage was required to be stable for ≥1 month. Patients whose serum phosphorus levels, before dialysis, after 1 week washout, were 6.5 mg/dl or more, but <10 mg/dl, showing an increase from the start of washout, were enrolled in the study.

Patients were asked to avoid intentional dietary changes and were prohibited from taking calcium-, aluminium- or magnesium-based phosphate binders. Patients who were on vitamin D derivatives did not change their dosage. No other change in haemodialysis treatment was made during the study.

Study design
A double-blind, randomized, placebo-controlled study was designed to evaluate MCI-196. Calcium carbonate was discontinued during a 2-week washout period (weeks –2 to 0). Following the washout period, eligible patients entered the treatment period. They were randomized to either the MCI-196 or the placebo group in a 2:1 ratio, and MCI-196 2 g (four tablets) or placebo was administered to patients three times a day with a meal for 2 weeks.

If at any time during the treatment period, serum phosphorus levels before dialysis increased to 10 mg/dl or more, the patient was withdrawn from the study.

The following laboratory tests were performed just prior to dialysis after the maximum inter-dialytic period: serum phosphorus, calcium, intact parathyroid hormone (iPTH), albumin, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, total cholesterol, haematology parameters, total protein, total bilirubin, direct bilirubin, aspartate aminotransferase, alanine aminotransferase, lactic dehydrogenase, alkaline phosphatase, {gamma}-glutamyl transpeptidase, cholinesterase, creatine phosphokinase, creatinine, uric acid, blood urea nitrogen, sodium, potassium, chloride, magnesium, triglyceride, 1{alpha},25(OH)2D3, and blood pH.

Haematology parameters, and pH were measured at the medical centres which conducted the study, and other laboratory parameters were measured at Mitsubishi Kagaku Bio-Clinical Laboratories, Inc. (Tokyo, Japan). An immunoradiometric assay was used for measuring iPTH (range of normal values 14–66 pg/ml). Serum calcium was adjusted for serum albumin by Payne's formula [8], when serum albumin was <4 g/dl.

The study was approved by institutional review boards of two medical centres (Kasukabe Shuwa Hospital and Meiyo Clinic Hemodialysis Center) and conducted from July 2002 to January 2003. Written informed consent was obtained from each patient.

Statistical analysis
Safety analyses were performed on all patients who received study drugs, and efficacy analyses were performed on all patients who had data for the evaluation of efficacy in the treatment period. In the event that a serum phosphorus concentration before dialysis increased to 10 mg/dl, a last observation carry forward approach was used to complete missing data in efficacy analyses.

All values are reported as means±SD. Median serum phosphorus values were also shown for reference. Changes from baseline (week 0) in efficacy and safety values in each group were analysed using paired t-test. Comparisons between two groups were conducted using a two-sample t-test for continuous variables and Fisher's exact test for categorical variables. Pearson's product–moment correlation coefficient was used to examine the relationship between the change in serum phosphorus and LDL-cholesterol. P-values <0.15, 0.05 and 0.05 were considered as statistically significant for patient characteristics, efficacy and safety analyses, respectively.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusion
 References
 
Patient disposition
Forty-six patients were enrolled and 14 patients withdrew from the study. Reasons for withdrawal are shown in Table 1.


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Table 1. Reasons for withdrawal

 
Efficacy data were not available for 13 patients (12 because of withdrawal without any efficacy data, and one because of lack of data), and consequently the efficacy of MCI-196 was evaluated in 33 patients (21 for MCI-196 and 12 for placebo). Demographic and clinical characteristics of the patient population are shown in Table 2. The safety of MCI-196 was evaluated in 46 patients (29 for MCI-196 and 17 for placebo).


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Table 2. Patient characteristics

 
Efficacy
Changes in efficacy parameters are summarized in Table 3.


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Table 3. Changes in efficacy parameters

 
Phosphorus
Serum phosphorus in the placebo group increased by 0.84±0.95 mg/dl, while serum phosphorus in the MCI-196 group decreased by 0.55±1.23 mg/dl (Figure 2). The difference between the two groups was statistically significant (P = 0.002).



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Fig. 2. Serum phosphorus levels. Filled circles, MCI-196 (n = 21); open triangles, placebo (n = 12); *P<0.05, **P<0.01, one-sample t-test (vs week 0), two-sample t-test (vs placebo).

 
A reduction of 1 mg/dl or more in serum phosphorus was observed in 43 and 0% of patients in the MCI-196 group and the placebo group, respectively (P = 0.0122).

Calcium, Ca x P product and iPTH
There was no significant change in serum calcium (mean change 0.04±0.31 vs –0.11±0.26 mg/dl, MCI-196 vs placebo, P = 0.1754).

Serum Ca x P product in the MCI-196 group decreased significantly compared with the placebo group (mean change –4.85±10.21 vs 6.21± 7.22 mg2/dl2, MCI-196 vs placebo, P = 0.0024).

Serum iPTH in the MCI-196 group decreased significantly compared with the placebo group (mean change –56.1±89.5 vs 16.3±58.3 pg/ml, MCI-196 vs placebo, P = 0.0176). As shown in Figure 3, serum iPTH decreased in patients with high baseline levels (iPTH ≥300 pg/ml), whereas it did not change in patients with normal or low baseline levels (iPTH <300 pg/ml).



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Fig. 3. Serum iPTH levels in the subgroups stratified by the baseline iPTH level. Filled circles, MCI-196 (n = 13); filled triangles, placebo (n = 7) for iPTH ≥ 300 pg/ml at week 0; open circles, MCI-196 (n = 8); open triangles, placebo (n = 5) for iPTH <300 pg/ml at week 0. *P<0.05, **P<0.01, one-sample t-test (vs week 0), two-sample t-test (vs placebo).

 
LDL-cholesterol, HDL-cholesterol and total cholesterol
Serum LDL-cholesterol and total cholesterol in the MCI-196 group decreased by 34.2 and 21.3% from baseline, respectively. Serum HDL-cholesterol was not changed significantly.

The correlation between changes in serum phosphorus and change rates of LDL-cholesterol is shown in Figure 4. There was no significant relationship between them (r = 0.5001).



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Fig. 4. Correlation between changes in serum phosphorus and change rate of LDL-cholesterol. Filled circles, MCI-196 (n = 21); open squares, placebo (n = 12); the correlation coefficient (r) in the MCI-196 group is 0.5001.

 
Safety
Adverse events were observed in 65.5% of the MCI-196 group and 41.2% of the placebo group (P = 0.1938). Adverse reactions, which could not be ruled out in relation to study drugs, are shown in Table 4. Adverse reactions were observed in 51.7% of the MCI-196 group and 29.4% of the placebo group (P = 0.2186). The most frequent adverse reactions in the MCI-196 group were gastrointestinal disorders, including constipation (34.5%) and abdominal distension (6.9%).


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Table 4. Adverse reactions

 
One patient in the MCI-196 group had a serious adverse reaction (constipation), which was resolved by discontinuation of the drug and appropriate treatment.

Abnormal changes in clinical laboratory tests are observed in 37.9% of the MCI-196 group and 41.2% of the placebo group (P = 1.0000). Major abnormal changes were a decline in and pH in the MCI-196 group. Serum chloride increased to 104.7 mEq/l in the MCI-196 group (mean change 3.1±2.0 vs –1.2±2.1 mEq/l, MCI-196 vs placebo, P = 0.0000) and serum magnesium increased to 2.81 mg/l in the MCI-196 group (mean change 0.13±0.19 vs –0.08±0.22 mg/l, MCI-196 vs placebo, P = 0.0051). However, the elevated levels remained approximately within the regularly observed range of haemodialysis patients. Although mean and pH in the MCI-196 group changed slightly, there were no statistically significant differences compared with the placebo group (P = 0.7577, 0.0602). In addition, serum 1{alpha},25(OH)2D3 in the MCI-196 group did not change (9.3±5.1 to 10.2±5.1 pg/ml, week 0 vs week 2, P = 0.8253). There were no remarkable changes in the other laboratory tests assessed.

No abnormal changes in physical examinations and electrocardiogram were observed.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusion
 References
 
Calcium-based phosphate binders are the most frequently used agents in the treatment of hyperphosphataemia. However, they induce hypercalcaemia, accelerating metastatic calcification, and often contraindicate the use of vitamin D derivatives due to hypercalcaemia.

Recently, non-calcium-containing phosphate binders have been developed. The Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Guidelines for Bone Metabolism and Disease recommend that the total dose of elemental calcium provided by calcium-based phosphate binders should not exceed 1500 mg/day, and non-calcium-containing phosphate binders are preferred in dialysis patients with severe vascular and/or other soft tissue calcifications [9].

Sevelamer hydrochloride (Renagel, GelTex Pharmaceuticals, Inc., MA, USA), an anion exchange resin, is available clinically for the treatment of hyperphosphataemia as a non-calcium-containing phosphate binder. Although MCI-196 was developed originally as an anti-hypercholesterolaemic drug, it may have a similar phosphate-lowering capacity to sevelamer hydrochloride.

Despite many studies on phosphate binders, there are few double-blind, randomized, placebo-controlled studies in patients with ESRD undergoing haemodialysis. In the placebo-controlled double-blind study of a 2-week administration of sevelamer hydrochloride conducted in the USA, a serum phosphorus-lowering effect of 1.2 mg/dl was observed in patients on sevelamer hydrochloride, compared with a mean increase of 0.2 mg/dl in those receiving placebo [10,11]. In our study, the observed decrease of serum phosphorus with MCI-196 was 0.55 mg/dl, while the increase of serum phosphorus with placebo was 0.84 mg/dl; the difference between MCI-196- and placebo-induced changes in serum phosphorus of 1.39 mg/dl was similar to that observed with sevelamer hydrochloride. Although a 2-week treatment with 6 g/day MCI-196 significantly reduced the mean serum phosphorus relative to baseline and relative to placebo, the mean serum phosphorus level at the end of the treatment period with MCI-196 did not return to the baseline value of 5.83 mg/dl, or to the K/DOQI target of 5.5 mg/dl [9]. These results suggest that a longer treatment period is required to achieve maximum efficacy. Additionally, as noted below, some patients in the MCI-196 group failed to show a response at the 2-week end-point, whereas others showed clinically significant reductions in serum phosphorus. This may reflect individual variability in sensitivity to the drug. It is also possible that higher doses or the combination with calcium-based agents may be required for a sufficient reduction of serum phosphorus in some patients.

Recent studies have demonstrated that phosphorus is involved in the vascular calcification process. High phosphorus levels directly increase vascular smooth muscle cell calcification in vitro and induce bone-associated proteins, core binding factor-1 (Cbfa-1) and osteocalcin, whose expression is associated with metastatic calcification [12,13]. Any reduction in serum phosphorus must be marked to prevent soft tissue calcification in haemodialysis patients

In addition to the phosphorus-lowering effect, MCI-196 reduced Ca x P product, iPTH and LDL-cholesterol, without changing serum calcium. These additional effects appear to be advantageous in the treatment of haemodialysis patients as well. First, the reduction in Ca x P product might decrease metastatic calcification, which is linked to the relative risk of death in dialysis patients [14–16]. Secondly, the reduction of higher serum iPTH might be a favourable effect in the treatment of hyperparathyroidism. Since MCI-196 did not change serum calcium, there is a possibility that MCI-196 may permit increases in the dose of vitamin D derivatives for patients with hyperparathyroidism, immediately favouring hypercalcaemia which is often observed when taking calcium-based agents concomitantly. Finally, the LDL-cholesterol-lowering effect would appear to be beneficial to prevent coronary heart disease [17,18] [National Cholesterol Education Program: Adult Treatment Panel III Report. (http://www.nhlbi.nih.gov/guidelines/cholesterol/)]. Furthermore, elevated LDL-cholesterol has been shown to be associated with coronary artery calcification [19]. Therefore, MCI-196 may have a potential to slow the progression of cardiovascular calcification through several pathways.

As shown in Figure 4, it is of interest that serum LDL-cholesterol decreased in all patients in the MCI-196 group, while serum phosphorus increased in ~20% of patients in the MCI-196 group. This result indicates that ~20% of patients did not respond to the dose of MCI-196 given in terms of phosphorus adsorption despite good compliance with MCI-196 administration. In the study with sevelamer hydrochloride, it was shown that serum phosphorus did not decrease in ~20% of patients [Renagel® Package Insert (http://www.fda.gov/cder/foi/label/2000/21179lbl.pdf)]. Characteristics of non-responders to phosphate binders are unknown and deserve further investigation.

The most frequent adverse reactions in the MCI-196 group were gastrointestinal disorders, especially constipation. Similar adverse reactions were obtained in the study of sevelamer hydrochloride conducted in Japan [20]. Constipation is a common complication in Japanese haemodialysis patients because of the restriction of water intake, a decline of physical activity, irregular daily life due to intermittent haemodialysis, and other factors. Therefore, patients with major disturbances of physiological functions should be given MCI-196 with caution.

As for changes in laboratory values, serum chloride and magnesium increased significantly in the MCI-196 group compared with the placebo group; however, they remained within the usually observed ranges of haemodialysis patients. Since MCI-196 is an anion exchange resin containing chloride, serum chloride would increase in exchange for phosphate, and possibly induce metabolic acidosis. These changes seem to be improved by an adequate dialysis dose or sodium bicarbonate supplements. However, metabolic acidosis should be watched carefully in further investigations.

Since there was no significant change in blood urea nitrogen, the dietary intake of protein and phosphorus was deduced to be unchanged during the study.



   Conclusion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusion
 References
 
In a double-blind, randomized, placebo-controlled short-term trial, MCI-196 significantly reduced serum phosphorus, Ca x P product, iPTH and LDL-cholesterol when compared with placebo, while serum calcium was unchanged. These results suggest that MCI-196 is effective for the treatment of hyperphosphataemia in haemodialysis patients. Additional longer term trials will be required to investigate the safety and efficacy of MCI-196 as an adequate phosphate binder for dialysis patients.



   Acknowledgments
 
This work was supported by Mitsubishi Pharma Corporation. These data were presented in part at the American Society of Nephrology 36th Annual Meeting and Scientific Exposition in San Diego, CA, USA, November 2003.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusion
 References
 

  1. Delmez JA, Slatopolsky E. Hyperphosphatemia: its consequences and treatment in patients with chronic renal disease. Am J Kidney Dis 1992; 19: 303–317[ISI][Medline]
  2. Hsu CH. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis 1997; 29: 641–649[ISI][Medline]
  3. Sperschneider H, Günther K, Marzoll I et al. Calcium carbonate (CaCO3): an efficient and safe phosphate binder in haemodialysis patients? A 3-year study. Nephrol Dial Transplant 1993; 8: 530–534[Abstract]
  4. Guérin AP, London GM, Marchais SJ, Metivier F. Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 2000; 15: 1014–1021[Abstract/Free Full Text]
  5. Goodman WG, Goldin J, Kuizon BD et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342: 1478–1483[Abstract/Free Full Text]
  6. Nakaya N, Goto Y. Colestilan: a new bile acids sequestrant resin. A review of its clinical study in hypercholesterolaemia in Japan. Atherosclerosis 2000; 151: 134–135
  7. Date T, Shigematsu T, Kawashita Y et al. Colestimide can be used as a phosphate binder to treat uraemia in end-stage renal disease patients. Nephrol Dial Transplant 2003; 18 [Suppl 3]: iii90–iii93[Medline]
  8. Payne RB, Little AJ, Williams RB, Milner JR. Interpretation of serum calcium in patients with abnormal serum proteins. Br Med J 1973; 4: 643–646[ISI][Medline]
  9. National Kidney Foundation. K/DOQI Clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42 [Suppl 3]: S1–S202
  10. Chertow GM, Burke SK, Lazarus JM et al. Poly[allylamine hydrochloride](RenaGel): a noncalcemic phosphate binder for the treatment of hyperphosphatemia in chronic renal failure. Am J Kidney Dis 1997; 29: 66–71[ISI][Medline]
  11. Slatoplsky EA, Burke SK, Dillon MA et al. Renagel®, a nonabsorbed calcium- and aluminum-free phosphate binder, lowers serum phosphorus and parathyroid hormone. Kidney Int 1999; 55: 299–307[CrossRef][ISI][Medline]
  12. Jono S, McKee MD, Murry CE et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 2000; 87: e10–e17[Abstract/Free Full Text]
  13. Cozzolino M, Dusso AS, Slatopolsky E. Role of calcium–phosphate product and bone-associated proteins on vascular calcification in renal failure. J Am Soc Nephrol 2001; 12: 2511–2516[Free Full Text]
  14. Raggi P. Detection and quantification of cardiovascular calcifications with electron beam tomography to estimate risk in hemodialysis patients. Clin Nephrol 2000; 54: 325–333[ISI][Medline]
  15. Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998; 31: 607–617[ISI][Medline]
  16. Block GA, Port FK. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: recommendation for a change in management. Am J Kidney Dis 2000; 35: 1226–1237[ISI][Medline]
  17. National Cholesterol Education Program: Second report of the expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Circulation 1994; 89: 1333–1445[Medline]
  18. National Cholesterol Education Program. Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). J Am Med Assoc 2001; 285: 2486–2497[Free Full Text]
  19. Raggi P. Effects of excess calcium load on the cardiovascular system measured with electron beam tomography in end-stage renal disease. Nephrol Dial Transplant 2002; 17: 332–335[Abstract/Free Full Text]
  20. Kinugasa E, Koshikawa S. The PB-94 study group. Effect of PB-94 (sevelamer hydrochloride), a phosphate binder, on the treatment on hyperphosphatemia in hemodialysis patients—a randomized, open label, dose titration study of PB-94 versus Caltan® Tablet 500 (calcium carbonate). J Am Soc Nephrol 2001; 12: 755A
Received for publication: 24. 6.04
Accepted in revised form: 17.11.04





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