Erythropoiesis-stimulating Agents Hyporesponsiveness Research Articles

Severe Hyporesponsiveness to Erythropoiesis-Stimulating Agents in Patients on Chronic Hemodialysis-Reconsidering the Relationship with Thrombo-Inflammation and Oxidative Stress.

Besides a multitude of consequences patients on chronic renal replacement therapy have, anemia is one of the most prominent factors making a significant number of patients dependent on erythropoiesis-stimulating agent (ESA) therapy. The aim of this study was to examine the relationship between the levels of a broad spectrum of thrombo-inflammatory and oxidative stress-related biomarkers and the presence and level of ESA hyporesponsiveness in patients undergoing regular chronic hemodialysis. This cross-sectional study included 96 patients treated with chronic hemodialysis. Levels of several thrombo-inflammatory and oxidative stress-related biomarkers, as well as demographic, clinical, and laboratory analyses, were collected and analyzed based on the calculated value of the ESA-hyporesponsiveness index (EHRI). In the analyzed sample, 58 patients received ESAs. Of all the investigated parameters, only body mass index (BMI), level of plasminogen activator inhibitor-1, and level of L-type fatty acid binding protein (L-FABP) were observed as significant predictors of EHRI. A significant diagnostic potential for ESA resistance has been observed in BMI and L-FABP between ESA-resistant and ESA-non-resistant groups of patients (p = 0.004, area under the curve 0.763 and p = 0.014, area under the curve 0.712, respectively) with the cut-off values of 25.46 kg/m2 and 5355.24 ng/mL, respectively. Having a BMI of 25.46 kg/m2 or less and an L-FABP level higher than 5355.24 ng/mL were observed as significant predictors of ESA resistance (odds ratio 9.857 and 6.125, respectively). EHRI was positively predicted by low BMI and high levels of plasminogen activator inhibitor-1 and L-FABP. High levels of L-FABP and low BMI have been observed as strong predictors of ESA resistance.

Erythropoiesis-stimulating agent hyporesponsiveness was associated with worse survival of hemodialysis patients independent of the serum ferritin level.

Ferritin level and erythropoiesis-stimulating agent (ESA) responsiveness are each associated with hemodialysis patient survival. We assessed interrelationships between these two vs. survival. Patients in the Japan Dialysis Outcomes and Practice Patterns Study Phases 4-6 (2009-2018) were included. All-cause mortality associations were assessed with progressive adjustment to evaluate covariate influence. During follow-up (median 2.6 years), 773 of 5154 patients died. After covariate adjustment, the mortality hazard ratio (HR) was 0.99 (95% CI: 0.81, 1.20) for low serum ferritin and 1.12 (CI: 0.89, 1.41) for high serum ferritin. By contrast, mortality risk with elevated ESA resistance index (ERI) persisted after covariate adjustment (HR 1.44, CI [1.17-1.78]). The serum ferritin and ERI interaction was not significant; p > 0.96 across all models. Japanese hemodialysis patients with high ERI experienced worse survival independent of serum ferritin levels, highlighting the importance of identifying and mitigating ESA hyporesponsiveness among dialysis patients.

#2352 Short-term effect of roxadustat combined with ESA treatment for anemia in patients undergoing hemodialysis with ESA hyporesponsiveness

Abstract Background and Aims The efficacy of roxadustat combined with erythropoiesis-stimulating agent (ESA) on renal anemia in maintenance hemodialysis (MHD) patients is rarely reported, especially for those with ESA hyporesponsiveness. Our study aimed to observe the short-term efficacy of roxadustat combined with ESA for those patients when they were first treated with roxadustat converted from ESA. Method Retrospective data pertaining to MHD patients with ESA hyporesponsiveness from September 2019 to June 2022 were collected. All patients had been on ESA for more than 6 months and were first treated with roxadustat. 19 patients treated with roxadustat combined with ESA and 19 patients treated with roxadustat alone were paired for analysis from 108 patients by propensity score matching. Parameters related to anemia, iron metabolism and adverse events were recorded. Results The haemoglobin (Hb) level was significantly improved in patients treated with roxadustat combined with ESA after 1 month (7.8 ± 1.54 g/dL vs 8.96 ± 1.38 g/dL, p = 0.003), which was not found in patients treated with roxadustat alone (8.2 ± 1.28 g/dL vs 8.35 ± 1.54 g/dL, p = 0.652). Patients treated with roxadustat combined with ESA had a higher Hb response rate (47.4%) than those treated with roxadustat alone (15.8%) during the first month (p = 0.036). In addition, the level of serum iron was increased, and serum ferritin (SF) was decreased in both groups. Conclusion Roxadustat combined with ESA treatment might be more beneficial for improving renal anemia in MHD patients with ESA hyporesponsiveness during the first month of roxadustat therapy replacement.

Clinical application and future perspectives of HIF-PH inhibitors

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

Contemporary Practice of Anemia Treatment Among Dialysis Patients in the United States

The treatment of anemia is a major activity in the care of patients undergoing maintenance hemodialysis (HD). The comparative effectiveness of new pharmacologic treatments, relative to erythropoiesis-stimulating agents (ESAs), should be anticipated on the bases of controlled trials and current practice. We describe the contemporary practice of anemia treatment in a national cohort of patients undergoing maintenance HD. We analyzed the United States Renal Data System (USRDS) data to identify adult patients undergoing in-facility HD in 2016 to 2019. Using the Consolidated Renal Operations in a Web-Enabled Network (CROWNWeb) dataset, we identified hemoglobin and ESA utilization (agent and cumulative dose) during each patient-month, as well as intravenous (IV) iron utilization, ferritin, and transferrin saturation. We compared ESA dosing during the study era to dosing in the Normal Hematocrit Cardiac Trial (NHCT), conducted in the 1990s. We assessed ESA hyporesponsiveness by estimating the prevalence of the following: (i) high erythropoietin resistance index (ERI) and (ii) either 3 or 6 consecutive months with hemoglobin<10 g/dl. Nearly two-thirds of patient-months had hemoglobin of 10.0 to 11.9 g/dl. Mean ESA utilization was 76.7% per month, with increasing use of pegylated epoetin beta. ESA dosing was stable; epoetin alfa dosing was slightly lower than in the low-target arm of the NHCT. The prevalence of ESA hyporesponsiveness was 22.2% if defined by high ERI, but only 2.1% to 6.0% if defined by 3 to 6 consecutive months with hemoglobin<10 g/dl. Median transferrin saturation was 22.3% with high ERI and persistently low hemoglobin. Hemoglobin and ESA dosing distributions are stable, with epoetin alfa dosing below the low-target arm of the NHCT. Persistently low hemoglobin occurs infrequently and may reflect iron depletion.

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.

#2962 EFFICACY AND SAFETY OF ROXADUSTAT IN NON-DIALYSIS-DEPENDENT CKD PATIENTS WITH OR WITHOUT INFLAMMATION: A POOLED ANALYSIS OF FOUR PHASE 3 STUDIES

Abstract Background and Aims Chronic kidney disease (CKD)-associated anemia is commonly treated with erythropoiesis-stimulating agents (ESAs); however, some patients respond inadequately to ESAs. Inflammation may be a cause of ESA hyporesponsiveness. Roxadustat, an oral medication, is a hypoxia-inducible factor prolyl hydroxylase inhibitor that has shown efficacy in patients with anemia of CKD. This pooled analysis examined the efficacy and safety of roxadustat in correcting hemoglobin (Hb) levels in subgroups of patients with non−dialysis-dependent (NDD) CKD with or without inflammation at baseline. Method Data from four phase 3, randomized, placebo-controlled (OLYMPUS [NCT02174627], ALPS [NCT01887600], ANDES [NCT01750190]) or erythropoiesis-stimulating agent−controlled (ESA; DOLOMITES [NCT02021318]) studies in patients with NDD CKD were pooled for this analysis. Mean Hb change from baseline to Weeks 28−52 and mean weekly total roxadustat dose (mg/kg body weight) at Week 24 in patients with or without inflammation at baseline (as determined by high-sensitivity C-reactive protein [hsCRP] levels divided into quintiles) were evaluated with an analysis of covariance model with baseline Hb and baseline estimated glomerular filtration rate as covariates. Safety data were summarized descriptively. Results In total, 3573 patients with NDD-CKD (roxadustat N = 2068; placebo = 1212; ESA N = 293) were evaluated. At baseline, the mean [SD] Hb levels (g/dL) for roxadustat (hsCRP quintiles 1−5: 9.17 [0.82], 9.26 [0.68], 9.18 [0.75], 9.15 [0.74], 9.08 [0.82]), placebo (hsCRP quintiles 1−5: 9.09 [0.74], 9.20 [0.71], 9.15 [0.69], 9.09 [0.71], 9.01 [0.76]), and ESA (hsCRP quintiles 1−5: 9.53 [0.69], 9.53 [0.64], 9.54 [0.73], 9.60 [0.66], 9.53 [0.71]) were similar across hsCRP quintiles. The mean Hb change from baseline to Weeks 28–52 was greater with roxadustat than with placebo, and comparable between roxadustat and ESA, regardless of inflammation at baseline (Fig. 1). At Week 24, roxadustat dose was not increased in patients across hsCRP quintiles (hsCRP quintiles 1−5: 3.3, 3.0, 2.7, 3.1, 3.1 mg/kg, respectively). Roxadustat dose was not significantly higher at Week 24 for patients with moderate-to-high baseline hsCRP levels (quintile 4, &amp;gt;3.48 to ≤8.67 mg/L; least squares mean [LSM], 3.05; 95% CI, 2.80−3.30; quintile 5, &amp;gt;8.67 mg/L; LSM, 3.10; 95% CI, 2.83−3.36) compared with patients with low baseline hsCRP levels (quintile 1, ≤0.71 mg/L; LSM, 3.30; 95% CI, 3.04−3.56; treatment comparison between quintile 1 and quintile 4: LSM difference, 0.25; 95% CI, −0.11 to 0.61; treatment comparison between quintile 1 and quintile 5: LSM difference, 0.20; 95% CI, −0.17 to 0.57; Fig. 2), indicating that patients with increased inflammation at baseline did not consistently require a higher roxadustat dose. The overall percentages of patients with at least one treatment-emergent adverse event were similar across hsCRP quintiles for patients treated with roxadustat (hsCRP quintiles 1−5: 88.7, 91.4, 90.3, 90.7, 90.5), placebo (hsCRP quintiles 1−5: 88.2, 84.5, 89.4, 88.5, 87.9), and ESA (hsCRP quintiles 1−5: 89.1, 90.9, 91.4, 94.1, 94.8). The most common treatment-emergent adverse events were hypertension (hsCRP quintiles 1−5 [%]; roxadustat: 16.8, 16.5, 17.4, 22.2, 18.9; placebo: 7.9, 9.5, 11.8, 9.3, 8.5; ESA: 45.7, 36.4, 39.7, 22.1, 31.2), end-stage renal disease (hsCRP quintiles 1−5 [%]; roxadustat: 21.3, 22.7, 21.1, 24.6, 23.1; placebo: 13.8, 15.9, 15.3, 18.1, 16.5; ESA: 32.6, 36.4, 34.5, 39.7, 36.4), and decreased glomerular filtration rate (hsCRP quintiles 1−5 [%]; roxadustat: 4.6, 5.0, 4.5, 5.3, 5.1; placebo: 2.0, 2.0, 2.4, 1.3, 3.1; ESA: 13.0, 22.7, 19.0, 13.2, 16.9). Conclusion Independent of baseline inflammation status, roxadustat increased Hb levels greater than placebo and comparable to ESA with a similar safety profile. Patients with high baseline hsCRP did not require increased roxadustat doses to maintain Hb levels up to Week 24. These data suggest that roxadustat is effective in patients with anemia of NDD CKD regardless of inflammation status.

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.

Not baseline but time-dependent erythropoiesis-stimulating agent responsiveness predicts cardiovascular disease in hemodialysis patients receiving epoetin beta pegol: A multicenter prospective PARAMOUNT-HD Study

BackgroundResponsiveness to erythropoiesis-stimulating agents (ESAs) has been reported to be associated with increased cardiovascular disease (CVD) and mortality in patients undergoing hemodialysis (HD). However, the association between hyporesponsiveness to the long-acting ESA, epoetin beta pegol (CERA), and CVD remains unknown. MethodsThis multicenter prospective study included 4034 patients undergoing maintenance HD. After shifting from prior ESA to CERA, we studied the association between erythropoietin resistance index (ERI) at six months and outcomes, including cardiac events, major adverse cardiovascular events (MACE), and all-cause mortality, using Cox proportional hazards models (Landmark analyses) and marginal structural models to adjust for time-dependent confounding factors, including iron-containing medications and hemodiafiltration (HDF). ResultsThe median dialysis vintage and the observational period were 5.0 years and 22.1 months, respectively. The landmark analyses revealed that the highest tertile of baseline ERI (T3) was associated with a significantly higher all-cause mortality than the lowest tertile (T1) (hazard ratio [HR]: 1.48, 95% CI: 1.03–2.13). Furthermore, marginal structural models revealed that time-dependent ERI T3 was significantly associated with increased cardiac events (HR: 1.59, 95% CI: 1.14–2.23), MACE (HR: 1.60, 95% CI: 1.19–2.15), all-cause mortality (HR: 1.97, 95% CI: 1.40–2.77), and heart failure (HF) (HR: 2.05, 95% CI: 1.23–3.40) compared to T1. A linear mixed effects model showed that iron-containing medications and HDF are negatively associated with time-dependent ERI. ConclusionsBaseline ERI at six months predicted only all-cause mortality; however, time-dependent ERI was a predictor of cardiac events, all-cause mortality, MACE, and HF. The widespread use of iron-containing medications and HDF would ameliorate ESA hyporesponsiveness.

Cardiovascular events by different target hemoglobin levels in ESA-hyporesponsive hemodialysis patients: a multicenter, open-label, randomized controlled study

BackgroundThe incidence of cardiovascular (CV) events is high in hemodialysis (HD) patients and is associated with hyporesponsiveness to erythropoiesis-stimulating agents (ESAs). However, there are no recommended target hemoglobin ranges for ESA-hyporesponsive patients.MethodsWe randomly assigned 304 ESA-treated HD patients with ESA hyporesponsiveness to a proactive treatment group (target hemoglobin level 11 g/dL) or maintenance treatment group (target hemoglobin level 9–10 g/dL), both of which received epoetin beta pegol. The primary outcome was time to the first CV event. CV events included cardiac death, heart failure, and acute coronary syndrome requiring hospitalization. The patients were followed for 24 months.ResultsThe proactive and maintenance treatment groups had mean baseline hemoglobin levels of 9.34 and 9.32 g/dL, respectively. Mean hemoglobin levels during the observation period were 10.58 and 10.26 g/dL (P < 0.001), and mean durations of hemoglobin level > 10.5 g/dL were 11.5 and 8.6 months (P < 0.001), respectively. Cox proportional hazards analysis demonstrated a significantly lower risk of CV events in the proactive group (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.19–0.96). This lower risk was driven by lower incidence of hospitalization-required congestive heart failure. A longer duration of hemoglobin level > 10.5 g/dL was associated with a lower risk of CV events (HR, 0.92/month; 95% CI, 0.87–0.98).ConclusionsTargeting hemoglobin levels of 11 g/dL with epoetin beta pegol reduces CV risk in Japanese HD patients with ESA hyporesponsiveness.Trial registration: University Hospital Medical Information Network (UMIN) database (UMIN000010138), registered on March 1, 2013.

Erythropoiesis-Stimulating Agent Hyporesponsiveness and Anemia Management in the ASCEND-D Trial

Erythropoiesis-Stimulating Agent Hyporesponsiveness and Anemia Management in the ASCEND-D Trial

Examining the Magnitude of Erythropoiesis-Stimulating Agent Hyporesponsiveness in Hemodialysis Patients

Examining the Magnitude of Erythropoiesis-Stimulating Agent Hyporesponsiveness in Hemodialysis Patients

Is HIF-PHI the Answer to Tackle ESA Hyporesponsiveness in the Elderly?

Anemia in chronic kidney disease (CKD) has become an important clinical issue with the increased prevalence of elderly patients living with CKD progressing to kidney failure. The causes of anemia in elderly individuals tend to be multifactorial, exacerbated by the physiological effects of aging, frailty and declining kidney function. Erythropoiesis-stimulating agents (ESAs) are the conventional therapeutic option for anemia in CKD. However, ESA hyporesponsiveness is a commonly observed issue in clinical practice and an issue that is more challenging to resolve in elderly patients living with frailty, kidney disease, and multi-morbidities. Following the emergence of oral hypoxia-induced factor prolyl-hydroxylase inhibitors (HIF-PHI) in recent years, there is discussion on whether it is a solution to the conundrum of ESA hyporesponsiveness, as HIF-PHI treats anemia via an alternative physiological pathway. There remains uncertainty on the suitability of HIF-PHI use in elderly patients, given a lack of data on its safety over long-term follow-up for the elderly population. Further study is needed to provide answers, considering the clinical significance of this issue within a public-health scale.

Prevalence, treatment status, and predictors of anemia and erythropoietin hyporesponsiveness in Japanese patients with non-dialysis-dependent chronic kidney disease: a cross-sectional study

Hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) has been highlighted as a potential risk factor for cardiovascular disease in patients with chronic kidney disease (CKD). We assessed cross-sectionally the prevalence, associated factors, and treatment status of anemia and ESA hyporesponsiveness in 4460 non-dialysis-dependent CKD patients enrolled in a multicenter cohort in Japan. Anemia was defined as a hemoglobin (Hb) level of less than 11g/dL or receiving ESA therapy. ESA hyporesponsiveness was defined by the erythropoietin-resistance index (ERI), which was the erythropoietin dose per week divided by body weight and Hb level (U/kg/week/g/dl). Of the 4460 patients, 1050 (23.5%) had anemia. ESAs were administered to 626 patients, reaching a percentage of 57.5% of patients with stage G5 CKD. However, the ESA treatment rate was only 49.0% in patients with a hemoglobin level of < 11g/dL. The proportion of patients receiving iron supplementation was lower than that of patients receiving ESAs regardless of CKD stage or hemoglobin level, and a significant proportion of patients did not receive iron supplementation, even those with iron deficiency. The ERI increased with CKD stage progression, and the multiple regression analysis showed that age, female sex, body mass index, cholesterol, glomerular filtration rate, and intact parathyroid hormone level were independent contributors. Our findings demonstrate that many Japanese patients with non-dialysis-dependent CKD receiving ESAs fail to maintain adequate hemoglobin levels. These results suggest the need for interventions for ESA hyporesponsiveness factors in addition to iron supplementation.

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.

Role of circulating endothelial progenitors in responsiveness to erythropoiesis-stimulating agents in hemodialysis patients

BackgroundThough treatment of anemia in chronic kidney disease (CKD) patients has been improved remarkably by erythropoiesis-stimulating agents (ESA), hypo-responsiveness to ESA poses a persistent problem in a subgroup of CKD patients, especially those on dialysis, with deteriorated mortality or cardiovascular risks. Pathomechanism of this condition including cardiovascular implications has not been sufficiently investigated.MethodsClinical parameters of 101 chronic hemodialysis patients which included those hospitalized in our university hospital were examined cross-sectionally. As a marker estimating ESA hypo-responsiveness, erythropoietin resistance index (ERI) was calculated. Numbers of circulating endothelial progenitor cells (EPC) were measured by flow cytometry. Associations among values were analyzed by methods including multiple linear regression.ResultsMajority (93%) of the subjects were hospitalized patients with various comorbidities. ERI (18.4 [7.2–33.0] IU/week/kg/g/dL) and ESA dose (161.6 [75.0–320.9] IU/week/kg) of all the subjects were relatively high. Factors negatively correlated with EPC included age, HD vintage, CRP, pulse rate, ESA dose and ERI, while male sex and systolic blood pressure were positively correlated. By multiple linear regression analysis, age, sex and ERI (standardized coefficient beta − 0.202, p = 0.039) remained as the independently predicting factors of EPC (log CD133/Flk1+ EPC). Darbepoetin alpha was used in 65 patients, especially predominant when requiring higher ESA doses, but by correlation or multivariable analyses, this did not substantially modify the negative association between ERI and EPC.ConclusionsERI was independently associated with EPC paucity in a cohort with various comorbidities. This may suggest a link which connects ESA hypo-responsiveness to compromised cardiovascular prognosis of dialysis patients.

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.

Hyporesponsiveness to long-acting erythropoiesis-stimulating agent is related to the risk of cardiovascular disease and death in Japanese patients on chronic hemodialysis: observational cohort study

BackgroundResponsiveness to erythropoiesis-stimulating agents (ESAs) is thought to be related to prognosis in patients on hemodialysis. A multi-center, prospective cohort study was conducted to investigate the effects of hyporesponsiveness to long-acting ESAs on cardiovascular events and mortality in Japanese patients on chronic hemodialysis.MethodsA total of 127 chronic hemodialysis patients treated with long-acting ESAs were followed-up prospectively. Responsiveness to ESA was evaluated using an erythropoietin resistance index (ERI) calculated by dividing the weekly body-weight-adjusted ESA dose by the hemoglobin concentration. The primary endpoint of this survey was defined as a combination of cardiovascular events and all-cause deaths. The association between hyporesponsiveness to ESAs evaluated by the highest quartile of the ERI and the primary endpoint was investigated.ResultsDuring the follow-up period (median 4.6 years), 32 patients reached the primary end point. Kaplan-Meier curve analysis showed that patients with ESA hyporesponsiveness belonging to the highest quartile of the ERI reached the primary end point more frequently than those without (P = 0.031). Cox regression analysis showed that an ERI in the highest quartile was an independent predictor of the primary end point, even after adjustment using a propensity score (hazard ratio 2.76, 95% confidence interval 1.19–6.40).ConclusionsESA hyporesponsiveness in hemodialysis patients treated with long-acting ESAs is related to cardiovascular events and death.

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.