Assessment of the safety of Roxadustat for cardiovascular events in chronic kidney disease-related anemia using meta-analysis and bioinformatics.

Objective: This study compares the cardiovascular risk in anemic chronic kidney disease patients treated with Roxadustat versus erythropoietin stimulating agents (ESAs). It also explores the cardiovascular impact of Roxadustat. Methods: We searched PubMed, EMBASE, Cochrane, Scopus, and Web of Science databases up to 13 August 2023, using terms such as "ESA," "Roxadustat," "MACE," "stroke," "death," "myocardial infarction," and "heart failure." Two researchers independently selected and extracted data based on predefined criteria. We assessed the risk of bias with the Cochrane tool and analyzed statistical heterogeneity using the Q and I2 tests. We conducted subgroup analyses by geographical region and performed data analysis with Stata 14.0 and RevMan 5.4 software. Data were sourced from the NCBI database by filtering for "Roxadustat" and "human," and differentially expressed genes were identified using R software, setting the significance at p < 0.01 and a 2-fold logFC, followed by GO enrichment analysis, KEGG pathway analysis, and protein interaction network analysis. Results: A total of 15 articles encompassing 1,43,065 patients were analyzed, including 1,38,739 patients treated with ESA and 4,326 patients treated with Roxadustat. In the overall population meta-analysis, the incidences of Major Adverse Cardiovascular Events (MACE), death, and heart failure (HF) were 13%, 8%, and 4% in the Roxadustat group, compared to 17%, 12%, and 6% in the ESA group, respectively, with P-values greater than 0.05. In the subgroup analysis, the incidences were 13%, 11%, and 4% for the Roxadustat group versus 17%, 15%, and 5% for the ESA group, also with p-values greater than 0.05. Bioinformatics analysis identified 59 differentially expressed genes, mainly involved in the inflammatory response. GO enrichment analysis revealed that these genes are primarily related to integrin binding. The main pathways identified were the TNF signaling pathway, NF-κB signaling pathway, and lipid metabolism related to atherosclerosis. The protein interaction network highlighted IL1B, CXCL8, ICAM1, CCL2, and CCL5 as the top five significantly different genes, all involved in the inflammatory response and downregulated by Roxadustat, suggesting a potential role in reducing inflammation. Conclusion: The meta-analysis suggests that the use of Roxadustat and ESA in treating anemia associated with chronic kidney disease does not significantly alter the likelihood of cardiovascular events in the overall and American populations. However, Roxadustat exhibited a safer profile with respect to MACE, death, and heart failure. The bioinformatics findings suggest that Roxadustat may influence integrin adhesion and affect the TNF and NF-κB signaling pathways, along with lipid and atherosclerosis pathways, potentially reducing inflammation.

Stabilizing Hypoxia-Inducible Factor to Manage Anemia in Chronic Kidney Disease: From Basic Theory to Clinical Study.

Background: Anemia is one of the common complications of chronic kidney disease (CKD), and its prevalence has been arising globally. The key cause of anemia in CKD patients is the diseased kidney's reduced ability to synthesize endogenous erythropoietin (EPO), yet this is not the sole reason. Inflammatory elements, functional iron deficiency, and uremic toxins together participate in the development of anemia. According to research data, anemia is an independent risk factor for cardiovascular events, all-cause mortality, and worsening renal function and affects the clinical prognosis and quality of life of CKD patients. Regular treatments for anemia in CKD patients include the use of erythropoiesis-stimulating agents (ESAs), iron supplements, and blood transfusions. Summary: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel and small-molecule pharmacological compounds that target the hypoxia-inducible factor (HIF) pathway and are another option for improving anemia in CKD patients. HIF-PHIs simulate hypoxia, stabilize HIF protein, stimulate EPO synthesis, reduce hepcidin level, boost iron utilization, induce the creation of red blood cells, and alleviate anemia. The results of several HIF-PHI phase III trials indicated that HIF-PHIs are similarly effective as ESA at raising hemoglobin concentration. Key Messages: This article summarizes the structure of HIF and the mechanism of stabilizing HIF to improve anemia, discusses the efficacy of HIF-PHIs in CKD patients with or without dialysis, as well as emphasizes the potential safety concerns with HIF-PHIs.

The Use of Anemia Control Model Is Associated with Improved Hemoglobin Target Achievement, Lower Rates of Inappropriate Erythropoietin Stimulating Agents, and Severe Anemia among Dialysis Patients.

INTRODUCTION: The Anemia Control Model (ACM) is a certified medical device suggesting the optimal ESA and iron dosage for patients on hemodialysis. We sought to assess the effectiveness and safety of ACM in a large cohort of hemodialysis patients. METHODS: This is a retrospective study of dialysis patients treated in NephroCare centers between June 1, 2013 and December 31, 2019. We compared patients treated according to ACM suggestions and patients treated in clinics where ACM was not activated. We stratified patients belonging to the reference group by historical target achievement rates in their referral centers (tier 1: <70%; tier 2: 70-80%; tier 3: >80%). Groups were matched by propensity score. RESULTS: After matching, we obtained four groups with 85,512 patient-months each. ACM had 18% higher target achievement rate, 63% smaller inappropriate ESA administration rate, and 59% smaller severe anemia risk compared to Tier 1 centers (all p < 0.01). The corresponding risk ratios for ACM compared to Tier 2 centers were 1.08 (95% CI: 1.08-1.09), 0.49 (95% CI: 0.47-0.51), and 0.64 (95% CI: 0.61-0.68); for ACM compared to Tier 3 centers, 1.01 (95% CI: 1.01-1.02), 0.66 (95% CI: 0.63-0.69), and 0.94 (95% CI: 0.88-1.00), respectively. ACM was associated with statistically significant reductions in ESA dose administration. CONCLUSION: ACM was associated with increased hemoglobin target achievement rate, decreased inappropriate ESA usage and a decreased incidence of severe anemia among patients treated according to ACM suggestion.

Proton Pump Inhibitors and Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Hemodialysis Patients: Results from the Japan Dialysis Outcomes and Practice Patterns Study.

INTRODUCTION: Hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is important problem in dialysis patients. While proton pump inhibitors (PPIs) may inhibit iron absorption, few studies have examined associations between PPIs and ESA-resistant anemia in hemodialysis patients. This study examined the associations between PPIs and ESA-resistant anemia in hemodialysis patients. METHODS: The present study was a cross-sectional study using repeated 4-month observations, up to eight observations/patient, from the Japan Dialysis Outcomes and Practice Patterns Study (J-DOPPS). The primary outcome was erythropoietin resistance index (ERI). ESA dose, hemoglobin, proportion of erythropoietin-resistant anemia, transferrin saturation (TSAT), and ferritin were also examined. Linear or risk-difference regression models were used with generalized estimating equations to account for repeated measurements. RESULTS: Of 1,644 patients, 867 patients had PPI prescriptions (52.7%). Patients prescribed PPI had higher ERI, higher ESA dose, and lower TSAT levels. Multivariable analysis for 12,048 four-month observations showed significantly greater ERI in PPI users (adjusted difference 0.95 IU/week/kg/[g/dL] [95% CI: 0.40-1.50]). Significant differences were also found in ESA dose (336 IU/week [95% CI: 70-602]) and the prevalence of erythropoietin-resistant anemia (3.9% [2.0-5.8%]) even after adjusted for TSAT and ferritin. Among possible mediators between the association of PPIs and anemia, TSAT was significantly different between PPI users and non-users (adjusted difference, -0.82% [95% CI: -1.56 to -0.07]). CONCLUSIONS: This study showed the associations between PPI and ERI, ESA dose, and TSAT in hemodialysis patients; physicians should consider anemia's associations with PPIs in hemodialysis patients.

The Impact of Recombinant Human Erythropoietin Administration in Critically ill COVID-19 Patients: A Multicenter Cohort Study.

The use of erythropoietin-stimulating agents (ESAs) as adjunctive therapy in critically ill patients with COVID-19 may have a potential benefit. This study aims to evaluate the effect of ESAs on the clinical outcomes of critically ill COVID-19 patients. A multicenter, retrospective cohort study was conducted from 01-03-2020 to 31-07-2021. We included adult patients who were ≥ 18 years old with a confirmed diagnosis of COVID-19 infection and admitted to intensive care units (ICUs). Patients were categorized depending on ESAs administration during their ICU stay. The primary endpoint was the length of stay; other endpoints were considered secondary. After propensity score matching (1:3), the overall included patients were 120. Among those, 30 patients received ESAs. A longer duration of ICU and hospital stay was observed in the ESA group (beta coefficient: 0.64; 95% CI: 0.31-0.97; P = < .01, beta coefficient: 0.41; 95% CI: 0.12-0.69; P = < .01, respectively). In addition, the ESA group's ventilator-free days (VFDs) were significantly shorter than the control group. Moreover, patients who received ESAs have higher odds of liver injury and infections during ICU stay than the control group. The use of ESAs in COVID-19 critically ill patients was associated with longer hospital and ICU stays, with no survival benefits but linked with lower VFDs.

Safety and Efficacy of Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors vs. Erythropoietin-Stimulating Agents in Treating Anemia in Renal Patients (With or Without Dialysis): A Meta-Analysis and Systematic Review.

Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) are a novel group of drugs used to treat renal anemia, but their benefits vary among different trials. Our meta-analysis aims to assess the safety and efficacy of HIF-PHI versus erythropoiesis-stimulating agents (ESA) in managing anemia among patients with chronic kidney disease (CKD), regardless of their dialysis status. PubMed, Embase, and Google Scholar were queried to discover eligible randomized controlled trials (RCTs). To quantify the specific effects of HIF-PHI, we estimated pooled mean differences (MDs) and relative risks (RR) with 95% CIs. Our meta-analysis involved 22,151 CKD patients, with 11,234 receiving HIF-PHI and 10,917 receiving ESA from 19 different RCTs. The HIF-PHI used included roxadustat, daprodustat, and vadadustat. HIF-PHI yielded a slight but significant increase in change in mean hemoglobin (Hb) levels (MD: 0.06, 95% CI (0.00, 0.11); p = 0.03), with the maximum significant increase shown in roxadustat followed by daprodustat as compared to ESA. There was a significant decrease in efficacy outcomes such as change in mean iron (MD: -1.54, 95% CI (-3.01, -0.06); p = 0.04), change in mean hepcidin (MD: -21.04, 95% CI (-28.92, -13.17); p < 0.00001), change in mean ferritin (MD: -16.45, 95% CI (-27.17,-5.73); p = 0.03) with roxadustat showing maximum efficacy followed by daprodustat. As for safety, HIF-PHI showed significantly increased incidence in safety outcomes such as diarrhea (MD: 1.3, 95% CI (1.11, 1.51); p = 0.001), adverse events leading to withdrawal (MD: 2.03, 95% CI (1.5, 2.74), p = 0.00001) among 25 various analyzed outcomes. This meta-analysis indicates that HIF-PHIs present a potentially safer and more effective alternative to ESAs, with increased Hb levels and decreased iron usage in CKD patients without significantly increasing adverse events. Therefore, in these patients, we propose HIF-PHI alongside renal anemia treatment.

An Overview of Safety and Efficacy Between Hypoxia-Inducible Factor-Prolyl-Hydroxylase Inhibitors and Erythropoietin-Stimulating Agents in Treating Anemia in Chronic Kidney Disease Patients.

Anemia is one of the common complications in chronic kidney disease (CKD) patients. Erythropoietin and iron deficiencies are the major causes to develop anemia in CKD patients. Untreated anemia is associated with increased morbidity and mortality. Erythropoietin-stimulating agents (ESA) with iron supplementation are the standard for treating renal anemia. Although ESA with iron supplementation is an effective therapy in maintaining serum hemoglobin (Hb) levels, it increases the risk of several life-threatening adverse events such as hypertension, thromboembolism, cardiovascular morbidity, and mortality with long-term use. Therefore, effective alternate therapy with better safety and efficacy is needed to treat renal anemia. The newer oral therapy hypoxia-inducible factor-prolyl-hydroxylase inhibitors (HIF-PHI) can potentially be an effective alternative therapy in treating renal anemia. This review article compares the safety and efficacy between HIF-PHI and ESA in treating anemia in CKD patients. We conducted a comprehensive literature review of articles, including clinical trials, meta-analyses, and reviews, that compared the safety and efficacy between HIF-PHI and ESA. Studies have shown that the newer oral therapy, HIF-PHI, was non-inferior to ESA to maintain serum Hb levels in CKD patients. Moreover, the adverse event profile was almost similar in both groups. However, as the studies we reviewed have small sample sizes and short duration periods, the long-term effectiveness and safety of HIF-PHI over ESA in treating renal anemia cannot be established.

Weight-based vs fixed dosing of darbepoetin alfa for anemia following kidney transplantation.

PURPOSE: Post-transplantation anemia (PTA) is common in kidney transplant recipients, with patients frequently treated with erythropoietin-stimulating agents such as darbepoetin alfa. The optimal dosing for darbepoetin alfa remains controversial. METHODS: This retrospective cohort study involved kidney transplant recipients who received darbepoetin alfa at 2 clinics. Patients were stratified into 2 groups: those who received a fixed dose of 200 µg and those who received a weight-based dose of 0.45 µg/kg. The dosing interval varied depending on clinical response, clinic visit timing, and frequency allowed by insurance. The primary outcome was achieving a hemoglobin concentration of at least 10 g/dL without blood transfusion by 12 weeks after darbepoetin alfa initiation. RESULTS: Of the 110 patients in the study, 45% received weight-based dosing and 55% received fixed dosing. Darbepoetin alfa was initiated significantly earlier after transplantation in the fixed-dose group (median of 14 vs 20 days; P = 0.003). The weight-based group received more doses of darbepoetin alfa (median of 4 vs 2 doses; P = 0.002) and had a significantly lower cumulative exposure to darbepoetin alfa (125 vs 590 µg; P < 0.001). The median time between doses was 9 days (interquartile range, 7-14 days) in the weight-based group and 12 days (7-32 days) in the fixed-dose group (P = 0.04). Patients in the weight-based group more frequently achieved the primary outcome (67.3% vs 47.5%; P = 0.059). There was no significant difference in secondary or safety outcomes between the groups. CONCLUSION: Weight-based and fixed dosing approaches for darbepoetin alfa were not different in the achievement of a hemoglobin concentration of at least 10 g/dL without blood transfusion at 12 weeks after darbepoetin alfa initiation, with significantly lower cumulative darbepoetin alfa utilization in the weight-based group. Weight-based dosing of darbepoetin alfa in PTA appears to be safe and effective, with the potential for significant patient and health-system cost savings.

Anemia after kidney transplantation.

Anemia is a frequent complication in pediatric kidney transplant recipients (KTR) with a variable reported prevalence estimated between 20 and 80% depending on how defined. Causes of and risk factors for post-transplantation anemia (PTA) are multifactorial with iron deficiency being the primary cause of early PTA (within the first 6 months after transplantation) and impaired glomerular filtration rate (GFR) commonly responsible for late PTA (after 6 months). Medications, viral infections, chronic inflammation, and comorbidities also play a role. PTA has relevant long-term consequences and is a potential risk factor for allograft dysfunction, cardiovascular morbidity, and mortality. Thus, an anemia evaluation, approximately 3 months post-transplantation, is recommended in order to start early treatment and improve prognosis. Iron status, vitamin B12, folate, markers of hemolysis, and viral PCR should be checked, and medications, in particular combinations of medications, should be carefully evaluated. PTA treatment may be challenging and should be directed to the underlying causes. Iron supplementation and erythropoietin therapy, not extensively used in KTR, may be indicated. Every effort should be made to avoid blood transfusions in the pre-transplant period to avoid allosensitization. Anemia should be corrected to prepare candidates for kidney transplantation in order to reduce the need for perioperative blood transfusions as well.

Medicare Bundled Payment Policy on Anemia Care, Major Adverse Cardiovascular Events, and Mortality among Adults Undergoing Hemodialysis.

BACKGROUND AND OBJECTIVES: In 2011, the Centers for Medicare & Medicaid Services implemented bundling of all services for patients receiving dialysis, including erythropoietin-stimulating agents use, and the Food and Drug Administration recommended conservative erythropoietin-stimulating agent dosing. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective cohort study investigated anemia care and clinical outcomes before and after the Centers for Medicare & Medicaid Services bundled payment and the revised Food and Drug Administration-recommended erythropoietin-stimulating agent labeling for Medicare-insured adults receiving hemodialysis using data from the United States Renal Data System from January 1, 2006 to December 31, 2016. Clinical outcomes included major adverse cardiovascular event (stroke, acute myocardial infarction, and all-cause mortality), cardiovascular mortality, and heart failure. Measurements were compared between prepolicy (2006-2010) and postpolicy (2012-2016) implementation using interrupted time series and Cox proportional hazards regression models. RESULTS: Of 481,564 patients, erythropoietin-stimulating agent use immediately decreased by 84.8 per 1000 persons (P<0.001), with a significant decrease in the slope of the trend line (both P=0.001). Blood transfusion use rapidly increased by 8.34 per 1000 persons in April 2012 and then gradually decreased (both P=0.001). The percentage of patients with hemoglobin >11 g/dl decreased from 68% in January 2006 to 28% in December 2016, whereas those with hemoglobin <9 g/dl increased from 5% to 9%. Overall major adverse cardiovascular event (adjusted hazard ratio, 0.95; 95% confidence interval, 0.94 to 0.96), stroke (adjusted hazard ratio, 0.83; 95% confidence interval, 0.80 to 0.86), all-cause mortality (adjusted hazard ratio, 0.87; 95% confidence interval, 0.86 to 0.89), cardiovascular mortality (adjusted hazard ratio, 0.81; 95% confidence interval, 0.79 to 0.83), and heart failure (adjusted hazard ratio, 0.86; 95% confidence interval, 0.84 to 0.88) risks were lower. Acute myocardial infarction risk (adjusted hazard ratio, 1.04; 95% confidence interval, 1.01 to 1.06) was higher after policies changed. CONCLUSIONS: The Medicare reimbursement policy and Food and Drug Administration-recommended erythropoietin-stimulating agent dosing changes were associated with lower erythropoietin-stimulating agent use and lower hemoglobin levels. These changes in anemia care were associated with lower risks of major adverse cardiovascular event, stroke, mortality, and heart failure but higher risk of acute myocardial infarction among adults receiving hemodialysis.

Evaluation of Erythropoietin Stimulating Agents (ESA) and Their Effect on Blood Optimization for Cardiac Surgery.

BACKGROUND: Cardiovascular surgeries increase the risk of receiving blood transfusions. Erythropoietin stimulating agents (ESAs) have been used to decrease the transfusion rate. The objective of this study was to evaluate the administration of blood products post-cardiothoracic surgery after receiving ESAs. METHODS: This is a single-center, retrospective cohort study. RESULTS: Between May 2017 to May 2018, 52 adult patients underwent cardiac surgery and received ESAs pre-operatively and/or post-operatively. A total of 35 patients were included in the study and 21 (60%) patients did not require a blood transfusion while 14 (40%) patients required a blood transfusion (p = 0.597). The change in hemoglobin (Hgb = 0.773 g/dL, 1.7 g/dL; p = 0.002) and hematocrit (Hct = 2.31%, 4.3%; p = 0.04) was significantly different in patients who received ESAs alone versus ESAs with blood transfusion. Adverse drug reactions showed no significant difference between groups. CONCLUSIONS: In patients undergoing cardiac surgery, ESAs did not significantly reduce the need for blood transfusion. Future and larger studies are necessary to evaluate the effect of ESAs on blood transfusion.

Neutrophil-to-Lymphocyte Ratio and Erythropoietin Resistance among Maintenance Hemodialysis Patients.

INTRODUCTION: Neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) are recent prognostic biomarkers associated with inflammation. Increased erythropoiesis resistance index (ERI) may predict the risk of all-cause and cardiovascular mortality in hemodialysis (HD) patients. However, the roles of NLR and PLR in erythropoietin (EPO) responsiveness remain unclear in HD patients. This study aims to investigate the relationship between NLR and PLR and EPO responsiveness in maintenance HD patients. METHODS: A total of 299 HD patients were included in this survey. Laboratory data and demographic details were collected. EPO responsiveness was evaluated by ERI. Pearson correlation analysis and logistic regressions were conducted to evaluate the factors that may be associated with EPO responsiveness. RESULTS: The EPO responsiveness was positively related to ferritin and negatively related to serum albumin, lymphocytes, and hemoglobin. A multivariate linear regression revealed that only NLR (standardized ß = 0.13, p = 0.024) but not PLR (standardized ß = 0.107, p = 0.063) was correlated with a higher ERI. CONCLUSION: A higher NLR level was shown to be a cheaper method to predict worse EPO responsiveness in HD patients.

Effectiveness of biosimilar drugs in the treatment of renal anemia: A case series. / Efectividad del uso de biosimilares en el tratamiento de la anemia en pacientes con enfermedad renal crónica: serie de casos.

INTRODUCTION: Patients with chronic kidney disease usually have anemia secondary to an erythropoietin deficit. The emergence of biosimilar drugs of erythro-poiesis-stimulating agents ensures broader access to these treatments. OBJECTIVE: This study analyzes the effectiveness of an epoetin α biosimilar drug in chronic kidney disease patients with anemia. METHODS: This observational retrospective study enrolled 111 consecutive outpatients with chronic kidney disease and anemia and criteria for using eryth-ropoietin-stimulating agents. We collected baseline epidemiological and comorbidity data, as well as hematological and renal function infor-mation. We analyzed the effectiveness of the biosimilar agent in naïve patients and those who already had other erythropoiesis-stimulating agents. RESULTS: The 111 included patients had a mean age of 83 ± 8 years, and 54% were males. We found that patients who previously received erythropoiesis-stimulating agents, maintained hemoglobin values at two months of treatment with the biosimilar, while the naïve group significantly raised their hemoglobin values (P < 0.001). Renal function remained stable within the whole sample. The cost of using erythropoiesis-stimulating agents was reduced by a mean of 82 ± 17% with the biosimilar drug. CONCLUSION: Using a biosimilar of epoetin α is effective in patients with chronic kidney disease and anemia and significantly reduces costs.

INTRODUCCIÓN: Los pacientes con enfermedad renal crónica presentan anemia que, en gran parte, se debe a un defecto en la producción de eritropoyetina. La aparición de fármacos biosimilares de agentes estimulantes de la eritropoyesis garantiza un acceso más generalizado a dichos fármacos. OBJETIVO: Los pacientes con enfermedad renal crónica presentan anemia que, en gran parte, se debe a un defecto en la producción de eritropoyetina. MÉTODO: Se trata de un estudio observacional retrospectivo, en el que analizamos datos de 111 pacientes consecutivos de las consultas de nefrología con enfermedad renal crónica, anemia y con criterios de uso de agentes estimulantes de la eritropoyesis. Recogimos datos basales epidemiológicos y de comorbilidad, así como hematológicos y de función renal. Analizamos la efectividad del fármaco en aquellos pacientes naïve así como en aquellos que ya tenían otros agentes estimulantes de la eritropoyesis, y que habían iniciado tratamiento con el biosimilar. RESULTADOS: De los 111 pacientes incluidos, el 54% eran varones y la edad media se situó en 83 ± 8 años. En los pacientes que ya estaban en tratamiento con agentes estimulantes de la eritropoyesis, el uso del biosimilar mantuvo los valores de hemoglobina a los dos meses de tratamiento, mientras que en el grupo naïve se produjo un ascenso significativo de los mismos (p < 0,001). No hubo cambios en la función renal en ninguno de los grupos. El costo del uso de agentes estimulantes de la eritropoyesis se redujo una media de 82 ± 17% con el uso del biosimilar. CONCLUSIONES: El uso de un biosimilar de epoetina αα es efectivo en pacientes con enfermedad renal crónica y genera una importante reducción de costos.

Anemia in heart failure: still an unsolved enigma.

BACKGROUND: Anemia affects one-third of heart failure patients and is associated with increased morbidity and mortality. Despite being one of the commonest comorbidities associated with heart failure, there is a significant knowledge gap about management of anemia in the setting of heart failure due to conflicting evidence from recent trials. MAIN BODY: The etiology of anemia in heart failure is multifactorial, with absolute and functional iron deficiency, decreased erythropoietin levels and erythropoietin resistance, inflammatory state and heart failure medications being the important causative factors. Anemia adversely affects the already compromised hemodynamics in heart failure, besides being commonly associated with more comorbidities and more severe disease. Though low hemoglobin levels are associated with poor outcomes, the correction of anemia has not been consistently associated with improved outcomes. Parenteral iron improves the functional capacity in iron deficient heart failure patients, the effects are independent of hemoglobin levels, and also the evidence on hard clinical outcomes is yet to be ascertained. CONCLUSION: Despite all the research, anemia in heart failure remains an enigma. Perhaps, anemia is a marker of severe disease, rather than the cause of poor outcome in these patients. In this review, we discuss the current understanding of anemia in heart failure, its management and the newer therapies being studied.

A faster decline of residual kidney function and erythropoietin stimulating agent hyporesponsiveness in incident hemodialysis patients.

INTRODUCTION: Erythropoietin stimulating agents (ESA) hyporesposiveness has been associated with increased mortality in hemodialysis (HD) patients. However, the impact of decline of residual kidney function (RKF) on ESA hyporesposiveness has not been adequately elucidated among patients receiving HD. METHODS: The associations of RKF decline with erythropoietin resistance index (ERI; average weekly ESA dose [units])/post-dialysis body weight [kg]/hemoglobin [g/dL]) were retrospectively examined across four strata of annual change in RKF (residual renal urea clearance [KRU] < -3.0, -3.0 to <-1.5, -1.5 to <0, ≥0 mL/min/1.73 m2 per year; urinary volume < -600, -600 to<-300, -300 to <0, ≥0 mL/day per year) using logistic regression models adjusted for clinical characteristics and laboratory variables in 5239 incident HD patients in a large US dialysis organization between 1 January 2007 and 31 December 2011. FINDINGS: The median values of the annual change in KRU and urinary volume were -1.2 (interquartile range [IQR]: -2.8 to 0.1) mL/min/1.73 m2 per year and -250 (IQR: -600 to 100) mL/day per year. A faster KRU decline in the first year of HD was associated with higher odds for ESA hyporesponsiveness: KRU decline of <-3.0, -3.0 to <-1.5, and -1.5 to <0/min/1.73 m2 per year were associated with adjusted odds ratios (OR) of 2.07 (95% confidence interval [CI]: 1.66-2.58), 1.54 (95%CI: 1.28-1.85), and 1.26 (95%CI: 1.07-1.49), respectively (reference: ≥0 mL/min/1.73 m2 per year). These associations were consistent across strata of baseline KRU, age, sex, race, diabetes, congestive heart failure, hemoglobin, and serum albumin. Sensitivity analyses using urinary volume as another index of RKF showed consistent associations. DISCUSSION: A faster RKF decline during the first year of dialysis was associated with ESA hyporesponsiveness and low hemoglobin levels among incident HD patients.

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.

A presumed case of Darbepoetin-induced myocardial infarction in the patient with MDS-RARS.

Our case is only the 2nd such reported case of atherothrombosis from ESAs and highlights the increased risk of cardiovascular events in patients receiving erythropoietin-stimulating agents specially patients with underlying MDS where targeting a lower hemoglobin goal and optimizing other cardiovascular risk factors might be beneficial in preventing future cardiovascular mortality.

Evaluation of the use of erythropoietin-stimulating agents in a hospital setting to assess the necessity of a protocol-driven anemia management service.

Erythropoietin-stimulating agents (ESA) have revolutionized the management of anemia. However, these agents are not always utilized with proper monitoring parameters, which can present significant safety concerns, unwarranted drug expenditures, and decreased ESA efficacy. This retrospective study assessed the utilization of all ESAs in non-intensive care unit hospitalized patients at a large academic medical center from August 18, 2018, to August 31, 2018, using established guideline-based assessment criteria. Among the 167 doses of ESA evaluated, 86% (n = 144) were utilized in accordance with guideline-based assessment criteria regarding laboratory monitoring of iron studies. However, 24% (n = 40) of ESA doses were administered to patients with active, untreated iron deficiency at the time of administration. Although most ESA doses were utilized in accordance with the guideline-based criteria, interventions can be implemented to further improve anemia treatment. Implementing a protocol-driven anemia management service is one strategy that can improve patient care, advance patient safety, and be cost-beneficial.

Recent update in the pathogenesis and treatment of chemotherapy and cancer induced anemia.

Cancer and chemotherapy-induced anemia (CIA) is commonly encountered among patients undergoing active chemotherapy with or without radiation therapy. Its pathogenesis is complex and is often difficult to identify. Symptoms related to CIA may have a negative impact on quality of life and may influence treatment efficacy, disease progression and even survival. The recent major setback of erythropoietin-stimulating agents (ESAs) and the reluctance to transfuse cancer patients with mild and even moderate anemia, had resulted in significant under-treatment of CIA. The discovery of hepcidin and its role in iron homeostasis has revolutionized our understanding of the pathogenesis of iron deficiency and iron overload states. In the present review we examine the multifactorial pathogenesis of CIA, addressing the main mechanisms by which the tumor and immune system affect anemia. Additionally, we discuss the treatment options with more focus on the utilization of the new intravenous iron formulations for this indication.