An open-label, crossover study of a new phosphate-binding agent in haemodialysis patients: ferric citrate

Wu-Chang Yang1, Chwei-Shiun Yang2, Chun-Chen Hou1, Tsai-Hung Wu1, Eric W. Young3 and Chen H. Hsu3,

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



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Hyperphosphataemia contributes to secondary hyperparathyroidism and renal osteodystrophy in patients with end-stage renal disease (ESRD). Calcium salts are widely employed to bind dietary phosphate (P) but they may promote positive net calcium balance and metastatic calcification. We recently reported that ferric compounds bind intestinal phosphate in studies of normal and azotemic rats.

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



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Phosphate accumulation is a frequent consequence of renal failure, leading to metastatic calcification, secondary hyperparathyroidism and other problems. Dietary phosphate restriction alone is usually insufficient to control hyperphosphataemia. Therefore, most patients are treated with orally administered aluminium or calcium salts that bind dietary phosphate and facilitate faecal elimination rather than intestinal absorption. Long-term use of aluminium compounds can cause bone and other toxicities [1]. Calcium therapy may be complicated by the development of hypercalcaemia and calcium retention, potentially contributing to soft-tissue mineralization and organ dysfunction [25]. Soft tissue mineralization is a problem for renal patients due to multiple factors including hyperphosphataemia, vitamin D therapy and hyperparathyroidism. The need for alternative phosphorus-binding agents has long been recognized, leading to the development of new agents. Previous studies have indicated that ferric compounds can bind dietary phosphate and alter phosphate metabolism [69]. The current clinical trial was designed to assess the efficacy, safety and tolerability of ferric citrate as a phosphate-binding agent in haemodialysis patients.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Study design
The study was an unblinded, crossover comparison of calcium carbonate vs ferric citrate, both administered in fixed doses. Haemodialysis patient-volunteers who appeared to meet the acceptability criteria (see below) were selected after a screening evaluation. The design and conduct of the study were explained in detail and patients were then asked to read and sign an informed consent statement, which had been approved by the responsible Institutional Review Board. Iron supplements (oral and parenteral) were withheld throughout the study beginning 1 month prior to the trial.

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 8–10 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 13–54 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.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Demographic data and adverse experiences
Of the 54 patients recruited, nine were withdrawn before the conclusion of the study. Two withdrawals were related to adverse events (see below). Seven withdrawals occurred for protocol-related issues including withdrawal of consent (four patients), hospitalization due to stroke (one patient), iron supplement taken during study (one patient) and missed blood collection (one patient). Protocol-related withdrawals occurred during calcium carbonate therapy in two patients, during ferric citrate therapy in two patients and during a non-treatment period in two patients. The study was completed by 23 female and 22 male subjects. The average age was 52.5±11.8 years and the average weight was 54.5±10.7 kg.

Table 1Go 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.


View this table:
[in this window]
[in a new window]
 
Table 1. Frequency of adverse experiences

 

Dietary phosphate and calcium intake
Table 2Go 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).


View this table:
[in this window]
[in a new window]
 
Table 2. Average dietary intake of phosphorus and calcium

 

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 3Go). 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.


View this table:
[in this window]
[in a new window]
 
Table 3. Serum measurements related to mineral metabolism

 
Table 3Go shows that at week 4 the serum phosphate concentration fell by approximately 2 mg/dl (from 7.2 to 5.2 mg/dl) with calcium treatment, and by 1 mg/dl (from 6.7 to 5.7 mg/dl) with ferric citrate (P<0.0001). The magnitude of the reduction in serum phosphate was influenced by the starting (i.e. washout) concentration and the binding capacity of the treatments. By chance, the washout phosphate concentration was lower prior to ferric citrate treatment (6.7+1.9 mg/dl) than calcium carbonate treatment (7.2+1.9 mg/dl). Furthermore, both agents were administered at a fixed dose of 1 g three times a day even though CaCO3 contains 40% calcium and FeC6H5O7 contains only 23% iron.

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 3Go).

The serum concentrations of other blood tests are shown in Tables 4GoGo6Go. There was a small increase in the serum ferritin concentration during the ferric citrate but not the calcium carbonate treatment (Table 4Go). Liver function and other laboratory measures were not significantly altered with either treatment (Tables 5Go and 6Go).


View this table:
[in this window]
[in a new window]
 
Table 4. Haemoglobin, haematocrit, and iron measurements

 

View this table:
[in this window]
[in a new window]
 
Table 5. Measurements associated with hepatic function

 

View this table:
[in this window]
[in a new window]
 
Table 6. Serum chemistry measurements

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Phosphate retention and the resulting hyperphosphataemia are associated with a variety of problems in patients with renal disease, including secondary hyperparathyroidism, soft tissue mineralization and, possibly, the progression of renal failure [10]. The problem is compounded in haemodialysis patients who are unable to excrete phosphate through the kidney [11]. In the present study, the average daily phosphate intake was approximately 800 mg/day. Even with this relatively low level of phosphate intake, patients experienced a significant increase in the serum phosphate concentration when their usual phosphate binders were stopped during the washout period (Table 2Go). This result illustrates the difficulty of controlling phosphate balance through diet and dialysis alone. End-stage renal disease (ESRD) patients usually require treatment with phosphate-binding agents to maintain an acceptably low serum phosphate concentration.

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 100–200 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 1Go). 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 1Go). 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 3Go), 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 3Go). 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 4Go). 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.



   Acknowledgments
 
The authors acknowledge the financial support by the Taiwan China Chemical and Pharmaceutical Company, Taipei, Taiwan, Republic of China.



   Notes
 
Correspondence and offprint requests to: Chen H. Hsu, 3914 Taubman Centre, Nephrology Division, University Hospital, Ann Arbor, MI 48105-0364, USA. Email: hsuc{at}umich.edu Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Slatopolsky E, Weerts C, Lopez HS et al. Calcium carbonate as a phosphate binder in patients with chronic renal failure undergoing dialysis. N Engl J Med1986; 315 [Suppl 3]: 157–161.[Abstract]
  2. Hsu CH. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis1997; 29: 641–649[ISI][Medline]
  3. Clarkson EM, McDonald SJ, De Wardener HE. The effect of high intake of calcium carbonate in normal subjects and patients with chronic renal failure. Clin Sci1966; 30: 425–438[ISI][Medline]
  4. Clarkson EM, Durrant C, Phillips ME, Gower PE, Jewkes RF, De Wardener HE. The effect of high intake of calcium and phosphate in normal subjects and patients with chronic renal failure. Clin Sci1970; 39: 693–704[Medline]
  5. Clarkson EM, Eastwood JB, Koutsaimanis KG, De Wardener HE. Net intestinal absorption of calcium in patients with chronic renal failure. Kidney Int1973; 3: 258–263[ISI][Medline]
  6. Cox G, Dodds M, Wigman H, Murphy F. The effects of high doses of aluminum and iron on phosphorus metabolism. J Biol Chem1931; 92: Xi–Xii
  7. Brock J, Diamond L. Rickets in rats by iron feeding. J Pediatr1934; 4: 442–453
  8. Hsu CH, Patel SR, Young EW. New phosphate binding agents: ferric compounds. J Am Soc Nephrol1999; 10: 1274–1280[Abstract/Free Full Text]
  9. Weaver CM, Schulze DG, Peck LW, Magnusen HM, Martin BR, Gruenhagen SE. Phosphate-binding capacity of ferrihydrite versus calcium acetate in rats. Am J Kidney Dis1999; 34: 324–327[ISI][Medline]
  10. Lau K. Phosphate excess and progressive renal failure: the precipitation–calcification hypothesis. Kidney Int1989; 36: 918–937[ISI][Medline]
  11. Ramirez JA, Emmett M, White MG et al. The absorption of dietary phosphorus and calcium in hemodialysis patients. Kidney Int1986; 30: 753–759[ISI][Medline]
  12. Liu SH, Chu HI. Studies of calcium and phosphorus metabolism with special reference to pathogenesis and effects of dihydrotachysterol (A.T. 10) and iron. Medicine (Baltimore)1943; 22: 103–161
  13. Slatopolsky E, Finch J, Denda M et al. Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest1996; 97 [Suppl 11]: 2534–2540[Abstract/Free Full Text]
  14. Walker JA, Sherman RA, Cody RP. The effect of oral bases on enteral aluminum absorption. Arch Intern Med1990; 150: 2037–2039[Abstract]
  15. Rudy D, Sica DA, Comstock T, Davis J, Savory J, Schoolwerth AC. Aluminum–citrate interaction in end-stage renal disease. Int J Artif Organs1991; 14: 625–629[ISI][Medline]
  16. Domingo JL, Gomez M, Llobet JM, Corbella J. Influence of some dietary constituents on aluminum absorption and retention in rats. Kidney Int1991; 39: 598–601[ISI][Medline]
  17. Sheikh MS, Maguire JA, Emmett M et al. Reduction of dietary phosphorus absorption by phosphorus binders. A theoretical, in vitro, and in vivo study. J Clin Invest1989; 83: 66–73[ISI][Medline]
  18. Conrad, Marcel E. Regulation of iron absorption. In: Prasad AS, ed. Essential and Toxic Trace Elements in Human Health and Disease: An Update. Wiley-Liss, Inc., New York, 1993; 203–219
  19. Gimenez L, Walker WG, Tew WP, Hermann JA. Prevention of phosphate-induced progression of uremia in rats by 3-phosphocitric acid. Kidney Int1982; 22: 36–41[ISI][Medline]
Received for publication: 27. 6.00
Revision received 10.10.01.