1 Consultant Renal Physician, 2 Renal Dietitian, Department of Renal Medicine, Derby City General Hospital, Derby, UK
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Abstract |
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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 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 (2.643.54) mmol/l to 2.56±0.03 (2.42.9) 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 (0.572.6) mmol/l to 1.63±0.11 (0.552.68) mmol/l, 1722% of patients having serum phosphate >2 mmol/l. Serum intact parathyroid hormone increased from 166±47 (12933) ng/l to 276±104 (201013) ng/l, P=0.02. Mean sevelamer dose was 2.77±0.36 (05.6) g per day. Elemental calcium dose fell from 2.05±0.23 (0.54.5) g to 1.03±0.1 (0.52.5) 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
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Introduction |
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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.
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Subjects and methods |
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All patients had been on HD for more than 6 months, mean period 40 (range 7120) months. Mean age was 61 (range 2480) years. Patient descriptive data are summarized in Table 1. 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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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 1. 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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Results |
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Mean serum calcium fell from 2.8±0.04 (2.643.54) mmol/l to 2.56±0.03 (2.42.9) 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 (0.572.6) mmol/l to 1.64±0.11 (0.52.68) 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 (12933) ng/l to 276±104 (201913) 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 2; Figure 2
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Discussion |
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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 (3.474.19 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 56 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 23 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 23 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 (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 600900 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.
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Notes |
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References |
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