Erythropoiesis-stimulating Agents Dose Research Articles

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.

Theranova versus FX80: The impact on anemia management in hemodialysis.

Middle uremic toxins (MUTs) can cause anemia and erythropoietin hyporesponsiveness. Theranova dialyzers may improve anemia management by removing MUTs. Hence, the impact of Theranova dialyzers on erythropoietin responsiveness was studied. This exploratory single-center prospective observational study, encompassing 50 patients undergoing dialysis with either the Theranova-400 or FX80 membrane for 6 months, involved monthly tracking of hemoglobin levels, weight-adjusted erythropoiesis-stimulating agent (w-ESA) dosing, and erythropoietin resistance index (ERI), with ESA treatment decisions guided by a proprietary algorithm. The groups were similar in terms of demographics and baseline laboratory test results. The median hemoglobin levels, w-ESA and ERI, were found to be similar between FX80 and Theranova-400 groups at both baseline (11.06 vs 10.57, p = 0.808; 92.3 vs 105.2, p = 0.838; 8.1 vs 10.48, p = 0.876) and the end of the study (11.43 vs 11.03, p = 0.076; 48.7 vs 71.5; 4.48 vs 6.41, p = 0.310), respectively. There was a trend toward lower w-ESA and ERI at the end of the study compared to baseline in both groups, but the difference was non-significant. Based on this study of 50 patients undergoing high-flux dialysis with near-target hemoglobin levels, switching to Theranova 400 dialyzers compared to FX80 dialyzers did not show statistically significant differences in maintaining hemoglobin levels, reducing ESA dose, or lowering ERI. The non-randomized design and small sample size limit the study's power to detect true differences. Larger, randomized trials are needed to confirm findings and definitively assess Theranova 400's benefits.

Impact of C-reactive protein on the effect of Roxadustat for the treatment of anemia in chronic kidney disease: a systematic review of randomized controlled trials

BackgroundChronic inflammation, reflected by an increased blood C-reactive protein (CRP) level, is common in patients with chronic kidney disease (CKD) and is involved in the development of renal anemia. This systematic review aims to investigate the impacts of CRP on the efficacy of hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) in the treatment of renal anemia in patients with CKD.MethodsWe conducted a comprehensive search of electronic databases including Pubmed, Web of Science, Embase, Cochrane Library, CNKI, Wanfang, and the International Clinical Trials Registry Platform (ICTRP), from their inception to May 19, 2022. We systematically reviewed evidence from randomized controlled trials using HIF-PHIs for renal anemia treatment. The mean difference (MD) in changes in hemoglobin concentration (∆Hb) before and after treatment served as the meta-analysis outcome, utilizing a random-effects model. We compared groups with CRP levels greater than or equal to the upper limit of normal (ULN) and less than the ULN. Additionally, further analysis was conducted in the CRP ≥ ULN group comparing HIF-PHIs and erythropoiesis-stimulating agents (ESA).ResultsA total of 7 studies from 6 publications were included in the analysis. In the comparison between the CRP ≥ ULN group and the CRP < ULN group, 524 patients from 4 studies were incorporated into the analysis. All patients received roxadustat as the primary intervention. The pooled results revealed no significant difference in ΔHb between patients with CRP ≥ ULN and CRP < ULN at baseline (Mean Difference: 0.00, 95% Confidence Interval: -0.32 to 0.33, P = 0.99). Moreover, within the CRP ≥ ULN group, three studies involving 1399 patients compared the efficacy of roxadustat and erythropoiesis-stimulating agents (ESAs). The results indicated no significant difference in ΔHb between patients treated with ESAs and HIF-PHIs (Mean Difference: 0.24, 95% Confidence Interval: -0.08 to 0.56, P = 0.14). In terms of medication dosage, an increase in ESA dose over time was observed across various studies, particularly evident in the CRP ≥ ULN group, while the dose of roxadustat remains constant over time and is not influenced by the baseline levels of CRP.ConclusionsOur systematic review demonstrates that roxadustat exhibits similar efficacy across different CRP levels. Moreover, within the CRP ≥ ULN group, roxadustat can maintain efficacy comparable to ESA without the necessity for dose escalation.Trial registrationCRD42023396704.

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

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. 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. 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]). 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 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.

Market Competition and Anemia Management in the United States Following Dialysis Payment Reform.

Whether market competition influences health care provider responses to national reimbursement reforms is unknown. We examined whether changes in anemia management after the expansion of Medicare's dialysis payment bundle varied with market competition. With data from the US dialysis registry, we used a difference-in-differences (DID) design to estimate the independent associations of market competition with changes in anemia management after dialysis reimbursement reform. A total of 326,150 patients underwent in-center hemodialysis in 2009 and 2012, representing periods before and after reimbursement reform. Outcomes were erythropoiesis-stimulating agent (ESA) and intravenous iron dosage, the probability of hemoglobin <9g/dL, hospitalizations, and mortality. We also examined serum ferritin concentration, an indicator of body iron stores. We used a dichotomous market competition index, with less competitive areas defined as effectively having <2 competing dialysis providers. Compared with areas with more competition, patients in less competitive areas had slightly more pronounced declines in ESA dose (60% vs. 57%) following reimbursement reform (DID estimate: -3%; 95% CI, -5% to -1%) and less pronounced declines in intravenous iron dose (-14% vs. -19%; DID estimate: 5%; 95% CI, 1%-9%). The likelihoods of hemoglobin <9g/dL, hospitalization, and mortality did not vary with market competition. Serum ferritin concentrations in 2012 were 4% (95% CI, 3%-6%) higher in less competitive areas. After the expansion of Medicare's dialysis payment bundle, ESA use declined by more, and intravenous iron use declined by less in concentrated markets. More aggressive cost-reduction strategies may be implemented in less competitive markets.

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.

#3258 MECHANISMS OF HEMOGLOBIN CYCLING IN ANEMIC END-STAGE RENAL DISEASE PATIENTS TREATED WITH ERYTHROPOIESIS-STIMULATING AGENTS

Abstract Background and Aims A considerable fraction of renal anemia patients treated with erythropoiesis-stimulating agents (ESAs) experience hemoglobin ‘cycling’ periods during which hemoglobin levels periodically over- and undershoot a specified target range [1]. This is an undesired condition, which also necessitates frequent adjustment of the drug dose. The causes of hemoglobin cycling are not understood on a fundamental level. Through a combination of biomedical simulations and quantitative data analysis, we aimed at identifying mechanisms of hemoglobin cycling and the physiological and treatment-related factors contributing to cycling. Method We developed a biomedical modeling and simulation scheme that captures the essential features of ESA therapy involving a minimal feedback model for the delayed hemoglobin response after ESA administration and a stereotypic ESA dosing algorithm [2]. In this model, hemoglobin cycling emerged as a consequence of the delayed feedback between a patient's physiological response to ESA administrations and the resulting dose adjustments, which mutually maintain themselves in a causal loop. Guided by this model, we developed a set of statistical indicators that can detect this type of self-sustained hemoglobin cycling in clinical time series, including the Pearson cross correlation between hemoglobin levels and given ESA doses and hemoglobin standard deviation. Results A model analysis showed that physiological and treatment-related delays in hemoglobin response and ESA dose adjustment and administration were a major driver of hemoglobin cycling. Such delays are caused, e.g., by the cell cycle and maturation times of erythroid progenitors in response to ESA administration on one hand and restrictions in ESA dose changes and typical administration intervals on the other hand. In clinical time series, this was reflected by a systematic delay between bursts of ESA administrations and hemoglobin cycles. We quantified 1134 such datasets from hemodialysis patients and found that more persistent cycling was associated with negative correlation coefficients between hemoglobin levels and ESA doses. Using model simulations with similar behavior, we found that many patient- and therapy-related factors affect the hemoglobin dynamics in several (sometimes competing) ways, obfuscating their overall effect. For example, a larger RBC lifespan generally both entails higher hemoglobin levels but also prolongs the effect of ESA misdosings. However, model simulations suggested that longer RBC lifespans generally have a favorable effect in requiring less ESA on average and preventing hemoglobin cycling. Moreover, the model showed that for a given patient, ESA-specific properties such as its half-life may have a ‘sweet spot’ range of values within which hemoglobin cycling was suppressed while still showing a desired effect on the hemoglobin dynamics. Furthermore, the choice of the hemoglobin target window had an impact on hemoglobin stability. If the window was chosen too small, more frequent dose adjustments could initiate and maintain a cycling behavior. Conclusion Hemoglobin cycling in renal anemia patients often emerges from a complex interplay of multiple physiological and ESA treatment-related factors, with delays between ESA administration, hemoglobin response and subsequent ESA dose adjustment being a key driver of cycling. Biomedical modeling and simulation can aid in systematically exploring these interplays and find improved dosing strategies.

#5864 EFFECT OF IV FERRIC CARBOXYMALTOSE ON PHYSICAL PERFORMANCE AND QOL IN PATIENTS WITH CKD NOT ON DIALYSIS, MILD ANEMIA AND IRON DEFICIENCY

Abstract Background and Aims Iron deficiency (ID) in patients with chronic kidney disease (CKD) is highly prevalent and contributes to a poorer quality of life. According to current guidelines, treatment with intravenous (IV) iron is limited to CKD patients with ID and anemia to avoid/delay the use of erythropoiesis-stimulating agents (ESAs) or the reduce the doses of ESA in patients treated with these drugs. Considering the effects of the correction of ID in other settings, we hypothetized that treatment with IV iron in patients with ID and borderline anemia can improve physical performance and their quality of life, independent of the effects on hemoglobin. Method Prospective, unicentric, single-arm study in CKD patients with ID, mild anemia and with-out heart failure. The inclusion criteria were: age ≥ 18 years, CKD patients stages 3–5 not on dialysis, iron deficiency (ferritin &amp;lt;100 ng/ml or ferritin &amp;lt;200 ng/ml if TSAT &amp;lt;20%), mild anaemia (Hb 10.5-11.5 g/dL). At the baseline visit, after all the studies were performed, iv ferric carboxymaltose was administered in a single dose, according to the degree of ID calculated by the Ganzoni´s formula. The co-primary outcome was the change in physical performance, evaluated through the 6 minute-walk test (6MWT) at one week and at four weeks. Secondary end-points: Patient's global assessment (PGA) and quality of life (EQ-5D), Piper's fatigue test, serum phosphorous at four week. Laboratory data, PGA, EQ-5D and Piper test questionnaires were evaluated at baseline, and at weeks 1 and 4 after receiving IV ferric carboximaltose. Results 41 patients completed the study. Primary end-point: the 6MWT increased significantly from 296 ± 101 m to 314 ± 106 m at week 1 (p&amp;lt;0.01), and to 325 ±111 meters at week 4 (p&amp;lt;0.01). at week 4 (p = 0.083). A significant improvement in the PGA test values was detected when compared baseline vs 4 weeks (adjusted p value = 0.031). No significant differences were found between the baseline and week 1 (adjusted p value = 0.083), and week 1 and week 4 visits (adjusted p value = 0.086). No significant differences were found between the initial, 1-week, and 4-week visits in the EQ-5D quality of life questionnaire nor Piper's fatigue test. Phosphorus levels decreased significantly at week 1 from baseline (3.16 ± 0.7 vs 3.72 ± 0.6) (adjusted p&amp;lt;0.001), with a partial recovery of serum levels in week 4 (3.57 ± 0.7 mg/dL). There were no significant increases in hemoglobin concentration between the different time periods. Conclusion IV ferric carboximaltose administration significantly improved the functional capacity of CKD patients with ID in short term. PGA also improved slightly but significantly. Effects that were independent of hemoglobin changes, suggesting a role of ID for a lower physical performance in CKD patients without heart failure, independent of the presence of anemia.

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

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

#3648 INDIVIDUALIZED ANEMIA THERAPY IMPROVES HEMOGLOBIN OUTCOMES AND DECREASES EPOETIN BETA DRUG EXPOSURE IN HEMODIALYSIS PATIENTS

Abstract Background and Aims Anemia is a common complication in hemodialysis (HD) patients. Its treatment with erythropoiesis-stimulating agents (ESAs) is challenging due to a nonlinear dose-response relationship and time delays between ESA administration and hemoglobin (Hgb) response. Anemia treatment protocols are frequently used in clinical settings. However, high variability of patient-specific disease characteristics complicate attainment and maintenance of desired Hgb levels. We developed a novel fully personalized ESA dose recommendation tool and present clinical results of a multi-center, randomized controlled trial (RCT) using this software. Method We conducted an RCT in adult HD patients in six dialysis facilities in the US. Patients were randomized 1:1 and treated with our personalized ESA dose recommendation tool for twenty-six weeks (intervention group) or continued to be treated using an anemia protocol that was used as part of standard of care in those clinics (control group). The recommendation tool utilized a physiology-based model of anemia to estimate patient-specific physiological key characteristics, such as red blood cell lifespan, to create a patient-individual model from recent routine clinical data (gender, height, weight, Hgb measurements, and ESA treatment). These key characteristics and model-based outcome predictions were used to generate patient-specific ESA dose recommendations to stabilize Hgb levels in a target window of 10–11 g/dL. Dose recommendations were disseminated to the anemia managers of patients enrolled in the study for evaluation and further decision-making (Figure 1). This procedure was repeated biweekly with updated clinical data. Results Ninety-six patients were enrolled in the RCT. Patients were included in the statistical analysis when they remained in the clinical study for at least 30 days (n = 45 control group, n = 46 intervention group). We evaluated outcome measures showing efficacy and efficiency of the treatment in achieving target Hgb levels. Hgb-related outcomes were significantly different between the two study groups, with an improved Hgb control in the intervention arm, manifesting in a reduction of the Hgb distance to target by more than 30%. Epoetin-beta utilization in the intervention group was decreased by over 20%, while iron-related parameters showed no difference between the two arms (Table 1). Acceptance rate of dose recommendations was high; roughly 95% of the recommendations were accepted and implemented by the clinical staff. Conclusion A therapy software for personalized anemia management was developed for use with epoetin beta. The model-based ESA dose recommendation tool was evaluated in a clinical RCT in HD patients. Hgb control improved significantly in the group using the novel software tool, while ESA usage decreased, thus providing more efficient anemia management for the individual patient while reducing epoetin-beta drug exposure.

Clinical outcomes by SF3B1 mutation status in patients (pts) with lower-risk myelodysplastic syndrome (LR-MDS) retreated with erythropoiesis-stimulating agents (ESAs).

7071 Background: Pts with SF3B1-mutated LR-MDS often have a more favorable prognosis versus those with SF3B1 wildtype. A sizeable number of pts with LR-MDS undergo ESA treatment even after experiencing ESA failure in first line. This study evaluated the outcomes of pts with LR-MDS retreated with ESAs in routine clinical practice, stratified by SF3B1 status. Methods: This retrospective cohort study included pts with LR-MDS in the US community setting who initiated ESAs as first-line therapy between January 1, 2016 and June 30, 2019, and were followed through June 30, 2021. Eligible pts discontinued ESAs (treatment gap ≥ 3 wk for epoetin alfa or ≥ 6 wk for darbepoetin alfa) and subsequently reinitiated ESA therapy at least once during follow-up. Ring sideroblasts (RS) ≥ 15% served as a surrogate for pts with unknown SF3B1 mutation status. Outcomes included ESA switches, dose reductions and escalations, ESA failure, and overall survival (OS). Primary ESA failure was defined as no rise in hemoglobin (Hb) ≥ 1.5 g/dL or no decrease in RBC transfusion requirement by 8 wk of treatment. Transfusion-dependent (TD) status was evaluated for pts who were transfusion independent (TI) at baseline. Results: A total of 82 pts with LR-MDS and repeat ESA treatment were included. Median age at start of ESA treatment was 79 y (interquartile range [IQR], 72–85). Diagnosis of MDS-RS, MDS with isolated del(5q), MDS with multilineage dysplasia, and MDS with single lineage dysplasia was reported in 30 (36%), 7 (9%), 9 (11%), and 9 (11%) pts, respectively; 27 (33%) had unknown classification. Median follow-up was 26 mo (IQR, 13–38) with 65% failing ESA therapy by 8 wk. Table shows pts’ SF3B1 mutation status, median OS, pts who had an ESA switch, dose reduction or escalation, experienced ESA failure, and pts who were TI at baseline and became TD during follow-up. Results were similar when RS was not used as a surrogate, and when analyses were limited to pts who were treated with ESAs only throughout follow-up. Conclusions: In this study of pts with LR-MDS retreated with ESAs, primary ESA failure was high with nearly half of TI pts becoming TD during follow-up. OS was poor regardless of SF3B1 status – 2–4 times lower than the remaining life expectancy for a 79-y-old (108 mo for men; 125 mo for women). Although treatment options were limited during the study period, the high primary failure rate suggests that pts with LR-MDS may benefit from alternatives to ESAs. [Table: see text]

Safety Endpoints With Vadadustat Versus Darbepoetin Alfa in Patients With Non–Dialysis-Dependent CKD: A Post Hoc Regional Analysis of the PRO2TECT Randomized Clinical Trial of ESA-Treated Patients

In the PRO2TECT trials, vadadustat was found to be noninferior to darbepoetin alfa in hematologic efficacy but not for major adverse cardiovascular events (MACE; all-cause death or nonfatal myocardial infarction or stroke) in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). We investigated the regional differences in MACE in the PRO2TECT trials. Phase 3, global, open-label, randomized, active-controlled clinical trial. A total of 1,725 erythropoiesis-stimulating agent (ESA)-treated patients with anemia and NDD-CKD. 1:1 randomization to receive vadadustat or darbepoetin alfa. The primary safety end point was the time to first MACE. At baseline, patients in Europe (n=444) were primarily treated with darbepoetin alfa, showed higher proportions on low ESA doses (<90U/kg/wk epoetin alfa equivalents) with a hemoglobin concentration of≥10g/dL compared with patients in the US (n=665) and non-US/non-Europe (n=614) regions. The MACE rates per 100 person-years in the 3 vadadustat groups across regions were 14.5 in the US, 11.6 in Europe, and 10.0 in the non-US/non-Europe groups, whereas event rates in the darbepoetin alfa group were considerably lower in Europe than in the US and non-US/non-Europe groups (6.7 vs 13.3 and 10.5, respectively). The overall hazard ratio for MACE for vadadustat vs darbepoetin alpha was 1.16; 95% CI, 0.93-1.45, but varied by geographical region, with a greater hazard ratio seen in Europe (US, 1.07; 95% CI, 0.78-1.46; Europe, 2.05; 95% CI, 1.24-3.39; non-US/non-Europe, 0.91; 95% CI, 0.60-1.37); interaction between study treatment and geographical region, P=0.07). In Europe, ESA rescue was associated with a higher risk of MACE in both groups. Several analyses are exploratory. In this trial, there was a low risk of MACE in the darbepoetin alfa group in Europe. Patients in Europe were generally on low doses of ESA, with hemoglobin already within target range. The low risk of MACE may have been related to a limited need to switch and titrate darbepoetin alfa compared with the non-US/non-Europe group. Akebia Therapeutics, Inc. ClinicalTrials.gov identifier: NCT02680574.

Dosing of iron supplementation for iron-deficient patients with heart failure: should we prefer more intensive or less intensive repletion targets?

Dosing of iron supplementation for iron-deficient patients with heart failure: should we prefer more intensive or less intensive repletion targets?

Extremely Low Dose of Erythropoiesis-Stimulating Agent May Be Associated with Increased Mortality in Hemodialysis Patients

Introduction: Although high-dose erythropoiesis-stimulating agent (ESA) has been shown to increase mortality risk and adverse cardiovascular events in hemodialysis patients, the safety of extremely low-dose ESA is unclear. Methods: We retrospectively analyzed the association between ESA dose and mortality in the monthly dosing range of 0–43,000 U of equivalent epoetin alfa in 304 Taiwan hemodialysis patients by using Cox proportional hazard model and cubic spline model. Results: Compared with mean monthly ESA dose of 15,000–25,000 U (mean ± standard deviation 20,609 ± 2,662 U), monthly ESA dose of less than 15,000 U (mean ± standard deviation 7,413 ± 4,510 U) is associated with increased mortality. Monthly ESA dose of 25,001–43,000 U (mean ± standard deviation 31,160 ± 4,304 U) is not associated with higher mortality risk than monthly ESA dose of 15,000–25,000 U. The results were consistent in Cox proportional hazard models and cubic spline models. Subgroup analyses showed no significant heterogeneities among prespecified subgroups. Conclusions: Extremely low dose of ESA in hemodialysis patients may be associated with increased mortality risk. Future studies are warranted to prove this association.

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.

Artificial Intelligence and Machine Learning in Dialysis: Ready for Prime Time?

Artificial Intelligence and Machine Learning in Dialysis: Ready for Prime Time?

Mechanisms of hemoglobin cycling in anemia patients treated with erythropoiesis-stimulating agents.

Patients with renal anemia are frequently treated with erythropoiesis-stimulating agents (ESAs), which are dynamically dosed in order to stabilize blood hemoglobin levels within a specified target range. During typical ESA treatments, a fraction of patients experience hemoglobin 'cycling' periods during which hemoglobin levels periodically over- and undershoot the target range. Here we report a specific mechanism of hemoglobin cycling, whereby cycles emerge from the patient's delayed physiological response to ESAs and concurrent ESA dose adjustments. We introduce a minimal theoretical model that can explain dynamic hallmarks of observed hemoglobin cycling events in clinical time series and elucidates how physiological factors (such as red blood cell lifespan and ESA responsiveness) and treatment-related factors (such as dosing schemes) affect cycling. These results show that in general, hemoglobin cycling cannot be attributed to patient physiology or ESA treatment alone but emerges through an interplay of both, with consequences for the design of ESA treatment strategies.

Maintenance intravenous iron in hemodialysis patients to minimize erythropoietin doses: a double-blinded, randomized controlled trial (the MAINTAIN IRON trial)

In patients on chronic hemodialysis, there is no standard protocol for maintenance iron supplementation. This study aimed to compare two fixed-dose intravenous (IV) iron protocols to reduce erythropoiesis-stimulating agents (ESA). We conducted a double-blinded, randomized controlled study on hemodialysis patients having ferritin levels between 200 and 700 ng/dl and transferrin saturation values between 20 and 40%. Patients were assigned to receive either 100 or 200 mg of IV iron each month. ESA was adjusted every month to keep Hb between 10 and 12 g/dl. ESA dose at 12 months was the primary outcome. The secondary outcomes were all-cause mortality, cardiovascular events, absolute iron deficiency anemia (IDA), blood transfusion, adverse events, and iron withholding rate. Of the 79 eligible patients, 40 received 100 mg of IV iron, while 39 received 200 mg. At month 12, the mean monthly ESA dose in the 100-mg IV iron group was 35,706 ± 21,637 IU, compared to 26,382 ± 14,983 IU in the 200-mg group (P = 0.03). IDA was found in twelve patients (30%) in the 100-mg group and four patients (10.5%) in the 200-mg group (P = 0.05). In each group, three patients died (P = 0.9). Hospitalization, venous access thrombosis, and infection rates were similar in both groups. The withholding rate of IV iron was higher in 200-mg group (25% vs. 64.1%), but the protocol compliance was found more in 100-mg group (50% vs. 28.2%) (P = 0.001). In conclusion, monthly 200-mg IV iron infusions significantly reduce ESA doses but have a higher withholding rate. (Funded by the Kidney Foundation of Thailand and the Research Group in Nephrology and Renal Replacement Therapy from the Faculty of Medicine, Thammasat University).Thai Clinical Trials Registry number, TCTR20190707001.

Pharmacist-driven epoetin alfa-epbx dosing for hospitalized patients.

To determine the effectiveness of pharmacy consultation in managing epoetin alfa-epbx dosing for inpatients on hemodialysis. This multisite, retrospective cohort study evaluated the implementation of an initial dose consultation for epoetin alfa-epbx by pharmacists. A pre-post cohort study evaluated patients from August 2020 through January 2021 and August 2021 through January 2022, respectively. Hospitalized patients were included if they were at least 18 years of age, received hemodialysis, and were administered an erythropoiesis-stimulating agent (ESA) for anemia due to chronic kidney disease. Patients were excluded for religious objections to receiving blood products or if patients were discharged or died before their first hemodialysis session. The primary outcome was the average epoetin alfa-epbx acquisition cost per patient. Secondary endpoints were the epoetin alfa-epbx overall pharmacy purchasing cost, the average dose, and the number of administered doses. A subgroup analysis was performed for patients in the post group with an outpatient ESA before admission to determine the epoetin alfa-epbx days saved. A total of 264 patients were included in the pre group, and 272 patients were included in the post group. The average acquisition cost was significantly lower in the post group ($1,681.77 vs $1,041.35, P < 0.0001). The overall pharmacy purchasing cost was also lower in the post group ($148,970.89 vs $127,873.25). The post group had a significantly lower average dose (13,694 vs 10,112 units, P = 0.0004), while the number of administered doses did not differ significantly between the groups (2.09 vs 1.79 doses, P = 0.0668). The subgroup analysis included 83 patients, which yielded 53 epoetin alfa-epbx days saved. Pharmacist-driven ESA dosing was associated with significant decreases in ESA average acquisition cost and average total dose per patient.