Sucroferric oxyhydroxide for hyperphosphatemia: a review of real-world evidence.

Hyperphosphatemia is a common complication in dialysis-dependent patients with chronic kidney disease. Most dialysis-dependent patients need oral phosphate binder therapy to control serum phosphorus concentrations. Most phosphate binders have a high daily pill burden, which may reduce treatment adherence and impair phosphorus control. Sucroferric oxyhydroxide is a potent iron-based phosphate binder approved for use in dialysis-dependent patients in 2013. A randomized controlled trial of sucroferric oxyhydroxide demonstrated its efficacy for reduction of serum phosphorus with a lower pill burden than sevelamer carbonate. Clinical trials carefully select patients, monitor adherence, and routinely titrate medications to a protocol-defined goal. Consequently, trials may not reflect real-world use of medications. Since its approval, we and others have performed retrospective and prospective analyses of sucroferric oxyhydroxide in real-world clinical practice in > 6400 hemodialysis and approximately 500 peritoneal dialysis patients in the USA and Europe. Consistent with the clinical trial data, real-world observational studies have demonstrated that sucroferric oxyhydroxide can effectively reduce serum phosphorus with a lower daily pill burden than most other phosphate binders. These studies have also shown sucroferric oxyhydroxide provides effective serum phosphorus control in different treatment settings, including as monotherapy in phosphate binder-naïve patients, in patients switching from other phosphate binders, or when used in combination with other phosphate binders. These observational studies indicate a favorable safety and tolerability profile, and minimal, if any, systemic iron absorption. This article reviews the key results from these observational studies of sucroferric oxyhydroxide and evaluates its role in the management of hyperphosphatemia in clinical practice.

Changes in serum albumin and other nutritional markers when using sucroferric oxyhydroxide as phosphate binder among hemodialysis patients: a historical cohort study.

BACKGROUND: Elevated serum phosphorus concentrations are common among maintenance hemodialysis patients. Protein is a major source of dietary phosphate, but restriction of protein intake can result in hypoalbuminemia and protein-energy wasting. We hypothesized that sucroferric oxyhydroxide (SO), a potent phosphate binder with a low pill burden, may reduce serum phosphorus levels in hemodialysis patients with hypoalbuminemia without adversely impacting albumin levels or dietary intake of protein. METHODS: We retrospectively examined de-identified data from 79 adult, in-center hemodialysis patients with baseline hypoalbuminemia (≤ 3.5 g/dL) switched to SO as part of routine clinical care for at least 1 year. Temporal changes (3-month intervals from baseline through Q4) in phosphate binder pill burden, serum phosphorous levels, nutritional markers, and equilibrated Kt/V were analyzed. Data from a matched reference group of non-hypoalbuminemic patients (N = 79) switched to SO were also examined. RESULTS: SO therapy was associated with a mean reduction of 45.7 and 45.1% in daily phosphate binder pill burden, and a mean reduction of 0.4 mg/dL and 0.51 mg/dL in serum phosphorus levels for the hypoalbuminemic and non-hypoalbuminemic patients, respectively. Hypoalbuminemic patients demonstrated significant increases in mean serum albumin levels from 3.50 mg/dL at baseline to 3.69, 3.74, 3.70, and 3.69 mg/dL during Q1 through Q4, respectively (P < 0.0001), whereas serum albumin levels remained unchanged in the non-hypoalbuminemic group. CONCLUSIONS: Both hypoalbuminemic and non-hypoalbuminemic patients switching to SO exhibited significant reductions in serum phosphorus concentrations and daily phosphate binder pill burden. Among hypoalbuminemic patients, the initiation of SO therapy was also associated with increases in serum albumin, suggesting therapy may have allowed patients to increase their dietary intake of protein.

Real-World Scenario Improvements in Serum Phosphorus Levels and Pill Burden in Peritoneal Dialysis Patients Treated with Sucroferric Oxyhydroxide.

BACKGROUND: A database analysis was conducted to assess the effectiveness of sucroferric oxyhydroxide (SO) on lowering serum phosphorus and phosphate binder (PB) pill burden among adult peritoneal dialysis (PD) patients prescribed SO as part of routine care. METHODS: Adult PD patients (n = 258) prescribed SO through a renal pharmacy service were analyzed. Baseline was 3 months before SO prescription. SO-treated follow-up was for 6 months or until either a new PB was prescribed, SO was not refilled, PD modality changed, or patient was discharged. In-range serum phosphorus was defined as ≤5.5 mg/dL. RESULTS: At baseline, mean serum phosphorus was 6.59 mg/dL with 10 prescribed PB pills/day. The proportion of patients achieving in-range serum phosphorus increased by 72% from baseline to month 6. Prescribed PB pills/day decreased by 57% (10 at baseline to 4.3 at SO follow-up, p < 0.0001). The mean length of SO follow-up was 5.1 months; SO follow-up ended for 38, 27, and 50 patients at months 4, 5, and 6, respectively, due to no further PB fills, and for 10, 11, and 4 patients at months 4, 5, and 6, respectively, due to another PB prescribed. In patients with baseline serum phosphorus >5.5 mg/dL who achieved in-range serum phosphorus during SO follow-up for ≥1 quarter, a notable improvement in serum phosphorus (6.54 to 5.10 mg/dL, p < 0.0001) was observed, and there was a 53% reduction in PB pill burden (9.9 to 4.7, p < 0.0001). CONCLUSION: Among PD patients prescribed SO as part of routine care, improvements in serum phosphorus control and >50% reduction in PB pills/day were observed.

Real-world effectiveness of sucroferric oxyhydroxide in patients on chronic hemodialysis: A retrospective analysis of pharmacy data
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AIMS: Hyperphosphatemia has been associated with an increased risk of mortality in patients with end-stage renal disease. We sought to assess the real-world effectiveness of sucroferric oxyhydroxide (SO), an iron-based phosphate binder (PB), in control of serum phosphorus levels, and to determine the associated pill burden in hemodialysis patients. MATERIALS AND METHODS: Adult, in-center hemodialysis patients first prescribed SO through a renal pharmacy service as part of routine clinical care between April 1, 2014 and March 31, 2015 were included in the analysis. The proportion of patients with phosphorus levels ≤ 5.5 mg/dL and the mean prescribed PB pills/day were compared between baseline (3 months prior to SO) and SO follow-up at 3 (SO 1 - 3) and 6 months (SO 4 - 6). Mineral bone disease markers, hemoglobin, iron indices, and erythropoiesis-stimulating agents and intravenous iron use were assessed. RESULTS: At baseline, all patients (n = 1,029) were prescribed PB, and 13.9% had mean serum phosphorus ≤ 5.5 mg/dL. Comparing baseline to SO 1 - 3, the mean prescribed PB pills/day declined from 9.6 to 3.8 pills/day (p < 0.001), and the proportion of patients with serum phosphorus ≤ 5.5 mg/dL increased from 13.9 to 26.1% (+88%). Comparing baseline to SO 4 - 6 (n = 424), the mean prescribed PB pills/day declined from 9.7 to 4.0 pills/day (p < 0.001), and the proportion of patients with serum phosphorus ≤ 5.5 mg/dL increased from 15.6 to 30.4% (+95%). CONCLUSIONS: Prescription of SO was associated with an increase in the proportion of patients achieving serum phosphorus levels ≤ 5.5 mg/dL along with fewer prescribed PB pills/day.
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Update on intravenous iron choices.

PURPOSE OF REVIEW: Iron deficiency is a major factor in the prevalence and severity of anemia in patients with chronic kidney disease (CKD). We review the pathophysiology impairing normal intestinal iron absorption in CKD and compare the characteristics of newer intravenous (i.v.) iron agents to the longstanding i.v. iron products in the market. RECENT FINDINGS: The newer iron products, ferumoxytol, ferric carboxymaltose, and iron isomaltoside, more avidly bind iron, minimizing the release of labile iron during infusions, thus permitting large dose infusions. These irons also have more complex carbohydrate shells than their predecessors, which may also diminish reactions. Newer agents can be routinely administered at higher single doses, in as little as 15 min, with an acceptable safety profile. SUMMARY: Newer i.v. iron products permit the rapid, and sometimes complete, repletion of iron-deficient patients with a single dose. However, further studies examining the long-term risks and benefits of i.v. iron repletion are needed.

Iron supplementation to treat anemia in patients with chronic kidney disease.

Iron deficiency is prevalent in patients with chronic kidney disease (CKD), and use of oral and intravenous iron in patients with CKD who do not require dialysis might obviate or delay the need for treatment with eythropoiesis-stimulating agents (ESAs). Patients on hemodialysis have lower intestinal iron absorption, greater iron losses, and require greater iron turnover to maintain the ESA-driven red cell mass than do healthy individuals. In these patients, intravenous iron reduces ESA dose requirements and increases the likelihood of maintaining levels of hemoglobin within the desired range. Oral iron is inferior to intravenous iron in patients on hemodialysis, in part because elevated serum levels of hepcidin prevent intestinal absorption of iron. Increased levels of hepcidin also impair the normal recycling of iron through the reticuloendothelial system. Levels of serum ferritin and transferrin saturation below 450 pmol/l and 20%, respectively are indicative of iron deficiency, but values above the normal range lack diagnostic value in patients with CKD on dialysis. The availability of various iron preparations and new developments in delivering iron should enable adequate provision of iron to patients with CKD. This Review examines the efficacy, safety and use of iron supplementation therapy for the treatment of anemia in patients with CKD.

The effect of oral niacinamide on plasma phosphorus levels in peritoneal dialysis patients.

BACKGROUND: Hyperphosphatemia remains a significant problem for patients requiring dialysis and is associated with increased mortality. Current treatment options include dietary restriction, dialysis, and phosphate binders. Treatment using the latter is frequently limited by cost, tolerability, and calcium loading. One open-label trial found niacinamide to be effective at decreasing serum phosphorus values in hemodialysis patients. Niacinamide may effectively reduce phosphorus levels in peritoneal dialysis (PD) patients already receiving standard phosphorus-lowering therapies. METHODS: An 8 week, randomized, double blind, placebo-controlled trial to evaluate the effectiveness of niacinamide to reduce plasma phosphorus levels in PD patients. Patients had to demonstrate a baseline phosphorus value > 4.9 mg/dL. Patients were randomized to niacinamide or placebo and prescribed 250 mg twice daily, with titration to 750 mg twice daily, as long as safety parameters were not violated. Phosphate binders, active vitamin D, and cinacalcet were kept constant during the study. The primary end point was change in plasma phosphorus. Secondary end points included changes in lipid parameters. RESULTS: 15 patients started on the study drug (8 niacinamide, 7 placebo) and 7 in each arm had at least one on-study phosphorus measurement. The niacinamide treatment group experienced an average 0.7 +/- 0.9 mg/dL decrease in plasma phosphorus and the placebo-treated group experienced an average 0.4 +/- 0.8 mg/dL increase. The treatment effect difference (1.1 mg/dL) was significant (p = 0.037). No significant changes in high- or low-density lipoproteins or triglycerides were demonstrated. Two of the 8 patients randomized to the niacinamide treatment arm had to withdraw from the study due to drug-related adverse effects. Adverse effects may limit the use of niacinamide in PD patients. CONCLUSION: Niacinamide, when added to standard phosphorus-lowering therapies, resulted in a modest yet statistically significant reduction in plasma phosphorus levels at 8 weeks. [ClinicalTrials.gov number NCT00508885].

Ferumoxytol for treatment of iron deficiency anemia in patients with chronic kidney disease.

BACKGROUND: Iron deficiency anemia (IDA) is a common problem in patients with chronic kidney disease (CKD). Use of intravenous (i.v.) iron effectively treats the resultant anemia, but available iron products have side effects or dosing regimens that limit safety and convenience. OBJECTIVE: Ferumoxytol (Feraheme) is a new i.v. iron product recently approved for use in treatment of IDA in CKD patients. This article reviews the structure, pharmacokinetics, and clinical trial results on ferumoxytol. The author also offers his opinions on the role of this product in clinical practice. METHODS: This review encompasses important information contained in clinical and preclinical studies of ferumoxytol and is supplemented with information from the US Food and Drug Administration. RESULTS/CONCLUSION: Ferumoxytol offers substantial safety and superior efficacy compared with oral iron therapy. As ferumoxytol can be administered as 510 mg in < 1 min, it is substantially more convenient than other iron products in nondialysis patients. Although further experience with this product is needed in patients at higher risk of drug reactions, ferumoxytol is likely to be highly useful in the hospital and outpatient settings for treatment of IDA.

A randomized, double-blind, placebo-controlled trial of niacinamide for reduction of phosphorus in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Niacinamide inhibits intestinal sodium/phosphorus transporters and reduces serum phosphorus in open-label studies. A prospective, randomized, double-blind, placebo-controlled crossover trial was performed for assessment of the safety and efficacy of niacinamide. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Hemodialysis patients with phosphorus levels > or =5.0 mg/dl were randomly assigned to 8 wk of niacinamide or placebo, titrated from 500 to 1500 mg/d. After a 2-wk washout period, patients switched to 8 wk of the alternative therapy. Vitamin D analogs and calcimimetics were held constant; phosphorus binders were not changed unless safety criteria were met. RESULTS: Thirty-three patients successfully completed the trial. Serum phosphorus fell significantly from 6.26 to 5.47 mg/dl with niacinamide but not with placebo (5.85 to 5.98 mg/dl). A concurrent fall in calcium-phosphorus product was seen with niacinamide, whereas serum calcium, intact parathyroid hormone, uric acid, platelet, triglyceride, LDL, and total cholesterol levels remained stable in both arms. Serum HDL levels rose with niacinamide (50 to 61 mg/dl but not with placebo. Adverse effects were similar between both groups. Among patients who were > or =80% compliant, results were similar, although the decrease in serum phosphorus with niacinamide was more pronounced (6.45 to 5.28 mg/dl) and the increase in HDL approached significance (49 to 58 mg/dl). CONCLUSIONS: In hemodialysis patients, niacinamide effectively reduces serum phosphorus when co-administered with binders and results in a potentially advantageous increase in HDL cholesterol. Further study in larger randomized trials and other chronic kidney disease populations is indicated.

Management of secondary hyperparathyroidism in stages 3 and 4 chronic kidney disease.

OBJECTIVE: To review approved treatment options for secondary hyperparathyroidism (SHPT) in patients with stages 3 and 4 chronic kidney disease (CKD). METHODS: Recently published data on the diagnosis and treatment of SHPT in patients with CKD were critically assessed. RESULTS: Early detection of SHPT is critical for effective treatment. Approximately 40% of patients with stage 3 CKD and 80% of patients with stage 4 have SHPT due to low serum 1,25-dihydroxyvitamin D levels. Appropriate treatment involves suppression of parathyroid hormone (PTH) to normal levels with active vitamin D therapy and phosphate binders. Ergocalciferol or cholecalciferol should be used to correct 25-hydroxyvitamin D levels either before or during active vitamin D therapy. Active vitamin D analogues include calcitriol, doxercalciferol, and paricalcitol. Calcitriol is effective, but has a narrow therapeutic window at higher doses because of hypercalcemia and hyperphosphatemia, which require frequent monitoring. Doxercalciferol is also effective, but has been associated with significant elevations in serum phosphorus requiring greater use of oral phosphate binders. Paricalcitol effectively suppresses PTH with minimal impact on serum calcium and phosphorus. Limited data exist on the use of cinacalcet in treating SHPT in stages 3 and 4 CKD, and it is only approved for use in patients receiving dialysis. CONCLUSION: SHPT is an early and major complication of CKD. Treatment involves suppression of PTH to prevent metabolic bone disease, bone loss, and metabolic complications that may result in marked morbidity and mortality. Early detection of elevated PTH levels with appropriate intervention using active vitamin D therapy, even in the absence of elevated serum phosphorus and reduced serum calcium, is critical.

Prevalence of vitamin D deficiency and the safety and effectiveness of monthly ergocalciferol in hemodialysis patients.

BACKGROUND: Vitamin D deficiency is common in CKD and dialysis patients. Studies suggest a physiologic autocrine and/or paracrine role for 1,25(OH)D produced via 1alpha-hydroxylase in tissues such as vascular smooth muscle, breast, prostate, and bone marrow. Studies have not yet defined the optimal dose and duration of vitamin D necessary to replete and maintain stores in dialysis patients, or whether it is safe or beneficial. METHODS: We performed a review of the prevalence of vitamin D deficiency and the safety and effectiveness of ergocalciferol oral supplementation (vitamin D(2), 50,000 IU monthly) given to hemodialysis patients during dialysis May to October 2005 in St. Louis (latitude 38 degrees ). RESULTS: Among the 119-patient cohort present for the entire 6 months, 25(OH)D was (mean +/- SD) 16.9 +/- 8.5 ng/ml, (91% < 30 ng/ml) and increased to 53.6 +/- 16.3 ng/ml (p < 0.001), (95% > 30 ng/ml, and none > 100 ng/ml). Initial versus 6 mo. serum calcium (9.1 +/- 0.56 vs. 9.2 +/- 0.70), phosphorus (5.25 +/- 1.38 vs. 5.11 +/- 1.31), Ca x P, and paricalcitol dose (10.3 +/- 9.6 vs. 11.3 +/- 9.2 mcg/week) were not significantly different. No hypercalcemia could be attributed to supplementation. Mean hemoglobin did not change significantly (11.96 +/- 1.4 vs. 11.69 +/- 1.4, p = 0.124), but most patients experienced a reduced weekly epoetin dose. Epoetin dose decreased in 64% of patients, and increased in 28%. CONCLUSIONS: We conclude that the vast majority of hemodialysis patients are vitamin D-deficient; monthly ergocalciferol 50,000 IU is safe and effective in normalizing serum 25(OH)D levels and may have an epoetin-sparing effect.

Drug insight: Safety of intravenous iron supplementation with sodium ferric gluconate complex.

Intravenous iron is necessary for optimal management of anemia in patients receiving hemodialysis and is utilized in the majority of these patients in the US. The availability of nondextran formulations of intravenous iron has significantly improved the safety of its use. The nondextran iron formulation sodium ferric gluconate complex (SFGC) has been extensively studied in the hemodialysis population, with two large phase IV trials documenting its safety. SFGC is efficacious and, at recommended doses, is associated with a low incidence of adverse events. There have been few comparative studies of the nondextran intravenous iron preparations; however, they are known to have different pharmacokinetic characteristics. There is also evidence to indicate that these compounds differ in terms of their cytotoxic and proinflammatory properties, and their propensity to induce oxidative stress. This paper reviews the current literature on the safety of SFGC and examines the emerging safety issues surrounding the use of intravenous iron.

Oral feeding acutely down-regulates serum PTH in hemodialysis patients.

BACKGROUND: Changes in serum parathyroid hormone (PTH) within minutes are known only to be mediated by changes in ionized calcium. Recent animal studies show ingestion of a low phosphorus meal can lower serum PTH within 15 min, before changes in serum ionized calcium or phosphorus occur, suggesting a rapid gastrointestinal signal may regulate PTH. METHODS: Eight hemodialysis patients with secondary hyperparathyroidism were admitted twice to a metabolic unit and ate a high and low phosphorus meal after an overnight fast. Serum PTH, total and ionized calcium, phosphorus, pH, and glucose were measured at 0, 15, 30, 60, 120 and 240 min. In the second protocol, we examined the possible role of volume or glucose changes in rapid PTH suppression by administering intravenous saline and glucose after an overnight fast to 6 patients, with similar testing. RESULTS: Intact PTH decreased 24% from 419 +/- 331 at baseline to 312 +/- 221 pg/ml (p = 0.002) 15 min after a meal. Total and ionized calcium and pH did not change, glucose rose by 15 min, and phosphorus changed only after 60-90 min. During the second protocol, saline and glucose infusions failed to change PTH. CONCLUSIONS: In dialysis patients, a glucose-containing meal, with or without phosphorus, rapidly suppresses serum PTH approximately 25% within 15 min. This effect is not mediated by changes in ionized calcium, phosphorus, pH, glucose, or insulin. These data suggest there may be an as yet unknown enteral signal that rapidly suppresses PTH.

Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

BACKGROUND: Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. METHODS: Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS: Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. CONCLUSIONS: Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.

Differential effects of acute administration of 19-Nor-1,25-dihydroxy-vitamin D2 and 1,25-dihydroxy-vitamin D3 on serum calcium and phosphorus in hemodialysis patients.

BACKGROUND: Treatment of hyperparathyroidism includes the use of 1,25-dihydroxy-vitamin D3 (1,25D3) to suppress parathyroid hormone (PTH), but dosing of 1,25D3 is limited by the development of hypercalcemia and a high calcium x phosphorus (Ca x P) product because of gut absorption of calcium and phosphorus and enhanced bone resorption. The vitamin D analogue 19-nor-1,25(OH)2-vitamin D2 (19-Nor) causes less hypercalcemia and elevated Ca x P, whereas it still suppresses PTH in rats. METHODS: To determine whether 19-Nor had similar effects in humans, we performed a prospective crossover study to assess bone mobilization. Ten hemodialysis patients on a low-calcium low-phosphorus diet were administered 20 microg of 1,25D3 and 120 and 160 microg of 19-Nor, and changes in calcium, phosphorus, and intact and whole PTH levels were measured over 36 hours. RESULTS: Ca x P product increased more after 1,25D3 administration than after a six- or eightfold greater dose of 19-Nor and was significantly greater at 6, 12, and 24 hours. Ca x P product at 36 hours was 60.9 +/- 3.4 (4.91 +/- 0.27 mmol2/2) after 1,25D3 administration, 53.2 +/- 2.7 (4.29 +/- 0.22 mmol2/L2) after administration of 120 microg of 19-Nor, and 54.2 +/- 2.7 (4.37 +/- 0.22 mmol2/L2) after administration of 160 microg of 19-Nor. Suppression of intact PTH at 36 hours was similar after administration of 1,25D3 (54.1% +/- 6.0%) and 120 microg of 19-Nor (54.4% +/- 3.4%) and significantly greater after administration of 160 microg of 19-Nor (63.6% +/- 2.3%). The whole PTH assay yielded values approximately 25% to 30% lower than the intact PTH assay, and the percentage of suppression was virtually identical. CONCLUSION: Consistent with animal studies, 19-Nor provides profound PTH suppression while stimulating bone resorption and/or intestinal absorption less than 1,25D3, resulting in less elevation of serum calcium and phosphorus levels.