Skip Navigation



NDT Advance Access published online on September 27, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn488
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
24/1/278    most recent
gfn488v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Evenepoel, P.
Right arrow Articles by Fan, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Evenepoel, P.
Right arrow Articles by Fan, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Efficacy and safety of sevelamer hydrochloride and calcium acetate in patients on peritoneal dialysis

Pieter Evenepoel1, Rafael Selgas2, Flavia Caputo3, Lukas Foggensteiner4, James G. Heaf5, Alberto Ortiz6, Alison Kelly7, Scott Chasan-Taber8, Ajay Duggal7 and Stanley Fan9

1 Division of Nephrology, Department of Medicine, University Hospital Gasthuisberg, Leuven, Belgium 2 Servicio de Nefrologia, Hospital Universitario La Paz, REDinREN Carlos III-RED 16/06, Madrid, Spain 3 Nefrologia 2 con Dialisi e Trapianto, Ospedale Civico e Benfratelli, Palermo, Italy 4 Queen Elizabeth Hospital, Birmingham, UK 5 Department of Nephrology, Copenhagen University Hospital at Herlev, Herlev, Denmark 6 Servicio de Nefrologia Unidad de Diálisis, Fundacion Jiménez Diaz, REDinREN Carlos III-RED 16/06, Madrid, Spain 7 Genzyme Research Europe, Cambridge, UK 8 Biostatistics, Genzyme Corporation, Cambridge, MA, USA 9 The Royal London Hospital, London, UK

Correspondence and offprint requests to: Pieter Evenepoel, Department of Medicine, Division of Nephrology, University Hospital Gasthuisberg, Leuven, Belgium. Tel: +32-16-34-45-80; Fax: +32-16-34-45-99; E-mail: pieter.evenepoel{at}uz.kuleuven.ac.be



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Inadequate phosphorus control is associated with increased morbidity and mortality in patients with CKD stage 5. Although phosphate binders are often used in patients on peritoneal dialysis (PD), no large randomized controlled studies evaluating their use solely in this population have previously been reported.

Methods. In this multicentre, open-label study, adult patients on PD with serum phosphorus >5.5 mg/dl were randomized (2:1) to 12 weeks of treatment with sevelamer hydrochloride or calcium acetate. Doses were titrated to achieve serum phosphorus of 3.0–5.5 mg/dl. Changes in serum phosphorus, calcium, intact parathyroid hormone (iPTH), lipids and plasma biomarkers were assessed.

Results. A total of 253 patients were screened, 143 of whom were randomized (sevelamer hydrochloride, n = 97; calcium acetate, n = 46). Treatment groups were well balanced with regard to baseline demographics. Serum phosphorus levels were significantly reduced after 12 weeks with both sevelamer hydrochloride and calcium acetate (P < 0.001). Serum PTH was also reduced in both groups while serum calcium increased in the calcium acetate group (P = 0.001) but not in the sevelamer hydrochloride group. Sevelamer hydrochloride was also associated with decreases in total cholesterol, low-density lipoprotein cholesterol and uric acid and an increase in bone-specific alkaline phosphatase (all P < 0.001 versus baseline). Both treatments were well tolerated and safety profiles were consistent with previous reports in haemodialysis patients. Hypercalcaemia was experienced by more calcium acetate-treated patients (18 versus 2%; P = 0.001).

Conclusions. In summary, sevelamer hydrochloride provides a reduction in serum phosphorus compared to that obtained with calcium-based binders in PD patients. The effects of sevelamer hydrochloride appear similar in both PD and haemodialysis populations.

Keywords: hyperphosphataemia; peritoneal dialysis; phosphate binders; sevelamer hydrochloride



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
Hyperphosphataemia is a frequent complication in patients with chronic kidney disease (CKD), and there is considerable evidence that inadequate phosphorus control is associated with increased morbidity and mortality in patients with CKD stage 5 [1–3]. Elevated serum phosphorus is also associated with calcification of vascular tissues, which itself is a strong independent predictor of increased mortality [4]. These data are primarily derived from studies in patients receiving haemodialysis (HD). However, recent research also indicates that elevated serum phosphorus is associated with increased coronary artery calcification and cardiovascular mortality in patients on peritoneal dialysis (PD) [5,6].

Although phosphate binders are often used in patients on PD, no large randomized controlled studies evaluating their efficacy and safety solely in this population have previously been reported. Sevelamer hydrochloride is a non-calcium, non-metal-based phosphate binder that provides effective control of serum phosphorus levels in patients on HD but with fewer episodes of hypercalcaemia and less suppression of parathyroid hormone (PTH) than calcium acetate or calcium carbonate [7]. Sevelamer hydrochloride is also associated with reduced progression of cardiovascular calcification compared to calcium binders in HD patients [7,8]. We now report the first large randomized controlled trial to assess the efficacy and tolerability of sevelamer hydrochloride compared with a calcium-based phosphate binder in patients on PD.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
This open-label, randomized, parallel-group design study was conducted at 15 sites across Europe (Belgium, n = 1; Denmark, n = 3; France, n = 1; Italy, n = 2; Spain, n = 2; The Netherlands, n = 1; UK, n = 5). The study was limited to adults (aged ≥18 years) who were stable on PD for ≥8 weeks. Patients were required to have a serum phosphorus >5.5 mg/dl and serum calcium within the normal range (8.4–10.4 mg/dl) following a 2-week phosphate binder washout period. Patients treated with vitamin D or its analogues for hyperparathyroidism needed to be on a stable dose for ≥1 month before screening. The use of magnesium and aluminium antacids or any other phosphate binder was forbidden for the study duration, although evening calcium supplements could be prescribed. Patients were also required to be compliant with dialysis and phosphate binder therapy. Exclusion criteria included a history of peritonitis (within previous 30 days or ≥2 episodes in previous 12 months); active dysphagia, other swallowing disorder, bowel obstruction or severe gastrointestinal (GI) motility disorder; any significant unstable concurrent clinical condition; use of anti-arrhythmic or anti-seizure medications for the control of these disorders; active alcohol or drug abuse or known hypersensitivity to sevelamer hydrochloride.

Written informed consent was obtained from all patients and the study was conducted in accordance with the Declaration of Helsinki and approved by Independent Ethics Committees at each site.

At screening, patients underwent a physical examination, and their medical history, prior medication and, if available, the adequacy of their PD (Kt/V and/or creatinine clearance) during the previous 6 months were reviewed. The patients were also asked to record the volume of urine collected over a 24-h period to assess whether they were anuric (≤200 ml).

Eligible patients entered a 2-week phosphate binder washout period, following which baseline blood samples were taken and patients meeting inclusion criteria for serum phosphorus and calcium were randomized. The patients were stratified (anuric or non-anuric) at each treatment site and were randomized to sevelamer hydrochloride or calcium acetate in a 2:1 ratio in order to maximize sevelamer hydrochloride data generation. They received either sevelamer hydrochloride (Renagel® 800 mg tablets, Genzyme Ireland Ltd, Waterford, Ireland) or calcium acetate (538 mg tablets; Pinewood Laboratories, Ballymacarbry, Ireland) three times daily (TID) with meals. Starting doses were 2 x 800 mg sevelamer hydrochloride tablets TID or 3 x 538 mg calcium acetate tablets TID (4.8 g/day for both treatments). Doses were titrated as necessary (by ±1 tablet TID) at each visit (Weeks 2, 4 and 8) to achieve a target serum phosphorus of 3.0–5.5 mg/dl.

If serum calcium fell below normal, an evening supplement could be prescribed. If serum calcium increased above normal in patients treated with calcium acetate, the dose could be decreased until levels returned to normal. Calcium concentration in the dialysate could also be adjusted to maintain serum calcium within the normal range. Vitamin D could be adjusted after 4 weeks to maintain intact PTH levels between 150 and 300 pg/dl.

After 12 weeks of treatment, the patients entered a 1-week follow-up period, after which adverse events (AEs) were recorded and the patients returned to their pre-study phosphate binder therapy.

As previous comparative studies using sevelamer hydrochloride and calcium acetate, this was an open-label study because treatment allocation could be readily identified by the lower incidence of hypercalcaemia and decrease in serum low-density lipoprotein (LDL) cholesterol with sevelamer hydrochloride.

Efficacy and safety assessments
The primary efficacy endpoint was change in serum phosphorus levels after 12 weeks in patients on PD. Blood samples were assessed for serum phosphorus at baseline and Weeks 2, 4, 8 and 12. Secondary efficacy endpoints were changes in serum calcium x phosphorus product, serum lipids [total cholesterol, LDL-cholesterol, non-high-density-lipoprotein (HDL)-cholesterol, HDL-cholesterol and triglycerides] and pre-specified plasma biomarkers [random blood glucose, glycosylated haemoglobin (HbA1c), bone-specific alkaline phosphatase (BSAP), uric acid and C-reactive protein (CRP)]. For secondary efficacy parameters, blood samples were assessed at baseline and Week 12. Changes in albumin-adjusted calcium and intact PTH (assessed by the DPC Biermann adapted Immulite 2000 assay) were also compared between groups. All blood samples were assessed at a central laboratory (MDS Pharma Service Central Lab GmbH, Hamburg, Germany).

Safety endpoints included the incidence of AEs and the number of hypercalcaemic episodes (defined as albumin–adjusted serum calcium ≥11.0 mg/dl).

Statistical analysis
The safety population included all randomized patients who received at least one dose of study medication. The intent-to-treat (ITT) population included all randomized patients who received study medication and had at least one post-baseline efficacy measure. The per-protocol (PP) population excluded patients with major protocol violations. Since the primary aim of the study was to show non-inferiority, the efficacy analysis was based on the PP population. An ITT analysis was performed to confirm findings. The last observation was carried forward for patients with at least one post-washout efficacy measurement who withdrew from the study before Week 12.

The sample size estimate, using a 2:1 ratio for randomization, indicated that a total of 102 PP patients were needed to have 80% power to show non-inferiority of sevelamer to calcium based on a one-sided Student's t-test with a 2.5% type 1 error and an expected standard deviation of 1.5 mg/dl (0.5 mmol/l). Therefore, ~138 patients were planned to be randomized to allow for a 25% dropout rate.

The primary efficacy analysis was an assessment of non-inferiority of sevelamer hydrochloride to calcium acetate with respect to the change from baseline to Week 12 in serum phosphorus. A one-sided 97.5% upper confidence limit was estimated for the difference in serum phosphorus change between groups (difference = mean change among sevelamer hydrochloride patients – mean change among calcium acetate patients). If this was found to be <0.94 mg/dl (0.3 mmol/l), non-inferiority was concluded.

Secondary efficacy parameters were assessed for differences between groups using two-sided Wilcoxon rank sum tests. AEs and hypercalcaemic episodes were compared between treatment groups using Fisher's exact test.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
A total of 253 patients were screened for this study, 143 of whom were randomized to sevelamer hydrochloride (n = 97) or calcium acetate (n = 46) (safety population, Figure 1). The study was completed by 76% of patients in the sevelamer hydrochloride group (n = 74) and 65% of patients in the calcium acetate group (n = 30). AEs were the main reason for premature withdrawal from the study (18% of sevelamer hydrochloride-treated patients and 28% of calcium acetate-treated patients). Four patients had no post-baseline efficacy assessment and so the ITT population consisted of 139 patients (sevelamer hydrochloride, n = 95; calcium acetate, n = 44). Thirty-six patients were excluded from the PP analysis, which consisted of 103 patients (sevelamer hydrochloride, n = 72; calcium acetate, n = 31). The main reasons for exclusion from the PP population were poor compliance [sevelamer hydrochloride, n = 15 (16%); calcium acetate, n = 10 (22%)] and duration on treatment of <3 weeks [sevelamer hydrochloride, n = 7 (7%); calcium acetate, n = 3 (7%)]. Other reasons were proscribed medication usage, inadequate washout duration and randomized treatment not used.


Figure 1
View larger version (17K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Disposition of patients.

 
Treatment groups were well balanced with regard to baseline demographics (Table 1). The majority of patients were Caucasian and male and the mean age was 54.4 ± 15.7 years. Twenty percent of patients were anuric. The median duration of PD before the study entry was 14.4 months (range 1.9–255.3). All patients were on phosphate binder therapy before the study, with the majority (52%) receiving calcium carbonate or acetate monotherapy. Therapy with active vitamin D was being given to 43% of patients.


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline demographic and clinical characteristics (safety population)

 
The median percentage compliance with study medication was 91% in the sevelamer hydrochloride group and 89% in the calcium acetate group and was established by counting the unused medication at each study visit. The mean actual daily dose was 5.8 ± 2.6 g for sevelamer hydrochloride and 4.5 ± 2.2 g for calcium acetate and pill burden was comparable (sevelamer hydrochloride = ~7 tablets/day and calcium acetate = ~8 tablets/day). The use of prior and concomitant medications was similar between groups. Among patients receiving vitamin D, the mean intake increased with sevelamer hydrochloride but decreased with calcium acetate (0.50 ± 4.76 versus –0.44 ± 0.95 µg/week; P = 0.023). Compared with calcium acetate, more patients treated with sevelamer hydrochloride increased their weekly vitamin D dose from baseline to study end (25 versus 6% of patients) and fewer reduced vitamin D use (9 versus 28%). Four patients in the sevelamer hydrochloride group received supplementary calcium during the treatment (59 mg daily). The mean dialysate calcium concentration at screening was 1.43 ± 0.24 mmol/l in the sevelamer hydrochloride group and 1.44 ± 0.25 mmol/l in the calcium acetate group and did not change over the course of the study in either group. Dialysate calcium was increased from 1.25 to 1.75 mmol/l in two patients (one per group) and reduced from 1.75 to 1.25 mmol/l in two patients (one per group) during treatment.

Efficacy
Serum phosphorus levels were significantly reduced after 12 weeks in both treatment groups. In the PP population, the mean serum phosphorus decreased from 7.48 ± 1.43 to 5.86 ± 1.57 mg/dl with sevelamer hydrochloride (–1.61 ± 1.16 mg/dl; P < 0.001) and from 7.29 ± 1.39 to 5.48 ± 1.40 mg/dl with calcium acetate (–1.81 ± 1.52 mg/dl; P < 0.001) (Figure 2). The difference in the mean change between groups was 0.197 mg/dl with an upper 97.5% confidence limit of 0.741 mg/dl establishing non-inferiority of sevelamer hydrochloride compared with calcium acetate. Comparable results, confirming the non-inferiority, were observed in the ITT population (Table 2). Similar proportions of patients in both the sevelamer hydrochloride and calcium acetate groups achieved the NKF Kidney Disease Outcomes Quality Initiative (K/DOQI) target of serum phosphorus <5.5 mg/dl after 12 weeks of treatment (49 versus 48% in the PP population and 46 versus 41% in the ITT population).


Figure 2
View larger version (18K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Mean (±SD) changes in serum phosphorus, serum calcium x phosphorus product and serum calcium during treatment with sevelamer hydrochloride or calcium acetate (per-protocol population); SD, standard deviation.

 

View this table:
[in this window]
[in a new window]

  		Table 2 Changes in serum phosphorus, calcium x phosphorus product, calcium and intact PTH after 12 weeks of treatment with sevelamer hydrochloride or calcium acetate (intent-to-treat population)

 
The mean calcium x phosphorus product was also significantly reduced (P < 0.001), with mean decreases after 12 weeks of 15.0 ± 12.1 mg2/dl2 in the sevelamer hydrochloride group and 15.3 ± 15.1 mg2/dl2 in the calcium acetate group (PP population). No between-group differences were observed. The mean serum calcium increased significantly in the calcium acetate group from 9.62 ± 0.43 to 10.1 ± 0.87 mg/dl (P = 0.005) but was unchanged in the sevelamer hydrochloride group (9.51 ± 0.59 to 9.55 ± 0.55 mg/dl; P = 0.94). The change from baseline in serum calcium was significantly different between treatment groups after 12 weeks (P = 0.012). The median serum intact PTH decreased in both the sevelamer hydrochloride (from 398 [7, 1458] to 317 [23, 1193] pg/ml; P = 0.001) and calcium acetate (524 [81, 1650] to 372 [6, 1627] pg/ml; P = 0.020) groups with no significant between-group difference.

Significant decreases in total cholesterol, LDL-cholesterol and non-HDL-cholesterol (all P < 0.001) were observed with sevelamer hydrochloride but not calcium acetate (Figure 3). These changes were significantly different between groups (P < 0.001). HDL-cholesterol did not change from baseline in either group. Mean percentage increases in triglycerides were statistically significant in both groups (sevelamer hydrochloride, P = 0.006; calcium acetate, P = 0.041): the mechanism for this increase is unclear. Treatment with sevelamer hydrochloride also resulted in a significant decrease in uric acid (–0.53 ± 0.79, P < 0.001) and a significant increase in BSAP (4.2 ± 12.3, P<0.001). Changes in both of these parameters were significantly different between groups (uric acid, P = 0.010; BSAP, P < 0.001). There were no significant within- or between-group differences in changes in random blood glucose, HbA1c or CRP (Table 3). Similar findings were observed in the ITT population.


Figure 3
View larger version (23K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Mean percentage changes in serum lipids after 12 weeks of treatment with sevelamer hydrochloride or calcium acetate (per-protocol population). C, cholesterol; HDL-C, high-density-lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides.

 

View this table:
[in this window]
[in a new window]

  		Table 3 Mean (±SD) changes in serum biomarkers after 12 weeks of treatment with sevelamer hydrochloride or calcium acetate

 
Safety
Overall, both treatments were well tolerated and the observed safety profiles were consistent with reports of previous studies of sevelamer hydrochloride and calcium acetate in HD patients.

The percentage of patients experiencing AEs considered to be related to treatment were similar in both groups (36% in the sevelamer hydrochloride group and 35% in the calcium acetate group; P = 1.0). More patients in the sevelamer hydrochloride group than in the calcium acetate group experienced GI AEs related to treatment (27 versus 13%). These events were only considered severe in 2% of patients in either group. Peritonitis occurred more often in the sevelamer hydrochloride group than the calcium acetate group (11 versus 4% of patients) but none of these events were considered to be treatment related and the frequency was consistent with reported rates of peritonitis in the PD population [9–11]. Hypercalcaemia was experienced by significantly more calcium acetate-treated patients (18 versus 2%; P = 0.001). No serious AEs related to treatment were reported. Two deaths occurred during the study, neither of which were considered to be treatment related.

There was a small statistically significant decrease from baseline in bicarbonate levels among sevelamer hydrochloride-treated patients (from 22.1 ± 2.7 to 21.3 ± 3.0 mmol/l; P = 0.003) and a statistically significant difference in the mean change between treatment groups (P = 0.008). The change in bicarbonate in the sevelamer hydrochloride group was not considered to be clinically meaningful.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Hyperphosphataemia in patients with stage 5 CKD is associated with serious clinical consequences including secondary hyperparathyroidism, renal bone disease and metastatic calcification. Elevated serum phosphorus levels are associated with increased morbidity and mortality in both HD and PD patients [1,3,5,6,12]. Dietary restriction and phosphate binders are the cornerstones of hyperphosphataemia therapy. Since the 1990s, calcium carbonate and acetate have been the most widely used phosphate binders. However, in recent years it has been recognized that calcium-containing phosphate binders may contribute to the epidemic problem of accelerated cardiovascular calcification in the dialysis population, by increasing the overall calcium burden [7,13]. This knowledge has encouraged interest in non-calcium-based phosphate binders, such as sevelamer hydrochloride.

The proportion of renal replacement therapy patients on PD varies greatly between and even within countries in Europe and the USA, ranging from 5 to 45% [14,15]. Despite the relatively high usage of this modality, however, data on the use of phosphate binders specifically in patients on PD are scarce with the majority of trials performed in HD or mixed populations.

The present study provides evidence that, in adult patients on PD, sevelamer hydrochloride is comparable to calcium acetate in controlling serum phosphorus levels, with serum phosphorus significantly declining from baseline levels in both groups. This confirms and extends findings from previous smaller studies in PD [16–20] and was not unexpected given previous experience in HD patients [7,8].

Both sevelamer hydrochloride and calcium acetate also resulted in reductions in calcium x phosphorus product, while serum calcium increased in the calcium acetate group but not in the sevelamer hydrochloride group. As expected from previous HD studies, hypercalcaemia was significantly more frequent in calcium acetate-treated patients. Intact PTH levels decreased to a similar degree in both groups, while BSAP increased with sevelamer hydrochloride but not calcium acetate. These findings are suggestive of an increase in bone turnover, as has been previously reported with sevelamer hydrochloride in patients on HD and may be important as it has been suggested that patients receiving PD are at increased risk for adynamic bone disease compared with HD patients [21–23]. One possible explanation for the increase in BSAP levels despite a decrease in PTH may be that sevelamer hydrochloride binds the uraemic toxin indoxyl sulfate within the GI tract, as has been shown in vitro, thereby reducing serum levels [24]. Recent findings have suggested that the accumulation of indoxyl sulfate in serum as a result of renal dysfunction is one of the factors that induce skeletal resistance to PTH [25]. Although we did not assess calcification in this study, previous reports have shown that changes in bone histomorphometry suggestive of low bone turnover and adynamic bone correlate with increased arterial calcification in HD patients [13].

The beneficial effects of sevelamer hydrochloride on serum lipids were anticipated from studies in HD patients [26,27]. Significant reductions in total, LDL- and non-HDL-cholesterol were seen with sevelamer hydrochloride but not with calcium acetate. Sevelamer hydrochloride also resulted in a significant decrease in uric acid not observed with calcium acetate, consistent with previous reports in HD patients [28,29]. Hyperuricaemia may be associated with a number of disorders in patients with CKD, including insulin resistance, dyslipidaemia, hypertension and cardiovascular disease [29].

Sevelamer hydrochloride was well tolerated, with an AE profile consistent with its known effects and the underlying renal disease of patients. Compared with calcium acetate, more patients treated with sevelamer hydrochloride experienced GI events. PD patients may be expected to have a greater sensitivity to GI tract content than HD patients, based on abdominal cavity loading with dialysate. However, a recent report suggested that GI complaints, although chronically underestimated, were not significantly different between PD and HD patients [30]. This study also suggests that GI AEs occur with a similar rate in PD as have been reported in studies conducted in HD patients.

The withdrawal rate in this study was comparatively high, with 24% of patients in the sevelamer hydrochloride group and 35% of patients in the calcium acetate group failing to complete the 12-week treatment period. This occurred despite patients having been received phosphate binders before entry into the trial and suggests that compliance with treatment pre-study was poor. Non-compliance with phosphate binder therapy is well recognized and a major reason why phosphorus control remains sub-optimal in many dialysis patients.

Although the consequences of inadequate phosphorus control appear to be similar in both HD and PD patients, there are potential differences between the two populations. For instance, patients on PD tend to be younger with fewer comorbidities than HD patients [15,31]. PD patients may also benefit from greater degrees of residual renal function, which plays an important role in maintaining serum phosphorus levels [32,33]. In a recent large-scale study, more patients on PD than HD reached the K/DOQI serum phosphorus target (3.5–5.5 mg/dl) [34]. This observation is in line with the general belief that phosphorus control is easier to achieve in PD patients, despite the tendency to higher dietary phosphorus intake [35]. Notwithstanding these differences between the two populations, our findings suggest that the effects of sevelamer hydrochloride are comparable in PD and HD, with the improvements in serum phosphorus, serum lipid profile and other biomarkers seen here similar to those previously reported in HD patients [36]. Mean daily doses of sevelamer hydrochloride (6.4 g) and calcium acetate (4.7 g) required to achieve these reductions were also similar to those reported in studies of patients on HD [7]. As such, treatment strategies for the control of serum phosphorus should be similar irrespective of dialysis modality.

A limitation of our study was the relatively short follow-up. However, considering long-term efficacy data from comparable long-term studies in HD patients [7,8], there is no reason to assume that the conclusions of the present study would be different if the follow-up had been longer.

In summary, treatment with sevelamer hydrochloride provides a reduction in serum phosphorus comparable to that obtained with calcium-based binders in PD patients with a similar daily pill burden and is also associated with an improved lipid profile and fewer episodes of hypercalcaemia. This confirms that, as has been previously demonstrated in HD patients, sevelamer hydrochloride is also an effective and well-tolerated treatment for the control of serum phosphorus in patients on PD.



   Acknowledgments
 
This study was supported by Genzyme Corporation. The authors would like to thank the following: John Vestergaard Povlsen, Aarhus, Denmark; Kjeld Erik Otte, Fredericia, Denmark; Jean-Philippe Ryckelynck, Caen, France; Claudio Ronco, Vicenza, Italy; Dirk Gijsbert Struijk, Amsterdam, The Netherlands; Stephen Riley, Cardiff, UK; Paul Altmann, Oxford, UK; Brian Junor, Glasgow, UK; Antonio Amato, Palermo, Italy; Maria-Auxiliadora Bajo, Gloria Del Peso, Madrid, Spain; and all others that assisted in the conduct of this study.

Conflict of interest statement. P.E. has received speakers’ honoraria from Genzyme Corporation. A.O. has received an honorarium from Genzyme Corporation. A.K., S.C. and A.D. are employees of Genzyme Corporation. No conflicts of interest declared by R.S., F.C., L.F., J.G.H. or S.F.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

  1. Block GA, Klassen PS, Lazarus JM, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol (2004) 15:2208–2218.[Abstract/Free Full Text]
  2. Slinin Y, Foley RN, Collins AJ. Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol (2005) 16:1788–1793.[Abstract/Free Full Text]
  3. Young EW, Albert JM, Satayathum S, et al. Predictors and consequences of altered mineral metabolism: the Dialysis Outcomes and Practice Patterns Study. Kidney Int (2005) 67:1179–1187.[CrossRef][Web of Science][Medline]
  4. Blacher J, Guerin AP, Pannier B, et al. Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease. Hypertension (2001) 38:938–942.[Abstract/Free Full Text]
  5. Ammirati AL, Dalboni MA, Cendoroglo M, et al. Coronary artery calcification, systemic inflammation markers and mineral metabolism in a peritoneal dialysis population. Nephron Clin Pract (2006) 104:c33–c40.[CrossRef][Web of Science][Medline]
  6. Noordzij M, Korevaar JC, Bos WJ, et al. Mineral metabolism and cardiovascular morbidity and mortality risk—peritoneal dialysis patients compared with haemodialysis patients. Nephrol Dial Transplant (2006) 21:2513–2520.[Abstract/Free Full Text]
  7. Chertow GM, Burke SK, Raggi P. Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int (2002) 62:245–252.[CrossRef][Web of Science][Medline]
  8. Block GA, Spiegel DM, Ehrlich J, et al. Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int (2005) 68:1815–1824.[CrossRef][Web of Science][Medline]
  9. Kavanagh D, Prescott GJ, Mactier RA. Peritoneal dialysis-associated peritonitis in Scotland 1999–2002. Nephrol Dial Transplant (2004) 19:2584–2591.[Abstract/Free Full Text]
  10. Hotchkiss JR, Hermsen ED, Hovde LB, et al. Dynamic analysis of peritoneal dialysis associated peritonitis. ASAIO J (2004) 50:568–576.[CrossRef][Web of Science][Medline]
  11. Verger C, Ryckelynck JP, Duman M, et al. French peritoneal dialysis registry (RDPLF): outline and main results. Kidney Int Suppl (2006) 103:S12–S20.[Medline]
  12. Stompor TP, Pasowicz M, Sulowicz W, et al. Trends and dynamics of changes in calcification score over the 1-year observation period in patients on peritoneal dialysis. Am J Kidney Dis (2004) 44:517–528.[Web of Science][Medline]
  13. London GM, Marty C, Marchais SJ, et al. Arterial calcifications and bone histomorphometry in end-stage renal disease. J Am Soc Nephrol (2004) 15:1943–1951.[Abstract/Free Full Text]
  14. ERA-EDTA Registry. ERA-EDTA Registry 2004 Annual Report (2006) Amsterdam, The Netherlands: Academic Medical Center, Department of Medical Informatics.
  15. U.S. Renal Data System. 2006 Annual Data Report. Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States (2006) Bethesda, MD: USRDS.
  16. Mahdavi H, Kuizon BD, Gales B, et al. Sevelamer hydrochloride: an effective phosphate binder in dialyzed children. Pediatr Nephrol (2003) 18:1260–1264.[CrossRef][Web of Science][Medline]
  17. Ortiz A, Rios F, Melero R, et al. Experience with sevelamer in peritoneal dialysis. Nefrologia (2003) 23:432–436.[Web of Science][Medline]
  18. Salusky IB, Goodman WG, Sahney S, et al. Sevelamer controls parathyroid hormone-induced bone disease as efficiently as calcium carbonate without increasing serum calcium levels during therapy with active vitamin D sterols. J Am Soc Nephrol (2005) 16:2501–2508.[Abstract/Free Full Text]
  19. Pieper AK, Haffner D, Hoppe B, et al. A randomized crossover trial comparing sevelamer with calcium acetate in children with CKD. Am J Kidney Dis (2006) 47:625–635.[CrossRef][Web of Science][Medline]
  20. Katopodis KP, Andrikos EK, Gouva CD, et al. Sevelamer hydrochloride versus aluminum hydroxide: effect on serum phosphorus and lipids in CAPD patients. Perit Dial Int (2006) 26:320–327.[Abstract/Free Full Text]
  21. Raggi P, James G, Burke SK, et al. Decrease in thoracic vertebral bone attenuation with calcium-based phosphate binders in hemodialysis. J Bone Miner Res (2005) 20:764–772.[CrossRef][Web of Science][Medline]
  22. Ferreira A, Frazao JM, Faugere M-C, et al. Effects of sevelamer and calcium carbonate on bone mineralisation and turnover in chronic maintenance haemodialysis patients [Abstract MO016]. Nephrol Dial Transplant (2006) 21(Suppl_4):iv293.[Free Full Text]
  23. Malluche HH, Mawad H, Monier-Faugere MC. The importance of bone health in end-stage renal disease: out of the frying pan, into the fire? Nephrol Dial Transplant (2004) 19(Suppl 1):i9–i13.[Abstract]
  24. De Smet R, Thermote F, Lamiere N, et al. Sevelamer hydrochloride (Renagel) adsorbs the uremic compounds indoxyl sulfate, indole and P-cresol [Abstract]. J Am Soc Nephrol (2004) 15:505.
  25. Nii-Kono T, Iwasaki Y, Uchida M, et al. Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells. Kidney Int (2007) 71:738–743.[CrossRef][Web of Science][Medline]
  26. Ferramosca E, Burke S, Chasan-Taber S, et al. Potential antiatherogenic and anti-inflammatory properties of sevelamer in maintenance hemodialysis patients. Am Heart J (2005) 149:820–925.[CrossRef][Web of Science][Medline]
  27. Yamada K, Fujimoto S, Tokura T, et al. Effect of sevelamer on dyslipidemia and chronic inflammation in maintenance hemodialysis patients. Ren Fail (2005) 27:361–365.[CrossRef][Web of Science][Medline]
  28. Castro R, Herman A, Ferreira C, et al. RenaGel efficacy in severe secondary hyperparathyroidism. Nefrologia (2002) 22:448–455.[Web of Science][Medline]
  29. Garg JP, Chasan-Taber S, Blair A, et al. Effects of sevelamer and calcium-based phosphate binders on uric acid concentrations in patients undergoing hemodialysis: a randomized clinical trial. Arthritis Rheum (2005) 52:290–295.[CrossRef][Web of Science][Medline]
  30. Kahvecioglu S, Akdag I, Kiyici M, et al. High prevalence of irritable bowel syndrome and upper gastrointestinal symptoms in patients with chronic renal failure. J Nephrol (2005) 18:61–66.[Web of Science][Medline]
  31. Xue JL, Chen SC, Ebben JP, et al. Peritoneal and hemodialysis: I. Differences in patient characteristics at initiation. Kidney Int (2002) 61:734–740.[CrossRef][Web of Science][Medline]
  32. Wang AY, Woo J, Sea MM, et al. Hyperphosphatemia in Chinese peritoneal dialysis patients with and without residual kidney function: what are the implications? Am J Kidney Dis (2004) 43:712–720.[CrossRef][Web of Science][Medline]
  33. Wang AY, Lai KN. The importance of residual renal function in dialysis patients. Kidney Int (2006) 69:1726–1732.[CrossRef][Web of Science][Medline]
  34. Noordzij M, Korevaar JC, Boeschoten EW, et al. The Kidney Disease Outcomes Quality Initiative (K/DOQI) guideline for bone metabolism and disease in CKD: association with mortality in dialysis patients. Am J Kidney Dis (2005) 46:925–932.[CrossRef][Web of Science][Medline]
  35. Winchester JF, Rotellar C, Goggins M, et al. Calcium and phosphate balance in dialysis patients. Kidney Int Suppl (1993) 41:S174–S178.[Medline]
  36. Braun J, Asmus HG, Holzer H, et al. Long-term comparison of a calcium-free phosphate binder and calcium carbonate–phosphorus metabolism and cardiovascular calcification. Clin Nephrol (2004) 62:104–115.[Web of Science][Medline]
Received for publication: 20.12.07
Accepted in revised form: 5. 8.08


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
24/1/278    most recent
gfn488v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Evenepoel, P.
Right arrow Articles by Fan, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Evenepoel, P.
Right arrow Articles by Fan, S.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?