Erythropoiesis-stimulating Agents Resistance Research Articles

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).

The Influence of Precursor Depletion and dose Regimens on Resistance to Erythropoiesis-Stimulating Agents: Insights from Simulations with Instantaneous Dose-Adaptation Algorithm

Erythropoiesis-stimulating agents (ESAs) have been a common treatment for anemia associated with chronic kidney disease (CKD), while 10–20 % of patients continue to suffer from persistent anemia despite receiving ESA treatments. Our previous findings suggested that intensive ESA usage can cause resistance by depleting the erythroid precursor cells. Here, we used a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model of ESAs and conducted simulations to evaluate the influence of dose regimens and other factors (such as administration route, individual PK/PD parameters, types of ESAs, and disease status) on ESA resistance with instantaneous dose adaptations in healthy populations and anemic patients. The simulated results show that instantaneous dose-adaptation can reduce ESA resistance, but up to 30 % of subjects still ended up developing ESA resistance in healthy populations. The Smax is markedly higher in hypo-responders than in normal-responders, while hypo-responders possess fewer precursors and experience a faster decline compared to normal-responders. There is a ceiling effect of increasing ESA dosage to improve HGB responses and reduce ESA resistance, and the limit is lower in anemic patients compared to healthy populations. Subcutaneous administrations and ESAs with longer half-lives lead to stronger HGB responses and less resistance at equivalent doses. Taken together, this study indicates that precursor depletion contributes to ESA resistance and dose regimens can greatly influence the occurrence of ESA resistance. Furthermore, ESA treatment for patients showing ESA resistance should avoid continuously increasing doses and instead consider stimulating the renewal of precursors.

Predictors of Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Patients with Non-Dialysis-Dependent Chronic Kidney Disease (RADIANCE-CKD Study)

Introduction: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality and cardiovascular events in patients with chronic kidney disease. We hypothesized that the prediction of ESA resistance during ESA administration would be very useful in deciding on a treatment plan. Methods: Patients enrolled in a randomized controlled trial to evaluate renal prognosis in anemic patients with non-dialysis-dependent chronic kidney disease with hyporesponsiveness to ESA were included; the patients had different target hemoglobin levels. A landmark analysis was performed at 3 months into the study. To construct a predictive model for the severe ESA hypo-responder group, in which there was no increase in hemoglobin even with active treatment, background factors and serum test items that affect anemia at study entry were included in a logistic regression model, the area under the curve (AUC) and 95% confidence intervals (CI) were estimated, and sensitivity and specificity were calculated. This study was a post hoc sub-analysis of a randomized controlled trial. Results: The AUC for the 19 existing risk factors as predictors was 0.783 (95% CI: 0.711–0.855). Among the 19 risk factors, the combination of six factors (hemoglobin level, systolic blood pressure, weight, gender, smoking status, and hypertensive retinopathy) with the largest χ² statistics were selected by multiple logistics regression. The AUC for these 6 predictors was 0.716 (95% CI: 0.634–0.799). To the six existing risk factors, five serum test items that affect anemia (vitamin B12, vitamin B6, folic acid, parathyroid hormone, and 25-hydroxyvitamin D) were added, for a total of 11 risk factors, with a similar AUC of 0.736 (95% CI: 0.655–0.817), sufficient to predict ESA resistance. Conclusions: Our results suggest that existing risk factors and serum test items can be used to predict ESA resistance in patients with non-dialysis-dependent chronic kidney disease on ESA.

Roxadustat alleviates the inflammatory status in patients receiving maintenance hemodialysis with erythropoiesis-stimulating agent resistance by increasing the short-chain fatty acids producing gut bacteria

BackgroundHypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) have improved the treatment of renal anemia, especially in patients resistant to erythropoiesis-stimulating agents (ESAs). HIF facilitates maintain gut microbiota homeostasis, which plays an important role in inflammation and iron metabolism, which are in turn key factors affecting ESA resistance. The current study aimed to investigate the effects of roxadustat on inflammation and iron metabolism and on the gut microbiota in patients with ESA resistance.MethodsWe conducted a self-controlled, single-center study including 30 patients with ESA resistance undergoing maintenance hemodialysis. All patients received roxadustat without iron agents for renal anemia. Hemoglobin and inflammatory factors were monitored. Fecal samples were collected before and after 3 months’ administration and the gut microbiota were analyzed by 16S ribosomal RNA gene sequencing.ResultsHemoglobin levels increased after treatment with roxadustat for 3 months (P < 0.05). Gut microbiota diversity and abundance also changed, with increases in short-chain fatty acid (SCFA)-producing bacteria (Acidaminococcaceae, Butyricicoccus, Ruminococcus bicirculans, Ruminococcus bromii, Bifidobacterium dentium, Eubacterium hallii) (P < 0.05). Serum SCFA levels also increased (P < 0.05). Inflammatory factors, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, interferon-γ, and endotoxin gradually decreased (P < 0.05). Serum hepcidin, ferritin, and total and unsaturated iron-binding capacities decreased (P < 0.05), while soluble transferrin receptor levels increased at each time point (P < 0.05). There were no significant differences in serum iron and transferrin saturation at each time point. The abundance of Alistipes shahii was significantly negatively correlated with IL-6 and TNF-α (P < 0.05).ConclusionsRoxadustat alleviated renal anemia in patients with ESA resistance by decreasing inflammatory factors and hepcidin levels and improving iron utilization. These effects were at least partly mediated by improved diversity and abundance of SCFA-producing gut bacteria, probably via activation of HIF.

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.

Direct antiglobulin test-negative autoimmune hemolytic anemia associated with erythropoiesis stimulating agent resistance in a CKD patient with IgG4-related disease: A case report

Rationale: Direct antiglobulin test (DAT)-negative autoimmune hemolytic anemia (AIHA) is an important differential diagnosis for erythropoiesis-stimulating agents-resistant renal anemia with hemolysis. Patient concerns: An 82-year-old female with a past medical history of diabetes, end-stage kidney disease (estimated glomerular filtration rate: 6.9 mL/min/1.73 m2), post-transcatheter aortic valve implantation, and IgG4-related retroperitoneal fibrosis on prednisolone therapy was referred to our department for assessment of severe anemia. The patient underwent immunohematological testing for serological evaluation. Diagnoses: DAT-negative AIHA and IgG4-RD was established based on DAT-negative and immunohematological tests. Interventions: Glucocorticoid was administered to the patient. Outcomes: The patient’s condition including hemoglobin level was relieved. Lessons: In chronic kidney disease, AIHA may contribute to the development of severe anemia and erythropoiesis-stimulating agents-resistance, irrespective of the results of Coombs test. Reticulocytosis, undetectable haptoglobin and a fall in hemoglobinA1c despite sustained hyperglycemia may be a clue to the diagnosis of hemolysis.

Regional Variation of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Global Daprodustat Dialysis Study (ASCEND-D)

Introduction: Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) affects 10–15% of the chronic dialysis population. We explored baseline characteristics and predictors of ESA hyporesponsiveness in a global randomized cardiovascular outcomes study comparing an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), daprodustat, with conventional ESA treatment. Methods: ASCEND-D (NCT02879305) recruited 2,964 chronic dialysis patients receiving ESA treatment (standardized to weekly intravenous [IV] epoetin) who were iron replete at baseline. The primary ESA hyporesponsiveness definition was an ESA Resistance Index (ERI, ESA units/kg/week/hemoglobin g/L) ≥2 or IV standardized ESA dose ≥450 units/kg/week. Predictors of ESA hyporesponsiveness were determined using a multivariable regression model. Alternative hyporesponder definitions were explored. Results: Using the primary definition, 354 (12%) patients were ESA hyporesponsive. Geographic region, notably Latin America, lower baseline body mass index and transferrin saturation, younger age, lower albumin concentration, and a higher baseline IV iron dose were identified as strongly associated (p < 0.001) with ESA hyporesponsiveness. Additional predictors of ESA hyporesponsiveness included female sex (p = 0.010), history of heart failure (p = 0.035), longer dialysis vintage (p = 0.077), smoking status (p = 0.247), aspirin use (p = 0.121), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (p = 0.214). Conclusion: This is the first global HIF-PHI study to report prespecified definitions and predictors of ESA hyporesponsiveness. While most of the predictors identified in our study have been previously reported, geographic region stands out as an unexpected finding, meriting further investigation.

Roxadustat: Do we know all the answers?

Anemia is a common complication of chronic kidney disease (CKD), and its prevalence rises as the disease progresses. Intravenous or subcutaneous erythropoiesis-stimulating agents (ESAs) are advised to treat CKD-associated anemia, since shortage of erythropoietin (EPO) and iron are the main cause of anemia. However, ESA resistance and safety have spurred a lot of interest in the development of alternate anemia therapies. Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that increases erythropoiesis and may modulate iron metabolism, was recently licensed in China, Chile, South Korea, Japan and the European Union for the treatment of CKD-related anemia. Despite this, clinical trials have shown a number of adverse effects, including cardiovascular disease, hyperkalemia, and infections. In addition, of concern is roxadustat's possible effects on other organs and systems. In this review, based on clinical evidence, we discuss the potentially detrimental effects of roxadustat to the known biology on systems other than kidney, and the need for long-term follow-up in order for roxadustat to be approved in more countries in the future.

Responsiveness to an erythropoiesis-stimulating agent is correlated with body composition in patients undergoing chronic hemodialysis.

Resistance to erythropoiesis-stimulating agents (ESA) is associated with adverse outcomes in patients undergoing chronic hemodialysis. However, the impact of body composition on ESA response remains uncertain. This study retrospectively investigated whether there is an association between the ESA resistance index (ERI) and body composition in patients undergoing chronic hemodialysis. Multifrequency bioelectrical impedance analysis was used to measure body composition every six months. The ERI was calculated by dividing the weekly body weight-adjusted erythropoietin dose by the hemoglobin concentration. The ERI values were recorded every three months. A total of 123 patients were followed up for 24 (interquartile range 5, 75) months. The ERI was negatively correlated with body mass index, arm circumference, arm muscle circumference, body fat percentage, and visceral fat area (P = 0.057, 0.001, 0.017, 0.063, and 0.041, respectively). Patients with a higher mean ERI during the study period had an increased risk of all-cause mortality, cardiovascular events, and infection requiring hospitalization than those with a lower mean ERI (P = 0.027, 0.021, and 0.037, respectively). We also evaluated the association between the slope of body composition parameters and the ERI trend over time and found that the ERI increased over time in patients who had an increased ratio of extracellular water to total body water (P = 0.002) as well as decreased arm circumference, arm muscle circumference, visceral fat area, and phase angle (P = 0.001, P < 0.001, P = 0.036, and 0.002). ESA responsiveness appears to be associated with body composition in patients undergoing chronic hemodialysis. Therefore, measures improving body composition, such as nutrition and exercise, may have a favorable effect on the response to ESA.

Characteristics and Distribution of Erythroid Progenitors and Precursors Correlate with Erythropoiesis Stimulating Agents (ESAs) Response in Lower Risk Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are an heterogenous group of clonal myeloid disorders characterized by dysplastic ineffective hematopoiesis, peripheral blood cytopenias and a variable risk of progression to acute myeloid leukemia (AML) evaluated by IPSS-R score. Early stage erythropoiesis is dependent on growth factors like EPO, whereas late erythroid differentiation is iron-dependent. The entire process requires a fine regulation between apoptosis and cell survival. Anemia is the most common cytopenia in IPSS-R lower risk MDS (LR-MDS) and the mechanism underlying dyserythropoiesis is multifactorial, leading to apoptosis of erythroid progenitors and precursors. LR-MDS anemia is mainly treated with ESAs (e.g., Erythropoietin or EPO), but response is not optimal and eventually patients will suffer from chronic anemia and transfusion dependence. Moreover, the only strong predictor of ESAs treatment is the endogenous concentration of serum EPO (sEPO). The primary aim of this study was to detect quantitative and qualitative flow cytometry (FC) alterations of erythroid populations in the bone marrow (BM) of LR-MDS patients associated with resistance or response to ESAs and compared them with age-matched non cytopenic BM controls (CTRLs, 6). Secondly, we wanted to investigate if different WHO diagnostic MDS subgroups displayed specific pattern of erythroid maturation and/or FC abnormalities. We selected 97 LR-MDS anemic patients treated with ESAs at MDS Unit, Hematology dpt. AOU Careggi (Florence) and divided them according to type of ESAs response (e.g., primary refractory, PR; long responders, LR, with DOR longer than 24 months and secondary refractory, SR, with DOR shorter than 24 months). Baseline BM FC analysis was performed using an erythroid panel containing antibodies for CD33, CD34, CD36, HLA-DR, CD45, CD71, CD105, CD117. We also measured the coefficient of variance (CV) of CD71 and CD36 to assess qualitative FC abnormalities within the erythroid populations. We then identified all stages of erythroid maturation from A) CD34+ committed erythroid cells (CD34+, CD45dim, CD117+, CD71+, CD33+, HLA-DR +), or erythroid progenitors (COM-E), expressed both as fraction of all CD34+ cells and all 117+ progenitor cells, to B) CD34- erythroid precursors (from proerythroblasts, PROE, to orthochromatic erythroblasts). CV CD71 was increased in PR patients compared to CTRLs (p=0,009) and to responders (p=0,008). COM-E/tot.CD34+ cells were increased in all response categories, but there was a significant trend of higher values in LR vs. PR (p=0,055). Finally, (COM-E + PROE)/tot.117+ progenitors were only enriched in LR compared to CTRLs (p=0,009). Regarding WHO subgroups, MDS 5q- displayed a decrease in COM-E/CD34+ cells and in (COM-E + PROE)/tot.117+ cells compared to MDS-RS (p=0,00094 and p=0,009 respectively) and to CTRLs for the latter population (p=0,03). Moreover, total erythroid precursors were significantly reduced compared to MDS-SLD, -MLD and -RS. MDS-RS showed a marked erythroid hyperplasia and elevation of CV CD71 compared to CTRLs (p=0,0079 and p=0,024 respectively). Taken together, these results show that in LR-MDS, the increase of CV CD71 in erythroid cells is associated with resistance to ESAs, whereas response to ESAs is present in cases with enriched EPO sensitive COM-E and PROE populations compared to CTRLs, especially for LR vs PR (p=0,055). Finally, MDS-5q- and MDS-RS were the WHO subgroups with the highest rate of PR in our cohort (46% and 59% respectively), irrespective of sEPO. These 2 subgroups of MDS exhibited different repartition of erythroid subpopulations with characteristics associated with ESAs resistance. In 5q- COM-E and PROE were depauperate and, consequently, erythroid precursors reduced, while MDS-RS displayed an expansion of erythroid precursors and higher CV of CD71 compared to CTRLs. Finally, these FC parameters, easily and rapidly assessed at baseline BM evaluation in MDS patients, correlate with response to ESAs and with different WHO subgroups. FC erythroid abnormalities could partly explain the complex pathobiology underlying dyserythropoiesis and its treatment. The different repartition of erythroid progenitors observed could lead to molecular and transcriptome analyses focused on these altered subpopulations in order to investigate the exact mechanism of anemia in LR-MDS(s). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effect of roxadustat on serum metabolome and lipidome in patients with end-stage renal disease and erythropoiesis-stimulating agent resistance.

Roxadustat is a newly marketed hypoxia-inducible factor prolyl hydroxylase inhibitor used to treat anemia in patients with end-stage renal disease (ESRD). While clinical trials have demonstrated the therapeutic effects of roxadustat in patients with ESRD who are resistant to erythropoiesis-stimulating agents (ESAs), its metabolic effects are still unclear. Thirty-two individuals with ESRD and ESA resistance from the Blood Purification Center of Dalian Municipal Central Hospital were included. A total of 96 fasting serum samples were obtained from participants before treatment with roxadustat, and after treatment for 15 and 30 days. Ultra-high performance liquid chromatography-mass spectrometry-based metabolomics and lipidomics strategies were applied to investigate the effects of roxadustat on serum metabolism. A total of 255 metabolites and 444 lipid molecular species were detected and quantified. Sphingolipids and phospholipids decreased significantly during treatment, possibly associated with changes in phospholipid and ceramide metabolism. Bile acid levels decreased and cholic acid/chenodeoxycholic acid increased, indicating changes in gut microbiota and bile acid metabolism. Amino acids also changed during the process of treatment. The present study showed sphingolipids, phospholipids, and bile acids were significantly altered, which may be associated with a changed metabolism caused by roxadustat. This approach provided a powerful tool for exploring the mechanisms of ESA resistance in ESRD patients and may represent a promising strategy for elucidating the complex therapeutic mechanisms of other drugs.

MO796: Short-Term Effect of Roxadustat Combined With Erythropoiesis Stimulating Agents (ESAS) Treatment for Anemia in Patients Undergoing Hemodialysis With ESA Resistance

Abstract BACKGROUND AND AIMS Renal anemia is a common complication of chronic kidney disease (CKD) that can decrease the quality of life of patients, especially for patients with maintenance hemodialysis (MHD). The current standard treatment for renal anemia consists of iron plus erythropoiesis-stimulating agents (ESAs). However, high-dose ESA supplementation may cause an increase in blood pressure and induce cardiovascular events and death [1]. Roxadustat (FG-4592) is a new small-molecule oral medication for the treatment of renal anemia that may improve anemia by increasing endogenous erythropoiesis, transferrin receptor expression, and iron absorption [2]. Currently, the use of roxadustat in the treatment of renal anemia is still being explored. Our study aimed to observe the short-term efficacy of roxadustat combined with ESAs on renal anemia in MHD patients with ESA resistance. METHOD This retrospective study included patients with renal anemia using roxadustat for the first time at West China Hospital of Sichuan University from September 2019 to March 2021. Study inclusion criteria: (1) MHD for &amp;gt;3 months (thrice weekly), (2) basal Hb ≤ 100 g/L and (3) ESAs therapy for &amp;gt;2 months, and the first time use of rosadustat for at least 1 month. We excluded those without hemoglobin data and those with a history of blood transfusion within the first month. Patients treated with roxadustat combined with ESAs were as an observation group, and those treated with roxadustat alone were included as a control group. RESULTS A total of 31 MHD patients were included, the baseline data was shown in Table 1. A total of 15 patients were treated with roxadustat combined with ESAs, and 16 patients were treated with roxadustat alone. In the first month, the mean hemoglobin level was significantly increased in the combined group (1.89 ± 1.45 g/dL) but decreased in the alone group (–0.25 ± 1.32 g/dL). According to an analysis of covariance (ANCOVA), after adjusting for basal hemoglobin levels, the combination therapy improved the hemoglobin level better than therapy alone (F = 6.329, P = .018). We defined the Hb response as: hemoglobin change from baseline ≥ 1 g/dL for patients with basal Hb &amp;gt;8.0 g/dL or ≥ 2.0 g/dL for patients with basal Hb ≤8.0 g/dL. Among the 15 patients treated with roxadustat combined with ESAs, 14 patients showed an increase in hemoglobin within the first month and 8 patients get the Hb response, with the Hb response rate of 53.3%. For the 16 patients treated with roxadustat alone, 7 patients showed an increase in hemoglobin, only 2 patients get the Hb response, with the Hb response rate 12.5%. Patients treated with roxadustat combined with ESAs had a higher Hb response rate (P = .023) than those with roxadustat alone within the first month. CONCLUSION Roxadustat combined with ESAs treatment might be more beneficial to improve renal anemia in MHD patients with ESA resistance during the first month of roxadustat therapy replacement.

Resistance to Erythropoiesis-Stimulating Agents among Patients on Hemodialysis Is Typically Transient

Introduction: This study examines factors associated with erythropoiesis-stimulating agent (ESA) hyporesponsiveness, the duration of ESA hyporesponsiveness, the frequency of new episodes, and variation across countries. Methods: We used international Dialysis Outcomes and Practice Patterns Study data from 2015 to 2018 (N = 26,656) to investigate changes in ESA Resistance Index (ERI), calculated as epoetin dose divided by [hemoglobin × body weight] in patients on hemodialysis. We illustrated the proportion of patients who moved to other ERI quintiles over 12 months, and we studied the incidence and duration of ESA resistance. We examined case-mix factors associated with quintiles of ERI. Results: Most patients migrated out of their original ERI quintile within 4 months. Only 22% of patients in the top quintile of ERI at baseline (4.4% of all patients) remained in the top quintile during all 12 months of follow-up. A total of 42% of patients manifested an upper-quintile ERI during at least 1 month. Median duration of a new episode of ESA resistance was 2 months. Catheter hemoaccess, elevated C-reactive protein, lower transferrin saturation, lower serum albumin concentration, and recent hospitalization occurred more frequently among patients in the highest ERI quintile at baseline. ERI values were highest in the USA, Italy, and Mideastern nations and lowest in Russia and Japan. Discussion/Conclusion: It is a misconception to envision a sizable, fixed segment of the population with permanent resistance to ESA – resistance fluctuates frequently. The implications of these findings for prescription of ESAs and of hypoxia-inducible factor-prolyl hydroxylase inhibitors are discussed.

Selenium Associates With Response to Erythropoiesis-Stimulating Agents in Hemodialysis Patients

IntroductionImpaired response to erythropoiesis-stimulating agents (ESAs) is associated with increased mortality in patients with end-stage kidney disease. However, the underlying mechanisms are not fully elucidated. Accumulating data reveal that selenium (Se), a trace element, plays a key role in stress erythropoiesis and erythrocyte homeostasis. We evaluated the relationship between serum Se levels and the response to ESAs in hemodialysis patients.MethodsIn this cross-sectional study, we determined serum Se levels in 173 hemodialysis patients. We analyzed the association of serum Se with ESA responsiveness, as defined by ESA resistance index.ResultsOf the study participants, 50% had lower Se levels than the population-based reference values. We found that serum Se levels were significantly and inversely correlated with erythropoiesis resistance index (ERI) but not transferrin saturation (TSAT) or ferritin levels. Multiple regression analyses confirmed the association between Se levels and ESA hyporesponsiveness, independently of other known factors, such as iron status, being female, and dialysis vintage (β = −0.11, P < 0.001). When patients were divided according to Se levels and iron status, both low serum Se (<10.5 μg/dl) and iron deficiency significantly affected the response to ESA. Conversely, serum Se levels were significantly different among groups when patients were divided according to ERI quartiles. The association of low serum Se with ESA hyporesponsiveness persisted after adjustment of confounding variables.ConclusionSerum Se levels are associated with the response to ESAs and can predict ESA resistance independently of iron status in Japanese hemodialysis patients. These data open the possibility to test whether Se supplementation reduces ESA demand.

Factors Affecting Doses of Roxadustat Versus Darbepoetin Alfa for Anemia in Nondialysis Patients

Introduction: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness. Methods: Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18–24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated. Results: Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] μg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] μg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m² were associated with requiring higher DA but not roxadustat doses. Discussion/Conclusion: The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.

Association of the erythropoiesis-stimulating agent resistance index and the geriatric nutritional risk index with cardiovascular mortality in maintenance hemodialysis patients.

Hyporesponsiveness to erythropoiesis-stimulating agent (ESA) may be associated with protein-energy wasting. We investigated the relationship of the ESA resistance index (ERI) and the geriatric nutritional risk index (GNRI) for cardiovascular mortality in hemodialysis (HD) patients. A total of 180 maintenance HD patients were enrolled. The patients were stratified by the GNRI of 91.2, a previously reported cut-off value, and the ERI of 13.7 (IU/week/kg/g/dL), a cut-off value for predicting cardiovascular-specific mortality, and they were classified into four groups (group 1[G1]: higher GNRI and lower ERI, G2: higher GNRI and higher ERI, G3: lower GNRI and lower ERI, G4: lower GNRI and higher ERI). The ERI was independently associated with the GNRI (β = -0.271, p = 0.0005). During a median follow-up of 4.6 years, higher ERI and lower GNRI were independently associated with cardiovascular mortality, respectively (adjusted hazard ratio [aHR], 3.10; 95% confidence interval [CI], 1.31-7.34, and aHR, 6.64; 95%CI, 2.60-16.93, respectively). The 7-year survival rates were 96.1%, 70.3%, 77.3%, and 50.1% in G1, G2, G3, and G4, respectively. The aHR values for G4 versus G1 were 12.63 (95%CI, 3.58-44.59). With regards to model discrimination, adding the GNRI alone, the ERI alone, and both to the traditional risk model significantly improved the net reclassification improvement by 0.421, 0.662, and 0.671, respectively. Similar results were obtained for all-cause mortality. The ERI was independently associated with the GNRI, and could predict cardiovascular mortality in HD patients. Moreover, the combination of GNRI and ERI could improve the predictability for cardiovascular mortality.

Association between Dipeptidyl Peptidase-4 Inhibitor Prescription and Erythropoiesis-Stimulating Agent Hyporesponsiveness in Hemodialysis Patients with Diabetes Mellitus

Introduction: Dipeptidyl peptidase-4 (DPP-4) has been hypothesized to improve responsiveness to erythropoiesis-stimulating agent (ESA). We aimed to describe the trend in DPP-4 inhibitor prescription patterns and assess the association between DPP-4 inhibitor prescription and ESA hyporesponsiveness (eHypo) in Japanese hemodialysis (HD) patients with diabetes mellitus (DM). Methods: We analyzed data from the Japan Dialysis Outcomes and Practice Patterns Study phase 4–6 (2009–2017) on patients with DM who underwent HD thrice per week for at least 4 months. The primary exposure of interest was having a DPP-4 inhibitor prescription. The primary analysis outcomes were a binary indicator of eHypo (mean hemoglobin <10 and mean ESA dose >6,000 units/week over 4 months) and the natural log-transformed ESA resistance index (ERI). We used conditional logistic regression to compare within-patient changes in eHypo before and after initial DPP-4 inhibitor prescription. We used linear generalized estimating equation models to compare continuous ERI outcomes while accounting for within-patient repeated measurements with an exchangeable correlation structure. Results: There was a monotonic increase in DPP-4 inhibitor prescription according to study year up to 20% in 2017. Moreover, 12.8% of patients with a DPP-4 inhibitor prescription were ESA hyporesponsive before the initial DPP-4 inhibitor prescription. After DPP-4 inhibitor prescription, the odds of eHypo and mean log-ERI remained unchanged in the whole cohort of our study. The interaction analysis of DPP-4 inhibitor and sideropenia showed that DPP-4 inhibitors attenuated eHypo in the patients without iron deficiency. Conclusion: Our findings indicate a recent increase in DPP-4 inhibitor prescription among Japanese HD patients with DM. DPP-4 inhibitors could improve ERI in patients undergoing HD without iron deficiency.

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

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. 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. 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. Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy. Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.

Medium cut-off dialyzer improves erythropoiesis stimulating agent resistance in a hepcidin-independent manner in maintenance hemodialysis patients: results from a randomized controlled trial

The response to erythropoiesis stimulating agents (ESAs) is affected by inflammation linked to middle molecules in hemodialysis (HD) patients. We evaluated the effect of a medium cut-off (MCO) dialyzer on ESA resistance in maintenance HD patients. Forty-nine patients who underwent high-flux HD were randomly allocated to the MCO or high-flux group. The primary outcome was the changes of erythropoietin resistance index (ERI; U/kg/wk/g/dL) between baseline and 12 weeks. The MCO group showed significant decrease in the ESA dose, weight-adjusted ESA dose, and ERI compared to the high-flux group at 12 weeks (p < 0.05). The generalized estimating equation models revealed significant interactions between groups and time for the ESA dose, weight-adjusted ESA dose, and ERI (p < 0.05). Serum iron and transferrin saturation were higher in the MCO group at 12 weeks (p < 0.05). The MCO group showed a greater reduction in TNF-α and lower serum TNF-α level at 12 weeks compared to the high-flux group (p < 0.05), whereas no differences were found in the reduction ratio of hepcidin and serum levels of erythropoietin, erythroferrone, soluble transferrin receptor and hepcidin between groups. HD with MCO dialyzer improves ESA resistance over time compared to high-flux HD in maintenance HD patients. The MCO dialyzer provides superior removal of the inflammatory cytokine and thus improves iron metabolism in a hepcidin-independent manner.

P0855ASSOCIATIONS BETWEEN A COMPREHENSIVE PANEL OF BIOMARKERS WITH ESA HYPORESPONSIVENESS: ROLE OF IMMUNE DYSFUNCTION IN THE PATHOPHYSIOLOGY OF CKD ANEMIA

Abstract Background and Aims An inadequate response to the treatment of anemia with erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease is a challenging and common clinical condition previously associated with signs of inflammation and episodic clinical events. The associations between different immune response pathways and ESA hyporesponsiveness remain poorly understood. Here we describe the associations between a comprehensive panel of inflammatory biomarkers and ESA resistance in a group of stable HD patients. Method This is post-hoc analysis of the baseline evaluation of patients enrolled in the HDFIT, a randomized controlled trial. A panel comprising a more general (CRP), innate (IL-1β and IL-6), adaptive (IFNγ, IFNα2) biomarkers of immune response, and also a specific vascular inflammation (MCP-1) biomarkers were simultaneously measured with the same serum sample through turbidimetry and Milliplex Human Cytokine Magnetic Bead Panel - EMD Milipore Corporation, USA. Multivariable analysis was used to assess the association of their concentrations with the erythropoietin resistance index (ERI), defined as the weekly ESA dose divided by hemoglobin level. Results A total of 155 patients were included in this analysis (mean age 52 ± 6; 70% male; 32% with diabetes; mean hemoglobin 11.7 ± 1.5; median ESA dose/week 8000 IU IQR: 4000-12.000). Patients in the highest ERI tercile were mostly female, younger, more diabetic and with slightly higher proportion of iron prescription compared to those in the lowest tercile of ERI. The multivariable models adjusted for age, sex, diabetes and vascular access demonstrated that higher serum levels of IL-1β and IFN-γ were associated with higher ESA resistance, while there were no detectable associations of serum levels of IL-6 or CRP and ERI. Conclusion Among the biomarkers included in this comprehensive panel of biomarkers representing the multilevel nature of immune dysfunction in CKD, we observed associations between higher concentrations of innate (IL-1β) and adaptive (IFN) immune response and ESA hyporesponsiveness. Our results support the role of immune dysfunction in the pathophysiology of CKD anemia.