A phase 3b, multicenter, open-label, single-arm study of roxadustat (ASPEN): Operational learnings within United States dialysis organizations.

INTRODUCTION: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in several regions for the treatment of anemia of chronic kidney disease (CKD). ASPEN evaluated the efficacy, safety, and feasibility of roxadustat in patients with anemia of CKD in US dialysis organizations. METHODS: This open-label, single-arm study (NCT04484857) comprised a 6-week screening period, followed by 24 weeks of treatment (with optional extension ≤1 year) and a 4-week follow-up. Patients aged ≥18 years, receiving chronic dialysis, with hemoglobin (Hb) 9.0-12.0 g/dL if converting from erythropoiesis-stimulating agents (ESAs), or <10.0 g/dL if receiving ESAs for <6 weeks, received oral roxadustat three times weekly in-center. Primary efficacy endpoints included proportion of patients with mean Hb ≥10 g/dL, averaged over weeks 16-24, and mean Hb change from baseline to the average over weeks 16-24. Safety was also assessed. FINDINGS: Overall, 283 patients were enrolled and treated, 282 (99.6%) were included in the full analysis set, and 216 (76.3%) continued into the extension period. Most patients enrolled were from DaVita sites (71%), with the rest from US Renal Care sites (29%). Mean (standard deviation [SD]) baseline Hb was 10.6 (0.7) g/dL. Nearly all patients were prior ESA users (n = 274; 97.2%). The proportion of patients with mean Hb ≥10 g/dL during weeks 16-24 was 83.7% (95% confidence interval 78.9-88.6). Mean (SD) Hb increase from baseline to the average over weeks 16-24 was 0.2 (1.0) g/dL. During the treatment period, 82 (29.0%) patients reported treatment-emergent serious adverse events (TESAEs). The most common TESAEs were COVID-19 pneumonia (n = 10; 3.5%), acute respiratory failure (n = 9; 3.2%), COVID-19 (n = 7; 2.5%), acute myocardial infarction (n = 7; 2.5%), and fluid overload (n = 6, 2.1%). DISCUSSION: Roxadustat was effective in maintaining Hb in patients with anemia of CKD on dialysis in large, community-based dialysis organizations.

Use of TIMP-2 and IGFBP-7 for prediction of postoperative acute kidney injury after cardiac surgery.

BACKGROUND: The following cell cycle arrest urinary biomarkers, tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP-7), have been used for early detection of acute kidney injury (AKI) in critically ill patients. The purpose of this study is to validate the use of these urinary biomarkers in patients undergoing open heart surgery. MATERIALS AND METHODS: In a single-center prospective observational study, urine samples were collected in 108 consecutive patients who underwent open heart surgery immediately after separation from cardiopulmonary bypass and on postoperative day 1, and were sent for the biomarker [TIMP-2]*[IGFBP7] analysis. Acute kidney injury was defined based on KDIGO criteria, and levels of [TIMP-2]*[IGFBP7] were analyzed for the ability to predict AKI. RESULTS: Of the 108 patients, 19 (17.6%) patients developed postoperative AKI within 48 hours of surgery. At the threshold of > 0.3 (ng/mL)2/1,000, post-cardiopulmonary bypass [TIMP-2]*[IGFBP-7] had a sensitivity of 13% and specificity of 82% for predicting postoperative AKI. Postoperative day-1 [TIMP-2]*[IGFBP-7] had a sensitivity of 47% and a specificity of 59% for predicting postoperative AKI. There were no differences in [TIMP-2]*[IGFBP-7] values at either timepoint between patients who developed postoperative AKI as compared to those who did not. CONCLUSION: Urinary [TIMP-2]*[IGFBP7] was not predictive of the risk of AKI after cardiac surgery in this single-center study population.

Changes in Iron Availability with Roxadustat in Nondialysis- and Dialysis-Dependent Patients with Anemia of CKD.

Background: Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, increases hemoglobin by stimulating erythropoietin synthesis and improving iron availability through facilitation of iron uptake and/or release from stores. In this exploratory analysis, we assessed the effect of roxadustat treatment on laboratory parameters related to iron metabolism in patients with anemia of chronic kidney disease (CKD). Methods: Data were pooled from pivotal, randomized, phase 3 roxadustat trials: three placebo-controlled, double-blind trials in nondialysis-dependent (NDD) CKD and three open-label, active-comparator (epoetin alfa) trials in dialysis-dependent (DD) CKD. In this exploratory analysis, mean changes from baseline in hemoglobin, iron parameters, and hepcidin, and intravenous (iv) iron use were evaluated. Pooled results in NDD CKD and DD CKD patients are reported. Results: Overall, 4277 patients with NDD CKD and 3890 patients with DD CKD were evaluated. Hemoglobin increases with roxadustat treatment were accompanied by increases in serum iron and total iron-binding capacity (TIBC) and decreases in serum ferritin and hepcidin from baseline through week 52. With epoetin alfa, the hemoglobin increase was accompanied by decreases in serum ferritin and hepcidin, but serum iron decreased, and there was no change in TIBC. With placebo, there were no changes in hemoglobin, iron parameters, or hepcidin. During treatment, iv iron use was reduced with roxadustat versus placebo and epoetin alfa. Conclusions: In patients with NDD CKD and DD CKD, roxadustat treatment is associated with increases in serum iron and TIBC, accompanied by reduced hepcidin and indicative of improved iron kinetics. Patients treated with roxadustat achieved target hemoglobin levels with less iv iron use versus comparators. Practitioners treating patients with anemia of CKD with roxadustat should consider its unique effects when interpreting iron parameters.

Ferric pyrophosphate citrate for parenteral administration of maintenance iron: structure, mechanism of action, clinical efficacy and safety.

Anemia is a common complication in patients with hemodialysis-dependent chronic kidney disease (HDD-CKD). Anemia is principally the result of erythropoietin deficiency, inflammation, and iron deficiency. High molecular weight iron oxide nanoparticles (IONP) are routinely administered intravenously to replace iron losses and, although effective, there are lingering concerns about possible safety issues. Ferric pyrophosphate citrate (FPC, Triferic, Triferic AVNU [Triferic and Triferic AVNU are the proprietary name for ferric pyrophosphate citrate. Triferic and Triferic AVNU are registered trademarks of Rockwell medical Inc.]) is a complex iron salt that donates iron directly to plasma transferrin. FPC is devoid of any carbohydrate moiety and is administered via the dialysate or intravenously during each hemodialysis session to replace iron and maintain hemoglobin. Controlled clinical trials of up to 48 weeks in duration have demonstrated the efficacy of regular administration of dialysate FPC for maintaining hemoglobin levels and iron balance in HDD-CKD patients. Clinical data also suggest that dialysate FPC may reduce the dose requirements for and use of erythropoiesis-stimulating agents and IONPs in HDD-CKD patients. Safety data from clinical studies and post-marketing surveillance show that FPC is well tolerated and not associated with an increased risk of infection, inflammation, iron overload, or serious hypersensitivity reactions. FPC represents an effective and well-tolerated choice for iron replacement and maintenance of hemoglobin in the long-term management of HDD-CKD patients.

Erythropoietic effects of vadadustat in patients with anemia associated with chronic kidney disease.

Patients with chronic kidney disease (CKD) develop anemia largely because of inappropriately low erythropoietin (EPO) production and insufficient iron available to erythroid precursors. In four phase 3, randomized, open-label, clinical trials in dialysis-dependent and non-dialysis-dependent patients with CKD and anemia, the hypoxia-inducible factor prolyl hydroxylase inhibitor, vadadustat, was noninferior to the erythropoiesis-stimulating agent, darbepoetin alfa, in increasing and maintaining target hemoglobin concentrations. In these trials, vadadustat increased the concentrations of serum EPO, the numbers of circulating erythrocytes, and the numbers of circulating reticulocytes. Achieved hemoglobin concentrations were similar in patients treated with either vadadustat or darbepoetin alfa, but compared with patients receiving darbepoetin alfa, those receiving vadadustat had erythrocytes with increased mean corpuscular volume and mean corpuscular hemoglobin, while the red cell distribution width was decreased. Increased serum transferrin concentrations, as measured by total iron-binding capacity, combined with stable serum iron concentrations, resulted in decreased transferrin saturation in patients randomized to vadadustat compared with patients randomized to darbepoetin alfa. The decreases in transferrin saturation were associated with relatively greater declines in serum hepcidin and ferritin in patients receiving vadadustat compared with those receiving darbepoetin alfa. These results for serum transferrin saturation, hepcidin, ferritin, and erythrocyte indices were consistent with improved iron availability in the patients receiving vadadustat. Thus, overall, vadadustat had beneficial effects on three aspects of erythropoiesis in patients with anemia associated with CKD: increased endogenous EPO production, improved iron availability to erythroid cells, and increased reticulocytes in the circulation.

Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production. METHODS: We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter). RESULTS: A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively. CONCLUSIONS: Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).

Roxadustat for Treating Anemia in Patients with CKD Not on Dialysis: Results from a Randomized Phase 3 Study.

BACKGROUND: Current anemia therapies for patients with non-dialysis-dependent CKD may require injection and medical visits. Roxadustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, stimulates erythropoiesis and improves iron homeostasis. METHODS: In this double-blind phase 3 study, we randomized patients with non-dialysis-dependent CKD stages 3-5 and hemoglobin <10.0 g/dl (1:1) to thrice-weekly 70-mg oral roxadustat or placebo. Doses were titrated throughout the study based on hemoglobin levels. The primary efficacy end point was mean change from baseline in hemoglobin averaged over weeks 28-52 versus placebo, irrespective of rescue therapy use. We assessed patients for adverse events. RESULTS: The study included 2781 patients, 1393 who received roxadustat and 1388 who received placebo. Mean baseline hemoglobin was 9.1 g/dl for both groups. The mean change in hemoglobin from baseline was 1.75 g/dl (95% confidence interval [95% CI], 1.68 to 1.81) with roxadustat versus 0.40 g/dl (95% CI, 0.33 to 0.47) with placebo, (P<0.001). Among 411 patients with baseline elevated high-sensitivity C-reactive protein, mean change in hemoglobin from baseline was 1.75 g/dl (95% CI, 1.58 to 1.92) with roxadustat versus 0.62 g/dl (95% CI, 0.44 to 0.80) with placebo, (P<0.001). Roxadustat reduced the risk of red blood cell transfusion by 63% (hazard ratio, 0.37; 95% CI, 0.30 to 0.44). The most common adverse events with roxadustat and placebo, respectively, were ESKD (21.0% versus 20.5%), urinary tract infection (12.8% versus 8.0%), pneumonia (11.9% versus 9.4%), and hypertension (11.5% versus 9.1%). CONCLUSIONS: Roxadustat effectively increased hemoglobin in patients with non-dialysis-dependent CKD and reduced the need for red blood cell transfusion, with an adverse event profile comparable to that of placebo. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Safety and Efficacy Study of Roxadustat to Treat Anemia in Patients With CKD, Not on Dialysis, NCT02174627.

Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation. METHODS: This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies. RESULTS: No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin. CONCLUSIONS: Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.

Biosimilar Erythropoiesis-Stimulating Agents in Chronic Kidney Disease.

Anemia is a well-known complication of advanced CKD and treatment with erythropoietin analogues (epoetin) remains a key component of management. Although biologic agents, including epoetin, play an extremely important role in the treatment of various medical conditions, their cost can be prohibitive. As a result, several biosimilar agents have now been approved by the U.S. Food and Drug Administration. Biosimilar epoetin has been used in Europe since 2007. In this article, we will review biosimilar development and focus on the first approved biosimilar epoetin in the United States, epoetin alfa-epbx.

Novel Oral Iron Therapies for Iron Deficiency Anemia in Chronic Kidney Disease.

Iron deficiency anemia (IDA) is a frequent complication of chronic kidney disease (CKD) and is associated with adverse outcomes in these patients. Patients with CKD and IDA remain largely undertreated. Conventional oral iron agents are insufficiently effective due to poor absorption and cause gastrointestinal side effects; thus, novel oral iron preparations are needed. This article covers current treatment guidelines for patients with anemia and CKD and clinical trial data for iron-repletion agents currently in use, as well as for novel oral iron therapies in development. Ferric citrate, a novel oral iron-repletion agent approved for patients with non-dialysis-dependent CKD and IDA, demonstrated improvements in hemoglobin levels and iron parameters, with good tolerability in patients with non-dialysis-dependent CKD. When used as a phosphate binder, ferric citrate also improves hemoglobin and iron parameters in dialysis-dependent CKD, but additional trials are needed to evaluate its efficacy as an iron-repletion agent in this setting. Other novel oral iron preparations in development for IDA in patients with CKD include ferric maltol, which is approved in Europe and the United States for IDA in adult patients, and sucrosomial iron, which has been evaluated in IDA associated with CKD and several other clinical settings.

Cardiovascular Safety and All-Cause Mortality of Methoxy Polyethylene Glycol-Epoetin Beta and Other Erythropoiesis-Stimulating Agents in Anemia of CKD: A Randomized Noninferiority Trial.

BACKGROUND AND OBJECTIVES: Erythropoiesis-stimulating agents correct anemia of CKD but may increase cardiovascular risk. We compared cardiovascular outcomes and all-cause mortality associated with monthly methoxy polyethylene glycol-epoetin beta with those of the shorter-acting agents epoetin alfa/beta and darbepoetin alfa in patients with anemia of CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a multicenter, open-label, noninferiority trial in which patients were randomized to receive methoxy polyethylene glycol-epoetin beta or reference erythropoiesis-stimulating agents, stratified by maintenance or correction treatment status and C-reactive protein level. The trial had a prespecified noninferiority margin of 1.20 for the hazard ratio (HR) for the primary end point (a composite of all-cause mortality, nonfatal myocardial infarction or stroke, adjudicated by an independent blinded committee). This trial is registered with ClinicalTrials.gov, number NCT00773513. RESULTS: In total, 2818 patients underwent randomization, received methoxy polyethylene glycol-epoetin beta or a reference agent, and were followed for a median of 3.4 years (maximum, 8.4 years). In the modified intention-to-treat analysis, a primary end point event occurred in 640 (45.4%) patients in the methoxy polyethylene glycol-epoetin beta arm, and 644 (45.7%) in the reference arm (HR 1.03; 95% confidence interval [95% CI], 0.93 to 1.15, P=0.004 for noninferiority). All-cause mortality was not different between treatment groups (HR 1.06; 95% CI, 0.94 to 1.19). Results in patient subgroups on dialysis or treated in the correction or maintenance settings were comparable to the primary analysis. CONCLUSIONS: In patients with anemia of CKD, once-monthly methoxy polyethylene glycol-epoetin beta was noninferior to conventional, shorter-acting erythropoiesis-stimulating agents with respect to rates of major adverse cardiovascular events or all-cause mortality.

Continuous Glucose Monitoring and Glycemic Control in Patients With Type 2 Diabetes Mellitus and CKD.

RATIONALE & OBJECTIVE: The accuracy of glycated hemoglobin (HbA1c) level for assessment of glycemic control in patients with chronic kidney disease (CKD) is uncertain. This study assessed the accuracy of HbA1c level using continuous glucose monitoring. STUDY DESIGN: Diagnostic test study of HbA1c and serum fructosamine. The continuous glucose monitor was worn for 14 days. Glucose was measured every 15 minutes (up to 1,344 measurements). Average glucose concentration was calculated for each patient from the patient's continuous glucose monitor measurements. Linear regression was applied to estimate the relationship between average glucose concentration and HbA1c and serum fructosamine levels. The influence of patient characteristics on the relationship between HbA1c and average glucose concentrations was examined in a multivariate regression model. SETTING & PARTICIPANTS: Patients with type 2 diabetes and CKD (estimated glomerular filtration rate, 7-45 mL/min, not receiving dialysis) seen in an academic nephrology clinic. TESTS ANALYZED: The accuracy of HbA1c level for assessment of chronic glycemia. A secondary objective was to study serum fructosamine levels. OUTCOMES: The degree of correlation between continuous glucose monitoring-derived average glucose concentration and HbA1c level; serum fructosamine level was studied as a secondary outcome. RESULTS: 80 patients wore the continuous glucose monitor for a mean of 12.7 ± 2.9 days. Average glucose concentration of all patients was 151.5 ± 55.7 mg/dL. Mean HbA1c level was 7.2% ± 1.5%. HbA1c level was highly correlated with average glucose concentration, described by the equation: average glucose concentration = 30.48 × HbA1c - 68.48; r = 0.82; P < 0.001. Serum fructosamine level was also significantly correlated with average glucose concentration; r = 0.55; P < 0.001. The strong correlation between average glucose concentration and HbA1c level was not affected by the severity of CKD, whereas the performance of serum fructosamine level, in contrast, degraded among patients with more severe CKD. LIMITATIONS: Relatively small sample size. CONCLUSIONS: HbA1c is an accurate measure of glycemic status among patients with CKD and type 2 diabetes. This relationship appears to hold true among patients with more severe CKD.

Medication discrepancies in late-stage chronic kidney disease.

BACKGROUND: Late-stage chronic kidney disease (LS-CKD) can be defined by glomerular filtration rate (GFR) 0-30 mL/min. It is a period of risk for medication discrepancies because of frequent hospitalizations, fragmented medical care, inadequate communication and polypharmacy. In this study, we sought to characterize medication discrepancies in LS-CKD. METHODS: We analyzed all patients enrolled in Northwell Health's Healthy Transitions in LS-CKD program. All patients had estimated GFR 0-30 mL/min, not on dialysis. Medications were reviewed by a nurse at a home visit. Patients' medication usage and practice were compared with nephrologists' medication lists, and discrepancies were characterized. Patients were categorized as having either no discrepancies or one or more. Associations between patient characteristics and number of medication discrepancies were evaluated by chi-square or Fisher's exact test for categorical variables, and two-sample t-test or Wilcoxon text for continuous variables. RESULTS: Seven hundred and thirteen patients with a median age of 70 (interquartile range 58-79) years were studied. There were 392 patients (55.0% of the study population) with at least one medication discrepancy. The therapeutic classes of medications with most frequently occurring medication discrepancies were cardiovascular, vitamins, bone and mineral disease agents, diuretics, analgesics and diabetes medications. In multivariable analysis, factors associated with higher risk of discrepancies were congestive heart failure [odds ratio (OR) 2.13; 95% confidence interval (CI) 1.44-3.16; P = 0.0002] and number of medications (OR 1.29; 95% CI 1.21-1.37; P < 0.0001). CONCLUSIONS: Medication discrepancies are common in LS-CKD, affect the majority of patients and include high-risk medication classes. Congestive heart failure and total number of medications are independently associated with greater risk for multiple drug discrepancies. The frequency of medication discrepancies indicates a need for great care in medication management of these patients.

Usefulness of Oral Ferric Citrate in Patients With Iron-Deficiency Anemia and Chronic Kidney Disease With or Without Heart Failure.

Patients with chronic inflammatory conditions including chronic kidney disease (CKD) and heart failure (HF) are undertreated with iron-deficiency anemia (IDA). Progressive inflammation and reduced iron transport associated with CKD and HF may reduce the efficacy of oral iron therapy. Oral ferric citrate improves anemia markers in CKD, but its effects in patients with CKD and concomitant HF have not been described. Patients with CKD not on dialysis and IDA from a phase 2 and 3 trial were treated with ferric citrate (n = 190) or placebo (n = 188); patients with HF were identified from medical histories. Hemoglobin response was defined as a ≥10.0-g/L increase in hemoglobin. Changes in hemoglobin, transferrin saturation, ferritin, and serum phosphate from baseline to week 12 and the incidence of adverse events potentially related to HF were evaluated. HF was reported in 22% (n = 81) of patients. The proportion of patients with hemoglobin response to ferric citrate treatment did not significantly differ in patients with and without HF (43% vs 49%, respectively; p = 0.47); changes from baseline in hemoglobin, iron parameters, and serum phosphate were similar. Adverse events potentially related to HF were noted more frequently in patients with HF (ferric citrate, 23%; placebo, 17%) versus those without HF (ferric citrate, 12%; placebo, 11%). In conclusion, these results indicate a potential role for ferric citrate in the treatment of IDA in patients with CKD not on dialysis and concomitant HF.

Intravenous Epoetin Alfa-epbx versus Epoetin Alfa for Treatment of Anemia in End-Stage Kidney Disease.

BACKGROUND AND OBJECTIVES: This study was conducted to compare the safety and efficacy of intravenous epoetin alfa-epbx, an epoetin alfa biosimilar, to epoetin alfa in patients on hemodialysis with ESKD and anemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this 24-week, multicenter, double-blind comparative efficacy and safety study, 612 patients on hemodialysis with ESKD and anemia who had stable hemoglobin and were receiving stable doses of intravenous epoetin alfa were randomized (1:1) to intravenous epoetin alfa or epoetin alfa-epbx. Dosing was adjusted according to the epoetin alfa prescribing information. The coprimary efficacy end points were the least squares mean difference between the two treatments in mean weekly hemoglobin level and mean weekly epoetin dose per kilogram of body weight during the last 4 weeks of treatment. RESULTS: The least squares mean difference between epoetin alfa-epbx and epoetin alfa in weekly hemoglobin was -0.12 g/dl and the 95% confidence interval (-0.25 to 0.01) was contained within the prespecified equivalence margin (-0.5 to 0.5 g/dl). The least squares mean difference between epoetin alfa-epbx and epoetin alfa in weekly epoetin dose per kilogram of body weight was 0.37 U/kg per week, and the 95% confidence interval (-10.40 to 11.13) was contained within the prespecified equivalence margin (-45 to 45 U/kg per week). Incidences of adverse events (77.1% versus 75.3%), serious adverse events (24.9% versus 27.0%), and deaths (n=5 versus 6) were similar between the epoetin alfa-epbx and epoetin alfa groups, respectively. Five patients tested positive for anti-recombinant human erythropoietin antibodies at baseline, and two additional patients (n=1 per group) developed anti-recombinant human erythropoietin antibodies while on study treatment. All patients tested negative for neutralizing antibodies, and no patient in either group experienced an event of pure red cell aplasia. CONCLUSIONS: This 24-week, comparative, clinical trial in patients on hemodialysis with ESKD and anemia demonstrated there is no clinically meaningful difference in efficacy or safety between epoetin alfa-epbx and epoetin alfa.

Is there an established hemoglobin target range for patients undergoing chronic dialysis?

Anemia is a common complication of advanced chronic kidney disease (CKD). Treatment with erythropoiesis-stimulating agents (ESAs) remains a common approach in managing anemia of CKD. The 2012 Kidney Disease Improving Global Outcomes Clinical Practice Guideline for Anemia in CKD suggests avoiding ESA therapy use to maintain Hb level above 11.5 g/dL. However, optimal Hb target range in adult patients undergoing chronic dialysis remains unknown. Clinical studies suggest risks associated with normalization of Hb levels in adult patients with CKD. In this article, we briefly review some of these studies and the concerns associated with higher Hb targets in this patient population. We also suggest a target Hb range for adult chronic dialysis patients receiving ESAs. It is currently undetermined if this target Hb range would apply to newer agents that are being studied for anemia management in this population.