A prospective study of combination therapy for hyperphosphataemia with calcium-containing phosphate binders and sevelamer in hypercalcaemic haemodialysis patients

Christopher W. McIntyre1,, Vandhana Patel2, Gail S. Taylor2 and Richard J. Fluck1

1 Consultant Renal Physician, 2 Renal Dietitian, Department of Renal Medicine, Derby City General Hospital, Derby, UK



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Introduction. Hyperphosphataemia is predictive of death, in haemodialysis (HD) patients. Sevelamer is a mineral-free phosphate binder not limited by the hypercalcaemia often encountered when utilizing calcium-containing phosphate binders. Highly positive calcium balance is associated with ectopic calcification and potentially accelerated vascular disease. Unfortunately, exclusive use of sevelamer entails a large cost differential, limiting its use in many centres. We report on a strategy of partial replacement of calcium with sevelamer for the management of hyperphosphataemia in hypercalcaemic chronic HD patients.

Methods. We identified 23 HD patients with serum calcium >2.6 mmol/l. Dietary phosphate and calcium intake were assessed and baseline serum calcium, phosphate and 1{alpha} calcidol and elemental calcium dose recorded. Fifty per cent of this initial calcium dose was exchanged for sevelamer. Vitamin D doses were left unchanged. If serum calcium was still >2.6 mmol/l after 4 weeks a further 50% of calcium was exchanged. If serum phosphate was >2 mmol/l the sevelamer dose was increased by 25%. The patients were followed up for a further 4 weeks.

Results. Seven patients complained of gastrointestinal intolerance of sevelamer. Serum calcium fell from a mean value of 2.8±0.04 (2.64–3.54) mmol/l to 2.56±0.03 (2.4–2.9) mmol/l, P<0.0005. The hypercalcaemic percentage of patients fell from 100 to 26%. Mean serum phosphate was not significantly changed, 1.59±0.1 (0.57–2.6) mmol/l to 1.63±0.11 (0.55–2.68) mmol/l, 17–22% of patients having serum phosphate >2 mmol/l. Serum intact parathyroid hormone increased from 166±47 (12–933) ng/l to 276±104 (20–1013) ng/l, P=0.02. Mean sevelamer dose was 2.77±0.36 (0–5.6) g per day. Elemental calcium dose fell from 2.05±0.23 (0.5–4.5) g to 1.03±0.1 (0.5–2.5) g, P<0.0001.

Conclusion. A regimen based on the combination of sevelamer and calcium is capable of effectively managing hyperphosphataemia, without hypercalcaemia, in the majority of hypercalcaemic HD patients. Such a minimally calcaemic approach might reduce the financial burden of sevelamer therapy, and enable a wider range of patients to be treated.

Keywords: calcium; calciumxphosphate product; haemodialysis; phosphate; sevelamer



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Hyperphosphataemia and a raised calciumxphosphate product are associated with an increased morbidity [13] and mortality risk [4] in patients on chronic haemodialysis (HD). Although hypercalcaemia alone is not associated with increased mortality [4]. Because of the limitations of current dialysis technology, HD falls far short of removing adequate amounts of phosphorus to prevent the development of hyperphosphataemia [5,6]. Dietary restriction below 1000 mg of phosphorus per day is difficult, particularly if an adequate protein intake is to be maintained. Widespread use of vitamin D for the management of uraemic hyperparathyroidism has also led to aggravated problems with hyperphosphataemia (and hypercalcaemia) due to increased intestinal absorption [7]. These factors have contributed to a reliance on oral phosphate binders for the control of serum phosphate. Aluminium-based binders are effective but associated with neurological, skeletal, and haematological toxicities, in this group of patients [8]. Therefore oral binders based on calcium (predominantly as carbonate or acetate) are the most widely used therapeutic options at present [9]. Calcium is also limited by toxicity in a significant proportion of patients [7,10]. Soft-tissue calcification may be associated with both a normal and hypercalcaemic state [11], and indeed an apparently paradoxical inverse link between vascular calcification extension and serum calcium has been reported [12]. Vascular calcification may be the result of a raised calciumxphosphate product, hyperphosphataemia alone [13] or in the presence of hypercalcaemia [14]. Even in the absence of hypercalcaemia, the use of calcium-based phosphate binders is often associated with the administration of large amounts of elemental calcium. This in itself may be associated with accelerated vascular calcification. Coronary and valvular calcifications are common and progressive findings in chronic HD patients [15]. It has been speculated that this may be an important factor in explaining the associated excess of cardiovascular morbidity and mortality seen in this group of patients.

Sevelamer is a hydro gel of cross-linked poly (allylamine hydrochloride), resistant to intestinal degradation or absorption. It is an effective phosphate binder in both short- and long-term studies [16,17]. Being mineral free, there is a markedly reduced propensity to hypercalcaemia, and the subsequent limitation of the dose that may be administered to obtain adequate control of serum phosphate. Furthermore, the reduction in elemental calcium load seen with the use of this agent may be important in reducing the development of cardiovascular and metastatic calcification [18]. Unfortunately, exclusive use of sevelamer entails a large treatment financial cost differential when compared to currently available products. Both the financial consequences, and the current lack of evidence to support the contention that a high calcium load is necessarily harmful to patients, have limited the use of sevelamer in many centres.

The aim of this study was to investigate prospectively whether a minimally calcaemic regime, using a combination of calcium-based phosphate binders and sevelamer, would be effective in controlling serum phosphate without attendant hypercalcaemia. Such a strategy would at least limit the amount of elemental calcium patients were exposed to, and by reducing the financial burden imposed by the use of sevelamer, might allow wider usage of this effective agent.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
We identified 23 patients within our HD programme who were hypercalcaemic (calcium >2.6 mmol/l) for at least the preceding 3 months, who were currently taking calcium-based phosphate binders. All patients were studied prospectively as a single contemporaneous cohort, acting as their own controls. Prior to inclusion, all patients had been managed using the same therapeutic strategy for control of serum phosphate and parathyroid hormone (PTH). Because of the critical role of phosphate in the management of these conditions, prior to introduction of vitamin D, oral calcium binders were introduced, aiming to reduce serum phosphate below 2 mmol/l. Vitamin D was introduced (and titrated to the minimum dose necessary) to ensure serum PTH within the Renal Association guideline of 2–3 times the upper limit of the normal range, and/or to maintain serum calcium within the normal range. Fifteen patients were on vitamin D (1{alpha} calcidol) at the start of the study period. No changes to vitamin D use or dosage were made during the study period.

All patients had been on HD for more than 6 months, mean period 40 (range 7–120) months. Mean age was 61 (range 24–80) years. Patient descriptive data are summarized in Table 1Go. All patients were dialysed for three 4-h sessions per week. Dialysis was performed using Hospal Integra dialysis monitors, bicarbonate buffering, Haemophan dialysers and a dialysate Ca concentration of 1.25 mmol/l.


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Table 1.  Patient characteristics on inclusion

 
Sixteen of the 23 patients were established on calcium carbonate and the remaining seven patients on calcium acetate. Baseline dietary phosphorus and calcium intake were recorded from food diaries. Serum calcium, phosphate, and intact PTH were measured prior to the introduction of sevelamer (Renagel® Genzyme).

Fifty per cent of the initial calcium dose was exchanged on a milligram for milligram basis for sevelamer. Serum calcium and phosphorus were measured after 4 weeks of this initial combination of therapy. If serum calcium was <2.6 mmol/l and serum phosphate <2 mmol/l, no changes to therapy were made. If serum calcium was >2.6 mmol/l, a further 50% substitution of calcium-based phosphate binder was made with sevelamer. In the setting of normocalcaemia but inadequately controlled hyperphosphataemia, an increase of 25% in the total dose of phosphate binder was made, utilizing sevelamer again. The patients were then followed for a further 4 weeks and their serum calcium, phosphate, and PTH measured again. The investigatory plan is summarized in Figure 1Go. At the end of the study, those patients with satisfactory biochemistry remained on unaltered medication. The distribution of tablets was optimized with respect to oral phosphate load by dietetic review. Likewise, continuous inquiries regarding compliance and treatment tolerability were made throughout this period.



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Fig. 1.  Summary of investigatory plan.

 
Statistical analysis
Unpaired and paired observations were analysed by Mann–Whitney and Wilcoxon rank sum tests respectively. All data were analysed using GraphPad Prism version 3.00 for Windows (GraphPad Software, San Diego, California, USA). Where not otherwise stated, data are expressed as mean±SEM with 95% confidence intervals.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The mean daily dietary phosphate intake was 998±48.5 (650–1430) mg/day, daily calcium intake was 613±50.0 (400–1260) mg/day. During the pre study period, eight of the 23 patients obtained satisfactory serum phosphate levels but without unacceptable hyperparathyroidism, and therefore had not been commenced on vitamin D. In these patients, hypercalcaemia had resulted (serum calcium 2.72±0.01 mmol/l) with oral phosphate binder alone. Fifteen of the patients had obtained adequate control of serum phosphate with calcium-containing oral binders, but unacceptable hyperparathyroidism (PTH 398±62.5 ng/l) had resulted. For this reason vitamin D had been added to their treatment, with resultant increase in serum calcium (to adequately suppress PTH). Vitamin D dosage did not alter during the study and remained at a mean of 0.25±0.14 (0–0.75) µg of 1{alpha} calcidol/day.

Mean serum calcium fell from 2.8±0.04 (2.64–3.54) mmol/l to 2.56±0.03 (2.4–2.9) mmol/l over the period of the study (P=0.0005). The percentage of patients with hypercalcaemia fell from 100 to 26%. Five of these six patients were either intolerant or poorly compliant with sevelamer.

Mean serum phosphate was statistically unchanged over the study period, changing from 1.59±0.10 (0.57–2.6) mmol/l to 1.64±0.11 (0.5–2.68) mmol/l. The percentage of patients with serum phosphate >2.0 mmol/l was 17% at the start of the study and 22% at completion. Four of these five patients were either intolerant or poorly compliant with sevelamer. Similarly, calciumxphosphate product was not altered to a statistically significant degree over the 8 weeks. Serum intact PTH rose from 166±47.5 (12–933) ng/l to 276±104 (20–1913) over the study period (P=0.02). The median rose from 94 ng/l (25th percentile 27, 75th percentile 237 ng/l) to 104 ng/l (25th percentile 57, 75th percentile 200 ng/ml) (Table 2Go; Figure 2Go).


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Table 2.  Summary of biochemical information and calcium and vitamin D doses over the study period

 


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Fig. 2.  Serum calcium, phosphate, and calciumxphosphate product at inclusion in study and completion.

 
Elemental calcium dose administered halved, falling from 2055±230 (500–4500) mg/day to 1033±106 (500–2500) mg/day. The mean sevelamer dose at study completion was 2768±367 range 0–5642, 95% CI 2006–3530 mg/day. Fifteen of the 23 patients required further treatment alteration at the 4-week midway point of the study. Five patients required alteration of therapy because of failure to reduce serum calcium below 2.5 mmol/l alone. Six of the patients required alteration because of inadequately controlled phosphate in the setting of normocalcaemia, and four patients for both reasons (Table 3Go).


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Table 3.  Summary of the percentage of patients with clinically acceptable biochemical indices over the study period

 
Seven patients in total complained of gastrointestinal intolerance, reporting variable degrees of abdominal bloating, discomfort, and diarrhoea. Two of the patients refused to continue with sevelamer at the mid-point and were converted back onto their previous calcium-based regime. A further four patients in the group complaining of gastrointestinal intolerance admitted to variable compliance but continued on sevelamer.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Hypercalcaemia is a common consequence of treatment with calcium-based phosphate binders (when combined with vitamin D therapy) [9]. Furthermore, there are increasing concerns that significant loading with elemental calcium may have undesirable effects, particularly on vascular calcification [15]. Sevelamer is an effective phosphate binder, without this risk, limited in its use largely by the current balance between the level of proof of the potential problems associated with high calcium loads, and the financial cost of this agent. We report on a minimally calcaemic strategy, involving the combination of sevelamer with a reduced dose of calcium containing phosphate binder. In hypercalcaemic HD patients, such a strategy is capable of controlling both phosphate and calciumxphosphate product, without hypercalcaemia, in the majority of patients.

Our patients were not on a diet with a marked excess of phosphorus. The mean intake was only around 1000 mg/day. This is largely a reflection of the difficulties in maintaining an adequate protein intake in this group of patients, who on average had been on HD for 40 months. There is no readily defined ideal for dietary calcium intake. However, this group of patients had a somewhat low intake of only around 600 mg per day on average. Data pertaining to vitamin status were not recorded. However, all patients benefited from dietetic advice to ensure an adequate input of vitamin D, and none were from racial groups with diets commonly associated with vitamin D nutritional deficiency.

The combination of sevelamer and calcium did result in three-quarters of the hypercalcaemic patients being rendered normocalcaemic. As already stated, the use of calcium-based phosphate binders is associated with a significant rate of hypercalcaemia, with up to 20% of patients developing hypercalcaemia with the use of calcium-based phosphate binders in comparative studies with sevelamer [16,17]. The patients who did not achieve normocalcaemia were largely those with intolerance and poor compliance to sevelamer. Slight increases in serum calcium have been reported with the use of sevelamer alone [17]. This has been attributed to several mechanisms. Firstly, sevelamer competes with dietary calcium for phosphate binding, and it has been suggested that more free calcium may be available to subsequently be absorbed. Secondly, if there is a reduction in calciumxphosphate product there may be mobilization of previously deposited tissue calcification.

Serum phosphate was equally well controlled with the combination of sevelamer and calcium-based binders as with calcium alone. Mean serum phosphate remained around 1.6 mmol/l with no significant change during the study. The patients with poorly controlled serum phosphate were all within the poorly compliant cohort. Calciumxphosphate product did reduce with the combination therapy, but failed to reach statistical significance. The mean level of 3.8 mmol2/l2 is, however, within the referent quintile (3.47–4.19 mmol2/l2) for no excess in mortality, as reported by Block et al. [4]. Again, although these patients represented a selected group already with established hypercalcaemia, it was possible to treat them to within generally accepted limits with this combination therapy.

The mean elemental calcium dose was halved to around 1000 mg per day. Given that the mean daily dietary intake was only 600 mg, these levels are not far in excess of a reasonable daily nutritional intake. High calcium loads have been postulated to be harmful, but no attempts have yet been made to define the threshold predisposing to vascular calcification (in the setting of an acceptable calciumxphosphate product). It seems unlikely that an intake of around 1500 mg/day in total in combination with good phosphate control is likely to contribute significantly. The mean sevelamer dose was 2.8 g/day. In a number of studies, the mean dose to reach the required levels of phosphate control has been 5–6 g/day [1618]. Given that both calcium and sevelamer dose were on average half of the expected requirement, it does not appear likely that there is a significant interference with the effect on phosphate binding, from one agent on the other. The lower dose of sevelamer might, however, result in a reduction in the expected lowering of LDL cholesterol levels. We did not study this effect.

The level of gastrointestinal intolerance was higher than reported in other studies, even given the lower doses used [1618]. This might be reflection that this was a somewhat different patient study group. They had been on HD somewhat longer than in other studies, and were selected as having established hypercalcaemia. There is, however, the possibility that the combination of therapies might be associated with an increased level of gastrointestinal tolerance than either used alone.

Vitamin D was used in 15 of these patients. The doses of which were unchanged during the course of the study. The concomitant use of vitamin D has been a feature of a number of other studies into the use of sevelamer [16,17]. The management strategy for these patients before the introduction of sevelamer involved initial introduction of calcium-containing phosphate binders to normalize serum phosphorus, and subsequent introduction of vitamin D to maintain serum calcium within the normal range and serum PTH at 2–3 times the upper limit of normality. This is an approach commonly adopted in clinical practice. This hypercalcaemic cohort represents the limitations of such an approach. It should be noted that 35% of the patients had become hypercalcaemic without the addition of vitamin D. The discussion concerning the optimal level of serum PTH is beyond the scope of this discussion. The choice of 2–3 times the upper limit reflects the recommendation within the national standards document [19].

The use of 1.25 mmol/l is common practice within the UK. We have adopted this as it allows maintenance of serum calcium without inducing a large positive balance from dialysate. This allows more ‘headroom’ for the use of calcium-containing phosphate binders. Maintaining serum calcium with the use of vitamin D allows further direct parathyroid suppression. The use of 1.25 mmol/l dialysate calcium (termed ‘low’) is still associated with a degree of calcium loading in chronic haemodialysis patients ({cong}450 mg/week in the study by Hsu [6]. The use of this concentration has been associated with a lower calcification risk [20]. There are clearly other approaches utilizing a higher positivity of calcium balance (by either dialysate concentration of 1.5 mmol/l, or large doses of oral calcium) [21]. Such other approaches may well be effective, but militate somewhat against the developing concerns about the long-term effects of significant positive calcium balance (exceeding the ability to buffer this excess into the skeleton). Again we report on the consequences of a widely practised treatment strategy and not on its advisability.

Mean serum PTH was higher in patients at completion of the study when compared to inclusion. There was, however, little difference in the median or 75th percentile values. Although a moderate level of hypercalcaemia (as a consequence of the calcium-containing phosphate binder dose necessary to maintain serum phosphate at acceptable levels) was not deliberately utilized in the run-in period to suppress PTH secretion, this would have been an inevitable corollary of the higher level of serum calcium. Removal of this tonic suppressant influence (with substitution with sevelamer) unsurprisingly resulted in an increase in PTH. We do not feel this led to significant clinical issues as the percentage of patients with PTH levels within the desired range were effectively unchanged. However, this may not be a reasonable assumption given the statistical evaluation of earlier data made by Chertow [22], demonstrating an increase in relative risk of mortality (1.08) when PTH is 600–900 ng/l. A previous study of sevelamer with and without calcium supplementation had noted an increase in PTH on cessation of calcium binders during the washout period [23].

In conclusion, these data support the use of a minimally calcaemic combination strategy for the management of hyperphosphataemia in chronic HD patients with established hypercalcaemia. This considerably reduces the burden both of calcium load for the patient and financial cost for the renal service. Such a combination strategy might be therapeutically applicable to the larger group of patients (who do not exhibit hypercalcaemia) presently managed with calcium-based phosphate binders, thus allowing the clinician to minimize exposure to calcium without full conversion to sevelamer.



   Notes
 
Correspondence and offprint requests to: Dr C. W. McIntyre, Department of Renal Medicine, Derby City General Hospital, Uttoxeter Road, Derby, DE22 3NE, UK. Email: chris\|[hyphen]\|mcintyre{at}lineone.net Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 26. 7.01
Accepted in revised form: 15. 2.02