1 Division of Nephrology, Department of Medicine, Veteran's General Hospital-Taipei and College of Medicine, National Yang-Ming University, Taipei, Taiwan, 2 Division of Nephrology, Cathay General Hospital, Taipei, Taiwan, Republic of China and 3 Division of Nephrology, University of Michigan Health System and VA Medical Center, Ann Arbor, Michigan, USA
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Abstract |
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Methods. To extend this observation, we performed an open-label, random order, crossover comparison study of ferric citrate and calcium carbonate in haemodialysis patients from two teaching hospitals. The study sample consisted of 23 women and 22 men with an average age of 52.5±11.8 (SD) years and an average weight of 54.5±10.7 kg. All forms of iron therapy were discontinued. Two weeks before the study, patients were instructed to discontinue all P-binding agents. The patients were randomly assigned to receive either calcium carbonate (3 g/day) or ferric citrate (3 g/day) for 4 weeks followed by a 2 week washout period, and then crossed over to the other P-binding agent for 4 weeks.
Results. From a baseline concentration of 5.6±1.5 mg/dl, the serum P increased during the washout period to 7.2±1.9 mg/dl prior to calcium carbonate treatment, and to 6.7±1.9 mg/dl prior to ferric citrate treatment. The serum P concentration fell significantly during treatment with both calcium carbonate (7.2±1.9 to 5.2±1.5 mg/dl, P<0.0001) and ferric citrate (6.7±1.9 to 5.7±1.6 mg/dl, P<0.0001). The results were not influenced by order of treatment. Under the conditions of the study protocol, ferric citrate was less effective than calcium carbonate at lowering the serum phosphate concentration. The serum Ca concentration increased during treatment with calcium carbonate but not ferric citrate. Ferric citrate treatment did not affect the serum concentration of aluminium. Ferric citrate treatment was associated with mild and generally tolerable gastrointestinal symptoms.
Conclusion. Ferric citrate shows promise as a means of lowering the serum phosphate concentration in haemodialysis patients. Further studies are needed to find the optimal dose.
Keywords: ferric citrate; haemodialysis; open-label crossover study; phosphate-binding agent
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Introduction |
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Subjects and methods |
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The order of administration of the test agents (calcium carbonate and ferric citrate) was chosen randomly. Patients underwent a 14-day washout period, then a 28-day treatment period, a second 14-day washout period and a second 28-day treatment period. All phosphate binders were withheld during the washout periods. At the end of each washout period, a set of laboratory measurements were performed in the fasting state including complete blood count, serum levels of urea nitrogen, creatinine, electrolytes, calcium, phosphorus, aluminium, iron, ferritin, liver function tests, calcitriol and parathyroid hormone (PTH). During the treatment phases, patients received either calcium carbonate or ferric citrate at a dose of 1 g three times a day with meals. Patients were queried about possible adverse events when they came for dialysis treatments during the study periods. Blood testing was repeated at the second (for selected analyses) and the fourth week of each treatment period.
Patient selection
Twenty haemodialysis patients at the Veteran's General Hospital and 34 patients at the Cathay General Hospital (both in Taiwan) were asked to participate in the study. Both institutions are certified as teaching hospitals by the Taiwanese government. The concentration of calcium in the dialysate used in both hospitals was 2.5 mEq/l. Eligibility for the study required that patients demonstrate predictable compliance with their medical regimen, serum iron or ferritin level within or below the normal range, and a serum calcium concentration of 810 mg/dl. Patients were deemed ineligible for any of the following reasons: age less than 18 years, pregnant, active GI bleeding, use of calcitriol, tertiary hyperparathyroidism, immediate post-operative parathyroidectomy (within the first 3 months or serum calcium below 7 mg/dl), severe congestive heart failure, anorexia and cachexia, diabetes mellitus with gastroparesis and malignancy.
Collection and handling of blood samples
All laboratory measurements were performed at the Veteran's General Hospital Biochemistry Laboratory in Taipei, Taiwan, a GLP certified laboratory. Serum calcium, phosphorus, bicarbonate, creatinine and liver function tests were measured by standard laboratory methods. Serum aluminium was determined by graphite furnace atomic absorption spectrometry. PTH was measured using a standard intact molecule assay (normal range 1354 pg/ml).
Study medications
Ferric citrate (FeC6H5O7, molecular weight 245) was purchased from Tanabe Company (Tokyo, Japan) and formulated into 500 mg capsules by the Taiwan China Chemical and Pharmaceutical Company (Taipei, Taiwan). Calcium carbonate (CaCO3) was administered as 500 mg tablets.
Dietary intake evaluation
Two experienced renal dieticians performed all dietary counselling and assessments. Before the start of the trial, patients were instructed to avoid large changes in daily dietary intake. They were also instructed in the use of a food intake chart for monitoring food intake. The charts were used to measure 24-h dietary intake on three non-dialysis days during the first week of each crossover period. The average dietary intake for each subject was estimated as the average of these six measurements.
Statistical methods
All data are expressed as mean±SD. Laboratory measurements that were performed at multiple times were analysed using repeated measures analysis of variance. The major endpoint was the change in the laboratory measurement (e.g. serum phosphorus) during treatment with each agent. When the time effect was statistically significant, post hoc contrasts were performed for each treatment time point (2 week vs baseline and 4 week vs baseline) using the Scheffe test. The assessment of treatment effect was a secondary goal as both agents were administered at a fixed dose with no effort to titrate the dose to a desired effect. Treatment effects were indicated by the treatmentxtime interaction coefficient. The effect of treatment order was also modelled. Measurements performed at the 4 week time point only were compared with the baseline using the paired t-test. A P value <0.05 was considered significant.
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Results |
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Table 1 summarizes the adverse experiences reported by patients. All patients reported black or dark-coloured stools while receiving ferric citrate. Most complaints were mild and gastrointestinal in nature. The patients who developed diarrhoea had uniformly failed to discontinue chronic laxative therapy. One patient was removed from the study due to a skin rash that developed during the fourth week of ferric citrate treatment. This patient had systemic lupus erythematosus. Skin biopsy disclosed no vasculitis. After a full evaluation, the rash was considered unrelated to ferric citrate. One patient withdrew following an episode of abdominal discomfort while taking ferric citrate.
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Dietary phosphate and calcium intake
Table 2 shows the average dietary intake of phosphorus and calcium. The subjects maintained stable intake during the study. Phosphorus and calcium intakes were relatively low compared with typical western patients, reflecting local dietary aversion toward dairy products and preference for low protein foods such as rice, vegetables and soy products. Despite the relatively low phosphate intake, the serum phosphate concentration rose significantly during the washout periods (see below).
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Biochemical data
The primary outcome of interest was the change in serum phosphate concentration and calcium phosphate product during treatment with calcium carbonate and ferric citrate (Table 3). The serum phosphate concentration increased from baseline to the end of the washout periods (from 5.6±1.5 to 7.2±1.9 mg/dl prior to calcium carbonate treatment, and to 6.7±1.9 mg/dl prior to ferric treatment). The serum phosphate concentration fell during treatment with both calcium carbonate and ferric citrate. The serum phosphate concentration declined significantly from baseline at both 2 and 4 weeks for both treatments. The findings were unaffected by the order of treatment.
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The serum calcium phosphate product also declined during both treatments. The serum calcium concentration increased during the calcium carbonate but not the ferric citrate treatment. Accordingly, the decrease in the calcium phosphate product was primarily due to the decrease in serum phosphate concentration.
The plasma intact PTH concentration decreased only with calcium carbonate treatment, in parallel with the increase in serum calcium concentration. The serum levels of calcitriol and aluminium did not change with either treatment (Table 3).
The serum concentrations of other blood tests are shown in Tables 4
6
. There was a small increase in the serum ferritin concentration during the ferric citrate but not the calcium carbonate treatment (Table 4
). Liver function and other laboratory measures were not significantly altered with either treatment (Tables 5
and 6
).
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Discussion |
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Dialysis patients also experience positive cumulative calcium balance, which is potentially exacerbated when calcium salts are used as phosphate-binding agents [2]. The retention of phosphate and calcium may promote soft tissue mineralization and attendant functional disturbances. Thus, there are potential advantages to phosphate-binding agents that lack calcium (as well as aluminium).
The current study is the first human trial to use a ferric compound as a phosphate-binding agent in dialysis patients. The potential phosphate-binding capacity of ferric compounds was suggested by prior observations involving human subjects [12] and experimental animals [8]. Based on these early reports, we recently demonstrated that ferric compounds decrease intestinal phosphate absorption in normal and azotemic rats [8]. The goal of the current study was to determine the tolerability and effectiveness of ferric citrate when used to lower the serum phosphate concentration in haemodialysis patients. In view of these focused initial goals, we treated patients with fixed doses of the study compounds. A dose of 1 g thrice daily was selected because most haemodialysis patients in Taiwan were already receiving this dose of calcium carbonate. This dose provides 528 mg of elemental iron and 1200 mg of elemental calcium. Many haemodialysis patients currently receive 100200 mg/day of elemental iron orally (usually in the ferrous form) and variable amounts of parenteral iron for prevention or treatment of iron deficiency associated with erythropoietin therapy.
We found that ferric citrate was generally tolerated by haemodialysis patients. Similarly to other iron compounds, patients noted black stools while taking ferric citrate but this was not perceived as a problem. Ferric citrate was associated with mild gastrointestinal symptoms including diarrhoea and constipation (Table 1). The diarrhoea was usually manageable by discontinuing stool softeners and laxatives. One patient failed to complete the study because of abdominal discomfort. The other withdrawals from the study occurred for reasons unrelated to the study drug such as undercurrent illness or protocol violations. Several other side effects reported during both ferric citrate and calcium carbonate treatment were probably not related to the treatments (Table 1
). Based on the short-term experience of this trial, it appears that patients find ferric citrate therapy quite acceptable.
The serum phosphate concentration fell significantly while patients received ferric citrate (Table 3), indicating that the compound has potential clinical utility as a phosphate binder. Calcium carbonate resulted in a larger absolute decrement in serum phosphate at the dose chosen for the study. These findings provide the impetus to conduct additional dose-ranging and dose-titration studies with ferric citrate.
Ferric citrate treatment did not suppress PTH over the relatively short duration of this study. The PTH concentration fell during the calcium carbonate phase, probably in response to the rise in serum calcium concentration. The magnitude or duration of phosphate reduction during ferric citrate treatment may not have been sufficient to suppress PTH. Also, studies have shown that hyperphosphataemia stimulates parathyroid cell proliferation and the effect persists even after normalizing the serum phosphate concentration [13].
Prior studies have shown that citrate salts and vitamin C can promote aluminium absorption in patients and rats receiving supplemental aluminium [1416]. It is less clear whether citrate enhances absorption of dietary aluminium to a clinically important degree. We observed no change in the serum aluminium concentration during treatment with ferric citrate (Table 3). Although there is no evidence that ferric citrate causes aluminium toxicity, this issue will require further monitoring, particularly in areas with a high aluminium concentration in drinking water. It is clear that ferric citrate should not be used in patients receiving aluminium compounds.
In animal studies, ferric citrate treatment produced small increases in the haematocrit, haemoglobin, and serum ferritin concentration, suggesting that a small amount of iron was absorbed [8]. The ferritin concentration increased slightly in our study patients during ferric citrate therapy (Table 4). In general, iron absorption is lower with ferric (Fe3+) than with ferrous (Fe2+) salts [17,18]. Nonetheless, low-level iron absorption may be desirable in ESRD patients who frequently develop functional iron deficiency associated with recombinant erythropoietin therapy. It should be noted that as a metabolic precursor to bicarbonate, citrate may also ameliorate the metabolic acidosis of renal failure. Citrate may also prevent metastatic calcification [19].
In summary, ferric citrate appears to be efficacious and well tolerated as a treatment for hyperphosphataemia in haemodialysis patients. Additional longer studies are needed to confirm the early promise of ferric citrate as a viable alternative to existing treatments.
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Acknowledgments |
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Notes |
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References |
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