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Background and Objectives: Daprodustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) being investigated for the treatment of anemia of CKD. In this noninferiority trial, we compared daprodustat administered three times weekly with epoetin alfa (epoetin) in patients on prevalent hemodialysis switching from a prior erythropoiesis-stimulating agent (ESA)., Design, Setting, Participants, & Measurements: Patients on hemodialysis with a baseline hemoglobin of 8-11.5 g/dl receiving an ESA were randomized 2:1 to daprodustat three times weekly ( n =270) or conventional epoetin ( n =137) for 52 weeks. Dosing algorithms aimed to maintain hemoglobin between 10 and 11 g/dl. The primary end point was mean change in hemoglobin from baseline to the average during the evaluation period (weeks 28-52). The principal secondary end point was average monthly intravenous iron dose. Other secondary end points included BP and hemoglobin variability., Results: Daprodustat three times weekly was noninferior to epoetin for mean change in hemoglobin (model-adjusted mean treatment difference [daprodustat-epoetin], -0.05; 95% confidence interval, -0.21 to 0.10). During the evaluation period, mean (SD) hemoglobin values were 10.45 (0.55) and 10.51 (0.85) g/dl for daprodustat and epoetin groups, respectively. Responders (defined as mean hemoglobin during the evaluation period in the analysis range of 10 to 11.5 g/dl) were 80% in the daprodustat group versus 64% in the epoetin group. Proportionately fewer participants in the daprodustat group versus the epoetin group had hemoglobin values either below 10 g/dl or above 11.5 g/dl during the evaluation period. Mean monthly intravenous iron use was not significantly lower with daprodustat versus epoetin. The effect on BP was similar between groups. The percentage of treatment-emergent adverse events was similar between daprodustat (75%) and epoetin (79%)., Conclusions: Daprodustat was noninferior to epoetin in hemoglobin response and was generally well tolerated., Clinical Trial Registry Name and Registration Number: Anemia Studies in Chronic Kidney Disease: Erythropoiesis via a Novel Prolyl Hydroxylase Inhibitor Daprodustat-Three Times Weekly Dosing in Dialysis (ASCEND-TD), NCT03400033., (Copyright © 2022 by the American Society of Nephrology.)

Iron deficiency is common in patients on chronic dialysis, and most require iron-replacement therapy. In addition to absolute iron deficiency, many patients have functional iron deficiency as shown by a suboptimal response to the use of erythropoietin-stimulating agents. Both absolute and functional iron-deficiency anemia have been shown to respond to intravenous (IV) iron replacement. Although parenteral iron is an efficacious method and superior to standard doses of oral iron in patients on hemodialysis, there are ongoing safety concerns about repeated exposure potentially enhancing infection risk and cardiovascular disease. Each IV iron product is composed of an iron core with a carbohydrate shell. The avidity of iron binding and the type of carbohydrate shell play roles in the safe maximal dose and the frequency and severity of acute infusion reactions. All IV iron products are taken up into the reticuloendothelial system where the shell is metabolized and the iron is stored within tissue ferritin or exported to circulating transferrin. IV iron can be given as large intermittent doses (loading therapy) or in smaller doses at frequent intervals (maintenance dosing regimen). Limited trial data and observational data suggest that a maintenance dosing regimen is more efficacious and possibly safer than loading therapy. There is no consensus regarding the preferred method of iron repletion in patients on peritoneal dialysis, although small studies comparing oral and parenteral iron regimens in these patients have shown the latter to be more efficacious. Use of IV iron in virtually all hemodialysis and many peritoneal dialysis patients remains the standard of care., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.)

Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population., (Copyright © 2015 by the American Society of Nephrology.)

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

The Normal Hematocrit Trial (NHT) was the largest trial of epoetin randomizing 1265 hemodialysis patients with cardiac disease to lower (9-11 g/dl) or higher (13-15 g/dl) hemoglobin (Hgb), hypothesizing that higher Hgb would reduce mortality, and improve survival and quality of life. The trial was terminated early, and a 1998 publication reported that targeting higher hematocrit levels led to an insignificant increase in the primary end points (death or myocardial infarct), or risk ratio 1.3, 95% confidence interval (CI), 0.9-1.90, but the P-value was not given, and all-cause death risk was not reported. A higher target reportedly did not increase hospitalization rates, but did significantly improve the 'physical function' domain of quality of life. Comparing the 1996 Food and Drug Administration (FDA)-filed clinical trial report to the 1998 publication, however, found several discrepancies. Among these, the 1998 article reported interim trial results with only the adjusted CI but did not state that the unadjusted CIs were 99.912th percentile, and despite being a secondary end point, reported only the association of achieved Hgb with higher quality of life score. Randomization to the higher target had actually increased the risk for the primary end point (risk ratio 1.28, 95% CI=1.06-1.56; P=0.0112; 99.92% CI=0.92-1.78), the risk of death (risk ratio 1.27, 95% CI=1.04-1.54), non-access thrombotic events (P=0.041), and hospitalization rate (P=0.04), while 'physical function' did not improve (P=0.88). Hence, disclosure of these results in the 1998 publication or access to the FDA-filed report on the NHT in the late 1990s would likely have led to earlier concerns about epoetin safety and greater doubts about its benefits.

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

Randomized trials of intravenous (IV) iron have repeatedly demonstrated a rise in hemoglobin (Hgb), an erythropoiesis-stimulating agent (ESA) dose-sparing effect, and apparent safety. Such benefits were confirmed in a trial in hemodialysis patients with high ferritin receiving high ESA doses. But long-term randomized safety trials of IV iron have not been performed, which critics blame on IV iron manufacturers, leading some to question widespread use of IV iron to optimize Hgb and reduce ESA dose. ESAs increase risks of cardiovascular events and death when used to target higher versus lower Hgb values. Association studies report increasing risk with higher ESA doses at approved Hgb targets. Nevertheless, ESAs remain essential in dialysis practice. After early termination of the Normal Hematocrit Trial in 1996, analysis suggested IV iron was a risk factor for harm. In 2006, dangers related to ESA use were recognized. Trial results demonstrating IV iron was efficacious and ESA-sparing even at higher serum ferritin have intensified the focus on iron safety. Two principal alternatives in the management of anemia among dialysis patients are: (1) more intensive ESA dosing sparing iron dosing and (2) more intensive iron dosing sparing ESA dosing. Extended safety trials of IV iron versus no iron will become confounded by ESA dose differences between arms. Similarly higher ESA doses are associated with increased mortality risk, but trials comparing ESA doses will be confounded by Hgb differences. Rather than focus on individual products, we should perform trials comparing anemia management strategies to assess safety, efficacy, and cost.

Commonly used iron indices, such as serum ferritin and transferrin saturation (TSAT), have limited utility in patients with chronic kidney disease. Both dialysis and nondialysis patients may have normal to high serum ferritin levels and little or no iron available for erythropoiesis. Inflammation can result in increased serum ferritin level and low TSAT and restrict the ability to mobilize iron stores. Management of anemia in patients with chronic kidney disease requires recognizing that not only decreased erythropoietin production, but also decreased iron availability, can lead to anemia. The Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) trial showed the efficacy of intravenous (IV) iron in anemic hemodialysis patients with serum ferritin levels of 500 to 1,200 ng/mL and TSAT of 25% or less receiving adequate erythropoiesis-stimulating agent doses. Withholding iron from these patients resulted in worsening iron-restricted erythropoiesis. To improve anemia management in patients receiving hemodialysis and being treated with ESAs, clinicians should consider the benefits of IV iron.

The Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study demonstrated the efficacy of intravenous ferric gluconate to improve hemoglobin levels in anemic hemodialysis patients who were receiving adequate epoetin doses and who had ferritin levels between 500 and 1200 ng/ml and transferrin saturation (TSAT) < or = 25%. The DRIVE-II study reported here was a 6-wk observational extension designed to investigate how ferric gluconate impacted epoetin dosage after DRIVE. During DRIVE-II, treating nephrologists and anemia managers adjusted doses of epoetin and intravenous iron as clinically indicated. By the end of observation, patients in the ferric gluconate group required significantly less epoetin than their DRIVE dose (mean change of -7527 +/- 18,021 IU/wk, P = 0.003), whereas the epoetin dose essentially did not change for patients in the control group (mean change of 649 +/- 19,987 IU/wk, P = 0.809). Mean hemoglobin, TSAT, and serum ferritin levels remained higher in the ferric gluconate group than in the control group (P = 0.062, P < 0.001, and P = 0.014, respectively). Over the entire 12-wk study period (DRIVE plus DRIVE-II), the control group experienced significantly more serious adverse events than the ferric gluconate group (incidence rate ratio = 1.73, P = 0.041). In conclusion, ferric gluconate maintains hemoglobin and allows lower epoetin doses in anemic hemodialysis patients with low TSAT and ferritin levels up to 1200 ng/ml.

Stage 3 chronic kidney disease (CKD), which is characterized by a glomerular filtration rate of 30 to 60 mL/min/1.73 m2 (reference range, 90-200 mL/min/1.73m2 for a 20-year-old, with a decrease of 4 mL/min per decade), affects approximately 8 million people in the United States. Anemia is common in patients with stage 3 CKD and, if not corrected, contributes to a poor quality of life. Erythropoiesis-stimulating agents (ESAs), introduced almost 2 decades ago, have replaced transfusions as first-line therapy for anemia. This review summarizes the current understanding of the role of ESAs in the primary care of patients with anemia of CKD and discusses pharmacological and pharmacoeconomic issues raised by recent data. Relevant studies in the English language were identified by searching the MEDLINE database (1987-2006). Two ESAs are currently available in the United States, epoetin alfa and darbepoetin alfa. More frequent dosing with epoetin alfa is recommended by the labeled administration guidelines because it has a shorter half-life than darbepoetin alfa. Clinical experience also supports extended dosing intervals for both these ESAs. Use of ESAs in the management of anemia of CKD is associated with improved quality of life, increased survival, and decreased progression of renal failure. Some evidence suggests that ESAs have a cardioprotective effect. However, correction of anemia to hemoglobin levels greater than 12 g/dL (to convert to g/L, multiply by 10) appears to increase the risk of adverse cardiac outcomes and progression of kidney disease in some patients. The prescription of ESAs in the primary care setting requires an understanding of the accepted use of these agents, the associated pharmacoeconomic challenges, and the potential risks. This review considers the need to balance effective ESA dosing intervals against the potential risks of treatment.

Few data exist to guide treatment of anemic hemodialysis patients with high ferritin and low transferrin saturation (TSAT). The Dialysis Patients' Response to IV Iron with Elevated Ferritin (DRIVE) trial was designed to evaluate the efficacy of intravenous ferric gluconate in such patients. Inclusion criteria were hemoglobin or=225 IU/kg per wk or >or=22,500 IU/wk. Patients with known infections or recent significant blood loss were excluded. Participants (n=134) were randomly assigned to no iron (control) or to ferric gluconate 125 mg intravenously with eight consecutive hemodialysis sessions (intravenous iron). At randomization, epoetin was increased 25% in both groups; further dosage changes were prohibited. At 6 wk, hemoglobin increased significantly more (P=0.028) in the intravenous iron group (1.6 +/- 1.3 g/dl) than in the control group (1.1 +/- 1.4 g/dl). Hemoglobin response occurred faster (P=0.035) and more patients responded after intravenous iron than in the control group (P=0.041). Ferritin 800 ng/ml had no relationship to the magnitude or likelihood of responsiveness to intravenous iron relative to the control group. Similarly, the superiority of intravenous iron compared with no iron was similar whether baseline TSAT was above or below the study median of 19%. Ferritin decreased in control subjects (-174 +/- 225 ng/ml) and increased after intravenous iron (173 +/- 272 ng/ml; P<0.001). Intravenous iron resulted in a greater increase in TSAT than in control subjects (7.5 +/- 7.4 versus 1.8 +/- 5.2%; P<0.001). Reticulocyte hemoglobin content fell only in control subjects, suggesting worsening iron deficiency. Administration of ferric gluconate (125 mg for eight treatments) is superior to no iron therapy in anemic dialysis patients receiving adequate epoetin dosages and have a ferritin 500 to 1200 ng/ml and TSAT

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

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.