Target Hb Research Articles

Prevalence of peripheral neuropathy in children with transfusion-dependent thalassemia: A hospital-based cross-sectional study

ABSTRACT Background: Our study aimed to determine the prevalence of Peripheral Neuropathy (using nerve conduction studies (NCS)) in children with transfusion-dependent thalassemia aged between 5 to 18 years and to study its correlation with chronic anemia, ferritin levels, chelation status, annual transfusion requirement, deficiency of serum Vitamin B12, and Folate levels. Methods: In this hospital-based cross-sectional study, 100 eligible children were enrolled in a tertiary care teaching hospital in New Delhi, India. Neurological examinations focusing on peripheral neuropathy followed by NCS were performed on all the patients. Age-wise cutoff values outside of 2.5 SD of normal were taken as abnormal. Results: None of the children had clinical features of peripheral neuropathy, although 77% had abnormalities in NCS. Of these, 33% had pure motor nerve changes, 7% had pure sensory nerve changes, 1% had abnormal F responses, and 26% had mixed nerve changes. These changes correlated significantly with chronic anemia and duration of iron chelation but not with other factors. Conclusion: In children with transfusion-dependent thalassemia who do not exhibit any neurological signs or symptoms, however, it is not uncommon to observe abnormal NCS at an average hemoglobin (Hb) level of less than 9.5 g/dl. Further comprehensive case-control studies are necessary to determine if a more specific Hb target range of 9.5 to 10.5 g/dl is appropriate and to investigate the potential impact of chelation therapy on these changes.

Appropriate Use of Inpatient Erythropoiesis Stimulating Agents

Background: Anemia is a significant global public health issue, and it is associated with lethargy, weakness, tiredness, and shortness of breath. Erythropoietin stimulating agents (ESAs) are recombinant / synthetic erythropoietin and can increase hemoglobin (Hb) levels. There are increased risks of cardiovascular events and death associated with the use of ESAs when raising Hb levels above 12 g/dL. Methods: This was a baseline safety assessment via a retrospective chart review, including patients who recently received an inpatient dose of an ESA within The Mount Sinai Hospital (MSH) from November 1, 2015 (after MSH ESA guideline revision) to August 1, 2023. All adult patients who received an ESA (originator or biosimilar products) during hospitalization were included. Data collection was in reverse chronology, and only the most recent dose administered to each unique patient was collected. Results: If an ESA dose was dispensed when the Hb was less than the upper limit of the target Hb for the specific indication, this was considered appropriate use. Based on data from June 15 to August 1, 2023 (~47 days of inpatient utilization), for the primary outcome, 169 out of 171 doses (98.8%) met the predefined criteria for appropriateness. One dose was dispensed when the Hb was 11.1 g/dL to a patient on renal replacement therapy, and one dose was dispensed when the Hb was 13.8 g/dL to a surgical patient who refused blood transfusions. Among secondary outcomes of interest, there was a difference in blood transfusions administered in critical versus non-critical care settings. Conclusion: Inpatient use of ESA at MSH was appropriate when looking at Hb targets. There are currently no formal order sets, service-line restrictions, or additional chairperson approvals needed at MSH. Despite this, there remained significant adherence to prevailing Hb targets, reflecting provider and pharmacy teams' knowledge and awareness of contemporary best practices.

Clinical Significance of IL-6 Gene Polymorphism on Erythropoietin Responsiveness in Hemodialysis Patients

Abstract Background The plasma levels of the cytokine interleukin-6 (IL-6) have been reported to be associated with risk of chronic kidney disease (CKD) and erythropoietin (EPO) responsiveness. The G/C promoter polymorphism of IL-6 is associated with expression and levels of IL-6, so it may confer increased risk to CKD and modulate EPO responsiveness. Aim of the Work This study aims to evaluate the frequency of 174G/C IL-6 gene promoter polymorphism in hemodialysis (HD) patients and to assess the impact of this allelic variation on erythropoietin (EPO) responsiveness. Patients and Methods This study was conducted on fifty Chronic Kidney Disease (CKD) patients undergoing hemodialysis (HD) recruited from Nephrology Medicine Department at Ain Shams University hospitals, and ten healthy age and sex matched controls. All patients received recombinant human erythropoeitin (rHu-Epo) regimens for treatment of anemia. All the patients were subjected to full history taking, basic laboratory investigations (CBC, Iron profile and kidney function tests) as well as determination of IL-6 rs1800795 (-174 G/C) gene polymorphism using Real time-polymerase chain reaction technique (RT-PCR). The patient’s group was further classified into two subgroups according to Hb level in response to erythropoietin stimulating agents (ESAs) in accordance with the European Best Practice Guidelines, in which responders have a Hb level ≥11 g/dl, and ESA non-responders have a Hb level<11 g/dl. The Erythropoietin resistance index (ERI) was calculated for all patients, with a median (IQR) of 16.5 (14.31 - 19.96). Accordingly all patients were further classified into tertiles according to the ERI. The higher tertile group is classified as more hypo-responsive/resistant. Results In the present study, The IL-6 -174 G/G genotype was the most common among the cases group. Seventy four percent of the patients had the wild GG genotype and 24% had heterozygous GC genotype while only 2% had the homozygous CC genotype. In the control group the G/G genotype was detected in (80%) of subjects followed by G/C genotype (20%). No statistically significant difference was observed between the control and cases group regarding the IL-6 genotype frequencies. Only eight out of fifty (16%) patients reached the target Hb, 4 of them (50%) had the GG genotype and the other 4 (50%) had the GC genotype. The non-responders genotypes were distributed as 78.6% GG genotype, 19% GC genotype and 2.4% with CC genotype. There was no statistical significant difference regarding the genotype frequencies of IL-6 gene polymorphism between the two groups. Similarly no statistically significant association was found between the IL-6 gene genotypes and the ERI tertiles. Conclusion IL-6 -174 G/C gene polymorphism was not found to be associated with EPO hypo-responsiveness in CKD patients in the studied group nor with the increased Erythropoeitin resistance index (ERI) values among them.

Usage of the Anemia Control Model Is Associated with Reduced Hospitalization Risk in Hemodialysis.

The management of anemia in chronic kidney disease (CKD-An) presents significant challenges for nephrologists due to variable responsiveness to erythropoietin-stimulating agents (ESAs), hemoglobin (Hb) cycling, and multiple clinical factors affecting erythropoiesis. The Anemia Control Model (ACM) is a decision support system designed to personalize anemia treatment, which has shown improvements in achieving Hb targets, reducing ESA doses, and maintaining Hb stability. This study aimed to evaluate the association between ACM-guided anemia management with hospitalizations and survival in a large cohort of hemodialysis patients. This multi-center, retrospective cohort study evaluated adult hemodialysis patients within the European Fresenius Medical Care NephroCare network from 2014 to 2019. Patients treated according to ACM recommendations were compared to those from centers without ACM. Data on demographics, comorbidities, and dialysis treatment were used to compute a propensity score estimating the likelihood of receiving ACM-guided care. The primary endpoint was hospitalizations during follow-up; the secondary endpoint was survival. A 1:1 propensity score-matched design was used to minimize confounding bias. A total of 20,209 eligible patients were considered (reference group: 17,101; ACM adherent group: 3108). Before matching, the mean age was 65.3 ± 14.5 years, with 59.2% men. Propensity score matching resulted in two groups of 1950 patients each. Matched ACM adherent and non-ACM patients showed negligible differences in baseline characteristics. Hospitalization rates were lower in the ACM group both before matching (71.3 vs. 82.6 per 100 person-years, p < 0.001) and after matching (74.3 vs. 86.7 per 100 person-years, p < 0.001). During follow-up, 385 patients died, showing no significant survival benefit for ACM-guided care (hazard ratio = 0.93; p = 0.51). ACM-guided anemia management was associated with a significant reduction in hospitalization risk among hemodialysis patients. These results further support the utility of ACM as a decision-support tool enhancing anemia management in clinical practice.

Study of the Efficacy and Safety of Darbepoetin Alfa versus Epoetin Alfa in the Treatment of Anemia in Pediatric Patients on Regular Hemodialysis

Abstract Background Anemia is a common comorbidity in patients with chronic kidney disease (CKD). That affects the vast majority and can have a significant impact on patient morbidity and mortality. Erythropoiesis-stimulating agents (ESAs) are the main lines in management of anemia in hemodialysis patients. Replacement therapy with recombinant human erythropoietin (r- HuEPO) has provided an effective treatment for patients with renal “Epoetin alfa” is a recombinant erythropoietin with the same amino acid sequence as human erythropoietin (EPO). In comparison to epoetin alfa, darbepoetin alfa (DPO) contains an increased amount of sialic acid-containing carbohydrate chains. It shows a much longer elimination half-life than epoetin alfa, with prolonged erythropoietic effect. Aim of the Work to evaluate whether darbpoetin and epopoetin alpha can be used interchangeably on the same patient, achieving the same desired effect and to detect any difference in the occurrence of side effects between both ESAs. Patient and Methods This was a crossover study that took place in the Pediatrics Dialysis unit, Children’s Hospital, Ain Shams University. The study was conducted on 40 children with end stage renal disease on regular hemodialysis over a period of 6 months. The patients were randomly put into two groups A and B, each group contained 20 patients. Each group received one type of ESA either ( darbpoetin alpha or epopoetin alpha )for 3 months and then shifted to the other type of ESA for another 3 months. The dosage of epoetin alfa used was (200 IU/kg/week) and a conversion rate of EPO: DPO, 300:1. A period of 6 weeks was agreed as a washout period after the first drug given in both groups in which no results were recorded but ESA was not stopped due to its essentiality. Blood tests (hemoglobin (Hb), serum urea, serum creatinine and iron profile; (S. iron, S. ferritin, TIBC, and transferrin saturation)) were withdrawn at the start and the end of the 3 months’ period of each drug. Results We found no difference on the Hb level with both drugs. The interchange between them did not yield any significant drop in the Hb levels. Hb target in both EPO and DPO was reached in 22.5% of total cases, and was not reached in 62.5%. This proved that both drugs give the same effect with nearly negligible difference. No serious Sside effect as convulsions, hypertension, and thrombosis were noticed in both groups. Conclusion The target Hb was not reached in most patients of both groups of ESRD on regular hemodialysis at the unit and none of both drugs showed superior results or less side effects than the other.

Treatment of Anemia Associated with Chronic Kidney Disease: Plea for Considering Physiological Erythropoiesis.

Traditionally, the treatment of anemia associated with chronic kidney disease (CKD) involves prescribing erythropoiesis-stimulating agents (ESAs) or iron preparations. The effectiveness and safety of ESAs and iron have been established. However, several clinical issues, such as hyporesponsiveness to ESAs or defective iron utilization for erythropoiesis, have been demonstrated. Recently, a new class of therapeutics for renal anemia known as hypoxia-inducible factor (HIF)/proline hydroxylase (PH) inhibitors has been developed. Several studies have reported that HIF-PH inhibitors have unique characteristics compared with those of ESAs. In particular, the use of HIF-PH inhibitors may maintain target Hb concentration in patients treated with a high dose of ESAs without increasing the dose. Furthermore, several recent studies have demonstrated that patients with CKD with defective iron utilization for erythropoiesis had a high risk of cardiovascular events or premature death. HIF-PH inhibitors increase iron transport and absorption from the gastrointestinal tract; thus, they may ameliorate defective iron utilization for erythropoiesis in patients with CKD. Conversely, several clinical problems, such as aggravation of thrombotic and embolic complications, diabetic retinal disease, and cancer, have been noted at the time of HIF-PH inhibitor administration. Recently, several pooled analyses of phase III trials have reported the non-inferiority of HIF-PH inhibitors regarding these clinical concerns compared with ESAs. The advantages and issues of anemia treatment by ESAs, iron preparations, and HIF-PH inhibitors must be fully understood. Moreover, patients with anemia and CKD should be treated by providing a physiological erythropoiesis environment that is similar to that of healthy individuals.

#1171 Effect of methoxy polyethylene glycol-epoetin beta on delaying dialysis in anemic patients with Stage 4-5 chronic kidney disease

Abstract Background and Aims The optimal hemoglobin (Hb) target for treating anemia in pre-dialysis chronic kidney disease (CKD) remains controversial. This study investigates the efficacy and safety of methoxy polyethylene glycol-epoetin beta, in delaying the initiation of kidney replacement therapy (KRT), all-cause mortality, CKD progression, and quality of life in stage 4-5 CKD patients. It compares outcomes between patients targeting an Hb level of 10.5-11.5 g/dL versus 8.5-9.5 g/dL. Method This was a single-center, open-label, parallel-group randomized controlled trial. Patients with estimated glomerular filtration rates (eGFR) of 8-15 ml/min/1.73 m2, who had not yet started dialysis, were randomized into two groups based on different Hb targets (Group A: 10.5-11.5 g/dL, Group B: 8.5-9.5 g/dL). Methoxy polyethylene glycol-epoetin beta (MIRCERA®) was prescribed by a pre-specified protocol to achieve these Hb targets. Iron supplements were administered to maintain transferrin saturation &amp;gt;20% or serum ferritin &amp;gt;200 ng/ml. Primary outcomes included a composite of all-cause death and KRT initiation, with secondary outcomes encompassing eGFR slope, hospitalization incidence, blood transfusion necessity, and quality of life measured by the 36-Item Short Form Health Survey (SF-36). Results A total of 62 participants were randomized. The mean age was 64.0 years (SD ±16.0), with 51.6% being female. The mean estimated Glomerular Filtration Rate (eGFR) at enrollment was 12.1 ml/min/1.73 m2 (SD ±3.1). Group A had a significantly higher time-averaged Hemoglobin (Hb) level (10.5 g/dL, SD ±1.2) compared to 8.5 g/dL (SD ±0.9) in the control group (p &amp;lt; 0.001). There was no significant difference in the composite endpoint of all-cause death and Kidney Replacement Therapy (KRT) initiation between the two groups (Hazard Ratio [HR] 0.69; 95% Confidence Interval [CI] 0.32-1.50; p = 0.35, as shown in the Figure). The eGFR slope was similar in both groups (−2.54 vs. −2.53 ml/min/1.73 m2 per year, p = 0.9). Time-averaged ferritin, transferrin saturation, blood pressure, and dietary sodium/protein intake showed no significant differences. Participants in the lower Hb target group required more blood transfusions (11 vs 1 unit, Incidence Rate Ratio [IRR] = 0.075, 95% CI 0.002-0.517, p = 0.001). Rates of hospital admissions, and changes in SF-36 quality of life domains were comparable between the groups, as detailed in the Table. Conclusion The study indicates that using methoxy polyethylene glycol-epoetin beta to maintain a higher Hb target in anemic patients with stage 4-5 CKD does not significantly alter the rate of all-cause mortality, the initiation of KRT, and rate of eGFR decline compared to a lower Hb target. However, a higher Hb target may reduce the need for blood transfusions without adversely affecting the progression of CKD, hospitalization rates, or quality of life. These findings suggest that while higher Hb targets may not dramatically alter key clinical outcomes, they could offer benefits in reducing transfusion requirements, thus providing a more nuanced approach to managing anemia in late-stage CKD.

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).

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

Chinese physician perception on the treatment of chemotherapy-induced anemia: online cross-section survey study.

The management of chemotherapy induced anemia (CIA) remains challenging. The potential risk and benefits in providing patient-centered care need to be balanced; the disease is multifactorial; and the major treatments including red blood cell (RBC) transfusions, erythropoiesis-stimulating agents (ESAs) and intravenous injection (i.v.)iron supplementation have a unique set of strengths and limitations. Also, most previous survey based on the patient data could not reveal the process of evaluation and decision-making for CIA treatment from a physician's perspective. As the comparison of China Society of Clinical Oncology (CSCO), National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) guidelines, the standard of CIA treatment in China will vary from United States and Europe, for example, the initial hemoglobin (Hb) for RBC transfusions. In order to understand the diagnosis, treatment, and unmet medical needs of CIA patients, the China Medical Education Association (CMEA), in conjunction with Cancer Hope Medium, initiated the first national survey of Chinese physicians regarding the diagnosis and treatment of CIA. The CMEA sent an online, 12-item questionnaire (via wjx.cn) to physicians across China from September 1, 2022 to October 22, 2022. Two hundred and sixty-five samples were calculated usingsurveyplanet.com. The questionnaire evaluated the impact of anemia on chemotherapy interruption, initial treatment, the target Hb level of CIA in, and the current status of ESAs prescription in clinical practice. Respondents were asked to score their reasons for not using ESAs (including safety issues, drug access in practice or adherence) and the risk options of the current treatment including ESAs, RBC transfusion, and i.v.iron. A total of 331 questionnaires among 5,000 web visits were gathered, covering 247 hospitals in 29 provinces across China, of which 130 (53%) were tier IIIA hospitals, 50 (20%) were tier III B hospitals, 59 (24%) were tier IIA hospitals, and 8 (3%) were tier II B hospitals. The frequency of chemotherapy dose delay/reduction due to anemia was 24% [standard deviation (SD) 49%]. Most responding physicians rated an initial Hb level for ESAs treatment to be 80 g/L, with a favorable Hb level for chemotherapy being 100 g/L (60%), which would not limit treatment availability. The majority (67.6%, n=221) of physicians who responded indicated that they had used ESAs for anemia correction, while the others (32.4%, n=106) reported never using them. This is the first study in conducting a large-scale survey on the diagnosis and treatment of CIA in China from a physicians' perspective. We found that in China, nearly one-quarter of patients undergoing chemotherapy with concurrent anemia may experience interruption of chemotherapy and that the initiation of anemia treatment is not adequately timed. In treating CIA, most physicians prioritize the completion of chemotherapy via Hb level over treating the symptoms of anemia.

Efficacy of roxadustat in maintenance hemodialysis patients with erythropoietin-hyporesponsive anemia.

To investigate the efficacy of roxadustat in hemodialysis patients with erythropoietin (EPO) hypo-responsive anemia. This retrospective study included 55 hemodialysis patients with erythropoietin hypo-responsive anemia at the First Affiliated Hospital of Chongqing Medical University from January to December 2020. We observed their hemoglobin (Hb) changes, inflammatory factors, and adverse reactions before and after 12 weeks of roxadustat treatment. Among the 55 patients, the average age was 60.75 ± 13.96 years old, and the median dialysis age was 48 months. All patients were taken off EPO and switched to roxadustat during the follow-up period. Compared with baseline, patients' Hb was significantly increased (90.64 ± 20.01 g/L, 98.52 ± 15.89 g/L, 104.34 ± 19.15 g/L, and 107.02 ± 20.54 g/L, respectively) (p &lt; 0.05). At 12 weeks of roxadustat treatment, 34 patients (61.82%) met the target Hb levels (100 - 130 g/L). The multivariate logistic analysis showed that Hb response positively correlated with the Hb level before roxadustat treatment (p = 0.046), while responding well to roxadustat negatively correlated with blood platelet-to-lymphocyte ratio (PLR) and duration of dialysis (p = 0.029 and p = 0.046) in patients with EPO hypo-responsive anemia. Roxadustat could effectively improve anemia; the PLR and dialysis age were independent predictors of roxadustat efficacy in dialysis patients with EPO hypo-responsive anemia.

Incidence and outcomes of type 2 myocardial infarction: a cohort study of a national population-based registry

Abstract Background/introduction Type 2 myocardial infarction (T2MI), caused by myocardial oxygen supply/demand mismatch without acute thrombotic plaque disruption, makes up 2-25% of reported MI. T2MI may be triggered by conditions such as arrhythmias, anaemia, sepsis, heart failure, but the incidence, outcomes and predictors of poor outcomes post-T2MI requires further study. Aims In this study, we characterised the incidence, outcomes and predictors of poor outcomes in T2MI in Singapore. Methods We performed an ambidirectional cohort study of 10720 consecutive T2MI patients from January 2012 to December 2018 from the national Singapore MI Registry (SMIR). The primary outcome was major adverse cardiovascular events (MACE; composite of MI, stroke and mortality) within 30 days and 1 year. The secondary outcomes were all-cause mortality, cardiovascular death and stroke. Results Of 10,724 patients with T2MI, 3852 (35.9%) had MACE within 30 days and 5947 (51.4%) had MACE within 1 year (Table 1). The incidence of T2MI increased from 20 per 100,000 residents in 2012 to 80 per 100,000 residents in 2017 (Figure 1A). Significant independent predictors of MACE at 30 days on multivariable analysis include age (hazard ratio [HR] 1.01, 95% confidence interval (CI) 1.00-1.01), history of hypertension (HR 1.23, 95% CI 1.06-1.42) or diabetes mellitus (HR 1.32, 95% CI 1.17-1.48), Killip classes 2-4 and left ventricular ejection fraction &amp;lt;50% during hospitalization. Low hemoglobin (Hb) 8-9 (HR 1.42, 95% CI 1.07-1.88) and 10-11 (HR 1.36, 95% CI 1.05-1.76) compared to Hb 14-15, were predictors of MACE at 30 days and Hb &amp;lt;13 showed significant associated with MACE at 1 year. Hb &amp;lt;12 was also significantly associated with all-cause mortality at 1 year, but not cardiovascular death or stroke. Significant predictors of stroke at 1 year included current smoking (HR 1.53, 95% CI 1.04-2.23) and atrial fibrillation (AF) (HR 1.54, 95% CI 1.21-1.97). Troponin levels were not significantly associated with MACE at 30 days or 1 year. Conclusions The incidence of T2MI has been increasing since 2012, with generally poor outcomes within 1 year. Predictors of poor outcomes include age, history of cardiovascular risk factors, AF, reduced LVEF during hospitalization, and low hemoglobin. A higher target Hb may be needed post-T2MI, and further research is needed to establish this.

Red Blood Cell Transfusion Guided by Hemoglobin Only or Integrating Perfusion Markers in Patients Undergoing Cardiac Surgery: A Systematic Review and Meta-Analysis With Trial Sequential Analysis

Strategies for red blood cell (RBC) transfusion in patients undergoing cardiac surgery have been traditionally anchored to hemoglobin (Hb) targets. A more physiologic approach would consider markers of organ hypoperfusion. The authors conducted a systematic review and meta-analysis with trial sequential analysis of randomized controlled trials (RCTs). Cardiac surgery. Adult patients. RBC transfusion targeting only Hb levels compared with strategies combining Hb values with markers of organ hypoperfusion. Primary outcomes were the number of RBC units transfused, the number of patients transfused at least once, and the average number of transfusions. Secondary outcomes were postoperative complications, intensive care (ICU) and hospital lengths of stay, and mortality. Only 2 RCTs were included (n=257 patients), and both used central venous oxygen saturation (ScvO2) as a marker of organ hypoperfusion (cut-off: <70% or ≤65%). A transfusion protocol combining Hb and ScvO2 reduced the overall number of RBC units transfused (risk ratio [RR]: 1.57 [1.33-1.85]; p < 0.0001, I2=0%), and the number of patients transfused at least once (RR: 1.33 [1.16-1.53]; p < 0.0001, I2=41%), but not the average number of transfusions (mean difference [MD]: 0.18 [-0.11 to 0.47]; p=0.24, I2=66%), with moderate certainty of evidence. Mortality (RR: 1.29, [0.29-5.77]; p=0.73, I2=0%), ICU length-of-stay (MD: -0.06 [-0.58 to 0.46]; p=0.81, I2=0%), hospital length-of-stay (MD: -0.05 [-1.49 to 1.39];p=0.95, I2=0%), and all postoperative complications were not affected. In adult patients undergoing cardiac surgery, a restrictive protocol integrating Hb values with a marker of organ hypoperfusion (ScvO2) reduces the number of RBC units transfused and the number of patients transfused at least once without apparent signals of harm. These findings were preliminary and warrant further multicentric research.

Opportunities to improve the management of anemia in peritoneal dialysis patients: lessons from a national study in routine clinical practice.

Current guidelines establish the same hemoglobin (Hb) and iron biomarkers targets for hemodialysis (HD) and peritoneal dialysis (PD) in patients receiving erythropoiesis-stimulating agents (ESAs) even though patients having PD are usually younger, more active and less comorbid. Unfortunately, specific renal anemia [anemia in chronic kidney disease (aCKD)] trials or observational studies on PD are scanty. The aims of this study were to describe current aCKD management, goals and adherence to clinical guidelines, identifying opportunities for healthcare improvement in PD patients. This was a retrospective, nationwide, multicentre study including patients from 19 PD units. The nephrologists collected baseline data, demographics, comorbidities and data related to anemia management (laboratory values, previously prescribed treatments and subsequent adjustments) from electronic medical records. The European adaptation of KDIGO guidelines was the reference for definitions, drug prescriptions and targets. A total of 343 patients (mean age 62.9years, 61.2% male) were included; 72.9% were receiving ESAs and 33.2% iron therapy [20.7% intravenously (IV)]. Eighty-two patients were receiving ESA without iron therapy, despite 53 of them having an indication according to the European Renal Best Practice guidelines. After laboratory results, iron therapy was only started in 15% of patients. Among ESA-treated patients, 51.9% had an optimal control [hemoglobin (Hb) 10-12g/dL] and 28.3% between 12-12.9g/dL. Seventeen patients achieved Hb >13g/dL, and 12 of them remained on ESA after overshooting. Only three patients had Hb <10g/dL without ESAs. Seven patients (2%) met criteria for ESA resistance (epoetin dose >300IU/kg/week). The highest tertile of erythropoietin resistance index (>6.3 UI/kg/week/g/dL) was associated with iron deficiency and low albumin corrected by renal replacement therapy vintage and hospital admissions in the previous 3months. Iron therapy continues to be underused (especially IV). Low albumin, iron deficiency and prior events explain most of the ESA hyporesponsiveness. Hb targets are titrated to/above the upper limits. Thus, several missed opportunities for adequate prescriptions and adherence to guidelines were identified.

#4445 ANAEMIA MANAGEMENT IN PERITONEAL DIALYSIS: FROM GUIDELINES TO ROUTINE CLINICAL PRACTICE

Abstract Background and Aims The evidence on the management of renal anemia in peritoneal dialysis (PD) is much weaker than in hemodialysis (HD). Current guidelines establish the same haemoglobin (Hb) target for patients under eritropoietin stimulating agents (ESAs) in both dialysis techniques (PD, HD), although patients in PD are usually younger, more active and lesss comorbid. Unfortunately, there is not randomized controlled trials evaluating the efficacy and safety the effect of different Hb target on clinical outcomes. The aim is to describe the current situation of anaemia prevalence, treatments, and achievement of clinical guidelines recommendations in this population. Method Retrospective nationwide multicenter study including patients from 19 PD units. All prevalent PD patients that were active in the technique in November 2019 for at least 3 months was included (to avoid COVID pandemic interferences). Exclusion criteria were a previous kidney transplant failure and being on PD due to a cardiorenal syndrome with a residual renal function over 20 ml/min/1.73 m2. The nephrologists collected baseline data, demographics, comorbidities, and data related to anemia management (ie, laboratory values, previously prescribed treatments, and subsequent adjustments) from electronic medical records. The European adaptation of KDIGO guidelines was the reference for iron and Hb limits, prescriptions and targets. Results A total of 343 patients (mean age 62.9 years, 61.2% male) were included. Regarding anaemia-treatment prescription, 72.9% were receiving ESAs and 33.2% iron therapy (20.7% intravenously-IV and 12.5% orally). Eighty-two (32.8%) patients were receiving ESA without iron therapy, despite to have an indication to do it according ERBP guidelines in 53 out of them. After knowing lab results, iron therapy was only started in 8 (15%) patients. Among ESA-treated patients, 58.8% had an optimal control (Hb 10–12 g/dl). Seventeen patients had haemoglobin over 13 g/dl, and 12 of them continued receiving ESA after knowing lab results. Only three patients had persistent haemoglobin &amp;lt;10 g/dl. Seven patients (2%) met criteria for ESA resistance (epoetin dose &amp;gt;300 IU/kg/week). Patients in the highest tertile of erythropoietin resistance index (ERI) (&amp;gt;6.3 UI/kg/week/g/dl) were more inflamed, had lower albumin levels and lower residual renal function. Conclusion Anaemia prevalence is high in this population and its management in PD Units could be improved according to the ERBP guidelines. The lack of iron therapy in patients who should have received it and the excessive tolerance to high Hb levels are the most relevant opportunities to improve compliance with clinical guidelines.

#2560 HEMOGLOBIN VARIABILITY AND ADVERSE CLINICAL EVENTS IN PATIENTS WITH NON-DIALYSIS-DEPENDENT CHRONIC KIDNEY DISEASE AND ANEMIA IN CONTINUOUS CARE

Abstract Background and Aims Anemia management in non-dialysis dependent chronic kidney disease (NDD-CKD) patients has attracted attention with the introduction of new treatment options, such as prolyl hydroxylase domain enzyme inhibitors (HIF-PHI). However, studies reporting comprehensive information on anemia management in NDD-CKD patients are limited. While previous studies reported increased risks of adverse clinical events associated with hemoglobin (Hb) fluctuation in hemodialysis patients, limited information is available in NDD-CKD patients. Method A retrospective cohort study was performed using a Japanese nationwide electronic medical record-based hospital database. Patients with stage ≥3a NDD-CKD, aged ≥18 years, and at least one recorded Hb &amp;lt;11 g/dL between January 1st 2013 and April 30th 2021 were included. Patients already receiving any anemia treatment (erythropoiesis stimulating agent (ESA), iron, or HIF-PHI) were excluded. Hb levels were collected at the index date (the date of the first recorded Hb &amp;lt;11 g/dL) and during the follow-up period. Clinical events included all-cause death, cardiovascular (CV) events (myocardial infarction, unstable angina pectoris, stroke, or hospitalization for heart failure), dialysis introduction, and red-blood-cell transfusion. Time-dependent Cox proportional hazard models, adjusted by clinically relevant variables were applied to assess the risk of clinical events associated with transitioning Hb fluctuation patterns, categorized into six groups: within the target Hb range (11–13 g/dL); consistently below the target (low); consistently above the target (high); low-amplitude fluctuation around the upper limit of the target (LAH); low-amplitude fluctuation around the lower limit of the target (LAL); and, high amplitude fluctuation across the target (HA). Results Of 162,170 patients with CKD, 26,626 (16.4%) NDD-CKD patients with Hb &amp;lt;11 g/dL were identified (median follow-up length, 1.9 years). The mean age was 75.9 years, and 37.8% were female. In overall patients, the mean (±SD) Hb levels at index and at 3, 6, and 12 months of follow up were 9.9±1.2 g/dL, 10.6±1.5 g/dL, 10.8±1.6 g/dL, and 10.9±1.6 g/dL, respectively. The proportion of patients with Hb &amp;lt;10 g/dL at index and at 12 months were 34.3% and 23.9%, respectively. In the subgroup of patients treated with ESA or HIF-PHI (n = 8,876), the mean Hb (±SD) levels had increased from 9.3±1.3 g/dL to 10.3±1.5 g/dL at 3 months, 10.5±1.5 g/dL at 6 months, and 10.6±1.5 g/dL at 12 months after treatment initiation. In this subgroup, the proportion of patients with Hb &amp;lt;10 g/dL had decreased from 70.0% to 30.1% at 12 months. Fig. 1 shows the Hb levels and proportions of patients with Hb &amp;lt;10 g/dL by treatment type. During the follow-up period, 5,991 (22.5%) deaths, 3,545 (13.3%) CV events, 4,231 (15.9%) dialysis introductions, and 5,561 (20.9%) red-blood-cell transfusions were observed. The risks of clinical events were significantly higher in the low and LAL Hb groups than in the target Hb group (Fig. 2). The hazard ratios (95% CIs) for death, CV events, dialysis introduction, and red-blood-cell transfusion in the low Hb group, compared to the target Hb group were 1.35 (1.20–1.52), 1.90 (1.58–2.27), 1.75 (1.39–2.20), and 2.80 (2.28–3.43), respectively, and in the LAL Hb group were 1.28 (1.14–1.43), 1.71 (1.43–2.04), 1.85 (1.48–2.33), and 1.64 (1.33–2.02), respectively. In HA Hb group, significantly higher risks for dialysis introduction and red-blood-cell transfusion were observed. Conclusion This study reports comprehensive information on anemia management in NDD-CKD patients in clinical practice. Despite treatment for Hb correction, 20–30% of patients persistently remained at low Hb levels. The increased risk of adverse clinical events associated with Hb fluctuations suggest that stable Hb control within the target range is important to reduce the risk of mortality and morbidity in patients with NDD-CKD and anemia.

#4140 DAPRODUSTAT VERSUS RECOMBINANT HUMAN ERYTHROPOIETIN FOR TREATING ANAEMIA OF CHRONIC KIDNEY DISEASE: COST EFFECTIVENESS MODEL METHODOLOGY AND FINDINGS

Abstract Background and Aims Anaemia is a common manifestation in patients with chronic kidney disease (CKD).1,2 Daprodustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, offers an alternative to conventional treatment with recombinant human erythropoietins (rhEPOs). This study reports the development of a cost-effectiveness analysis to support reimbursement discussions for daprodustat in Canada. Method A Markov model was developed to conduct a cost-utility analysis to compare expected costs and outcomes associated with daprodustat, vs two rhEPO treatment comparators (darbepoetin alfa [DA] or epoetin alfa [EA]), which represent standard of care. The model used a lifetime time horizon, and a publicly funded Canadian healthcare payer perspective for adults with anaemia of CKD (on/not on dialysis). Clinical inputs for the model were obtained from two Phase 3 clinical trials: ASCEND-D1 (daprodustat vs DA or EA in 2964 dialysis patients) and ASCEND-ND2 (daprodustat vs DA in 3872 non-dialysis patients). Efficacy and adverse event profiles of both rhEPOs were assumed equal. Patients entering the model (Figure) receive daprodustat, DA or EA. The model includes five health states informed by ASCEND-D and ASCEND-ND: non-dialysis, dialysis, kidney transplant, post-transplantation and terminal care. While in the dialysis or non-dialysis health state, costs and utilities are assigned based on three haemoglobin (Hb) levels: &amp;lt;10g/dL, 10–11.5g/dL or &amp;gt;11.5g/dL. A monthly cycle length is utilised and aligned with the ASCEND study visits and observations up to Week 52. Hb concentrations from ASCEND-D and ASCEND-ND are used to estimate proportions of patients in the target Hb range of 10–11.5g/dL, and non-target Hb levels. They were assumed to have different utility values. Patients could transition from non-dialysis to dialysis; in the latter state, patients could die or receive a kidney transplant, and transition to a post-transplantation state. Transition probabilities were derived from ASCEND-D and ASCEND-ND data and the literature. The median follow-up durations in ASCEND-D and ASCEND-ND were 2.5 and 1.9 years, respectively, necessitating extrapolation to the model time horizon; increases over time in the transition probabilities were applied. It is assumed that patients cannot transition back to non-dialysis from the dialysis state. Patients may transition to death from any health state, with mortality risks informed by the ASCEND trials and Canadian all-cause mortality data. Costs in the model included treatment acquisition and administration, cold-chain storage, dialysis, kidney transplant, transfusions of red blood cells and iron, and adverse events (AEs). All costs were sourced from fee schedules (2022 $CAD) or the literature. Utilities for health states and Hb levels were obtained from the ASCEND trials; AE-associated utility decrements could not be estimated from ASCEND data due to low event rates – hence, disutilities were sourced from the literature. Results In the probabilistic reference case analysis, daprodustat was less costly (comparison with DA: −$8763; EA:−$13,864) and produced more quality-adjusted life years (DA: +0.012; EA: +0.018; Table). The incremental savings with daprodustat versus DA and EA were −$860 and −$1033, respectively, in the non-dialysis state, and −$7904 and −$12,831 in the dialysis state. Contributors to the cost savings with daprodustat include an absence of cold-chain storage costs and reduced administration costs. Conclusion This study indicates that daprodustat is less costly and originates more QALYs than DA and EA in the treatment of anaemia due to CKD. In this setting, daprodustat may provide cost savings from a Canadian public payer perspective. The model described here could be adapted to other perspectives, including European countries.

#6131 ANEMIA IN PERITONEAL DIALYSIS

Abstract Background and Aims Anemia is one of the most frequent complications of chronic kidney disease (CKD), affects quality of life and increases morbidity and mortality. Prevalence of anemia in patients on peritoneal dialysis (PD) is 83% according to the RIKAS study. Diagnosis of anemia in CKD is set at a hemoglobin (Hb) below 13 g/dL in men and less than 12 g/dL in women. These values serve to define the diagnosis, but not to indicate treatment. Treatment is based on the use of erythropoiesis stimulating agents (ESA) and iron therapy. Absolute iron deficiency (ferritin less than 100 ng/ml and transferrin saturation index (TSAT) less than 20%) and functional iron deficiency (TSAT less than 20% with normal ferritin), require correction with oral or intravenous iron before the use of ESA. Treatment with ESA is indicated when Hb is below 10g/dL despite adequate iron stores. The goal is to achieve Hb values between 10-12g/dL. The aims are evaluating the situation of patients in our PD program with respect to anemia, its prevalence, treatment and its results. Method This is an observational, descriptive, cross-sectional and single-center study. Inclusion criteria were patients older than 18 years with at least 3 months of permanence in our PD program. We collected: age, sex, cause of CKD, type of PD, time on PD, origin (pre-dialysis, hemodialysis, kidney transplant), residual diuresis, diabetes mellitus (DM), high blood pressure (HBP), ischemic heart disease, bleeding, urea, creatinine, albumin, calcium, phosphorus, Hb, hematocrit, iron, ferritin, TSAT, C-reactive protein (CRP), transfusions and treatments (ESA and/or iron therapy). Descriptive statistical analysis (mean, standard deviations, maximums and minimums) and comparative analysis between variables was performed using Chi-square test and ANOVA for qualitative and quantitative variables, respectively. Results N = 58 patients, 64% men and 36% women. The mean age was 61.3+/- 15.54 years. 31% of patients were CKD secondary to glomerulonephritis (predominant etiology). 5% had no cardiovascular risk factors (CVRF), 48% between one and two and 47% more than three. 74% on continuous ambulatory peritoneal dialysis (CAPD). Mean time on dialysis 28.74 +/- 25.05 months. Mean residual diuresis in 24 hours 1199.22 +/- 703.14 cc. Prevalence of anemia 74%. Mean Hb of 10.97 +/-1.29 g/dL with 78% of patients with values between 10-12 g/dl. Mean ferritin of 356.79 +/-226.84 mg/dL with 79% of patients between 100-500 mg/dl. 83% received treatment with ESA, 33% with intravenous iron. No patient received oral iron. 4 patients needed of blood transfusion and 3 of them due to bleeding (2 gastrointestinal bleeding and 1 urinary bleeding). We observed a statistically significant association between higher residual diuresis volume and adequate anemia control (P = .042) and between lower creatinine values and target Hb values (P = .0005). No statistically significant association was observed between adequate anemia control and type of dialysis (p= 0.106), time on dialysis (P = .28), sex (P = .224) and DM (p= 0.139). Conclusion The high prevalence of anemia continues to be a major problem in PD in our program, but similar to other series. Under treatment (ESA and iron therapy) is achieved an adequate control in most patients, although in approximately 20% of patients do not reach the established target. Higher residual diuresis and lower creatinine values (probably due to increased residual renal function) are associated with better anemia control.

#4927 DARBEPOETIN ALFA ONCE IN 4 WEEKS CORRECTS ANEMIA IN PATIENTS WITH CHRONIC KIDNEY DISEASE NOT ON DIALYSIS

Abstract Background and Aims In anemia management in patients with CKD not on dialysis (CKD ND), darbepoetin alfa (DA), which has shorter half-life but lower cost than continuous erythropoietin receptor activator (C.E.R.A.), is preferred in actual clinical practice in Korea. The current study evaluated the efficacy and safety of DA every 4 weeks (Q4W) compared to C.E.R.A. Q4W administration for in erythropoiesis-stimulating agent (ESA)-naïve patients with CKD ND. Method In this randomized, prospective, noninferiority study, 40 ESA-naïve patients with CKD ND were randomized 1:1 to receive either DA or C.E.R.A. Q4W during a 12-week correction period and 24-week efficacy evaluation period (EEP). Two primary efficacy end points were analysed: 1) the mean difference in the changes in haemoglobin (Hb) levels between baseline and EEP and 2) the Hb response rates defined as the proportion of patients who reached the target Hb level range (10-11 g/dL) during correction period. The non-inferiority margin is pre-defined as: 1) The lower limit of the 95% confidence interval (CI) is &amp;gt;-0.75 g/dL for the mean difference in the changes in Hb levels and 2) &amp;gt;60% for Hb response rates. Safety profiles including changes in blood pressure (BP), laboratory safety parameters, and frequency of all adverse events (AEs) were monitored and analysed during study period. Results The mean difference in the changes in Hb levels between the two groups was [0.375 g/dL; 95% confidence interval (CI), -0.446 to 1.196)] and [-0.070 g/dL; 95% CI, -0.730 to -0.590] in the intent-to-treat (ITT) and per-protocol (PP) population, respectively (Fig. 1). The Hb response rates in correction period were comparable between DA and C.E.R.A. group; [100%; 95% CI, 81.4 to 100] versus [94.1%; 95% CI, 71.3 to 99.8)] and [100%; 95% CI, 79.4 to 100] versus [100%; 95% CI: 88.2 to 100)] in ITT and PP population, respectively (Fig. 2). The mean estimated glomerular filtration rate, systolic and diastolic BP, sodium, and potassium level over time were not different during total study period between two groups (P = 0.264, 0.999, 0.823, 0.941, and 0.978). All of the AEs in each group were reported to be mild to moderate in intensity. Peripheral edema, neck pain, herpes zoster, and dyspnea occurred in DA group (20%) and urinary tract infection, dyspnea, and femur neck fracture occurred in C.E.R.A. group (15%). There were no serious AEs which led to discontinuation of the treatment. All AEs were mild to moderate in severity, and they are probably not associated with the study drugs and were successfully cured. The reasons for discontinuation of the drugs were starting HD or follow-up loss, but not due to the administered study drugs. No subjects received RBC transfusion or iron replacement therapy in both groups. There was no death during the study period. Conclusion These study results suggest that DA Q4W has non-inferiority in anemia correction efficacy and similar safety profiles compared to C.E.R.A. Q4W in ESA-naïve patients with CKD ND.

#3715 THE EFFECT OF DAPRODUSTAT ON INTRAVENOUS IRON USE IN PATIENTS WITH CKD-RELATED ANAEMIA ON DIALYSIS IN THE ASCEND TRIALS

Abstract Background and Aims Intravenous (IV) iron is frequently needed in patients with chronic kidney disease (CKD) to ensure sufficient iron is available for erythropoiesis. However high doses of IV iron and erythropoiesis stimulating agents (ESAs) may be associated with risks in these patients [1]. The hypoxia-inducible factor-prolyl hydroxylase domain inhibitor daprodustat was non-inferior to comparator ESAs for the primary endpoint of efficacy (change-in-Hb) in the multicentre, randomised, Phase 3 trials ASCEND-D (NCT02879305) [2] and ASCEND-TD (NCT03400033) [3], also for the safety (major adverse cardiovascular [CV] events) coprimary endpoint in ASCEND-D [2]. This analysis of ASCEND-D and ASCEND-TD compared daprodustat to active ESAs on measures of IV iron use in dialysis patients. Method Daprodustat and ESAs were compared in patients with CKD anaemia on haemodialysis/peritoneal dialysis (ASCEND-D); haemodialysis (ASCEND-TD). ASCEND-D (N = 2,964) was an open-label CV outcome study using daprodustat once daily, while ASCEND-TD (N = 407) was a double-blind, double-dummy, 52-week study investigating three times weekly dosing of daprodustat. In both studies, following randomisation, treatment dosage was titrated to achieve the Hb target range of 10.0–11.0g/dL, with Hb efficacy assessed during the evaluation period (EP), Weeks 28–52. All patients were required to have ferritin &amp;gt;100 ng/mL and/or transferrin saturation (TSAT) &amp;gt;20% at baseline for inclusion. Throughout the study, iron therapy was administered if ferritin was ≤100 ng/mL and/or TSAT was ≤20% so patients would remain iron replete throughout the study. Investigators chose the route and dose of iron administration per patient iron status and clinical judgement. Stopping threshold criteria of 800 ng/mL ferritin + TSAT &amp;gt;20%, or TSAT&amp;gt;40% were implemented to avoid iron overload, but investigators could stop administration of iron at levels below the protocol-defined stopping thresholds. The average monthly IV iron dose (mg)/patient to Week 52 was a principal secondary endpoint, while the proportion of patients who met iron management criteria with a decrease in monthly IV iron dose during the EP relative to baseline and until patients received first transfusion were exploratory endpoints. The baseline monthly IV iron dose was defined as the average monthly IV iron (mg) over the 16 weeks prior to randomisation for ASCEND-D and over the 12 weeks prior to randomisation for ASCEND-TD. Results The proportion of patients with IV iron use at baseline was similar in both treatment arms for ASCEND-D (64%) but lower in the daprodustat group in ASCEND-TD (63% vs 72% in the ESA group). In both studies the proportion of patients receiving IV iron during the EP decreased (ASCEND-D: daprodustat 49%, ESA 52%; ASCEND-TD: daprodustat 38%, ESA 40%). The average monthly IV iron dose during the EP and from Day 1 to Week 52 was lower than monthly IV iron dose at baseline, however daprodustat was not associated with a statistically significant reduction in monthly IV iron per patient to Week 52 vs ESA comparator (Table 1). After a period of IV iron requirements decreasing, based on adjustment to protocol-specified levels, IV iron dosage remained relatively stable for daprodustat and ESA (Figure 1). In ASCEND-D, 3 of 23 pre-defined subgroups (prior ESA dose group, ESA hyporesponders2, history of myocardial infarction) showed a trend towards heterogeneity (interaction p-value &amp;lt;0.1), with differences in monthly IV iron use in the prior ESA dose group receiving ≥7000 U/week (-21.2 mg/month) and in the ESA hyporesponder group (-31.7 mg/month) in favour of daprodustat. Fewer patients met the criteria for stopping iron while on daprodustat vs ESA, whereas the converse was observed in ASCEND-TD (Table 1). Conclusion In ASCEND-D and -TD, no clinically or statistically significant reduction in monthly IV iron use was seen with daprodustat vs ESA comparators, although there was a numerical decrease in the proportion of patients receiving IV iron during the EP for the daprodustat group in both studies.