Long-term efficacy and safety of iron-based phosphate binders, ferric citrate hydrate and sucroferric oxyhydroxide, in hemodialysis patients
Tadashi YoshidaKohkichi MorimotoNoriko KaburagiTeppei FujinoTomoko TakemitsuNorimasa YamashitaMototsugu Oya
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Phosphate binder
Transferrin saturation
Nephrology
Hyperphosphatemia is recognized as a principal mineral disorder in chronic kidney disease (CKD) that leads to the development of secondary hyperparathyroidism. Recent data indicate that hyperphosphatemia is associated with accelerated cardiac calcification and increased mortality in patients with CKD. Control of serum phosphorus is accomplished with phosphate binder therapies that include calcium and aluminum salts. Recently, calcium-based binders have undergone reevaluation because of their association with cardiac calcification. The non-calcium, non-aluminum binder sevelamer hydrochloride has been associated with slower progression of cardiac calcification in clinical trials. Lanthanum carbonate is a newer phosphate binder with phosphate binding activity similar to aluminum salts making this agent a compelling alternative; however, more data are needed to evaluate long-term safety and effects on cardiovascular end points.
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Hyperphosphatemia is an inevitable consequence of end stage chronic kidney disease and is present in the majority of dialysis patients. Recent observational data has associated hyperphosphatemia with increased cardiovascular mortality among dialysis patients. Dietary restriction of phosphate and current dialysis prescription practices are not enough to maintain serum phosphate levels within the recommended range so that the majority of dialysis patients require oral phosphate binders. Unfortunately, conventional phosphate binders are not reliably effective and are associated with a range of limitations and side effects. Aluminium-containing agents are highly efficient but no longer widely used because of well established and proven toxicity. Calcium based salts are inexpensive, effective and most widely used but there is now concern about their association with hypercalcemia and vascular calcification. Sevelamer hydrochloride is associated with fewer adverse effects, but a large pill burden and high cost are limiting factors to its wider use. In addition, the efficacy of sevelamer as a monotherapy in lowering phosphate to target levels in severe hyperphosphatemia remains debatable. Lanthanum carbonate is a promising new non-aluminium, calcium-free phosphate binder. Preclinical and clinical studies have demonstrated a good safety profile, and it appears well tolerated and effective in reducing phosphate levels in dialysis patients. Its identified adverse events are apparently mild to moderate in severity and mostly GI related. It appears to be effective as a monotherapy, with a reduced pill burden, but like sevelamer, it is significantly more expensive than calcium-based binders. Data on its safety profile over 6 years of treatment are now available.
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Management of hyperphosphatemia in patients with end-stage renal disease: focus on lanthanum carbonate Veerle P Persy, Geert J Behets, Marc E De Broe, Patrick C D'HaeseLaboratory of Pathophysiology, University of Antwerp, BelgiumAbstract: Elevated serum phosphate levels as a consequence of chronic kidney disease (CKD) contribute to the increased cardiovascular risk observed in dialysis patients. Protein restriction and dialysis fail to adequately prevent hyperphosphatemia, and in general treatment with oral phosphate binding agents is necessary in patients with advanced CKD. Phosphate plays a pivotal role in the development of vascular calcification, one of the factors contributing to increased cardiovascular risk in CKD patients. Treatment of hyperphosphatemia with standard calcium-based phosphate binders and vitamin D compounds can induce hypercalcemic episodes, increase the Ca × PO4 product and thus add to the risk of ectopic mineralization. In this review, recent clinical as well as experimental data on lanthanum carbonate, a novel, non-calcium, non-resin phosphate binding agent are summarized. Although lanthanum is a metal cation no aluminium-like toxicity is observed since the bioavailability of lanthanum is extremely low and its metabolism differs from that of aluminium. Clinical studies now document the absence of toxic effects of lanthanum for up to 6 years of follow-up. The effects of lanthanum on bone, vasculature and brain are discussed and put in perspective with lanthanum pharmacokinetics.Keywords: lanthanum carbonate, phosphate binding, chronic kidney disease
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Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients
Background.Hyperphosphatemia necessitates the use of phosphate binders in most dialysis patients.Long-term efficacy and tolerability of the iron-based phosphate binder, sucroferric oxyhydroxide ( previously known as PA21), was compared with that of sevelamer carbonate (sevelamer) in an open-label Phase III extension study.Methods.In the initial Phase III study, hemo-or peritoneal dialysis patients with hyperphosphatemia were randomized 2:1 to receive sucroferric oxyhydroxide 1.0-3.0g/day (2-6 tablets/
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Objective: Cardiovascular disease is a major cause of mortality in patients with chronic kidney disease (CKD). Elevated serum phosphate and FGF23 are associated with cardiovascular disease in patients with CKD. Current therapy focuses on decreasing serum phosphorus using phosphate binders. PA21 is a new iron-based phosphate binder. Few studies have analysed how to suppress FGF23 up-regulation using phosphate binders. To evaluate the effects of PA21 compared with other phosphate binders as lanthanum carbonate (La) and sevelamer carbonate (Se) on serum FGF23, phosphorus, calcium, iPTH concentrations and to investigate a potential effect on the development of vascular calcifications in an adenine-induced rat model of CRF. Design and method: After induction of chronic renal failure through a 4 week adenine-diet, renal function was significantly impaired in all groups. All uremic rats developed severe hyperphosphatemia and serum PTH increased significantly. Phosphate binders were then given for 4 weeks to all uremic rats, except for the uremic control rats. The concentration of each binder (% of binder added to the diet) was chosen to deliver approximately the same amount of active pharmaceutical moiety to each rat: PA21 5% (corresponding to 1% iron), La 2% (1% lanthanum), Se 1.5% (1% sevelamer). A computer-assisted automated quantitative measurement was used to assess the degree of calcification from von Kossa stained vessel sections. Results: Hyperphosphatemia and increased serum PTH levels were controlled in the phosphate binder treated groups to the same extent. PA21 was the only phosphate binder that was associated with a decrease of FGF23. In uremic control rats, vascular calcifications were more prominently present in the thoracic aorta compared to the carotids and the abdominal aorta. Vascular calcifications of thoracic aorta were significantly decreased by the three phosphate binders to a similar extent. PA21 was more efficient than lanthanum carbonate to prevent calcifications in the upper part of the thoracic aorta. Conclusions: PA21 was as effective in the control of hyperphosphatemia, secondary hyperparathyroidism and vascular calcifications as La and Se. The role of FGF23 as a potential factor of calcification needs to be confirmed.
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Hyperphosphatemia is an inevitable complication for patients undergoing dialysis, as is the resulting need for treatment with phosphate binders. Currently, various phosphate binders are clinically available. In addition to their phosphate-lowering activity, individual phosphate binders have differing safety profiles and off-target actions.This paper reviews the safety of phosphate binders and issues to be resolved.Calcium-based phosphate binders are well tolerated but may increase calcium overload risk. Sevelamer reduces serum cholesterol levels and exerts anti-inflammatory effects. Compared to sevelamer, bixalomer is associated with fewer gastrointestinal symptoms. Aluminum-containing binders, lanthanum carbonate, and sucroferric oxyhydroxide exhibit strong phosphate-lowering activity. Although ferric citrate reduces erythropoiesis-stimulating agents and intravenous iron doses, its use requires monitoring of iron metabolic markers to avoid overload. Occasionally, combined use of multiple phosphate binders can offer the advantages of each phosphate binder while minimizing their drawbacks; thus, this may be desirable according to individual patients' conditions and comorbidities. However, increased pill burden and nonadherence to phosphate binders emerge as new problems. We expect that novel therapeutic strategies will be developed to resolve these issues.
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Henson, Julie C. DO; Christiansen, Kaitlynn A. MD; Braun, Michael M. DO Author Information
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