Erythropoiesis-stimulating Agents Research Articles

Consensus commentary and position of the Italian Society of Nephrology on KDIGO controversies conference on novel anemia therapies in chronic kidney disease.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new drugs developed for the treatment of anemia associated with chronic kidney disease (CKD). This class of drugs stimulates endogenous erythropoietin production and, at the same time, improves iron absorption and mobilization of iron stores (less evident with daprodustat, vadadustat and enarodustat). Several studies have been published in the last few years showing that these agents are not inferior to standard therapy in correcting anemia associatedwith CKD. The efficacy of HIF-PHIs is coupled with a safety profile comparable to that of standard erythropoiesis stimulating agent (ESA) treatment. However, studies with HIF-PHIs were not long enough to definitively exclude the impact of new drugs on adverse events, such as cancer, death and possibly cardiovascular events, that usually occur after a long follow-up period. Kidney Disease: Improving Global Outcomes (KDIGO) recently reported the conclusions of the Controversies Conference on HIF-PHIs held in 2021. The goal of the present position paper endorsed by the Italian Society of Nephrology is to better adapt the conclusions of the latest KDIGO Conference on HIF-PHIs to the Italian context by reviewing the efficacy and safety of HIF-PHIs as well as their use in subpopulations of interest as emerged from more recent publications not discussed during the KDIGO Conference.

[Clinical application and future perspectives of HIF-PH inhibitors].

Anemia in chronic kidney disease (CKD) occurs due to insufficient production of erythropoietin to compensate for the decrease in hemoglobin. Anemia in CKD has traditionally been treated with periodic injections of erythropoiesis-stimulating agents (ESAs), which are recombinant human erythropoietin preparations. Although ESA improved anemia in CKD and dramatically improved the quality of life of patients, there are some patients who are hyporesponsive to ESA, and the use of large doses of ESA in these patients may have a negative impact on patient prognosis. Currently, HIF prolyl hydroxylase (HIF-PH) inhibitors have been approved in Japan as a new treatment for anemia in CKD. HIF-PH inhibitors activate HIF and promote the production of endogenous erythropoietin. The 2019 Nobel Prize in Physiology or Medicine was awarded for groundbreaking research that uncovered the HIF pathway. Because HIF-PH inhibitors improve both erythropoietin production and iron metabolism, they are expected to be effective in treating ESA hyporesponsiveness and solve the inconvenience of injectable preparations. On the other hand, its effects are systemic and multifaceted, and long-term effects must be closely monitored.

Nephrology referral slows the progression of chronic kidney disease, especially among patients with anaemia, diabetes mellitus, or hypoalbuminemia: A single-centre, retrospective cohort study.

The Kidney Disease Improving Global Outcomes guidelines recommend nephrology referral for patients with chronic kidney disease (CKD) stages 4 to 5, significant proteinuria and persistent microscopic haematuria. However, the recommendations are opinion-based and which patients with CKD benefit more from nephrology referral has not been elucidated. In this retrospective cohort study, patients referred to our nephrology outpatient clinic from April 2017 to March 2019 were included. We excluded patients considered to have an acute decline in kidney function (annual decline in estimated glomerular filtration rate [eGFR] >10 mL/min/1.73 m2). The slopes of eGFR before and after nephrology referral were estimated and compared by linear mixed effects models. Interaction between time and referral status (before or after referral) was assessed and effect modifications by the presence of diabetes, proteinuria (defined by urine dipstick protein 2+ or more), urine occult blood, hypoalbuminemia (defined by albumin levels less than 3.5 g/dL) and anaemia (defined by haemoglobin levels less than 11.0 g/dL) were evaluated. The eGFR slope significantly improved from -2.05 (-2.39 to -1.72) to -0.96 (-1.36 to -0.56) mL/min/1.73 m2/year after nephrology referral (p < .001). The improvement in eGFR slope was more prominent among those with diabetes mellitus, anaemia, and hypoalbuminemia (all p-values for three-way interaction <.001 after adjustment for covariates). Further adjustments for time-dependent haemoglobin levels, the use of erythropoiesis-stimulating agents, iron supplementation, anti-hypertensives and anti-diabetic medications did not change the significance of the interactions. Nephrology referral slows CKD progression, especially among those with hypoalbuminemia, diabetes or anaemia. Patients with hypoalbuminemia, diabetes or anaemia might benefit more from specialized care and lifestyle modifications by nephrologists. The inclusion of anaemia and hypoalbuminemia in nephrology referral criteria should be considered.

Prognostic impact of erythropoietin-stimulating agent use during front-line chemotherapy in patients with ovarian cancer: A Korean multicenter cohort study.

To evaluate whether treatment with erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia affects progression-free survival (PFS) in patients receiving front-line chemotherapy following surgery for ovarian cancer (OC). We retrospectively reviewed all consecutive patients who received front-line chemotherapy after surgery between 2013 and 2019 at six institutions. The patients were divided according to the use of ESAs during front-line chemotherapy. The primary endpoint was PFS. The secondary endpoint was the occurrence of thromboembolism. Propensity score matching (PSM) analysis was used to compare survival between matched cohorts. Overall, 2147 patients (433 receiving ESA and 1714 for no-ESA) were identified, with a median follow-up of 44.0 months. The ESA group showed a significantly higher proportion of stage III/IV disease (81.8% vs 61.1%; P < 0.001) and postoperative gross residual disease (32.3% vs 21.2%; P < 0.001) than the no-ESA group. In the multivariable Cox regression analysis, the use of ESAs did not affect PFS (adjusted hazard ratio, 1.03; 95% confidence interval [CI]: 0.89-1.20; P = 0.661). The incidence of thromboembolism was 10.2% in the ESA group and 4.6% in the no-ESA group (adjusted odds ratio, 6.58; 95% CI: 3.26-13.28; P < 0.001). When comparing the well-matched cohorts after PSM, PFS did not differ between the ESA (median PFS 23.5 months) and no-ESA groups (median PFS 22.2 months) (P = 0.540, log-rank test). The use of ESAs during front-line chemotherapy did not negatively affect PFS in patients with OC after surgery but increased the risk of thromboembolism.

Identification and management of preoperative anaemia in adults: A British Society for Haematology Guideline update.

This updated British Society for Haematology guideline provides an up-to-date literature review and recommendations regarding the identification and management of preoperative anaemia. This includes guidance on thresholds for the diagnosis of anaemia and the diagnosis and management of iron deficiency in the preoperative context. Guidance on the appropriate use of erythropoiesis-stimulating agents and preoperative transfusion is also provided.

A retrospective study on the efficacy of Roxadustat in peritoneal dialysis patients with erythropoietin hyporesponsiveness.

Roxadustat, an oral medication for treating renal anemia, is a hypoxia-inducible factor prolyl hydroxylase inhibitor used for regulating iron metabolism and promoting erythropoiesis. To investigate the efficacy and safety of roxadustat in patients undergoing peritoneal dialysis (PD) with erythropoietin hyporesponsiveness. Single-center, retrospective study, 81 PD patients (with erythropoietin hyporesponsiveness) were divided into the roxadustat group (n = 61) and erythropoiesis-stimulating agents (ESAs) group (n = 20). Hemoglobin (Hb), total cholesterol, intact parathyroid hormone (iPTH), brain natriuretic peptide (BNP), related indicators of cardiac function and high-sensitivity C-reactive protein (hs-CRP) were collected. Additionally, adverse events were also recorded. The follow-up period was 16 weeks. The two groups exhibited similar baseline demographic and clinical characteristics. At baseline, the roxadustat group had a mean Hb level of 89.8 ± 18.9 g/L, while the ESAs group had a mean Hb level of 95.2 ± 16.0 g/L. By week 16, the Hb levels had increased to 118 ± 19.8 g/L (p < 0.05) in the roxadustat group and 101 ± 19.3 g/L (p > 0.05) in the ESAs group. The efficacy of roxadustat in improving anemia was not influenced by baseline levels of hs-CRP and iPTH. Cholesterol was decreased in the roxadustat group without statin use. An increase in left ventricular ejection fraction and stabilization of BNP were observed in the roxadustat group. For PD patients with erythropoietin hyporesponsiveness, roxadustat can significantly improve renal anemia. The efficacy of roxadustat in improving renal anemia was not affected by baseline levels of hs-CRP0 and iPTH.

Early erythroferrone levels can predict the long-term haemoglobin responses to erythropoiesis-stimulating agents.

Our previous study reported that erythroferrone (ERFE), a newly identified hormone produced by erythroblasts, responded to recombinant human erythropoietin (rHuEPO) sensitively but its dynamics was complicated by double peaks and circadian rhythm. This study intends to elucidate the underlying mechanisms for the double peaks of ERFE dynamics and further determine whether early ERFE measurements can predict haemoglobin responses to rHuEPO. By using the purified recombinant rat ERFE protein and investigating its deposition in rats, the production of ERFE was deconvoluted. To explore the role of iron in ERFE production, we monitored short-term changes of iron status after injection of rHuEPO or deferiprone. Pharmacokinetic/pharmacodynamic (PK/PD) modelling was used to confirm the mechanisms and examine the predictive ability of ERFE for long-term haemoglobin responses. The rRatERFE protein was successfully purified. The production of ERFE was deconvoluted and showed two independent peaks (2 and 8 h). Transient iron decrease was observed at 4 h after rHuEPO injection and deferiprone induced significant increases of ERFE. Based on this mechanism, the PK/PD model could characterize the complex dynamics of ERFE. In addition, the model predictions further revealed a stronger correlation between ERFE and haemoglobin peak values than that for observed values. The complex dynamics of ERFE should be composited by an immediate release and transient iron deficiency-mediated secondary production of ERFE. The early peak values of ERFE, which occur within a few hours, can predict haemoglobin responses several weeks after ESA treatment.

Treatment of Myelodysplastic Syndromes for Older Patients: Current State of Science, Challenges, and Opportunities.

Myelodysplastic syndromes/neoplasms (MDS) represent a diverse group of pathologically distinct diseases with varying prognoses and risks of leukemia progression. This review aims to discuss current treatment options for elderly patients with MDS, focusing on patients ineligible for intensive chemotherapy or allogenic hematopoietic stem cell transplantation (HSCT). The challenges associated with treatment in this population and emerging therapeutic prospects are also explored. Recent advancements in molecular diagnostics have enhanced risk stratification by incorporating genetic mutations, notably through the molecular International Prognostic Scoring System (IPSS-M). Lower-risk MDS (LR-MDS) treatment ranges from observation to supportive measures and erythropoiesis-stimulating agents (ESAs), with emerging therapies like luspatercept showing promise. High-risk MDS (HR-MDS) is treated with hypomethylating agents (HMAs) or allogenic HSCT, but outcomes remain poor. Elderly MDS patients, often diagnosed after 70, pose challenges in treatment decision-making. The IPSS-M aids risk stratification, guiding therapeutic choices. For LR-MDS, supportive care, ESAs, and novel agents like luspatercept are considered. Treatment of HR-MDS involves HMAs or allogenic HSCT. Emerging treatments, including oral HMAs and novel agents targeting FLT3, and IDH 1/2 mutations, show promise. Future research should refine treatment strategies for this elderly population focusing on quality-of-life improvement.

Strategies for Managing Anemia in Chronic Kidney Disease

Anemia is a common complication in chronic kidney disease (CKD) and is associated with decreased quality of life, deteriorating kidney function, increased illness, higher mortality rates, and elevated healthcare costs. Management of CKD-related anemia aims to enhance renal function (when feasible) and bolster red blood cell production. Anemia in chronic kidney disease (CKD) stems from a variety of factors, including reduced erythropoietin (EPO) production, inadequate iron availability or functionality, and inflammation leading to heightened levels of hepcidin, among other causes. Typical treatment for CKD-related anemia involves administering oral or intravenous iron supplements in conjunction with erythropoiesis-stimulating agents (ESAs). Over the past decade, erythropoiesis-stimulating agents (ESAs) have proven effective in boosting hemoglobin (Hb) levels for many patients. However, concerns about their safety, particularly regarding increased cardiovascular risk—especially at high doses and in hyporesponsive patients—have emerged. As a result, there's been a shift towards adopting more cautious Hb targets. Iron deficiency is widespread among CKD patients, particularly in those not undergoing dialysis. While iron supplementation has traditionally been used to support anemia management, there's growing recognition of the potential benefits of intravenous iron therapy, especially in the context of heart failure. HIF prolyl hydroxylase inhibitors are promising new drugs being clinically evaluated as alternatives to ESAs for anemia treatment in CKD patients. Initial data suggest they effectively boost endogenous erythropoietin production with potential benefits like lower peak concentrations, efficacy in inflamed patients, and improved iron utilization. However, further research is needed to confirm their safety and efficacy in the long term use.&#x0D; Keywords: anemia, chronic kidney disease, erythropoiesis-stimulating agents, iron, HIF-prolyl-hydroxylase inhibitors

Daprodustat: A Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor for Anemia of Chronic Kidney Disease.

The objective was to review the safety and efficacy of daprodustat, a hypoxia-inducible factor-prolyl hydroxylase inhibitor (HIF-PHI) in the treatment of anemia of chronic kidney disease (CKD). A literature search was conducted in MEDLINE, EMBASE, and ClinicalTrials.gov using the keywords "daprodustat," "GSK1278863," and "hypoxia-inducible factor-prolyl hydroxylase inhibitors" from January 2010 through November 2023. Literature was included if it evaluated pharmacology, pharmacokinetics, efficacy, and/or safety of daprodustat in human subjects and was reported in English. The manufacturer's product monograph was also utilized. Daprodustat significantly increased hemoglobin levels in CKD patients on dialysis (difference 0.18 g/dL) and not on dialysis (difference 0.08 g/dL) over 52-week treatment periods compared with erythropoiesis stimulating agents (ESA) in Anemia Studies in CKD: Erythropoiesis via a Novel PHI Daprodustat (ASCEND)-D and ASCEND-ND, respectively. First occurrence of major adverse cardiovascular events (MACEs) was similar between daprodustat and ESAs in both trials. Daprodustat can be used in patients with CKD on dialysis and already receiving an ESA for at least 6 weeks to further increase serum hemoglobin levels without increasing the risk of MACE. Adverse effects of daprodustat that may occur more than ESAs include headache, emesis, and thrombosis. Daprodustat is a novel oral, non-iron therapy for treatment of anemia of CKD. It was Food and Drug Administration approved in 2023 in patients already receiving dialysis for at least 4 months but not in non-dialysis patients. Long-term data for safety and additional benefits are pending.

The impact of myelosuppression on quality of life of patients treated with chemotherapy.

Side effects from chemotherapy-induced myelosuppression can negatively affect patients' quality of life (QoL). Neutropenia increases infection risk, and anemia frequently results in debilitating fatigue. Additionally, the bleeding risk associated with thrombocytopenia can lead to fear and anxiety. However, traditional interventions for myelosuppression fall short of the ideal. Granulocyte colony-stimulating factors reduce the risk of severe neutropenia but commonly lead to bone pain. Erythropoiesis-stimulating agents are not always effective and may cause thromboembolic events, while transfusions to correct anemia/thrombocytopenia are associated with transfusion reactions and volume overload. Trilaciclib, which is approved for reducing myelosuppression in patients with extensive-stage small cell lung cancer, together with several investigational agents in development for managing myelosuppression have the potential to improve QoL for patients on chemotherapy.

HSR24-133: Real-World (RW) Effectiveness of Erythropoiesis-Stimulating Agents (ESAs) After Luspatercept in Patients (pts) With Myelodysplastic Syndromes (MDS): A Retrospective Analysis of a Large Healthcare Claims Database in the United States.

HSR24-133: Real-World (RW) Effectiveness of Erythropoiesis-Stimulating Agents (ESAs) After Luspatercept in Patients (pts) With Myelodysplastic Syndromes (MDS): A Retrospective Analysis of a Large Healthcare Claims Database in the United States.

Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in chronic kidney disease: a document by the European Renal Best Practice board of the European Renal Association.

Anaemia is a common complication of chronic kidney disease (CKD) and is associated with poor long-term outcomes and quality of life. The use of supplemental iron, erythropoiesis stimulating agents (ESAs) and blood transfusions has been the mainstay of treatment of anaemia in CKD for more than three decades. Despite available treatments, CKD patients with anaemia are undertreated and moderate-to-severe anaemia remains prevalent in the CKD population. Anaemia has consistently been associated with greater mortality, hospitalisation, cardiovascular events, and CKD progression in patients with CKD, and the risk increases with anaemia severity. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) inhibitors have a novel mechanism of action by mimicking the body's response to hypoxia and have emerged as an alternative to ESAs for the treatment of anaemia in CKD. Their efficacy in correcting and maintaining haemoglobin has been demonstrated in over 30 phase 3 clinical trials. Additionally, HIF activation results in various pleiotropic effects beyond erythropoiesis with cholesterol reduction and improved iron homeostasis and potential anti-inflammatory effects. The long-term safety of these agents, particularly with respect to cardiovascular and thromboembolic events, and their possible effect on tumor growth requires to be fully elucidated. This document presents in detail the effects of HIF-PH inhibitors, describes their mechanisms of action and pharmacologic properties, and discusses their place in the treatment of anaemia in CKD according to the available evidence.

Short versus long-acting erythropoiesis-stimulating agents for anemia management in Egyptian hemodialysis patients.

Chronic kidney disease (CKD) often results in renal anemia, impacting the well-being of patients and causing various negative consequences. Erythropoiesis-stimulating agents (ESAs) offer promising solutions for managing anemia in CKD. This study aimed to evaluate and compare the effectiveness, safety profile, and cost-effectiveness of short-acting (Eprex®) and long-acting (Aranesp®) ESAs. This comparative prospective cohort cost-effectiveness study was carried out over 6 months among adult Egyptian hemodialysis patients of either gender. Participants were categorized into two groups based on the type of ESA administered: the Eprex group, receiving epoetin alfa, and the Aranesp group, receiving darbepoetin alfa. These two treatment groups' efficacy, safety, and cost were analyzed and compared. Of 127 hemodialysis patients, 60 (47.2%) received Eprex, while 67 (52.8%) were treated with Aranesp. Target hemoglobin (Hb) was achieved by 50.6% of patients in the Eprex group versus 63.4% in the Aranesp group, with a significant difference (P < 0.001). Both treatment groups exhibited a similar safety profile, while Aranesp® was considered the cost-saving protocol. In hemodialysis Egyptian patients, Aranesp with extended dosing intervals proved to be more effective in achieving target Hb with comparable adverse effect profiles, a substantial cost-saving strategy, and offered time-saving advantages for medical staff workload compared to Eprex. The Clinicaltrial.gov registration ID is NCT05699109 (26/01/2023).

Anemia in patients receiving anticancer treatments: focus on novel therapeutic approaches.

Anemia is common in cancer patients and impacts on quality of life and prognosis. It is typically multifactorial, often involving different pathophysiological mechanisms, making treatment a difficult task. In patients undergoing active anticancer treatments like chemotherapy, decreased red blood cell (RBC) production due to myelosuppression generally predominates, but absolute or functional iron deficiency frequently coexists. Current treatments for chemotherapy-related anemia include blood transfusions, erythropoiesis-stimulating agents, and iron supplementation. Each option has limitations, and there is an urgent need for novel approaches. After decades of relative immobilism, several promising anti-anemic drugs are now entering the clinical scenario. Emerging novel classes of anti-anemic drugs recently introduced or in development for other types of anemia include activin receptor ligand traps, hypoxia-inducible factor-prolyl hydroxylase inhibitors, and hepcidin antagonists. Here, we discuss their possible role in the treatment of anemia observed in patients receiving anticancer therapies.

221 Anemia treatment, clinical event rates, and healthcare resource utilization (HCRU) in a US prevalent hemodialysis (HD) cohort hyporesponsive to erythropoietin stimulating agents (ESAs)

221 Anemia treatment, clinical event rates, and healthcare resource utilization (HCRU) in a US prevalent hemodialysis (HD) cohort hyporesponsive to erythropoietin stimulating agents (ESAs)

Outcomes of Early Versus Delayed Anemia Treatment in Nondialysis-Dependent CKD

IntroductionThe association of hemoglobin level at treatment initiation with renal and cardiovascular outcomes in patients with anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) is unclear. MethodsThis retrospective cohort study utilized two Japanese databases (Medical Data Vision [MDV] and Real World Data [RWD]). Patients initiated long-acting erythropoiesis-stimulating agent treatment were divided into early (hemoglobin levels ≥9.0 g/dL) and delayed (<9.0 g/dL) treatment groups. The primary outcome was a renal composite (renal replacement therapy, ≥50% estimated glomerular filtration rate [eGFR] reduction, eGFR <6.0 mL/min/1.73 m2, and all-cause mortality), and secondary outcomes were a cardiovascular composite (hospitalization by ischemic heart disease including myocardial infarction, hospitalization by stroke and heart failure, and cardiovascular death) and components of the composite outcomes. ResultsAfter propensity score matching, 1472 (MDV) and 1264 (RWD) patients were evaluated. Delayed treatment was not associated with a risk of the renal composite outcome (MDV: hazard ratio [HR] 1.15, 95% confidence intervals [CI] 0.99–1.33; RWD: 1.08, 0.92–1.28). However, delay was associated with higher risks of the cardiovascular composite outcome (MDV: HR 1.47, 95% CI 1.16–1.84; RWD: 1.34, 1.09–1.64), heart failure (MDV: HR 1.50, 95% CI 1.13–2.00; RWD: 1.53, 1.20–1.96) and all-cause mortality (MDV: HR 1.83, 95% CI 1.32–2.54; RWD: 1.64, 1.21–2.22). ConclusionAlthough the risk of renal events was not increased following delayed treatment of anemia in patients with NDD-CKD, the risks of cardiovascular events and all-cause mortality were increased, suggesting the importance of early intervention before hemoglobin fall below 9.0 g/dL.

Isoquinoline-based intrinsic fluorescence assessment of erythropoiesis-stimulating agent, Roxadustat (FG-4592), in tablets: applications to content uniformity and human plasma evaluation.

In the present study, a first validated and green spectrofluorimetric approach for its assessment and evaluation in different matrices was investigated. After using an excitation wavelength of 345 nm, Roxadustat (ROX) demonstrates a highly native fluorescence at an emission of 410 nm. The influences of experimental factors such as pH, diluting solvents, and different organized media were tested, and the most appropriate solvent choice was ethanol. It was confirmed that there was a linear relationship between the concentration of ROX and the relative fluorescence intensity in the range 60.0-1000.0 ng ml-1, with the limit of detection and limit of quantitation, respectively, being 17.0 and 53.0 ng ml-1. The mean recoveries % [±standard deviation (SD), n =5] for pharmaceutical preparations were 100.11% ± 2.24%, whereas for plasma samples, they were 100.08 ± 1.08% (±SD, n =5). The results obtained after the application of four greenness criteria, Analytical Eco-Scale metric, NEMI, GAPI, and AGREE metric, confirmed its eco-friendliness. In addition, the whiteness meter (RGB12) confirmed its level of sustainability. The International Council for Harmonisation (ICH) criteria were used to verify the developed method through the study in both spiked plasma samples and content uniformity evaluation. An appropriate standard for various applications in industry and quality control laboratories was developed.

Factors affecting responsiveness of vadadustat in patients with anemia associated with chronic kidney disease: a post-hoc subgroup analysis of Japanese phase 3 randomized studies

BackgroundVadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed for treating anemia in chronic kidney disease (CKD). The purpose of this post-hoc analysis was to investigate the factors affecting the responsiveness to vadadustat in anemia patients with nondialysis-dependent (NDD) or hemodialysis-dependent (HDD) CKD in two Japanese phase 3 studies.MethodsOf 151 and 162 patients enrolled in NDD-CKD and HDD-CKD studies, 136 and 140 patients, respectively, were included and divided into subgroups for the analysis. To assess vadadustat responsiveness, the resistance index was defined as the mean body weight-adjusted dose of vadadustat (mg/kg) at weeks 20–24 divided by the mean hemoglobin (g/dL) at weeks 20–24. Multivariate analysis was performed to identify the variables affecting the resistance index.ResultsIndependent factors identified as determinants for better response to vadadustat were as follows: high baseline hemoglobin, low baseline eGFR, high week-20–24 ferritin, and CKD not caused by autoimmune disease/glomerulonephritis/vasculitis in NDD-CKD; and male sex, high baseline C-reactive protein, and low baseline erythropoiesis-stimulating agent resistance index (ERI) in HDD-CKD.ConclusionsIn this post-hoc analysis, several factors were identified as affecting the response to vadadustat. These results may provide useful information leading to an appropriate dose modification for vadadustat.Clinical trial registrationNCT03329196 (MT-6548-J01) and NCT03439137 (MT-6548-J03).

Copper deficiency anemia due to zinc supplementation in a chronic hemodialysis patient.

Zinc deficiency causes dysgeusia and dermatitis as well as anemia. As approximately half of dialysis patients have zinc deficiency, zinc supplementation should be considered in case of erythropoiesis-stimulating agent (ESA)-hyporesponsive anemia. We report a case of a chronic dialysis patient with copper deficiency anemia caused by standard-dose zinc supplementation. The patient was a 70-year-old woman who had received maintenance hemodialysis for 8years due to diabetic nephropathy. She had been treated with weekly administration of darbepoetin 30μg for renal anemia, which resulted in Hb 12 to 14g/dL. She had no dysgeusia. When zinc deficiency (44μg/dL) had been identified 4months earlier, 50mg daily zinc acetate hydrate (Nobelzin®), which is the standard dose, was started. Unexpectedly, her anemia progressed slowly with macrocytosis together with granulocytopenia. Her platelet count did not decrease at that time. Laboratory tests revealed a marked decrease of serum copper (< 4μg/dL) and ceruloplasmin (< 2mg/dL), although serum zinc was within the normal limit (125μg/dL). We discontinued zinc acetate and started copper supplementation including cocoa for 1month. Her anemia and granulocytopenia were dramatically restored coincident with the increase in both serum copper and ceruloplasmin. Copper supplementation also improved her iron status as assessed by transferrin saturation and ferritin. Clinicians should monitor both zinc and copper status in anemic dialysis patients during zinc supplementation, as both are important to drive normal hematopoiesis.