1 Divisions of Nephrology, Moffitt-Long Hospitals and UCSF-Mt. Zion Medical Center, Department of Medicine, University of California, San Francisco, 2 GelTex Pharmaceuticals, Inc., Waltham, MA and 3 Renal Division, Department of Internal Medicine, Barnes-Jewish Hospitals, Washington University Medical Center, Washington University School of Medicine, St Louis, MO, USA
Correspondence and offprint requests to: Glenn M. Chertow, MD, MPH, Division of Nephrology, University of California, San Francisco, 672 Health Sciences East, San Francisco, CA 94143-0532, USA.
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Abstract |
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Methods. To determine the long-term effectiveness of sevelamer hydrochloride, we performed an open-label clinical trial in 192 adult patients with end-stage renal disease on haemodialysis. Drug-related changes in the concentrations of serum phosphorus, calcium, calciumxphosphate product, parathyroid hormone, and low- and high-density lipoprotein cholesterol concentrations were the major outcomes of interest.
Results. Treatment with sevelamer was associated with a mean change in serum phosphorus of -0.71±0.77 mmol/l, serum calcium of 0.08±0.22 mmol/l, and calciumxphosphate product of -1.46±1.78 mmol/l (P<0.0001 for all comparisons). There were no significant overall treatment-related changes in parathyroid hormone. Serum levels of LDL cholesterol decreased by 0.81±0.75 mmol/l (mean -30%, P<0.0001) and HDL cholesterol increased by a mean of 0.15±0.29 mmol/l (mean +18%, P<0.0001). Drug-related adverse events were infrequent and most were of mild intensity.
Conclusion. Sevelamer is a safe and effective phosphate binder that leads to significant improvements in the calciumxphosphate product and lipid profile of haemodialysis patients.
Keywords: end-stage renal disease; hyperphosphataemia; hyperparathyroidism; haemodialysis; cholesterol; phosphate; calcium
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Introduction |
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Dietary restriction of phosphorus is limited by the need to provide adequate daily protein intake to maintain neutral nitrogen balance, estimated at roughly 1.01.2 g protein per kg body weight in most ambulatory patients. Therefore, most patients with advanced chronic renal failure or ESRD require an exogenous phosphate binder to prevent hyperphosphataemia. This stands in contrast to patients with renal insufficiency who may maintain normal or near normal levels of serum phosphorus as a consequence of hyperparathyroidism, due to the effect of PTH in augmenting renal phosphorus excretion. Aluminum hydroxide is effective at binding intestinal phosphorus, although its systemic absorption over time can lead to a microcytic, hypochromic anaemia, osteomalacia, myopathy, and rarely, dementia [1113]. Calcium salts (usually carbonate or acetate) have become the treatment of choice for hyperphosphatemia [14,15], although the provision of calcium can lead to hypercalcaemia and increase the risk of metastatic calcification in a substantial fraction of patients, particularly among patients on vitamin D replacement, and others with low bone turnover rates (adynamic bone disease) evidenced by low levels of PTH, serum osteocalcin, and alkaline phosphatase [16].
Sevelamer hydrochloride (herein referred to as sevelamer) is a non-aluminum, non-calcium-containing hydrogel of cross-linked poly [allylamine hydrochloride] that is resistant to digestive degradation and is not absorbed from the gastrointestinal tract. Its mechanism of action relates to the presence of partially protonated amines spaced one carbon from the polymer backbone (Figure 1), which interact with phosphate ions by ionic and hydrogen bonding. Several short-term clinical studies in patients with ESRD have established that sevelamer is as efficacious as calcium carbonate or acetate at lowering serum phosphorus, and is well-tolerated [1719]. Furthermore, short-term control of hyperparathyroidism has proved to be adequate, with maintenance of normal serum calcium concentrations, and significant decreases in the calciumxphosphate product. In addition, short-term favourable effects on the lipid profile have been observed, with a 2030% decrease in low density lipoprotein (LDL) cholesterol, and a 515% increase in high density lipoprotein (HDL) cholesterol concentrations, presumably related to the binding of bile acids by the compound.
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Methods |
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Protocol
Subjects who completed a dose titration study with sevelamer were eligible to continue on sevelamer longer-term. Written informed consent was obtained from all subjects, after consultation with their primary nephrologist. Following screening, when medical history, physical examination, and laboratory studies were reviewed, there were 2 weeks of `pre-treatment' washout, when all phosphate binders were discontinued. The investigator determined the initial sevelamer dose based on the subject's previous experience, the estimated dietary phosphorus intake, and overall clinical judgment. Phosphorus and calcium levels were monitored every 4 weeks during the treatment period; levels of PTH, cholesterol, and other laboratory tests were monitored at weeks 2, 10, 18, 26, 34, and 46. Laboratory tests were drawn before the mid-week dialysis session, timed in accordance with the subject's dialysis schedule. Therefore, some subjects had laboratory tests performed at night, others in the morning, although the timing was uniform within subject. The dose of sevelamer was titrated monthly if necessary. There were no protocols in place or restrictions enforced on the provision of vitamin D metabolites, supplemental calcium, or other conventional or alternative drug therapies during the course of the study. Dialysate calcium concentration was chosen by the primary nephrologist, as were other details of the dialysis prescription. This approach allowed the physician a degree of flexibility that simulated a non-clinical trial setting. A second 2-week washout (`post-treatment') followed the treatment period, and constituted study completion.
Statistical analysis
Continuous variables, expressed as mean±SD or median when the data were highly skewed, were compared with Student's t-test, the Wilcoxon signed rank test, or the KruskalWallis test, where appropriate. Categorical variables were compared with Fisher's Exact test. The effect of treatment was analysed using the change from the end of the initial washout to the end of the treatment period. In the event of study withdrawal, the final value obtained was carried forward. The dose-response was tested by linear regression, using change in the laboratory parameter of interest as the dependent variable, and sevelamer dose as a continuous independent variable.
Primary analyses were based on the entire study sample. Pre-specified subgroup analyses categorized by the average prescribed daily sevelamer dose (low <5.0 g, medium 5.06.75 g, high >6.75 g, a proxy for the severity of hyperphosphataemia) were performed for the phosphorus, calcium, calciumxphosphate product, and PTH determinations. Serum lipids were evaluated among pre-specified subgroups based on the initial LDL cholesterol concentration (LDL <2.58, LDL 2.583.33, LDL 3.364.11, LDL 4.13 mmol/l). Post-hoc analyses of phosphorus, calcium, calciumxphosphate product, and PTH were performed based on whether subjects had been prescribed an increase (i.e. new start or increase in dose) in vitamin D metabolite therapy (n=66, 34%) over the course of the study. Additional analyses were restricted to subjects who completed the study protocol (n=123, 64%). Because of multiple comparisons, two-tailed probability values <0.01 were considered significant.
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Results |
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Subjects were categorized by the mean prescribed daily sevelamer dose (low, n=57, medium, n=48, high, n=87). The mean prescribed daily dose was 6.3 g. The average adherence with therapy (determined by pill counts) was 84%. Therefore, the mean actual daily dose consumed was 5.3 g. Age was inversely correlated with sevelamer dose (mean age 61.7 vs 56.2 vs 52.3 years in low-, medium-, and high-dose groups, respectively, P=0.0008). Mean weight was directly correlated with dose (mean weight 77.9 vs 79.3 vs 83.0 kg in corresponding groups) although the difference among the three sevelamer dose groups was not statistically significant. Other demographic and clinical characteristics were not different across the three sevelamer dose groups. There was a trend toward less frequent use of vitamin D metabolites among subjects who required higher sevelamer doses (84% vs 79% vs 66% in the low-, medium- and high-dose groups, P=0.03).
Phosphorus
The mean serum phosphorus after pre-treatment washout was 2.81±0.71 mmol/l and at the end of treatment was 2.06±0.61 mmol/l, corresponding to a mean change of -0.71±0.77 mmol/l (P<0.0001). After 2 weeks of post-treatment washout, the mean serum phosphorus increased by 0.55±0.61 mmol/l (P<0.0001). The reduction in serum phosphorus was most pronounced in the high-dose group. The mean change in serum phosphorus was -0.61, -0.52, and -0.87 mmol/l, in the low-, medium-, and high-dose groups, respectively. The mean pre-treatment serum phosphorus levels were 2.42, 2.74, and 3.06 mmol/l with corresponding end of treatment values of 1.77, 2.23, and 2.19 mmol/l. Sevelamer lowered serum phosphorus whether or not an increase in vitamin D metabolite therapy was prescribed. The mean change in serum phosphorus among patients who increased vitamin D was -0.55±0.65 mmol/l and -0.81±0.81 mmol/l among patients with no change or a decrease in vitamin D dosage (P<0.001 for both comparisons). For those subjects who were not withdrawn from the study prematurely, the mean serum phosphorus at study completion was 1.97 mmol/l (median 1.87 mmol/l, corresponding to 5.79 mg/dl).
Calcium
The mean serum calcium after pre-treatment washout was 2.28±0.20 mmol/l and after treatment 2.35±0.20 mmol/l, corresponding to a mean change in serum calcium of 0.08±0.22 mmol/l (P<0.0001). There was no significant change in serum calcium concentration from the end of treatment to the end of the post-treatment washout. The small but significant increase in serum calcium was evident across sevelamer dose groups, with no apparent dose effect. The magnitude of the increase in serum calcium was not dependent on whether vitamin D dosage was increased (mean increase 0.12±0.20 vs 0.05±0.22 mmol/l in patients with an increase, and patients with no change or a decrease in vitamin D dosage, respectively). The average incidence of hypercalcaemia (serum calcium 2.75 mmol/l) was <2%, confirming prior reports that sevelamer does not promote hypercalcaemia.
Calciumxphosphate product
The mean calciumxphosphate product after the pre-treatment washout was 6.32±1.60 mmol/l, and at the end of treatment was 4.86±1.45 mmol/l, corresponding to a mean change of -1.46±1.78 mmol/l (P<0.0001). After 2 weeks of post-treatment washout, the calciumxphosphate product increased by 1.24±1.31 mg/dl (P<0.0001). The reduction in the calciumxphosphate product was most pronounced in the high-dose sevelamer group (mean change -1.20, -1.10, -1.82 mmol/l in the low-, medium-, and high-dose groups, respectively), mirroring the trend observed for the serum phosphorus concentration. The mean pre-treatment levels of the calciumxphosphate product were 5.45, 6.37, and 6.86 mmol/l in the low-, medium-, and high-dose groups, respectively, and the corresponding end of treatment values were 4.25, 5.26, and 5.05 mmol/l. The calciumxphosphate product was reduced in subjects whether or not they were prescribed an increase in vitamin D dosage, although the reduction was more pronounced in those subjects whose vitamin D dosage was not increased (-1.73±1.82 vs -0.94±1.60 mmol/l). For those subjects who were not withdrawn from the study prematurely, the mean calciumxphosphate product at study completion was 4.67±1.36 mmol/l (median 4.41 mmol/l, corresponding to 54.6 mg/dl). Figure 3 depicts the trends over time in phosphorus, calcium, and calciumxphosphate product for all subjects throughout the study period.
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LDL and HDL cholesterol
The mean change in LDL cholesterol with treatment was -0.82±0.74 mmol/l (P<0.0001), corresponding to an average decrease of 30% from baseline. The mean change in HDL cholesterol was 0.15±0.29 mmol/l (P<0.0001), corresponding to an average increase of 18% from baseline. Triglyceride levels were not significantly changed (median change -0.07 mmol/l). Changes in LDL and HDL cholesterol were dependent on the starting LDL cholesterol concentration (Table 3). Subjects with higher baseline LDL concentrations experienced more pronounced changes in the lipid profile after treatment with sevelamer (Figure 4
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Discussion |
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Serum calcium was slightly but significantly increased, even among patients with no change or a decrease in their vitamin D dosage. There are two likely explanations for this phenomenon. First, since sevelamer competes with dietary calcium for phosphate binding, more free calcium may be absorbed with sevelamer treatment. Second, with reduction in the serum phosphorus concentration and the calciumxphosphate product induced by sevelamer, there may be less deposition of calcium phosphate crystals in tissue, thereby raising the calcium concentration in serum.
The slight increase in bicarbonate concentration confirms the fact that sevelamer does not promote metabolic acidosis, either directly or secondary to the loss of base (carbonate or acetate with calcium). The mild hypouricaemic effect of sevelamer has not been previously observed, and may relate to the competitive binding of urate, another organic anion. The increase in alkaline phosphatase has been previously observed, and most likely relates to the effect of sevelamer on bile acid metabolism. Similar laboratory changes have been observed in studies of cholestyramine and other bile acid sequestrants, without any clinically apparent hepatic or systemic effects over time [2022]. It is noteworthy that there was no change in the serum albumin concentration over time, suggesting no adverse effect on nutritional status or the inflammatory response.
The reduction in the calciumxphosphate product may prove to be among the most important of sevelamer's benefits. A recent study by Block et al. [23] utilized laboratory data collected on two representative cohorts of US haemodialysis patients. With a calciumxphosphate product of 3.474.19 mmol/l as a referent category (quintile 2 of 5), there was a steady increase in the relative risk (RR) of death with higher levels of calciumxphosphate product (unadjusted RR 1.08, 1.13, and 1.34 for 4.274.84, 4.925.81, and 5.8910.65 mmol/l, respectively). These and other authors have hypothesized that higher levels of the calciumxphosphate product might promote vascular calcification, and lead to decreased survival related to cardiovascular disease. While the mechanism remains to be proved, a relative reduction in the calciumxphosphate product of as little as 0.40.8 mmol/l might appreciably improve survival in this population.
The relative benefits of modifying the lipid profile in haemodialysis patients are also unknown. Although large cohort studies have shown that patients with total cholesterol levels in the 5.176.46 mmol/l range experience the lowest all-cause mortality rates [24], these and other studies of cholesterol and mortality are confounded by malnutrition, hepatic, and inflammatory diseases [25]. The risk of myocardial ischaemia and infarction is increased by more than an order of magnitude in patients with ESRD compared with non-uraemic age- and sex-matched individuals [26] and elevated serum cholesterol concentrations have been shown to predict cardiac death in patients with ESRD and diabetes [27]. As might be expected, patients with ESRD have been excluded from large clinical trials of HMG-CoA reductase inhibitors and other lipid profile-modifying agents. Nevertheless, changes in LDL and HDL cholesterol of the magnitude induced by sevelamer in this study would be expected to reduce the rate of cardiovascular disease, and potentially increase survival in this population. Prevention may be a particularly effective strategy in this setting, given that survival rates for patients with ESRD and acute myocardial infarction are less than 50% at 1 year [28]. Whether there might be an additive or synergistic effect of modifying the lipid profile and lowering calciumxphosphate product is unknown. Evaluation of the cost-effectiveness of sevelamer is another important area of inquiry. Finally, although control of phosphorus was similar to that observed in other clinical trials of phosphate binders, levels in the range of 2 mmol/l should not be considered `optimal'. More intensive dose titrations, more aggressive management of hyperparathyroidism (to limit the contribution to hyperphosphataemia of endogenous, non-dietary phosphorus), and alternative analytic techniques (note that the `last value carried forward' method biases toward nil effect) might highlight the efficacy of sevelamer and other phosphate binders in future clinical investigations.
In summary, a 1-year, open-label trial of the non-aluminum-and non-calcium-containing phosphate binder sevelamer in haemodialysis patients demonstrated sustained reductions in serum phosphorus, and adequate control of hyperparathyroidism without promoting hypercalcaemia. Treatment with sevelamer resulted in sustained, favourable changes in the calciumxphosphate product and lipid profile. Further experience with this agent will help to define its ultimate role in the management of hyperphosphataemia and other metabolic complications of ESRD.
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Appendix: Other Participating Investigators |
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Paul Bolin, MD, Greenville, NC
Kenneth Boren, MD, Mesa, AZ
Douglass T. Domoto, MD, St. Louis, MO
Bruce Garrett, MD, Washington, DC
Mary Gellens, MD, St. Louis, MO
Thomas A. Golper, Little Rock, AR
Fred Jones, MD, Raleigh, NC
K. Shashi Kant, MD, Cincinnati, OH
C. J. Kaupke, MD, Orange, CA
Robert Levinson, MD, Hollywood, FL
David Lynch, MD, Coon Rapids, MN
William Mattern, MD, Chapel Hill, NC
Michael Marx, PharmD, Minneapolis, MN
Mark S. Paller, MD, Minneapolis, MN
Noor Rahman, MD, Houston, TX
Patricia Schoenfeld, San Francisco, CA
Maryella D. Simon, MD, Mobile, AL
Isaac Teitelbaum, MD, Denver, CO
James van Gelder, MD, Hollywood, FL
John Wagner, MD, New Hyde Park, NY
Marc Weinberg, MD, Providence, RI
Barry Wilkes, MD, Manhasset, NY
Steven Zeig, MD, Hollywood, FL
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Acknowledgments |
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Notes |
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References |
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