Long-acting Erythropoiesis-stimulating Agents Research Articles

Short versus long-acting erythropoiesis-stimulating agents for anemia management in Egyptian hemodialysis patients.

Chronic kidney disease (CKD) often results in renal anemia, impacting the well-being of patients and causing various negative consequences. Erythropoiesis-stimulating agents (ESAs) offer promising solutions for managing anemia in CKD. This study aimed to evaluate and compare the effectiveness, safety profile, and cost-effectiveness of short-acting (Eprex®) and long-acting (Aranesp®) ESAs. This comparative prospective cohort cost-effectiveness study was carried out over 6 months among adult Egyptian hemodialysis patients of either gender. Participants were categorized into two groups based on the type of ESA administered: the Eprex group, receiving epoetin alfa, and the Aranesp group, receiving darbepoetin alfa. These two treatment groups' efficacy, safety, and cost were analyzed and compared. Of 127 hemodialysis patients, 60 (47.2%) received Eprex, while 67 (52.8%) were treated with Aranesp. Target hemoglobin (Hb) was achieved by 50.6% of patients in the Eprex group versus 63.4% in the Aranesp group, with a significant difference (P < 0.001). Both treatment groups exhibited a similar safety profile, while Aranesp® was considered the cost-saving protocol. In hemodialysis Egyptian patients, Aranesp with extended dosing intervals proved to be more effective in achieving target Hb with comparable adverse effect profiles, a substantial cost-saving strategy, and offered time-saving advantages for medical staff workload compared to Eprex. The Clinicaltrial.gov registration ID is NCT05699109 (26/01/2023).

Comparative Safety of Long-Acting vs. Short-Acting Erythropoiesis-Stimulating Agents Among Patients Undergoing Hemodialysis.

Both short-acting (epoetin alfa or beta) and long-acting (darbepoetin alfa or PEG-epoetin) erythropoiesis-stimulating agents (ESAs) are commonly prescribed for patients with kidney failure undergoing maintenance hemodialysis. We compared the risks of major adverse cardiovascular events (MACE) and of all-cause mortality associated with receipt of short- vs. long-acting ESAs. This retrospective cohort analysis included Medicare hemodialysis beneficiaries aged ≥ 18 years in the United States Renal Data System from January 2015 to December 2017. We included adults who survived > 90 days after initiating hemodialysis and received either short- or long-acting ESAs. Outcomes were MACE (first occurrence of stroke, acute myocardial infarction, or cardiovascular-related mortality) and all-cause mortality. After stabilized inverse probability of treatment weighting, Cox proportional hazards regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for each outcome. Of 68,607 patients (mean age: 65 years, 45% females), 33,658 (49%) received long-acting ESAs and 34,949 (51%) received short-acting ESAs. There was no difference in the risk of MACE associated with receipt of short- vs. long-acting ESAs (HR: 1.02 (95% CI: 0.98-1.08)). However, long-acting (vs. short-acting) ESA receipt was associated with a lower risk of all-cause mortality (HR: 0.91 (95% CI: 0.87-0.96)). Compared with short-acting ESAs, long-acting ESAs were associated with a lower risk of all-cause mortality, with no difference in the risk of MACE. Future studies with a longer follow-up are needed to confirm these findings.

Outcomes of Early Versus Delayed Anemia Treatment in Nondialysis-Dependent CKD

IntroductionThe association of hemoglobin level at treatment initiation with renal and cardiovascular outcomes in patients with anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) is unclear. MethodsThis retrospective cohort study utilized two Japanese databases (Medical Data Vision [MDV] and Real World Data [RWD]). Patients initiated long-acting erythropoiesis-stimulating agent treatment were divided into early (hemoglobin levels ≥9.0 g/dL) and delayed (<9.0 g/dL) treatment groups. The primary outcome was a renal composite (renal replacement therapy, ≥50% estimated glomerular filtration rate [eGFR] reduction, eGFR <6.0 mL/min/1.73 m2, and all-cause mortality), and secondary outcomes were a cardiovascular composite (hospitalization by ischemic heart disease including myocardial infarction, hospitalization by stroke and heart failure, and cardiovascular death) and components of the composite outcomes. ResultsAfter propensity score matching, 1472 (MDV) and 1264 (RWD) patients were evaluated. Delayed treatment was not associated with a risk of the renal composite outcome (MDV: hazard ratio [HR] 1.15, 95% confidence intervals [CI] 0.99–1.33; RWD: 1.08, 0.92–1.28). However, delay was associated with higher risks of the cardiovascular composite outcome (MDV: HR 1.47, 95% CI 1.16–1.84; RWD: 1.34, 1.09–1.64), heart failure (MDV: HR 1.50, 95% CI 1.13–2.00; RWD: 1.53, 1.20–1.96) and all-cause mortality (MDV: HR 1.83, 95% CI 1.32–2.54; RWD: 1.64, 1.21–2.22). ConclusionAlthough the risk of renal events was not increased following delayed treatment of anemia in patients with NDD-CKD, the risks of cardiovascular events and all-cause mortality were increased, suggesting the importance of early intervention before hemoglobin fall below 9.0 g/dL.

Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled trials.

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new therapeutic agents for anaemia in chronic kidney disease (CKD). We evaluated by meta-analysis and meta-regression the efficacy and safety of HIF-PHIs in patients with CKD-related anaemia. We selected phase 3 randomized clinical trials (RCTs) comparing HIF-PHIs and erythropoiesis-stimulating agents (ESAs) in dialysis and non-dialysis patients. Efficacy outcomes were the changes from baseline of haemoglobin, iron parameters (hepcidin, serum iron, TIBC, TSAT, ferritin) and intravenous iron dose; as safety outcomes we considered cancer, adjudicated major adverse cardiovascular events (MACE), MACE+ (MACE plus hospitalization for hearth failure or unstable angina or thromboembolic event), thrombotic events (deep vein thrombosis, pulmonary embolism), arterovenous fistula (AVF) thrombosis and death. We included 26 RCTs with 24387 patients. Random effect meta-analysis of the unstandardized mean difference between HIF-PHIs and ESAs showed a significant change in haemoglobin levels from baseline of 0.10g/dL (95% CI 0.02 to 0.17). Meta-regression analysis showed a significantly higher haemoglobin change for HIF-PHIs in younger patients and versus short-acting ESA (0.21g/dL, 95% CI 0.12 to 0.29 versus -0.01, 95% CI -0.09 to 0.07 in studies using long-acting ESA, P<.001). No significant effect on heterogeneity was found for type of HIF-PHIs. In comparison with ESAs, HIF-PHIs induced a significant decline in hepcidin and ferritin and a significant increase in serum iron and TIBC, while TSAT did not change; intravenous iron dose was lower with HIF-PHI (-3.1mg/week, 95% CI -5.6 to -0.6, P=.020). Rate ratio of cancer (0.93, 95% CI 0.76 to 1.13), MACE (1.00, 95% CI 0.94 to 1.07), MACE+ (1.01, 95% CI 0.95 to 1.06), thrombotic events (1.08, 95% CI 0.84 to 1.38), AVF thrombosis (1.02, 95% CI 0.93 to 1.13) and death (1.02, 95% CI 0.95 to 1.13) did not differ between HIF-PHIs and ESAs. HIF-PHIs at the doses selected for the comparisons are effective in correcting anaemia in comparison with ESA therapy with a significant impact on iron metabolism without notable difference among various agents. No safety signals emerge with use of HIF-PHIs.

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

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

MO1041: C.E.R.A. (Continuous Erythropoietin Receptor Activator—Methoxy Polyethylene Glycol Epoetin Beta) In Paediatric Dialysis Patients with Anaemia of Chronic Kidney Disease: Real-World Evidence from the IPDN and IPHN Registries

Abstract BACKGROUND AND AIMS Continuous erythropoietin receptor activator—methoxy polyethylene glycol epoetin beta (C.E.R.A.) is a long-acting erythropoiesis-stimulating agent (ESA) approved for the treatment of anaemia associated with chronic kidney disease (CKD) in adults. In June 2018, the Food and Drug Administration approved the use of C.E.R.A. administered intravenously in patients on haemodialysis aged 5–&amp;lt;18 years switching from another ESA. This observational real-world study (MH40258) assessed the safety, dosing and haemoglobin (Hb) levels associated with C.E.R.A. in paediatric patients with CKD on dialysis. METHOD This was a non-interventional real-world study of patients from the International Paediatric Peritoneal Dialysis Network (IPPN) and the International Paediatric Hemodialysis Network (IPHN) registries. Demographics, clinical characteristics, dialysis information, treatment, laboratory parameters, number and causes of hospitalization events and deaths were reported in patients treated with C.E.R.A. from both registries (IPPN: 2007–2021; IPHN: 2013–2021). RESULTS Overall, 229 patients had at least one observation while being treated with C.E.R.A. and were analysed in this study; 177 on peritoneal dialysis (PD) (median age 10.6 years, interquartile range [IQR] 4.2–14.6) and 52 on haemodialysis (HD) (median age 14.1 years, IQR 10.4-16.2). The median observation time under C.E.R.A. exposure was 6 months (IQR 0–12.5) for PD patients and 12 months (0–18) for HD patients. 121 PD patients (68%) and 36 HD patients (69%) had ≥ 1 hospitalization, of whom 102/121 (84%) and 32/36 (89%), respectively, had non-elective hospitalizations. Median hospitalization surveillance time/patient was 13.5 months in the PD and 18.3 months in the HD cohorts. The most frequent causes for non-elective hospitalization were infections, reported as a cause in 56/177 (32%) patients in the PD cohort and 14/52 (27%) in the HD cohort and technique complications, in 41/177 (23%) patients in the PD cohort and 20/52 (38%) in the HD cohort. There were seven deaths (PD: 5 patients; HD: 2 patients), corresponding to an overall mortality rate of 19.8 cases per 1000 observation years. Causes of death were infections (n = 2), intracranial bleeding (n = 2), congestive heart failure (n = 2) and one case of sudden death at home. Hb levels remained stable over time with 47% of PD patients and 48% of HD patients having a Hb value within the range of 10–12 g/dL at their last observation. Mean [standard deviation (SD)] Hb levels at last observation were 10.9 (1.7) g/dL in the PD and 10.4 (1.7) g/dL in the HD cohort. The median monthly dose of C.E.R.A. at first visit was 100 (IQR 50–120) µg in the PD and 107 (80–129) µg in the HD cohort, while at last visit it was 100 (50–150) µg (PD) and 80 (54–129) µg (HD). While absolute C.E.R.A. dose increased with age, weight-related doses decreased substantially with age in both cohorts: in groups aged &amp;lt; 2, 2–&amp;lt;5, 5–&amp;lt;12 and 12–&amp;lt;18 years, respectively, the median monthly dose was 7.9, 5.4, 3.2 and 2.6 µg/kg at first observation and 5.1, 5.2, 3.0 and 3.0 µg/kg at last observation in the PD cohort. The age-related dosing differences were smaller when doses were normalized to body surface area (BSA) rather than body weight, with median doses at last visit of 114, 121, 87 and 98 µg/m2/month, respectively in the PD cohort. In the HD cohort, a similar pattern wasobserved regarding weight and BSA-based dosing, but overall C.E.R.A.dosing was generally lower over the course of the study in HD compared with PD patients. The median monthly C.E.R.A. dose at last observation was 3.5 (IQR 2.3– 5.1) µg/kg, or 95 (62–145) µg/m2 in the PD cohort and 2.1 (1.2–3.4) µg/kg, or 63 (40–98) µg/m2 in the HD cohort (Table). CONCLUSION Real-world data from the IPPN and IPHN registries indicated that C.E.R.A. treatment is associated with efficient maintenance of Hb levels in paediatric patients with CKD on dialysis. C.E.R.A. appeared to have a favourable safety profile; analysis of hospitalization rate and causes as well as patient mortality did not reveal any safety signals.

Long-acting erythropoiesis-stimulating agent (ESA) induces physiological erythropoiesis via improvement of iron availability.

Previous studies reported that the long-acting erythropoiesis-stimulating agent (ESA) significantly suppresses the expression of hepcidin, which regulates iron availability. In this study, we compared the iron availability for erythropoiesis between short and long-acting ESA over a long period. We enrolled 69 hemodialysis patients in this study. All patients were treated with short-acting ESA (epoetin-α or epoetin-β) for the first 30months. Then, all patients switched to long-acting ESA (continuous erythropoietin receptor activator-methoxy polyethylene glycol-epoetin beta) for the next 30months. We measured their blood levels of Hb, ferritin, iron, total iron-binding capacity, intact-parathyroid hormone, calcium, phosphate, albumin, and highly sensitive CRP level. There was no significant change in the dose of short or long-acting ESA during the study period. Compared with the short-acting ESA period, the mean hemoglobin (Hb) and transferrin saturation levels were significantly increased in the long-acting ESA period (from 10.3 ± 0.2 to 10.6 ± 0.3g/dL). On the other hand, the mean serum ferritin level (from 72 ± 22.2 to 56.3 ± 14ng/mL) and the dose of IV iron (from 108 ± 63 to 53 ± 27mg/month) were significantly decreased in the long-acting ESA period. In this study, we found that anemia treatment with long-acting ESA attenuated the iron utilization for erythropoiesis and maintained target Hb levels without requiring a higher dose of IV iron or ESA.

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

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

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.

Prolonged Duration of Erythropoiesis-Stimulating Agents’ Action Delays Disease Progression in Anti-Thy 1 Antibody-Induced Chronic Glomerulonephritis Rats

Background: Although erythropoiesis-stimulating agents (ESAs) exert renoprotective effects in renal disease models, it has not been revealed whether the prolonged duration of action of ESAs contributes to their renoprotective effects. Objective: We examined whether the prolonged duration of ESAs’ action contributes to their renoprotective effects by comparing a divided administration of a short-acting ESA, epoetin beta (EPO), or a single administration of a long-acting ESA, epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.), to a single administration of EPO in chronic glomerulonephritis (GN) rats. Materials and Methods: Chronic GN was induced by intravenous injection of anti-Thy 1.1 antibody (0.6 mg/kg) into uninephrectomized rats (day 0). Chronic GN rats were intravenously injected once with vehicle (disease control; DC), EPO 5,000 IU/kg (single EPO), or C.E.R.A. 25 μg/kg (single C.E.R.A.) on day 1; or 3 times during the first week with EPO 1,667 IU/kg from day 1 (divided EPO; total 5,000 IU/kg). Hemoglobin (Hb) level and urinary total protein (U-TP) level which are the indexes of hematopoiesis and renoprotective effects, respectively, were measured several times over 8 weeks. Results: Divided EPO and single C.E.R.A. increased Hb levels more greatly than did single EPO. In all chronic GN rats, elevated U-TP levels decreased transiently 2 weeks after chronic GN induction and then flared again. Single EPO significantly suppressed this exacerbation of U-TP levels compared to DC. Divided EPO and single C.E.R.A. each significantly suppressed the exacerbation of U-TP levels compared to single EPO. Conclusion: Prolonged duration of ESAs’ action contributed significantly to their renoprotective effects.

Erythropoiesis stimulating agents are associated with serum fibroblast growth factor 23 metabolism in patients on hemodialysis.

BackgroundThis study aimed to determine associations among short- and long-acting erythropoiesis stimulating agents (ESAs), changes in serum fibroblast growth factor 23 (FGF23) and biomarkers of iron metabolism.MethodsAmong 108 patients on hemodialysis (HD), 44 received every 2 weeks or monthly doses of continuous erythropoiesis receptor activator (CERA), 31 received weekly doses of darbepoetin-α, 24 received three doses per week of epoetin-β and 9 were not treated with an ESA. Intact and C-terminal FGF23 and transferrin saturation (TSAT), ferritin, erythroferrone and hepcidin 25 were measured in blood samples collected before the HD session at the end of the dialysis week (baseline, Day 0) and on Days 3, 5, 7 and 14 thereafter.ResultsLevels of ferritin, hepcidin 25 and erythroferrone as well as TSAT were significantly decreased or elevated in patients treated with CERA compared with other types of ESAs. Levels of C-terminal FGF23 increased in all groups during the observation period. Levels of intact FGF23 and ratios of intact FGF23 to C-terminal FGF23 gradually decreased between Days 3 and 7 in the CERA but not in the other groups. Multivariate models associated changes in hepcidin 25 and phosphate with those of intact FGF23.ConclusionThe long-acting ESA CERA might influence levels of intact FGF23 by increasing FGF23 cleavage in patients on HD in association with prolonged hepcidin 25 suppression.

Correlation between haemoglobin level and type of erythropoiesis-stimulating agent at initiation of haemodialysis

Background Renal anaemia worsens because of the uraemic status immediately before the initiation of haemodialysis. The haemoglobin level in patients with chronic kidney disease is correlated with cardiovascular disease and mortality. Objective This study was performed to determine whether short- and long-acting erythropoiesis-stimulating agents are correlated with the pre-haemodialysis haemoglobin level in patients with chronic kidney disease. Setting This study was conducted at the Blood Purification Center in Wakayama Medical University. Method We enrolled 364 patients undergoing initiation of haemodialysis from January 2009 to June 2015 and analysed them for > 3months prior to the initiation of haemodialysis. In total, 168 patients were included in the final analysis based on the inclusion and exclusion criteria. Main outcome measures The correlation of the haemoglobin level at the initiation of haemodialysis with various factors according to the type of erythropoiesis-stimulating agent used. Results The median haemoglobin level was 8.8g/dL, and long-acting erythropoiesis-stimulating agents were used by 69.6% of the patients. Long-acting erythropoiesis-stimulating agents were used significantly more often in patients with high than low haemoglobin levels. The haemoglobin levels at the initiation of haemodialysis and 1month prior tended to be significantly higher in patients taking long-than short-acting erythropoiesis-stimulating agents. The serum levels of iron and albumin and the use of long-acting erythropoiesis-stimulating agents were independently correlated with the haemoglobin level at the initiation of haemodialysis in the multivariate regression analysis. In addition, the left ventricular mass index was significantly correlated with the haemoglobin level at the initiation of haemodialysis. Conclusion Long-acting erythropoiesis-stimulating agents were correlated with higher haemoglobin levels and may be more useful for patients with a low left ventricular mass index at the initiation of haemodialysis.

Analysis of Other Confounding Factors Is Mandatory before Considering That Long-Acting Erythropoiesis Stimulating Agents Are Deleterious to Patients on Dialysis

In their recently published article, Sakaguchi et al.1 analyzed data from the renal registry of the Japanese Society for Dialysis Therapy (comprising 194,698 patients on hemodialysis followed for a median time of 2 years) and found increased mortality (13%) in patients treated with long-acting erythropoiesis-stimulating agents, namely darbepoetin and epoetin β pegol, when compared with epoetins (α, β, and κ) with a shorter biologic t1/2. These authors performed a survival analysis using Cox proportional hazard models adjusted for various covariates known to influence survival in patients on dialysis.1 In addition to the factors included in their models, other confounding factors are also known to influence mortality in patients with ESKD on hemodialysis and should also be analyzed as covariates. These include the Charlson comorbidity index (validated in both patients on hemodialysis and peritoneal dialysis worldwide, and which includes items other than age, diabetes, and cardiovascular disease per se) and also the type of vascular access (native fistula versus catheter, although the percentage of dialysis catheters is known to be low in Japan).2 Most importantly, two other factors related to the dialysis technique itself should also be analyzed in Cox proportional hazard models as time-dependent covariates because they could strongly influence mortality and lead to spurious conclusions: First, the type of dialysis membrane: Abe et al.3 (who were involved in the study published in JASN) analyzed the same registry in Japan in 2017 and elegantly showed that polymethyl methacrylate and polyethersulfone dialysis membranes were associated with a lower probability of death after 2 years of follow-up in patients with ESKD treated by hemodialysis (polymethyl methacrylate, −16%; polyethersulfone, −12%). Second, more recently, Mercadal et al.4 of the French dialysis registry (Renal Epidemiology and Information Network) highlighted an increased risk of death as high as 40% in French patients with ESKD on hemodialysis that was associated with the use of citrate dialysates as compared with classic dialysates containing either acetate or hydrochloric acid, leading the French Drugs and Devices Agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé) to implement a national materiovigilance survey. Finally, in Sakaguchi et al.’s study,1 the lack of analysis of the influence (protective, neutral, or detrimental) of oral and parental (low-dose) iron therapy limits the validity of the conclusions. Thus, detailed analyses of all possible confounding factors are mandatory before considering that long-acting erythropoiesis-stimulating agents (darbepoetin and epoetin β pegol) are deleterious in patients with ESKD on hemodialysis. Disclosures None.

Treatment for renal anemia and outcomes in non-dialysis patients with chronic kidney disease: the current status of regional medicine according to the Kyoto Fushimi Renal Anemia (KFRA) study.

The baseline data obtained in the CKD-JAC demonstrated that insufficient treatment was being provided for renal anemia by institutions specializing in renal disease. The objective of this study was to investigate the status of treatment for renal anemia, including renal/cardiovascular outcomes and mortality, at regional medical facilities since the development of long-acting erythropoiesis-stimulating agents (LA-ESA). Non-dialysis outpatients with chronic kidney disease and renal anemia were eligible. Anemia was treated based on the clinical condition of each patient and targeted hemoglobin (Hb) levels. A total of 283 patients from 21 institutions were enrolled and followed up for a maximum of 3years. A doubling of the serum creatinine level was observed in 89 patients, and renal replacement therapy was initiated in 57 patients. Multivariate Cox regression analysis revealed that a lower mean Hb level (mHb) and receiving fewer frequency of ESA during the follow-up period were independent determinants of the composite renal outcome and overall mortality. During the follow-up period, the percentages of patients with mHb of 10-10.9g/dL and ≥ 11g/dL were increased. Similar trends were seen regardless of whether the patients were treated by nephrologists or non-nephrologists. The frequency of ESA treatment was increased among the patients treated by non-nephrologists; however, it was much lower than nephrologists. This study demonstrated that, in the era of LA-ESA treatment, higher Hb levels are associated with reduced composite renal outcomes at regional medical facilities. The importance of renal anemia management should be highlighted, even among non-nephrologists.

Эффективность и безопасность применения первого российского оригинального эритропоэз-стимулирующего препарата длительного действия в терапии анемии у пациентов с хронической почечной недостаточностью. Результаты международного многоцентрового рандомизированного клинического исследования II фазы

Эффективность и безопасность применения первого российского оригинального эритропоэз-стимулирующего препарата длительного действия в терапии анемии у пациентов с хронической почечной недостаточностью. Результаты международного многоцентрового рандомизированного клинического исследования II фазы

PUK5 - The Financial Impact of Introducing Darbepoetin Alfa (DA) as a New Long-Acting Erythropoiesis-Stimulating Agent Alternative for Non-Adherent Peritoneal Dialysis Patients in the Ministry of Health (MOH) Malaysia

PUK5 - The Financial Impact of Introducing Darbepoetin Alfa (DA) as a New Long-Acting Erythropoiesis-Stimulating Agent Alternative for Non-Adherent Peritoneal Dialysis Patients in the Ministry of Health (MOH) Malaysia

Patterns of Erythropoiesis-Stimulating Agent Use in European Hemodialysis Patients: The Dialysis Outcomes and Practice Patterns Study

Background: Clinicians providing dialysis care have numerous erythropoiesis-stimulating agents (ESAs) available for treating anemia. We sought to provide a contemporary description of ESA types used in hemodialysis (HD) settings in nine European countries. Methods: Our study uses Dialysis Outcomes and Practice Patterns Study phase 5 (2012–2015) data from nine European countries (Belgium, France, ­Germany, Italy, Russia, Spain, Sweden, Turkey, and the United Kingdom). A total of 164 facilities and 3,281 patients contributed cross-sectional data. ESA types captured included short-acting epoetins (e.g., epoetin alfa, beta, etc., including biosimilars), darbepoetin alfa, and continuous erythropoietin receptor agonist (CERA; methoxy polyethylene glycol-epoetin beta). Results: We observed broad variability across countries in prescription of ESA types: prescription of epoetin alfa or epoetin beta ranged from 22% (France) to 78% (Russia), darbepoetin alfa prescription ranged from 13% (Russia) to 53% (UK), and CERA prescription ranged from <3% (Sweden) to 26% (France). Prescription of different ESA types varied substantially within some European countries from 2012–2015 but not across all countries in aggregate. Number of ESA types prescribed by a facility varied from 1, 2, 3, or 4 different ESA types in 32, 40, 21, and 8% of facilities, respectively. No differences were seen in the unadjusted distributions of achieved hemoglobin values by ESA type. Conclusion: A variety of short- and long-acting ESAs are commonly used in European HD facilities to maintain hemoglobin at remarkably similar levels with each ESA type. The availability of numerous ESA options for managing anemia has allowed European providers to optimize anemia management according to the particular circumstances of each patient.

A quick scoping review of efficacy, safety, economic, and health-related quality-of-life outcomes of short- and long-acting erythropoiesis-stimulating agents in the treatment of chemotherapy-induced anemia and chronic kidney disease anemia.

Erythropoiesis-stimulating agents (ESAs) are man-made forms of erythropoietin used in the treatment of anemia. This quick-scoping review of systematic literature reviews (SLRs) was conducted to define the clinical, economic, and health-related quality of life (HRQoL) outcomes for short-acting and long-acting ESAs in patients with chronic kidney disease-induced anemia (CKD-IA) and patients with chemotherapy-induced anemia (CIA). Embase, Medline, and the Cochrane Database of Systematic Reviews were searched from their establishment until October 2017. SLRs related to the use of short-acting and long-acting ESAs in the treatment of CIA and CKD-IA were included. Forty-eight studies met the inclusion criteria. The evidence suggests little difference in efficacy, HRQoL, and safety outcomes among ESA types. Cost-effectiveness and market price are likely to become determining factors driving the choice of agent. Comparative studies and costing models accounting for the utilization of biosimilars are needed to establish which ESAs are more cost-effective.

Lower Hb at the initiation of dialysis does not adversely affect 1-year mortality rate

BackgroundThe management of renal anemia in the pre-dialysis period has been remarkably improved by long-acting erythropoiesis-stimulating agents (ESA). However, many incident dialysis patients cannot achieve target hemoglobin (Hb) levels (> 10 g/dL) and sometimes require blood transfusions. Anemia at the time of dialysis initiation is reportedly correlated with cardiomegaly and early cardiovascular events. Here, we investigated whether this V-shaped depression in Hb level at dialysis initiation adversely affects short-term prognosis.MethodsThe medical charts of 166 patients who underwent initial dialysis were retrospectively reviewed for Hb level, ESA treatment status, dry weight (DW), cardiothoracic rate (CTR), and brain natriuretic peptide (BNP) level at dialysis initiation and 1 year later. Patients were subdivided into three groups according to the tertile of Hb levels. The risk of mortality within 1 year after initiation was analyzed using multivariable-adjusted Cox proportional hazard model.ResultMean Hb level at initiation was 8.6 ± 1.3 g/dL despite the administration of sufficient ESA. After initiation, Hb levels rapidly increased and the Hb time course showed a V-shape with the bottom at initiation. Hb level, CTR, and log BNP showed a significant negative correlation. The Hb level and CTR 1 year after initiation did not correlate with Hb levels at initiation. Lower Hb levels at initiation as a V-shaped depression do not adversely affect 1-year mortality rate by multivariable-adjusted Cox proportional hazard model.ConclusionHb level around dialysis initiation showed a V-shaped depression despite ESA use. Our findings suggest that the V-shaped Hb depression at initiation does not affect short-term prognosis.

Administration of erythropoiesis-stimulating agents in patients undergoing haemodialysis: A time and motion study.

International guidelines recommend treatment of anaemia due to chronic kidney disease (CKD) with erythropoiesis-stimulating agents (ESAs). To document the time required and the cost in terms of nursing time to prepare and administer ESAs to patients on facility based haemodialysis (HD) with anaemia due to CKD before and after the introduction of long-acting ESAs. A time and motion study was implemented at four HD units in Australia to determine the time and costs associated with preparing and administering ESAs before and after the introduction of long-acting ESAs. This was a prospective, observational study of workplace practices at four HD units in Australia. Outcome data included the time taken to prepare, and administer ESAs. The time costs of preparation and administration per patient per year had a wide variability within each unit and ranged from Australian AUD$55.75 (38 euros) to AUD$90.49 (62 euros) before the introduction of long-acting ESAs. This dropped by 73-80% following the introduction of long-acting ESAs, representing an annual cost savings of between AUD$2,591 and AUD$5,914 if all patients on HD were switched to a long acting ESA. Switching from a short-acting to a long-acting ESA in HD units leads to a significant reduction in time costs of health professionals in preparation and administration of ESAs by up to 80%. Practical application: This time and motion study has added further evidence on reduction of human effort by taking advantages of new research development, such as the long acting ESAs.