Erythropoietin-stimulating Agents Dose Research Articles

#4399 ALGORITHM-MANAGED DOSING AND PHARMACIST-MANAGED DOSING OF ERYTHROPOIETIN STIMULATING AGENTS IN RENAL ANEMIA: A SYSTEMATIC REVIEW

Abstract Background and Aims In clinical practice, the treatment of renal anemia is challenging. The attainment of target levels for hemoglobin is often low, due to the high incidence of infections, hyporesponsiveness to erythropoietin stimulating agents (ESA), and suboptimal prescribing of ESA and iron. Several interventions to improve the treatment of renal anemia have been developed, two of them being algorithm-managed dosing and pharmacist-managed dosing of ESA. We performed a systematic review to identify and summarize these two types of interventions and to determine their effectiveness in improving the treatment of renal anemia. Method We followed the PRISMA guidelines for systematic reviews. Studies that explored the effect of algorithm-managed and pharmacist-managed dosing of ESA in adult patients with renal anemia were evaluated for inclusion. No restrictions were set on outcome parameters. All observational and interventional studies that included a control group and had a follow-up of at least six months, were eligible for inclusion. Only full-length articles were considered for inclusion. PubMed, Embase, Web of Science, and the Cochrane Library were searched from their inception through July 2022. All included studies were evaluated by two independent reviewers. The quality of studies was assessed by the Newcastle Ottawa Scale and the risk of bias was assessed by the ROBINS-I and RoB1 tools. Data were summarized and tabulated. Studies were grouped according to intervention type, study design, and risk of bias. The protocol of this study was registered in PROSPERO (International Prospective Register of Systematic Reviews) with ID CRD42021243678. This study was funded by the Franciscus Gasthuis and Vlietland hospital. Results A total of 120 articles were assessed for inclusion, and after screening, 16 articles were included with a total number of 3777 patients. Available evidence was scarce and generally of low to moderate quality; only two RCTs could be identified. All but one of the other studies were observational in nature. The risk of bias was serious in all but one study. Study follow-up was relatively short, varying between six and thirteen months. In six studies, ESA dosing was pharmacist-managed and in one study ESA dosing was algorithm-managed, in nine studies a combination was used. The quality of the intervention description was low to moderate and interventions generally were not reproducible. Although heterogeneity was substantial for outcome parameters, four types of outcome parameters could be determined: hemoglobin/hematocrit, ESA dose and expenditure, iron status, and iron dose. Quantitative synthesis of data was not possible due to the substantial heterogeneity in outcome parameters and the high risk of bias. Therefore, the effectiveness of algorithm-managed and pharmacist-managed dosing of ESA in renal anemia could only be qualitatively assessed for the four types of outcome parameters. In six of the fifteen studies that reported on hemoglobin or hematocrit, the percentage of patients within target levels was significantly higher for the intervention group, whereas in four studies no significant difference was found. Six of the ten studies that reported on ESA dose or ESA expenditure found a significant decrease in ESA dose or expenditure in the intervention group, whereas two studies reported no significant difference. In five of the seven studies that reported on iron status, a significantly higher iron status was found in the intervention group, whereas one non-inferiority study reported no significant difference. In three of the four studies that reported on the iron dose, no significant difference was found between the intervention and the control group, whereas in one study the iron dose was significantly higher in the intervention group. Conclusion Available evidence was scarce with a high risk of bias, and quantitative data synthesis was not possible. Therefore, no definite conclusions could be drawn on the effectiveness of algorithm-managed and pharmacist-managed dosing of ESA in renal anemia. Consequently, no recommendations on the implementation of either of the two interventions could be made.

The Switch from Ferric Gluconate to Ferric Carboxymaltose in Hemodialysis Patients Acts on Iron Metabolism, Erythropoietin, and Costs: A Retrospective Analysis.

Background and Objectives: Iron deficiency and anemia characterize patients on chronic hemodialysis (HD). Available intravenous iron agents, such as ferric gluconate (FG) and ferric carboxymaltose (FCM), vary in dosing regimens and safety profiles. The aim of the present study was to analyze the modification of the iron status, the correction of anemia, and the economic implications after the shift from FG to FCM therapy in chronic HD patients. We evaluated, during the study, the variations in iron metabolism, assessing ferritin and transferrin saturation, erythropoietin-stimulating agent (ESA) doses and the number of administrations, the effects on anemic status, and consequent costs. Materials and Methods: A retrospective study was performed with a follow-up period of 24 months, enrolling forty-two HD patients. The enrolment phase started in January 2015, when patients were treated with iv FG, and continued until December 2015, when FG was discontinued, and, after a wash-out period, the same patients were treated with FCM. Results: The iron switch reduced the administered dose of ESA by 1610.500 UI (31% of reduction; p < 0.001) during the entire study period and reduced the erythropoietin resistance index (ERI) (10.1 ± 0.4 vs. 14.8 ± 0.5; p < 0.0001). The FCM group had the highest percentage of patients who did not require ESA treatment during the study period. The FCM patients were characterized by higher levels of iron (p = 0.04), ferritin (p < 0.001), and TSAT levels (p < 0.001) compared to the FG patients. The annual cost during FG infusion was estimated at EUR 105,390.2, while one year of treatment with FCM had a total cost of EUR 84,180.7 (a difference of EUR 21,209.51 (20%), saving EUR 42.1 per patient/month (p < 0.0001). Conclusions: FCM was a more effective treatment option than FG, reducing ESA dose requirements, increasing Hb levels, and improving iron status. The reduced ESA doses and the decreased number of patients needing ESA were the main factors for reducing overall costs.

Multi-head self-attention mechanism enabled individualized hemoglobin prediction and treatment recommendation systems in anemia management for hemodialysis patients

Anemia is a critical complication in hemodialysis patients, but the response to erythropoietin-stimulating agents (ESA) treatment varies from patient to patient and is not linear across different time points. The aim of this study was to develop deep learning algorithms for individualized anemia management. We retrospectively collected 36,677 data points from 623 hemodialysis patients, including clinical data, laboratory values, hemoglobin levels, and previous ESA doses. To reduce the computational complexity associated with recurrent neural networks (RNN) in processing time-series data, we developed neural networks based on multi-head self-attention mechanisms in an efficient and effective hemoglobin prediction model. Our proposed model achieved a more accurate hemoglobin prediction than the state-of-the-art RNN model, as shown by the smaller mean absolute error (MAE) of hemoglobin (0.451 vs. 0.593 g/dL, p = 0.014). In ESA (including darbepoetin and epoetin) dose recommendation, the simulation results by our model revealed a higher rate of achieved hemoglobin targets (physician prescription vs. model: 86.3 % vs. 92.7 %, p < 0.001), a lower rate of hemoglobin levels below 10 g/dL (13.7 % vs. 7.3 %, p < 0.001) and smaller change in hemoglobin levels (0.6 g/dL vs. 0.4 g/dL, p < 0.001) in all patients. Our model holds great potential for individualized anemia management as a computerized clinical decision support system for hemodialysis patients. Further external validation with other datasets and prospective clinical utility studies are warranted.

Iron status and anemia control are related to peritoneal membrane properties in peritoneally dialyzed patients.

Characteristics of peritoneal membrane is unique and individually different in peritoneal dialysis patients. Relationship between specific nature of peritoneal transport, anemia and inflammation has not yet been extensively studied. We attempted to outline the complex interplay of several biomarkers of iron status and their association with peritoneal transport, degree of inflammation and residual renal function. A total of 58 patients treated with peritoneal dialysis either CAPD or APD for at least 3 months were enrolled in this study. Full blood count, traditional markers of iron status (transferrin saturation-TSAT and ferritin), serum erythroferrone-ERFE, soluble transferrin receptor (sTfR), hepcidin, zonulin, growth differentiation factor -15 (GDF15), IL-16, hsCRP and hypoxia-inducible factor-α (HIF-1-α; in serum and dialysate) were measured using commercially available tests. We also performed Peritoneal Equilibrium Test and assessed GFR level. Hb levels above 10 g/dL was found in 74% of patients. Hb levels positively correlated with residual renal function and nutritional status. Adequate iron status was diagnosed in 69% of subjects, only in 9% of patients, criteria for absolute iron deficiency were met. Serum ERFE correlated inversely with hepcidin levels but was not associated with erythropoietin stimulating agent dose. Peritoneal transport had strong correlation with dialysate sTfR (p < 0.05), dialysate hepcidin (p < 0.05), dialysate GDF15 (p < 0.01) and dialysate zonulin (p < 0.001) levels, as well as serum IL6 (p = 0.03), serum hs-CRP (p = 0.04) and dialysate hs-CRP (p = 0.04). Residual kidney function contributes considerably to better control of anemia. Various degree of inflammation is inherent to PD patients. Additionally, fast-average peritoneal transport is associated with greater degree of inflammation and higher concentration of markers of iron status, GDF15 and zonulin in dialysate. This finding may indicate more effective clearance of higher-range middle molecules in fast-average transporters. The role of ERFE as a marker of erythropoiesis in PD patients requires further investigation.

Gout among Patients with Dialysis: Prevalence, Associated Factors, Treatment Patterns, and Outcomes-Population-Based Retrospective Cohort Study.

Key Points Population-based retrospective cohort study to evaluate clinical correlates of gout and its impact on patients undergoing chronic dialysis.13.5% of US dialysis-dependent patients had gout and were older and male, with a higher prevalence of hypertension and cardiovascular disease.Gout diagnosis was associated with a higher incidence of cardiovascular conditions, levels of anemia, hospitalization, and mortality. Background An association between gout and nondialysis chronic renal disease has long been recognized, yet limited research exists regarding prevalence, treatment, anemia management, and outcomes in patients with ESKD undergoing dialysis. Methods Using data from United States Renal Data System, we conducted a population-based retrospective cohort study in adult patients covered by Medicare and on dialysis in 2017. Multivariate logistic regression models were used to estimate potential factors and odds of gout diagnosis. Antigout medications and impact on anemia management were assessed and compared between gout and nongout dialysis patients using descriptive and regression analyses. Associations for all-cause mortality and cardiovascular-related hospitalizations during 1 year of study follow-up were compared between gout and nongout patients using multivariate Cox regression models. Results Of 231,841 ESKD Medicare patients in 2017 undergoing continuous dialysis, 31,300 (13.5%) had one or more gout diagnostic code(s). Increased odds of having a gout diagnosis were independently associated with older age, male sex, Asian race, obesity, hypertension, and cardiovascular disease. Gout diagnosis was associated with higher prevalence for anemia as indicated by increased erythropoietin-stimulating agent requirements (odds ratio=1.18 for high versus low erythropoietin-stimulating agent dose, 95% confidence interval [95% CI], 1.14 to 1.22) and likelihood of blood transfusions (odds ratio=1.34, 95% CI, 1.30 to 1.38). During the 1-year study follow-up, mortality among gout versus nongout patients was higher by 3% (95% CI, 0 to 6) and a composite association of mortality and cardiovascular disease hospitalization was higher by 6% (95% CI, 3 to 9) after adjusting for comorbid conditions. Conclusions A gout diagnosis was found in 13.5% of US dialysis-dependent patients and was associated with a higher burden of comorbid cardiovascular conditions as well as an elevated incidence of hospitalization and mortality. These observations improve our current understanding of gout among the dialysis population and highlight the importance of new and better treatments to improve outcomes.

Erythropoietin-Resistant Therapy in Routine Hemodialysis Patients: A Case Report

Background: Anemia in chronic kidney disease can be caused by erythropoietin deficiency. Erythropoietin stimulating agent (ESA) is the treatment of choice for anemia in patients with chronic kidney disease. Some patients for some reason fail to reach target hemoglobin levels despite maximal ESA doses. Case illustration: We reported a 58-year-old man suffering from CKD with recurrent anemia despite the maximum dose of ESA. The investigations showed secondary hyperparathyroidism due to complications of chronic kidney disorders. Discussion: Our patient's resistance to erythropoietin therapy was caused by inadequate dialysis and secondary hyperparathyroidism. The management is focused on the adequacy of hemodialysis and the management of secondary hyperparathyroidism with nutrition and medication. Keywords: anemia, kidney failure, hemodialysis, hyperparathyroidism.

MO521: Paricalcitol Direct Increases Hemoglobin Levels. A Repurposing Possibility for Treating Renal Anemia

Abstract BACKGROUND AND AIMS The anti-inflammatory properties of the paricalcitol have been related to benefits in renal anemia; however, in chronic kidney disease (CKD) patients, the presence of secondary hyperparathyroidism (SHPT) represents a bias for determining the real effect of paricalcitol in hemoglobin levels. Whether the paricalcitol directly increases hemoglobin regardless of SHPT should be considered an opportunity for treating renal anemia, where the current treatments have safety concerns. To determine the effect of the oral paricalcitol on hemoglobin levels administered in different types of patients. Group A: n = 10, CKD patients not on dialysis under erythropoietin stimulating agents (ESA), Group B: n = 37, CKD patients not receiving ESA. A sub-group of patients without SHPT (Group C, n = 20) and glomerulonephritis patients without CKD (Group D, n = 18). Seven patients had hyperparathyroidism without CKD (plasma creatinine &amp;lt;1,2 mg/dL) and five CKD patients without SHPT (iPTH: 24–100 pg/mL). We also evaluated the effect of the paricalcitol according to Hb at baseline (≤10, ≤11 and ≤ 12 g/dL). METHOD A total of 52 consecutive patients were included and followed up by 6 months. Exclusion criteria were bleeding or recent blood transfusion history. No changes in ESA doses and iron supplements were required for inclusion. The mean paricalcitol dose was 6 mcg/week (min: 2–max: 7). RESULTS Age: 71(14) years, female 21(40%). As a whole, hemoglobin [mean: 95% confidence interval (CI)] increased 0.8 g/dL (0.4–1.2), partial η2: 0.24, P &amp;lt; .001. In group A: Hb increased 0.9 (0.2–1.6) g/dL, partial η2: 0.15, P = .015; in group B: 1.0 (0.4–1.5) g/dL, partial η2: 0.32, P &amp;lt; .001; in group C: 0.7 (0.2–1.2) g/dL, partial η2: 0.31, P = .008 and in group D: 0.4 (−0.02–0.9) g/dL, partial η2: 0.18, P = .06. In the seven patients only with hyperparathyroidism, Hb increased 1.3 (0.4–2.1) g/dL, partial η2: 0.67, P = .012 and in the five patients only with CKD the hemoglobin change 0.5 (−0.3–1.3) g/dL, partial η2: 0.40, P = .174. Interestingly, according to the baseline hemoglobin levels: ≤10, ≤11 and ≤ 12 g/dL, it significantly increased to 2.6, 2.3 and 1.2 g/dL, respectively. CONCLUSION The paricalcitol significantly increased the hemoglobin levels independently of ESA therapy, the renal function and the degree of hyperparathyroidism. A greater effect was observed in patients with lower baseline hemoglobin levels. Our results suggest that paricalcitol is a potential repurposing drug for treating renal anemia.

MO532: Cardiovascular Events in Patients With Non–Dialysis-Dependent Chronic Kidney Disease and Anemia: Regional Analysis of Patients Previously Treated With Erythropoiesis-Stimulating Agents in the PRO2TECT Trial

Abstract BACKGROUND AND AIMS Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor being investigated for the treatment of anemia due to chronic kidney disease (CKD). In global phase 3 trials, vadadustat has demonstrated non-inferiority to darbepoetin alfa for time to major adverse cardiovascular event (MACE) in patients with dialysis-dependent CKD (INNO2VATE trials), but not with non–dialysis-dependent CKD (NDD-CKD; PRO2TECT trials) [1, 2]. In a prespecified subgroup analysis of the PRO2TECT trials, a difference in the relative safety between vadadustat and darbepoetin alfa was observed between the US and non-US regions [1]. We investigated regional differences in MACE in patients with NDD-CKD-administered vadadustat and darbepoetin alfa who were previously treated with erythropoietin-stimulating agents (ESAs) in the PRO2TECT trials. METHOD Two phase 3, open-label, randomized, active-controlled clinical trials comparing vadadustat with darbepoetin alfa were conducted in North America, Latin America, Europe, Africa, and the Asia-Pacific region. This post hoc analysis evaluated MACE in patients in the PRO2TECT trial who were actively maintained on ESAs at study entry with ≥1 dose received within 6 weeks before or during screening (Conversion trial; NCT02680574) and who received ≥1 dose of trial drug, stratified by region (USA versus Europe versus non-US/non-Europe). MACE was defined as a composite of death from any cause, nonfatal myocardial infarction or nonfatal stroke. Expanded MACE was defined as MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access failure. RESULTS A total of 1723 ESA-treated patients were randomized in the conversion trial of the PRO2TECT program and received ≥1 dose of study drug, including 665 patients in the USA, 444 in Europe, and 614 outside the USA and Europe. Europe had a lower proportion of patients with diabetes and more patients who had received intravenous (IV) iron, while patients in the non-US/non-European region were younger and had a lower prevalence of cardiovascular (CV) disease. A higher proportion of patients in Europe were using darbepoetin alfa at baseline than in other regions (59%–63% versus 14%–28%), though ESA dose was lower (57–61 versus 93–149 IV epoetin equivalent U/kg/week). The hazard ratio for MACE in the overall population for vadadustat versus darbepoetin alfa was 1.16 (95% CI 0.93–1.45). Across regions, event rates were similar in the vadadustat groups, but event rates in the darbepoetin alfa group were lower in Europe compared with the US and non-US/non-Europe (Table 1), which was driven by fewer total deaths (non-CV and CV) reported in Europe in the darbepoetin alfa arm (n = 24/220) compared with the vadadustat arm (n = 38/224) (Table 2). Additional post hoc analyses of MACE accounting for several baseline characteristics, including ESA dose, did not alter the outcomes of the study. CONCLUSION Regional differences in time to first MACE were observed in patients with NDD-CKD who were treated with ESA and randomized to receive vadadustat or darbepoetin alfa as part of the PRO2TECT program. It remains unclear if the lower risk of MACE observed in Europe with the darbepoetin alfa group was related to differences in unobserved baseline characteristics, regional treatment practices, methodological reasons or chance.

MO540CARDIOVASCULAR OUTCOMES ASSOCIATED WITH ACHIEVED HAEMOGLOBIN LEVEL IN POOLED PHASE 3 STUDIES OF ROXADUSTAT IN NON-DIALYSIS-DEPENDENT PATIENTS WITH ANAEMIA

Abstract Background and Aims Randomised clinical trials evaluating anaemia correction using erythropoietin-stimulating agents (ESAs) in chronic kidney disease (CKD) patients have demonstrated an association between ESA use and increased risk of cardiovascular (CV) complications and mortality. Although the mechanism for this increased risk remains unclear, possibilities include rapid rates of rise (ROR) in haemoglobin (Hb), exposure to high ESA dose and dose escalation, a high Hb target range, and off-target effects of ESAs. Thus, current recommendations generally state that Hb levels should be maintained between 10 and 12 g/dL. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), is used for the treatment of anaemia of CKD; roxadustat stimulates endogenous production of erythropoietin and enhances iron availability, thereby supporting red blood cell production. In this pooled analysis, we explored the relationship between 1) achieved Hb levels and 2) preliminary data for ROR of Hb and subsequent incidence rates of CV events in non–dialysis-dependent (NDD) CKD patients who received roxadustat. Method We analysed pooled data from four phase 3 studies in NDD patients (placebo-controlled: ALPS, ANDES, OLYMPUS; ESA-controlled: DOLOMITES) with anaemia of CKD who received any dose of roxadustat. The reported events occurred during the treatment period and within 7 days of the last dose of roxadustat. Incidence rates of adjudicated major adverse CV events (MACE: all-cause mortality [ACM], myocardial infarction, and stroke), MACE+ (MACE plus heart failure and unstable angina requiring hospitalisation), and ACM were examined relative to 1) most recent Hb level before the event and 2) the preliminary data for ROR of Hb within the 4 weeks of treatment immediately prior to the event. Results Overall, 2709 patients were randomised and received roxadustat. Incidence rates of MACE, MACE+, and ACM were 3- or 4-fold higher in patients with lower reported Hb levels (Hb &amp;lt;10 g/L) compared with those who achieved Hb ≥10 g/dL. Incidence rates of MACE, MACE+, and ACM were similar or lower in patients with a maximum rise of &amp;gt;2 g/dL in Hb within the 4-week period prior to the event compared to those with a change of ≤2 g/dL within the same period (Table). However, it should be noted that patient-exposure years (PEY) were low for the subgroup of patients with ROR &amp;gt;2 g/dL (∼3.3% of overall PEY), and patients with a decreasing Hb were included in the ≤2 g/dL/4 weeks subgroup. Conclusion In this analysis of roxadustat-treated patients with NDD CKD, incidence rates of MACE, MACE+, and ACM were lower in patients who achieved target Hb levels of 10-12 g/dL compared with patients who achieved Hb &amp;lt;10 g/dL. Risk of MACE, MACE+, or ACM did not appear to be associated with the proximal preliminary data for ROR of Hb; however, further characterisation of the ROR of Hb and ROR in relation to baseline Hb are warranted.

Skeletal muscle mass is associated with erythropoietin response in hemodialysis patients

BackgroundHyporesponsiveness to erythropoietin stimulating agent (ESA) is associated with poor outcomes in patients with chronic kidney disease. Although ESA hyporesponsiveness and sarcopenia have a common pathophysiological background, clinical evidence linking them is scarce. The purpose of the study was to investigate the relationship between ESA responsiveness and skeletal muscle mass in hemodialysis patients.MethodsThis cross-sectional study analyzed 70 patients on maintenance hemodialysis who were treated with ESA. ESA responsiveness was evaluated by erythropoietin resistance index (ERI), calculated as a weekly dose of ESA divided by body weight and hemoglobin (IU/kg/week/dL), and a weekly dose of ESA/hemoglobin (IU/week/dL). A dose of ESA is equivalated to epoetin β. Correlations between ESA responsiveness and clinical parameters including skeletal muscle mass were analyzed.ResultsAmong the 70 patients, ERI was positively correlated to age (p < 0.002) and negatively correlated to height (p < 0.001), body weight (p < 0.001), BMI (p < 0.001), skeletal muscle mass (p < 0.001), transferrin saturation (TSAT) (p = 0.049), and zinc (p = 0.006). In the multiple linear regression analysis, TSAT, zinc, and skeletal muscle mass were associated with ERI and weekly ESA dose/hemoglobin.ConclusionsSkeletal muscle mass was the independent predictor for ESA responsiveness as well as TSAT and zinc. Sarcopenia is another target for the management of anemia in patients with hemodialysis.

Evaluation of the Cost of a High-Dose Intravenous Iron Protocol in a Regional Hemodialysis Program: Research Letter.

Background:Intravenous (IV) iron and erythropoietin stimulating agents (ESAs) are standard treatments for anemia in patients receiving maintenance hemodialysis. These medications are associated with significant costs to hemodialysis programs and patients. Recent trial evidence demonstrated that a high-dose IV iron protocol reduces ESA usage and improves cardiovascular outcomes. The cost of implementing a high-dose iron protocol within the Canadian public healthcare context remains unknown.Objective:Our primary aim was to estimate the costs of a high-dose IV iron protocol in a large Canadian hemodialysis program that currently uses a low-dose and reactive IV iron strategy. Our secondary aim was to estimate the reduction in ESA use required to maintain cost neutrality with a high-dose IV iron protocol.Design:In this modeling study of IV iron and ESA utilization from a regional hemodialysis program, changes in medication utilization were calculated based on observed effects from published trial data. Using data from a quality improvement audit of regional anemia management and medication utilization, we estimated potential cost differences under various modeling conditions.Setting:Four adult hospital-based and 9 community in-center hemodialysis units in the Alberta Kidney Care—South renal program during the observation period of September 1, 2018, to November 30, 2018.Patients:In total, data from 826 patients were included.Measurements:Mean monthly IV iron and ESA doses were obtained from routine audit data captured within an electronic medical record. Costs were determined from provincially negotiated medication prices.Methods:Current IV iron and erythropoietin dosages were aggregated at the hemodialysis unit level. We used the results from the PIVOTAL trial to estimate the expected increase in IV iron dose and reduction in ESA dose with a high-dose IV iron protocol. We assumed the split between various manufactures of IV iron and ESA were maintained in our cost model. Total medication costs were aggregated by hemodialysis unit, and the mean costs in each unit were used to estimate per-patient costs. Sensitivity analyses included models that assumed 100% IV iron sucrose usage, as well as models where community hemodialysis units and hospital-based hemodialysis units were examined separately. Finally, we calculated a break-even point for ESA dose reduction required to maintain cost neutrality.Results:Actual baseline IV iron and ESA dose utilization across 13 adult HD units were 118 mg/patient/month (95% confidence interval [CI]: 102-134 mg) and 20,764 IU/pt./mo. (95% CI: 18,104-23,424 IU), respectively. The mean combined cost of ESA and IV iron was $315/pt./mo. (95% CI: $274-$355). In comparison, using the results of the PIVOTAL trial and assuming a high-dose IV iron scenario, we estimated mean IV iron use of 215 mg/pt./mo. (95% CI: 187-243 mg/pt./mo.) and a reduction in mean ESA use to 15,923 IU/pt./mo. (95% CI: 13,883-17,962 IU/pt./mo.). This resulted in an estimated cost savings of $38/pt./mo. (95% CI: $33–$42/pt./mo.) and a total program savings of $370,000 per year (95% CI: $325,000-$420,000). Sensitivity analyses under various alternate conditions also showed potential cost savings. We estimated that a dose reduction of ESA of 10% would be required for cost neutrality with a high-dose IV iron protocol.Limitations:Our study is limited in its use of data from a single randomized controlled trial (RCT) to estimate cost savings rather than actualized utilization. Our models do not take into consideration anticipated reductions in transfusions and hospitalizations that could be realized from a high-dose IV iron protocol.Conclusions:Based on cost modeling, a high-dose IV iron protocol could be integrated in large Canadian regional hemodialysis program in a cost saving manner. Programs implementing such a protocol should monitor IV iron and EPO use prospectively to determine if the trial protocol as applied in a real-world setting translates into cost savings.

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

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

P1093BENEFITS OF HOME HEMODIALYSIS

Abstract Background and Aims Home hemodialysis (HOHD) has been available as a modality of renal replacement therapy since the 1960s, in our center since 1972. Despite better patients’ outcome provided by HOHD comparing to hospital hemodialysis (HHD), its adoption has been limited worldwide. The aim of this study was to compare anemia, nutrition, mineral metabolism and morbidity in patients on HOHD and HHD. Method we analyzed dialysis and uremia related complications and morbidity in 19 HOHD patients in comparison with patients on HHD (N= 57). Each HOHD patient was previously matched with three patients on HHD by sex, age and reason for end stage renal disease (ESRD). Patients on HHD were on dialysis 3x4 h per week while patients on HOHD had dialysis on consecutive days in duration of 5-6 hours. Also, patients on HOHD were more frequent on hemodiafiltration (HDF), 89.5% of them, as compared to HHD patients (only 21.4%). Results All patients on HOHD were using AVF as vascular access for HD, and most of the analyzed HHD patients (only 5.3% used AVG). As revealed by hemoglobin level (Hgb) patients on HOHD had significantly better anemia control than HHD patients (12±2.3 vs. 10.2±1g/dl, p=0.004), despite the lower ferritin level (94±117 vs. 256±175ng/ml, p=0,001) and less frequent use of erythropoietin-stimulating agents (ESA), (and only 31% on HOHD vs 80% patients on HHD, p=0,001). By analyzing patients that used ESA therapy, we revealed that HOHD patients had lower weekly dose of ESA (5333±3265 IU vs. 6068±4145 IU). The values of intact parathyroid hormone (iPTH), did not differ significantly between HOHD (311±419pg/ml ; min 5,25, max 1529) and HHD (233±212pg/ml; min 19,25, max 926), but higher percentage of patients in HOHD group underwent parathyroidectomy (63% vs. 3.5%). The average values of calcium, and phosphorus did not significantly differ between HOHD and HHD patients (2.4±0.3 vs. 2.3±0.2mmol/l; 1.5±0.5 vs. 1.6±0.5mmol/l, respectively). HOHD patients had significantly higher albumin level (43±4.5 vs. 40.6±4g/l, p=0,035). There was no difference in annual hospital admission rate (0.4±0.5 vs. 0.6±0.7, p=0.35) between groups, but HHD patients had longer in-hospital stay. (4.8±5.3 days for HOHD vs. 7.3±9.3 days for HHD; p=0.16). Vascular access complications were most frequent reason for hospitalization in both groups (37%), followed by cardiovascular complications 13.6%, in HOHD group and infectious complications in HHD group 24%. Conclusion Our study has shown that HOHD provides some advantages over HHD including better quality of life and better anemia and nutrition control, better control of parathyroid function and shorter in-hospital stay. More frequent and longer dialysis sessions may be possible reason including HDF.

Anemia management in dialysis patients: a PIVOT and a new path?

We will examine the current and future options in management of anemia in dialysis patients focusing on recent trials in iron supplementation and alternatives to erythropoietin-stimulating agents (ESAs). We review the literature on Erythropoietin (EPO)-stimulating agents, focusing on the risk benefits of various options available. We review the recent practice changing trial in iron supplementation in dialysis patients with chronic kidney disease and movements in the research on alternatives to EPO-stimulating agents primarily hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). ESAs constitute the mainstay of treatment of anemia in dialysis and evidence does not support the preference of any one type over the other. But concerns exist about the cardiovascular safety of supra-physiological ESA levels. Iron supplementation has been shown to be a well tolerated method to decrease ESA doses while maintaining hemoglobin levels and recent evidence should result in a revisiting of the guidelines for iron supplementation. HIF-PHIs are potentially safe alternatives to ESAs that correct and maintain hemoglobin while maintaining physiological levels of erythropoietin. Ongoing phase III trials for these drugs will likely answer questions of long-term safety regarding these drugs.

24‐hour Urinary Epinephrine and Interleukin‐6 are Independent Correlates of Endogenous Erythropoietin among Overweight Premenopausal Women

PurposeAfrican American (AA) women frequently exhibit lower hemoglobin (Hb) and are less responsive to erythropoietin stimulating agents (ESAs) compared to European American (EA) women. These differences have led to the practice of AA receiving higher doses of ESAs compared to EA to achieve a similar level of improvement in Hb for treatment of anemia. However, higher doses of ESAs are associated with a greater risk of mortality. To date, it remains unclear whether differences in ESA responsiveness are due to race‐related differences in endogenous erythropoietin (EPO) production or other contributing factors. The objectives of the present work were two‐fold: 1) compare EPO between a cohort of AA and EA women and 2) identify potential physiological correlates of EPO using variables linked with ESA hyporesponsiveness.MethodsSecondary analyses were performed on 36 (AA; n = 14) overweight (28.3 ± 1.4 kg/m2), premenopausal women. Measurements were conducted following a 4‐week period wherein participants were held in energy balance (i.e., weight stable &lt; 1% weekly fluctuation) via dietary control. Whole blood was collected after an overnight fast during the follicular phase of the menstrual cycle. Serum inflammatory biomarkers (interleukin‐6, tumor necrosis factor alpha) were measured in duplicate, while 24‐hour urinary fractionated catecholamines (epinephrine, norepinephrine, and dopamine) were measured with high‐performance liquid chromatography. Group allocation was based on self‐reported race. Non‐normally distributed data were log‐transformed. Between‐group comparisons were performed with independent t‐tests. Substantive differences were quantified using Hedges’ g. Following significant zero‐order correlations, a stepwise multiple linear regression was used to test the independent effects of variables on the variance in EPO.ResultsConsistent with previous work, AA had lower Hb (g·dL−1) (11.3 ± 0.7 vs. 12.6 ± 0.8 g·dL−1; p &lt; 0.001; g = 1.67) and higher EPO (mIU·mL−1) (13.3 ± 6.8 vs. 8.0 ± 2.4; p = 0.014; g = 1.12). Significant between‐group differences were also observed for dopamine (p = 0.001) and total urinary catecholamines (p = 0.003). Among AA, Hb, interleukin‐6, and urinary epinephrine were significant correlates of EPO (all p &lt; 0.05). Whereas only Hb correlated with EPO (p = 0.019) in EA. In the combined sample, regression modeling revealed Hb, interleukin‐6, and urinary epinephrine were significant correlates of EPO (R2 = 0.68; p &lt; 0.001) independent of race. Of note, interleukin‐6 and urinary epinephrine respectively accounted for 17% and 19% of the variance in EPO.ConclusionsCompared with EA, AA women had higher EPO concentrations, however; other factors including systemic adrenergic activity and inflammation may explain these differences.Support or Funding InformationThis investigation was supported by the following grants from the National Institutes of Health: R25CA47888, R01AG027084‐01, R01AG027084‐S, P30DK056336, P60DK079626, and UL1RR025777.

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

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

Effects of Erythropoietin-Stimulating Agents on Blood Pressure in Patients with Non-Dialysis CKD and Renal Anemia

Introduction: Erythropoietin-stimulating agents (ESAs) are used to treat renal anemia in patients with non-dialysis CKD, but this can lead to increases in blood pressure (BP). Objective: We investigated the effects of continuous erythropoietin receptor activator (CERA) and darbepoetin alfa (DA) on office/ambulatory BP in 36 patients with non-dialysis CKD and renal anemia who did not receive ESA treatment. Methods: Participants were randomly assigned to CERA or DA, and received ESA treatment for 24 weeks. ESA doses were adjusted to maintain hemoglobin (Hb) at 10–12 g/dL. Primary outcomes were office/ambulatory BP after 24 weeks of ESA treatment. Hb levels were within the target range at 24 weeks. Results: Office/ambulatory BP, renal function, and other parameters were not significantly different between groups. However, we could not exclude the possibility that differences may exist because our sample size was small. Therefore, we also performed analysis of all of the data that were compiled from the groups of per-protocol population. Although office/ambulatory BP profiles had not worsened after 24 weeks of ESA treatment, more than half of the patients required an increase in the antihypertensive agent dose. Conclusions: CERA and DA may have similar effects on BP profiles in patients with non-dialysis CKD and renal anemia. ESA treatment often requires increases in the doses of antihypertensive agents.

Factors associated with erythropoiesis-stimulating agent hyporesponsiveness anemia in chronic kidney disease patients.

Anemia is one of the most common problems in chronic kidney disease (CKD). Despite comprehensive investigations in several cases, definite causes of anemia frequently remain unknown. Our study aimed to analyze the factors that possibly affect anemia in CKD patients who were referred for hematology consultation. A total of 87 patients were retrospectively included in the cohort. Forty-four cases were excluded, including 30 cases with unavailable intact parathyroid hormone (iPTH) data, 11 cases with bone marrow diseases (8 Pure red cell aplasia, 3 Myelodysplastic syndrome) and 3 cases with thalassemia. In total, 43 patients were analyzed. Patients with high iPTH had a significantly lower Hemoglobin (Hb) level and required a higher dose of erythropoiesis stimulating agents (ESAs) compared with the normal iPTH group (Hb 8.29 vs 9.24 mg/dL, P=0.032 and ESAs dose of 16,352.94 vs. 12,444.44 U/week, P=0.024). Univariate, followed by stepwise multivariate analysis was performed and determined that serum phosphate (PO4) was significantly associated with lower Hb level (P=0.01 and P=0.013, respectively). In addition, Hb level was inversely correlated with iPTH and serum phosphate (PO4) level (r=-0.54, P<0.001 and r=-0.47, P=0.005; respectively). Mineral disequilibrium is an important factor associated with anemia in ESA hyporesponsive CKD. Also, hyperphosphatemia and secondary hyperparathyroidism are significantly correlated with low Hb. As a result, we strongly suggest correction of mineral disequilibrium factors prior to performing bone marrow study.

S1630 A PHASE IIA STUDY TO EVALUATE THE SAFETY, PK AND PD OF REPEATED ADMINISTRATIONS OF THE HEPCIDIN ANTAGONIST PRS‐080 IN ANEMIC CHRONIC KIDNEY DISEASE PATIENTS UNDERGOING HEMODIALYSIS

Background:Patients suffering with chronic kidney disease (CKD) commonly present with anemia. Current treatment regimens consist of iron, erythropoietin stimulating agents (ESAs), or both, but a significant number of patients remain anemic despite these therapies. Hepcidin, a liver‐derived hormone, is a central regulator of iron homeostasis, frequently elevated in CKD patients and thought to represent a root cause of the hypoferremia. Therefore, hepcidin inhibition has the potential to ameliorate functional iron deficiency anemia in CKD patients. PRS‐080 is a pegylated Anticalin® hepcidin protein antagonist that has been shown to induce dose dependent serum iron mobilization and increased transferrin saturation (TSAT) in single ascending dose phase 1 clinical studies, both in healthy male volunteers and dialysis dependent CKD patients (PLOS‐One, in press).Aims:To determine the safety and tolerability of 5 repeated intravenous administrations of PRS‐080 at doses of 4 and 8 mg/kg body weight (BW) compared to placebo, in anemic, hemodialysis dependent stage 5 CKD patients, as well as to assess pharmacokinetics, pharmacodynamics and immunogenicity.Methods:Twelve patients were enrolled. Four patients per cohort each received PRS‐080 at a dose of 4 or 8 mg/kg, with two patients per cohort receiving placebo. The study included a screening period of 4 weeks; the mean of 3 hemoglobin (Hb) values during the screening period, each obtained at least 7 days apart, was required to be ≤10.5 g/dL with a difference of ≤1.0 g/dL between the lowest and highest values. Additional inclusion criteria included Ferritin &gt; 300 ng/mL and TSAT ≤30%. The ESA dose had to remain stable for at least 4 weeks prior to screening, as well as through the treatment period, and iron therapy had to be withdrawn 1 week before randomization. Study medication was administered by infusion over 60 minutes using an infusion pump on day 0, day 7, day 14, day 21, and day 28. Patients were observed with regard to safety up until day 112. Safety was monitored continuously by a data safety monitoring board (DSMB), including prior to dose escalation.Results:There were no treatment related adverse events (AEs) or serious adverse events (SAEs). Robust iron mobilization with increases in both serum iron and TSAT were consistently observed following each weekly dose in both dose cohorts. Peak iron concentrations were higher in the 8 mg/kg cohort than in the 4 mg/kg cohort.Whereas there was no clear difference in Hb values between placebo and PRS‐080 patients in the 4 mg/kg cohort over the course of treatment, evidence of a Hb response with clear separation of Hb values between placebo and PRS‐080 could be shown in the 8 mg/kg cohort during the treatment period, consisting of an increase of Hg in drug treated patients and a decline in placebo patients, potentially related to the withdrawal of iron treatment.Summary/Conclusion:PRS‐080 was safe and well tolerated at both dose levels in this exploratory phase 2a multiple ascending dose clinical study in anemic dialysis‐dependent CKD patients. Promising results were achieved in terms of both iron mobilization and increased TSAT, as well as initial evidence of an increase in Hb levels in the higher dose group. Further studies to determine the optimal treatment regimen with PRS‐080 are warranted.

Parenteral versus oral iron therapy for adults and children with chronic kidney disease.

Background The anaemia seen in chronic kidney disease (CKD) may be exacerbated by iron deficiency. Iron can be provided through different routes, with advantages and drawbacks of each route. It remains unclear whether the potential harms and additional costs of intravenous (IV) compared with oral iron are justified. Objectives To determine the benefits and harms of IV iron supplementation compared with oral iron for anaemia in adults and children with CKD. Search methods In March 2010 we searched the Cochrane Renal Group's specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE and EMBASE without language restriction. Selection criteria We included randomised controlled trials (RCTs) and quasi-RCTs in which oral and IV routes of iron administration were compared in adults and children with CKD. Data collection and analysis Two authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes and for continuous outcomes the mean difference (MD) was used or standardised mean difference (SMD) if different scales had been used. Statistical analyses were performed using the random-effects model. Subgroup analysis and univariate meta-regression were performed to investigate between study differences. Main results Twenty eight studies (2098 participants) were included. Risk of bias attributes were poorly performed and/or reported with low risk of bias reported in 12 (43%) studies for sequence generation, incomplete outcome reporting and selective outcome reporting and in 6 (16%) studies for allocation concealment. No study was blinded for participants, investigators and outcome assessors but all were considered at low risk of bias because the primary outcome of haemoglobin was a laboratory outcome and unlikely to be influenced by lack of blinding. Haemoglobin (22 studies, 1862 patients: MD 0.90 g/dL, 95% CI 0.44 to 1.37); ferritin (24 studies, 1751 patients: MD 243.25 μg/L, 95% CI 188.74 to 297.75); and transferrin saturation (18 studies, 1457 patients: MD 10.20%, 95% CI 5.56 to 14.83) were significantly increased by IV iron compared with oral iron. There was a significant reduction in erythropoiesis-stimulating agent (ESA) dose in patients receiving dialysis who were treated with IV iron (9 studies, 487 patients: SMD -0.76, 95% CI -1.22 to -0.30). There was a high level of heterogeneity in all analyses. Mortality and cardiovascular morbidity did not differ significantly, but were reported in few studies. Gastrointestinal side effects were more common with oral iron, but hypotensive and allergic reactions were more common with IV iron. Authors' conclusions The included studies provide strong evidence for increased ferritin and transferrin saturation levels, together with a small increase in haemoglobin, in patients with CKD who were treated with IV iron compared with oral iron. From a limited body of evidence, we identified a significant reduction in ESA requirements in patients treated with IV iron, and found no significant difference in mortality. Adverse effects were reported in only 50% of included studies. We therefore suggest that further studies that focus on patient-centred outcomes are needed to determine if the use of IV iron is justified on the basis of reductions in ESA dose and cost, improvements in patient quality of life, and with few serious adverse effects.