Sevelamer hydrochloride (Renagel®), a non-calcaemic phosphate binder, arrests parathyroid gland hyperplasia in rats with progressive chronic renal insufficiency
Nobuo Nagano1,,
Sonoe Miyata1,
Sachiko Obana1,
Masako Ozai1,
Nami Kobayashi1,
Naoshi Fukushima2,
Steven K. Burke3 and
Michihito Wada1
1 Pharmaceutical Development Laboratories, Kirin Brewery Co., Ltd, Takasaki,
2 Fuji Gotenba Research Laboratory, Chugai Pharmaceutical Co., Ltd, Shizuoka, Japan, and
3 GelTex Pharmaceuticals, Inc., Massachusetts, USA
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Abstract
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Background. It has been demonstrated that dietary phosphate restriction suppresses parathyroid hormone (PTH) secretion and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI) independently of serum calcium and 1,25(OH)2D3 levels. This study was conducted to examine whether sevelamer hydrochloride (Renagel®; hereafter referred to as sevelamer), a non-calcaemic phosphate binder could inhibit the parathyroid gland (PTG) hyperplasia in rats with progressive CRI.
Methods. Male SpragueDawley rats were injected twice with low doses of adriamycin (ADR). Two weeks after the last injection of ADR, rats were fed a diet containing 1 or 3% sevelamer for 84 days. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of study, serum 1,25(OH)2D3 levels were measured and the maximal two-dimension area of the PTG in paraffin section was calculated using an imaging analyser.
Results. Dietary sevelamer treatment inhibited the elevations of serum phosphorus, calciumxphosphorus product, and PTH levels that occurred as the study progressed. Sevelamer also suppressed maximal PTG area and there existed positive strong correlation between maximal PTG area and serum PTH levels at the end of the study. Serum phosphorus levels positively correlated well with serum PTH levels and maximal PTG area. In contrast, serum calcium or 1,25(OH)2D3 levels did not show any correlation with serum PTH levels and maximal PTG area.
Conclusions. Sevelamer treatment arrested hyperphosphataemia and PTG hyperplasia accompanied by the elevation of serum PTH levels. The correlation analysis suggests that reduced serum phosphorus levels contributed to the suppression of PTG hyperplasia and resulted in the reduction of PTH levels in this animal model after the sevelamer treatment. The management of phosphorus control started from early stage of CRI could prevent PTG hyperplasia and facilitate later management of secondary hyperparathyroidism.
Keywords: parathyroid hormone (PTH); parathyroid-gland hyperplasia; phosphate binder; serum phosphorus; sevelamer hydrochloride (Renagel®)
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Introduction
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Secondary hyperparathyroidism (HPT), characterized by hyperplasia of the parathyroid gland (PTG) is one of common consequences of chronic renal insufficiency (CRI) [13]. Secondary HPT accompanied by renal bone disease is initiated at an early stage of CRI and PTG hyperplasia is positively associated with the magnitude of circulating levels of serum parathyroid hormone (PTH). In addition, PTG hyperplasia is rarely reversible and often develops to nodular hyperplasia, which is refractory to vitamin D therapy. Therefore it is important to prevent the progression of PTG hyperplasia at an early stage.
Although not precisely defined, several factors contribute to PTG hyperplasia. It has been proposed for a long time that lowered blood calcium and 1,25(OH)2D3 levels play pivotal roles in secondary HPT development and PTG cell proliferation [13]. Phosphorus retention is traditionally considered to increase PTH secretion through inhibition of 1,25(OH)2D3 production, which in turn produces hypocalcaemia. However, an increasing volume of information has been accumulating on direct effect of phosphorus on PTG function and cell proliferation independently of calcium and 1,25(OH)2D3. A high-phosphorus diet increases PTH mRNA and PTH secretion and causes PTG hyperplasia in normal rats [46] and rats with CRI [6]. Conversely, a low-phosphorus diet reverses secondary HPT in uraemic dogs [7], and inhibits PTH mRNA and PTG hyperplasia in rats with CRI [6,8,9] independently of serum calcium and 1,25(OH)2D3. Furthermore, the direct effect of phosphorus has been confirmed by recent in vitro studies demonstrating that high-phosphate media stimulate PTH secretion in PTG tissue preparations [9,10].
Sevelamer hydrochloride (Renagel®, cross-linked poly[allylamine hydrochloride], hereafter referred to as sevelamer) is a novel non-calcaemic phosphate binding polymer marketed for the treatment of hyperphosphataemia in patients undergoing haemodialysis [11]. Many beneficial effects of sevelamer have been demonstrated in clinical trials, such as lowering effects on serum phosphorus, calciumxphosphorus product, PTH, and low-density lipoprotein (LDL) cholesterol levels without increasing serum calcium levels. However, the effect of sevelamer on PTG hyperplasia has not been investigated.
It is known that two intravenous injections of low-dose of adriamycin (ADR), an antineoplastic agent, produce progressive CRI in rats. We have recently demonstrated that rats treated with ADR develop progressive secondary HPT with low-turnover bone and osteomalacia [12]. ADR-injected rats produce massive proteinuria and show chronic decreases in serum 1,25(OH)2D3 levels mainly caused by urinary loss of vitamin D-binding protein. However, in contrast to ADR-injected rats, we have observed that the serum 1,25(OH)2D3 of partially nephrectomized rats widely used as experimental animal model of CRI does not keep at a low concentration, and gradually increases, probably due to compensatory tubular hyperplasia [1315]. In the present study we examined whether dietary treatment of sevelamer could prevent PTG hyperplasia in this ADR-induced animal model. In addition, the factors influencing secondary HPT and PTG hyperplasia were analysed.
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Subjects and methods
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Experimental protocol
The experimental protocol was approved by the Experimental Animal Ethical Committee of Kirin Brewery Co., Ltd, and is shown in Figure 1
. Male SpragueDawley rats, 6 weeks of age, were purchased from Charles River Japan (Tokyo, Japan) and fed a standard powder diet containing 0.93% phosphorus, 1.09% calcium, 25.2% crude protein, and 2.5 IU/g vitamin D3 (CE-2, CLEA Japan, Tokyo, Japan). After an acclimatization period of 11 days, a blood sample was collected from the tail artery to measure serum phosphorus, calcium, and PTH levels on experimental day -29. The rats were divided into two groups that were matched with respect to body weight, serum phosphorus, and calcium levels (Grouping I). On day -28, rats were injected with 3 mg/kg of ADR (doxorubicin HCl, Kyowa Hakko Kogyo, Tokyo, Japan) via the tail vein (ADR group). Rats of the control group were injected with the same volume (2 ml/kg) of saline. Fourteen days after the first injection of ADR (day -14), 2 mg/kg of ADR was injected, again via the tail vein, in the ADR group. Similarly, the same volume (2 ml/kg) of saline was injected in the control group. On day -2 (Grouping II), a blood sample was collected from the tail artery and the rats of the control and ADR group were divided into two and four groups respectively, each containing nine rats that were matched with respect to body weight, serum phosphorus levels, and blood urea nitrogen (BUN). At this stage, five rats from the control group and 15 rats from the ADR group were eliminated from the study to minimize the variation of the parameters used for the grouping.
Nine rats each from the ADR and the control groups (baseline group) were kept singly in metabolic cages to collect 24-h urine on days -1 to 0. After collecting the urine (day 0), rats of the baseline group were anaesthetized with ether and blood was collected by abdominal aortic puncture, and then thyroid-parathyroid complexes were sampled. On the same day (day 0), rats of the ADR group were given free access to a diet containing 0, 1, or 3% sevelamer for 84 days. The control group was fed a normal diet. The body weight and food intake volume were measured every week. Blood samples were collected on days 7, 14, 28, 42, 56, 70, and 84 from the tail artery. On days 8182, rats were kept singly in metabolic cages to collect 24-h urine. At the end of the study (day 84), blood was collected by abdominal aortic puncture under ether anaesthesia to measure serum 1,25(OH)2D3 levels, and then bilateral thyroidparathyroid complexes were immediately dissected out.
Serum and urinary chemistry
Serum phosphorus, calcium, albumin, total cholesterol, and BUN and urinary phosphorus, calcium, and protein were measured by commercial test kits (Wako Pure Chemical Industries, Ltd, Osaka, Japan) and standard calorimetric methods with a spectrophotometer (U-2000, Hitachi Ltd, Tokyo, Japan). Serum and urinary creatinine were measured using enzyme method assay (CRE-EN, Kynos, Tokyo, Japan). Creatinine clearance (CCr), fractional excretion of phosphorus (FEP), and calcium (FECa) were calculated by standard formulae. Serum PTH and 1,25(OH)2D3 levels were measured using rat PTH-(1-34) immunoradiometric assay kit (IRMA) (Nichols Institute Diagnostics, CA, USA) and radio receptor assay kit (RRA) (SRL, Yamasa, Tokyo, Japan) respectively.
Maximal PTG area
The bilateral thyroidparathyroid complexes were fixed in Bouin's fixative composed of picric acid, formalin, and acetic acid at 4°C overnight. After dehydration by passage through an ethanol/xylene series, tissues were embedded in TissuePrep (Fisher Scientific Co., NJ, USA) and cut into 3 µm serial sections. After sequential dewaxing, slides were stained with H&E. The maximal two-dimensional area of the right or left PTG in the thyroidparathyroid complex was determined from about 10 serial sections before and after the presumed largest section/animal. The slides were projected using a light microscope (Axiophoto, Carl Zeiss, Germany) connected to a high-resolution television monitor (PVM-1454Q, Sony, Japan). The outside edge of the PTG was carefully traced by a digitizer tablet and the area inside the circle was calculated by image analysis system (IBAS, Carl Zeiss, Germany). The reproducibility of the measurements of the maximal PTG area was very high. Repeated measurements of the preparation shown in Figure 5A
by the same investigator six times and by six different investigators showed very small coefficient of variation (CV %) of 0.172 and 0.472 respectively.

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Fig. 5. Representative histological observation of maximal parathyroid gland in the thyroidparathyroid complex in control rats fed a normal diet (A), and adriamycin rats fed a normal diet (B), a diet containing 1% (C), or 3% sevelamer (D) for 84 days. H&E stain.
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Drugs
Sevelamer was synthesized by The Dow Chemical Company (Midland, Michigan, USA) and supplied via Chugai Pharmaceutical Co., Ltd (Tokyo, Japan).
Statistics
All values are expressed as means±SEM. The data obtained from control and ADR rats receiving normal diet at baseline were compared using the Student t-test. Multiple comparisons were performed among control group vs three ADR groups using parametric Dunnett's test. The correlation between serum parameters and serum PTH levels and maximal PTG area was analysed using multiple regression analysis. P<0.05 was taken to indicate statistical significance.
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Results
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Body weight and food intake volume
Body weight was lower in the ADR rats than in control rats and this difference increased as the study progressed. Sevelamer treatment did not significantly affect the body weight at any point. The body weight of each group at baseline and the end of the study is shown in Table 1
. The mean food intake volume (g/rat, day) measured weekly throughout the study was as follows: control, 28.4±0.2; ADR rats receiving normal diet, 23.3±0.4; 1% sevelamer, 24.9±0.3; 3% sevelamer, 25.6±0.5. The mean administered sevelamer doses (mg/rat, day) through the study were calculated as 248.8±3.3 and 767.7±14.3 in 1 and 3% sevelamer groups respectively. One animal in ADR rats receiving normal diet, one animal in 1% sevelamer group, and one animal in 3% sevelamer group died from severe uraemia on days 76, 65, and 75 respectively. The maximal PTG area on these days and serum chemistries except 1,25(OH)2D3 on day 56 or 70 were involved in the correlation analysis.
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Table 1. Body weight, blood urea nitrogen (BUN), serum albumin, total cholesterol, 1,25(OH)2D3, urinary protein, fractional excretion of phosphorus (FEP), fractional excretion of calcium (FECa), and creatinine clearance (CCr) in control rats and adriamycin (ADR) rats at baseline and effects of dietary treatment of sevelamer on these parameters at the end of the study
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Serum and urinary parameters
A significant hypocalcaemia followed by a slight hypercalcaemia was observed in ADR rats when compared to control group rats. Sevelamer treatment had no significant effect on serum calcium levels at any point (Figure 2A
). Serum phosphorus levels progressively increased in ADR rats receiving normal diet as the study progressed. In contrast, 1% sevelamer treatment suppressed the occurrence of hyperphosphataemia and 3% sevelamer treatment kept serum phosphorus levels below the control level through the study (Figure 2B
). The changes in serum calciumxphosphorus product of all groups were similar to those of serum phosphorus changes through the study (Figure 2C
). At the end of study, FEP and FECa were elevated in ADR rats receiving a normal diet (Table 1
). Sevelamer treatment markedly decreased FEP but did not affect FECa.
Serum PTH progressively and steeply rose in ADR rats receiving a normal diet as the study progressed. Sevelamer 1% treatment significantly inhibited the elevation of serum PTH levels in the early period. However, in the later period, mild elevation of serum PTH levels was observed in the sevelamer 1% group. In contrast, sevelamer 3% treatment continued to keep PTH levels below the normal level until the end of the study, but there was no statistical difference between control and sevelamer 3% group throughout the experiment (Figure 3
).
In ADR rats, BUN and serum creatinine gradually increased as the study progressed, while these parameters were within normal ranges in the control group. Neither 1 nor 3% sevelamer treatments significantly affected these two parameters at any time. BUN levels at the baseline and end of the study are shown in Table 1
. At baseline, CCr and serum 1,25(OH)2D3 levels declined significantly in ADR rats compared to control rats. At the end of the study, CCr significantly lowered in ADR rats and sevelamer treatment did not affect CCr. The reduction of serum 1,25(OH)2D3 levels was observed in ADR rats receiving normal diet but this was not statistically significant. Sevelamer treatment tended to decrease serum 1,25(OH)2D3 levels but theses differences were not statistically significant compared to ADR rats receiving normal diet. In contrast, serum 1,25(OH)2D3 concentrations in 1 and 3% sevelamer-treatment groups fell significantly when compared to control rats (Table 1
). Marked hypoalbuminaemia, hypercholesterolaemia, and proteinuria were observed in ADR rats at baseline (Table 1
). This hypoalbuminaemia remained at the baseline level, while hypercholesterolaemia and proteinuria developed toward the end of study. Sevelamer treatment did not affect these three abnormalities in ADR rats.
Maximal PTG area
There was no difference in the maximal PTG area between control and ADR rats at baseline. In contrast, significant and more than twofold elevation of maximal PTG area was observed in ADR rats receiving a normal diet compared to control rats; 1% sevelamer treatment tended to suppress this elevation and 3% sevelamer treatment significantly suppressed maximal PTG area almost to control levels (Figure 4
). Representative histological observation of maximal PTG in the thyroid-parathyroid complex of each group is shown in Figure 5
. The nodule formation known in human nodular PTG hyperplasia was never observed in any of the preparations.

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Fig. 4. Maximal parathyroid gland (PTG) area in control and adriamycin (ADR) rats at baseline and effect of dietary treatment of sevelamer for 84 days on maximal PTG area at the end of the study. Values are means±SE (n=9). ##P<0.01 vs control rats fed a normal diet. **P<0.01 vs ADR rats fed a normal diet.
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Correlation analysis
There existed positive strong correlation between maximal PTG area and serum PTH levels at the end of the study (Figure 6
). Serum phosphorus levels positively correlated with serum PTH and maximal PTG area. In contrast, serum calcium or 1,25(OH)2D3 levels did not show any correlation with serum PTH levels and maximal PTG area (Figures 7
, 8
).
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Discussion
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Long-term treatment of sevelamer (84 days) affected neither food intake volume, body weight, nor serum albumin levels in ADR rats throughout the study. These results suggest that sevelamer does not possess direct nutritional adverse effects. Although nutritional status is also considered to be affected by the nephrosis, proteinuria in ADR rats was not affected by sevelamer treatment in this study. In clinical trials, it has also been confirmed that sevelamer does not alter dietary intake and serum albumin and total protein levels [11]. Nutritional condition has anecdotally been recognized to affect PTG activity and serum PTH levels in patients with CRI. In this study, however, we can exclude the influences of nutritional status in ADR rats on the development of secondary HPT. It has been reported that sevelamer treatment decreases serum total and LDL cholesterol levels in haemodialysis patients [11]. In contrast, the marked hypercholesterolaemia in ADR rats was not affected by sevelamer treatment in the present study. This discrepancy might be due to species-differences, such as that the rat secretes bile acid at all times because it lacks a gall bladder and possesses higher capacity of induction of cholesterol biosynthesis compared to the human.
Sevelamer treatment inhibited the progressive elevation of serum phosphorus and serum calciumxphosphorus product without affecting serum calcium levels in rats with CRI. Sevelamer suppressed the incidence of hyperphosphataemia by diminished gastrointestinal absorption of phosphorus as a phosphate binder, and did not affect serum calcium levels because it does not contain calcium. Therefore serum calciumxphosphorus product paralleled serum phosphorus changes. FEP increased in ADR rats receiving a normal diet and sevelamer treatment significantly and dose-dependently decreased FEP. We have also observed very potent inhibitory effect of sevelamer on FEP in normal rats [16]. This inhibitory effect on FEP is accounted for by the reduction of serum PTH and phosphorus per se, because PTH is a major inhibitory hormone acting on renal phosphorus reabsorption.
Sevelamer treatment dose-dependently suppressed increases in serum PTH levels and maximal PTG area in ADR rats. High-dose treatment of sevelamer suppressed PTH levels below the normal level; 3% treatment of sevelamer is considered to be an overdose in this experiment because over-suppressed PTH levels might result in the suppression of 1,25(OH)2D3 production as discussed later. Recent studies have demonstrated that phosphate load stimulates PTG cell proliferation [6,8,9] and directly increase PTH secretion [9,10]. A clinical study has also suggested that elevated serum phosphorus is the most important factor with the development of secondary HPT [17]. Indeed, serum phosphorus levels correlated strongly with serum PTH levels in this study. The lowered serum phosphorus levels by sevelamer treatment are considered to reduce serum PTH levels. It is known that PTG enlargement is positively correlated with the magnitude of PTH levels in patients [1,2] and rats with CRI [14,15]. The present study showed a strong positive correlation between these two parameters at the end of the study. It is therefore considered that the suppression of PTG hyperplasia by sevelamer treatment chronically results in decreased levels of serum PTH. We have demonstrated that PTG enlargement is caused predominantly by PTG cell hyperproliferation in a rat remnant kidney model [14,15]. Likewise, the increased PTG maximal area observed in this study is considered to be mainly due to increased cell numbers rather than increased cell volume (hypertrophy). It is interesting that serum PTH levels in the 3% sevelamer group fell below the normal control levels although the maximal PTG area in the 3% sevelamer was a little larger than in the normal control group. Theses two differences were not statistically significant, but this result indicates that the amount of PTH secreted from one PTG cell in the 3% sevelamer group is smaller than that of the normal control group. Similarly to the serum levels of PTH, serum phosphorus levels in the 3% sevelamer group still fell below the normal control levels at the end of the study. This result may contribute to the result that differences in PTH secretion did not match with the differences in PTG size.
It has been established that phosphorus overload accelerates and phosphorus restriction prevents PTG hyperplasia in rats with CRI [6,8]. In this study, serum phosphorus levels correlated strongly with maximal PTG area. Therefore, a lowering effect on serum phosphorus levels is considered to be a main mechanism for the suppressive effect of sevelamer on PTG hyperplasia. How phosphorus induces PTG hyperplasia and hypersecretion of PTH should be investigated. Abnormalities of expressions of proto-oncogenes, 1,25(OH)2D3 receptor, acidic FGF and its receptor, and phospholipase A2arachidonic acid pathways, which are known to regulate PTG cell proliferation and PTH secretion [13,18] might be improved by sevelamer treatment. Furthermore, it has been reported that parathyroid calcium receptor, which regulates PTH secretion and PTG hyperplasia, declines in the enlarged PTG of haemodialysis patients [1,2]. It was recently reported that the decreased expression of parathyroid calcium receptor in remnant kidney rats fed a high-phosphorus diet can be prevented by reducing the dietary phosphorus content [19]. Thus, it might be intriguing to compare the expression of parathyroid calcium receptor between ADR rats treated with normal diet and sevelamer.
It is well known that serum calcium and 1,25(OH)2D3 are other potent factors causing secondary HPT and PTG hyperplasia [13]. It is interesting that there was no difference in the maximal PTG area between control and ADR rats at baseline although significant reductions of serum calcium, 1,25(OH)2D3 levels, and CCr were observed in ADR rats at this point. This observation might suggest that reductions of serum calcium and 1,25(OH)2D3 levels would not be a driving force for the PTG hyperplasia. In contrast to the present study, it has been shown that an increase in PTG size can be observed within 5 days after the renal ablation in remnant kidney rats fed a high-phosphorus diet [8]. The lack of PTG hyperplasia at baseline may be due to dietary phosphorus content and renal function. In addition, another two explanations might be possible. First, ADR rats with hypocalcaemia also showed significant hypoalbuminaemia at baseline. Thus the serum calcium levels in ADR rats are underestimated by the existence of hypoalbuminaemia, as we measured only total serum calcium levels in this study. Therefore it is considered that plasma calcium ion levels might rather increase in ADR rats compared to control rats, and this might block the PTG hyperplasia in ADR rats at baseline. Second, ADR might directly inhibit PTG cell proliferation in the initial phase of uraemia. To our knowledge, there is no report on the distribution and accumulation of injected ADR in the rat PTG. Although it is known that the turnover of PTG cells is originally very low [1,2], we cannot exclude the possibility. By switching the diet from high phosphorus to low phosphorus in remnant kidney rats, the PTG size remains enlarged and there is no apoptosis in the PTG cells [3]. Although it is controversial, apoptosis rarely occurs in experimental animals [13,6]. Therefore it can be considered that 3% sevelamer treatment would continue to keep the PTG size observed at baseline rather than decrease the size of enlarged PTG.
Long-term treatment with sevelamer tended to decrease serum 1,25(OH)2D3 levels in the present study. The decreased serum levels of phosphorus and PTH achieved by sevelamer treatment should stimulate and suppress 1,25(OH)2D3 production respectively. These two opposite regulations should cancel each other, but the regulation by suppressed PTH levels is considered to be more dominant in this experiment. Neither serum calcium nor 1,25(OH)2D3 levels correlated with serum PTH levels and maximal PTG area at the end of the study. The present observation is consistent with the results using remnant kidney rats fed low- or high-phosphorus diets [3,9]. Therefore it may be concluded that serum phosphorus but not serum calcium or 1,25(OH)2D3 levels can determine the secondary HPT development and PTG hyperplasia. However, in contrast to the present results, we have recently demonstrated that an apparent hypercalcaemic condition produced by a calcimimetic compound, acting as a specific agonist at the parathyroid calcium receptor, inhibits the parathyroid cell proliferation occurring rapidly just after the ablation of renal function [20], and chronically prevents PTG hyperplasia in remnant kidney rats fed normal- or high-phosphorus diets [14,15]. In this study, despite the existence of long-lasting hyperphosphataemia, calcimimetics can completely suppresses PTH hyperplasia and a significant inverse correlation between serum calcium levels and PTG cell number was observed after calcimimetic compound treatment [14,15]. In addition, it has also been known that administration of 1,25(OH)2D3 can inhibit PTG cell proliferation [2]. Therefore, the factors influencing and determining the PTG activity and hyperplasia seem to be affected by what kind of treatment has been achieved. Clearly, depending on the model used, calcium or 1,25(OH)2D3 may play important roles in PTG hyperplasia. Sevelamer treatment did not significantly affect the elevation of BUN, decline of CCr, or proteinuria in ADR rats. It is known that dietary phosphate restriction prevents deterioration of renal function in experimental animal models. Actually, in our other study we have observed that dietary treatment of sevelamer slows renal functional deterioration in WistarKyoto rats with CRI induced by nephrotoxic serum. The reason for the discrepancy that we did not observe an obvious protecting effect of sevelamer on renal function in ADR rats is unclear, but partly due to the different characteristic of each experimental animal model. In any case, it is clear that the suppressive effect of sevelamer on PTG hyperplasia observed in this study is independent of renal function.
In conclusion, sevelamer treatment arrested hyperphosphataemia and PTG hyperplasia accompanied by the elevation of serum PTH levels. The correlation analysis suggests that reduced serum phosphorus levels contributed to the suppression of PTG hyperplasia and resulted in the reduction of PTH levels in this animal model after the sevelamer treatment. Because PTG hyperplasia is initiated at an early stage of CRI and often develops refractory to medical treatment, the management of phosphorus control started from early stage of CRI could prevent the PTG hyperplasia and facilitate later management of secondary HPT.
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Acknowledgments
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We thank Dr Hideya Ohashi (Kirin Brewery Co., Ltd) and Mr Fumio Kumagai (Chugai Pharmaceutical Co., Ltd) for leading and coordinating the collaborative study among Kirin, Chugai, and GelTex.
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Notes
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Nobuo Nagano PhD, Pharmaceutical Development Laboratories, Kirin Brewery Co., Ltd, 3 Miyahara-cho, Takasaki-shi, Gunma 370-1295, Japan. 
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Received for publication: 23.11.00
Revision received 4. 4.01.