Nephrol Dial Transplant (2003) 18: III90-III93
© 2003 European Renal Association-European Dialysis and Transplant Association
Original Article
Colestimide can be used as a phosphate binder to treat uraemia in end-stage renal disease patients
Toshiyuki Date1,
Takashi Shigematsu2,,
Yoshiteru Kawashita1,
Nobuyoshi Satake1 and
Kyoko Morita1
1 Jinaikai Date Clinic and
2 Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
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Abstract
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Colestimide is a potent therapeutic compound used widely for
treatment of hypercholesterolaemia, and it was discovered coincidentally
that it can be used to lower the serum phosphate concentration
in cases of secondary hyperparathyroidism with refractory hyperphosphataemia. Colestimide
is useful for treating hyperphosphataemia in end-stage renal
disease (ESRD) patients undergoing haemodialysis. Twenty-eight
patients who were being treated for hyperphosphataemia with
3.5±1.1 g/day calcium carbonate were enrolled in the
study. Colestimide was added to their prescription for 4 weeks
at a mean dosage of 2.3 g/day. The serum phosphate concentration
decreased significantly from 6.1±1.1 mg/dl before treatment
to 5.3±1.1 mg/dl at 4 weeks (
P<0.0001). The calcium–phosphate
product also decreased significantly from 59.6±11.3 mg/dl
2 before treatment to 50.5±12.0 mg/dl
2 (
P<0.0001). The
serum total cholesterol significantly (
P<0.001) decreased
at 1 week and remained constant until the end of treatment.
Colestimide is a cationic polymer with chloride as the counterion.
Its chemical structure resembles that of sevelamer hydrochloride,
which is already being used clinically as a phosphate binder.
This suggests that colestimide uses the same mechanism as sevelamer
hydrochloride to treat hyperphosphataemia. The present results
demonstrate that colestimide can function as a Ca-free, aluminium-free,
non-absorbable, phosphate binder in ESRD patients. In addition,
colestimide can reduce the serum phosphate concentration in
combination with calcium carbonate.
Keywords: colestimide; end-stage renal disease; hyperphosphataemia; phosphate binder
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Introduction
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The control of hyperphosphataemia is important in end-stage
renal disease (ESRD) patients undergoing renal replacement therapy
to prevent secondary hyperparathyroidism or renal osteodystrophy,
and also to improve prognosis, including quality of life (QOL)
[
1]. However, the effects of a phosphorus-restricted diet and
phosphorus removal by dialysis are limited, making the use of
a phosphate binder important in the treatment of ESRD. Although
aluminium compounds were administered in the past, they are
no longer prescribed regularly because of their cumulative toxicity,
which can cause encephalopathy and osteopathies such as osteomalacia
[
2]. Currently, calcium (Ca) compounds are used widely as phosphate
binders, but recognition of the adverse effects of Ca overdose,
such as hypercalcaemia, low turnover bone disease and ectopic
calcification [
3], has made the use of colestimide as a Ca-free,
aluminium-free phosphate binder a step forward in the treatment
of ESRD patients. One component of the new compounds is sevelamer
hydrochloride, which is used in the clinical setting to reduce
serum phosphate and serum cholesterol [
4]. Colestimide (colestimide:
JAN, colestilan: INN) currently is being used clinically to
treat high serum cholesterol. We found coincidentally that serum
phosphate was reduced in a patient being treated for high cholesterol
with colestimide (Figure 1
). The present study was designed
to elucidate prospectively whether colestimide has a therapeutic
effect on hyperphosphataemia.
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Fig. 1. The clinical course of our first case showing the therapeutic effect of colestimide on hyperphosphataemia. This patient (a 53-year-old woman) suffered from secondary hyperparathyroidism and was treated with combination therapy of vitamin D, and calcium carbonate as a phosphate binder. In addition, we had to prescribe an aluminium compound. However, we achieved poor control of the serum phosphate concentration. The patient was treated with colestimide for elevated serum cholesterol and, quite coincidentally, the serum phosphate concentration dropped. As the result of this observation, we discovered the serum phosphate-reducing effect of colestimide.
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Subjects and methods
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Twenty-eight ESRD patients without hypercalcaemia (11.0 mg/dl)
but who suffered from hyperphosphataemia (4.0 mg/dl) despite
daily calcium carbonate (1.5 g/day) were selected. Each subject
gave informed consent for the study. The age of subjects was
54.3±12.4 years (mean±SD), the F/M ratio was 14:14
and the dialysis period was 9.6±6.8 years (mean±SD).
Twenty-four of these patients had chronic glomerulonephritis,
three had diabetic nephropathy and one had polycystic kidney
disease. Eighteen patients were on daily oral alfacalcidol therapy
with a mean dose of 0.38±0.13 µg/day, seven patients
were on oral calcitriol pulse therapy with a mean dose of 4.14±2.19
µg/week, and three patients were not prescribed vitamin
D. All patients were being treated for hyperphosphataemia with
calcium carbonate (mean dose: 3.5±1.1 g/day) immediately
after meals, as a phosphate binder. All subjects were treated
for uraemia with three haemodialysis sessions per week using
2.5 mEq/l Ca dialysate. These conditions were not changed during
the study.
We administered colestimide to each patient at a dosage of 3.0 g/day immediately before every meal for 4 weeks. In some cases, it was necessary to reduce the colestimide dosage to 1.5 g/day because of constipation and/or meteorism. Every 2 weeks, we monitored serum phosphate, total calcium/ionized calcium, parathyroid hormone (PTH), total cholesterol and uric acid. The PTH concentration was measured by intact PTH (i-PTH) assay using an Allegro i-PTH IRMA kit (Sumitomo-Metaphysics Pham, Osaka, Japan). Other assays were performed using enzyme techniques as the basic procedure. All data are shown as the mean±SD. Statistical analysis was performed by analysis of covariance (ANOVA) with multiple comparisons. The significance level was set at 5%.
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Results
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Colestimide was administered at a dosage of 3.0 g/day in 15/24
patients (54%), and 1.5 g/day in 13/28 patients (46%); the mean
colestimide dosage was 2.3±0.8 g/day. The serum phosphate
decreased significantly from a mean value of 6.1±1.1
mg/dl before treatment to 5.5±1.2 mg/dl at 2 weeks (
P<0.0001).
Figure 2
shows serum phosphate, serum total calcium and calcium–phosphate
product (Ca
xPi) results during the study. The serum phosphate
was maintained significantly at the lower concentration (5.3±1.1
mg/dl) at week 4 (
P<0.0001). The decrease in serum phosphate
was greater at 4 weeks, with a maximum reduction of 40.7%. Accompanying
this change in phosphate levels, the Ca
xPi decreased significantly
from 59.6±11.3 mg/dl
2 before the treatment to 53.0±12.1
mg/dl
2 at 2 weeks (
P<0.0001), and continued to decrease thereafter
to 50.5±12.0 mg/dl
2 at 4 weeks, with a maximum reduction
of 47.7%. There was no significant change in the total serum
Ca and ionized Ca during the study. The total serum cholesterol
was significantly reduced from 157±26 mg/dl before treatment
to 134±25 mg/dl at 2 weeks, and remained constant (
P<0.0001).
Figure 3
shows the change in the i-PTH as the result of the
4 week colestimide treatment. The PTH was unchanged in the three
patients not receiving vitamin D therapy, ranging from 64.3±51.3
to 68.0±71.6 pg/ml (Figure 3A
). In the 18 patients receiving
daily alfacalcidol therapy, the PTH was also unchanged, ranging
from 39.3±31.5 to 35.6±32.1 pg/ml (Figure 3B
).
Only the seven patients being treated with oral calcitriol pulse
therapy showed a significant reduction in PTH from 297.0±124.2
to 234.6±110.9 pg/ml during colestimide administration
(
P<0.05) (Figure 3C
).
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Fig. 2. Effects of colestimide on total serum calcium, phosphate and CaxPi. Serum phosphate level was reduced significantly at 2 weeks after commencing colestimide administration and continued to reduce significantly during the therapy. Colestimide also had the effect of simultaneously reducing the CaxPi.
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Fig. 3. Effects of colestimide on serum i-PTH for each patient on vitamin D3 therapy. In three patients not receiving vitamin D, PTH did not change in spite of colestimide. The PTH concentration also did not show any change in ESRD patients with daily vitamin D therapy per os. However, the PTH concentration decreased significantly in patients treated with intermittent high-dose oral calcitriol therapy, probably because of successful treatment of hyperphosphataemia.
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Discussion
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The fundamental treatment for hyperphosphataemia is a phosphorus-restricted
diet, but the strict reduction of the intake of proteins rich
in phosphorus can induce malnutrition, which in ESRD patients
undergoing long-term haemodialysis is a risk factor affecting
prognosis [
5]. Nevertheless, the treatment of hyperphosphataemia,
a pathogenic factor for secondary hyperparathyroidism, is important
[
6]. In the present clinical trial, we demonstrated that colestimide,
a medication originally developed for hypercholesterolaemia
treatment [
7], also reduces serum phosphate concentration. Moreover,
colestimide therapy did not cause hypercalcaemia or high Ca
xPi
as is observed when using conventional calcium treatment as
a phosphate binder. High Ca
xPi is a risk factor for vascular
calcification, including the coronary arteries, in patients
undergoing haemodialysis and has been shown to be closely related
to their survival [
8,
9].
Figure 4 shows the cationic polymer chemical structures of sevelamer hydrochloride and colestimide. Each can act as an anion exchanger with Cl- as the counterion. Sevelamer hydrochloride has been developed as a phosphate binder [4], whereas colestimide, with its bile acid-adsorbing activity, has been developed to treat hypercholesterolaemia [7]. Sevelamer can also reduce the serum cholesterol concentration in chronic dialysis patients [4]. The mechanism of action of colestimide on serum phosphate is still obscure but, because of its similar structure, it may work as a phosphate binder in the same way as sevelamer, with similar clinical effects.
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Fig. 4. The chemical structure of colestimide and sevelamer hydrochloride is similar. Both compounds are cation co-polymers with chlorine as a counterion, and may work as anion exchangers.
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Using colestimide as a treatment for hyperphosphataemia is not
associated with any changes in serum calcium concentration,
and colestimide does not contain aluminium. Colestimide is therefore
a new, potent Ca- and aluminium-free treatment for hyperphosphataemia
in ESRD patients. The clinical effect of colestimide occurs
relatively early, and it can be used additively with calcium
carbonate. Chertow
et al. have also reported combination therapy
with sevelamer hydrochloride and a calcium compound [
10], and
they stated that the serum phosphate concentration was reduced
by an average of 2.3 mg/dl after combination therapy. In the
present study, the decrease in the serum phosphate was only
1.0 mg/dl. However, the mean final dosage of sevelamer hydrochloride
used by Chertow
et al. was 4.7 g/day, almost double the mean
colestimide dosage (2.3 g/day) used in the present study. In
our study, the serum phosphate concentration (6.1±1.1
mg/dl) before colestimide treatment was already being controlled
by calcium carbonate, so the clinical potency of the treatment
for hyperphosphataemia by colestimide and sevelamer hydrochloride
cannot be compared by the present data alone. A controlled comparative
prospective study is required to answer this question.
The CaxPi decreased significantly in association with the reduction in the serum phosphate concentration in the present study. Block and Port reported the impact of CaxPi on ESRD patients' survival [1]. Recent studies have shown that hyperphosphataemia stimulates the parathyroid by both direct and indirect mechanisms [6,11]. In the present study, it was observed that in patients with a high degree of secondary hyperparathyroidism, the decrement of the PTH concentration required aggressive vitamin D pulse therapy. Patients with severe secondary hyperparathyroidism usually have a high degree of hyperphosphataemia, and colestimide in conjunction with vitamin D pulse therapy may improve the secondary hyperparathyroidism by having a therapeutic effect on hyperphosphataemia.
In conclusion, the present study has shown that colestimide is clinically useful for improving the survival of ESRD patients by controlling hyperphosphataemia. The therapeutic potency on uraemia is an additive effect to treatment with calcium carbonate acting as a phosphate binder. However, some patients complained of gastrointestinal symptoms, such as constipation and meteorism, which also sometimes occur with sevelamer treatment [4,10]. Further investigation into these adverse effects, and also the safety and long-term clinical effects of colestimide as a phosphate binder in ESRD patients undergoing long-term dialysis therapy is required.
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Notes
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Correspondence and offprint requests to: Takashi Shigematsu,
MD, PhD, Assistant Professor, Division of Nephrology and Dialysis
Unit, Department of Internal Medicine, Jikei University School
of Medicine, Aoto-General Hospital, 6-41-2 Aoto, Katsushika-Ku,
Tokyo 125-8506, Japan. Email:
aotaki{at}jikei.ac.jp 
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References
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- Van de Vyver FL, De Broe ME. Aluminum in tissues. Clin Nephrol 1985; 24 [Suppl 1]:S37–S57
- Hsu CH. Are we mismanaging calcium and phosphate metabolism in renal failure? Am J Kidney Dis 1997; 29:641–649[Web of Science][Medline]
- Chertow GM, Burke SK, Dillon MA, Slatopolsky E for the RenaGel Study Group. Long-term effect of sevelamer hydrochloride on the calciumxphosphate product and lipid profile of haemodialysis patients. Nephrol Dial Transplant 1999; 14:2907–2914[Abstract/Free Full Text]
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- Almaden Y, Hernandez A, Torregrosa V et al. High phosphate level directly stimulates parathyroid hormone secretion and synthesis by human parathyroid tissue in vitro. J Am Soc Nephrol 1998; 9:1845–1852[Abstract]
- Saito Y and MCI-196 Study Group. The long-term study of MCI-196 on hypercholesterolemia. J Clin Ther Med 1996; 12:1305–1347
- Block GA, Hulbert-Shearon TE, Levin NW et al. Association of serum phosphorus and calciumxphosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 1998; 31:607–617[Web of Science][Medline]
- 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]
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Abstract
Introduction