Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients

Elevated serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Unlike calcium-based binders, sevelamer attenuates arterial calcification but it is unknown whether sevelamer affects mortality or morbidity. In a multicenter, randomized, open-label, parallel design trial we compared sevelamer and calcium-based binders on all-cause and cause-specific mortality (cardiovascular, infection, and other) in prevalent hemodialysis patients. A total of 2103 patients were initially randomized to treatment and 1068 patients completed the study. All-cause mortality rates and cause-specific mortality rates were not significantly different. There was a significant age interaction on the treatment effect. Only in patients over 65 years of age was there a significant effect of sevelamer in lowering the mortality rate. There was a suggestion that sevelamer was associated with lower overall, but not cardiovascular-linked, mortality in older patients. We suggest that further research is needed to confirm these findings.     

Length of interdialytic interval influences serum calcium and phosphorus concentrations.

BACKGROUND: Higher levels of serum phosphorus and calcium are associated with increased haemodialysis (HD) patient mortality. Both of these factors act synergistically to promote vascular smooth muscle differentiation to an osteoblast-like phenotype and subsequent vascular calcification. The aim of this study was to investigate the influence of interdialytic interval on serum levels, as well as the influence of oral calcium-based phosphate binder load on the magnitude of the observed differences. METHODS: We studied 100 patients undergoing HD three times per week, over a 2 week period. Haemoglobin, albumin, calcium and phosphate were measured pre-dialysis before each HD session. Oral phosphate binder usage was recorded. All patients were treated with dialysate containing 1.25 mEq/l calcium. RESULTS: Both mean serum phosphate and calcium were higher after the long interdialytic interval (1.59+/-0.05 vs 1.45+/-0.04 mmol/l, P = 0.0005, and 2.46+/-0.03 vs 2.4+/-0.02 mmol/l, P = 0.001, for serum phosphate and uncorrected calcium, respectively). There were no significant differences in haemoglobin or serum albumin, indicating that variable dilution from an increased hydration status in the long interdialytic interval was unlikely to contribute to these observed differences. A total of 74 patients were treated with calcium-containing binders and 26 patients with sevelamer. Patients on sevelamer did not exhibit the observed cyclical increase in serum calcium seen in patients on calcium-containing binders (mean difference in serum calcium 0.09+/-0.01 mmol/l in the calcium-treated group vs 0.01+/-0.01 mmol/l in the sevelamer-treated patients, P = 0.0004). The increase in serum calcium after the long interval as compared with the short interval was proportional to the daily amount of the oral calcium-containing binder load ingested (r = 0.63, P<0.0001). CONCLUSION: Cyclical differences in interdialytic interval and overall exposure to both dietary phosphate and oral calcium load influence serum levels. This may have consequences for registry reporting, therapy modulation and potentially the pathogenesis of accelerated vascular calcification seen in HD patients.     

Long-term comparison of sevelamer hydrochloride to calcium-containing phosphate binders

AIM: In patients with end-stage renal disease (ESRD), hyperphosphataemia and an elevated calcium-phosphorus (Ca-P) product contribute to morbidity and mortality. Suggested target goals for serum phosphorus concentration and calcium-phosphorus product have recently been lowered. As a result, long-term comparative studies of the efficacy of phosphate binders are critical. This study compares the long-term efficacy of sevelamer hydrochloride to calcium-containing binders (CCB). METHODS: A retrospective chart review was conducted in 30 patients receiving sevelamer hydrochloride for >1 years and 25 patients receiving CCB. RESULTS: Patients on sevelamer hydrochloride had lower serum bicarbonate concentration than those on CCB, 18.6 +/- 2.7 versus 20.3 +/- 1.8 mmol/L (P = 0.0017). Serum phosphorus concentration was higher in patients on sevelamer hydrochloride compared to CCB 2.10 +/- 0.87 versus 1.74 +/- 0.28 mmol/L (P = 0.0013), as was the Ca-P product 4.97 +/- 0.94 mmol2L2 (62.1 +/- 11.8 mg2/dL2) versus 3.97 +/- 1.18 mmol2/L2 (49.7 +/- 14.7 mg2/dL2), P = 0.0009). Only 36% of patients on sevelamer hydrochloride compared with 68% on CCB (P = 0.015) met the serum phosphorus goal of < or =1.78 mmol/L. CONCLUSION: Patients on sevelamer hydrochloride for >1 years compared to those on CCB had a lower serum bicarbonate concentration, a higher serum phosphorus concentration and a higher Ca-P product. Clinicians should balance the increase in calcium load with CCB versus the cost and effectiveness of sevelamer hydrochloride in choosing a phosphate binder for ESRD patients.     

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

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 1alpha 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.     

Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients: results of a randomized clinical trial.

BACKGROUND: Elevated serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Sevelamer, a phosphate-binding polymer, attenuates the progression of arterial calcification; it is unknown whether this improves outcomes. PATIENTS AND INTERVENTIONS: A randomized comparison of sevelamer and calcium-based phosphate binders was performed in hemodialysis patients treated up to 45 months. The primary endpoint was mortality. Secondary endpoints included cause-specific mortality and hospitalization; 2103 patients were randomized, 2040 received treatment, and 1065 completed treatment. RESULTS: Overall mortality was not significantly reduced by sevelamer (adjusted relative risk = 0.92; 95% confidence interval, 0.78 to 1.09; log-rank P = .40). Among patients > or = 65 years of age, sevelamer reduced the risk of death (adjusted relative risk = 0.77; 95% confidence interval, 0.62 to 0.97; log-rank P = .02). Sevelamer patients had a trend toward fewer hospitalizations (P = .06) and fewer hospital days (P = .09). CONCLUSIONS: A statistically significant reduction in mortality in the overall study population was not observed. Sevelamer was associated with a survival benefit among patients > or = 65 years of age.     

Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis

Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis. Hyperphosphatemia in patients with ESRD leads to secondary hyperparathyroidism, renal osteodystrophy, and is independently associated with mortality risk. The exact mechanism by which hyperphosphatemia increases mortality risk is unknown, but it may relate to enhanced cardiovascular calcification. National Kidney Foundation K/DOQI bone metabolism and disease guidelines recommend maintenance of serum phosphorus (P) below 5.5 mg/dL, and Ca x P product less than 55 mg(2)/dL(2). Although calcium-based phosphate binders (CBPB) are cost effective, long-term safety concerns relate to their postulated role in progression of cardiovascular calcification. Sevelamer hydrochloride has been recommended as an alternative noncalcium phosphate binder. Results from the Calcium Acetate Renagel Evaluation (CARE study) indicate that calcium acetate is more effective than sevelamer in controlling serum phosphorous and Ca x P product in hemodialysis patients. In the Treat-to-Goal study, dialysis patients treated with sevelamer had slower progression of coronary and aortic calcification than patients treated with CBPB. The mechanism underlying the beneficial effect of sevelamer is unknown, but may relate to decreased calcium loading or to dramatic reductions in LDL cholesterol in sevelamer-treated patients. At present, evidence incriminating CBPB in the progression of cardiovascular calcification in ESRD remains largely circumstantial. As calcium acetate is more efficacious and cost effective than sevelamer, it remains an accepted first-line phosphate binder. In this review, we will examine these issues and provide rational guidelines for the use of calcium-based phosphate binders in patients on maintenance hemodialysis.     

Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients

The risk of death in hemodialysis patients treated with calcium-containing phosphate binders or sevelamer is not known. We assessed all-cause mortality in 127 patients new to hemodialysis assigned to calcium-containing binders or sevelamer after a median follow-up of 44 months from randomization. This was a predetermined secondary end point of a randomized clinical trial designed to assess progression of coronary artery calcium (CAC) scores in the two treatment arms. Thirty-four deaths occurred during the follow-up period: 23 in subjects randomized to calcium-containing phosphate binders and 11 in subjects randomized to sevelamer. Baseline CAC score was a significant predictor of mortality after adjustment for age, race, gender, and diabetes with increased mortality proportional to baseline score (P=0.002). Mortality was borderline significantly lower in subjects randomized to sevelamer (5.3/100 patient years, confidence interval (CI) (2.2-8.5) compared to those randomized to calcium-containing binders (10.6/100 patient years, CI 6.3-14.9) (P=0.05). The greater risk of death for patients treated with calcium-containing phosphate binders persisted after full multivariable adjustment (P=0.016, hazard ratio 3.1, CI 1.23-7.61). In subjects new to hemodialysis baseline CAC score was a significant predictor of all-cause mortality. Treatment with sevelamer was associated with a significant survival benefit as compared to the use of calcium-containing phosphate binders.     

Sevelamer reduces calcium load and maintains a low calcium-phosphorus ion product in dialysis patients.

BACKGROUND: Sevelamer HCl, a non-aluminum, non-calcium containing hydrogel, has proved an effective phosphate binder in North American hemodialysis patients. This single-center, open-label, dose titration study assessed the efficacy of sevelamer in a cohort of European hemodialysis patients with different dietary habits, in particular with lower phosphate intake. The aim of the study was to obtain a calcium x phosphate product lower than 60 mg2/dL2 in all patients. METHODS: Administration of calcium- or aluminum-based phosphate binders was discontinued during a two-week washout period. Nineteen patients whose serum phosphate level at the end of washout was greater than 5.5 mg/dL (1.78 mmol/L) qualified to receive sevelamer for six weeks. Based on the degree of hyperphosphatemia during washout, patients were started on 403 mg sevelamer capsules with a dose schedule different from previous studies. Only one capsule was administered at breakfast, and the rest of the phosphate binder was divided equally at the two main meals. Sevelamer could be increased by two capsules per day every two weeks, if necessary. A second two-week washout period followed. RESULTS: Mean serum phosphorus rose from a baseline of 5.3 +/- 1.0 to 7.4 +/- 1.4 mg/dL at the end of washout, then declined to 5.4 +/- 0.8 mg/dL (p < 0.001) by the end of the six-week treatment period and rebounded significantly to 7.1 +/- 1.1 mg/dL after the second two-week washout. Calcium x phosphate product showed a similar pattern, decreasing significantly from 64.1 +/- 14.1 to 46.9 +/- 7.4 mg2/dL2 (p < 0.001) after six weeks of sevelamer. A level of less than 50 mg2/dL2 was reached by 68% of patients, and 95% had less than 60 mg2/dL2. The mean dose of sevelamer at the end of treatment was 3.1 +/- 0.6 g per day. As expected, calcium declined from 9.2 +/- 0.5 to 8.7 mg/dL (p < 0.01) during the initial washout after stopping calcium-based phosphate binders, but remained stable thereafter. Ionized calcium did not change significantly throughout the washout and sevelamer treatment. However, interruption of calcium salts led to a 81% reduction of total calcium intake. CONCLUSIONS: We confirmed in an European sample of hemodialysis patients that sevelamer can reduce phosphate levels without inducing hypercalcemia. The drug can also be successfully used to reduce mean calcium x phosphate levels below 50 mg2/dL2, closer to normal values. Although similar results can be obtained with other phosphate binders, a concomitant accumulation of aluminum, calcium or magnesium could be detrimental to patients.     

The effects of non-calcium-based phosphate binders versus calcium-based phosphate binders on cardiovascular calcification and bone remodeling among dialysis patients: a meta-analysis of randomized trials

Background: Vascular calcification significantly increases the rates of cardiovascular mortality in hemodialysis (HD) patients. Abnormalities in mineral metabolism may play a role in the pathogenesis of arterial calcification. Whether patients treated with non-calcium-based phosphate binders had reduced aortic vascular calcification compared to those treated with calcium-based phosphate binders is still unclear. Methods: We searched multiple databases for studies published through August 2013 that evaluated the effects of non-calcium-based phosphate binders (NCBP) versus calcium-based phosphate binders (CBP) on cardiovascular calcification and bone remodeling among dialysis patients. We summarized test performance characteristics with the use of forest plots, fixed and random effects models, and Egger regression test. Results: Eighteen eligible randomized controlled trials totaling 3676 patients were included. Meta-analysis results showed NCBP could significantly attenuate the progression of coronary artery calcification than CBP (WMD: ?144.62, 95% CI: ?285.62 to ?3.63). The serum calcium levels significant lower in NCPB group than in CPB groups (WMD: ?0.26, 95% CI: ?0.37 to ?0.14), but the serum iPTH levels were significantly higher in NCPB groups (WMD: 57.1, 95% CI: 13.42 to 100.78). The osteoid volume and osteoblast numbers were significant higher in NCPB group than in CPB group (WMD: 1.75, 95% CI: 0.78 to 2.73 for osteoid volume; WMD: 4.49, 95% CI: 1.83 to 7.15 for osteoblast numbers). The Egger regression test also showed no potential publication bias (p?=?0.725). Conclusions: Based on available data, NCBPs have equally effective with CBPs for serum phosphate control. But there was significantly lower incidence of coronary artery calcification and a significant higher bone formatting rate in NCBP groups than in CBP groups. So we recommend NCBPs as phosphate binders for HD patients.     

Audit of the use of calcium carbonate as a phosphate binder in 100 patients treated with continuous ambulatory peritoneal dialysis.

We studied the effect of converting 100 established CAPD patients from aluminium- to calcium-based phosphate binders. After a follow-up of 1 year only 60% of patients remained on calcium carbonate. Hypercalcaemia was the major problem, with more than 40% of patients having a serum calcium in excess of 3.0 mmol/l. Several patients required hospitalization for symptomatic hypercalcaemia. Hypercalcaemia was more common in patients with normal serum parathyroid hormone concentrations (65 versus 25%, P less than 0.01). Serum phosphate control was better prior to commencing calcium carbonate when patients were treated with aluminium phosphate binders mean 1.71 +/- 0.15 mmol/l (SEM) than at the time of maximum serum calcium concentration, 1.81 +/- 0.25, P less than 0.05. This study does not confirm the findings of others, which have suggested that calcium carbonate is a safe and effective phosphate binder for patients with end-stage renal failure.     

Arterial calcification in chronic kidney disease

Hyperphosphatemia is associated with soft-tissue calcification and bone disease. Nephrologists prescribe phosphate binders to decrease dietary phosphate absorption, reduce serum phosphorus concentrations, and minimize the risk for soft-tissue calcification and bone disease. Recent data suggest that the dose of calcium used as a phosphate binder may contribute to the risk for cardiovascular calcification. Chronic positive calcium balance from diet, dialysis, and calcium-based phosphate binders or intermittent hypercalcemia may favor precipitation of calcium and phosphate into tissues. Calcium suppresses parathyroid hormone (PTH) secretion and bone turnover, limiting the ability of bone to incorporate calcium and phosphorus. Sevelamer, a non-absorbed polymer, allows physicians to bind dietary phosphate and decrease serum phosphorus without unwanted absorption of metals or calcium or over-suppression of PTH. In a comparative trial, calcium-based phosphate binders were associated with progressive coronary artery and aortic calcification that was attenuated by sevelamer. The optimal phosphate binder is one that controls hyperphosphatemia prevents soft-tissue calcification and preserves bone health.     

Long-term comparison of a calcium-free phosphate binder and calcium carbonate--phosphorus metabolism and cardiovascular calcification

BACKGROUND: Calcium carbonate used as a phosphate binder may contribute to cardiovascular calcification. Long-term comparisons of sevelamer, a non-calcium polymeric phosphate binder, and calcium carbonate (CC) are lacking. METHODS: 114 adult hemodialysis patients were randomly assigned to open label sevelamer or CC for 52 weeks. Study efficacy endpoints included changes in serum phosphorus, calcium, calcium-phosphorus product, and lipids. In addition, initial and sequential electron beam computerized tomography scans were performed to assess cardiovascular calcification status and change during follow-up. Safety endpoints were serum biochemistry, blood cell counts and adverse events. RESULTS: Patients receiving sevelamer had a similar reduction in serum phosphorus as patients receiving CC (sevelamer -0.58 +/- 0.68 mmol/l, CC -0.52 +/- 0.50 mmol/l; p = 0.62). Reductions in calcium-phosphorus product were not significantly different (sevelamer -1.4 +/- 1.7 mmol2/l2, CC -0.9 +/- 1.2 mmol2/l2; p = 0.12). CC produced significantly more hypercalcemia (> 2.8 mmol/l in 0% sevelamer and 19% CC patients, p < 0.01) and suppressed intact parathyroid hormone below 150 pg/ml in the majority of patients. Sevelamer patients experienced significant (p < 0.01) reductions in total (-1.2 +/- 0.9 mmol/l, -24%) and LDL cholesterol (-1.2 +/- 0.9 mmol/l, -30%). CC patients had significant increases in coronary artery (median +34%, p < 0.01) and aortic calcification (median +32%, p < 0.01) that were not observed in sevelamer-treated patients. Patients on sevelamer required more grams of binder (sevelamer 5.9 g vs. CC 3.9 g) and experienced more dyspepsia than patients on calcium carbonate. CONCLUSIONS: Sevelamer is an effective phosphate binder that unlike calcium carbonate is not associated with progressive cardiovascular calcification in hemodialysis patients.     

Predictive factors of low HCO3- levels in peritoneal dialysis patients

BACKGROUND: Metabolic acidosis is a major metabolic abnormality in end-stage renal disease (ESRD) and alkali is provided with dialysis treatment to patients on chronic peritoneal dialysis (CPD) to keep their acid-base balance within normal serum HCO3- levels. METHODS AND RESULTS: We examined the levels of venous serum HCO3- in 163 patients on CPD and the predictive factors for HCO3- levels low enough to indicate metabolic acidosis. The mean value for HCO3- was 26+/-2.4 mmol/l and for anion gap was 13.1+/-3.1 mEq/l. A serum bicarbonate concentration of less than 24 mmol/l, compatible with metabolic acidosis, was observed in 13.5% of the patients. In a multivariate analysis HCO3- levels were directly correlated with older age and use of CaCO3- as phosphate binders, and inversely associated with serum potassium, the use of sevelamer and low lactate dialysis solutions. Higher serum urea levels, the use of low lactate solutions and sevelamer instead of CaCO3 were significantly predictive factors for HCO3- levels < 24 mmol/l. CONCLUSIONS: Venous HCO3- and anion gap values were within the normal ranges in stable CPD patients. In 13.5% of them, however, chronic metabolic acidosis was observed based on venous HCO3- levels < 24 mmol/l. Dietary protein intake, the use of sevelamer and low (35 mmol/l) concentration of lactate in dialysis solutions are important predictive factors for chronic metabolic acidosis in these patients.     

Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients

BACKGROUND: Cardiovascular disease is frequent and severe in patients with end-stage renal disease. Disorders of mineral metabolism may contribute by promoting cardiovascular calcification. METHODS: We conducted a randomized clinical trial comparing sevelamer, a non-absorbed polymer, with calcium-based phosphate binders in 200 hemodialysis patients. Study outcomes included the targeted concentrations of serum phosphorus, calcium, and intact parathyroid hormone (PTH), and calcification of the coronary arteries and thoracic aorta using a calcification score derived from electron beam tomography. RESULTS: Sevelamer and calcium provided equivalent control of serum phosphorus (end-of-study values 5.1 +/- 1.2 and 5.1 +/- 1.4 mg/dL, respectively, P = 0.33). Serum calcium concentration was significantly higher in the calcium-treated group (P = 0.002), and hypercalcemia was more common (16% vs. 5% with sevelamer, P = 0.04). More subjects in the calcium group had end-of-study intact PTH below the target of 150 to 300 pg/mL (57% vs. 30%, P = 0.001). At study completion, the median absolute calcium score in the coronary arteries and aorta increased significantly in the calcium treated subjects but not in the sevelamer-treated subjects (coronary arteries 36.6 vs. 0, P = 0.03 and aorta 75.1 vs. 0, P = 0.01, respectively). The median percent change in coronary artery (25% vs. 6%, P = 0.02) and aortic (28% vs. 5%, P = 0.02) calcium score also was significantly greater with calcium than with sevelamer. CONCLUSIONS: Compared with calcium-based phosphate binders, sevelamer is less likely to cause hypercalcemia, low levels of PTH, and progressive coronary and aortic calcification in hemodialysis patients.     

Decrease in thoracic vertebral bone attenuation with calcium-based phosphate binders in hemodialysis.

We performed a post hoc analysis of a 52-week randomized trial conducted in adult hemodialysis patients that compared the effects of calcium-based phosphate binders and sevelamer, a nonabsorbable polymer, on parameters of mineral metabolism and vascular calcification by electron beam tomography. In this analysis, we evaluated the relative effects of calcium and sevelamer on thoracic vertebral attenuation by CT and markers of bone turnover. Subjects randomized to calcium salts experienced a significant reduction in trabecular bone attenuation and a trend toward reduction in cortical bone attenuation, in association with higher concentrations of serum calcium, lower concentrations of PTH, and reduced total and bone-specific alkaline phosphatase. INTRODUCTION: In patients with chronic kidney disease, hyperphosphatemia is associated with osteodystrophy, vascular and soft tissue calcification, and mortality. Calcium-based phosphate binders are commonly prescribed to reduce intestinal phosphate absorption and to attenuate secondary hyperparathyroidism. Clinicians and investigators have presumed that, in hemodialysis patients, calcium exerts beneficial effects on bone. MATERIALS AND METHODS: We performed a post hoc analysis of a 52-week randomized trial conducted in adult hemodialysis patients that compared the effects of calcium-based phosphate binders and sevelamer, a nonabsorbable polymer, on parameters of mineral metabolism and vascular calcification by electron beam tomography. In this analysis, we evaluated the relative effects of calcium and sevelamer on thoracic vertebral attenuation by CT and markers of bone turnover. RESULTS AND CONCLUSIONS: The average serum phosphorus and calcium x phosphorus products were similar for both groups, although the average serum calcium concentration was significantly higher in the calcium-treated group. Compared with sevelamer-treated subjects, calcium-treated subjects showed a decrease in thoracic vertebral trabecular bone attenuation (p = 0.01) and a trend toward decreased cortical bone attenuation. More than 30% of calcium-treated subjects experienced a 10% or more decrease in trabecular and cortical bone attenuation. On study, sevelamer-treated subjects had higher concentrations of total and bone-specific alkaline phosphatase, osteocalcin, and PTH (p < 0.001). When used to correct hyperphosphatemia, calcium salts lead to a reduction in thoracic trabecular and cortical bone attenuation. Calcium salts may paradoxically decrease BMD in hemodialysis patients.     

Meta-analysis of the effect of sevelamer on phosphorus,calcium, PTH,and serum lipids in dialysis patients

Hyperphosphatemia and dyslipidemia are common clinically significant conditions in end-stage renal disease (ESRD). Hyperphosphatemia management is essential; however, use of calcium-based phosphate binder has been associated with elevated risk of cardiac calcification in ESRD, increasing risks for cardiovascular disease and death. An alternative to calcium-based phosphate binders is sevelamer hydrochloride, a calcium-free, metal-free, nonabsorbed polymer that binds phosphate effectively. We conducted a meta-analysis on the effects of sevelamer hydrochloride on parameters of mineral metabolism (serum phosphorous, calcium, Ca x P, and iPTH) and the lipid profile (total, LDL, HDL, and non-HDL cholesterol, and triglycerides) in dialysis patients. After application of inclusion/exclusion criteria, 17 core studies were statistically analyzed to determine the sevelamer treatment effect on the study parameters as demonstrated by simple, n-weighted, and inverse variance-weighted mean changes. Analysis of inverse variance-weighted mean changes indicated that sevelamer treatment was associated with a 2.14 mg/dL drop in serum phosphorus (P <.001), no significant overall effect on calcium (0.09 mg/dL, P =.364), significant decline in Ca x P product (15.91 mg(2)/dL(2), P <.001), 35.99 pg/mL reduction in iPTH (P =.026), significant reduction in total cholesterol (30.58 mg/dL, P <.001), 31.38 mg/dL drop in LDL cholesterol (P <.001), significant increase in HDL cholesterol (4.09 mg/dL, P =.008), and a significant reduction in triglycerides (22.04 mg/dL, P x.001). This meta-analysis suggests that sevelamer offers a dual therapeutic benefit in dialysis patients-a population at high risk for cardiovascular disease-by improving phosphorus control and the lipid profile, without altering serum calcium.     

Phosphate binder therapy for attainment of K/DOQI bone metabolism guidelines

Hyperphosphatemia in patients with chronic kidney disease leads to secondary hyperparathyroidism and renal osteodystrophy, and it is independently associated with mortality risk. The exact mechanism by which hyperphosphatemia increases mortality risk is unknown, but it may relate to enhanced cardiovascular calcification. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease recommends maintenance of serum phosphorus below 5.5 mg/dL, calcium-phosphorus (Ca x P) product less than 55 mg(2)/dL(2), intact parathyroid hormone (iPTH) 150 pg/mL to 300 pg/mL, and bicarbonate (HCO(3)) greater than 22 mEq/L. Although calcium-based phosphate binders (CBPB) are cost effective, there are long-term safety concerns pertaining to their postulated role in the progression of cardiovascular calcification. Sevelamer hydrochloride has been recommended as an alternative noncalcium phosphate binder. Results from the Calcium Acetate Renagel Evaluation (CARE) study indicate that calcium acetate is more effective than sevelamer hydrochloride in controlling serum phosphorous, Ca x P product, and HCO(3) in hemodialysis patients. In the Treat-to-Goal study, dialysis patients treated with sevelamer hydrochloride had slower progression of coronary and aortic calcification than patients treated with CBPB. The mechanism underlying the beneficial effect of sevelamer hydrochloride is unknown but may relate to decreased calcium loading, or to dramatic reductions in low-density lipoprotein (LDL) cholesterol in sevelamer hydrochloride-treated patients. At present, evidence incriminating CBPB in the progression of cardiovascular calcification in end-stage renal disease (ESRD) remains largely circumstantial. As calcium acetate is more efficacious and cost effective than sevelamer hydrochloride, it remains an accepted first-line phosphate binder. This review examines these issues and provides rational guidelines for the use of CBPB in patients on maintenance hemodialysis.     

Long-term effects of sevelamer hydrochloride on the calcium x phosphate product and lipid profile of haemodialysis patients.

BACKGROUND: Short-term studies have suggested that sevelamer hydrochloride, a non-aluminium- and non-calcium-containing hydrogel, is an effective phosphate binder in haemodialysis patients, and may produce favourable changes in the lipid profile. 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, calcium x phosphate 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 calcium x phosphate 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 calcium x phosphate product and lipid profile of haemodialysis patients.     

Phosphate Binders in Chronic Kidney Disease and End-Stage Renal Disease: A Patient-Centered Approach

Disorders of calcium and phosphorus metabolism are associated with significant morbidity and mortality in patients with advanced chronic kidney disease. These patients typically require oral phosphate binders to maintain phosphorus homeostasis, but the choice of which among several agents to use has been actively investigated and debated. Recent debate has been polarized between those who favor calcium-based binders for their proven efficacy and relatively low cost and those who favor sevelamer for its putative beneficial effects on inflammatory biomarkers and vascular calcification. This review summarizes the current state of the art of prescribing phosphate binders, ranging from large-scale clinical trials to focused mechanistic studies, and proposes that the available evidence does not conclusively prove the relative superiority of any one binder.     

Accelerated vascular calcification and relative hypoparathyroidism in incident haemodialysis diabetic patients receiving calcium binders.

BACKGROUND: Vascular calcification and low bone turnover with a relatively low parathyroid hormone (PTH) often coexist in diabetic patients undergoing haemodialysis. Since calcium salts (CaS) are used extensively as primary phosphate binders and have been associated with progressive vascular calcification, we studied the effects of CaS on coronary arteries and parathyroid activity in incident haemodialysis diabetic patients. METHODS: We measured the change in coronary artery calcium scores (CACS) with sequential electron beam computed tomography (EBCT) in 64 diabetic and 45 non-diabetic patients, randomized to CaS or sevelamer within 90 days of starting haemodialysis. CACS measurements were repeated after 6, 12 and 18 months. Serum intact PTH (iPTH), calcium and phosphorus were serially tested. RESULTS: During the study period, serum phosphate was similar in diabetic and non-diabetic patients. Serum calcium levels were similar at baseline (2.3+/-0.25 mmol/l for both) and increased significantly with CaS treatment (P<0.05) both in diabetic and non-diabetic patients but not with sevelamer. Diabetic patients treated with CaS showed a significantly greater CACS progression than sevelamer-treated patients (median increase 177 vs 27; P=0.05). During follow-up, diabetic patients receiving CaS were significantly more likely to develop serum iPTH values<16 pmol/l than diabetic patients treated with sevelamer (33% vs 6%, P=0.005) and had a lower mean iPTH level (24+/-16 vs 31+/-14 pmol/l; P=0.038). CONCLUSIONS: The management of hyperphosphataemia with CaS in haemodialysis diabetic patients is associated with a significantly greater progression of CACS than with sevelamer. These effects are accompanied by iPTH changes suggestive of low bone turnover.