Erythropoiesis-stimulating Agents Dose Research Articles

The association of erythropoietin-stimulating agents and increased risk for AV-fistula dysfunction in hemodialysis patients. A retrospective analysis

BackgroundPatients in maintenance hemodialysis (HD) need a patent vascular access for optimal treatment. The recommended first choice is a native arteriovenous fistula (AVF). Complications of AVF are frequent and include thrombosis, stenosis and infections leading to worsening of dialysis efficacy. Some known risk factors are age, gender and the presence of diabetes mellitus. The aim was to investigate if further risk variables are associated with dysfunctional AVF.MethodsThis retrospective observational study included 153 chronic HD patients (Cases) referred to a total of 473 radiological investigations due to clinically suspected complications of their native AVF. Another group of chronic HD patients (n = 52) who had a native AVF but were without history of previous complications for at least 2 years were controls. Statistical analyses included ANOVA, logistic regression, parametric and non-parametric methods such as Student’s T-test and Mann-Whitney test.ResultsAmong Cases, at least one significant stenosis (> 50% of the lumen) was detected in 348 occasions. Subsequent PTA was performed in 248 (71%). Median erythropoiesis-stimulating agent (ESA) weekly doses were higher in Cases than in Controls (8000 vs 5000 IU, p < 0.001). Cases received higher doses of intravenous iron/week than the Controls before the investigation (median 50 mg vs 25 mg, p = 0.004) and low molecular weight heparin (LMWH, p = 0.028). Compared to Controls, Cases had a lower level of parathyroid hormone (median 25 vs 20 ρmol/L, p = 0.009). In patients with diabetes mellitus, HbA1c was higher among Cases than Controls (50 vs 38 mmol/mol, p < 0.001). Multiple regression analysis revealed significant associations between Cases and female gender, prescription of doxazocin, and doses of ESA and LMWH.There was no difference between the groups regarding hemoglobin, CRP or ferritin.ConclusionIn conclusion, the present study indicated that the factors associated with AVF problems were high doses of ESA, iron administration, and tendency of thromboembolism (indicated by high LMWH doses); the use of doxazocin prescription, however, requires further investigation.

Efficacy of ferumoxytol versus sodium ferric gluconate in anemia management in outpatient hemodialysis patients: Aprospective cohort study.

Intravenous iron is one of the main therapies for anemia management in hemodialysis-dependent patients. Data comparing the efficacy of ferumoxytol versus other parenteral iron supplements are scarce. The objective of the study was to compare the efficacy of ferumoxytol with that of sodium ferric gluconate in outpatient hemodialysis patients. A prospective, observational study was conducted in outpatients receiving ferumoxytol 510mg once or twice quarterly compared to sodium ferric gluconate 125mg weekly in a single center hemodialysis center in Ontario, Canada. Patient demographics, hemoglobin levels, iron indices, iron doses, and erythropoiesis-stimulating agent (ESA) doses were collected. The study sample consisted of 291 observations from 173 patients. Generalized estimating equations of multiple linear regression modeling were conducted to compare the outcomes while adjusting for baseline scores. Approximately 25% of the study participants received ferumoxytol while 75% received sodium ferric gluconate. Patients treated were mainly males (58.4%), and the mean age was 68.73 (SD±13.03) years. Both groups did not show significant differences in their hemoglobin levels (Wald z=0.54; p=0.46), ESA utilization at 3 months (Wald z=0.20; p=0.65), and TSAT levels (Wald z=3.45; p=0.06). However, the iron levels (Wald z=4.24; p=0.04) and ferritin levels (Wald z=5.14; p=0.02) were higher in the ferric gluconate group (Wald z=58.78; p≤0.001), and patients who received ferumoxytol received more blood transfusions as compared to those who received sodium ferric gluconate (χ2=16.71; p≤0.001). Both iron products maintained hemoglobin levels, but patients receiving ferumoxytol had lower iron indices and received more blood transfusions compared to patients who received sodium ferric gluconate.

Intravenous Iron Replacement Therapy Improves Cardiovascular Outcomes in Hemodialysis Patients.

More than half of deaths among hemodialysis patients are due to cardiovascular disease. This study examined whether intravenous administration of ferric carboxymaltose (FCM) has an impact on cardiovascular events in iron-deficient hemodialysis patients. We performed a retrospective study concerning patients undergoing hemodialysis in our center from September 2016 to December 2019. We identified those who began FCM therapy (FCM group) during this period and those who did not (control group). We analyzed clinical, echocardiographic and laboratory parameters at the beginning (t0) and after one year (t1), to detect differences between the two groups. We identified 53 patients for the FCM group and 19 for the control group. Median follow-up was 1 year±3 months for both groups. In the FCM group, we observed a reduction in the doses of erythropoiesis-stimulating agents (ESA) (p<0.001) and a significative difference in cardiovascular events (p<0.01), but no differences in echocardiographic parameters. Patients who received FCM reached satisfactory values of transferrin saturation and ferritin, presented fewer coronary artery events and cardiovascular events, and could reduce doses of ESA.

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

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

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

Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation. This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies. No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin. Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy. Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.

Serum trace metal association with response to erythropoiesis stimulating agents in incident and prevalent hemodialysis patients

Alterations in hemodialysis patients’ serum trace metals have been documented. Early studies addressing associations levels of serum trace metals with erythropoietic responses and/or hematocrit generated mixed results. These studies were conducted prior to current approaches for erythropoiesis stimulating agent (ESA) drug dosing guidelines or without consideration of inflammation markers (e.g. hepcidin) important for regulation of iron availability. This study sought to determine if the serum trace metal concentrations of incident or chronic hemodialysis patients associated with the observed ESA response variability and with consideration to ESA dose response, hepcidin, and high sensitivity C-reactive protein levels. Inductively-coupled plasma-mass spectrometry was used to measure 14 serum trace metals in 29 incident and 79 prevalent dialysis patients recruited prospectively. We compared these data to three measures of ESA dose response, sex, and dialysis incidence versus dialysis prevalence. Hemoglobin was negatively associated with ESA dose and cadmium while positively associated with antimony, arsenic and lead. ESA dose was negatively associated with achieved hemoglobin and vanadium while positively associated with arsenic. ESA response was positively associated with arsenic. Vanadium, nickel, cadmium, and tin were increased in prevalent patients. Manganese was increased in incident patients. Vanadium, nickel, and arsenic increased with time on dialysis while manganese decreased. Changes in vanadium and manganese were largest and appeared to have some effect on anemia. Incident and prevalent patients’ chromium and antimony levels exceeded established accepted upper limits of normal.

Replicating Randomized Trial Results with Observational Data Using the Parametric g-Formula: An Application to Intravenous Iron Treatment in Hemodialysis Patients.

BackgroundReproducibility of clinical and epidemiologic research is important to generalize findings and has increasingly been scrutinized. A recently published randomized trial, PIVOTAL, evaluated high vs low intravenous iron dosing strategies to manage anemia in hemodialysis patients in the UK. Our objective was to assess the reproducibility of the PIVOTAL trial findings using data from a well-established cohort study, the Dialysis Outcomes and Practice Patterns Study (DOPPS).MethodsTo overcome the absence of randomization in the DOPPS, we applied the parametric g-formula, an extension of standardization to longitudinal data. We estimated the effect of a proactive high-dose vs reactive low-dose iron supplementation strategy on all-cause mortality (primary outcome), hemoglobin, two measures of iron concentration (ferritin and TSAT), and erythropoiesis-stimulating agent dose over 12 months of follow-up in 6325 DOPPS patients.ResultsComparing high- vs low-iron dose strategies, the 1-year mortality risk difference was 0.020 (95% CI: 0.008, 0.031) and risk ratio was 1.20 (95% CI: 1.07, 1.33), compared with null 1-year findings in the PIVOTAL trial. Differences in secondary outcomes were directionally consistent but of lesser magnitude than in the PIVOTAL trial.ConclusionOur findings are somewhat consistent with the recent PIVOTAL trial, with discrepancies potentially attributable to model misspecification and differences between the two study populations. In addition to the importance of our results to nephrologists and hence hemodialysis patients, our analysis illustrates the utility of the parametric g-formula for generalizing results and comparing complex and dynamic treatment strategies using observational data.

Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin.

Anemia is a frequent comorbidity of chronic kidney disease (CKD) and is associated with a considerable burden because of decreased patient health-related quality of life and increased healthcare resource utilization. Based on observational data, anemia is associated with an increased risk of CKD progression, cardiovascular events, and all-cause mortality. The current standard of care includes oral or intravenous iron supplementation, erythropoiesis-stimulating agents, and red blood cell transfusion. However, each of these therapies has its own set of population-specific patient concerns, including increased risk of cardiovascular disease, thrombosis, and mortality. Patients receiving dialysis or those who have concurrent diabetes or high blood pressure may be at greater risk of developing these complications. In particular, treatment with high doses of erythropoiesis-stimulating agents has been associated with increased rates of hospitalization, cardiovascular events, and mortality. Resistance to erythropoiesis-stimulating agents remains a therapeutic challenge in a subset of patients. Hypoxia-inducible factor transcription factors, which regulate several genes involved in erythropoiesis and iron metabolism, can be stabilized by a new class of drugs that act as inhibitors of hypoxia-inducible factor prolyl-hydroxylase enzymes to promote erythropoiesis and elevate hemoglobin levels. Here, we review the burden of anemia of chronic kidney disease, the shortcomings of current standard of care, and the potential practical advantages of hypoxia-inducible factor prolyl-hydroxylase inhibitors in the treatment of patients with anemia of CKD.

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

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

Shortened red blood cell age in patients with end-stage renal disease who were receiving haemodialysis: a cross-sectional study

BackgroundThe causes of anaemia in patients with end-stage renal disease include a relative deficiency in erythropoietin production and complex clinical conditions. We aimed to investigate the underlying mechanisms of anaemia in patients with end-stage renal disease who were undergoing maintenance dialysis by measuring erythrocyte creatine levels.MethodsIn a cross-sectional study, we evaluated 69 patients with end-stage renal disease who were receiving haemodialysis (n = 55) or peritoneal dialysis (n = 14). Erythrocyte creatine level, a quantitative marker of mean red blood cell (RBC) age, was measured.ResultsThe mean RBC age was significantly shorter in the haemodialysis group than in the peritoneal dialysis group (47.7 days vs. 59.8 days, p < 0.0001), although the haemoglobin levels were comparable between the groups. A Spearman correlation coefficient analysis revealed that shortened RBC age positively correlated with transferrin saturation (r = 0.54), ferritin level (r = 0.47), and haptoglobin level (r = 0.39) but inversely related with reticulocyte (r = − 0.36), weekly doses of erythropoiesis-stimulating agents (ESAs; r = − 0.62), erythropoietin resistance index (r = − 0.64), and intradialytic ultrafiltration rate (r = − 0.32).ConclusionsShortened RBC age was observed in patients who were receiving maintenance haemodialysis and was associated with iron deficiency, greater haptoglobin consumption, higher ESA requirements, and poor erythropoietin responsiveness, as well as with greater intradialytic fluid extraction.

Types of erythropoiesis-stimulating agents and risk of end-stage kidney disease and death in patients with non-dialysis chronic kidney disease.

Despite the widespread use of erythropoiesis-stimulating agents (ESAs) to treat anaemia, the risk of adverse outcomes associated with the use of different types of ESAs in non-dialysis chronic kidney disease (CKD) is poorly investigated. From a pooled cohort of four observational studies, we selected CKD patients receiving short-acting (epoetin α/β; n = 299) or long-acting ESAs (darbepoetin and methoxy polyethylene glycol-epoetin β; n = 403). The primary composite endpoint was end-stage kidney disease (ESKD; dialysis or transplantation) or all-cause death. Multivariable Cox models were used to estimate the relative risk of the primary endpoint between short- and long-acting ESA users. During follow-up [median 3.6 years (interquartile range 2.1-6.3)], the primary endpoint was registered in 401 patients [166 (72%) in the short-acting ESA group and 235 (58%) in the long-acting ESA group]. In the highest tertile of short-acting ESA dose, the adjusted risk of primary endpoint was 2-fold higher {hazard ratio [HR] 2.07 [95% confidence interval (CI) 1.37-3.12]} than in the lowest tertile, whereas it did not change across tertiles of dose for long-acting ESA patients. Furthermore, the comparison of ESA type in each tertile of ESA dose disclosed a significant difference only in the highest tertile, where the risk of the primary endpoint was significantly higher in patients receiving short-acting ESAs [HR 1.56 (95% CI 1.09-2.24); P = 0.016]. Results were confirmed when ESA dose was analysed as continuous variable with a significant difference in the primary endpoint between short- and long-acting ESAs for doses >105 IU/kg/week. Among non-dialysis CKD patients, the use of a short-acting ESA may be associated with an increased risk of ESKD or death versus long-acting ESAs when higher ESA doses are prescribed.

Clinical and Economic Outcomes of Erythropoiesis-Stimulating Agent Hyporesponsiveness in the Post-Bundling Era

Rationale & ObjectiveSince the change in erythropoiesis-stimulating agent (ESA) labeling and bundling of dialysis services in the United States, few studies have addressed the clinical importance of ESA hyporesponsiveness and none have considered health care resource use in this population. We aimed to further explore ESA hyporesponsiveness and its consequences.Study DesignRetrospective observational cohort study.Setting & ParticipantsUS Renal Data System Medicare participants receiving dialysis with a minimum 6 months of continuous ESA use from 2012 to 2014.PredictorsErythropoietin resistance index (≥2.0 U/kg/wk/g/L) and ESA dose were used to identify ESA hyporesponders and hyporesponsive subgroups: isolated, intermittent, and chronic.OutcomesAssociations between ESA responsiveness and mortality, cardiovascular hospitalization rates, and health care resource use were evaluated and compared across subgroups.Analytical ApproachBaseline characteristics were compared using Wilcoxon rank sum tests for continuous variables and χ2 tests for categorical variables. Incidence rates of health care resource use were modeled using an unadjusted and adjusted generalized linear model.ResultsOf 834,115 dialysis patients in the CROWNWeb database, 38,891 ESA hyporesponders and 59,412 normoresponders met all inclusion criteria. Compared with normoresponders, hyporesponders were younger women, weighed less, and had longer durations of dialysis (all P < 0.001). Hyporesponders received 3.8-fold higher ESA doses (mean, 94,831 U/mo) and erythropoietin resistance index was almost 5 times higher than in normoresponders. Hyporesponders had lower hemoglobin levels and parathyroid hormone levels > 800 pg/mL, and iron deficiency was present in 26.5% versus 10.9% in normoresponders. One-year mortality was higher among hypo- compared with normoresponders (25.3% vs 22.6%). Hyporesponders also had significantly higher rates of hospitalization for cardiovascular events, emergency department visits, inpatient stays, home health agency visits, skilled nursing facility, and hospice days.LimitationsOnly US Medicare patients were included and different hyporesponder definitions may have influenced the results.ConclusionsThis study explored ESA hyporesponsiveness using new definitions and incorporated clinical and economic outcomes. It established that ESA-hyporesponsive dialysis patients had higher mortality, cardiovascular hospitalization rates, and health care costs as compared with ESA-normoresponsive patients.

Evolution of Treatment for Anemia in Chronic Kidney Disease

Evolution of Treatment for Anemia in Chronic Kidney Disease

Role of nephrology pharmacists in the management of anemia in outpatient dialysis units: A Canadian model .

Hemodialysis patients frequently suffer from anemia. Proper utilization of therapies such as iron and erythropoiesis-stimulating agents (ESAs) is crucial to attain symptom management and established hemoglobin targets. The purpose of this study was to evaluate the clinical and financial impact of nephrology-trained pharmacists on anemia management in these patients. A retrospective study of outpatient hemodialysis patients observed between January 2010 and December 2011. In December 2010, pharmacists were tasked to manage anemia under a medical directive. Primary endpoints were compared across years using a mixed-effects model strategy. An unstructured random effects correlation matrix was utilized to capture patient-level variation in 2010 and 2011, separately. Of 202 patients identified, 163 contributed in both years, 57% were males, aged 65.18 ± 16.3 years. Hemoglobin levels were 10.95 ± 0.95 and 10.83 ± 0.94 g/dL in 2010 vs. 2011, respectively (p = 0.158), while the transfusion rate was 1.3% and 1.8%, respectively (p = 0.196). Ferritin levels of 273.5 ± 22 and 317.1 ± 12 ng/mL (p = 0.0019), iron saturation 0.30 ± 0.11 and 0.30 ± 0.05 (p = 0.838), and parenteral iron dose of 215.4 ± 100.2 and 317.1 ± 123.7 mg, respectively (p = 0.996), were identified. Finally, the average weekly ESA dose in 2010 was higher and trending up as compared to 2011 where it significantly trended down. The amount of intravenous erythropoietin alfa was 12,315.6 ± 76 vs. 11,364.1 ± 52 units/week, respectively (p = 0.0556) with expenditure of 2.8 million Canadian dollars in 2010 vs. 2.3 million Canadian dollars in 2011. The participation of a nephrology pharmacist resulted in favorable outcomes in dose optimization, decreased expenditure, and positive trends in therapeutic goal achievement.

P1374DEVELOPMENT OF HEMOGLOBIN PREDICTION AND ERYTHROCYTE STIMULATING AGENT RECOMMENDATION ALGORITHM (HPERA) USING RECURRENT NEURAL NETWORK IN END-STAGE KIDNEY DISEASE PATIENTS

Abstract Background and Aims The optimization of anemia management is a challenging task due to the complexities of underlying diseases and heterogeneous responses to erythropoiesis-stimulating agents (ESA) in patients with end-stage kidney disease (ESKD). Recent studies have shown that machine learning (ML) algorithms can be an effective tool to predict hemoglobin (Hb) levels and determine the ESA doses in these patients. However, most of the proposed ML approaches are not designed to handle multivariate longitudinal patient data. Thus, we developed Hb prediction and ESA doses recommendation algorithm (HPERA) using recurrent neural networks (RNN). Method A total of 466 participants, who underwent hemodialysis in 7 hospitals in the Republic of Korea, were included in the present study. We selected 15 variables from an extreme gradient boosting (XGBoost) algorithm. The outcome of the prediction algorithm was Hb levels in next month. In the recommendation algorithm, the outcome was the ESA dose for target Hb next month. Among various types of RNN families, gated recurrent units (GRU) were used to build both the prediction and recommendation algorithms. In addition to holding out a separate validation dataset, we used a Gaussian noise layer following each input layer to avoid overfitting. We also performed linear regression, multilayer perceptrons, and extreme gradient boosting with an extensive hyperparameter search to validate our GRU-based prediction algorithm. The performances of each model were evaluated in terms of the mean absolute error (MAE). Results The mean age of the study population was 57.8 years, 248 (53.2%) participants are male, and the mean observation period is 30.0 months. The best result of our prediction algorithm in terms of MAE was 0.59 g/dL and was obtained by two stacked GRU layers followed by a single hidden feedforward network with 6-month follow-up patient data. The best recommendation algorithm had 43.2 μg in MAE and this was obtained by one GRU layer followed by two layers of a feedforward network. The HPERA had a lower overall ESA dose (μg/months) [155 (80–240) vs. 140 (70–210), P&amp;lt;0.001], decreased Hb difference (g/dL) [0.8 (0.4–1.4) vs. 0.6 (0.3–1.0), P&amp;lt;0.001)], and had a higher success and a lower failure rates of reaching target Hb compared to those in real practice. Conclusion The GRU-based prediction model outperformed previous ML methodologies, though hyperparameter turning was much simpler. Using the HPERA showed the possibility of a reduced amount of ESA, decreased Hb difference, and increased the reaching rate of target Hb levels. Our study revealed a great potential direction of anemia management using ML in ESKD patients.

P1228IMPROVEMENT OF BODY WEIGHT MANAGEMENT, BETA2-MICROGLOBULIN LEVEL AND RESISTANCE TO ERYTHROPOIESIS-STIMULATING AGENTS BY HYBRID PERITONEAL DIALYSIS PLUS HEMODIALYSIS THERAPY

Abstract Background and Aims Peritoneal dialysis (PD) has the advantages of not causing rapid changes in the body fluid levels or solute contents in the blood due to the continuous treatment on all days of the week, and of not needing the patients to visit the hospital 3 times a week or lie on a bed for 4 hours to receive treatment. PD alone can, however, not adequately remove all the uremic toxins and excess water, and the patients are likely to be resistant to erythropoiesis-stimulating agents (ESA). These drawbacks could be potentially improved if PD and hemodialysis (HD) were used together. The aims of the present study were to clarify the changes in the body weight, serum β2-microglobulin (β2MG) level, and resistance to ESA in PD patients switched from PD alone to PD-HD hybrid therapy (hybrid therapy). Methods The data of seven patients who were switched from PD alone to PD-HD hybrid therapy at our hospital were retrospectively analyzed to determine the changes in the body weight, serum β2MG level, dose of ESA (Darbepoetin Alfa) and the hemoglobin level before and at 3 months after the switch to hybrid therapy; in hybrid therapy, the patient received HD once a week and did not receive PD on that day. We also carried out a questionnaire survey to determine the changes in the feeling of well-being and quality of life of the patients after the switch to hybrid therapy. Results and Discussion The body weight decreased significantly from 67.4 ± 11.8 kg to 63.7 ± 8.7kg (p = 0.0345) after the switch from PD alone to PD-HD hybrid therapy, indicating that the control of the body fluids was much easier with hybrid therapy than with PD alone. The mean serum β2MG level in the patients decreased from 37.3 ± 11.6 μg/mL to 32.6 ± 5.9 μg/mL (p = 0.1607, not significant), ; in particular, in those patients in whom the serum β2MG levels were over 30 μg/mL, the level decreased significantly from 42.5 ± 8.7 μg / mL to 34.4 ± 6.1 μg / mL (p = 0.0337). The dose of ESA decreased significantly in all patients from 193 ± 74 μg/month to 69 ± 38 μg/month (p = 0.006), while the hemoglobin level remained unchanged (from 10.2 ± 1.7 g/dL to 11.2 ± 1.2 g/dL, p = 0.1406). In the questionnaire survey, almost all the patients expressed positive feelings about the switch of the treatment modality, such as “it became easier to go up the stairs,” “improved working efficiency,” and “comfortable feeling.” Since the peritoneum was allowed to rest once in a week, on the day of the HD, it could also preserve peritoneal functions. Therefore, hybrid therapy was also considered to be effective from the viewpoint of performing PD over the long term. Conclusion We can expect easier management of the body fluid, efficient β2MG removal, and improvement of ESA resistance by switching the dialysis treatment modality from PD alone to HD-PD hybrid therapy.

SO073IRON-RELATED PARAMETERS AND ANTI-ANAEMIC THERAPY IN HAEMODIALYSIS PATIENTS TREATED WITH SUCROFERRIC OXYHYDROXIDE: A 1-YEAR RETROSPECTIVE EUROPEAN CLINICAL DATABASE (EUCLID) ANALYSIS

Abstract Background and Aims This retrospective analysis of data from the European Clinical Database (EuCliD®) evaluated changes in iron-related parameters and use of concomitant anti-anaemic therapies in European haemodialysis (HD) patients treated with sucroferric oxyhydroxide (SFOH). Previous Phase 3 clinical studies and non-clinical studies have indicated that there is minimal iron absorption from SFOH. This study aimed to evaluate the changes in iron-related parameters among patients treated with SFOH in the real-world setting. Method De-identified patient data were extracted from a clinical database (EuCliD®) for adult HD patients newly prescribed SFOH routinely for up to 1 year (1 Jan 2015–1 Jan 2019). Levels of serum ferritin, transferrin saturation (TSAT) and haemoglobin were compared between baseline (BL; 3-month period before starting SFOH) and each quarterly period in the year after starting SFOH treatment (Q1–Q4). Proportions of patients receiving intravenous (IV) iron and erythropoiesis-stimulating agent (ESA) therapies, in addition to their mean weekly doses, during each quarter were recorded. Results The cohort included 1,096 patients with recorded SFOH prescriptions (mean age: 60.6 years; 65.8% male). There were small, but significant increases in ferritin from BL to Q1–Q4 (P&amp;lt;0.05 for all periods vs BL). There were also increases in TSAT (P&amp;lt;0.05 at Q1 and Q2 vs BL) and haemoglobin (P&amp;lt;0.001 at Q1 and Q3 vs BL) (Table). During the 1-year SFOH treatment period, the proportion of patients receiving IV iron therapy decreased (P&amp;lt;0.05 at Q2 and Q3 vs BL) and there was a significant reduction in the mean weekly dose of IV iron administered (P&amp;lt;0.05 at Q2 and Q3 vs BL). The use of ESA therapy also declined (P&amp;lt;0.05 at Q3 and Q4) and there was a significant decrease in the mean weekly dose of ESA during the 1-year SFOH follow-up period (P&amp;lt;0.05 for all periods vs BL). Conclusion This real-world study showed that SFOH treatment in routine clinical practice for up to 1 year was associated with small increases in iron-related parameters and decreases in the use and mean dose of concomitant anti-anaemic therapies in European HD patients. The results from this study indicate that SFOH treatment may be associated with the reduction in concomitant IV iron and ESA use in HD patients, in line with previous findings from the Phase 3 study.

P1398EFFECTS OF CONVERTING FROM CINACALCET TO ETELCALCETIDE

Abstract Background and Aims Secondary hyperparathyroidism is a common problem in patients undergoing chronic hemodialysis and its treatment includes vitamin D analogs and calcimimetics which act upon the calcium-sensing receptor. Etelcalcetide was introduced as an intravenous calcimimetic easy to administer at the end of the hemodialysis session with improved adherence. Hypocalcemic episodes have raised some concerns although this side effect is not unanimously described. As an institutional policy most patients from 2 hemodialysis units were switched from cinacalcet to etelcalcetide between July 2017 and January 2018. We aimed at evaluating the impact of this conversion upon laboratory values and ongoing medication. Method We collected data from patients in 2 hemodialysis units including monthly serum values of calcium, phosphorus, hemoglobin and albumin, quarterly parathormone (PTH) values from 3 months previous to conversion until 3 months post-conversion as well as the calcimimetic dose during the same time frame. Descriptive statistics concerning mean and median values of the previous 3 and next 3 months following conversion were used. A paired sample t-test was performed to compare values before and after conversion. Results Of the approximately 200 patients, 22 were on cinacalcet and were switched to etelcalcetide. These had a mean age of 66.9 years and included 9 women and 8 diabetics. Mean PTH value before conversion was 728±391 (range 371-1900pg/mL) and did not differ significantly from that after conversion 717±330 (p=0.9). No significant statistical difference between values before and after conversion was found for serum calcium (9.3±0.5 vs 9.2±0.6; p=0.43), phosphorus (5.4±0.8 vs 5.1±1.0; p=0.15), albumin (4.1±0.2 vs 4.1±0.2; p=0.83) and hemoglobin (11.3±0.8 vs 11.4±0.9; p=0.50). The mean number of hypocalcemic values during the 3 months before and after conversion was identical (0.6±1 vs 0.6±0.9; p=0.86). The median cinacalcet dose on the month before conversion was 30mg/day (IQR 22.5) and the median etelcalcetide dose at conversion was 2.5mg three times per week (IQR 1.9). The conversion factor was 27mg cinacalcet: 1mg etelcalcetide, because even patients on high cinacalcet doses were initially started at low etelcalcetide doses. However, at 3 months following conversion, the median etelcalcetide dose was 8.75 (IQR 7.5). The doses of erythropoiesis-stimulating agents (ESA), vitamin D analogues and phosphorus binders were not significantly affected. Conclusion Switching from cinacalcet to etelcalcetide in all patients on hemodialysis in a particular institution did not change laboratory values or increased the number of hypocalcemic measurements. The etelcalcetide dose was adjusted up for the first 3 months and the mean PTH value did not change significantly. Treatment with ESA, vitamin D analogues and phosphorus binders remained unchanged after conversion. Secondary hyperparathyroidism is a chronic condition and etelcalcetide provides a useful means to control it with an easy administration regimen.

P0758THE CORRELATION BETWEEN THE MANAGEMENT OF COMORBIDITIES AND THE PROGRESSION OF THE RENAL DYSFUNCTION OR ADVERSE EVENTS OF CHRONIC KIDNEY DISEASE

Abstract Background and Aims Several factors, such as anemia, hypertension, hyperuricemia, metabolic acidosis, and chronic kidney disease (CKD)-mineral and bone disorder (MBD), are associated with the progression of CKD or adverse events in CKD patients. However, the significant factors associated with the progression of CKD or adverse events in patients under the condition of appropriate control according to guidelines have not been clarified. Method The study was a 3-year observational study conducted in a single center. In 88 patients with various stages of CKD (not on renal replacement therapy (RRT)) who were treated by nephrologists, blood levels of Hb, ferritin, iron, total iron-binding capacity, and albumin were measured every 3 months, and high-sensitivity C reactive protein (hCRP), β2-microglobulin (MG), HCO3-, and intact-parathyroid hormone (int-PTH), in addition to urinary sodium, potassium, calcium, phosphorus, protein, and β2-MG levels, were measured every 6 months. We also evaluated the doses of iron, erythropoiesis-stimulating agent (ESA), vitamin D, phosphate binder, anti-hypertensive agents, and anti-hyperuricemic agents. All patients were treated according to the clinical practice guidelines for CKD (Japanese Society of Nephrology 2013). A time-dependent Cox hazard model was applied to evaluate the associations between clinical parameters and adverse events (initiation of RRT and hospitalization resulting in cardiovascular disease or infection). Results Unexpectedly, under the condition of appropriate control by nephrologists, hypertension, hyperuricemia, metabolic acidosis, iron metabolism, and inflammation were not selected as significant predictors of the progression of renal dysfunction or adverse events. (Factors associated with the progression of renal dysfunction) In multiple regression analysis, lower baseline blood levels of Hb (β=0.497, P&amp;lt;0.001) and vitamin D 125 (β=0.258, P=0.006) and higher baseline blood levels of int-PTH (β=-0.334, P=0.001), urinary phosphorus (β=0.328, P=0.001), urinary β2-MG (β=-0.225, P=0.031) and urinary protein (β=0.280, P=0.02) were selected as significant predictors of reduced estimated glomerular filtration rate (eGFR) or 1/creatinine (Cr) at the end of the study. (Factors associated with the initiation of RRT and adverse events) In the Cox hazard model, low calcium (HR: 0.37, P=0.026), high phosphate (HR: 5.90, P&amp;lt;0.001), low 1,25-vitamin D (HR: 0.94, P=0.013), high int-PTH (HR: 1.02, P&amp;lt;0.001), use of a phosphate binder (HR: 4.95, P=0.012), and use of vitamin D analogs (HR: 3.75, P=0.014) were selected as risks for adverse events, including the initiation of RRT. Conclusion In this study, we found that among several factors, anemia and CKD-MBD-related factors (phosphate, calcium, vitamin D, int-PTH) were selected as significant predictors of the progression of renal dysfunction. Furthermore, although phosphate binders or vitamin D analogs were administered appropriately, CKD-MBD-related factors (phosphate, calcium, vitamin D, and int-PTH) were associated with RRT initiation or adverse events in these patients. From these results, we presumed that early intervention or strict control of CKD-MBD factors might attenuate the risk for adverse events in CKD patients.

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

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