ESA Dose Research Articles

#2654 Erythropoietin hypo-responsiveness in haemodialysis patients, contributing factors and outcome

Abstract Background and Aims Erythropoietin (ESA) resistance or hypo-responsiveness (HR) is a condition when patients do not achieve the desired haemoglobin concentration or require incremental ESA doses to maintain stable Hb concentration. Contributing factors include iron deficiency, inflammation, infection, mineral bone disease (CKD-MBD), insufficient dialysis, malnutrition, and hematologic abnormalities. This study aimed to determine the prevalence of HR in maintenance haemodialysis (HD) population and its contributing factors. The outcome in terms of all-cause mortality and need for hospitalization over 6 months follow-up was studied. Method We prospectively studied 100 maintenance HD patients above 18 years age over one and a half years. Those with a known haematological disorder, malignancy or active infection were excluded. Enrolled patients were classified into 2 groups: 1) Initial ESA Group: Initiated on ESA therapy and had Hb less than 10 gm/dl. These were also incident HD patients. Initial ESA HR for the study was defined as any Hb increase less than 0.8 gm/dl over 1 month after initiating ESA. The ESA dose and modification remained as per current existing practice in the dialysis unit. 2) Subsequent ESA Group: Already receiving ESA therapy and on HD for at least 3 months. Patients on previously stable doses of ESA who required two increments in ESA doses up to 50% beyond the previous dose to maintain Hb were taken as HR. Patients who required Epoetin or equivalent ESA dose of more than 300 IU/kg/week were also included in HR. All underwent anaemia workup at start and monthly haemoglobin estimation. They were also tested for CRP and CKD-MBD. All were followed for 6 months; hospitalization (excluding vascular access) and mortality was noted. The Charlson comorbidity index was used to ensure equitability. Results Seventeen cases were in Initial ESA group and 83 cases were in subsequent ESA group. ESA type was not associated with responsiveness in either group. In the ‘initial’ group, 8/17 were HR. Iron deficiency was noted in 75 and 33 percent of HR vs R patients (p =0.15). Median CRP in HR group was significantly higher at 10 mg/dL (7.4-20.4) as compared to R 2.8mg/dl (1.5-4), p=0.034. Distribution of other bio-chemical parameters was comparable. HR patients had more hospitalizations (62.5% vs 22.2%; p =0.153). In subsequent ESA group 10/83 (12%) cases were HR. Mean average weekly ESA dose (IU/Kg/week) in HR (286 ± 28) was significantly higher than R group (137 ± 44, p <0.0001). Median CRP (mg/dL) in HR was 20.2 (8.8-27.6) and was significantly higher than R 2.6 (1.2-5.4, p=0.0001). Median iPTH (pg/mL) in HR group was 899 (801-1053) significantly higher than R 418 (242-632; p =<0.0001). Mean serum phosphorus (mg/dL) in HR was 6.4 ± 1.7 which was significantly higher as compared to R (5.3 ± 1.6, p value=0.038). Median ALP of 366 (276-408) IU/L in HR was significantly higher than in R 126 (93-196, p=0.0007). Both groups were equitable in adequacy. Hospitalization rate was not (60 vs 30%, p=0.09) different. Mortality rate was significantly higher in HR as compared to R (40% vs 1.4%, p=0.0005). Conclusion The study revealed a substantial occurrence of ESA hypo-responsiveness in HD population. High CRP, signifying inflammation and CKD-MBD turned out to be significant contributors to development of hypo-responsiveness. ESA hypo-responsiveness is associated with higher mortality over short term.

#1174 Prevalence and factors contributing to erythropoietin hyporesponsiveness in CKD patients on hemodialysis: a single center, cross sectional study

Abstract Background and Aims Anemia, one of the most frequent early complications of CKD is associated with a reduced QOL, cardiovascular morbidity, accelerated CKD progression, and it is an independent predictor of mortality. The successful management of anemia is a vital part of patient care, that improves clinical outcomes. According to the literature, 90% of renal anemia patients responded in a dose-dependent manner to rHu EPO, whereas the remaining 5–10% of patients had either a blunted or absent response to this agent, despite high-dose therapy. Erythropoietin hyporesponsiveness is a strong, independent predictor of mortality risk. Various factors have been associated with ESA hypo responsiveness in different studies. Both the inability to achieve a target hemoglobin and administration of high dose epoetin -alpha are associated with increased risk of CVD complications. AIMS AND OBJECTIVES Method STUDY PERIOD: December 2021 to DECEMBER 2022 STUDY DESIGN: Observational cross sectional study. SAMPLE SIZE: N = 144: Patients older than 18 years old undergoing hemodialysis for at least 3 months before the study were enrolled. History of inpatient treatment, infection, bleeding or transfusion within the last month, hematologic disorders sickle cell disease, MDS and active malignancies were excluded. Required parameters were recorded on every month follow up;Demographic data, Cause of ESRD, Dialysis vintage, ESAs dose (Unit/week), type, Medications history; Dose (mg/week) of iron preparation & use of medication like ACEi, ARBs, dialysis adequacy(Kt/V), haemogram, Liver function test, Kidney function test Iron profile, Serum parathyroid hormone, Serum calcium & phosphorus, CRP, Anti EPO antibodies(if required). We used the European Best Practice Guideline (EBPG) II definition to define ESA hyporesponsiveness for our study purpose(Increase in erythropoietin dose ≥25% to maintain the same Hgb level or < 1 mg/dL gain in Hgb after 4 weeks. EHRI was calculated by dividing weekly ESA dose per kilogram of body weight (IU/Kg/W) by hemoglobin level (g/dL). Based on EHRI, patients were assigned or divided into 2 groups. Group I (EHRI<16) and Group II (EHRI ≥ 16). Patients in the Group II were labeled as erythropoietin hyporesponsive patients and they were compared with others in order to identify the impact of different factors on ESA. Results Among 144 patients, 80 were male and 64 females and 28.4% were diabetic. Mean EHRI were calculated for all patients and based on EHRI pts were divided into two study groups, Gr-I (EHRI<16) & Gr-II(EHRI ≥16). EHRI ≥16 group was considered as ESA hyporesponsive groups. The study parameters were compared between the groups and its statistical significance measured. The overall prevalence of ESA hyporesponsive in our study was 26.3%. Conclusion The overall prevalence of ESA hyporesponsive in our study was 26.3%. Iron deficiency anemia, inadequate dialysis, chronic inflammation, malnutrition, secondary hyperparathyroidism and increased dialysis vintage were the factors associated with ESA hyporesponsiveness.

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.

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

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

#6030 CARDIAC ULTRASOUND ASSESSMENT AND THE NOVEL INFLAMMATION, FIBROSIS AND CALCIFICATION BIOMARKERS IN ESKD PATIENTS ON HD THERAPY: A PILOT STUDY

Abstract Background and Aims Novel biomarkers for inflammation, fibrosis, and vascular calcification have been recently used for further assessment of cardiovascular risk. The aim of our prospective study is to assess the relation between the novel cardiovascular biomarkers and biomarkers for vascular calcification with cardiac ultrasound function/morphology alteration in high cardiovascular risk patients with end stage kidney disease (ESKD) on haemodialysis (HD) therapy. Baseline findings are discussed in this pilot paper Method The study included 58 ESKD patients [55% men, mean age of 60.3 ± 11.7 years, and median hemodialysis therapy duration of 6.2 years (1.2 -25.7)], treated with HD (3 sessions of 4 hours /week with high flux dialyzers). Personal and laboratory data have been retrieved from the patients HD files. Cardiac ultrasound assessment was performed during the second HD session of the week, after 2 hours of HD therapy. Blood samples have been taken before the same HD session in order to determine FGF 23, BMP 2, IL 1 beta, Galectin 3 and soluble ST 2 levels. All patients signed an informed consent for the study participation and the use of personal and laboratory data for scientific purposes. The study was approved by the medical ethics committee of the “Victor Babes” University of medicine and pharmacy and of the ethics committee of the HD center. Results On cardiac ultrasound assessment the patients presented aorta atheroma in 74.1%, aorta valve fibrosis in 74.1%, mitral valve fibrosis in 74.1% of the cases. Calcifications have been evidenced at aorta valve level in 58.6%, mitral valve level in 75.8% and endomyocardial level in 67.2% of the cases. Increased left ventricular mass was present in 82.7%, enlarged interventricular septum in 74.1% of the cases. Decreased left ventricle diastolic filing (Appleton pattern - E/A) was evidenced in 55,1% of the cases and decreased left ventricular ejection fraction in 37.9%. Right ventricle enlargement was detected in 24.1% of the patients. At baseline, FGF 23 was inversely corelated with HD therapy duration (p = 0.01), ESA dose (p = 0.016), and directly with galectin 3 levels (p &amp;lt; 0.05) but not with the ultrasound findings. BMP 2 levels corelated directly with serum albumin levels and inversely with left ventricle diastolic filing (E/A) (p &amp;lt; 0.05). IL1 levels were inversely corelated with iPTH (p = 0.046), calcium (p = 0.046 and phosphate (p = 0.030) levels but not ultrasound findings, Galectin 3 inversely corelated with cu Hb (p = 0.002), Urea (p = 0.036) and K levels (p = 0.001) and directly with bicarbonate (p = 0.035), FGF 23 (p &amp;lt; 0.05) and CRP levels (p&amp;lt;0.0001), ST2 inversely corelated with ESA dose (p = 0.009) and decreased left ventricle diastolic filing (E/A) (p &amp;lt; 0.05). At one year follow-up 12% of the patients died and mortality was significantly influenced by inter ventricle sept and right ventricle enlargement. Conclusion At baseline, though the investigated ESKD patients on HD therapy presented extensive cardiac valve fibrosis and heart valve and endomyocardial calcifications the investigated biomarker changes were not significantly supporting the ultrasound findings. One- and two-years follow-up results may reveal the utility of biomarker assessment for cardiovascular outcomes in HD treated ESKD patients.

Predictors of iron versus erythropoietin responsiveness in anemic hemodialysis patients.

Anemia protocols for hemodialysis patients usually titrate erythropoietin (ESA) according to hemoglobin and iron according to a threshold of ferritin, with variable response seen. A universally optimum threshold for ferritin may be incorrect, and another view is that ESA and iron are alternative anemia treatments, which should be selected based on the likely response to each. Hemodialysis patients developing moderate anemia were randomised to treatment with either an increase in ESA or a course of intravenous iron. Over 2423 patient-months in 197 patients, there were 133 anemia episodes with randomized treatment. Treatment failure was seen in 20/66 patients treated with ESA and 20/67 patients treated with iron (30.3 vs. 29.9%, p=1.0). Successful ESA treatment was associated with lower C-reactive protein (13.5 vs. 28.6 mg/L, p=0.038) and lower previous ESA dose (6621 vs. 9273 μg/week, p=0.097). Successful iron treatment was associated with lower reticulocyte hemoglobin (33.8 vs. 35.5 pg, p=0.047), lower hepcidin (91.4 vs. 131.0 μg/ml, p=0.021), and higher C-reactive protein (29.5 vs. 12.6 mg/L, p=0.085). A four-variable iron preference score was developed to indicate the more favorable treatment, which in a retrospective analysis reduced treatment failure to 17%. Increased ESA and iron are equally effective, though treatment failure occurs in almost 30%. Baseline variables including hepcidin can predict treatment response, and a four-variable score shows promise in allowing directed treatment with improved response rates.

MO801: Use of the Anemia Control Model is Associated With Improved Hemoglobin Target Achievement, as Well as Lower Rates of Inappropriate ESA USE And Severe Anemia Among Dialysis Patients

Abstract BACKGROUND AND AIMS Renal anemia management remains challenging for the nephrologist. Chronic inflammation, EPO resistance, uremia, malnutrition, iron deficiency, dialysis modalities, bleeding, infections, hydration status all interfere with erythropoiesis and erythrocytes half-life. Since 2013, &amp;gt;100 clinics in the FMC Nephrocare network have been using the Anemia Control Model (ACM), an artificial-intelligence based, certified medical device, decision support tool, to assist nephrologists in optimizing the monthly ESA and iron dose based on the specific characteristics of the patient and the amount of ESA dose already taken in the last 90 days. Based on this widespread experience, we sought to evaluate the real-world effectiveness of the use of ACM to facilitate hemoglobin target achievement among dialysis patients. METHOD In this historical cohort study, we analyzed electronic health records (EHR) of adult patients receiving in-center hemodialysis therapy in Fresenius Medical Care European dialysis clinics between 1 January 2015 and 31 December 2018 registered in the European Clinical Database (EuCliD®). We compared the rate of target achievement between patients treated with the ESA dose, suggested by ACM, against three control groups of patients treated in clinics without ACM and stratified by different target achievement rates for hemoglobin (Hb in the range of 10–12 g/dL or &amp;gt; 12 g/dL without ESA administration) (Fig. 1). To decrease indication bias, we matched patients belonging to the four comparison groups by a propensity-score assessing the likelihood of receiving the same dose suggested by ACM based on patients’ characteristics (i.e. demographic, comorbidities, anemia-related biomarkers and dialysis vintage). Centers where Hb target achievement &amp;lt; 70% were classified as Tier 1 centers; centers where Hb target achievement was between 70% and 80% were classified as Tier 2 centers, and centers where Hb target achievement was &amp;gt;80% were classified as Tier 3 centers. Performance was evaluated in the month before the index date for all the patients in any given clinic. For each matched group, the index date corresponds to the date of dose suggestion (ACM group) or to the last Hb assessment date (for all matched patients belonging to other three control groups). The study endpoints were Hb target achievement, inappropriate ESA administration (ESA administration despite Hb &amp;gt; 12 g/dL) and severe anemia (Hb &amp;lt; 9 g/dL). All endpoints have been evaluated in the month following the index date. RESULTS After matching, we obtained four groups accounting for 8 5512 patient-months each. There were negligible differences in patients’ characteristics across the four matched groups (Table 1). In the ACM group, the Hb target achievement rate was 87.52/100 patient-months 95% confidence interval (95% CI): 86.89–88.15], inappropriate ESA use rate was 4.13/100 patient-months (95% CI: 3.99–4.27) and the incidence of severe anemia was 2.14/100 patient-months (95% CI: 2.04–2.24); the Hb target achievement rate ratio (95% CI) was 1.18 (1.17–1.2), 1.08 (1.07–1.09), 1.01 (1–1.02) for ACM versus Tier 1 centers, ACM versus Tier 2 centers and ACM versus Tier 3 centers, respectively. Rate ratio for inappropriate ESA administration were 0.37 (0.36–0.39), 0.49 (0.47–0.51), 0.66 (0.64–0.69) for ACM versus Tier 1 centers, ACM versus Tier 2 centers and ACM versus Tier 3 centers, respectively. The risk ratios for severe anemia were 0.43 (0.41–0.46), 0.65 (0.62–0.7), 0.95 (0.89–1.02) for ACM versus Tier 1 centers, ACM versus Tier 2 centers and ACM versus Tier 3 centers, respectively. CONCLUSION In this matched historical cohort study, we observed an increased hemoglobin target achievement rate, decreased inappropriate ESA usage and a decreased incidence of severe anemia among patients treated according to ACM suggestions. Target achievement rate among patients treated according to ACM suggestions was 87%. The magnitude of the effect in favor of ACM was larger in centers with a lower target achievement rate.

Use of erythropoiesis-stimulating agents in children with chronic kidney disease: a systematic review.

ABSTRACTBackgroundErythropoiesis-stimulating agents (ESAs) revolutionized the management of anaemia in chronic kidney disease (CKD) when introduced in the late 1980s. A range of ESA types, preparations and administration modalities now exist, with newer agents requiring less frequent administration. Although systematic reviews and meta-analyses have been published in adults, no systematic review has been conducted investigating ESAs in children.MethodsThe Preferred Reporting Items for Systematic Reviews and Meta-analyses statement for the conduct of systematic reviews was used. All available literature on outcomes relating to ESAs in children with CKD was sought. A search of the MEDLINE, CINAHL and Embase databases was conducted by two independent reviewers. Inclusion criteria were published trials in English, children with chronic and end-stage kidney disease and use of any ESA studied against any outcome measure. An assessment of risk of bias was carried out in all included randomized trials using the criteria from the Cochrane Handbook for Systematic Reviews of Interventions. Two tables were used for data extraction for randomized and observational studies. Study type, participants, inclusion criteria, case characteristics, follow-up duration, ESA type and dosage, interventions and outcomes were extracted by one author.ResultsOf 965 identified articles, 58 were included covering 54 cohorts. Six were randomized trials and 48 were observational studies. A total of 38 studies assessed the efficacy of recombinant human erythropoietin (rHuEPO), 11 of darbepoetin alpha (DA) and 3 of continuous erythropoietin receptor activator (CERA), with 6 studies appraising secondary outcome measures exclusively. Recruitment to studies was a consistent challenge. The most common adverse effect was hypertension, although confounding effects often limited direct correlation. Two large cohort studies demonstrated a greater hazard of death independently associated with high ESA dose. Secondary outcome measures included quality of life measures, growth and nutrition, exercise capacity, injection site pain, cardiovascular function, intelligent quotient, evoked potentials and platelet function.ConclusionsAll ESA preparations and modes of administration were efficacious, with evidence of harm at higher doses. Evidence supports individualizing treatments, with strong consideration given to alternate treatments in patients who appear resistant to ESA therapy. Further research should focus on randomized trials comparing the efficacy of different preparations, treatment options in apparently ESA-resistant cohorts and clarification of meaningful secondary outcomes to consolidate patient-relevant indices.

MO556TREATMENT OF ANAEMIA WITH ERYTHROPOIESIS STIMULATION AGENTS (ESAS) AND CONCOMITANT THERAPIES AMONG PATIENTS WITH NON-DIALYSIS DEPENDENT CHRONIC KIDNEY DISEASE (NDD-CKD) IN GERMANY, SPAIN AND THE UK: A RETROSPECTIVE CHART REVIEW

Abstract Background and Aims Among patients with CKD, prevalence of anaemia increases with CKD severity,1 and is accompanied by elevated risk of hospitalisation and mortality.2 Treatment options include iron therapy and ESAs; international guidelines recommend initiating ESA therapy when haemoglobin (Hb) declines &amp;lt;10 g/dL, and to monitor Hb and iron status every 3 months during ESA treatment.3 This study aimed to describe the routine clinical management of patients with NDD-CKD and anaemia following ESA initiation, in Germany, Spain and the UK. Method This was a non-interventional, retrospective cohort study of adults with NDD-CKD stages 3b–5 (as defined in KDIGO 2012 guidelines)1 diagnosed with anaemia (Hb &amp;lt;13.0 g/dL [males] or &amp;lt;12.0 g/dL [females]), who began ESA treatment 01 Jan 2015–31 Dec 2015 inclusive. Data for ≤24 months after ESA initiation were extracted from medical records: patient characteristics; anaemia diagnosis and treatment (including iron and ESA use); Hb, serum ferritin and transferrin saturation (TSAT) measurements; and CKD-related outcomes. Patients were excluded if they had been diagnosed with end-stage kidney disease at baseline, or previously received a kidney transplant or dialysis. Results In total, 848 patient records (Germany, 211; Spain, 430; UK, 207) were included. Average age was 66 years (Table). Most patients were white and almost half had &amp;gt;2 comorbidities. Prior to ESA initiation, at least half of all patients in each country received either oral or intravenous (IV) iron therapy. The average (mean ± SD) number of months between anaemia diagnosis and initiation of ESA therapy was 8.4 ± 19.2. Hb levels were recorded at ESA initiation for almost all (91.3%) patients and averaged 9.8 ± 1.0 g/dL for the total cohort; this initial Hb level was similar between countries (Table). Mean ± SD estimated glomerular filtration rate (eGFR) at ESA initiation was 28.0 ± 10.4 ml/min/1.73m2. Across countries, 72–88% of patients received ESAs at home. The mean ± SD duration of therapy (at the time of data collection) was 41.2 ± 18.2 months, and the median weekly dose of short-acting and long-acting ESAs was 3238 IU and 20 μg, respectively. During their initial course of therapy, three-quarters of patients had either an increase or decrease in ESA dose. Less than 10% of patients switched ESAs, while approximately one-third discontinued within 2 years of initiation. At 3 and 6 months post-ESA initiation, only 64.7% of the sample had a documented Hb measurement despite continuing ESA treatment; this proportion was further reduced to 60.0% by 12 months after initiation. The Hb target was maintained by 88.7%, 74.6% and 49.4% of patients at 3, 6 and 12 months, respectively. Mean ferritin levels were 167.3 ng/mL at initiation and 198.7 ng/mL at 12 months (among the 85% and 48% of the sample, respectively, with recorded data). Mean TSAT was 22.1% at initiation and 25.6% at 12 months (among the 67% and 38%, respectively, with recorded data). Approximately three-quarters of patients (77.3%) received iron therapy concomitantly with ESA treatment; in the UK, most of these received IV iron, while in Germany and Spain, a majority received oral iron (Table). Blood transfusions were more common in Spain (24.2%) than in Germany (5.1%) or the UK (8.4%). Approximately one-fifth of patients required dialysis. Conclusion Initiation of ESAs to treat anaemia among patients with NDD-CKD in Germany, Spain and the UK follows current guidelines. However, recommendations to regularly monitor Hb were not routinely followed or were poorly documented. As most patients with NDD-CKD anaemia were treated at home, oral therapies may be of benefit to these patients

FC 075POST-MORTEM HEPATIC AND BONE MARROW IRON CONTENT IN HEMODIALYSIS PATIENTS: A PROSPECTIVE COHORT STUDY

Abstract Background and Aims Studies using T2 MRI liver scans among Hemodialysis (HD) patients raised concern about the presence of iron overload in this population, regularly treated with intravenous (IV) iron. Histological evidence of tissue iron overload is scarce, since the majority of studies were performed in pre-erythropoiesis- stimulating agents (ESA’s) era, when blood transfusions were common. Primary objective: to quantify iron in the liver and bone marrow by biochemical and histological analysis, in adult CKD stage 5-HD. Secondary objectives: To explore association of clinical, laboratorial parameters, IV iron therapy and iron stores. Method After approval of local Ethical committee and informed consent from families, liver biopsy and bone marrow aspirate were obtained in the first 24h post-mortem from 21 chronic HD patients with anemia or under anemia treatment who died in Hospital Fernando Fonseca. Exclusion criteria: blood transfusion in the previous 2 weeks, acute or chronic liver disease, HIV infection, known hematologic or oncologic disease. Clinical, laboratorial and anemia therapy data were retrieved from hospital registry and outpatient HD centers. Biochemical liver iron content (LIC) was quantified by atomic absorption spectrophotometry. Histological semi-quantitative grading of iron storage was made in the liver and bone marrow using Scheuer’s and Gale’s criteria of grading Perls’ stain, respectively. Results Of 21 patients included, 10 (47,6%) were male, median (IQR) age 76.0 (67.5-85.5) years old, 18 (85.7%) white, 3 (14.3%) black, dialysis vintage was 47.0 (12.5-104.0) months. Charlson Comorbidity index was 10.0 (7.5-11.0), 7 (33%) patients had diabetes, and 11 (52.4%) used an arteriovenous fistula as vascular access. The cause of death was infection (n=9, 42.9%), cardiovascular (N=6, 28.6%), HD withdrawal (n=2, 9.5%) and unknown =3 (14.3%). Median (IQR) hemoglobin was 9.8 (8.5-11.4) g/dl and 11 (52.3%) patients had hemoglobin &amp;lt;10 g/dl. Ferritin was 494.0 (136.0-850.5) ng/ml and TSAT 19.9 % (13.3-26.0). 19 (90.5%) patients were receiving IV iron therapy. Median (IQR) IV iron administered in the previous 6 and 12 months before death was 800 (300-1250) mg and 1500 (650-2175) mg, respectively. All patients were on ESA therapy, median (IQR) dose 5000 (3000-9000) UI/week and erythropoietin resistance index was 9.6 (4.2-16.6). Median (IQR) liver iron content determined by atomic absorption was 42.5 (22.9-69.7) µmol/g. 9 patients (42.9%) had normal LIC (&amp;lt;36 μmol/g), while the remainder had mild to moderate overload. Median (IQR) Scheuer grade was 2 (1-3) and 13 (62%) of liver biopsies had increased (Scheuer grade &amp;gt; 1) iron deposition at histology. Median (IQR) grade of Perls staining in the bone marrow was 3 (3-4) and 9 (45%) had increased (Gale’s grade &amp;gt;3) iron content in the bone marrow. Iron semi-quantitative scores in liver and bone marrow had strong positive correlation (r=0.71, p&amp;lt;0.001). There was a strong positive correlation between LIC and ferritin (r=0.86, p &amp;lt; 0.001) and also TSAT (r=0.56, n=16, p=0.02). Hemoglobin was negatively associated with LIC (r= -0.46, p=0.04), and with iron content in the bone marrow (p=0.04). LIC did not associate with ESA dose, C-reactive protein, dialysis vintage or other clinical parameters. There was no statistically significant association between the dose of IV iron administered in the previous 6 and 12 months with LIC, ferritin,TSAT or iron scores in bone marrow and liver. Conclusion In these HD patients, there was biochemical and histological evidence of iron accumulation in liver and bone marrow. Ferritin and TSAT showed strong correlation with iron deposits, but none was found with the dose of IV iron administered. In this study, anemia severity was associated with higher degree of iron storage both in the liver and bone marrow, suggesting a multilevel blocking mechanism of iron’s utilization.

MO672HIGH FLUX VERSUS LOW FLUX HEMODIALYSIS: A PRE-POST STUDY

Abstract Background and Aims High flux hemodialysis has largely replaced low flux hemodialysis in developed countries. Clinical trials, in particular the Hemo and the MPO studies, conducted many years ago, showed that the survival benefit was mainly for patients on long term hemodialysis for the first one and for high risk patients with low albumin level (less than 40g/dl) for the latter. Moreover, the effect on hematopoiesis or mineral balance is not unequivocally established in the literature. In Lebanon, following the recommendations of the ministry of health, we switched patients undergoing hemodialysis at our center from low to high flux starting April 2019. We aimed in this study to assess the effect of this switch on hemoglobin level, dose of ESA used, mineral metabolism parameters and nutritional parameters. Method This is an observational pre-post study where each patient is his own control. Subjects included are adults on chronic hemodialysis for more than 6 months at Hotel Dieu de France University Hospital. Patients who needed transfusion for bleeding, admission to the hospital or parathyroidectomy during the study period were excluded from the study. Demographic parameters, medical history and laboratory values were extracted from the patients’ files. Paired t- test was used to compare values obtained in the 6 months on low flux compared to the 6 months on high flux hemodialysis. Results Seventy four patients received sequentially both techniques (45 males and 29 females). Mean age was 66 years, mean dialysis vintage 65 months, diabetic and vascular diseases were the most frequent causes of ESRD found in 27 and 15% of the cases. Hemoglobin level significantly increased from 11 +/- 0.82 to 11.26 +/- 0.67 mg/dl (p=0.04) with a non-significant trend towards a lower ESA dose: 11620 UI/week (+/-2275 UI) in the first period versus 10860 UI/week (+/-2609 UI) during the second period (p=0.15). Ferritin levels were higher in the second part of the study (416 v/s 476 ng/ml) which may have contributed to the increase in hemoglobin. Phosphorus level decreased from 1.55 to 1.48 mmol/l (p=0.008) at the same doses of binders and practically stable levels of calcium and PTH. Most interestingly, albumin level increased from 38 to 40.3 g/dl (p&amp;lt;0.001). Finally urea reduction ratio increased from 73.1% to 74.5% with a p value of 0.001. Conclusion Assuring quality ultrapure water is still a challenge in many developing countries. Lack of firm evidence on beneficial effect in terms of mortality may delay sanitary authorities from imposing high flux hemodialysis. In our study, switching from low to high flux hemodialysis showed positive impact on phosphorus levels but most interestingly increased albumin levels a major predictor of mortality in hemodialysis patients.

Association of erythropoietin resistance and fibroblast growth factor 23 in dialysis patients: Results from the Japanese Dialysis Outcomes and Practice Patterns Study.

BackgroundFibroblast growth factor 23 (FGF23) plays an important role in chronic kidney disease (CKD)‐related mineral and bone disorders. High FGF23 levels are associated with increased risk of anaemia in non‐haemodialysis CKD patients. FGF23 also negatively regulates erythropoiesis in mice. We hypothesized that higher FGF23 levels are associated with increased erythropoietin hyporesponsiveness among haemodialysis patients.MethodsThe study included 1044 patients from the Japanese Dialysis Outcomes and Practice Patterns Study (J‐DOPPS) phase 5 (2012‐2015). The outcome was erythropoiesis‐stimulating agent hyporesponsiveness (ESA‐hypo), defined as mean Hgb <10 g/dL and standardized mean ESA dose >6000 u/week over 4 months following FGF23 measurement. The association between ESA‐hypo and FGF23 was estimated using multivariable‐adjusted logistic generalized estimating equation regression models.ResultsPatients with higher levels of FGF23 were younger and had higher levels of serum albumin, creatinine, albumin‐corrected calcium, phosphorus, PTH, 25(OH)‐vitamin D, and had higher percentages of intravenous (IV) iron, IV vitamin D and cinacalcet use. ESA‐hypo was present in 144 patients (13.8%). Compared with the third quintile of FGF23 levels, the odds ratio (95% CI) of ESA‐hypo was 2.14 (0.99, 4.62) and 1.74 (0.74, 4.11) for the first and fifth quintiles, respectively.ConclusionThe lowest and highest levels of FGF23 were associated with higher odds of ESA‐hypo in patients on maintenance haemodialysis, although the associations were not statistically significant. The relationship between FGF23 and anaemia, and particularly the increased risks of ESA‐hypo at low FGF23 levels which might be the result of energy saving, must be confirmed in larger clinical studies.

P1381SWITCHING FROM IRON GLUCONATE TO FERRIC CARBOXYMALTOSE CAN BE ASSOCIATED WITH A BETTER CONTROL OF IRON STATUS AND ANEMIA IN HEMODIALYSIS PATIENTS?

Abstract Background and Aims Before evaluating any ESA treatment, International guidelines (NICE-2015, KDIGO-2012, ERBP–2013) suggest to administer iron first to patients with iron deficiency anemia and not still on ESA therapy. Moreover anemic CKD patients treated with ESA should be iron supplemented (unless ferritin is&amp;gt; 800 mcg/l) to maximize the benefits of ESAs. A recent retrospective study of switching iron sucrose to ferric carboxymaltose (FCM), conducted by Hofman et al., showed a better control of iron status in hemodialysis (HD) patients. New generation drugs, like carboxymaltose, may change the iron administration methods on dialysis, due to their different properties: therefore more experience is needed. In the following evaluation we report the results of switching from iron gluconate (our previous standard therapy) to FCM in HD patients. Primary Endpoint switching effects on iron parameters (TSAT, ferritin) and hemoglobin. Secondary Endpoints switching effects on iron and ESA doses administered Method Study design: retrospective review of data from 106 HD patients from 2 Italian different dialysis centers, who were switched from iron gluconate to ferric carboxymaltose in a 1: 1 ratio. Study duration: 9 months (3 months pre-switch, 6 months post-switch) Treatment schedule: -ferritin &amp;lt;100 ng/ml and/or TSAT &amp;lt;20%: 100 mg of iron/weekly -ferritin &amp;lt;200 μg/l, or TSAT&amp;lt;20%: 100 mg of iron/weekly -ferritin 200–500 μg/l, and/or TSAT 20–30%: 100 mg of iron/every 2 weeks -ferritin 500–800 μg/l and/or TSAT 30–50%: 100 mg of iron/monthly -ferritin&amp;gt; 800 μg/l and/or TSAT&amp;gt;50%: no iron. Hb, TSAT, Ferritin and PCR evaluation every 4 weeks. Results after switching from iron gluconate to FCM, Hb levels were stable or improved, reaching a significantly higher percentage of target patients (from 60% to 80% with Hb &amp;gt; 10,5 g/l). The switch was also associated with a significant improvement of iron status, unrelated to iron dose: the percentage of patients with a target TSAT (TSAT &amp;gt;=20%) has doubled after six months, moving from 30% to 70%, while the average consumption trend of FCM decreasing over time (-48% after six months). It was also shown a marked reduction in ESA consumption: the ESA dose was decreased on average by -1907 IU per patient/month. Conclusion The switch from iron gluconate to FCM is associated with a better control of iron status and iron anemia in CKD patients on hemodialysis. The treatment schedule proposed has guaranteed to reach the primary and secondary endpoints, underlining the importance and the effectiveness of a tailored therapeutic protocol.

P0673INVERSE ASSOCIATION OF TRANSFERRIN SATURATION WITH MORTALITY RISK IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims Transferrin saturation (TSAT) is an indicator of iron deficiency or overload, but its relationship with mortality in patients with different stages of chronic kidney disease (CKD) is unclear. We investigated the association of TSAT with mortality in CKD patients. Method In 479 CKD patients (97 CKD3-4 patients, 298 CKD5 non-dialysis patients and 84 peritoneal dialysis patients; median age 58 years, 67% males, 33% cardiovascular disease, CVD, and 29% diabetes), biomarkers of iron status (plasma iron, TSAT, transferrin and ferritin), systemic inflammation (high sensitivity C-reactive protein, hsCRP, and interleukin-6, IL-6) and nutritional status were assessed. During median follow-up of 35.6 months, 139 (29%) patients died, and 176 (37%) patients underwent renal transplantation. Patients were stratified into low (n=157) and high (n=322) TSAT tertile groups. All-cause and CVD mortality risk were analyzed with competing risk regression with renal transplantation as competing risk. Results TSAT [median 23% (IQR 17-30%)] was negatively associated with presence of DM and CVD, body mass index, hsCRP, IL-6, Framingham´s CVD risk score (FRS), erythropoietin resistance index (ERI) and iron supplementation, and positively associated with hemoglobin, ferritin and s-albumin. In competing risk analysis, low tertile of TSAT was independently associated with increased all-cause mortality risk (sHR=1.50, 95%CI 1.05-2.14) after adjusting for CKD stages, 1-SD of FRS, 1-SD of hemoglobin, 1-SD of hsCRP, 1-SD of ESA dose and iron supplementation (Figure 1). Conclusion TSAT was inversely associated with mortality risk in CKD patients. When evaluating clinical outcomes of CKD patients, iron status using TSAT as a predictive marker, should be considered.

SUN-291 PREDICTIVE FACTORS OF ESA HYPORESPONSIVENESS IN PRE-DIALYSIS CKD PATIENTS: SECONDARY ANALYSIS OF THE RADIANCE-CKD STUDY

Erythropoiesis-Stimulating Agents [ESA] hyporesponsiveness is related to poor renal outcome in management of renal anemia; however, it is difficult to predict which patients will be hyporesponsive. We previously reported on the RADIANCE-CKD study, a multicenter, open-label, randomized controlled study to evaluate renal outcome by different target hemoglobin [Hb] levels using epoetin beta pegol [CERA] in pre-dialysis CKD patients with poor response to ESA (ASN 2018). The aim of the present study was to predict the patients with ESA hyporesponsiveness among pre-dialysis CKD patients. Pre-dialysis CKD patients (362 patients) with poor response to ESA were randomly assigned to an intensive treatment group (I-group; target Hb level of ≥11 g/dl) or a conservative treatment group (C-group; target Hb level of baseline Hb ±1g/dl). The primary renal composite endpoint was a transition to renal replacement therapy, reduction of eGFR to <6 ml/min/1.73 m2, or >30% reduction of eGFR. In the 3-month landmark analysis, the incidence of renal outcome was evaluated in 3 categories of Hb levels (<10, 10 to <11, ≥11 g/dl) according to tertiles of ESA dose. ESA hyporesponsiveness patients (HYPO) were defined as achieved Hb level <11 g/dl with high tertile and achieved Hb level <10 g/dl with mid-tertile in I-group. The predictive factors of hyporesponsiveness patients were then assessed using a logistic regression model and estimated area under the receiver operating characteristic (ROC) curve. Mean age was 74.7 years and 58.6% of patients were male. Mean baseline eGFR in I-group and C-group were 15.3 and 15.9 ml/min/1.73 m2, respectively. Kaplan-Meier analysis and Cox proportional hazards analysis showed no significant difference in the primary end point between the two groups (99 and 109 events) during the 21-month observation period. In the 3-month landmark analysis, achieved Hb level and required ESA dose were higher in I-group. The incidence of the renal composite endpoint had a tendency to increase in accordance with decrease of Hb levels regardless of the ESA dose in both groups. A total of 30 (54.5%) HYPO patients had the renal composite endpoint, as compared with 54 (50.9%) non-HYPO. Based on the logistic regression analysis, 19 background characteristics (age, BW, eGFR, Alb, ferritin, Hb, CRP, etc.) and 14 biomarkers (IL-6, Hepcidin, TGFβ, CD147, PTH, 25Vitamin-D, etc.) were evaluated as predictive factors of HYPO. The obtained area under the ROC curve (AUC) was 0.88, with sensitivity of 84% and specificity of 84%. Using a branch-and-bound algorithm to find the highest likelihood score statistic for 6 variables, the selected variables were age, Hb, Hepcidin, TGFβ, CD147, and PTH; then, the estimated AUC was 0.82. The patients with ESA hyporesponsiveness among Japanese CKD patients can be predicted based on clinical characteristics and biomarkers in pre-dialysis.

Switching iron sucrose to ferric carboxymaltose associates to better control of iron status in hemodialysis patients

BackgroundAlthough the efficacy of iron sucrose (IS) and ferric carboxymaltose (FCM) in treating anemia in hemodialysis (HD) patients has been studied individually, a comparison of these two intravenous iron formulations has not yet been performed in HD patients.MethodsWe performed a retrospective audit on records of 221 stable HD patients from different HD centers in the Netherlands, who were switched from IS to FCM on a 1:1 ratio. To assess the effect of the switch on iron status parameters, data from 3 time points before and 3 time points after the switch were analyzed using linear mixed effects models. Subanalyses were done in 2 subgroups of patients anemic or iron deficient at baseline.ResultsHemoglobin increased in all groups (anemic [1.4 g/dL, P < 0.001] iron deficient [0.6 g/dL, P < 0.001]), while the weekly iron dose was significantly lower when patients received FCM compared to IS (48 vs 55 mg/week, P = 0.04). Furthermore, serum ferritin and transferrin saturation increased in all groups (anemic [64 μg/L, 5.0%, P < 0.001] iron deficient [76 μg/L, 3.6%, P < 0.001]). Finally, the darbepoetin α dose decreased significantly in all groups (anemic [− 16 μg/wk., P = 0.01] iron deficient [− 11 μg/wk., P < 0.001]).ConclusionsIn this real-life study in HD patients, a switch from IS to FCM resulted in an improvement of iron status parameters despite a lower weekly dose of FCM. Furthermore, the ESA dose was reduced during FCM, while hemoglobin levels increased.

Using dynamic treatment regimes to understand erythropoietin-stimulating agent hyporesponsiveness.

Erythropoietin-stimulating agent hyporesponsiveness (ESAH) is associated with increased cardiovascular mortality in patients with end-stage renal disease (ESRD) on hemodialysis. Dynamic treatment regimes (DTR), a clinical decision support (CDS) tool that guides the prescription of specific therapies in response to variations in patient states, have been used to guide treatment for chronic illnessesthat require frequent monitoring and therapy changes. Our objective is to explore the role of utilizing a DTR to reduce ESAH in pediatric hemodialysis patients. Retrospective analysis of ESRD patients on hemodialysis who received ESAs. Dosing was adjusted using a locally developed protocol designed to target a hemoglobin between 10 and 12g/dl. Analyzing this protocol as a DTR, we assessed adherence to the protocol over time measuring how the hyporesponse index (ESA dose/hemoglobin value) changed due to varying levels of adherence. Eighteen patients met study criteria. Median hemoglobin was 11.4g/dl (range 6.1-15.4), and median weekly ESA dose (darbepoetin-equivalent) was 0.4mcg/kg/dose (range 0-2.1). Full adherence to the DTR was identified in 266 (71%) of the 4-week periods, with a median average adherence score of 0.80 (range 0.63-0.91). As adherence to the DTR improved, ESAH decreased. During the last 12weeks, 13 out of 18 patients had lower average ESA/hemoglobin ratio than the first 12weeks. A DTR appears to be well-suited to the treatment of anemia in ESRD and reduces ESAH. Our work shows the potential of DTRs to drive the development and evaluation of clinical practice guidelines.

Efficacy and safety of low-dose heparin in hemodialysis.

The dose of unfractionated heparin (UFH) administered during hemodialysis (HD) varies widely. This prospective study evaluated the safety and efficacy of UFH dose de-escalation. Sixty-six prevalent patients on HD receiving UFH per standard-dose protocol (load dose [LD] 50-75 units/kg, maintenance dose [MD] 500-1000 units/hour) had heparin prescription converted to low-dose protocol (start LD 15 units/kg and MD 500 units/hour; dose adjusted in small increments based on assessments of extracorporeal blood circuit). Coagulation parameters, dialysis adequacy, dialyzer clotting, anemia management, and dialyzer reuse rates were compared based on the heparin protocol. Mean(SD) UFH dose per HD session, before and after protocol conversion, was 6178(2644) and 2913(1116) units, respectively (P < 0.0001). This corresponded to LD 52.1(16.6) units/kg and MD 615(207) units/hour with standard-dose protocol, and LD 18.3(6.5) units/kg and MD 505(27) units/hour with low-dose protocol (P < 0.0001). Mid and postdialysis aPTT was 55.3(31.2) and 35.1(7.8) seconds before, and 37.3(12.9) and 31.5(5.3) seconds after conversion (P = 0.007 and 0.003, respectively); no significant changes in D-dimer levels occurred. Low-dose UFH was associated with a small increase in URR and spKt/V (73.0 and 1.54) compared with dialysis clearance on standard-dose UFH (71.2 and 1.48, respectively, P = 0.02). Weekly dose of ESA decreased by 2388 units postconversion (P = 0.03), while hemoglobin levels and the weekly dose of intravenous iron did not change (P = 0.16 and 0.78). A small rise in the rate of moderate dialyzer clotting at the end of HD was noted with low-dose UFH (5.7% vs. 7.5%, P = 0.002); the rate of severe dialyzer clotting events did not change (P = 0.91). No change in the dialyzer reuse rate was noted (18.5 vs. 17.0 treatments, P = 0.26). Low-dose heparinization did not compromise dialysis adequacy and permitted ESA dose reduction. Our findings suggest that in prevalent patients on HD, UFH dose of 15-20 units/kg loading and 500 units/hour maintenance was medically safe and effective.

Use of iron sucrose and red blood cell transfusions in anaemic cancer patients in France (OncoFer study).

This report describes the results of an observational, retrospective cohort study, evaluating the use of iron sucrose (IS) and red blood cell (RBC) transfusions in patients with cancer in routine clinical practice in France. A parallel investigated cohort treated with ferric carboxymaltose (FCM) has been reported earlier. Data of patients with a solid tumour or haematological malignancy who have received IS or an RBC transfusion during 2010 from 3months prior (M-3) to 3months post first treatment (M+3) were analysed. Data from 46 patients who had received IS (400mg median total iron dose) and 357 patients who had received RBC transfusions as first treatment (baseline) were included. Median haemoglobin levels improved from 9.9g/dL (interquartile range 9.2; 11.0g/dL) at baseline to 12.4g/dL (11.4; 13.1g/dL) at M+3 in IS-treated patients and from 8.2g/dL (7.8; 8.8g/dL) at baseline to 10.1g/dL (8.8; 11.1g/dL) in transfused patients. An erythropoiesis-stimulating agent was given to 54.3 and 28.9% of patients in the IS and the RBC transfusion groups, respectively, resulting in slightly better mean haemoglobin increase in both groups (2.4 vs 1.5g/dL and 2.0 vs 1.6g/dL, respectively). No severe nor serious adverse reaction and no hypersensitivity reactions were reported. Both IS and RBC transfusions effectively increased Hb levels in patients with cancer. IS was safe and well tolerated in this population. Considering prior reported results with FCM, using FCM may reduce ESA dose requirements and the required number of infusions.

Plasma vitamin C levels in ESRD patients and occurrence of hypochromic erythrocytes.

The achievement of erythropoiesis in hemodialysis (HD) patients is typically managed with erythropoiesis-stimulating-agents (ESA's) and intravenous iron (IV-iron). Using this treatment strategy, HD patients frequently show an elevated fraction of red blood cells (RBC) with hemoglobin (Hb) content per cell that is below the normal range, called hypochromic RBC. The low Hb content per RBC is the result of the clinical challenge of providing sufficient iron content to the bone marrow during erythropoiesis. Vitamin C supplements have been used to increase Hb levels in HD patients with refractory anemia, which supports the hypothesis that vitamin C mobilizes iron needed for Hb synthesis. We conducted a cross-sectional survey in 149 prevalent HD patients of the percent hypochromic RBC, defined as RBC with Hb < 300 ng/uL of packed RBC, in relation to plasma vitamin C levels. We also measured high-sensitivity CRP, (hs-CRP), iron, and ferritin levels. and calculated ESA dose. High plasma levels of vitamin C were negatively associated with hypochromic RBC (P < 0.003), and high ESA doses were positively associated (P < 0.001). There was no significant association of hs-CRP with percent hypochromic RBC. This finding supports the hypothesis that vitamin C mobilizes iron stores, improves iron delivery to the bone marrow, and increase the fraction of RBC with normal Hb content. Further research is warranted on development of protocols for safe and effective use of supplemental vitamin C for management of renal anemia.