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Glenn M Chertow - One of the best experts on this subject based on the ideXlab platform.

  • a randomized trial of tenapanor and Phosphate Binders as a dual mechanism treatment for hyperPhosphatemia in patients on maintenance dialysis amplify
    Journal of The American Society of Nephrology, 2021
    Co-Authors: Pablo E Pergola, David P Rosenbaum, Yang Yang, Glenn M Chertow
    Abstract:

    BACKGROUND HyperPhosphatemia is associated with cardiovascular morbidity and mortality in patients receiving maintenance dialysis. It is unknown whether combining two therapies with different mechanisms of action-tenapanor, an inhibitor of paracellular Phosphate absorption, and Phosphate Binders-is safe and effective for the management of hyperPhosphatemia in patients receiving maintenance dialysis. METHODS This double-blind phase 3 trial enrolled 236 patients undergoing maintenance dialysis with hyperPhosphatemia (defined in this trial as serum phosphorus 5.5-10 mg/dl inclusive) despite receiving Phosphate binder therapy (sevelamer, nonsevelamer, sevelamer plus nonsevelamer, or multiple nonsevelamer Binders). These participants were randomly assigned to receive oral tenapanor 30 mg twice daily or placebo for 4 weeks. The primary efficacy end point was the change in serum phosphorus concentration from baseline to week 4. RESULTS Of the 236 randomized patients, 235 (99.6%) were included in the full analysis set; this included 116 in the tenapanor plus binder group and 119 in the placebo plus binder group. A total of 228 patients (96.6%) completed the 4-week treatment period. In the full analysis set (mean age 54.5 years, 40.9% women), patients treated with tenapanor plus binder achieved a larger mean change in serum phosphorus concentration from baseline to week 4 compared with placebo plus binder (-0.84 versus -0.19 mg/dl, P<0.001). Diarrhea was the most commonly reported adverse event, resulting in study drug discontinuation in four of 119 (3.4%) and two of 116 (1.7%) patients receiving tenapanor plus binder or placebo plus binder, respectively. CONCLUSIONS A dual-mechanism treatment using both tenapanor and Phosphate Binders improved control of hyperPhosphatemia in patients undergoing maintenance dialysis compared with Phosphate Binders alone. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER AMPLIFY, NCT03824587.

  • differential effects of Phosphate Binders on vitamin d metabolism in chronic kidney disease
    Nephrology Dialysis Transplantation, 2020
    Co-Authors: Charles Ginsberg, Bryan Kestenbaum, Geoffrey A Block, Andrew N Hoofnagle, Leila R Zelnick, Glenn M Chertow, Michel Chonchol, Ian H De Boer
    Abstract:

    BACKGROUND Phosphate Binders are commonly used in the treatment of patients with hyperPhosphatemia. While Phosphate Binders are used to lower Phosphate, the effects of specific Phosphate binder types on vitamin D metabolism are unknown. METHODS We performed a secondary analysis of the Phosphate Normalization Trial in which patients with moderate to advanced chronic kidney disease were randomized to receive either placebo, sevelamer carbonate, lanthanum carbonate or calcium acetate for 9 months. We evaluated changes in serum concentrations of vitamin D metabolites including 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the ratio of 24,25(OH)2D3 to 25-hydroxyvitamin D [the vitamin D metabolite ratio (VMR)] and the ratio of serum 1,25(OH)2D to 25-hydroxyvitamin D. RESULTS Compared with placebo, randomization to the calcium acetate arm was associated with a 0.6 ng/mL (95% CI 0.2, 1) and 13.5 pg/ng (95% CI 5.5, 21.5) increase in 24,25(OH)2D and VMR, respectively, and a 5.2 pg/mL (95% CI 1.1, 9.4) reduction in 1,25(OH)2D. Randomization to sevelamer carbonate was associated with a 0.5 ng/mL (95% CI -0.9, -0.1) and 11.8 pg/ng (95% CI -20, -3.5) reduction in 24,25(OH)2D3 and VMR, respectively. There was no association of the sevelamer arm with the change in 1,25(OH)2D3, and randomization to lanthanum carbonate was not associated with a change in any of the vitamin D metabolites. CONCLUSION Administration of different Phosphate Binders to patients with moderate to severe CKD results in unique changes in vitamin D metabolism.

  • The case against calcium-based Phosphate Binders.
    Clinical Journal of The American Society of Nephrology, 2006
    Co-Authors: Glenn M Chertow
    Abstract:

    Disturbances of mineral metabolism are associated with significant morbidity and mortality in patients with chronic kidney disease. Unfortunately, some of the treatments for these disturbances also have been found to be associated with morbidity. More recently, there is increasing evidence in the form of prospective, randomized trials that the use of calcium-based Phosphate Binders contributes to progressive coronary artery and aorta calcification compared with the non–calcium-containing binder sevelamer. Moreover, there is compelling biologic plausibility that hyperPhosphatemia and excess exogenous calcium administration can accelerate vascular calcification. Unfortunately, there is no bedside test that can determine whether there is a dose of calcium salts (either as maintenance or as cumulative dose) that can be administered safely, and, unfortunately, the serum calcium concentration does not reflect calcium balance. Therefore, calcium-based Phosphate Binders should be avoided in many, if not most, patients who are undergoing dialysis.

  • effects of sevelamer and calcium based Phosphate Binders on uric acid concentrations in patients undergoing hemodialysis a randomized clinical trial
    Arthritis & Rheumatism, 2005
    Co-Authors: Jay Garg, Paolo Raggi, Scott Chasantaber, Andrew T Blair, Melissa Plone, Juergen Bommer, Glenn M Chertow
    Abstract:

    Objective Gout affects a large fraction of persons with advanced chronic kidney disease, and hyperuricemia may increase the risk of cardiovascular disease. Several hypouricemic agents are contraindicated in patients with end-stage renal disease. Sevelamer is a nonabsorbed hydrogel that binds phosphorus and bile acids in the intestinal tract. Results of short-term and open-label studies suggest that sevelamer might lower the concentration of uric acid, another organic anion. We undertook this study to test our hypothesis that the reduction in serum uric acid concentration induced by sevelamer would be confirmed in a long-term, randomized, clinical trial comparing sevelamer with calcium-based Phosphate Binders. Methods Two hundred subjects undergoing maintenance hemodialysis were randomly assigned to receive either sevelamer or calcium-based phosphorus Binders in an international, multicenter, clinical trial. Data on baseline and end-of-study uric acid concentrations were available in 169 subjects (85%); the change in uric acid concentration from baseline to the end of the study was the outcome of interest. Results Baseline clinical characteristics, including mean uric acid concentrations, were similar in subjects randomly assigned to receive sevelamer and calcium-based Phosphate Binders. The mean change in uric acid concentration (from baseline to the end of the study) was significantly larger in sevelamer-treated subjects (−0.64 mg/dl versus −0.26 mg/dl; P = 0.03). The adjusted mean change in uric acid concentration was more pronounced when the effects of age, sex, diabetes, vintage (time since initiation of dialysis), dialysis dose, and changes in blood urea nitrogen and bicarbonate concentrations were considered (−0.72 mg/dl versus −0.15 mg/dl; P = 0.001). Twenty-three percent of sevelamer-treated subjects experienced a study-related reduction in the concentration of uric acid equal to −1.5 mg/dl or more, compared with 10% of calcium-treated subjects (P = 0.02). Conclusion In a randomized clinical trial comparing sevelamer and calcium-based Phosphate Binders, treatment with sevelamer was associated with a significant reduction in serum uric acid concentrations.

  • decrease in thoracic vertebral bone attenuation with calcium based Phosphate Binders in hemodialysis
    Journal of Bone and Mineral Research, 2004
    Co-Authors: Paolo Raggi, George James, Steven K Burke, Jurgen Bommer, Scott Chasantaber, Herwig Holzer, Johan Braun, Glenn M Chertow
    Abstract:

    We performed a posthoc 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 posthoc 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 × 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.

Giovanni F M Strippoli - One of the best experts on this subject based on the ideXlab platform.

  • Phosphate Binders for preventing and treating chronic kidney disease mineral and bone disorder ckd mbd
    Cochrane Database of Systematic Reviews, 2018
    Co-Authors: Marinella Ruospo, Grahame J Elder, Suetonia C Palmer, Patrizia Natale, Jonathan C Craig, Mariacristina Vecchio, Giovanni F M Strippoli
    Abstract:

    BACKGROUND Phosphate Binders are used to reduce positive Phosphate balance and to lower serum Phosphate levels for people with chronic kidney disease (CKD) with the aim to prevent progression of chronic kidney disease-mineral and bone disorder (CKD-MBD). This is an update of a review first published in 2011. OBJECTIVES The aim of this review was to assess the benefits and harms of Phosphate Binders for people with CKD with particular reference to relevant biochemical end-points, musculoskeletal and cardiovascular morbidity, hospitalisation, and death. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 12 July 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) or quasi-RCTs of adults with CKD of any GFR category comparing a Phosphate binder to another Phosphate binder, placebo or usual care to lower serum Phosphate. Outcomes included all-cause and cardiovascular death, myocardial infarction, stroke, adverse events, vascular calcification and bone fracture, and surrogates for such outcomes including serum Phosphate, parathyroid hormone (PTH), and FGF23. DATA COLLECTION AND ANALYSIS Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of Bias' tool and used the GRADE process to assess evidence certainty. We estimated treatment effects using random-effects meta-analysis. Results were expressed as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) or standardised MD (SMD) for continuous outcomes. MAIN RESULTS We included 104 studies involving 13,744 adults. Sixty-nine new studies were added to this 2018 update.Most placebo or usual care controlled studies were among participants with CKD G2 to G5 not requiring dialysis (15/25 studies involving 1467 participants) while most head to head studies involved participants with CKD G5D treated with dialysis (74/81 studies involving 10,364 participants). Overall, seven studies compared sevelamer with placebo or usual care (667 participants), seven compared lanthanum to placebo or usual care (515 participants), three compared iron to placebo or usual care (422 participants), and four compared calcium to placebo or usual care (278 participants). Thirty studies compared sevelamer to calcium (5424 participants), and fourteen studies compared lanthanum to calcium (1690 participants). No study compared iron-based Binders to calcium. The remaining studies evaluated comparisons between sevelamer (hydrochloride or carbonate), sevelamer plus calcium, lanthanum, iron (ferric citrate, sucroferric oxyhydroxide, stabilised polynuclear iron(III)-oxyhydroxide), calcium (acetate, ketoglutarate, carbonate), bixalomer, colestilan, magnesium (carbonate), magnesium plus calcium, aluminium hydroxide, sucralfate, the inhibitor of Phosphate absorption nicotinamide, placebo, or usual care without binder. In 82 studies, treatment was evaluated among adults with CKD G5D treated with haemodialysis or peritoneal dialysis, while in 22 studies, treatment was evaluated among participants with CKD G2 to G5. The duration of study follow-up ranged from 8 weeks to 36 months (median 3.7 months). The sample size ranged from 8 to 2103 participants (median 69). The mean age ranged between 42.6 and 68.9 years.Random sequence generation and allocation concealment were low risk in 25 and 15 studies, respectively. Twenty-seven studies reported low risk methods for blinding of participants, investigators, and outcome assessors. Thirty-one studies were at low risk of attrition bias and 69 studies were at low risk of selective reporting bias.In CKD G2 to G5, compared with placebo or usual care, sevelamer, lanthanum, iron and calcium-based Phosphate Binders had uncertain or inestimable effects on death (all causes), cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. Sevelamer may lead to constipation (RR 6.92, CI 2.24 to 21.4; low certainty) and lanthanum (RR 2.98, CI 1.21 to 7.30, moderate certainty) and iron-based Binders (RR 2.66, CI 1.15 to 6.12, moderate certainty) probably increased constipation compared with placebo or usual care. Lanthanum may result in vomiting (RR 3.72, CI 1.36 to 10.18, low certainty). Iron-based Binders probably result in diarrhoea (RR 2.81, CI 1.18 to 6.68, high certainty), while the risks of other adverse events for all Binders were uncertain.In CKD G5D sevelamer may lead to lower death (all causes) (RR 0.53, CI 0.30 to 0.91, low certainty) and induce less hypercalcaemia (RR 0.30, CI 0.20 to 0.43, low certainty) when compared with calcium-based Binders, and has uncertain or inestimable effects on cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. The finding of lower death with sevelamer compared with calcium was present when the analysis was restricted to studies at low risk of bias (RR 0.50, CI 0.32 to 0.77). In absolute terms, sevelamer may lower risk of death (all causes) from 210 per 1000 to 105 per 1000 over a follow-up of up to 36 months, compared to calcium-based Binders. Compared with calcium-based Binders, lanthanum had uncertain effects with respect to all-cause or cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification and probably had reduced risks of treatment-related hypercalcaemia (RR 0.16, CI 0.06 to 0.43, low certainty). There were no head-to-head studies of iron-based Binders compared with calcium. The paucity of placebo-controlled studies in CKD G5D has led to uncertainty about the effects of Phosphate Binders on patient-important outcomes compared with placebo.It is uncertain whether the effects of Binders on clinically-relevant outcomes were different for patients who were and were not treated with dialysis in subgroup analyses. AUTHORS' CONCLUSIONS In studies of adults with CKD G5D treated with dialysis, sevelamer may lower death (all causes) compared to calcium-based Binders and incur less treatment-related hypercalcaemia, while we found no clinically important benefits of any Phosphate binder on cardiovascular death, myocardial infarction, stroke, fracture or coronary artery calcification. The effects of Binders on patient-important outcomes compared to placebo are uncertain. In patients with CKD G2 to G5, the effects of sevelamer, lanthanum, and iron-based Phosphate Binders on cardiovascular, vascular calcification, and bone outcomes compared to placebo or usual care, are also uncertain and they may incur constipation, while iron-based Binders may lead to diarrhoea.

  • Phosphate Binders for preventing and treating bone disease in chronic kidney disease patients
    Cochrane Database of Systematic Reviews, 2011
    Co-Authors: Sankar D Navaneethan, Grahame J Elder, Suetonia C Palmer, Jonathan C Craig, Mariacristina Vecchio, Giovanni F M Strippoli
    Abstract:

    Background Phosphate Binders are widely used to lower serum phosphorus levels in people with chronic kidney disease (CKD) but their impact in CKD remains controversial. Objectives To review the effects of various Phosphate Binders on biochemical and patient-level end-points in CKD stages 3 to 5D. Search methods In March 2010 we searched MEDLINE, EMBASE, the Cochrane Renal Group's Specialised Register and CENTRAL for relevant studies. Selection criteria Randomised controlled trials (RCTs) or quasi-RCTs that assessed the effects of various Phosphate Binders in adults with CKD. Data collection and analysis Two authors independently reviewed search results and extracted data. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using a random-effects model. Main results Sixty studies (7631 participants) were included. There was no significant reduction in all-cause mortality (10 studies, 3079 participants: RR 0.73, 95% CI 0.46 to 1.16), or serum calcium by phosphorus (Ca x P) product with sevelamer hydrochloride compared to calcium-based agents. There was a significant reduction in serum phosphorus (16 studies, 3126 participants: MD 0.23 mg/dL, 95% CI 0.04 to 0.42) and parathyroid hormone (PTH) (12 studies, 2551 participants; MD 56 pg/mL, 95% CI 26 to 84) but a significant increase in the risk of hypercalcaemia (12 studies, 1144 participants: RR 0.45, 95% CI 0.35 to 0.59) with calcium-based agents compared to sevelamer hydrochloride. There was a significant increase in the risk of adverse gastrointestinal events with sevelamer hydrochloride in comparison to calcium salts (5 studies, 498 participants: RR 1.58, 95% CI 1.11 to 2.25). Compared with calcium-based agents, lanthanum significantly reduced serum calcium (2 studies, 122 participants: MD -0.30 mg/dL, 95% CI -0.64 to -0.25) and the Ca x P product, but not serum phosphorus levels. The effects of calcium acetate on biochemical end-points were similar to those of calcium carbonate. The phosphorus lowering effects of novel agents such as ferric citrate, colestilan and niacinamide were only reported in a few studies. Authors' conclusions Available Phosphate-binding agents have been shown to reduce phosphorus levels in comparison to placebo. However, there are insufficient data to establish the comparative superiority of novel non-calcium binding agents over calcium-containing Phosphate Binders for patient-level outcomes such as all-cause mortality and cardiovascular end-points in CKD.

  • benefits and harms of Phosphate Binders in ckd a systematic review of randomized controlled trials
    American Journal of Kidney Diseases, 2009
    Co-Authors: Sankar D Navaneethan, Grahame J Elder, Suetonia C Palmer, Jonathan C Craig, Giovanni F M Strippoli
    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.

Grahame J Elder - One of the best experts on this subject based on the ideXlab platform.

  • Phosphate Binders for preventing and treating chronic kidney disease mineral and bone disorder ckd mbd
    Cochrane Database of Systematic Reviews, 2018
    Co-Authors: Marinella Ruospo, Grahame J Elder, Suetonia C Palmer, Patrizia Natale, Jonathan C Craig, Mariacristina Vecchio, Giovanni F M Strippoli
    Abstract:

    BACKGROUND Phosphate Binders are used to reduce positive Phosphate balance and to lower serum Phosphate levels for people with chronic kidney disease (CKD) with the aim to prevent progression of chronic kidney disease-mineral and bone disorder (CKD-MBD). This is an update of a review first published in 2011. OBJECTIVES The aim of this review was to assess the benefits and harms of Phosphate Binders for people with CKD with particular reference to relevant biochemical end-points, musculoskeletal and cardiovascular morbidity, hospitalisation, and death. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 12 July 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) or quasi-RCTs of adults with CKD of any GFR category comparing a Phosphate binder to another Phosphate binder, placebo or usual care to lower serum Phosphate. Outcomes included all-cause and cardiovascular death, myocardial infarction, stroke, adverse events, vascular calcification and bone fracture, and surrogates for such outcomes including serum Phosphate, parathyroid hormone (PTH), and FGF23. DATA COLLECTION AND ANALYSIS Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of Bias' tool and used the GRADE process to assess evidence certainty. We estimated treatment effects using random-effects meta-analysis. Results were expressed as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) or standardised MD (SMD) for continuous outcomes. MAIN RESULTS We included 104 studies involving 13,744 adults. Sixty-nine new studies were added to this 2018 update.Most placebo or usual care controlled studies were among participants with CKD G2 to G5 not requiring dialysis (15/25 studies involving 1467 participants) while most head to head studies involved participants with CKD G5D treated with dialysis (74/81 studies involving 10,364 participants). Overall, seven studies compared sevelamer with placebo or usual care (667 participants), seven compared lanthanum to placebo or usual care (515 participants), three compared iron to placebo or usual care (422 participants), and four compared calcium to placebo or usual care (278 participants). Thirty studies compared sevelamer to calcium (5424 participants), and fourteen studies compared lanthanum to calcium (1690 participants). No study compared iron-based Binders to calcium. The remaining studies evaluated comparisons between sevelamer (hydrochloride or carbonate), sevelamer plus calcium, lanthanum, iron (ferric citrate, sucroferric oxyhydroxide, stabilised polynuclear iron(III)-oxyhydroxide), calcium (acetate, ketoglutarate, carbonate), bixalomer, colestilan, magnesium (carbonate), magnesium plus calcium, aluminium hydroxide, sucralfate, the inhibitor of Phosphate absorption nicotinamide, placebo, or usual care without binder. In 82 studies, treatment was evaluated among adults with CKD G5D treated with haemodialysis or peritoneal dialysis, while in 22 studies, treatment was evaluated among participants with CKD G2 to G5. The duration of study follow-up ranged from 8 weeks to 36 months (median 3.7 months). The sample size ranged from 8 to 2103 participants (median 69). The mean age ranged between 42.6 and 68.9 years.Random sequence generation and allocation concealment were low risk in 25 and 15 studies, respectively. Twenty-seven studies reported low risk methods for blinding of participants, investigators, and outcome assessors. Thirty-one studies were at low risk of attrition bias and 69 studies were at low risk of selective reporting bias.In CKD G2 to G5, compared with placebo or usual care, sevelamer, lanthanum, iron and calcium-based Phosphate Binders had uncertain or inestimable effects on death (all causes), cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. Sevelamer may lead to constipation (RR 6.92, CI 2.24 to 21.4; low certainty) and lanthanum (RR 2.98, CI 1.21 to 7.30, moderate certainty) and iron-based Binders (RR 2.66, CI 1.15 to 6.12, moderate certainty) probably increased constipation compared with placebo or usual care. Lanthanum may result in vomiting (RR 3.72, CI 1.36 to 10.18, low certainty). Iron-based Binders probably result in diarrhoea (RR 2.81, CI 1.18 to 6.68, high certainty), while the risks of other adverse events for all Binders were uncertain.In CKD G5D sevelamer may lead to lower death (all causes) (RR 0.53, CI 0.30 to 0.91, low certainty) and induce less hypercalcaemia (RR 0.30, CI 0.20 to 0.43, low certainty) when compared with calcium-based Binders, and has uncertain or inestimable effects on cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. The finding of lower death with sevelamer compared with calcium was present when the analysis was restricted to studies at low risk of bias (RR 0.50, CI 0.32 to 0.77). In absolute terms, sevelamer may lower risk of death (all causes) from 210 per 1000 to 105 per 1000 over a follow-up of up to 36 months, compared to calcium-based Binders. Compared with calcium-based Binders, lanthanum had uncertain effects with respect to all-cause or cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification and probably had reduced risks of treatment-related hypercalcaemia (RR 0.16, CI 0.06 to 0.43, low certainty). There were no head-to-head studies of iron-based Binders compared with calcium. The paucity of placebo-controlled studies in CKD G5D has led to uncertainty about the effects of Phosphate Binders on patient-important outcomes compared with placebo.It is uncertain whether the effects of Binders on clinically-relevant outcomes were different for patients who were and were not treated with dialysis in subgroup analyses. AUTHORS' CONCLUSIONS In studies of adults with CKD G5D treated with dialysis, sevelamer may lower death (all causes) compared to calcium-based Binders and incur less treatment-related hypercalcaemia, while we found no clinically important benefits of any Phosphate binder on cardiovascular death, myocardial infarction, stroke, fracture or coronary artery calcification. The effects of Binders on patient-important outcomes compared to placebo are uncertain. In patients with CKD G2 to G5, the effects of sevelamer, lanthanum, and iron-based Phosphate Binders on cardiovascular, vascular calcification, and bone outcomes compared to placebo or usual care, are also uncertain and they may incur constipation, while iron-based Binders may lead to diarrhoea.

  • Phosphate Binders for preventing and treating bone disease in chronic kidney disease patients
    Cochrane Database of Systematic Reviews, 2011
    Co-Authors: Sankar D Navaneethan, Grahame J Elder, Suetonia C Palmer, Jonathan C Craig, Mariacristina Vecchio, Giovanni F M Strippoli
    Abstract:

    Background Phosphate Binders are widely used to lower serum phosphorus levels in people with chronic kidney disease (CKD) but their impact in CKD remains controversial. Objectives To review the effects of various Phosphate Binders on biochemical and patient-level end-points in CKD stages 3 to 5D. Search methods In March 2010 we searched MEDLINE, EMBASE, the Cochrane Renal Group's Specialised Register and CENTRAL for relevant studies. Selection criteria Randomised controlled trials (RCTs) or quasi-RCTs that assessed the effects of various Phosphate Binders in adults with CKD. Data collection and analysis Two authors independently reviewed search results and extracted data. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using a random-effects model. Main results Sixty studies (7631 participants) were included. There was no significant reduction in all-cause mortality (10 studies, 3079 participants: RR 0.73, 95% CI 0.46 to 1.16), or serum calcium by phosphorus (Ca x P) product with sevelamer hydrochloride compared to calcium-based agents. There was a significant reduction in serum phosphorus (16 studies, 3126 participants: MD 0.23 mg/dL, 95% CI 0.04 to 0.42) and parathyroid hormone (PTH) (12 studies, 2551 participants; MD 56 pg/mL, 95% CI 26 to 84) but a significant increase in the risk of hypercalcaemia (12 studies, 1144 participants: RR 0.45, 95% CI 0.35 to 0.59) with calcium-based agents compared to sevelamer hydrochloride. There was a significant increase in the risk of adverse gastrointestinal events with sevelamer hydrochloride in comparison to calcium salts (5 studies, 498 participants: RR 1.58, 95% CI 1.11 to 2.25). Compared with calcium-based agents, lanthanum significantly reduced serum calcium (2 studies, 122 participants: MD -0.30 mg/dL, 95% CI -0.64 to -0.25) and the Ca x P product, but not serum phosphorus levels. The effects of calcium acetate on biochemical end-points were similar to those of calcium carbonate. The phosphorus lowering effects of novel agents such as ferric citrate, colestilan and niacinamide were only reported in a few studies. Authors' conclusions Available Phosphate-binding agents have been shown to reduce phosphorus levels in comparison to placebo. However, there are insufficient data to establish the comparative superiority of novel non-calcium binding agents over calcium-containing Phosphate Binders for patient-level outcomes such as all-cause mortality and cardiovascular end-points in CKD.

  • benefits and harms of Phosphate Binders in ckd a systematic review of randomized controlled trials
    American Journal of Kidney Diseases, 2009
    Co-Authors: Sankar D Navaneethan, Grahame J Elder, Suetonia C Palmer, Jonathan C Craig, Giovanni F M Strippoli
    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.

Jonathan C Craig - One of the best experts on this subject based on the ideXlab platform.

  • Phosphate Binders for preventing and treating chronic kidney disease mineral and bone disorder ckd mbd
    Cochrane Database of Systematic Reviews, 2018
    Co-Authors: Marinella Ruospo, Grahame J Elder, Suetonia C Palmer, Patrizia Natale, Jonathan C Craig, Mariacristina Vecchio, Giovanni F M Strippoli
    Abstract:

    BACKGROUND Phosphate Binders are used to reduce positive Phosphate balance and to lower serum Phosphate levels for people with chronic kidney disease (CKD) with the aim to prevent progression of chronic kidney disease-mineral and bone disorder (CKD-MBD). This is an update of a review first published in 2011. OBJECTIVES The aim of this review was to assess the benefits and harms of Phosphate Binders for people with CKD with particular reference to relevant biochemical end-points, musculoskeletal and cardiovascular morbidity, hospitalisation, and death. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 12 July 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) or quasi-RCTs of adults with CKD of any GFR category comparing a Phosphate binder to another Phosphate binder, placebo or usual care to lower serum Phosphate. Outcomes included all-cause and cardiovascular death, myocardial infarction, stroke, adverse events, vascular calcification and bone fracture, and surrogates for such outcomes including serum Phosphate, parathyroid hormone (PTH), and FGF23. DATA COLLECTION AND ANALYSIS Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of Bias' tool and used the GRADE process to assess evidence certainty. We estimated treatment effects using random-effects meta-analysis. Results were expressed as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) or standardised MD (SMD) for continuous outcomes. MAIN RESULTS We included 104 studies involving 13,744 adults. Sixty-nine new studies were added to this 2018 update.Most placebo or usual care controlled studies were among participants with CKD G2 to G5 not requiring dialysis (15/25 studies involving 1467 participants) while most head to head studies involved participants with CKD G5D treated with dialysis (74/81 studies involving 10,364 participants). Overall, seven studies compared sevelamer with placebo or usual care (667 participants), seven compared lanthanum to placebo or usual care (515 participants), three compared iron to placebo or usual care (422 participants), and four compared calcium to placebo or usual care (278 participants). Thirty studies compared sevelamer to calcium (5424 participants), and fourteen studies compared lanthanum to calcium (1690 participants). No study compared iron-based Binders to calcium. The remaining studies evaluated comparisons between sevelamer (hydrochloride or carbonate), sevelamer plus calcium, lanthanum, iron (ferric citrate, sucroferric oxyhydroxide, stabilised polynuclear iron(III)-oxyhydroxide), calcium (acetate, ketoglutarate, carbonate), bixalomer, colestilan, magnesium (carbonate), magnesium plus calcium, aluminium hydroxide, sucralfate, the inhibitor of Phosphate absorption nicotinamide, placebo, or usual care without binder. In 82 studies, treatment was evaluated among adults with CKD G5D treated with haemodialysis or peritoneal dialysis, while in 22 studies, treatment was evaluated among participants with CKD G2 to G5. The duration of study follow-up ranged from 8 weeks to 36 months (median 3.7 months). The sample size ranged from 8 to 2103 participants (median 69). The mean age ranged between 42.6 and 68.9 years.Random sequence generation and allocation concealment were low risk in 25 and 15 studies, respectively. Twenty-seven studies reported low risk methods for blinding of participants, investigators, and outcome assessors. Thirty-one studies were at low risk of attrition bias and 69 studies were at low risk of selective reporting bias.In CKD G2 to G5, compared with placebo or usual care, sevelamer, lanthanum, iron and calcium-based Phosphate Binders had uncertain or inestimable effects on death (all causes), cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. Sevelamer may lead to constipation (RR 6.92, CI 2.24 to 21.4; low certainty) and lanthanum (RR 2.98, CI 1.21 to 7.30, moderate certainty) and iron-based Binders (RR 2.66, CI 1.15 to 6.12, moderate certainty) probably increased constipation compared with placebo or usual care. Lanthanum may result in vomiting (RR 3.72, CI 1.36 to 10.18, low certainty). Iron-based Binders probably result in diarrhoea (RR 2.81, CI 1.18 to 6.68, high certainty), while the risks of other adverse events for all Binders were uncertain.In CKD G5D sevelamer may lead to lower death (all causes) (RR 0.53, CI 0.30 to 0.91, low certainty) and induce less hypercalcaemia (RR 0.30, CI 0.20 to 0.43, low certainty) when compared with calcium-based Binders, and has uncertain or inestimable effects on cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. The finding of lower death with sevelamer compared with calcium was present when the analysis was restricted to studies at low risk of bias (RR 0.50, CI 0.32 to 0.77). In absolute terms, sevelamer may lower risk of death (all causes) from 210 per 1000 to 105 per 1000 over a follow-up of up to 36 months, compared to calcium-based Binders. Compared with calcium-based Binders, lanthanum had uncertain effects with respect to all-cause or cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification and probably had reduced risks of treatment-related hypercalcaemia (RR 0.16, CI 0.06 to 0.43, low certainty). There were no head-to-head studies of iron-based Binders compared with calcium. The paucity of placebo-controlled studies in CKD G5D has led to uncertainty about the effects of Phosphate Binders on patient-important outcomes compared with placebo.It is uncertain whether the effects of Binders on clinically-relevant outcomes were different for patients who were and were not treated with dialysis in subgroup analyses. AUTHORS' CONCLUSIONS In studies of adults with CKD G5D treated with dialysis, sevelamer may lower death (all causes) compared to calcium-based Binders and incur less treatment-related hypercalcaemia, while we found no clinically important benefits of any Phosphate binder on cardiovascular death, myocardial infarction, stroke, fracture or coronary artery calcification. The effects of Binders on patient-important outcomes compared to placebo are uncertain. In patients with CKD G2 to G5, the effects of sevelamer, lanthanum, and iron-based Phosphate Binders on cardiovascular, vascular calcification, and bone outcomes compared to placebo or usual care, are also uncertain and they may incur constipation, while iron-based Binders may lead to diarrhoea.

  • Phosphate Binders for preventing and treating bone disease in chronic kidney disease patients
    Cochrane Database of Systematic Reviews, 2011
    Co-Authors: Sankar D Navaneethan, Grahame J Elder, Suetonia C Palmer, Jonathan C Craig, Mariacristina Vecchio, Giovanni F M Strippoli
    Abstract:

    Background Phosphate Binders are widely used to lower serum phosphorus levels in people with chronic kidney disease (CKD) but their impact in CKD remains controversial. Objectives To review the effects of various Phosphate Binders on biochemical and patient-level end-points in CKD stages 3 to 5D. Search methods In March 2010 we searched MEDLINE, EMBASE, the Cochrane Renal Group's Specialised Register and CENTRAL for relevant studies. Selection criteria Randomised controlled trials (RCTs) or quasi-RCTs that assessed the effects of various Phosphate Binders in adults with CKD. Data collection and analysis Two authors independently reviewed search results and extracted data. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using a random-effects model. Main results Sixty studies (7631 participants) were included. There was no significant reduction in all-cause mortality (10 studies, 3079 participants: RR 0.73, 95% CI 0.46 to 1.16), or serum calcium by phosphorus (Ca x P) product with sevelamer hydrochloride compared to calcium-based agents. There was a significant reduction in serum phosphorus (16 studies, 3126 participants: MD 0.23 mg/dL, 95% CI 0.04 to 0.42) and parathyroid hormone (PTH) (12 studies, 2551 participants; MD 56 pg/mL, 95% CI 26 to 84) but a significant increase in the risk of hypercalcaemia (12 studies, 1144 participants: RR 0.45, 95% CI 0.35 to 0.59) with calcium-based agents compared to sevelamer hydrochloride. There was a significant increase in the risk of adverse gastrointestinal events with sevelamer hydrochloride in comparison to calcium salts (5 studies, 498 participants: RR 1.58, 95% CI 1.11 to 2.25). Compared with calcium-based agents, lanthanum significantly reduced serum calcium (2 studies, 122 participants: MD -0.30 mg/dL, 95% CI -0.64 to -0.25) and the Ca x P product, but not serum phosphorus levels. The effects of calcium acetate on biochemical end-points were similar to those of calcium carbonate. The phosphorus lowering effects of novel agents such as ferric citrate, colestilan and niacinamide were only reported in a few studies. Authors' conclusions Available Phosphate-binding agents have been shown to reduce phosphorus levels in comparison to placebo. However, there are insufficient data to establish the comparative superiority of novel non-calcium binding agents over calcium-containing Phosphate Binders for patient-level outcomes such as all-cause mortality and cardiovascular end-points in CKD.

  • benefits and harms of Phosphate Binders in ckd a systematic review of randomized controlled trials
    American Journal of Kidney Diseases, 2009
    Co-Authors: Sankar D Navaneethan, Grahame J Elder, Suetonia C Palmer, Jonathan C Craig, Giovanni F M Strippoli
    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.

Eli A. Friedman - One of the best experts on this subject based on the ideXlab platform.

  • Calcium-Based Phosphate Binders Are Appropriate in Chronic Renal Failure
    Clinical Journal of The American Society of Nephrology, 2006
    Co-Authors: Eli A. Friedman
    Abstract:

    Many nephrologists feel threatened by the allegation that, in patients with chronic renal failure, treatment with calcium-based Phosphate Binders (calcium acetate and calcium carbonate) may induce coronary artery and cardiac calcification, thereby imposing a greater risk for death compared with sevelamer, a non–calcium-based binder. Acknowledging that drug manufacturers are not unaware of the marketing advantage to their product consequent to destabilizing demand for competing drugs, the case for and against abandoning calcium-based Phosphate Binders in favor of sevelamer is reviewed in this study. The case for continuing prescription of calcium-based Phosphate Binders stands on the following: (1) flawed clinical trials that favor sevelamer as a replacement; (2) weak evidence that oral calcium intake modulates vascular and/or cardiac calcification; (3) clinical trials that reinforce the safety and efficacy of calcium-based Phosphate Binders; and (4) the inordinate relative cost of sevelamer. Recognizing that established as well as novel Phosphate Binders are currently undergoing clinical evaluation, an open mind and an awareness of developing literature are necessary when deciding how to manage hyperPhosphatemia in renal failure.

  • an introduction to Phosphate Binders for the treatment of hyperPhosphatemia in patients with chronic kidney disease
    Kidney International, 2005
    Co-Authors: Eli A. Friedman
    Abstract:

    An introduction to Phosphate Binders for the treatment of hyperPhosphatemia in patients with chronic kidney disease. Chronic kidney disease has the potential to induce sequelae that can have severe and mortal outcomes. In particular, impaired glomerular filtration can cause a hyperPhosphatemic state, which, if left unchecked, can lead to secondary hyperparathyroidism, vascular calcification, and renal osteodystrophy. Therapeutic management of hyperPhosphatemia must maintain both phosphorus and calcium serum concentrations within the recommended guidelines. The balance of both minerals is regulated by parathyroid hormone; thus, an imbalance of one affects the other. In end-stage renal disease, patients often present with hypocalcemic levels due to the kidneys' inability to generate active vitamin D to promote calcium absorption in the intestine. Absorption of calcium can be increased by the administration of active vitamin D analogues. Minimizing phosphorus intake through a strict dietary regimen, combined with the use of Phosphate Binders to absorb excess ingested Phosphate, can help to maintain serum Phosphate levels near the recommended concentration of 5.5 mg/dL. Phosphate-binding compounds have evolved from the original aluminum-based Binders pioneered in the 1970s to calcium-based Binders such as calcium acetate, and more recently, to the following additions to the nephrologist's armamentarium: sevelamer—a polyhydrochloride polymer, and lanthanum carbonate. One of the top 2 common clinical treatments for hyperPhosphatemia, calcium acetate, has an established history of efficacy since the 1980s, and has been shown to be cost effective and well tolerated, as well.