ferric-oxide--saccharated and Renal-Insufficiency--Chronic

Hyperphosphatemia is a common complication as chronic kidney disease (CKD) progresses and most patients undergoing dialysis are prescribed oral phosphate binder therapy to control serum phosphate concentrations. Sucroferric oxyhydroxide is an iron-based phosphate binder approved for the treatment of hyperphosphatemia in CKD patients on dialysis.. This article reviews key safety and effectiveness data for sucroferric oxyhydroxide from both prospective clinical trials and real-world observational studies.. Sucroferric oxyhydroxide potently binds dietary phosphate in the gastrointestinal (GI) tract, resulting in effective reduction of serum phosphate concentrations with a relatively low daily pill burden. Data from clinical trials and real-world observational studies show sucroferric oxyhydroxide has a favorable safety and tolerability profile. The most frequent side effects observed with sucroferric oxyhydroxide are GI-related, mainly discolored (black) stools and mild or moderate transient diarrhea, both of which are manageable. There is minimal systemic iron absorption from sucroferric oxyhydroxide, and therefore the drug is associated with a low risk of iron accumulation. Sucroferric oxyhydroxide also displays low potential for drug-drug interactions with other commonly prescribed oral medications. Overall, sucroferric oxyhydroxide offers an effective and well-tolerated treatment option for the management of hyperphosphatemia.

Topics: Chelating Agents; Drug Combinations; Drug Interactions; Ferric Compounds; Humans; Hyperphosphatemia; Renal Dialysis; Renal Insufficiency, Chronic; Sucrose

Iron Deficiency (ID) is increasingly recognized as a prevalent comorbid condition in Heart Failure (HF). Despite this, the pathophysiological mechanisms for progressive ID in either chronic or acute HF are still poorly understood. Beyond the traditional factors for iron deficit in the general population, we ought to review the specificities of such paucity in the HF patient, particularly focusing on the interplay between heightened inflammation, overactivity of the sympathetic nervous system and the so-called cardio-renal-anaemia-ID syndrome. Currently, ID constitutes not only an independent prognostic marker but also a novel safe therapeutic target. Particularly, in selected stable HF patients with reduced left ventricular ejection fraction, intravenous (IV) iron improves symptomatic burden and reduces hospitalizations due to worsening HF. On this topic, the main trials of IV iron with either iron sucrose (Toblli et al., FERRIC-HF and IRON-HF) or ferric carboxymaltose (FAIR-HF, CONFIRM-HF and EFFECT-HF) will be summarized and discussed. Finally, we debate the gaps in knowledge of ID in special populations, namely the unreliability of routine plasmatic surrogate markers to assess iron status in acute and advanced HF, the challenging patient with both HF and Chronic Kidney Disease, as well as efficacy and safety concerns in these settings and the potential role of iron correction in cardiac resynchronization therapy candidates.

Topics: Acute Disease; Anemia, Iron-Deficiency; Chronic Disease; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Heart Failure; Hematinics; Hospitalization; Humans; Quality of Life; Renal Insufficiency, Chronic

Sucroferric oxyhydroxide is a non-calcium, iron-based phosphate binder indicated for the treatment of hyperphosphatemia in patients with chronic kidney disease undergoing dialysis. Areas covered: Herein, the preclinical development and clinical data for sucroferric oxyhydroxide are reviewed, including the key data from the Phase III registration study and the latest evidence from the real-world clinical setting. Expert opinion: Sucroferric oxyhydroxide displays potent phosphate-binding capacity and clinical studies demonstrate its effectiveness for the long-term reduction of serum phosphorus levels in dialysis patients. Observational study data also show that sucroferric oxyhydroxide provides effective serum phosphorus control for hyperphosphatemic patients in the real-world clinical setting. The serum phosphorus reductions with sucroferric oxyhydroxide can be achieved with a relatively low pill burden in comparison with other phosphate binders, which may translate into better treatment adherence in clinical practice. The Phase III data also indicate that sucroferric oxyhydroxide has a favorable impact on other chronic kidney disease-related mineral bone disease parameters, including a fibroblast growth factor-23-lowering effect. Sucroferric oxyhydroxide is well tolerated and associated with low systemic iron absorption, minimizing the potential for iron accumulation or overload. These attributes render sucroferric oxyhydroxide an attractive non-calcium-containing phosphate binder for the treatment of hyperphosphatemia.

Topics: Chelating Agents; Clinical Trials as Topic; Drug Combinations; Ferric Compounds; Government Regulation; Humans; Hyperphosphatemia; Phosphates; Renal Dialysis; Renal Insufficiency, Chronic; Sucrose; Treatment Outcome

Management of serum phosphorus in patients with chronic kidney disease remains a significant clinical challenge. A pivotal component of the clinical approach to maintaining serum phosphorus concentrations towards the normal range is the use of phosphate binding agents in addition to comprehensive dietary counseling. The available agents work similarly by capitalizing on a cation within the agent to bind negatively charged phosphorus, forming an insoluble complex and reducing ingested phosphorus absorption. Despite several effective options for phosphate binder therapies, patient adherence remains an issue, mainly due to adverse effect profiles and large daily pill burdens.. Two new iron-based phosphate binder therapies have recently become available in the United States, sucroferric oxyhydroxide and ferric citrate. These agents have both been shown to effectively reduce serum phosphorus comparably to widely used calcium-based binders and sevelamer salts.. The two new iron-based binders differ substantially with regard to phosphate binding chemistry and iron absorption profiles. Their place in therapy is still evolving and the impact of pill burden, gastrointestinal adverse effect profiles, potential cost reduction of anemia therapies and physiologic effects of long-term iron exposure need to be further evaluated.

Topics: Animals; Drug Combinations; Ferric Compounds; Humans; Hyperphosphatemia; Medication Adherence; Phosphates; Renal Insufficiency, Chronic; Sevelamer; Sucrose

Hyperphosphatemia is common in chronic kidney disease (CKD) and is treated by dietary measures, dialysis techniques and/or phosphate binders. For the present review PubMed was searched for new publications on phosphate binders appearing between January 2010 and October 2015. This review summarizes the latest information on non-pharmacological measures and their problems in lowering phosphate in CKD patients, effects of phosphate binders on morbidity and mortality, adherence to phosphate binder therapy as well as new information on specific aspects of the various phosphate binders on the market: calcium acetate, calcium carbonate, magnesium-containing phosphate binders, polymeric phosphate binders (sevelamer, bixalomer, colestilan), lanthanum carbonate, ferric citrate, sucroferric oxyhydroxide, aluminum-containing phosphate binders, and new compounds in development. The review also briefly covers the emerging field of drugs targeting intestinal phosphate transporters.

Topics: Drug Combinations; Ferric Compounds; Humans; Hyperphosphatemia; Lanthanum; Phosphates; Polyamines; Renal Insufficiency, Chronic; Sevelamer; Sucrose

In contrast to managing patients on hemodialysis in whom iron strategies are more focused on intravenous iron, nondialysis chronic kidney disease (CKD) patients may receive either oral or intravenous iron. There are advantages and disadvantages for both strategies. Oral iron is simple and cheap to administer and does not require hospital visits, but is poorly absorbed in advanced CKD and is associated with unpleasant gastrointestinal side effects. Intravenous iron, on the other hand, guarantees iron bioavailability and avoids problems of variable absorption of iron from the gastrointestinal tract, but requires specialist clinic services. Intravenous iron also is associated with hypersensitivity reactions, albeit very rarely. The efficacy of intravenous iron in improving hemoglobin, ferritin, and transferrin saturation is well established, and superior to oral iron, but the long-term safety of this route of administration has not been established and there are theoretical concerns that patients may be exposed to increased oxidative stress and exacerbation of infections. The final choice of iron management strategy will depend on individual physician preference, as well as the facilities that are available.

Topics: Administration, Intravenous; Administration, Oral; Anemia, Iron-Deficiency; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Ferrous Compounds; Glucaric Acid; Hematinics; Hemoglobins; Humans; Iron Compounds; Maltose; Renal Insufficiency, Chronic; Severity of Illness Index; Transferrin

Sucroferric oxyhydroxide (Velphoro®), an iron-based oral phosphate binder, is available for the control of serum phosphorus levels in patients with chronic kidney disease (CKD) on dialysis. In a pivotal phase III trial, sucroferric oxyhydroxide 1000-3000 mg/day for 24 weeks was noninferior to sevelamer carbonate 4800-14,400 mg/day with regard to lowering serum phosphorus levels. Additionally, sucroferric oxyhydroxide at maintenance dosages was significantly more effective than low dosage sucroferric oxyhydroxide (250 mg/day) with regard to maintaining controlled serum phosphorus levels during weeks 24-27 of treatment. Sucroferric oxyhydroxide had a numerically lower mean daily pill burden and better treatment adherence than sevelamer carbonate. Treatment with sucroferric oxyhydroxide was generally well tolerated over 24 weeks' treatment, with the most frequently reported treatment-emergent adverse events being mild, transient diarrhoea and discoloured faeces. In a 28-week extension study, the efficacy and tolerability profile of sucroferric oxyhydroxide remained similar to sevelamer carbonate for up to 52 weeks. In conclusion, sucroferric oxyhydroxide is a valuable treatment option for hyperphosphataemia in CKD patients on dialysis, providing an effective and generally well tolerated noncalcium-based phosphate binder therapy with a lower pill burden than sevelamer carbonate and the potential for improved treatment adherence.

Topics: Chelating Agents; Drug Combinations; Drug Interactions; Ferric Compounds; Humans; Hyperphosphatemia; Phosphates; Practice Guidelines as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Sucrose

Fibroblast growth factor 23 (FGF23) is an essential hormone for phosphate metabolism. It has been shown that intravenous administration of some iron formulations including saccharated ferric oxide induces hypophosphatemic osteomalacia with high FGF23 levels. On the other hand, iron deficiency promotes FGF23 and induces hypophosphatemia in patients with autosomal dominant hypophosphatemic rickets (ADHR). While iron and phosphate metabolism is connected, the detailed mechanism of this connection remains to be clarified.

Topics: Anemia, Iron-Deficiency; Ferric Compounds; Ferric Oxide, Saccharated; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucaric Acid; Humans; Hypophosphatemia; Injections, Intravenous; Iron; Osteomalacia; Phosphates; Renal Insufficiency, Chronic; Rickets, Hypophosphatemic

Hyperphosphatemia is a frequent complication of chronic kidney disease and is associated with increased mortality. Despite side effects, risk of accumulation and high costs, phosphate binders (PBs) have become the crucial cornerstone of therapy. The iron-containing PB sucroferric oxyhydroxide (SO) and ferric citrate hydrate (FCH) have entered the market and other candidates are prior market entry.. A literature search was performed using MEDLINE and EMBASE databases to identify references on iron-containing PB with particular regard to efficacy, safety and potential benefits. Additional hand searches were conducted along with a full-text review of any citation that appeared relevant.. On the highly competitive market, where the 'ideal' PB is still unknown, novel substances that offer clear benefits over available drugs are desired. Although SO and FCH showed similar efficacy and safety compared to sevelamer, head-to-head studies with lanthanum carbonate are absent. Clinical 1-year data in a limited patient cohort suggested improved adherence for SO and a large randomized controlled trial showed significant reduction in hospitalizations and costs for FCH. Additional large randomized controlled trials have now to prove these possible advantages. Cost-effectiveness in comparison to other PB and the exclusion of significant harms under long-term treatment will determine the future use of both drugs.

Topics: Animals; Carbonates; Clinical Trials as Topic; Drug Combinations; Ferric Compounds; Humans; Hyperphosphatemia; Iron; Lanthanum; Magnesium; Phosphates; Renal Insufficiency, Chronic; Sevelamer; Starch; Sucrose

Sucroferric oxyhydroxide is the newest phosphate binder to receive US Food and Drug Administration approval for patients on dialysis. The purpose of this review is to critically evaluate the studies that have been conducted with this medication and determine where it may fit in the clinician's overall treatment plan for hyperphosphatemia in patients with chronic kidney disease.. Literature searches were performed in the PubMed database and www.ClinicalTrials.gov using the search terms sucroferric oxyhydroxide, and PA21 phosphate binder. Limits were set to include only clinical trials performed in human subjects.. Four completed clinical trials and 3 ongoing studies were identified. Completed clinical trials included Phase I, Phase II, and Phase III studies that all demonstrated the ability of sucroferric oxyhydroxide to lower serum phosphorus concentrations. One study compared sucroferric oxyhydroxide with sevelamer and reported no statistically significant difference in serum phosphorus-lowering ability. The ongoing trials are evaluating sucroferric oxyhydroxide for long term use, in peritoneal dialysis patients, and compared with calcium-based phosphate binders.. Sucroferric oxyhydroxide is an effective phosphate binder for chronic kidney disease patients receiving hemodialysis and may offer an advantage in terms of pill burden. Gastrointestinal side effects are similar to those of current phosphate binders. Advantages of other phosphate binders (ie, the lipid- and uric acid-lowering abilities of sevelamer) may outweigh the pill burden benefits of sucroferric oxyhydroxide.

Topics: Chelating Agents; Drug Combinations; Ferric Compounds; Humans; Hyperphosphatemia; Renal Dialysis; Renal Insufficiency, Chronic; Sucrose; United States

Sucroferric oxyhydroxide (VELPHORO) is a polynuclear iron-based phosphate binder recently approved for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD). As a number of the available phosphate binders do not provide the optimal combination of good efficacy, adequate tolerability and low pill burden, sucroferric oxyhydroxide constitutes a promising alternative. Among the attributes of an ideal phosphate binder is minimal absorption and, hence, low risk of systemic toxicity. Accordingly, the iron-releasing properties and absorption, distribution, metabolism and excretion (ADME) profile of sucroferric oxyhydroxide, as well as the possibility of iron accumulation and toxicity, were investigated in a series of preclinical studies. The effect of sucroferric oxyhydroxide on the progression of vascular calcification was also investigated. Sucroferric oxyhydroxide exhibited a high phosphate-binding capacity and low iron-releasing properties across the physiological pH range found in the gastrointestinal tract. In the ADME studies, uptake of (59)Fe-radiolabelled sucroferric oxyhydroxide was low in rats and dogs (<1% from a 50 mg Fe/kg bodyweight dose), with the majority of absorbed iron located in red blood cells. Long-term (up to 2 years) administration of sucroferric oxyhydroxide in rats and dogs was associated with modest increases in tissue iron levels and no iron toxicity. Moreoever, in uraemic rats, sucroferric oxyhydroxide was associated with reduced progression of vascular calcification compared with calcium carbonate. In conclusion, sucroferric oxyhydroxide offers a new option for the treatment of hyperphosphataemia, with a high phosphate-binding capacity, minimal iron release, and low potential for iron accumulation and toxicity.

Topics: Animals; Chelating Agents; Disease Models, Animal; Dogs; Drug Combinations; Ferric Compounds; Gastrointestinal Absorption; Humans; Hyperphosphatemia; Kidney; Phosphates; Rats; Renal Insufficiency, Chronic; Risk Assessment; Sucrose; Uremia; Vascular Calcification

To review clinical trials conducted in hemodialysis patients of the 4 intravenous iron products available in the US in an attempt to discern strengths and inferiorities between products and evaluate current safety data that can be used to assist the clinician in selecting the most appropriate agent.. Literature was accessed through PubMed (January 2000-October 2010). In some cases, reference citations from selected review articles were evaluated as well.. Clinical trials published in the English language were selected using the search terms iron dextran, iron sucrose, sodium ferric gluconate, and ferumoxytol. Studies were further pared down to include only those enrolling hemodialysis patients.. There are currently 4 intravenous iron formulations in the US used to treat iron-deficiency anemia in hemodialysis patients. Ferumoxytol has not yet been directly compared to the other 3 agents. Eight studies have been conducted in hemodialysis patients directly comparing iron dextran, iron sucrose, and/or sodium ferric gluconate. These studies were further categorized for evaluation based on iron products compared. Four studies directly compared iron dextran to iron sucrose, 1 study compared iron dextran to sodium ferric gluconate, 1 study compared iron sucrose to sodium ferric gluconate, and 2 studies compared all 3 agents. Of the 3 agents, iron dextran appears to have the least favorable safety profile, while iron sucrose appears most favorable.. The newest intravenous iron product, ferumoxytol, has not been directly compared to the other 3 agents. Large well-controlled studies of these products specifically in the hemodialysis population would further help clinicians determine appropriate therapy. Iron sucrose appears to offer the most favorable safety profile when compared to iron dextran and sodium ferric gluconate in treating hemodialysis patients. Oxidative stress and hypersensitivity reactions are common problems encountered when administering intravenous iron.

Topics: Administration, Intravenous; Anemia, Iron-Deficiency; Clinical Trials as Topic; Ferric Compounds; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Ferrous Compounds; Glucaric Acid; Humans; Iron-Dextran Complex; Renal Dialysis; Renal Insufficiency, Chronic

Intravenous iron is widely used to maintain adequate iron stores and prevent iron deficiency anemia in patients with chronic kidney disease, yet concerns remain about its long-term safety with respect to oxidative stress, kidney injury, and accelerated atherosclerosis, which are the subjects of this review. Three parenteral iron formulations are available for use in the United States: Iron dextran, iron gluconate, and iron sucrose. Iron dextran, especially the high molecular form, has been linked with anaphylactoid and anaphylactic reactions, and its use has been declining. A portion of intravenous iron preparations is redox-active, labile iron available for direct donation to transferrin. In vitro tests show that commonly available intravenous iron formulations have differing capacities to saturate transferrin directly: Iron gluconate > iron sucrose > iron dextran. Intravenous iron treatment produces oxidative stress, as demonstrated by increases in plasma levels of lipid peroxidation products (malondialdehyde), at a point that is much earlier than the time to peak concentration of catalytically active iron, suggesting a direct effect of iron sucrose on oxidative stress. Furthermore, iron sucrose infusion produces endothelial dysfunction that seems to peak earlier than the serum level of free iron. Intravenous iron sucrose infusion also has been shown to produce acute renal injury and inflammation as demonstrated by increased urinary albumin, enzyme (N-acetyl-beta-glucosaminidase), and cytokine (chemokine monocyte chemoattractant protein-1) excretions. Although the long-term dangers of intravenous iron are unproved, these data call for examination of effects of intravenous iron on the potential for long-term harm in patients with chronic kidney disease.

Topics: Acute Kidney Injury; Anemia, Iron-Deficiency; Animals; Atherosclerosis; Endothelium, Vascular; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Humans; Inflammation; Infusions, Intravenous; Iron-Dextran Complex; Oxidative Stress; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors; Transferrin

Ferric iron (Fe)-carbohydrate complexes are widely used for treating Fe deficiency in patients who are unable to meet their Fe requirements with oral supplements. Intravenous Fe generally is well tolerated and effective in correcting Fe-deficient states. However, the complexing of Fe to carbohydrate polymers does not block its potent pro-oxidant effects; systemic free radical generation and, possibly, tissue damage may result. The purpose of this review is to (1) underscore the capacity of currently used parenteral Fe formulations to induce oxidative stress, (2) compare the severity of these oxidant reactions with those that result from unshielded Fe salts and with each other, and (3) speculate as to the potential of these agents to induce acute renal cell injury and augment systemic inflammatory responses. The experimental data that are reviewed should not be extrapolated to the clinical setting or be used for clinical decision making. Rather, it is hoped that the information provided herein may have utility for clinical hypothesis generation and, hence, future clinical studies. By so doing, a better understanding of Fe's potential protean effects on patients with renal disease may result.

Topics: Acute Kidney Injury; Adenosine Triphosphate; Anemia, Iron-Deficiency; Animals; Endothelial Cells; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Humans; Inflammation; Infusions, Intravenous; Iron Compounds; Iron-Dextran Complex; Kidney Cortex; Kidney Tubules, Proximal; Lipid Peroxidation; Mitochondria; Oxidative Stress; Renal Dialysis; Renal Insufficiency, Chronic; Tumor Necrosis Factor-alpha

Whether iron supplementation in patients on hemodialysis could be delivered by less frequent but higher single doses compared with the currently more common higher-frequency schedules of lower single iron doses is unknown.. In total, 108 patients completed the study. At 40 weeks, hemoglobin changed by -0.27 g/dl (95% confidence interval, -0.64 to 0.09) in the iron sucrose arm and by -0.74 g/dl (95% confidence interval, -1.1 to -0.39) in the ferric carboxymaltose arm compared with baseline. Noninferiority was not established in the per-protocol population as hemoglobin changes compared with baseline differed by -0.47 g/dl (95% confidence interval, -0.95 to 0.01) in the ferric carboxymaltose arm compared with the iron sucrose arm. Proportional changes from baseline to week 40 differed by -31% (98.3% confidence interval, -52 to -0.1) for ferritin, by 1% (98.3% confidence interval, -7 to 10) for transferrin, and by -27% (98.3% confidence interval, -39 to -13) for transferrin saturation in the ferric carboxymaltose arm compared with the iron sucrose arm. Erythropoiesis-stimulating agent dosing did not differ between groups. The overall number of adverse events was similar; however, more infections were observed in the iron sucrose arm.. An equal cumulative dose of ferric carboxymaltose administered less frequently did not meet noninferiority for maintaining hemoglobin levels compared with iron sucrose administered more frequently.. Comparison Study of Two Iron Compounds for Treatment of Anemia in Hemodialysis Patients (COPEFER), NCT02198495.

Topics: Adult; Aged; Anemia, Iron-Deficiency; Austria; Biomarkers; Drug Administration Schedule; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Hematinics; Hemoglobins; Humans; Infusions, Intravenous; Male; Maltose; Middle Aged; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors; Transferrin; Treatment Outcome

The optimal intravenous (IV) iron would allow safe correction of iron deficiency at a single infusion over a short time. The FERWON-NEPHRO trial evaluated the safety and efficacy of iron isomaltoside 1000/ferric derisomaltose (IIM) in patients with non-dialysis-dependent chronic kidney disease and iron deficiency anaemia.. In this randomized, open-label and multi-centre trial conducted in the USA, patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg IV injections up to five times within a 2-week period. The co-primary endpoints were serious or severe hypersensitivity reactions and change in haemoglobin (Hb) from baseline to Week 8. Secondary endpoints included incidence of composite cardiovascular adverse events (AEs).. A total of 1538 patients were enrolled (mean estimated glomerular filtration rate 35.5 mL/min/1.73 m2). The co-primary safety objective was met based on no significant difference in the incidence of serious or severe hypersensitivity reactions in the IIM and IS groups [0.3% versus 0%; risk difference: 0.29% (95% confidence interval: -0.19; 0.77; P > 0.05)]. Incidence of composite cardiovascular AEs was significantly lower in the IIM versus IS group (4.1% versus 6.9%; P = 0.025). Compared with IS, IIM led to a more pronounced increase in Hb during the first 4 weeks (P ≤ 0.021), and change in Hb to Week 8 showed non-inferiority, confirming that the co-primary efficacy objective was met.. Compared with multiple doses of IS, a single dose of IIM induced a non-inferior 8-week haematological response, comparably low rates of hypersensitivity reactions, and a significantly lower incidence of composite cardiovascular AEs.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Disaccharides; Female; Ferric Compounds; Ferric Oxide, Saccharated; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Male; Middle Aged; Prospective Studies; Renal Insufficiency, Chronic; Time Factors

Pediatric patients with advanced chronic kidney disease (CKD) are often prescribed oral phosphate binders (PBs) for the management of hyperphosphatemia. However, available PBs have limitations, including unfavorable tolerability and safety.. This phase 3, multicenter, randomized, open-label study investigated safety and efficacy of sucroferric oxyhydroxide (SFOH) in pediatric and adolescent subjects with CKD and hyperphosphatemia. Subjects were randomized to SFOH or calcium acetate (CaAc) for a 10-week dose titration (stage 1), followed by a 24-week safety extension (stage 2). Primary efficacy endpoint was change in serum phosphorus from baseline to the end of stage 1 in the SFOH group. Safety endpoints included treatment-emergent adverse events (TEAEs).. Eighty-five subjects (2-18 years) were randomized and treated (SFOH, n = 66; CaAc, n = 19). Serum phosphorus reduction from baseline to the end of stage 1 in the overall SFOH group (least squares [LS] mean ± standard error [SE]) was - 0.488 ± 0.186 mg/dL; p = 0.011 (post hoc analysis). Significant reductions in serum phosphorus were observed in subjects aged ≥ 12 to ≤ 18 years (LS mean ± SE - 0.460 ± 0.195 mg/dL; p = 0.024) and subjects with serum phosphorus above age-related normal ranges at baseline (LS mean ± SE - 0.942 ± 0.246 mg/dL; p = 0.005). Similar proportions of subjects reported ≥ 1 TEAE in the SFOH (75.8%) and CaAc (73.7%) groups. Withdrawal due to TEAEs was more common with CaAc (31.6%) than with SFOH (18.2%).. SFOH effectively managed serum phosphorus in pediatric patients with a low pill burden and a safety profile consistent with that reported in adult patients.

Topics: Adolescent; Child; Drug Combinations; Ferric Compounds; Humans; Hyperphosphatemia; Phosphorus; Renal Dialysis; Renal Insufficiency, Chronic; Sucrose

Ferric derisomaltose (FDI) is an intravenous (IV) high-dose iron formulation approved in the US for the treatment of iron deficiency anemia in adults who are intolerant of/have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FERWON-NEPHRO was a randomized, open-label, multicenter clinical trial evaluating the safety and efficacy of a single infusion of FDI 1,000 mg versus up to 5 doses of iron sucrose (IS) 200 mg (recommended cumulative dose, 1,000 mg) over 8 weeks in patients with NDD-CKD and iron deficiency anemia. Of 1,525 patients included in the safety analysis, 244 (16%) had a history of heart failure (HF). Overall, the rate of serious or severe hypersensitivity reactions was low and did not differ between treatment groups. Cardiovascular adverse events (AEs) were reported for 9.4% of patients who had HF and 4.2% who did not. Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% CI: 0.37, 0.92]; p=0.0185), a difference that was similar in patients with or without HF (p=0.908 for interaction). Patients achieved a faster hematological response (assessed by changes in hemoglobin and ferritin concentrations, and increase in transferrin saturation) with FDI versus IS. In conclusion, in patients with NDD-CKD, a single infusion of FDI was safe, well tolerated, and was associated with fewer cardiovascular AEs and a faster hematological response, compared to multiple doses of IS. These effects were similar for patients with and without HF.

Topics: Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Case-Control Studies; Disaccharides; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Heart Failure; Hematinics; Hemoglobins; Humans; Infusions, Intravenous; Male; Middle Aged; Proportional Hazards Models; Renal Insufficiency, Chronic; Severity of Illness Index; Transferrin; Treatment Outcome

Anaemia is common in haemodialysis (HD) patients and associated with significant morbidity and mortality. Intravenous (IV) iron combined with erythropoiesis-stimulating agents (ESA) is the mainstay treatment of anaemia in these patients. The comparative efficacy and risk of adverse events with IV iron preparations have been assessed in only a few trials.. This was a retrospective observational study in 2 centres designed to compare the safety and efficacy of iron sucrose (IS-Venofer®) versus iron isomaltoside (IIM-Diafer®) in haemodialysis patients. The study included patients currently on dialysis and receiving Venofer who were switched to Diafer® and monitored for at least 12 months for each iron preparation.. A total of 190 patients were included and had a mean age of 65.8 years (SD ± 15.5). Non-inferiority was confirmed with no change in mean haemoglobin per mg of iron administered over a 12-month period. In total there were 41,295 prescriptions of iron isomaltoside and 14,685 of iron sucrose with no difference in the number of reported adverse events during the study period (7 each, none were severe). There was a statistically significant effect on Hb over time after conversion, including adjustment for multiple comparisons. There were significant improvements in ferritin over time, which remained at 6 months (P < 0.01). The weekly iron dose was similar after adjustment (P = 0.02). The EPO dose did not differ significantly after month 0 in patients switched to IIM.. This study demonstrates the comparative safety and efficacy of iron isomaltoside versus iron sucrose, with similar dosing schedules in dialysis patients. Iron isomaltoside is non-inferior to iron sucrose in maintaining Hb in patients on regular haemodialysis/haemodiafiltration with no difference in the number of reported adverse events.

Topics: Aged; Anemia, Iron-Deficiency; Disaccharides; Ferric Compounds; Ferric Oxide, Saccharated; Hematinics; Hemoglobins; Humans; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies

Control of hyperphosphatemia in patients on dialysis remains a major challenge.. This study evaluated predictors of serum phosphorus (sP) control among dialysis patients treated with noncalcium, oral phosphate binder therapy in a phase 3 clinical trial.. Post hoc analyses were performed using data for patients with hyperphosphatemia who received 52 weeks of treatment with sucroferric oxyhydroxide (SFOH) or sevelamer carbonate (sevelamer). Patients were categorized into those who achieved sP control (n = 302; defined as sP ≤ 5.5 mg/dL at week 52), and those with uncontrolled sP (n = 195; sP >5.5 mg/dL at week 52). Because SFOH and sevelamer have previously demonstrated similar effects on chronic kidney disease-mineral-bone disorder parameters in this study, the treatment groups were pooled.. Average age at baseline was higher among sP-controlled versus sP-uncontrolled patients (56.9 vs. 53.4 years; p = 0.005). Baseline sP levels were significantly lower among sP-controlled versus sP-uncontrolled patients (7.30 vs. 7.85 mg/dL; p < 0.001), and sP reductions from baseline were significantly greater in the sP-controlled group (-2.89 vs. -0.99 mg/dL at week 52; p < 0.001). Logistic regression analysis identified higher baseline sP levels (odds ratio [OR] = 0.86, 95% confidence interval [CI]: 0.765-0.960), no concomitant active vitamin D therapy use (OR = 0.51, 95% CI: 0.328-0.804), and higher body mass index at baseline (OR = 0.96, 95% CI: 0.937-0.992) as significant predictors of uncontrolled sP.. This analysis indicates that sP control may be more challenging in younger patients with high sP levels. Closer monitoring and management of serum phosphorus levels may be required in this population.

Topics: Adult; Age Factors; Aged; Calcimimetic Agents; Chelating Agents; Drug Combinations; Female; Ferric Compounds; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperphosphatemia; Logistic Models; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Renal Dialysis; Renal Insufficiency, Chronic; Sevelamer; Sucrose; Vitamin D

Patients with chronic kidney disease (CKD) undergoing dialysis often require intravenous iron for iron deficiency anemia (IDA).. The Ferumoxytol for Anemia of CKD Trial (FACT), a randomized, multicenter, open-label, phase 4 study, compared the long-term safety and efficacy of ferumoxytol with iron sucrose for the treatment of IDA in patients with CKD undergoing hemodialysis. Patients with IDA and CKD undergoing hemodialysis were randomized 2:1 to ferumoxytol 1.02 g (2 × 510 mg) or iron sucrose 1.0 g (10 × 100 mg) for a 5-week treatment period (TP). Over 11 months, patients underwent additional 5-week TPs whenever IDA (hemoglobin < 11.5 g/dL and transferrin saturation < 30%) was detected. The primary efficacy endpoint was mean change in hemoglobin from baseline to week 5 for each TP. Adverse events were recorded during the study.. Overall, 293 patients received ferumoxytol (n = 196) or iron sucrose (n = 97). Ferumoxytol was noninferior to iron sucrose regarding hemoglobin change from baseline to week 5. The mean change in hemoglobin in the ferumoxytol and iron sucrose groups was 0.5 and 0.4 g/dL, respectively, in TP 1 (least-squares mean difference, 0.13; 95% confidence interval, -0.11 to 0.36) and 0.6 and 0.3 g/dL, respectively, in TP 2 (0.30; 0.06 - 0.55). Treatment-related and serious adverse events were similar in both groups; no new safety signals emerged.. Long-term administration of ferumoxytol has noninferior efficacy and a similar safety profile to iron sucrose when used to treat IDA in patients with CKD undergoing hemodialysis.
.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Female; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Young Adult

Intravenous (IV) iron is frequently used to treat iron deficiency/anemia in patients who are unable to tolerate oral iron or the oral iron is not sufficient toreplete iron requirements. However, safety concerns regarding the potential increase in oxidative stress and other adverse effects persist and it remains unclear whether all iron preparations are equivalent. Indeed, the comparative risk of adverse events with IV iron preparations has not been extensively assessed. We hypothesize that IV iron leads to changes in oxidative stress, endothelial function, and potential renal damage depending on the iron formulation (related to the generation of "free" or catalytic labile iron) and this may result in more tubular and glomerular injury manifested as increased proteinuria and raised neutrophil gelatinase-associated lipocalin (NGAL) levels in patients with chronic kidney disease (CKD).. IRON-CKD is a prospective, open-label, explorative, randomized, single-center study designed to compare the safety and efficacy of three parenteral iron preparations: low-molecular-weight iron dextran-Cosmofer, iron sucrose-Venofer, and iron isomaltoside-Monofer. The study includes 40 adults who have established CKD stages 3-5 and serum ferritin (SF) of less than 200 μg/L or transferrin saturation (TS) of less than 20% (or both); they were randomly assigned in a 1:1:1:1 ratio to 200 mg iron dextran, 200 mg iron sucrose, 200 mg iron isomaltoside, or 1000 mg iron isomaltoside. After randomization, participants undergo baseline assessments and then an iron infusion. Each participant is followed up at 2 h, day 1, week 1, and months 1 and 3. At each follow-up visit, patients undergo clinical review, measurement of pulse wave velocity (PWV), blood tests for renal function, and collection of serum/plasma samples for oxidative stress and inflammatory markers. The primary outcomes are measures of oxidative stress, inflammatory markers, and markers of acute renal injury in comparison with baseline measures of each iron preparation and between each of the iron preparations. Secondary objectives include effects on hematinic profiles and hemoglobin concentrations, changes in arterial stiffness, incidence of significant side effects, and change in patients' quality of life.. Between October 2015 and April 2018, 521 individuals were identified as potential participants; 216\ were contacted, 56 expressed an interest, 49 attended a screening visit, and 40 were confirmed to meet the eligibility criteria and were randomly assigned. The mean age was 58.8 (standard error of the mean 2.2) years, and 23 (58%) were male. All patients were white and English-speaking. The mean SF was 68.8 μg/L, TS was 21.4%, and haemoglobin was 122.6 g/L at randomization for the whole group. The mean estimated glomerular filtration rate was 28.2 mL/min/1.73 m2 the urinary protein/ creatinine ratio was 154.2 mg/mmol, and CRP was 7.5 mg/L.. IRON-CKD will provide important information on the short-term effects of three preparations of IV iron in CKD patients with biochemical functional or absolute iron deficiency on measures of oxidative stress, inflammation, endothelial function, and renal injury.. European Clinical Trials Database (EudraCT) number 2010-020452-64 .

Topics: Acute Kidney Injury; Anemia, Iron-Deficiency; Biomarkers; Disaccharides; England; Female; Ferric Compounds; Ferric Oxide, Saccharated; Hematinics; Hemoglobins; Humans; Inflammation Mediators; Infusions, Intravenous; Iron-Dextran Complex; Kidney; Lipocalin-2; Male; Middle Aged; Oxidative Stress; Prospective Studies; Proteinuria; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome

Iron administration affects serum levels of intact (I-) fibroblast growth factor-23 (FGF23) and its cleavage product C-terminal (C-) FGF23 in iron-deficient patients on maintenance hemodialysis (MHD). The objective of this study was to compare the effect of oral or intravenous iron administration on serum levels of I-FGF23 and C-FGF23 in iron-deficient patients on MHD.. A prospective randomized study.. Participants on MHD with severe iron deficiency (n = 61).. Participants were randomized to receive oral iron (50 mg of sodium ferrous citrate daily; oral group, n = 29) or intravenous iron (40 mg of saccharated ferric oxide weekly; IV group, n = 32).. Changes in I-FGF23 and C-FGF23 after 10 weeks of treatment.. Iron supplementation significantly increased hemoglobin, mean corpuscular volume, ferritin, and transferrin saturation rate, and decreased erythropoiesis-stimulating agent dose and erythropoiesis-stimulating agent resistance index value. Serum phosphate, calcium, and intact parathyroid hormone levels did not change significantly during the study. I-FGF23 levels increased significantly in the IV group and did not change in the oral group, whereas C-FGF23 levels were significantly reduced in both groups. Serum interleukin-6 and tumor necrosis factor-α levels were increased in both groups. Multiple regression analysis indicated the relationship between iron or erythropoiesis and FGF23 metabolism.. Iron administration to patients on MHD with severe iron deficiency decreased C-FGF23 levels, whereas intravenous iron increased I-FGF23 levels though oral iron did not. If the target of chronic kidney disease-mineral and bone disorder therapy is reducing I-FGF23 levels, we suggest the use of oral iron.

Topics: Administration, Intravenous; Administration, Oral; Aged; Anemia, Iron-Deficiency; Citric Acid; Dietary Supplements; Female; Ferric Oxide, Saccharated; Ferrous Compounds; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Male; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

We aimed to investigate the non-inferiority of PA21 (sucroferric oxyhydroxide) to sevelamer hydrochloride (sevelamer) in terms of efficacy and safety in Japanese haemodialysis patients with hyperphosphataemia.. In this Phase III, open-label, multicentre study, 213 haemodialysis patients with hyperphosphataemia were randomized to PA21 or sevelamer treatment for 12 weeks. The primary outcome was adjusted serum phosphorus concentration at the end of treatment; the non-inferiority of PA21 was confirmed if the upper limit of the two-sided 95% confidence interval (CI) is ≤0.32 mmol/L. Secondary outcomes were corrected serum calcium and intact-parathyroid hormone concentrations. Adverse events (AEs) and adverse drug reactions (ADRs) were evaluated.. The adjusted mean serum phosphorus concentration at the end of treatment confirmed the non-inferiority of PA21 for lowering serum phosphorus compared with sevelamer (1.62 vs 1.72 mmol/L; difference, -0.11 mmol/L; 95% CI, -0.20 to -0.02 mmol/L). The mean daily tablet intake was 5.6 ± 2.6 and 18.7 ± 7.1 tablets in the PA21 and sevelamer groups, respectively. The incidences of AEs and ADRs were not significantly different between the two groups.. The non-inferiority of PA21 to sevelamer was confirmed for the treatment of Japanese haemodialysis patients with hyperphosphataemia. PA21 was effective, safe, and well tolerated, while having a considerably lower pill burden than sevelamer.

Topics: Administration, Oral; Aged; Biomarkers; Calcium; Chelating Agents; Drug Administration Schedule; Drug Combinations; Female; Ferric Compounds; Humans; Hyperphosphatemia; Japan; Male; Middle Aged; Parathyroid Hormone; Phosphorus; Renal Dialysis; Renal Insufficiency, Chronic; Sevelamer; Sucrose; Tablets; Time Factors; Treatment Outcome

Many patients with chronic kidney disease are prescribed vitamin D receptor agonists (VDRAs) for the management of secondary hyperparathyroidism. Oral phosphate binders may interact with, and potentially reduce the therapeutic activity of, oral VDRAs. This post hoc analysis of a Phase 3 study evaluated the pharmacodynamic effects of the iron-based phosphate binder sucroferric oxyhydroxide (SFOH) and sevelamer (SEV) carbonate on VDRA activity in dialysis patients.. One thousand and fifty nine patients were randomized to SFOH 1.0-3.0 g/day (n = 710) or SEV 2.4-14.4 g/day (n = 349) for up to 52 weeks. Potential interactions of SFOH and SEV with VDRAs were assessed using serum intact parathyroid hormone (iPTH) concentrations as a pharmacodynamic biomarker. Three populations of SFOH- and SEV-treated patients were analyzed: Population 1 (n = 187), patients taking concomitant stable doses of oral VDRAs only; Population 2 (n = 250), patients taking no concomitant VDRAs; Population 3 (n = 68), patients taking concomitant stable doses of intravenous paricalcitol only. Populations were compared using a mixed-effects model to obtain the least squares mean change in iPTH from baseline to Week 52. Differences between treatment groups were also compared.. In Population 1, iPTH decreased from baseline to Week 52 in the SFOH group (-25.3 pg/ml) but increased in the SEV group (89.8 pg/ml) (p = 0.02). In Population 2, iPTH increased to a similar extent in both treatment groups. In Population 3, iPTH concentrations in both treatment groups decreased to a similar degree (-29.6 and -11.4 pg/ml for SFOH and SEV, respectively; p = 0.87).. In contrast with SEV, SFOH did not appear to impact the iPTH-lowering effect of oral VDRAs.

Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Biomarkers, Pharmacological; Bone Density Conservation Agents; Chelating Agents; Drug Combinations; Drug Interactions; Ergocalciferols; Female; Ferric Compounds; Humans; Hyperparathyroidism, Secondary; Hyperphosphatemia; Male; Middle Aged; Parathyroid Hormone; Receptors, Calcitriol; Renal Dialysis; Renal Insufficiency, Chronic; Sevelamer; Sucrose

Intravenous iron affects serum levels of intact fibroblast growth factor-23 (iFGF23) and its cleavage product c-terminal FGF23 (cFGF23) in iron-deficient people with normal renal function. We hypothesized that intravenous iron modulates iFGF23 and cFGF23 in haemodialysis patients differently according to the type of iron used.. Prevalent, stable haemodialysis patients requiring protocol-based intravenous iron therapy were randomized to a single 200 mg dose of either ferric carboxymaltose (FCM) or iron sucrose (IS). The primary outcome was change in iFGF23 and cFGF23 from pre-infusion to Day 2 post-infusion. Serum hepcidin, ferritin and phosphate were also measured. Pair-wise comparisons utilised the Wilcoxon rank sum test; linear mixed models with an interaction term for treatment and time evaluated between-group effects.. Forty-two participants completed the study. In those randomized to FCM (n = 22), median (interquartile range) values pre-infusion and Day 2, respectively, were 843 pg/mL (313-1922) and 576 pg/mL (356-1296, p = 0.05) for iFGF23, 704RU/mL (475-1204) and 813RU/mL (267-1156, p = 0.04) for cFGF23, and 1.53 mmol/L (1.14-1.71) and 1.37 (1.05-1.67, p = 0.03) for phosphate. These parameters did not change following IS. Both serum ferritin (p < 0.001) and hepcidin (p < 0.001) increased in both groups, and the increase in hepcidin was greater in the FCM group (p = 0.03 for between-group difference).. Contrary to iron-deficient people with normal renal function, haemodialysis patients given protocol-driven intravenous FCM demonstrated a fall in iFGF23 and a rise in cFGF23, changes not evident with IS. This suggests a differential effect of intravenous iron treatment according to both formulation and renal function.. Australian and New Zealand Clinical Trials Register ACTRN12614000548639 . Registered 22 May 2014 (retrospectively registered).

Topics: Administration, Intravenous; Aged; Female; Ferric Compounds; Ferric Oxide, Saccharated; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Glucaric Acid; Hematinics; Humans; Male; Maltose; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic

Treatment of iron deficiency helps to improve cardiac and renal function in patients with chronic heart failure. However, the mechanism by which this occurs is currently unclear.. We undertook a double-blind, randomised, placebo-controlled study of intravenous iron sucrose treatment (200mg/mL weekly for five weeks) in patients with chronic heart failure, chronic kidney disease and iron-deficiency anaemia receiving optimal treatment for chronic heart failure (N=60). Markers of disease severity, iron status, anaemia and inflammation were measured during a six-month follow-up period, and evaluation of echocardiographic parameters was performed at baseline and six months after treatment.. At six months after treatment initiation, intravenous iron was associated with reduced severity of the symptoms of chronic heart failure and improved renal function (both p<0.001 versus control). Also, ferritin and transferrin saturation levels were increased, as were haemoglobin levels, whereas inflammatory markers were reduced (all p<0.001 versus control). Left ventricular systolic and diastolic diameters were increased and improved left ventricular function correlated with iron status in patients receiving intravenous iron but not patients in the control group.. Intravenous iron treatment was associated with improved myocardial functional parameters and cardiac dimensions in patients with anaemia and chronic kidney disease.

Topics: Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Double-Blind Method; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Heart Failure; Hematinics; Humans; Iron; Iron Deficiencies; Male; Pilot Projects; Renal Insufficiency, Chronic; Ventricular Function, Left

Iron deficiency anaemia is common in patients with chronic kidney disease, and intravenous iron is the preferred treatment for those on haemodialysis. The aim of this trial was to compare the efficacy and safety of iron isomaltoside 1000 (Monofer®) with iron sucrose (Venofer®) in haemodialysis patients.. This was an open-label, randomized, multicentre, non-inferiority trial conducted in 351 haemodialysis subjects randomized 2:1 to either iron isomaltoside 1000 (Group A) or iron sucrose (Group B). Subjects in Group A were equally divided into A1 (500 mg single bolus injection) and A2 (500 mg split dose). Group B were also treated with 500 mg split dose. The primary end point was the proportion of subjects with haemoglobin (Hb) in the target range 9.5-12.5 g/dL at 6 weeks. Secondary outcome measures included haematology parameters and safety parameters.. A total of 351 subjects were enrolled. Both treatments showed similar efficacy with >82% of subjects with Hb in the target range (non-inferiority, P = 0.01). Similar results were found when comparing subgroups A1 and A2 with Group B. No statistical significant change in Hb concentration was found between any of the groups. There was a significant increase in ferritin from baseline to Weeks 1, 2 and 4 in Group A compared with Group B (Weeks 1 and 2: P < 0.001; Week 4: P = 0.002). There was a significant higher increase in reticulocyte count in Group A compared with Group B at Week 1 (P < 0.001). The frequency, type and severity of adverse events were similar.. Iron isomaltoside 1000 and iron sucrose have comparative efficacy in maintaining Hb concentrations in haemodialysis subjects and both preparations were well tolerated with a similar short-term safety profile.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Disaccharides; Early Intervention, Educational; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Hematinics; Hemoglobins; Humans; Maintenance Chemotherapy; Male; Middle Aged; Prospective Studies; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome; Young Adult

Although iron is commonly used to correct iron deficiency anemia (IDA) in chronic kidney disease (CKD), its effect on kidney function is unclear. To assess this, we randomly assigned patients with stage 3 and 4 CKD and IDA to either open-label oral ferrous sulfate (69 patients to 325 mg three times daily for 8 weeks) or intravenous iron sucrose (67 patients to 200 mg every 2 weeks, total 1 g). The primary outcome was the between-group difference in slope of measured glomerular filtration rate (mGFR) change over two years. The trial was terminated early on the recommendation of an independent data and safety monitoring board based on little chance of finding differences in mGFR slopes, but a higher risk of serious adverse events in the intravenous iron treatment group. mGFR declined similarly over two years in both treatment groups (oral -3.6 ml/min per 1.73 m(2), intravenous -4.0 ml/min per 1.73 m(2), between-group difference -0.35 ml/min per 1.73 m(2); 95% confidence interval -2.9 to 2.3). There were 36 serious cardiovascular events among 19 participants assigned to the oral iron treatment group and 55 events among 17 participants of the intravenous iron group (adjusted incidence rate ratio 2.51 (1.56-4.04)). Infections resulting in hospitalizations had a significant adjusted incidence rate ratio of 2.12 (1.24-3.64). Thus, among non-dialyzed patients with CKD and IDA, intravenous iron therapy is associated with an increased risk of serious adverse events, including those from cardiovascular causes and infectious diseases.

Topics: Administration, Intravenous; Administration, Oral; Aged; Anemia, Iron-Deficiency; Biomarkers; Disease Progression; Early Termination of Clinical Trials; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferrous Compounds; Glomerular Filtration Rate; Glucaric Acid; Hematinics; Hemoglobins; Humans; Indiana; Kidney; Male; Middle Aged; Quality of Life; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome

Iron-deficiency anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) frequently requires parenteral iron replacement, but existing therapies often require multiple administrations. We evaluated the efficacy and cardiovascular safety of ferric carboxymaltose (FCM), a non-dextran parenteral iron permitting large single-dose infusions, versus iron sucrose in patients with iron-deficiency anemia and NDD-CKD.. A total of 2584 participants were randomized to two doses of FCM 750 mg in one week, or iron sucrose 200 mg administered in up to five infusions in 14 days. The primary efficacy endpoint was the mean change to highest hemoglobin from baseline to Day 56. The primary composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, congestive heart failure, arrhythmias and hyper- and hypotensive events.. The mean hemoglobin increase was 1.13 g/dL in the FCM group and 0.92 g/dL in the iron sucrose group (95% CI, 0.13-0.28). Similar results were observed across all subgroups, except Stage 2 CKD. More subjects in the FCM group achieved a hemoglobin increase of ≥ 1.0 g/dL between baseline and Day 56 (48.6 versus 41.0%; 95% CI, 3.6-11.6%). There was no significant difference between FCM and iron sucrose recipients with respect to the primary composite safety endpoint, including the major adverse cardiac events of death, myocardial infarction, or stroke. A significant difference in the number of protocol-defined, predominantly transient hypertensive episodes was observed in the FCM group.. Two 750-mg infusions of FCM are a safe and effective alternative to multiple lower dose iron sucrose infusions in NDD-CKD patients with iron-deficiency anemia.

Topics: Aged; Anemia, Iron-Deficiency; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glomerular Filtration Rate; Glucaric Acid; Hematinics; Hemoglobins; Humans; Infusions, Intravenous; Iron; Male; Maltose; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

Few randomized controlled trials have compared intravenous iron products head to head in CKD patients with iron deficiency anemia. This study compared the efficacy and safety of two intravenous iron products (ferumoxytol [Feraheme injection] and iron sucrose [Venofer]) in patients with CKD and iron deficiency anemia.. In this phase II, randomized, open-label, active-controlled, multicenter clinical trial, patients were randomized 1:1 to either 1.02 g ferumoxytol (2 × 510-mg injections) or 1.0 g iron sucrose administered as either a slow injection or infusion (10 doses for dialysis patients and 5 doses for nondialysis patients). Inclusion criteria included hemoglobin<11.0 g/dl, transferrin saturation<30%, and eGFR<60 ml/min per 1.73 m(2) or a diagnosis of underlying CKD (e.g., nephropathy or nephritis). The primary end point was change in hemoglobin from baseline to week 5.. In total, 162 patients were randomized. Demographics were balanced between the treatment groups. Adverse event profiles of the two regimens were fairly similar: overall adverse events, 48% ferumoxytol versus 65% iron sucrose; related adverse events, 10% ferumoxytol versus 16% iron sucrose; and adverse events leading to study discontinuation, 1% ferumoxytol versus 5% iron sucrose. Rates of serious adverse events and related serious adverse events were similar between the ferumoxytol and iron sucrose groups: serious adverse events, 9% versus 7%, respectively and related serious adverse events, 1% versus 1%, respectively. Overall, increases in hemoglobin were similar between treatment groups. Based on an ANOVA model adjusted for baseline hemoglobin level and dialysis status, the least squares mean change from baseline to week 5 was 0.8 ± 0.1 g/dl in the ferumoxytol-treated group and 0.7 ± 0.1 g/dl in the iron sucrose group. The difference in the mean change from baseline between the two treatment groups was 0.1 g/dl (95% confidence interval, -0.2 to 0.4).. In this randomized, controlled trial, ferumoxytol and iron sucrose showed comparable efficacy and adverse events rates.

Topics: Aged; Anemia, Iron-Deficiency; Biomarkers; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Glucaric Acid; Hematinics; Hemoglobins; Humans; Infusions, Intravenous; Injections, Intravenous; Least-Squares Analysis; Male; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Time Factors; Treatment Outcome

Iron deficiency is a common cause of anemia in young persons with chronic kidney disease (CKD). Iron repletion with intravenous (IV) iron formulations has been studied in children; maintenance IV iron regimens have not been reported extensively.. A multicenter randomized trial of IV iron sucrose.. 145 children, adolescents, and young adults with CKD receiving erythropoiesis-stimulating agent (ESA) therapy were stratified by dialysis category (hemodialysis, peritoneal dialysis, or non-dialysis dependent) and weight (<50 and ≥50 kg).. Patients were randomly assigned to 1 of 3 dosing arms: 0.5, 1.0, or 2.0 mg/kg (maximum single dose, 100 mg), stratified into hemodialysis versus nonhemodialysis (peritoneal dialysis or non-dialysis-dependent CKD) groups. Patients treated with hemodialysis received study medication once every other week for 6 doses. Patients in the nonhemodialysis group received study medication once every 4 weeks for 3 doses.. We assessed adverse event rates between dosing groups. The main clinical end point was a composite of hemoglobin level ≥10.5-14.0 g/dL, inclusive; transferrin saturation ≥20%-50%, inclusive; and stable ESA dosing (±25% of baseline dose).. Between-group difference for composite clinical end point rate attainment was -3.9% (95% CI, -21.4% to 13.7%) for the 1.0-mg/kg group versus 0.5-mg/kg group, +3.9% (95% CI, -15.1% to 23.0%) for the 2-mg/kg group versus 0.5-mg/kg group, and +7.8% (95% CI, -10.9% to 26.5%) for the 2-mg/kg group versus 1-mg/kg group. No differences were noted between regimens in reported adverse effects, which were all minor.. Absence of a control group receiving no IV iron. Short duration of intervention and observation. A small proportion of patients having achieved the primary clinical outcome.. IV iron sucrose at a dose of 0.5 mg/kg at the intervals prescribed is noninferior to higher doses in maintaining hemoglobin levels >10.5 g/dL in children, adolescents, and young adults receiving ESA therapy.

Topics: Adolescent; Adult; Anemia, Iron-Deficiency; Child; Child, Preschool; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Humans; Infusions, Intravenous; Male; Peritoneal Dialysis; Prospective Studies; Renal Insufficiency, Chronic; Young Adult

Non-dextran intravenous (i.v.) iron preparations seem to differentially affect proteinuria in patients with chronic kidney disease. To study effects of ferric gluconate and iron sucrose on proteinuria, we conducted a crossover trial in 12 patients with stage 3-4 chronic kidney disease. These patients were randomized to receive the same dose of either drug 1 week apart. Urine samples were obtained immediately before and at frequent intervals after the drug. The urine total protein/creatinine ratio was significantly greater after iron sucrose than ferric gluconate treatment with the effect noted within 15 min post-infusion. Furthermore, when iron sucrose was given first, a significantly greater protein/creatinine ratio was seen subsequently with ferric gluconate than with the reverse order of treatment. The urine albumin/creatinine ratio was also significantly greater with iron sucrose than with ferric gluconate. There was no significant difference, however, between the two i.v. irons in the measured urine N-acetyl-beta-D-glucosaminidase/creatinine ratio. Although our study showed that acutely, iron sucrose increased proteinuria, the long-term effects of repeated i.v. non-dextran iron on kidney function requires further study.

Topics: Aged; Cross-Over Studies; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Male; Middle Aged; Proteinuria; Renal Insufficiency, Chronic; Treatment Outcome

Our objective was to evaluate in a double-blind, randomized, placebo-controlled study possible modifications in NT-pro-brain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) levels together with clinical and functional parameters, in a group of anemic patients with chronic heart failure (CHF) and chronic renal failure (CRF) receiving intravenous iron therapy, without recombinant human erythropoietin (rhEPO), versus placebo.. Chronic heart failure and CRF associated with absolute or relative iron deficiency anemia is a common problem. This situation is linked with a variable inflammatory status. Both NT-proBNP and CRP are recognized markers for left ventricular dysfunction and inflammatory status, respectively. In this double-blind, randomized, placebo-controlled study, modifications in NT-proBNP and CRP level and clinical and functional parameters, in anemic patients with CHF and CRF receiving intravenous iron therapy, without rhEPO, versus placebo were evaluated.. Forty patients with hemoglobin (Hb) <12.5 g/dl, transferrin saturation <20%, ferritin <100 ng/ml, creatinine clearance (CrCl) <90 ml/min, and left ventricular ejection fraction (LVEF) < or =35% were randomized into 2 groups (n = 20 for each). For 5 weeks, group A received isotonic saline solution and group B received iron sucrose complex, 200 mg weekly. Minnesota Living with Heart Failure Questionnaire (MLHFQ) and 6-min walk (6MW) test were performed. NT-pro brain natriuretic peptide and CRP were evaluated throughout the study. No patients received erythroprotein any time.. After 6 months follow-up, group B showed better hematology values and CrCl (p < 0.01) and lower NT-proBNP (117.5 +/- 87.4 pg/ml vs. 450.9 +/- 248.8 pg/ml, p < 0.01) and CRP (2.3 +/- 0.8 mg/l vs. 6.5 +/- 3.7 mg/l, p < 0.01). There was a correlation initially (p < 0.01) between Hb and NT-proBNP (group A: r = -0.94 and group B: r = -0.81) and after 6 months only in group A: r = -0.80. Similar correlations were observed with Hb and CRP. Left ventricular ejection fraction percentage (35.7 +/- 4.7 vs. 28.8 +/- 2.4), MLHFQ score, and 6MW test were all improved in group B (p < 0.01). Additionally, group B had fewer hospitalizations: 0 of 20 versus group A, 5 of 20 (p < 0.01; relative risk = 2.33).. Intravenous iron therapy without rhEPO substantially reduced NT-proBNP and inflammatory status in anemic patients with CHF and moderate CRF. This situation was associated with an improvement in LVEF, NYHA functional class, exercise capacity, renal function, and better quality of life.

Topics: Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Biomarkers; C-Reactive Protein; Double-Blind Method; Exercise Tolerance; Female; Ferric Compounds; Ferric Oxide, Saccharated; Follow-Up Studies; Glucaric Acid; Heart Failure; Hematinics; Hospitalization; Humans; Infusions, Intravenous; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Pilot Projects; Prospective Studies; Quality of Life; Renal Insufficiency, Chronic; Treatment Outcome

Although iron deficiency frequently complicates anemia in patients with nondialysis-dependent CKD (ND-CKD), the comparative treatment value of IV iron infusion and oral iron supplementation has not been established.. In a randomized, controlled multicenter trial, we compared the efficacy of iron sucrose, given as 1 g in divided IV doses over 14 days, with that of ferrous sulfate, given 325 mg orally thrice daily for 56 days in patients with ND-CKD stages 3 to 5, Hb < or =11 g/dL, TSAT < or =25%, and ferritin < or =300 ng/mL. Epoetin/darbepoetin therapy, if any, was not changed for eight weeks prior to or during the study.. The proportion of patients achieving the primary outcome (Hb increase > or =1 g/dL) was greater in the IV iron treatment group than in the oral iron treatment group (44.3% vs. 28.0%, P= 0.0344), as was the mean increase in Hb by day 42 (0.7 vs. 0.4 g/dL, P= 0.0298). Compared to those in the IV iron group, patients in the oral iron treatment group showed a greater decline in GFR during the study (-4.40 vs. -1.45 mL/min/1.73m2, P= 0.0100). No serious adverse drug events (ADE) were seen in patients administered IV iron sucrose as 200 mg IV over two to five minutes, but drug-related hypotension, including one event considered serious, occurred in two females weighing less than 65 kg after 500 mg doses were given over four hours.. IV iron administration using 1000 mg iron sucrose in divided doses is superior to oral iron therapy in the management of ND-CKD patients with anemia and low iron indices.

Topics: Administration, Oral; Aged; Anemia; Erythropoiesis; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hemoglobins; Humans; Injections, Intravenous; Iron; Male; Middle Aged; Patient Compliance; Quality of Life; Renal Insufficiency, Chronic; Treatment Outcome

Chronic kidney disease (CKD) is often complicated by anemia, which seriously affects the quality-of-life and prognosis of patients. These patients usually need iron replacement therapy. Oral iron affects the composition and abundance of intestinal flora by increasing intestinal iron concentration.. We undertook an interventional study to investigate the effects of oral versus intravenous iron therapy on the gut microbiota. Oral ferrous succinate tablets (n = 14) or intravenous iron sucrose (n = 14) was administered to anemic maintenance hemodialysis (MHD) patients for 2 months.. Oral and intravenous iron treatments had different effects on gut microbial composition and diversity. After oral iron treatment, the α-diversity was decreased, while at the phylum level, the abundance of Firmicutes was reduced and the abundance of Bacteroides was increased. At the genus level, the abundance of Blautia and Coprococcus was decreased, and the abundance of Bacteroidetes was increased. Oral iron therapy was associated with a higher abundance of Lactobacillus compared with that measured in intravenous iron-treated patients. According to metagenome function prediction analysis, oral iron increased the metabolic processes of phenylalanine, valine, leucine, and isoleucine. These changes may increase uremic toxin levels, thereby increasing the progression of renal disease.. Iron therapy affects the diversity and composition of gut flora in MHD patients. Oral iron affects the number of bacteria and increases amino acid metabolism compared with intravenous iron. These results indicate that intravenous iron may be more appropriate for MHD patients.

Topics: Anemia; Ferric Oxide, Saccharated; Gastrointestinal Microbiome; Humans; Iron; Renal Dialysis; Renal Insufficiency, Chronic

Anemia and chronic kidney disease-mineral and bone disorder (CKD-MBD) are common and begin early in CKD. Limited studies have concurrently compared the effects of ferric citrate (FC) versus intravenous (IV) iron on CKD-MBD and iron homeostasis in moderate CKD.. We tested the effects of 10 weeks of 2% FC versus IV iron sucrose in rats with moderate CKD (Cy/+ male rat) and untreated normal (NL) littermates. Outcomes included a comprehensive assessment of CKD-MBD, iron homeostasis and oxidative stress.. CKD rats had azotemia, elevated phosphorus, parathyroid hormone and fibroblast growth factor-23 (FGF23). Compared with untreated CKD rats, treatment with FC led to lower plasma phosphorus, intact FGF23 and a trend (P = 0.07) toward lower C-terminal FGF23. FC and IV iron equally reduced aorta and heart calcifications to levels similar to NL animals. Compared with NL animals, CKD animals had higher bone turnover, lower trabecular volume and no difference in mineralization; these were unaffected by either iron treatment. Rats treated with IV iron had cortical and bone mechanical properties similar to NL animals. FC increased the transferrin saturation rate compared with untreated CKD and NL rats. Neither iron treatment increased oxidative stress above that of untreated CKD.. Oral FC improved phosphorus homeostasis, some iron-related parameters and the production and cleavage of FGF23. The intermittent effect of low-dose IV iron sucrose on cardiovascular calcification and bone should be further explored in moderate-advanced CKD.

Topics: Animals; Biomarkers; Chronic Kidney Disease-Mineral and Bone Disorder; Ferric Compounds; Ferric Oxide, Saccharated; Fibroblast Growth Factors; Homeostasis; Iron; Male; Minerals; Parathyroid Hormone; Phosphorus; Rats; Renal Insufficiency, Chronic; Transferrins

The high incidence of vascular calcification (VC) in patients with chronic kidney disease (CKD) has become an important clinical subject. Hyperphosphatemia is a primary cause of CKD-related VC. Intravenous iron sucrose (IS) is commonly used to treat anemia in CKD patients, and is effective and well tolerated worldwide. However, the interaction between iron and VC remains controversial, and the underlying mechanisms are yet to be clarified. In the present study, ex vivo normal rat aortic rings were cultured with various concentrations of phosphate and IS, and the levels of calcium and iron depositions, oxidative injury, as well as phenotypic marker genes were detected. To the best of our knowledge, the present study is the first to report that IS is a double-edged sword in high phosphate media-induced VC which not only alleviates VC in a dose-dependent manner but also leads to iron overload in vasculature when in high concentration. IS is a promising agent for VC prevention in patients with hyperphosphatemia and iron deficiency. Meanwhile, the appropriate blood concentration of IS in patients with hyperphosphatemia needs to be explored clinically.

Topics: Animals; Ferric Oxide, Saccharated; Humans; Hyperphosphatemia; Phosphates; Rats; Renal Insufficiency, Chronic; Vascular Calcification

Iron sucrose (FeS) administration induces a state of renal preconditioning, protecting against selected forms of acute kidney injury (AKI). Recent evidence suggests that recombinant hepcidin also mitigates acute renal damage. Hence the goals of this study were to determine whether a new proprietary FeS formulation ('RBT-3') can acutely activate the hepcidin (HAMP1) gene in humans, raising plasma and renal hepcidin concentrations; assess whether the kidney participates in this posited RBT-3-hepcidin generation response; test whether RBT-3 can mitigate a clinically relevant AKI model (experimental cisplatin toxicity) and explore whether mechanisms in addition to hepcidin generation are operative in RBT-3's cytoprotective effects.. Healthy human volunteers (n = 9) and subjects with Stages 3-4 CKD (n = 9) received 120, 240 or 360 mg of RBT-3 (intravenously over 2 h). Plasma and urine samples were collected and assayed for hepcidin levels (0-72 h post-RBT-3 injection). In complementary mouse experiments, RBT-3 effects on hepatic versus renal hepcidin (HAMP1) messenger RNA (mRNA) and protein levels were compared. RBT-3's impact on the mouse Nrf2 pathway and on experimental cisplatin nephrotoxicity was assessed. Direct effects of exogenous hepcidin on in vivo and in vitro (HK-2 cells) cisplatin toxicity were also tested.. RBT-3 induced rapid, dose-dependent and comparable plasma hepcidin increases in both healthy volunteers and chronic kidney disease subjects (∼15 times baseline within 24 h). Human kidney hepcidin exposure was confirmed by 4-fold urinary hepcidin increases. RBT-3 up-regulated mouse hepcidin mRNA, but much more so in kidney (>25 times) versus liver (∼2 times). RBT-3 also activated kidney Nrf2 [increased Nrf2 nuclear binding; increased Nrf2-responsive gene mRNAs: heme oxygenase-1, sulfiredoxin-1, glutamate-cysteine ligase catalytic subunit and NAD(P)H quinone dehydrogenase 1]. RBT-3 preconditioning (18 h time lapse) markedly attenuated experimental cisplatin nephrotoxicity (∼50% blood urea nitrogen/creatinine decrements), in part by reducing renal cisplatin uptake by 40%. Exogenous hepcidin (without RBT-3) treatment conferred protection against mild in vivo (but not in vitro) cisplatin toxicity.. RBT-3 acutely and dramatically up-regulates cytoprotective hepcidin production, increasing renal hepcidin levels. However, additional cytoprotective mechanisms are activated by RBT-3 (e.g. Nrf2 activation; reduced cisplatin uptake). Thus RBT-3-induced preconditioning likely confers renal resistance to cisplatin via an interplay of multiple cytoprotective activities.

Topics: Aged; Animals; Antineoplastic Agents; Case-Control Studies; Cisplatin; Drug Resistance; Female; Ferric Oxide, Saccharated; Gene Expression Regulation; Hepcidins; Humans; Kidney; Liver; Male; Mice; Middle Aged; Renal Insufficiency, Chronic

Decreased erythropoietin levels and impaired iron metabolism due to excessive hepcidin levels are responsible for renal anaemia in patients undergoing haemodialysis. Recently, erythroferrone (ERFE) has been identified as a factor that regulates hepcidin. In addition, fibroblast growth factor 23 (FGF23), which has been recognized as a phosphorus-regulating hormone, appears to be involved in haematopoietic regulation. Clarification of the detailed mechanism of haematopoiesis could lead to the improvement of renal anaemia treatment.. Epoetin beta pegol (CERA) was administered to patients undergoing haemodialysis at week 0, and the same amount of CERA with saccharated ferric oxide (SFO) was administered at week 4. The changes in haematopoiesis-related biomarkers, including ERFE, intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23), and inflammatory markers, were examined.. Administration of CERA increased ERFE levels, decreased hepcidin levels, and stimulated iron usage for haematopoiesis, leading to an increase in reticulocytes (Ret) and haemoglobin (Hb). Simultaneous administration of SFO with CERA (CERA + SFO) significantly attenuated the responses of ERFE, Ret, and Hb compared with CERA alone. Although iFGF23 levels were not affected by either CERA or CERA + SFO, cFGF23 was significantly elevated from baseline after CERA. Since cFGF23 levels were not affected by CERA + SFO, cFGF23 levels after CERA + SFO were significantly lower than those after CERA alone. The ratio of iFGF23 to cFGF23 (i/cFGF23 ratio) was significantly higher after CERA + SFO than that after CERA alone. In addition, high-sensitivity C-reactive protein (hsCRP) levels were significantly higher after CERA + SFO than after CERA alone.. Administration of SFO suppressed haematopoietic responses induced by CERA. Elevation of i/cFGF23 ratio and hsCRP could account for the inhibitory effects of SFO on haematopoiesis.. This study was registered with the University Hospital Medical Information Network (ID UMIN000016552 ).

Topics: Aged; Anemia; Biomarkers; Erythropoiesis; Erythropoietin; Female; Ferric Oxide, Saccharated; Fibroblast Growth Factor-23; Humans; Iron; Male; Peptide Hormones; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

Scientific data regarding intravenous iron supplementation in peritoneal dialysis (PD) patients are scarce. In attempting to administer the minimum monthly IV iron dose that could improve erythropoiesis, we wanted to assess the safety and efficacy of monthly maintenance intravenous administration of 100 mg iron sucrose in PD patients.. In a 9-month prospective study, all clinically stable PD patients received intravenously 200 mg of iron sucrose as a loading dose, followed by monthly doses of 100 mg for five consecutive months. Levels of hemoglobin (Hb), ferritin, transferrin saturation (TSAT), reticulocyte hemoglobin content (CHr) and C-reactive protein (CRP) were measured before each administration and 3 months after the last iron infusion. Also, doses of concurrent erythropoietin administration were recorded.. Eighteen patients were eligible for the study. Mean levels of Hb and ferritin increased significantly (from 10.0 to 10.9 mg/dL, p = 0.01 and from 143 to 260 ng/mL, p = 0.005), as well as the increase in TSAT levels approached borderline significance (from 26.2 to 33.1%, p = 0.07). During the 6 months of iron administration, the erythropoietin dose was reduced in five patients and discontinued in one. During the 3 months following the last iron infusion, three of them again raised the erythropoietin dose to previous levels. None of the patients experienced any side effects related to IV iron administration.. A monthly maintenance intravenous dose of 100 mg iron sucrose may be a practical, effective, and safe in the short term, treatment of anemia in PD patients resulting in improved hemoglobin levels, iron indices, and erythropoietin response.

Topics: Administration, Intravenous; Aged; Aged, 80 and over; Anemia; C-Reactive Protein; Erythropoiesis; Erythropoietin; Female; Ferric Oxide, Saccharated; Ferritins; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Peritoneal Dialysis; Prospective Studies; Renal Insufficiency, Chronic; Reticulocytes; Transferrin

In patients with chronic kidney disease (CKD), dysbiosis in the gastrointestinal microbiome is thought to be associated with increased production of uremic toxins, such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS). Sucroferric oxyhydroxide (SFO), an iron-based phosphate binder, may affect the gastrointestinal microbiome and the production of uremic toxins. We aimed to examine whether SFO administration affected distribution of gastrointestinal microbiome and serum uremic toxin levels in CKD patients undergoing hemodialysis.. In this single-center, open-label, interventional study, 18 maintenance hemodialysis patients with hyperphosphatemia were prescribed with SFO. We collected serum samples before and after 3 months of administration, and serum levels of IS and PCS were measured. A control group of 20 hemodialysis patients without SFO was evaluated. We evaluated gastrointestinal microbiome of patients pre- and post-SFO administration by 16S rDNA sequencing and bioinformatics analysis.. Serum IS and PCS levels were significantly elevated after administration of SFO (IS before 2.52 ± 1.60 mg/dl vs. after 3.13 ± 1.51 mg/dl, P = 0.008; PCS before 2.32 ± 2.44 mg/dl vs. after 3.45 ± 2.11 mg/dl, P = 0.002), while serum IS and PCS levels did not change in the control group. Microbiome analysis in the SFO group showed no significant change in diversity and major components in phylum, class, order, family, gene, and species.. Administration of SFO increased the serum levels of IS and PCS with no change of major components of gastrointestinal microbiome.

Topics: Aged; Aged, 80 and over; Case-Control Studies; Cresols; Drug Combinations; Dysbiosis; Feces; Ferric Compounds; Gastrointestinal Microbiome; Humans; Indican; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic; Sucrose; Sulfuric Acid Esters

Experimental data suggest that iron sucrose (FeS) injection, used either alone or in combination with other prooxidants, can induce "renal preconditioning," in part by upregulating cytoprotective ferritin levels. However, the rapidity, degree, composition (heavy vs. light chain), and renal ferritin changes after FeS administration in humans remain to be defined. To address these issues, healthy human volunteers (

Topics: Acute Kidney Injury; Adult; Aged; Animals; Biomarkers; Female; Ferric Oxide, Saccharated; Ferritins; Healthy Volunteers; Humans; Infusions, Parenteral; Ischemic Preconditioning; Kidney; Kidney Diseases; Male; Mice; Middle Aged; Renal Insufficiency, Chronic; RNA, Messenger; Spleen

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.. 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.. 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.. 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.

Topics: Cohort Studies; Creatinine; Dietary Proteins; Drug Combinations; Drug Substitution; Female; Ferric Compounds; Humans; Hypoalbuminemia; Male; Middle Aged; Parathyroid Hormone; Phosphates; Phosphorus; Renal Dialysis; Renal Insufficiency, Chronic; Retrospective Studies; Serum Albumin; Sucrose

Recent clinical studies indicate that the disturbed phosphate metabolism in chronic kidney disease (CKD) may facilitate kidney injury; nonetheless, the causal role of phosphate in CKD progression remains to be elucidated. Here, we show that intestinal phosphate binding by sucroferric oxyhydroxide (SF) ameliorates renal injury in the rat remnant kidney model. Sprague-Dawley rats received 5/6 nephrectomy (RK) and had a normal chow or the same diet containing SF (RK + SF). RK rats showed increased plasma FGF23 and phosphate levels, which were suppressed by SF administration. Of note, albuminuria in RK rats was significantly ameliorated by SF at both 4 and 8 weeks. SF also attenuated glomerulosclerosis and tubulointerstitial injury. Moreover, several different approaches confirmed the protective effects on podocytes, explaining the attenuation of glomerulosclerosis and albuminuria observed in this study. As a possible mechanism, we found that SF attenuated renal inflammation and fibrosis in RK rats. Interestingly, von Kossa staining of the kidney revealed calcium phosphate deposition in neither RK nor RK + SF rats; however, plasma levels of calciprotein particles were significantly reduced by SF. These data indicate that latent positive phosphate balance accelerates CKD progression from early stages, even when overt ectopic calcification is absent.

Topics: Animals; Biomarkers; Biopsy; Disease Models, Animal; Disease Susceptibility; Drug Combinations; Ferric Compounds; Glomerulosclerosis, Focal Segmental; Immunohistochemistry; Male; Phosphates; Podocytes; Rats; Renal Insufficiency, Chronic; Sucrose

Topics: Adult; Anemia, Iron-Deficiency; Female; Ferric Compounds; Ferric Oxide, Saccharated; Hematinics; Humans; Infusions, Intravenous; Male; Maltose; Middle Aged; Renal Insufficiency, Chronic

Topics: Administration, Intravenous; Anemia, Iron-Deficiency; Child; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Humans; Renal Insufficiency, Chronic

To investigate the impact of anemia correction with erythropoiesis stimulants on the serum level of the circulating morphogenetic protein α-Klotho in patients with Stages 3B--4 chronic kidney disease (CKD).. 64 patients aged 42±8 years with Stages 3B--4 nondiabetic CKD were examined and divided into 2 groups: 1) 32 patients with anemia (the target hemoglobin levels could be achieved and kept with erythropoietin and iron saccharate in 20 patients (Group A) and those could not be done in 12 patients (Group 1B). A control group (Group 2) consisted of 32 non-anemic patients matched for gender, age, and degree of a glomerular filtration rate (GFR) reduction. Along with iron exchange indicators, the time course of changes in serum Klotho levels were examined in all the 64 patients during screening and one year after the end of the study. For correction of anemia, 32 patients with this condition (Groups 1A and 1B) took short-acting epoetin (hypodermic recormon 2,000 IU thrice per week + iron (intravenous venofer 5 ml of 100 mg once per week)) under control of hemoglobin levels and serum transferrin iron and ferritin saturation. After achieving the target hemoglobin level of 110-120 g/l, for its keeping, all the patients received, instead of short-acting epoetin, long-acting hypodermic darbepoetin-α 1.5 µg once every 2 months and intravenous iron saccharate 100 mg once every 2 weeks.. Among the 32 anemic patients in Group 1, 20 (63%) (Group 1 A) could achieve the target hemoglobin level (110--120 g/l) and maintain it within this range, by performing therapy with epoitin-β + iron saccharate; anemia (the hemoglobin level of <110 g/l) persisted in 12 (37%) patients (Group 1B) despite the fact that epoetin and iron saccharate had been administered. Group 1A was noted to have an increase in α-Klotho concentrations by an average of 100±11.6-pg/ml as compared to Group 1B (by only 72±4.2 pg/ml). At the same time, the α-Klotho levels in the control group by the end of the follow-up decreased by an average of 210±12.9 pg/ml as compared to the prescreening value. There was a direct correlation between hemoglobin and serum ferritin concentrations and iron ferritin saturation percentage and α-Klotho levels. It was ascertained that the hemoglobin concentration of ≥110 g/l with a sensitivity of 89% and a specificity of 75% could predict higher serum α-Klotho levels in CKD. The same patients were found to have an inverse relationship between the serum level of α-Klotho and the risk of cardiovascular events.. The serum level of the protein Klotho is not only a marker for the severity of CKD and its complications (anemia, left ventricular hypertrophy, and heart failure), but also a pathogenetic factor of CKD progression. Anemia correction with erythropoiesis stimulants has been shown to enhance the renal and extrarenal production of α-Klotho.. Цель исследования. Изучить влияние коррекции анемии препаратами, стимулирующими эритропоэз, на уровень в сыворотке крови циркулирующей формы морфогенетического белка α-Klotho у больных хронической болезнью почек (ХБП) 3Б-4 стадии. Материалы и методы. Обследовали 64 больных ХБП недиабетической этиологии 3Б-4 стадии в возрасте 42±8 лет, которых распределили в 2 группы: 1-я - 32 больных с анемией (у 20 с помощью эритропоэтина и железа сахарата удалось достичь и поддерживать целевой уровень гемоглобина - группа 1А, и 12, которым назначенная терапия не позволила достигнуть целевого уровня гемоглобина - группа 1Б). Группу контроля (2-я) составили 32 больных без анемии, сопоставимых с больными 1-й группы по полу, возрасту и степени снижения скорости клубочковой фильтрации (СКФ). У всех 64 больных во время скрининга и через 1 год после окончания исследования наряду с показателями обмена железа изучена динамика уровня Klotho в сыворотке. Для коррекции анемии 32 пациента с анемией (группы 1А и 1Б) получали эпоэтин короткого действия (рекормон по 2000 ЕД 3 раза в неделю подкожно) + железо (венофер 5 мл 100 мг 1 раз в неделю внутривенно) под контролем уровня гемоглобина, насыщения трансферрина железом и ферритина сыворотки. После достижения целевого уровня гемоглобина 110-120 г/л для его поддержания всем пациентам вместо эпоэтина короткого действия вводили эпоэтин длительного действия дабепоэтин-α 1,5 мкг на 1 кг 1 раз в 2 мес подкожно и железа сахарат 100 мг 1 раз в 2 нед внутривенно. Результаты. Среди 32 больных 1-й группы с анемией у 20 (63%) (группа 1А) терапия эпоэтином-β + железа сахаратом позволила достигнуть целевого уровня гемоглобина (110-120 г/л) и поддерживать его в этом диапазоне; у 12 (37%) больных (группа 1Б), несмотря на введение эпоэтина и железа сахарата, сохранялась анемия (уровень гемоглобина <110 г/л). У больных группы 1А отмечено увеличение концентрации α-Klotho в среднем на 100±11,6 пг/мл по сравнению с таковой у больных группы 1Б (только на 72±4,2 пг/мл). В то же время в контрольной группе к концу наблюдения уровень α-Klotho уменьшился в среднем на 210±12,9 пг/мл по сравнению с таковой до скрининга. Отмечена прямая связь между концентрацией гемоглобина, ферритина в сыворотке крови и процентом насыщения железом трансферрина и уровнем α-Klotho. Выявлено, что концентрация гемоглобина ≥110 г/л с чувствительностью 89% и специфичностью 75% позволяет прогнозировать выявление более высокого уровня α-Klotho в сыворотке крови при ХБП. У тех же больных о

Topics: Adult; Anemia; Biomarkers; Disease Progression; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Glucuronidase; Hematinics; Hemoglobins; Humans; Iron; Klotho Proteins; Male; Middle Aged; Outcome Assessment, Health Care; Renal Dialysis; Renal Insufficiency, Chronic; Severity of Illness Index

Ferumoxytol was first approved for clinical use in 2009 solely based on data from trial comparisons with oral iron on biochemical anemia efficacy end points. To compare the rates of important patient outcomes (infection, cardiovascular events and death) between facilities predominantly using ferumoxytol versus iron sucrose (IS) or ferric gluconate (FG) in patients with end-stage renal disease (ESRD)-initiating hemodialysis (HD).. Using the United States Renal Data System, we identified all HD facilities that switched (almost) all patients from IS/FG to ferumoxytol (July 2009-December 2011). Each switching facility was matched with three facilities that continued IS/FG use. All incident ESRD patients subsequently initiating HD in these centers were studied and assigned their facility exposure. They were followed for all-cause mortality, cardiovascular hospitalization/death or infectious hospitalization/death. Follow-up ended at kidney transplantation, switch to peritoneal dialysis, transfer to another facility, facility switch to another iron formulation and end of database (31 December 2011). Cox proportional hazards regression was then used to estimate adjusted hazard ratios [HR (95% confidence intervals)].. In July 2009-December 2011, 278 HD centers switched to ferumoxytol; 265 units (95.3%) were matched with 3 units each that continued to use IS/FG. Subsequently, 14 206 patients initiated HD, 3752 (26.4%) in ferumoxytol and 10 454 (73.6%) in IS/FG centers; their characteristics were very similar. During 6433 person-years, 1929 all-cause, 726 cardiovascular and 191 infectious deaths occurred. Patients in ferumoxytol (versus IS/FG) facilities experienced similar all-cause [0.95 (0.85-1.07)], cardiovascular [0.99 (0.83-1.19)] and infectious mortality [0.88 (0.61-1.25)]. Among 5513 Medicare (Parts A + B) beneficiaries, cardiovascular events [myocardial infarction, stroke and cardiovascular death; 1.05 (0.79-1.39)] and infectious events [hospitalization/death; 0.96 (0.85-1.08)] did not differ between the iron exposure groups.. In incident HD patients, ferumoxytol showed similar short- to mid-term safety profiles with regard to cardiovascular, infectious and mortality outcomes compared with the more commonly used intravenous iron formulations IS and FG.

Topics: Administration, Intravenous; Aged; Anemia; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferrosoferric Oxide; Glucaric Acid; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Prognosis; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency, Chronic; Stroke; United States

High-dose intravenous iron supplementation is associated with adverse cardiovascular outcomes in patients with CKD, but the underlying mechanism is unknown. Our study investigated the causative role of iron sucrose in leukocyte-endothelium interactions, an index of early atherogenesis, and subsequent atherosclerosis in the mouse remnant kidney model. We found that expression levels of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and adhesion of U937 cells increased in iron-treated human aortic endothelial cells through upregulated NADPH oxidase (NOx) and NF-κB signaling. We then measured mononuclear-endothelial adhesion and atherosclerotic lesions of the proximal aorta in male C57BL/6 mice with subtotal nephrectomy, male apolipoprotein E-deficient (ApoE(-/-)) mice with uninephrectomy, and sham-operated mice subjected to saline or parenteral iron loading. Iron sucrose significantly increased tissue superoxide production, expression of tissue cell adhesion molecules, and endothelial adhesiveness in mice with subtotal nephrectomy. Moreover, iron sucrose exacerbated atherosclerosis in the aorta of ApoE(-/-) mice with uninephrectomy. In patients with CKD, intravenous iron sucrose increased circulating mononuclear superoxide production, expression of soluble adhesion molecules, and mononuclear-endothelial adhesion compared with healthy subjects or untreated patients. In summary, iron sucrose aggravated endothelial dysfunction through NOx/NF-κB/CAM signaling, increased mononuclear-endothelial adhesion, and exacerbated atherosclerosis in mice with remnant kidneys. These results suggest a novel causative role for therapeutic iron in cardiovascular complications in patients with CKD.

Topics: Animals; Atherosclerosis; Cell Adhesion; Endothelial Cells; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Injections, Intravenous; Intercellular Adhesion Molecule-1; Leukocytes; Lipid Peroxidation; Male; Mice, Inbred C57BL; Monocytes; NF-kappa B; Renal Insufficiency, Chronic; Superoxides; U937 Cells; Up-Regulation; Vascular Cell Adhesion Molecule-1

Historically, the Renal Unit at King's College Hospital used intravenous (IV) iron sucrose (IS) to treat iron deficiency anaemia in patients with chronic kidney disease who were not on dialysis (CKD-ND). As part of a service initiative to improve patient experience, new products were considered as alternatives. This study investigated the potential impact on patient experience and service costs by switching from IS to ferric carboxymaltose (FCM).. A decision analytical model was used to calculate the impact of switching from IS to FCM for a cohort of CKD-ND patients. Service provision data were collected for 365 patients who received 600 mg IS within a 12 month period, creating the IS data set. The service provision data, along with a clinically relevant FCM administration protocol (stipulating total doses of 500 mg FCM), were used to calculate a corresponding theoretical data set for FCM for the same cohort of patients.. The FCM protocol saved each patient two hospital visits and 2.66 hours of time (equating to approximately a saving of £36.21 in loss of earnings) and £19 in travel costs. Direct attributable costs for iron administration (which included drug, disposables, nursing staff, and hospital-provided patient transport costs) were £58,646 for IS vs £46,473 for FCM. Direct overhead costs (which included nursing preparation time, administration staff, clinic space, and consultant time costs) were £40,172 for the IS service vs £15,174 for the FCM service.. Based on clinical experience with the products, this analysis assumes that 500 mg FCM is therapeutically equivalent to 600 mg IS. Consultant time costs are assumed to be the same between the two treatment groups. IV iron administration protocols and data are specific to King's College Hospital. The design is retrospective and changes to the management of the clinic, including service delivery optimization, may also affect real costs.. FCM was associated with fewer hospital visits and reduced transport costs for CKD-ND patients receiving IV iron and has the potential to save 19-37% in service costs. Owing to increased administration efficiency, FCM can improve the overall patient experience while reducing the total cost of the King's College Hospital IV iron service for CKD-ND patients, compared with treatment with IS.

Topics: Administration, Intravenous; Ambulatory Care Facilities; Anemia, Iron-Deficiency; Clinical Protocols; Costs and Cost Analysis; Decision Support Techniques; Efficiency, Organizational; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Hospitalization; Humans; Maltose; Patient Preference; Renal Insufficiency, Chronic; Transportation; United Kingdom

Low-molecular-weight iron dextran (CosmoFer) is the only form of parenteral iron that can be administered as a total dose infusion (TDI) in the United Kingdom (UK). This study aimed to evaluate the safety and efficacy of TDI CosmoFer in comparison to intravenous iron sucrose infusion (Venofer) in patients with chronic kidney disease (CKD).. A retrospective study of outpatients with CKD undergoing intravenous TDI CosmoFer or Venofer infusion was conducted at Salford Royal Hospital and Sunderland Royal Hospital. A total of 979 doses of CosmoFer and 504 doses of Venofer were administered. There were three minor adverse events in patients receiving CosmoFer compared with one minor event in a Venofer treated patient. There were no anaphylactoid-type reactions in either group. Serum haemoglobin, ferritin and transferrin saturation (TSAT) improved significantly 4-6 months postinfusion in both treatment groups.. TDI CosmoFer is an efficacious method of replenishing iron stores in CKD patients in an outpatient setting. Furthermore, TDI CosmoFer is safe and not associated with an increase in adverse events compared to Venofer.

Topics: Anemia, Iron-Deficiency; Drug-Related Side Effects and Adverse Reactions; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Humans; Infusions, Intravenous; Iron-Dextran Complex; Male; Middle Aged; Renal Insufficiency, Chronic; Retrospective Studies; Sucrose