Benefits and Harms of Phosphate Binders in CKD
Benefits and Harms of Phosphate Binders in CKD
Background: Phosphate binders are widely used to control serum phosphorus levels in patients with chronic kidney disease (CKD). We analyzed the effects of phosphate binders on biochemical and patient-level end points in patients with CKD.
Study Design: Systematic review and meta-analysis by searching MEDLINE (1966 to April 2009), EMBASE (1980 to April 2009), and the Cochrane Renal Group Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL).
Setting & Population: Patients with CKD.
Selection Criteria for Studies: Randomized controlled trials.
Intervention: Phosphate binders.
Outcomes: Serum phosphorus, calcium, and parathyroid hormone levels; incidence of hypercalcemia; all-cause mortality; adverse effects.
Results: 40 trials (6,406 patients) were included. There was no significant decrease in all-cause mortality (10 randomized controlled trials; 3,079 patients; relative risk [RR], 0.73; 95% confidence interval [CI], 0.46 to 1.16), hospitalization, or end-of-treatment serum calcium-phosphorus product levels with sevelamer compared with calcium-based agents. There was a significant decrease in end-of-treatment phosphorus and parathyroid hormone levels with calcium salts compared with sevelamer and a significant decrease in risk of hypercalcemia (RR, 0.47; 95% CI, 0.36 to 0.62) with sevelamer compared with calcium-based agents. There was a significant increase in risk of gastrointestinal adverse events with sevelamer in comparison to calcium salts (RR, 1.39; 95% CI, 1.04 to 1.87). Compared with calcium-based agents, lanthanum significantly decreased end-of-treatment serum calcium and calcium-phosphorus product levels, but with similar end-of-treatment phosphorus levels. Effects of calcium acetate on biochemical end points were similar to those of calcium carbonate. Existing data are insufficient to conclude for a differential impact of any phosphate binder on cardiovascular mortality or other patient-level outcome.
Limitations: Few long-term studies of the efficacy of phosphate binders on mortality and musculoskeletal morbidity, significant heterogeneity for many surrogate outcomes, and suboptimal reporting of study methods to determine trial quality.
Conclusion: Currently, there are insufficient data to establish the comparative superiority of non–calcium-binding agents over calcium-containing phosphate binders for such important patient-level outcomes as all-cause mortality and cardiovascular end points. Additional trials are still required to examine the differential effects of phosphate-binding agents on these end points and the mineral homeostasis pathway.
The incidence of chronic kidney disease (CKD) is increasing worldwide, with about $23 billion (6.6% of the Medicare budget) spent on the care of patients with end-stage renal disease in 2006 in the United States alone. Worsening kidney function results in impaired clearance of the dietary phosphorus load, which directly and indirectly increases parathyroid hormone (PTH) secretion. Secondary hyperparathyroidism is characterized by high bone turnover, exaggerated marrow fibrosis, and increased musculoskeletal morbidity. Recently, epidemiological data have shifted the focus of altered mineral metabolism in CKD from renal bone disease to a broader recognition that hyperphosphatemia is associated with increased morbidity, mortality, and hospitalization; reduced quality of life; and increased costs of care.
Cardiovascular disease accounts for more than half the deaths in dialysis patients, and the development of vascular calcification of the arterial media has been advocated as a major contributing factor. Because abnormalities in mineral metabolism involve a paradigm incorporating bone disease and vascular and soft-tissue calcification that have potential effects on fracture, cardiovascular outcomes, and mortality, the concept of CKD-mineral and bone disorder has been introduced. This condition is the target of several interventions, including phosphate binders, vitamin D analogues, and calcimimetics, all of which may suppress the development or progression of CKD-mineral and bone disorder.
Phosphate binders containing aluminum and calcium have been used widely since 1970, and the non–calcium- or aluminum-based agents, sevelamer hydrochloride and lanthanum carbonate, more recently have become available. Their use is increasing in current practice, and although they are more expensive, the potential decrease in risk of vascular calcification and toxicity advocates for broader adoption. For control of hyperphosphatemia, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) recommends the use of calcium-based binders in patients with CKD stages 3 and 4 (glomerular filtration rate, 30 to 59 and 15 to 29 mL/min/1.73 m, respectively) and both calcium-based and calcium- and aluminum-free binders in patients with CKD stages 5 and 5D (glomerular filtration rate < 15 mL/min/1.73 m and dialysis). The relative merits of available phosphate-binding agents are controversial. We have conducted a systematic review of the benefits and harms of phosphate binders compared with calcium salts or placebo to determine whether newer agents deliver improved biochemical and patient-level outcomes, with particular reference to musculoskeletal and cardiovascular morbidity, hospitalization, and mortality.
Abstract and Introduction
Abstract
Background: Phosphate binders are widely used to control serum phosphorus levels in patients with chronic kidney disease (CKD). We analyzed the effects of phosphate binders on biochemical and patient-level end points in patients with CKD.
Study Design: Systematic review and meta-analysis by searching MEDLINE (1966 to April 2009), EMBASE (1980 to April 2009), and the Cochrane Renal Group Specialised Register and the Cochrane Central Register of Controlled Trials (CENTRAL).
Setting & Population: Patients with CKD.
Selection Criteria for Studies: Randomized controlled trials.
Intervention: Phosphate binders.
Outcomes: Serum phosphorus, calcium, and parathyroid hormone levels; incidence of hypercalcemia; all-cause mortality; adverse effects.
Results: 40 trials (6,406 patients) were included. There was no significant decrease in all-cause mortality (10 randomized controlled trials; 3,079 patients; relative risk [RR], 0.73; 95% confidence interval [CI], 0.46 to 1.16), hospitalization, or end-of-treatment serum calcium-phosphorus product levels with sevelamer compared with calcium-based agents. There was a significant decrease in end-of-treatment phosphorus and parathyroid hormone levels with calcium salts compared with sevelamer and a significant decrease in risk of hypercalcemia (RR, 0.47; 95% CI, 0.36 to 0.62) with sevelamer compared with calcium-based agents. There was a significant increase in risk of gastrointestinal adverse events with sevelamer in comparison to calcium salts (RR, 1.39; 95% CI, 1.04 to 1.87). Compared with calcium-based agents, lanthanum significantly decreased end-of-treatment serum calcium and calcium-phosphorus product levels, but with similar end-of-treatment phosphorus levels. Effects of calcium acetate on biochemical end points were similar to those of calcium carbonate. Existing data are insufficient to conclude for a differential impact of any phosphate binder on cardiovascular mortality or other patient-level outcome.
Limitations: Few long-term studies of the efficacy of phosphate binders on mortality and musculoskeletal morbidity, significant heterogeneity for many surrogate outcomes, and suboptimal reporting of study methods to determine trial quality.
Conclusion: Currently, there are insufficient data to establish the comparative superiority of non–calcium-binding agents over calcium-containing phosphate binders for such important patient-level outcomes as all-cause mortality and cardiovascular end points. Additional trials are still required to examine the differential effects of phosphate-binding agents on these end points and the mineral homeostasis pathway.
Introduction
The incidence of chronic kidney disease (CKD) is increasing worldwide, with about $23 billion (6.6% of the Medicare budget) spent on the care of patients with end-stage renal disease in 2006 in the United States alone. Worsening kidney function results in impaired clearance of the dietary phosphorus load, which directly and indirectly increases parathyroid hormone (PTH) secretion. Secondary hyperparathyroidism is characterized by high bone turnover, exaggerated marrow fibrosis, and increased musculoskeletal morbidity. Recently, epidemiological data have shifted the focus of altered mineral metabolism in CKD from renal bone disease to a broader recognition that hyperphosphatemia is associated with increased morbidity, mortality, and hospitalization; reduced quality of life; and increased costs of care.
Cardiovascular disease accounts for more than half the deaths in dialysis patients, and the development of vascular calcification of the arterial media has been advocated as a major contributing factor. Because abnormalities in mineral metabolism involve a paradigm incorporating bone disease and vascular and soft-tissue calcification that have potential effects on fracture, cardiovascular outcomes, and mortality, the concept of CKD-mineral and bone disorder has been introduced. This condition is the target of several interventions, including phosphate binders, vitamin D analogues, and calcimimetics, all of which may suppress the development or progression of CKD-mineral and bone disorder.
Phosphate binders containing aluminum and calcium have been used widely since 1970, and the non–calcium- or aluminum-based agents, sevelamer hydrochloride and lanthanum carbonate, more recently have become available. Their use is increasing in current practice, and although they are more expensive, the potential decrease in risk of vascular calcification and toxicity advocates for broader adoption. For control of hyperphosphatemia, the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) recommends the use of calcium-based binders in patients with CKD stages 3 and 4 (glomerular filtration rate, 30 to 59 and 15 to 29 mL/min/1.73 m, respectively) and both calcium-based and calcium- and aluminum-free binders in patients with CKD stages 5 and 5D (glomerular filtration rate < 15 mL/min/1.73 m and dialysis). The relative merits of available phosphate-binding agents are controversial. We have conducted a systematic review of the benefits and harms of phosphate binders compared with calcium salts or placebo to determine whether newer agents deliver improved biochemical and patient-level outcomes, with particular reference to musculoskeletal and cardiovascular morbidity, hospitalization, and mortality.
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