Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study

Tarek Sadek1, Hakim Mazouz1, Hedi Bahloul1, Roxana Oprisiu1, Najeh El Esper1, Isabelle El Esper2, Francis Boitte3, Michel Brazier3, Philippe Moriniere1 and Albert Fournier1,

1 Department of Nephrology, 2 Department of Nuclear Medicine and 3 Biochemistry Laboratory, Amiens CHU, Amiens, France



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
Background. Sevelamer hydrochloride was recently proposed as a phosphate binder to prevent hypercalcaemia in place of calcium alkaline salts in dialysis patients. So far, it has been evaluated only in patients receiving calcitriol, without comparison with CaCO3 alone, although the latter was found to be as effective as the combination of calcitriol and Al(OH)3 in suppressing parathyroid hormone (PTH) without inducing hypercalcaemia and to have a better lowering effect on serum phosphate. Moreover, this bile salt binder may decrease serum 25-OH vitamin D. Therefore, we compared for 5 months two strategies for controlling moderate hyperparathyroidism: CaCO3 alone vs sevelamer in conjunction with measures to increase calcium balance.

Methods. Forty-two patients were randomized: 21 continued their treatment with 4.8 g/day CaCO3 and 21 were switched to sevelamer (initial dose: 2.4 g/day, increased to 4.4 g/day). Each month, when serum-corrected calcium decreased below 2.30 mmol/l, dialysate calcium was increased or alphacalcidol was given at each dialysis session, according to serum PO4 levels. The following parameters were monitored: serum Ca, PO4, bicarbonate and protein, weekly; and serum PTH, 25-OH vitamin D and total, LDL and HDL cholesterol monthly.

Results. Except for higher serum phosphate at month 1, lower serum bicarbonate at month 2 and lower LDL cholesterol at month 5 in the sevelamer group, no difference was found between the two groups. Compared with baseline levels, PTH increased and 25-OH vitamin D decreased significantly in both groups, these two parameters being inversely correlated.

Conclusions. Given comparable control of plasma calcium, phosphate and 25-OH vitamin D, PTH control is comparable in both strategies. Sevelamer does not induce greater vitamin D depletion than CaCO3. The transient decrease of serum bicarbonate after discontinuation of CaCO3 in the sevelamer group suggests a less optimal prevention of acidosis. The sevelamer-induced decrease in LDL cholesterol gives this drug a potential advantage in cardiovascular prevention.

Keywords: bicarbonate; calcium carbonate; LDL cholesterol; parathyroid hormone; sevelamer hydrochloride; 25-OH vitamin D



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
Sevelamer hydrochloride (sevelamer) is a non-aluminic, non-calcic phosphate binder recently introduced for the treatment of hyperphosphataemia in dialysis patients [1]. Its long-term use, however, may fail to suppress parathyroid hormone (PTH) hypersecretion, in spite of the marked reduction of phosphate and the marked increase of serum calcium, bicarbonate, magnesium and presumably calcitriol (since the dose of calcitriol given at each dialysis was increased by 34%) [1].

Calcium carbonate (CaCO3) has been given to our dialysis patients since 1980 instead of aluminium phosphate as a binder for controlling hyperphosphataemia, and it has been shown to correct hyperparathyroidism as efficiently by itself as the combination of 1-{alpha}-OH vitamin D and aluminium phosphate binder [2]. This satisfactory experience has been recently validated by the randomized trial of Indridason and Quarles [3], who showed that in dialysis patients with mild hyperparathyroidism (baseline PTH around 300 pg/ml, as in the sevelamer studies) 13 g/day of CaCO3 was as efficient as calcitriol plus Al(OH)3 and 5 g of CaCO3 in suppressing PTH with the same moderate increase in serum calcium but with a better control of hyperphosphataemia. This difference in serum phosphate control is explained by the opposite effects of calcitriol and oral calcium on phosphate absorption, the former increasing it [4] and the latter decreasing it [5].

This more recent approach was recently criticized, however, by authors who promote the systematic intravenous use of 1-{alpha}-OH vitamin D derivatives at each dialysis—as in the comparative cross-over study of sevelamer with calcium acetate [6] or in the study that evaluated the benefit of giving, at bedtime, 2.25 g of CaCO3 supplement combined with sevelamer compared with sevelamer alone [7]. Indeed, the frequency of hypercalcaemia was significantly higher in the groups receiving oral calcium than in the groups receiving sevelamer alone, in spite of the fact that the majority of the patients were dialysed with a dialysate low in calcium (<1.25 mmol/l) and that the PTH suppression was only marginally greater in the groups receiving calcium. On the other hand, without the administration of 1-{alpha}-OH vitamin D, as in our cross-over comparative study of CaCO3 vs half the dose of elemental calcium given as calcium acetate [8], we observed a much lower incidence of hypercalcaemia (8% with both salts), with exactly the same control of PTH—the dialysate calcium used in both groups being 1.5 mmol/l.

Although two older longitudinal studies in dialysis patients did not relate the progression of vascular calcification to the CaCO3 dose or to hypercalcaemia [9,10], but rather to hyperphosphataemia and hypercalcitriolaemia [10] and hypertriglyceridaemia and hypertension [9], a recent prospective study has incriminated oral-calcium-induced hypercalcaemia in the increase of coronary and aortic calcifications, since this increase did not occur when calcium phosphate binders were replaced by sevelamer [11]. In this study, however, factors other than calcium load could have contributed to this higher risk of arterial calcification—namely, the over-suppression of PTH below the targeted range; the alkalinizing effect of calcium salts, which was absent when sevelamer was used; as well as the higher LDL cholesterol, which promotes atherosclerosis and therefore intimal calcification, since only sevelamer decreased its levels.

Therefore, we decided to compare, head to head, over the long-term, our strategy of controlling mild hyperparathyroidism and phosphocalcic disorders in dialysis patients exclusively with CaCO3 taken with lunch and dinner [12] with the use of sevelamer combined with increased dialysate calcium concentrations or with increasing the dose of alphacalcidol. The aim of the study was to see whether we could maintain a comparable control of PTH secretion with comparable serum calcium and phosphate levels. In addition, serum 25-OH vitamin D, total cholesterol, LDL and HDL cholesterol were monitored in order to see to what extent sevelamer, which complexes with bile salts as well as phosphate, will decrease serum cholesterol levels and promote vitamin D depletion by interrupting its enterohepatic cycle [13].



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
Patients and protocol
The protocol was submitted to the Amiens ethic committee and explained to 60 stable and reliable patients who were dialysed three times 4 h a week and whose usual PTH levels were <400 pg/ml while using CaCO3 as the only phosphate binder and without vitamin D supplementation. The patients were randomized into two groups with stratification for PTH values: 21 continued their pre-existing treatment with CaCO3 without change in their dialysate calcium concentration and 21 were switched to sevelamer at the initial dose of 1.2 g at lunch and dinner. This dose was progressively increased to 4.4 g/day in order to maintain their pre-dialysis serum PO4 below 1.70 mmol/l. Each month, if the values of serum corrected calcium decreased below 2.30 mmol/l, the following measures were taken in the sevelamer group: (i) if serum phosphate was >1.70 mmol/l, alphacalcidol was not given since it increases PO4 absorption [4]—instead, the dialysate calcium concentration was increased by 0.25 mmol/l since it has been shown to decrease serum PTH [14]; and (ii) if serum phosphate was <=1.70 mmol/l, an oral bolus of alphacalcidol was given at the end of each dialysis session at an increasing dose starting from 0.25 µg.

Otherwise, no other change in the dialysis treatment was introduced. The dialysate concentrations of bicarbonate and magnesium were, respectively, 39 and 0.50 mmol/l, while dialysate calcium varied as indicated in Table 1Go. Patients who were on statins for dyslipidaemia did not change their dose.


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Table 1.  Comparison of biological and therapeutic data between the two groups (means±SD) at baseline (month 0=November) and after 2 (January) and 5 months (April)

 
A dietary diary was recorded in months 0 (M0) and 5 (M5) for evaluating protein, calcium and phosphorus intake.

Analytical methods
Before the first dialysis of the week, blood was drawn to determine serum calcium, phosphate, bicarbonate, protein, urea and creatinine. In addition, serum total cholesterol, LDL and HDL cholesterol, triglycerides, magnesium, 25-OH vitamin D and PTH were measured every month. After extraction by acetonitrile, 25-OH vitamin D (normal range: 10–40 ng/ml) was measured by radioimmunoassay (Incstar Corp.). Intact PTH (normal range: 10–55 pg/ml) was measured by immunochemiluminometry (Nichols Institute of Diagnostics). Serum corrected calcium was calculated according to the Parfitt formula: Go

Statistical methods
The two groups were compared by the Student's t-test and the Wilcoxon test for unpaired data while parameter variations within the same group were compared by paired t-test or the Wilcoxon test. Correlations were tested using univariate and multivariate analyses with Statview Software. A P-value of <0.05 was considered significant.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
The results could be analysed in only 16 patients of the CaCO3 group and 15 of the sevelamer group because of the following exclusions: (i) in the CaCO3 group, one patient was transplanted, three died (one sudden death in a diabetic patient with coronary heart disease, one septicaemia and one colon cancer) and one was hospitalized 3 months for an ischaemic stroke; and (ii) in the sevelamer group, five patients discontinued the drug because of digestive intolerance and one patient with a dilated cardiomyopathy had a sudden death.

Phosphocalcic metabolism survey
Table 1Go summarizes the data (means±SD) at the beginning of the study (month 0=early November 2000) and then 2 months later (month 2=early January 2001) and 5 months later (month 5=early April 2001).

After randomization at month 0 the two groups were comparable with regards to their serum concentrations of 25-OH vitamin D, PTH, corrected calcium, phosphate, bicarbonate and magnesium as well as in the therapeutic parameters: the dose of CaCO3 was, respectively, 4.85 and 4.75 g/day, the dialysate calcium concentration was mainly 1.5 mmol/l (in nine patients of each group), but lower or higher concentrations were used in only three or four patients of each group. Protein, calcium and phosphate dietary intake also were comparable.

In the sevelamer group, after the first month, when serum phosphate was >1.70 mmol/l while serum calcium decreased below 2.30 mmol/l, dialysate calcium was increased in three patients at month 2 and in an additional one thereafter. When serum phosphate was controlled <1.70 mmol/l while serum calcium was <2.30 mmol/l, alphacalcidol was introduced in five patients at the dose of 1 µg/week and later on in six patients at a higher dose of 2.4 µg/week.

Figure 1Go shows the monthly tracking of serum corrected calcium with its stability in the CaCO3 group and the expected decrease at month 1 in the sevelamer group. This decrease was corrected afterwards using increased dialysate calcium concentrations or alphacalcidol so that at month 5 serum calcium was at 2.41 and 2.40 mmol/l in the sevelamer and Ca groups, respectively.



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Fig. 1.  Follow-up of serum corrected calcium. Significance of the change vs month 0: *P<0.05. Difference between the two groups: NS.

 
Hypercalcaemia, defined by a serum corrected calcium >=2.60 mmol/l, was initially present in one patient (13%) of the sevelamer group and three patients (18.7%) of the calcium group and reoccurred at least once in the follow-up period in, respectively, one (6.6%) and five patients (31%)—the highest level being, however, only 2.80 mmol/l.

Figure 2Go shows the monthly tracking of serum PO4 with a transient unexpected decrease in the CaCO3 group at month 1 and the expected increase in the sevelamer group to 1.91 mmol/l at month 1, which was corrected afterwards to 1.84 mmol/l by increasing the sevelamer dose to 3.3 and 4.4 g/day at month 2 and month 5.



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Fig. 2.  Follow-up of serum phosphate. Significance of the change vs month 0 in each group: *P<0.05. Significance of the difference between the two groups at each month: +P<0.02.

 
Table 1Go shows that the serum calcium x serum PO4 product was not significantly different between the two groups at baseline as well as at month 2 and month 5 (3.90 and 4.43 mmol/l or 47.2 and 53.2 mg/dl at month 5 in the Ca and sevelamer groups, respectively).

Figure 3Go shows the monthly tracking of serum PTH with a significant progressive increase from 145 to 180 pg/ml in the CaCO3 group and the rapid increase from 186 to 247 pg/ml at month 1 followed by a plateau up to month 5 in the sevelamer group. At no time, however, was the difference between the PTH levels of the two groups significant, although the PTH levels were always lower in the CaCO3 group.



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Fig. 3.  Follow-up of serum PTH. Significance of the change vs month 0 in each group: *P<0.05; **P<0.02. Difference between the two groups at each month: NS.

 
Figure 4Go shows the tracking of serum 25-OH vitamin D with a comparable decrease in both groups, from 20 to 9 ng/ml with CaCO3 and from 18 to 7.6 ng/ml with sevelamer.



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Fig. 4.  Follow-up of 25-OH vitamin D. Significance of the change vs month 0 in each group: *P<0.05; **P<0.02. Difference between the groups at each month: NS.

 
With regards to serum bicarbonate, Table 1Go shows a transient decrease at month 2 only in the sevelamer group. Serum magnesium remained constant at the upper limit of normal in both groups. The dietary intakes of protein, calcium and phosphate at month 5 were comparable to those evaluated at month 1 (Table 1Go).

Correlation between serum PTH and serum 25-OH vitamin D
In univariate analysis, serum PTH changes were inversely correlated to changes in serum 25-OH vitamin D only during the first month (r=0.46, n=31; P=0.01), but thereafter no correlation was found.

Significant negative correlations between simultaneously measured serum concentrations of PTH and 25-OH vitamin D were found at the beginning of the study (month 0) (r=0.27, n=31; P=0.0002) and at month 5 (r=0.35, n=24; P=0.0004).

Blood lipid survey
Table 1Go shows that serum total and LDL cholesterol significantly decreased in the sevelamer group by 12% and 18%, respectively, but not in the CaCO3 group. At month 5, the difference between the two groups was significant only for LDL cholesterol. Triglycerides and HDL cholesterol did not change in either group.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 
Sevelamer and the control of hyperparathyroidism
This study is the first long-term (5 months), head to head comparison of the use of the new non-calcic, non-aluminic phosphate binder sevelamer hydrochloride (sevelamer) combined with measures preventing serum calcium decrease (higher dialysate calcium and/or alphacalcidol), with CaCO3 alone (i.e. without 1-{alpha}-OH vitamin D) in dialysis patient with mild hyperparathyroidism.

It is not surprising that the PTH increase during the first month was greater (although not significantly) in the sevelamer group than in the CaCO3 group since the serum calcium decrease and the serum phosphate increase, which are known to stimulate PTH secretion, occurred only in this group, while serum 25-OH vitamin D comparably decreased in both groups. Indeed, the serum-calcium-increasing measures were implemented in the sevelamer group only after the first month.

In spite of the increased sevelamer dose to 4.4 g/day, mean pre-dialysis serum phosphate at month 5 was higher in the sevelamer group (1.84 mmol/l) than in the CaCO3 group (1.64 mmol/l) on 4.8 g/day of CaCO3. This difference, however, was not statistically significant. The relatively poor efficacy of sevelamer in our study is in agreement with the ‘Treat to goal’ study [11], which used a higher dose of sevelamer (6.5 g/day) to achieve a mean serum phosphate of 1.7 mmol/l.

In spite of serum calcium and phosphate stability (except for the first month in the sevelamer group), serum PTH increased significantly in both groups. The brisker increase of PTH observed in the sevelamer group during the first month is explained, obviously, by the delay in taking measures to increase serum calcium and lower serum phosphate. The discrepancy between the continuous increase of serum PTH in the CaCO3 group and the serum PTH, which plateaued in the sevelamer group after the first month, is likely explained by the presumed differences in the changes of serum calcitriol levels. Indeed, below a 25-OH vitamin D threshold of ~20 ng/ml, serum calcitriol concentration is directly related to 25-OH vitamin D concentration [15]. The winter decrease of serum 25-OH vitamin D being comparable in both groups should result in the same decrease of serum calcitriol in both groups. Since this decrease is prevented, however, by the administration of alphacalcidol only in the sevelamer group, this may explain the stability of PTH in this group after the first month and the progressive increase of PTH in the CaCO3 group.

In contrast to our hypothesis—that the lack of PTH suppression by the long-term administration of sevelamer may be due to the vitamin D-depletive effect of this bile salt binder (which may decrease fatty acid intestinal absorption and therefore interrupt the enterohepatic cycle of vitamin D [13])—the present study did not document a greater decrease of serum 25-OH vitamin D with sevelamer than with CaCO3.

A transient decrease of serum bicarbonate was observed at the second month in the sevelamer group. This is in disagreement with the unexplained bicarbonate increase reported in the long-term sevelamer study [1]. This observation, however, has already been made by Gallieni et al. [16] and attributed not to sevelamer hydrochloride per se, but to CaCO3 discontinuation. Indeed, those authors observed this phenomenon only after CaCO3 discontinuation. Since secondary bone buffering may explain the transient nature of this decrease of bicarbonate after the discontinuation of CaCO3, one might conjecture that the substitution of sevelamer for CaCO3 may have deleterious long-term effects on bone mineral density. This hypothesis proposed by Gallieni et al. stresses the need for further studies on acid–base and bone balances during long-term treatment with sevelamer.

Our study cannot support a clear advantage for sevelamer over CaCO3 for the treatment of renal osteodystrophy in dialysis patients with mild hyperparathyroidism who do not need 1{alpha}-OH vitamin D therapy in order to maintain PTH levels within the optimal American consensual PTH range of 150–300 pg/ml [11] (when using ‘intact PTH’ kits). However, this does not mean that sevelamer would not be particularly valuable when higher doses of CaCO3 are used along with 1{alpha}-OH vitamin D derivatives for suppressing more severe hyperparathyroidism and when hypercalcaemia occurs in spite of low dialysate calcium. Another interesting indication for sevelamer would be in pre-dialysis patients when, in spite of optimal native vitamin D levels (40–60 ng/ml serum 25-OH vitamin D), CaCO3 fails to control hyperparathyroidism and hyperphosphataemia at non-hypercalcaemic doses. Substitution of sevelamer for CaCO3 and concomitant use of 1{alpha}-vitamin D may then allow waiting for other clinical parameters of dialysis requirement, without performing a surgical parathyroidectomy. Indeed, this latter course may accelerate the progression of renal failure, whereas adequate dialysis sometimes may reverse severe hyperparathyroidism.

Sevelamer effect on dyslipidaemia, arterial calcifications and cardiovascular risk in dialysis patients
This issue has to be discussed in the light of the promising results of the ‘Treat to goal’ study that compared sevelamer and calcium phosphate binders regarding the risk of the extension of coronary and aortic artery calcification in dialysis patients treated with calcitriol. In fact, these calcifications increased significantly only in the calcium-treated group. This, however, was observed while the percentage of patients with at least one episode of hypercalcaemia was higher with CaCO3 (43 vs 17%). It is noteworthy that these percentages were higher than in our study because of the more widespread use of calcitriol not only in the sevelamer group but also in the CaCO3 group. Higher serum calcium may also explain why PTH decreased below the targeted range of 150–300 pg/ml only in the CaCO3 group. Reciprocally, the lower bone formation rate expected with this range of PTH may also account for the higher frequency of hypercalcaemia in the CaCO3 group. In addition, the better correction of acidosis in the CaCO3 group of the ‘Treat to goal’ study may have contributed to the greater extension of arterial calcification. Finally, LDL cholesterol was lower by 1 mmol/l in the sevelamer group so that the higher arterial calcium content in the CaCO3 group could also be explained by more severe atherosclerosis favouring endothelial calcification. Anyhow, the partial responsibility of oral calcium loads for the occurrence of arterial calcification that this study suggested, cannot be interpreted as an increased cardiovascular risk, since in haemodialysis patients who underwent coronary angioplasty the cardiovascular morbidity and mortality have been reported lower in those with coronary artery calcifications than in those without [17]. The 1 mmol/l lower LDL cholesterol observed in the sevelamer group in this study, however, is of unequivocal prognostic significance since such a decrease has been shown in the Heart Protection Study (HPS) trial to decrease cardiovascular mortality by 17% and the morbidity by 24% [18] and that the absolute global cardiovascular risk for dialysis patients is about 10 times higher than in a non-uraemic population [19].

Therefore, if the second step of the ‘Treat to goal’ study is to show that sevelamer decreases cardiovascular morbimortality more effectively than CaCO3 by decreasing the risk of hypercalcaemia and arterial calcifications, the CaCO3 group should also show a comparable decrease of its LDL level. A cost-effectiveness study of sevelamer vs CaCO3 combined with a hypolipidaemic drug like a statin should be performed for that purpose, since the cost of using sevelamer for phosphate binding presently is 10 times higher (137 vs 13.7 €/month) and remains about twice higher when the cost of statins is included.

Tolerance of sevelamer
In our experience, tolerance of sevelamer was relatively poor since five out of 21 patients discontinued the drug (76% adherence) because of gastrointestinal complaints, which prevented increasing the dose above 4.4 g/day. Presumably the gastric sensitivity of uraemia and the multi-medication of our patients contributed to our higher discontinuation rate. The decreased bulk of sevelamer on the stomach achieved by using the 800 mg tablets instead of the 400 mg capsules has improved its tolerance according to the ‘Target to goal’ study [11], in which patient adherence was 86% to a much higher dose of 6.5 g/day.

Seasonal variation of serum 25-OH vitamin D
As expected, serum 25-OH vitamin D decreased in both groups between November and April in keeping with the seasonal decrease of the intensity of the ultraviolet rays. Serum PTH showed a significant inverse correlation with serum 25-OH vitamin D both at the beginning and the end of the study, in agreement with our previous larger cross-sectional study [15] where this correlation was shown to be independent of calcitriol, calcium and phosphate levels, suggesting a direct suppressive role of 25-OH vitamin D on PTH secretion. Since according to EDTA-ERA experts [20] supplementation with native vitamin D (1000 IU/day) is recommended when serum 25-OH vitamin D is <20 ng/ml, the fact that in November half of our patients and by April all of our patients were under this threshold, justifies this supplementation not only on a systematic basis in winter but also throughout the year for half the dialysis population. This also justifies determination of serum 25-OH vitamin D, at least before therapy with 1{alpha}-OH vitamin D derivatives is considered for poor control of PTH levels, and once a year at the beginning of spring when its levels are the lowest.



   Conclusions
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 

  1. For controlling mild hyperparathyroidism, sevelamer hydrochloride in combination with measures that increase calcium balance (higher dialysate calcium concentration, alphacalcidol or both) presents no therapeutic advantage over a moderate dose of CaCO3 alone (5 g/day) with respect to the serum calcium phosphate and PTH concentrations, but is more expensive.
  2. Sevelamer-induced LDL cholesterol reduction (18%) may help to decrease the high cardiovascular risk as well as the atherome-induced intimal calcification of dialysis patient arteries.
  3. The transient decrease in serum bicarbonate observed 2 months after CaCO3 discontinuation in the sevelamer group suggests that this latter does not have an alkalinizing effect like CaCO3 does, which would imply a lower bone sparing effect, but a higher risk of arterial calcification.
  4. Although sevelamer complexes with bile salts, no greater decrease of serum 25-OH vitamin D was documented in the sevelamer treatment group.
  5. The winter-dependent serum 25-OH vitamin D decrease may have contributed to the observed increase of PTH levels and justifies systematic vitamin D supplementation, especially during this season in our country.



   Notes
 
Correspondence and offprint requests to: Professor Albert Fournier, Hôpital Sud, Department of Nephrology, F-80054 Amiens cedex 1, France. Email: Fournier.Albert{at}chu-amiens.fr Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Conclusions
 References
 

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Received for publication: 2. 7.02
Accepted in revised form: 13. 9.02