NDT Advance Access originally published online on April 3, 2008
Nephrology Dialysis Transplantation 2008 23(9):2861-2867; doi:10.1093/ndt/gfn151
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Calcium load during administration of calcium carbonate or sevelamer in individuals with normal renal function
1 Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 2 Department of Endocrinology, Limbach Laboratory, 69126 3 Institute for Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer Feld 305, 69120 4 Heimdialyse, Bergheimerstr. 59-61, 69115, Heidelberg, Germany
Correspondence and offprint requests to: Jürgen Bommer, Heimdialyse, Bergheimerstr. 59-61, 69115 Heidelberg, Germany. Tel: +49-6221-97900; Fax: +49-6221-979039; E-mail: juergen_bommer{at}t-online.de
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Abstract |
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Background. Under steady-state conditions urinary calcium (Ca) excretion corresponds to the Ca load in healthy subjects. However, in chronic haemodialysis patients reliable data on Ca load are not available. In these patients Ca-containing phosphate binders are suspected to play a role in the progression of arteriosclerosis via increased but not quantified Ca load. The present study evaluated the effect of calcium carbonate (CC) and sevelamer hydrochloride (SEV), a calcium-free phosphate binder, on serum Ca and urinary Ca excretion in healthy individuals.
Methods. Twelve healthy male individuals were included in a monocentre, randomized, single-blind, placebo-controlled, three-way crossover phase I study. Concurrently with their meals, participants received 4 x 2 tablets of SEV (800 mg), CC (500 mg) or placebo for 6 days with 1-week washout between the treatment periods. During the study, weekly blood samples were taken and 24-h urine was collected each day for measurement of calcium, magnesium, phosphorus, chloride and iPTH.
Results. Mean daily urinary phosphorus excretion was significantly lower in subjects undergoing SEV treatment compared to those taking placebo (P < 0.001). Mean daily total urinary excretion of calcium was significantly higher in CC-treated participants compared to those receiving placebo (P < 0.001). Mean 24-h calcium excretion during the 6 treatment days was 6.60 ± 2.62 mmol [265 ± 105 mg] (CC) versus 5.15 ± 2.16 mmol [206 ± 87 mg] (SEV) versus 4.95 ± 1.63 mmol [198 ± 65 mg] (Placebo). Taking into account nutritional calcium intake estimated from dietary records fractional calcium absorption was 8.7% (CC), 13.3% (placebo) and 14.8% (sevelamer).
Conclusion. Intake of calcium carbonate compared to placebo in contrast to sevelamer in healthy individuals was associated with increased total urinary calcium excretion indicating an increased calcium load due to increased intestinal calcium absorption.
Keywords: calcium carbonate; calcium load; serum calcium; sevelamer; urinary calcium excretion
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Introduction |
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Hyperphosphataemia and secondary hyperparathyroidism are common complications of end-stage renal disease [1]. Correction of serum phosphorus (inorganic phosphate, Pi) levels is undertaken by appropriate use of phosphate binding agents including calcium-based (calcium carbonate and calcium acetate) and calcium-free salts [2,3]. In the recent past, there has been growing evidence that hyperphosphataemia, hypercalcaemia and calcium load may play a major role in the progression of arteriosclerosis in patients undergoing dialysis [4]. These findings raised marked concern about the routine use of calcium-containing phosphate binders that were suspected to promote calcium load and hypercalcaemia. The introduction of calcium-free phosphate binders such as sevelamer (Renagel®) was accompanied by several studies suggesting positive effects of these agents as compared to calcium carbonate in terms of preventing the progression of arterial calcification [5–7].
Progressing renal insufficiency is associated with reduced ability to excrete calcium in the urine. Therefore, in patients with severe CKD or in dialysis patients, it is not possible to easily quantify intestinal calcium absorption, i.e. calcium load by the measurement of urinary calcium excretion. As a consequence, in studies investigating the use of calcium-containing phosphate binders in haemodialysis patients the calcium load remained unknown. Considering the concerns regarding calcium-containing phosphate binders and their potential effect on the vascular system, it appears important to obtain additional information about the intestinal calcium absorption and calcium load during administration of calcium-containing or calcium-free phosphate-binding agents.
In adults with intact renal function, excess calcium can be excreted in the urine. In these subjects with normal mineral metabolism and without osteopathy, urinary calcium excretion can be assumed to reflect the calcium load due to intestinal calcium absorption if the total body calcium remains constant under steady-state conditions [8]. The present study was designed to provide additional information about the calcium load during administration of calcium-containing or calcium-free phosphate-binding agents. It comprises healthy adults with normal mineral metabolism, including unimpaired urinary excretion, and investigates possible differences in urinary calcium excretion during intake of sevelamer or calcium carbonate that might reflect altered intestinal calcium absorption associated with the use of calcium-containing phosphate binders.
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Materials and methods |
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The study was approved by the Ethics Committee of the Medical Faculty of the University of Heidelberg and was conducted at the Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, in accordance with the standards of good clinical practice (GCP, as defined in the ICH E6 Guideline for Good Clinical Practice), in agreement with the Declaration of Helsinki, and the specific legal requirements in Germany. The study was carried out between April and July 2006.
Participants
Twelve healthy male participants (eleven Caucasian and one African participant) were included after each gave written informed consent. Participants were between 19 and 27 years old and mentally and physically healthy including normal mineral metabolism as defined by medical history, physical examination, electrocardiogram and routine laboratory analyses that included haematology, blood chemistry, iPTH, 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3, urine analysis, and a urine drug screening. None of the participants had taken any medication for 2 months prior to or during the study. All participants were non-smokers. Exclusion criteria included inability to communicate with the investigator, a history of allergic reactions, blood donation or participation in a clinical trial within the last 2 months, or excessive alcohol drinking (>30 g alcohol per day).
Procedures
The study was conducted as a randomized, single-blind, placebo-controlled, threefold crossover phase I study with three treatment periods. The three study treatments included calcium carbonate (Dreisacarb®; GRY-Pharma, Kirchzarten) 4 g daily (4 x 2 x 500 mg), sevelamer (Renagel®; Genzyme, Neu-Isenburg) 6.4 g daily (4 x 2 x 800 mg) or placebo (P tablets 10 mm Lichtenstein®, Winthrop-Arzneimittel, Fürstenfeldbruck). The medication was administered daily for a treatment period of 6 days each (Days 1–6). Between treatment periods a washout time of 7 days was required. The sequence of administration of the three treatments was randomized. During the treatment periods, after an overnight fast, participants received the first daily dose at the Clinical Pharmacology Research Centre. The remaining doses were taken with meals at intervals of 
4 h. Immediately before the administration of the study medication the participants emptied their bladder completely. Urine was collected for 24 h on each study day (Day 1 = pre-dose and Days 2–7 = during treatment). Venous blood samples (7.5 ml) were drawn before the administration of the study drugs on Days 1–6, and on the morning of Day 7. For determination of iPTH and vitamin D (1,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3) on the first, third, fifth and seventh day of each period, 2.7 ml blood samples were drawn before administration (Days 1, 3, 5) of the study drugs. After the morning drug administration the participants were allowed to have a standardized breakfast at the Clinical Pharmacology Research Centre. In order to maintain a comparable calcium intake during the three study periods the participants were instructed to avoid relevant dietary changes and were requested to keep a dietary record for the assessment of daily calcium and phosphate intake.
Analytical techniques
Serum and urinary calcium and phosphorus were determined by photometry on the automated analyzer Modular P (Roche Diagnostics, Mannheim, Germany). Serum creatinine, chloride, total protein, AP (IFCC method at 37°C) and albumin were also determined on the analyser Modular P by photometry chloride by ion-selective electrode with reagents obtained from Roche Diagnostics. Serum and urinary magnesium were determined by atomic absorption spectrophotometry. Intact PTH was determined by electroluminescence immunoassay on the automated analyser E170 (Roche Diagnostics, Mannheim, Germany). The 25-hydroxyvitamin D was determined by a competitive chemiluminescence immunoassay (CLIA) on the LIAISON analyser (DiaSorin Inc., Stillwater, MN 55082, USA). The 1,25-dihydroxyvitamin D3 (calcitriol) was determined by a radioimmunoassay after extraction and isolation with a combination of Extrelut-1-minicolumns and Sep-Pak silica cartridges as previously described [9].
Statistical analysis
We calculated a two-way repeated-measures ANOVA considering three treatments (placebo, calcium carbonate and sevelamer) and measurements on six consecutive days for 12 healthy individuals. Between each of these three treatments, enough time passed for complete washout of medication; hence, the sequence of randomized treatment allocation can be neglected. Furthermore, in our crossover study it is statistically not appropriate to consider the independence of treated subjects because each subject received each treatment during 1 week and repeated measurements are taken on consecutive days. We primarily explored the effect of treatments and secondarily the effect of time and interaction between treatments and time.
Twenty-two two-way repeated-measures ANOVA were calculated corresponding to 22 parameters for each subject. To avoid an increase of 5% global type 1 error due to multiple testing, we used Bonferroni-Holm correction. This way, treatment results were kept confirmatory, but the P-value of each treatment effect had to be quite low to be considered significant (P < 0.05/22 = 0.0023).
In the case of a significant treatment effect, we used simple contrast definition, which means that calcium carbonate and sevelamer are each compared with placebo. This comparison is confirmatory according to the closed test procedure. For explorative comparison of trend over different days we used repeated contrast definition, which means that each day is compared to the preceding day. Medication was given starting on Day 2; the first day is considered as reference day for a baseline value. With Mauchly's test we checked the hypothesis that the variances of differences between the conditions are equal (sphericity). In the case of sphericity deviation, the P-value was corrected according to Greenhouse-Geisser.
For descriptive purposes we report the sample mean of each parameter under each treatment condition and the 95% confidence interval covering the true mean for healthy men. All calculations were done using SPSS 15TM.
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Results |
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The study drugs were well tolerated, all adverse events (AE) were mild and transient, and no serious AEs occurred. Three participants reported mild, intermittent nausea and flatulence. These AEs were observed during the administration of placebo in one participant and during the administration of sevelamer in two participants. No other AEs were observed.
Results are reported in Tables 1 (urine data) and 2 (serum or plasma data). Mean daily urinary phosphorus excretion was significantly lower in subjects undergoing SEV treatment compared to those taking placebo (P < 0.001) and was also reduced but not significantly different in subjects treated with calcium carbonate as compared to those taking placebo (Figure 1). Urinary magnesium excretion was not significantly different during the three treatment periods. Mean daily urinary excretion of calcium was significantly higher in CC-treated subjects compared to those receiving placebo (P < 0.001) (Figure 1). Mean 24-h calcium excretion during the 6-day treatment was 6.60 ± 2.62 mmol [265 ± 105 mg] (CC) versus 5.15 ± 2.16 mmol [206 ± 87 mg] (SEV) versus 4.95 ± 1.63 mmol [198 ± 65 mg] (placebo). Alimentary calcium intake as assessed by analysis of the dietary records was comparable between the three treatment groups (Table 3). Additional calcium supply due to CC intake was associated with diminished fractional absorption of calcium in the CC group (8.7%) as compared to placebo (13.3%) and sevelamer (14.8%) (Table 3).
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Mean daily creatinine excretion was significantly higher under calcium carbonate treatment compared to placebo (P < 0.001) (Figure 2). Mean daily creatinine clearance was also increased for calcium carbonate treatment compared to placebo, but this difference was not statistically significant after correction for multiple testing. Mean daily chloride excretion was not different for the three treatment periods. The mean 24-h urine volume was slightly lower for sevelamer as compared to placebo, but this difference was not statistically significant (P = 0.071).
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In contrast, there were no significant changes in mean daily serum calcium, phosphorus and magnesium concentrations during administration of CC or SEV compared to placebo (Table 2). Serum magnesium concentrations were somewhat lower during sevelamer treatment, but were not statistically different as compared to placebo. Serum AP (alkaline phosphatase) was slightly higher during both treatments (calcium carbonate and sevelamer), but this difference again was not statistically significant after correction for multiple testing. Similarly, serum creatinine and chloride as well as plasma iPTH and vitamin D levels (1,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3) were not different for the three treatment periods. Mean serum albumin and total protein levels were similar for all treatment periods. Albumin was slightly lower (
4% as compared to placebo) under sevelamer administration. There was no significant time effect or interaction between time and treatment after correction for multiple testing; therefore, no P-values are reported for these secondary effects.
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Discussion |
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As would be expected for the treatment with phosphate-binding agents, the present study indicated a reduced phosphate excretion in the urine of healthy subjects during the treatment with both phosphate binders, sevelamer or CC, even though a statistically significant reduction could be shown only for sevelamer. However, the main objective of our study was to investigate the calcium load associated with the use of these two substances. The results of the present study demonstrate that intake of calcium carbonate as compared to placebo in healthy volunteers was associated with increased urinary calcium excretion indicating an increase in the total amount of calcium absorbed while measured serum concentrations of calcium remained unaffected. To minimize a potential effect of alimentary factors on the calcium load, calcium intake was assessed by analysis of dietary records. These records did not show differences in alimentary calcium intake between the three treatment groups (Table 3). The dose of 4 g CaCO3 (1600 mg Ca2+ and 40 mmol Ca2+) in our study led to a mean increase in the amount of calcium absorbed (represented by the amount excreted in the urine) of 1.65 mmol/day [67 mg/day] as compared to placebo. However, the relative amount (% of dose) of calcium absorbed was lowest during CC treatment (8.7%) while values found for placebo (13.3%) and sevelamer (14.8%) were similar to data reported in the literature [10] (Table 3). The reduction of fractional calcium absorption was already observed on the first day of calcium carbonate treatment and was not associated with any changes of iPTH, 25-hydroxyvitamin D3 or 1,25-dihydroxyvitamin D3 plasma levels. Whether this finding indicates a saturable intestinal process leading to a decrease in absorption capacity with increasing total amount of calcium available for absorption or might result from an endocrine/paracrine effect of vitamin D or other processes regulating calcium absorption in the intestine cannot be decided from our data. The fact that an increase in calcium absorption left the serum calcium concentration unaffected can be explained by the intact renal function of healthy individuals that allows for excretion of excess calcium via the urine.
Recently, the effect of sevelamer and calcium-containing phosphate binders on coronary calcification has been investigated by electron beam computed tomography in haemodialyis patients. Treatment with sevelamer was associated with reduced progression of calcification in the coronary arteries and aorta after 1- and 2-year follow-up as compared to treatment with calcium-containing phosphate binders [6,11]. During steady-state mean serum calcium levels were found to be elevated by only 0.1 mmol/l in patients treated with calcium-containing (as opposed to calcium-free) phosphate binders and remained within the DOQI targets [6,12]. As an acute effect, in anuric haemodialysis patients an increase of the mean serum calcium concentration of <0.1 mmol/l was found after a test meal containing 1 g of calcium had been given. This increase was observed 30 min after the test meal, but was only a transient phenomenon and 30 min later could no longer be detected [13]. Obviously, an additional calcium load is not adequately reflected by a change of serum calcium in dialysis patients. In haemodialysis patients with essentially stable predialytic serum calcium levels the standard dialysis with 3 x 3 l ultrafiltrate per week can remove only 450 mg calcium per week. This amount would be insufficient when compared to the weekly calcium load of 1400 mg under placebo or sevelamer treatment and 1855 mg under CC treatment in our healthy individuals. It is not clear, however, to what extent our present data can be extrapolated to a potential calcium accumulation in patients with impaired or even absent renal function (ESRD), in whom intestinal absorption and removal of calcium during dialysis cannot easily be quantified. However, this issue was not addressed by our study.
It has been reported previously [14] that serum albumin concentrations tended to be lower under sevelamer administration in a long-term study in patients on maintenance dialysis. Data presented here, however, refer to the short-term treatment of healthy individuals. Since differences in albumin concentrations in our investigation were rather small, not statistically significant, and all within the normal range for all treatment periods, this finding is not clinically relevant.
In our study, we observed an increase in urinary creatinine excretion during the calcium carbonate period. Serum creatinine concentrations were not statistically different. It is not clear at the moment, whether the finding of an increased urinary creatinine excretion actually represents a physiological effect associated with the observed increase in calcium excretion or whether is merely a coincidental phenomenon. Because of the randomized crossover design we used, it is reasonable to assume that any systematic collection error that could possibly influence creatinine recovery would equally occur in all three periods. It is known that dietary meat intake can influence renal creatinine excretion. However, meat intake was not different between the three study periods and, so far, there is no reason to assume that calcium carbonate treatment could increase a possible effect of oral meat intake on renal creatinine excretion.
Mean 24-h urinary volume was somewhat lower during the sevelamer treatment period; this might reflect the gel-like character of sevelamer that can be assumed to hinder fluid absorption in the intestine and subsequent fluid excretion. There were no symptoms of increased fluid retention like oedema or increased blood pressure.
The present study was performed in healthy subjects with intact renal function and normal mineral metabolism documented by serum concentrations of calcium, phosphorus, magnesium, iPTH, 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3. The stable serum concentrations of all the relevant laboratory parameters indicate that possible transient fluctuations of serum concentrations of calcium, phosphorus and magnesium after food and phosphate binder intake could easily be corrected by appropriate urinary excretion. There is no reason to suspect an increased mineral storage in the organism and soft tissue calcification, as may occur in patients with impaired renal function. Renal insufficiency is associated with an impaired excretion followed by an accumulation of calcium and phosphate in the vascular wall and other soft tissues as documented in dialysis patients as well as already in patients before dialysis therapy started [15]. The precise quantification of intestinal mineral absorption in such CKD patients would require the undesirable use of radiolabelled isotopes or implicate extreme costs. Therefore, the present study included healthy individuals in whom the urinary excretion corresponds to the intestinal absorption of minerals.
In conclusion, our study revealed that intake of calcium carbonate as compared to placebo was associated with an increase in the total amount of calcium absorbed and increased urinary calcium excretion in healthy individuals while serum calcium concentrations remained unaffected. In contrast, calcium absorption and urinary calcium excretion were unaffected by sevelamer hydrochloride. The increased urinary calcium excretion was found already on the first day of calcium carbonate treatment despite a reduction of fractional calcium absorption and constant concentrations of iPTH and 1,25-dihydroxyvitamin D3.
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Acknowledgments |
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The authors thank Genzyme GmbH and Neu-Isenburg Germany for their financial support.
Conflict of interest statement. Prof. Bommer received honoraria for lectures from Genzyme GmbH, Abbott and Fresenius Medical Care.
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Accepted in revised form: 26. 2.08
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