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Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.
Bhandari, S, Kalra, PA, Berkowitz, M, Belo, D, Thomsen, LL, Wolf, M
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2021;(1):111-120
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Abstract
BACKGROUND The optimal intravenous (IV) iron would allow safe correction of iron deficiency at a single infusion over a short time. The FERWON-NEPHRO trial evaluated the safety and efficacy of iron isomaltoside 1000/ferric derisomaltose (IIM) in patients with non-dialysis-dependent chronic kidney disease and iron deficiency anaemia. METHODS In this randomized, open-label and multi-centre trial conducted in the USA, patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg IV injections up to five times within a 2-week period. The co-primary endpoints were serious or severe hypersensitivity reactions and change in haemoglobin (Hb) from baseline to Week 8. Secondary endpoints included incidence of composite cardiovascular adverse events (AEs). RESULTS A total of 1538 patients were enrolled (mean estimated glomerular filtration rate 35.5 mL/min/1.73 m2). The co-primary safety objective was met based on no significant difference in the incidence of serious or severe hypersensitivity reactions in the IIM and IS groups [0.3% versus 0%; risk difference: 0.29% (95% confidence interval: -0.19; 0.77; P > 0.05)]. Incidence of composite cardiovascular AEs was significantly lower in the IIM versus IS group (4.1% versus 6.9%; P = 0.025). Compared with IS, IIM led to a more pronounced increase in Hb during the first 4 weeks (P ≤ 0.021), and change in Hb to Week 8 showed non-inferiority, confirming that the co-primary efficacy objective was met. CONCLUSIONS Compared with multiple doses of IS, a single dose of IIM induced a non-inferior 8-week haematological response, comparably low rates of hypersensitivity reactions, and a significantly lower incidence of composite cardiovascular AEs.
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The association of erythropoietin-stimulating agents and increased risk for AV-fistula dysfunction in hemodialysis patients. A retrospective analysis.
Wärme, A, Hadimeri, H, Nasic, S, Stegmayr, B
BMC nephrology. 2021;(1):30
Abstract
BACKGROUND Patients 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. METHODS This 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. RESULTS Among 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. CONCLUSION In 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.
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Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: "Can the Promise Be Kept?".
Crugliano, G, Serra, R, Ielapi, N, Battaglia, Y, Coppolino, G, Bolignano, D, Bracale, UM, Pisani, A, Faga, T, Michael, A, et al
International journal of molecular sciences. 2021;(22)
Abstract
Anemia is a common complication of chronic kidney disease (CKD). The prevalence of anemia in CKD strongly increases as the estimated Glomerular Filtration Rate (eGFR) decreases. The pathophysiology of anemia in CKD is complex. The main causes are erythropoietin (EPO) deficiency and functional iron deficiency (FID). The administration of injectable preparations of recombinant erythropoiesis-stimulating agents (ESAs), especially epoetin and darbepoetin, coupled with oral or intravenous(iv) iron supplementation, is the current treatment for anemia in CKD for both dialysis and non-dialysis patients. This approach reduces patients' dependence on transfusion, ensuring the achievement of optimal hemoglobin target levels. However, there is still no evidence that treating anemia with ESAs can significantly reduce the risk of cardiovascular events. Meanwhile, iv iron supplementation causes an increased risk of allergic reactions, gastrointestinal side effects, infection, and cardiovascular events. Currently, there are no studies defining the best strategy for using ESAs to minimize possible risks. One class of agents under evaluation, known as prolyl hydroxylase inhibitors (PHIs), acts to stabilize hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase (PH) enzymes. Several randomized controlled trials showed that HIF-PHIs are almost comparable to ESAs. In the era of personalized medicine, it is possible to envisage and investigate specific contexts of the application of HIF stabilizers based on the individual risk profile and mechanism of action.
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Factors associated with hepcidin-25 levels in maintenance hemodialysis patients.
Savković, M, Simić-Ogrizović, S, Dopsaj, V
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2021;(5):565-574
Abstract
This study aimed to investigate the factors that are independently associated with hepcidin-25 and its relationship with doses of erythropoiesis-stimulating agents (ESAs) and intravenous iron in stable maintenance hemodialysis patients (smHD) stratified by ESAs administration. In 103 adult smHD (ESAs therapy (N = 64) and ESAs-free (N = 39)), median values of biologically active hepcidin-25 (chemiluminescent direct ELISA assay) and ferritin levels were significantly higher whereas red blood cell count, hemoglobin, and hematocrit values were lower in ESAs therapy compared to ESAs-free group (P < .001, for all). Our results suggest that ESAs-independent smHD exhibit supposedly normal hepcidin-25 levels and preserved iron homeostasis, with a lower degree of anemia. The results of our multivariable model indicate that hepcidin-25 levels are independently and positively associated with iron stores and inflammation, and inversely with active erythropoiesis, regardless of ESAs administration. Maintenance ESAs and the intravenous iron dose were not related to hepcidin-25 levels.
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Oral Sucrosomial Iron Is as Effective as Intravenous Ferric Carboxy-Maltose in Treating Anemia in Patients with Ulcerative Colitis.
Bertani, L, Tricò, D, Zanzi, F, Baiano Svizzero, G, Coppini, F, de Bortoli, N, Bellini, M, Antonioli, L, Blandizzi, C, Marchi, S
Nutrients. 2021;(2)
Abstract
Anemia is a frequent complication of ulcerative colitis, and is frequently caused by iron deficiency. Oral iron supplementation displays high rates of gastrointestinal adverse effects. However, the formulation of sucrosomial iron (SI) has shown higher tolerability. We performed a prospective study to compare the effectiveness and tolerability of oral SI and intravenous ferric carboxy-maltose (FCM) in patients with ulcerative colitis in remission and mild-to-moderate anemia. Patients were randomized 1:1 to receive 60 mg/day for 8 weeks and then 30 mg/day for 4 weeks of oral SI or intravenous 1000 mg of FCM at baseline. Hemoglobin and serum levels of iron and ferritin were assessed after 4, 8, and 12 weeks from baseline. Hemoglobin and serum iron increased in both groups after 4 weeks of therapy, and remained stable during follow up, without significant treatment or treatment-by-time interactions (p = 0.25 and p = 0.46 for hemoglobin, respectively; p = 0.25 and p = 0.26 for iron, respectively). Serum ferritin did not increase over time during SI supplementation, while it increased in patients treated with FCM (treatment effect, p = 0.0004; treatment-by-time interaction effect, p = 0.0002). Overall, this study showed that SI and FCM displayed similar effectiveness and tolerability for treatment of mild-to-moderate anemia in patients with ulcerative colitis under remission.
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Managing Anemia across the Stages of Kidney Disease in Those Hyporesponsive to Erythropoiesis-Stimulating Agents.
Weir, MR
American journal of nephrology. 2021;(6):450-466
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Abstract
BACKGROUND Patients with CKD frequently have anemia that results from iron-restricted erythropoiesis and inflammation. Anemia of CKD is currently managed with iron supplements and erythropoiesis-stimulating agents (ESAs) to promote erythropoiesis and with RBC transfusion in severe cases. Hyporesponse to ESAs, or the need for larger than usual doses to attain a given hemoglobin (Hb) level, is associated with increased morbidity and mortality and presents a pressing clinical challenge, particularly for patients on dialysis. This paper reviews ESA hyporesponse and potential new therapeutic options in the management of anemia of CKD. SUMMARY The most common causes of ESA hyporesponse include iron deficiency and inflammation, and to a lesser degree, secondary hyperparathyroidism, inadequate dialysis, malnutrition, and concomitant medications. Management of ESA hyporesponse is multipronged and involves treating low level infections, ensuring adequate nutrition, and optimizing iron status and dialysis modality, although some patients can remain refractory. Inflammation directly increases production and secretion of hepcidin, contributes to an impaired response to hypoxia, and suppresses proliferation of erythroid progenitors. Coordination of renal and hepatic erythropoietin (EPO) production and iron metabolism is under the control of hypoxia-inducible factors (HIF), which are in turn regulated by HIF-prolyl hydroxylases (HIF-PHs). HIF-PHs and hepcidin are therefore attractive potential drug targets particularly in patients with ESA hyporesponse. Several oral HIF-PH inhibitors have been evaluated in patients with anemia of CKD and have been shown to increase Hb and reduce hepcidin regardless of inflammation, iron status, or dialysis modality. These sustained effects are achieved through more modest increases in endogenous EPO compared with ESAs. Key Messages: Treatments that address ESA hyporesponse remain a significant unmet clinical need in patients with anemia of CKD. New therapies such as HIF-PH inhibitors have the potential to address fundamental aspects of ESA hyporesponse and provide a new therapeutic option in these patients.
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Factors affecting the doses of roxadustat vs darbepoetin alfa for anemia treatment in hemodialysis patients.
Akizawa, T, Yamaguchi, Y, Majikawa, Y, Reusch, M
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2021;(5):575-585
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Abstract
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease (CKD). Emerging evidence suggests that roxadustat may be beneficial for patients who inadequately respond to erythropoiesis-stimulating agents (ESAs). This post-hoc analysis of a Japanese, double-blind, randomized, phase 3 study in hemodialysis-dependent CKD patients treated with traditional ESAs assessed the impact of factors associated with ESA hyporesponsiveness on roxadustat and darbepoetin alfa (DA) doses required to maintain target hemoglobin. Endpoints included mean of average doses of roxadustat and DA per administration in the last 6 weeks (AAD/6W) by prior ESA-resistance index (ERI), iron repletion (transferrin saturation; ferritin), and high-sensitivity C-reactive protein (hs-CRP). Of 415 enrolled patients, 303 were randomized (roxadustat, n = 151; DA, n = 152). Weight-adjusted AAD/6W increased with increasing ERI for roxadustat (ERI <3.3, 0.89 mg/kg; ERI ≥8.4, 1.51 mg/kg) and DA (ERI <3.3, 0.26 μg/kg; ERI ≥8.4, 0.91 μg/kg); the weight-adjusted AAD/6W relative to within-arm mean AAD/6W showed a trend toward increased DA doses for the ERI ≥8.4 category (P = .089). AAD/6W remained stable for roxadustat but increased for DA with decreasing baseline iron repletion markers. The relationship between roxadustat doses and end of treatment (EoT) hs-CRP was not significant (estimated slope, -0.494; P = .814); a trend toward increased DA doses was observed with increasing EoT hs-CRP (estimated slope, 2.973; P = .075). Roxadustat doses required to maintain target hemoglobin appear to be less affected by factors that underlie ESA hyporesponsiveness, relative to DA; roxadustat may be beneficial for patients hyporesponsive to ESAs.
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Effects of altitude and recombinant human erythropoietin on iron metabolism: a randomized controlled trial.
Breenfeldt Andersen, A, Bonne, TC, Bejder, J, Jung, G, Ganz, T, Nemeth, E, Olsen, NV, Huertas, JR, Nordsborg, NB
American journal of physiology. Regulatory, integrative and comparative physiology. 2021;(2):R152-R161
Abstract
Current markers of iron deficiency (ID), such as ferritin and hemoglobin, have shortcomings, and hepcidin and erythroferrone (ERFE) could be of clinical relevance in relation to early assessment of ID. Here, we evaluate whether exposure to altitude-induced hypoxia (2,320 m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a 4-wk baseline, a 4-wk intervention at either sea level or altitude, and a 4-wk follow-up. Participants (n = 39) were randomly assigned to 20 IU·kg body wt-1 rHuEPO or placebo injections every second day for 3 wk during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE (P ≤ 0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE (P < 0.05) and hepcidin levels (P < 0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared with altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin (P < 0.05) and ERFE (P ≤ 0.001) parallel with increases in hematocrit (P < 0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found (R2 = 0.13, P < 0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an antidoping context.
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Factors Affecting Doses of Roxadustat Versus Darbepoetin Alfa for Anemia in Nondialysis Patients.
Akizawa, T, Tanaka-Amino, K, Otsuka, T, Yamaguchi, Y
American journal of nephrology. 2021;(9):702-713
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Abstract
INTRODUCTION Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness. METHODS Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18-24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated. RESULTS Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] μg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] μg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m2 were associated with requiring higher DA but not roxadustat doses. DISCUSSION/CONCLUSION The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.
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Safety and Efficacy of Intravenous Ferric Derisomaltose Compared to Iron Sucrose for Iron Deficiency Anemia in Patients with Chronic Kidney Disease With and Without Heart Failure.
Ambrosy, AP, von Haehling, S, Kalra, PR, Court, E, Bhandari, S, McDonagh, T, Cleland, JGF
The American journal of cardiology. 2021;:138-145
Abstract
Ferric derisomaltose (FDI) is an intravenous (IV) high-dose iron formulation approved in the US for the treatment of iron deficiency anemia in adults who are intolerant of/have had an unsatisfactory response to oral iron, or who have non-dialysis-dependent chronic kidney disease (NDD-CKD). FERWON-NEPHRO was a randomized, open-label, multicenter clinical trial evaluating the safety and efficacy of a single infusion of FDI 1,000 mg versus up to 5 doses of iron sucrose (IS) 200 mg (recommended cumulative dose, 1,000 mg) over 8 weeks in patients with NDD-CKD and iron deficiency anemia. Of 1,525 patients included in the safety analysis, 244 (16%) had a history of heart failure (HF). Overall, the rate of serious or severe hypersensitivity reactions was low and did not differ between treatment groups. Cardiovascular adverse events (AEs) were reported for 9.4% of patients who had HF and 4.2% who did not. Time to first cardiovascular AE was longer following administration of FDI compared with IS (hazard ratio: 0.59 [95% CI: 0.37, 0.92]; p=0.0185), a difference that was similar in patients with or without HF (p=0.908 for interaction). Patients achieved a faster hematological response (assessed by changes in hemoglobin and ferritin concentrations, and increase in transferrin saturation) with FDI versus IS. In conclusion, in patients with NDD-CKD, a single infusion of FDI was safe, well tolerated, and was associated with fewer cardiovascular AEs and a faster hematological response, compared to multiple doses of IS. These effects were similar for patients with and without HF.