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Kula A. Drug Development in Pediatric Chronic Kidney Disease: A Review of Promising Treatments, Old Challenges, and New Strategies. Paediatr Drugs 2025; 27:283-291. [PMID: 39928268 DOI: 10.1007/s40272-025-00684-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/15/2025] [Indexed: 02/11/2025]
Abstract
Youth under the age of 18 years represent a distinct subset of the population living with chronic kidney disease (CKD). The etiology of CKD differs greatly between children and adults, and young people with CKD face an extended lifetime living with their disease. Few rigorous randomized controlled trials in CKD have included people under the age of 18 years. As such, the recent success of CKD trials with sodium glucose co-transporter 2 inhibitors, mineralocorticoid antagonists, dual endothelin agonists, and hypoxia-induced factor prolyl hydroxylase inhibitors have largely not extended to children and adolescents. There are many reasons to believe these medications could prove as transformative in youth as they have in older adults, but trial data are missing. Innovative strategies are required to ensure that trials of recent, and future, agents in youth with CKD are successful.
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Affiliation(s)
- Alexander Kula
- Division of Pediatric Nephrology, Ann and Robert H. Lurie Children's Hospital of Chicago, 225 Chicago Ave, Chicago, IL, 60611, USA.
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Kang SH, Park SY, Lim YJ, Kim BY, Choi JY, Do JY, Kim AY. The Association Between Erythropoiesis Resistance Index and Clinical Outcomes in Hemodialysis Patients: A Nationwide Study. J Clin Med 2025; 14:2812. [PMID: 40283642 PMCID: PMC12028047 DOI: 10.3390/jcm14082812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 04/14/2025] [Accepted: 04/16/2025] [Indexed: 04/29/2025] Open
Abstract
Background: Although erythropoiesis-stimulating agent (ESA) therapy is fundamental for correcting anemia, excessive ESA administration is associated with increased risks. This study aimed to investigate the impact of the erythropoietin resistance index (ERI) on clinical outcomes in a population-based cohort of hemodialysis (HD) patients. Methods: This retrospective study analyzed datasets from patients who underwent periodic HD quality assessments and their claims data. Overall, we included 35,913 patients. Participants were divided into quartiles based on the ERI during the 6-month assessment period: Q1, Q2, Q3, and Q4 groups. Results: The 5-year survival rates were 68.8% (Q1), 67.8% (Q2), 66.9% (Q3), and 60.2% (Q4) (p < 0.001). Multivariable analysis showed the same trends as the univariable analysis. Additionally, a spline curve using the multivariable model indicated that the increased ERI was linked to all-cause mortality. However, cardiovascular events were not associated with ERI quartiles in Cox regression analyses. Subgroup analysis revealed that in most subgroups, the all-cause mortality was significantly higher in those with a high ERI than in those with a low ERI. Further analysis using the balanced cohort, which attenuated baseline characteristic differences, confirmed that the high mortality in those with a high ERI was maintained. Conclusions: Our population-based cohort study reveals an association between the ERI and all-cause mortality in HD patients.
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Affiliation(s)
- Seok-Hui Kang
- Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea; (S.-H.K.)
| | - So-Young Park
- Department of Physiology, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea
| | - Yu-Jeong Lim
- Quality Assessment Department, Health Insurance Review and Assessment Service, Wonju 26465, Republic of Korea
| | - Bo-Yeon Kim
- Quality Assessment Department, Health Insurance Review and Assessment Service, Wonju 26465, Republic of Korea
| | - Ji-Young Choi
- Quality Assessment Department, Health Insurance Review and Assessment Service, Wonju 26465, Republic of Korea
| | - Jun-Young Do
- Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea; (S.-H.K.)
| | - A-Young Kim
- Division of Nephrology, Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Republic of Korea; (S.-H.K.)
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Liu N, Sun Y, Liu J, Zhang Y, Yi X, Yan W, Cui X, Guo T, Zhao W, Han S, Ma W, Cao Y, Chen L. Nobiletin: a potential erythropoietin receptor activator protects renal cells against hypoxia. Apoptosis 2025; 30:842-860. [PMID: 39755823 DOI: 10.1007/s10495-024-02067-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/20/2024] [Indexed: 01/06/2025]
Abstract
Tangerine peel is a traditional Chinese herb and has been widely applied in foods and medicine for its multiple pharmacological effects. Erythropoietin receptor (EPOR), a member of the cytokine receptor family, is widely expressed in multiple tissues in especial kidney and plays protective effects in adverse physiological and pathological conditions. We hypothesized that it might be EPOR agonists existing in Tangerine peel bring such renal benefits. To test our hypothesis, an EPOR/cell membrane chromatography (CMC)-high performance liquid chromatography (HPLC)-mass spectrometry (MS) analytical system was developed to screen EPOR targeted compounds from tangerine peel extra out. A fraction was retained on the EPOR/CMC column, separated, and further identified as nobiletin. Frontal analysis, non-linear chromatography, and molecular docking assay were applied to determine the binding force and sites between nobiletin and EPOR. Intracellular Ca2+ mobilization, cAMP accumulation, and phosphorylation of JAK2 and STAT5 were determined to confirm the EPOR activation effect of nobiletin. CoCl2 was applied to construct a renal hypoxic cell model, and cell viability and apoptosis of human glomerular mesangial cells (HMC) were carried out to assess the pharmacological effect of nobiletin. Apoptosis-related proteins including Bcl-2, Bcl-xL, Bax, Cleaved caspase 3, caspase 3, caspase 9, and Cytochrome C were determined. SiRNA and lentivirus were used to silence or overexpress EPOR. Our results indicated that nobiletin is a potential EPOR agonist, reflected on its explicit binding force and downstream signal activating effects. Furthermore, EPOR-overexpressing enhanced the hypoxia-tolerance of renal cells. Our mechanism research indicated that the protective effect of nobiletin against hypoxia was depended on its pro-proliferation and anti-apoptosis effects. In conclusion, nobiletin, a potential small molecular agonist of EPOR, protects HMC against hypoxia through positively activating EPOR.
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Affiliation(s)
- Na Liu
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yuzhuo Sun
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Jieyun Liu
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yangyang Zhang
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xinyao Yi
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Wenhui Yan
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xin Cui
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Tingli Guo
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Wenzhuo Zhao
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Shengli Han
- School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Weina Ma
- School of Pharmacy, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China
| | - Yapeng Cao
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China.
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
| | - Lina Chen
- Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, 710061, China.
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, Xi'an, 710061, China.
- Cardiometabolic Innovation Center, Ministry of Education, Xi'an, 710061, China.
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Tsuruya K, Sugamori H, Tanaka Y, Wakasugi N, Ito Y. Real-world safety and effectiveness of roxadustat in patients with anemia of chronic kidney disease: interim results from a post-marketing surveillance study in Japan. Expert Opin Pharmacother 2025; 26:503-517. [PMID: 39899733 DOI: 10.1080/14656566.2025.2462181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 01/27/2025] [Accepted: 01/30/2025] [Indexed: 02/05/2025]
Abstract
BACKGROUND This planned interim analysis of a mandatory post-marketing surveillance study in Japan evaluated the safety and effectiveness of roxadustat, the first approved hypoxia-inducible factor prolyl hydroxylase inhibitor in the world, in real-world clinical use. RESEARCH DESIGN AND METHODS This prospective observational study has a planned 104-week observation period. We report data obtained through 16 December 2023, as a planned interim analysis. Adverse drug reactions (ADRs), mean hemoglobin level change from baseline to 12 weeks of roxadustat treatment, and subgroup analyses stratified by either baseline C-reactive protein or albumin levels were reported. RESULTS Overall, 2084 patients were treated with roxadustat (total patient-years of exposure: 1579.2). In the non-dialysis-dependent (NDD) group (n = 1075), ADRs and serious ADRs occurred in 209 (19.4%) and 109 (10.1%) patients, respectively. In patients receiving hemodialysis (HD; n = 856), ADRs and serious ADRs occurred in 224 (26.2%) and 142 (16.6%) patients, respectively. In patients receiving peritoneal dialysis (PD; n = 146), ADRs and serious ADRs occurred in 46 (31.5%) and 26 (17.8%) patients, respectively. Mean hemoglobin levels reached target levels at 12 weeks in most patients (NDD: 54.6%; HD: 56.3%; PD: 45.4%). CONCLUSIONS Roxadustat safety was demonstrated in real-world clinical settings. No new safety concerns were identified.Trial Registration: NCT04408820.
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Arici M, Al-Ghamdi SMG, Assounga AG, El-Koraie AF, McMillan A, Camidge LJ, Sumarsono B, Blogg M, Ng DB, Lansang EP. Treatment Inertia and Symptom Burden in Anemia of CKD: Insights from the SATISFY Survey in the Middle East, South Africa, and Türkiye. Int J Nephrol Renovasc Dis 2025; 18:27-42. [PMID: 39866642 PMCID: PMC11766225 DOI: 10.2147/ijnrd.s474716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 12/13/2024] [Indexed: 01/28/2025] Open
Abstract
Introduction Limited data exist regarding treatment patterns and symptom burden of patients with anemia of chronic kidney disease (CKD) in the Middle East, South Africa, and Türkiye. Methods This real-world study explored clinical characteristics, symptom burden, and treatment patterns of patients with anemia of CKD living in the Middle East, South Africa, and Türkiye. Physician and patient perceptions of treatment were captured via cross-sectional surveys; patients' clinical characteristics were recorded by retrospective review of medical records. Results Data were collected from 1788 patients and 217 physicians. A high proportion of patients had never received treatment for their anemia (n = 701, 39.2%); the most common treatment was erythropoietin-stimulating agents (ESAs) + intravenous iron (n = 457, 50.3%). High symptom burden was reported, with lack of energy being the most common symptom (n = 394, 75.6% treated and n = 133, 59.9% non-treated patients). Patients' self-reported symptom burden was higher than physician-reported burden; less agreement was seen for non-dialysis-dependent (NDD) patients (kappa = 0.193, standard deviation [SD]: 0.081) than dialysis-dependent (DD) patients (kappa = 0.442, SD: 0.103). Median hemoglobin thresholds that physicians reported using for initiating treatment (NDD: <10.5 [interquartile range, 9.5-12.0] g/dL; DD: <9.3 [9.0-10.0] g/dL) were higher than actual test levels at treatment initiation (NDD: 9.2 [8.7-10.0] g/dL; DD: 9.0 [8.1-10.0] g/dL). Conclusion Treatment inertia is apparent despite high symptom burden in the Middle East, South Africa, and Türkiye, and disagreement was seen in physician and patient perspectives on symptomology. Improved awareness of this disagreement may help facilitate physician-patient dialogue to improve patient experience.
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Affiliation(s)
- Mustafa Arici
- Department of Nephrology, Hacettepe University Faculty of Medicine, Ankara, Türkiye
| | - Saeed M G Al-Ghamdi
- Department of Medicine, Nephrology Section, King Abdulaziz University and King Faisal Specialist Hospital & Research Center, Jeddah, Saudi Arabia
| | - Alain G Assounga
- Department of Nephrology, Division of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Ahmed F El-Koraie
- Nephrology Unit, Alexandria Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | | | | | | | | | - Daniel Bin Ng
- Astellas Pharma Singapore Pte. Ltd, Singapore, Singapore
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Choukroun G, Strutz F, Harkavyi A, Santos V, Jiletcovici A, Del Vecchio L. Efficacy and Safety of Roxadustat in Patients with CKD: Pooled Analysis by Baseline Inflammation Status. J Clin Med 2025; 14:303. [PMID: 39860312 PMCID: PMC11765649 DOI: 10.3390/jcm14020303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/19/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Inflammation may contribute to hyporesponsiveness to erythropoiesis-stimulating agents (ESAs) and is often present in patients with chronic kidney disease (CKD). Roxadustat is approved in multiple countries for the treatment of anemia of CKD. This pooled analysis evaluated the efficacy and safety of roxadustat in patients with dialysis-dependent (DD) or non-dialysis-dependent (NDD) CKD by inflammation status. Methods: Data from five studies comparing roxadustat versus ESAs were pooled by patient populations in this analysis (NDD: DOLOMITES; DD: ROCKIES, SIERRAS, HIMALAYAS, PYRENEES). The mean change from baseline in hemoglobin levels to Weeks 28-52 and mean weekly dose of roxadustat or ESA at Week 24 were assessed by baseline inflammation levels (determined by high-sensitivity C-reactive protein [hsCRP] levels, divided into quintiles). Safety data were summarized descriptively. Results: In total, 613 patients with NDD CKD (roxadustat n = 320; ESA n = 293) and 4072 patients with DD CKD (roxadustat n = 2022; ESA n = 2050) were evaluated. Roxadustat increased hemoglobin levels in a manner similar to ESAs, independent of baseline inflammation status. In both the NDD and DD populations, roxadustat doses did not increase at Week 24 in patients with higher hsCRP levels at baseline. Patients with high baseline hsCRP levels required greater ESA doses at Week 24 compared with patients who had lower baseline hsCRP levels in both patient populations. The incidence rates of treatment-emergent adverse events were generally comparable with those of roxadustat and ESA across hsCRP quintiles in both the NDD and DD populations. Conclusions: Roxadustat addresses the multiple causes of anemia of CKD, regardless of inflammatory status, without requiring dose increases.
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Affiliation(s)
- Gabriel Choukroun
- Nephrology Dialysis Transplantation Department, CHU Amiens Picardie and Jules Verne University, 80000 Amiens, France
| | - Frank Strutz
- Department of Nephrology, DKD Helios Klinik Wiesbaden, KfH und Nierenzentrum-Rheumatologie, 65191 Wiesbaden, Germany;
| | | | - Vicki Santos
- Astellas Pharma, Inc., Northbrook, IL 60062, USA; (V.S.); (A.J.)
| | | | - Lucia Del Vecchio
- Department of Nephrology and Dialysis, Sant’Anna Hospital, ASST Lariana, 22042 Como, Italy;
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Fliser D, Bhandari S, Ortiz A, Santos V, Khalife N, Jiletcovici A, Akizawa T. Roxadustat Efficacy and Safety in Patients Receiving Peritoneal Dialysis: Pooled Analysis of Four Phase 3 Studies. J Clin Med 2024; 13:6729. [PMID: 39597872 PMCID: PMC11595076 DOI: 10.3390/jcm13226729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 11/01/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024] Open
Abstract
Background/Objectives: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved to treat anemia of chronic kidney disease (CKD). The efficacy and safety of roxadustat compared with parenteral erythropoiesis-stimulating agents (ESAs) were evaluated in patients with anemia of CKD receiving peritoneal dialysis (PD). Methods: This analysis pooled data from four phase 3, multicenter, randomized, open-label, active-comparator studies (PYRENEES, SIERRAS, HIMALAYAS, ROCKIES). The primary endpoints evaluated were hemoglobin change from baseline (CFB) to Weeks 28-36 without rescue therapy and hemoglobin CFB to Weeks 28-52 regardless of rescue therapy use. Safety data were reported. Results: This analysis included 422 patients (215 roxadustat, 207 ESA). Hemoglobin CFB to Weeks 28-36 without rescue therapy and hemoglobin CFB to Weeks 28-52 regardless of rescue therapy achieved non-inferiority for roxadustat vs. ESAs. The mean weekly dose of roxadustat was maintained over time (Weeks 1-4, 3.86 mg/kg/week; Weeks 101-104, 3.27 mg/kg/week), whereas the mean weekly ESA dose increased by 24% (Weeks 1-4, 115.70 IU/kg/week; Weeks 101-104, 143.40 IU/kg/week). Fewer patients treated with roxadustat received intravenous iron supplementation and rescue therapy, and patients treated with an ESA required blood transfusions sooner. Roxadustat-treated patients experienced a greater decrease in low-density lipoprotein cholesterol levels relative to baseline vs. ESA-treated patients. Treatment-emergent adverse events were similar in both treatment groups. Major adverse cardiovascular event (MACE), MACE plus unstable angina or congestive heart failure, and all-cause mortality hazard ratios were <1; the lower limit of the 95% CIs was <0.6, and the upper limit was >1.3. Conclusions: Roxadustat was non-inferior to ESAs in correcting and maintaining hemoglobin levels, with stable dosing and a comparable safety profile, in anemic patients receiving PD.
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Affiliation(s)
- Danilo Fliser
- Saarland University Medical Center, 66424 Homburg, Germany
| | - Sunil Bhandari
- Hull University Teaching Hospitals NHS Trust, Hull York Medical School, Hull HU3 2JZ, UK;
| | - Alberto Ortiz
- UAM, IIS-Fundacion Jimenez Diaz, 28015 Madrid, Spain;
| | - Vicki Santos
- Astellas Pharma, Inc., Northbrook, IL 60062, USA; (V.S.); (A.J.)
| | - Najib Khalife
- Astellas Pharma Europe Ltd., Addlestone KT15 2NX, UK;
| | | | - Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo 142-8666, Japan;
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Bengelloun Zahr S, Allata Y, El Mansoury M, Chouhani BA, Kabbali N, El Bardai G, Sqalli Houssaini T. Oral Liposomal Iron Versus Injectable Iron Sucrose for Anemia Treatment in Non-dialysis Chronic Kidney Disease Patients: A Non-inferiority Study. Cureus 2024; 16:e70114. [PMID: 39449947 PMCID: PMC11501097 DOI: 10.7759/cureus.70114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2024] [Indexed: 10/26/2024] Open
Abstract
Introduction Anemia is a prevalent and persistent complication in chronic kidney disease (CKD), particularly in advanced stages, contributing to the deterioration of renal function and diminishing patients' quality of life. Iron supplementation constitutes a cornerstone of anemia management in this population. Among various iron formulations, liposomal iron has emerged as a promising option due to its enhanced efficacy in replenishing iron reserves and improved tolerability. Objective This study aims to assess the comparative effects of intravenous and liposomal oral iron on hemoglobin levels in non-dialysis CKD patients. Additionally, it seeks to evaluate the rate of hemoglobin correction, iron reserve status during treatment, and therapeutic tolerance to these interventions. Materials and methods A randomized controlled trial enrolled CKD patients (stages 3-5, not on dialysis) with iron deficiency anemia (hemoglobin ≤ 12 g/dL, ferritin ≤ 100 ng/mL, transferrin saturation ≤ 25%). Participants were allocated to receive either daily oral liposomal iron (Group OS) at a dosage of 30 mg or intravenous iron-hydroxide sucrose complex weekly (Group IV) for three months. Follow-up extended through the treatment phase and two months post-withdrawal. Results Thirty-one CKD patients were randomized into two groups: 14 received intravenous iron (IV group) and 17 received oral iron (OS group). After excluding four patients, the final cohort comprised 27 individuals (IV group: n=13, OS group: n=14). Both iron treatments resulted in progressive hemoglobin increases, with the IV group showing a mean increase of 14.65% (p=0.049) compared to 4.78% (p=0.003) in the OS group. Secondary analysis revealed significant increases in ferritin levels (p<0.001) and transferrin saturation (TSAT) levels (p=0.031) in the IV group. Post-treatment follow-up demonstrated stable hemoglobin levels in the OS group and a consistent increase in ferritin levels in the IV group. Adverse reactions predominantly included hypotension in the IV group (4 (30.7%)) and constipation in the OS group (4 (28.4%)). Discussion and conclusion Anemia remains a significant challenge in CKD patients. Our study compares oral liposomal iron to injectable iron for anemia treatment, aiming to minimize hospitalizations for iron infusion, preserve venous capital, and mitigate potential harmful side effects. We found oral liposomal iron to be a safe and effective option for correcting anemia in non-dialysis CKD patients, albeit with lower efficacy in replenishing iron stores compared to IV iron. Comparative analysis with similar studies supports the non-inferiority of oral liposomal iron, although IV iron retains superiority in replenishing iron reserves.
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Affiliation(s)
| | - Yassine Allata
- Nephrology, Dialysis, and Transplantation, Hassan II University Hospital, Fez, MAR
- Laboratory of Epidemiology and Health Science Research, Faculty of Medicine, Sidi Mohammed Ben Abdellah University, Fez, MAR
| | - Mouna El Mansoury
- Nephrology, Dialysis, and Transplantation, Hassan II University Hospital, Fez, MAR
| | - Basmat Amal Chouhani
- Nephrology, Dialysis, and Transplantation, Hassan II University Hospital, Fez, MAR
- Laboratory of Epidemiology and Health Science Research, Faculty of Medicine, Sidi Mohammed Ben Abdellah University, Fez, MAR
| | - Nadia Kabbali
- Nephrology, Dialysis, and Transplantation, Hassan II University Hospital, Fez, MAR
- Laboratory of Epidemiology and Health Science Research, Faculty of Medicine, Sidi Mohammed Ben Abdellah University, Fez, MAR
| | - Ghita El Bardai
- Nephrology, Dialysis, and Transplantation, Hassan II University Hospital, Fez, MAR
- Laboratory of Epidemiology and Health Science Research, Faculty of Medicine, Sidi Mohammed Ben Abdellah University, Fez, MAR
| | - Tarik Sqalli Houssaini
- Laboratory of Epidemiology and Health Science Research, Faculty of Medicine, Sidi Mohammed Ben Abdellah University, Fez, MAR
- Nephrology, Dialysis, and Transplantation, Hassan II University Hospital, Fez, MAR
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Xu Q, Huang J, Liu Q, Wang X, Liu H, Song Y, Dou F, Lv S, Liu G. Short-term effect of low-dose roxadustat combined with erythropoiesis-stimulating agent treatment for erythropoietin-resistant anemia in patients undergoing maintenance hemodialysis. Front Endocrinol (Lausanne) 2024; 15:1372150. [PMID: 39010898 PMCID: PMC11246906 DOI: 10.3389/fendo.2024.1372150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 06/18/2024] [Indexed: 07/17/2024] Open
Abstract
Background Erythropoietin resistance is present in some patients with chronic kidney disease, especially in those undergoing hemodialysis, and is often treated using roxadustat rather than iron supplements and erythropoiesis-stimulating agents (ESAs). However, some patients cannot afford full doses of roxadustat. This retrospective study investigated the efficacy of low-dose roxadustat combined with recombinant human erythropoietin (rhuEPO) therapy in 39 patients with erythropoietin-resistant renal anemia undergoing maintenance hemodialysis (3-4 sessions/week). Methods The ability of the combination of low-dose roxadustat and rhuEPO to increase the hemoglobin concentration over 12 weeks was assessed. Markers of iron metabolism were evaluated. Eligible adults received 50-60% of the recommended dose of roxadustat and higher doses of rhuEPO. Results The mean hemoglobin level increased from 77.67 ± 11.18 g/dL to 92.0 ± 8.35 g/dL after treatment, and the hemoglobin response rate increased to 72%. The mean hematocrit level significantly increased from 24.26 ± 3.99% to 30.04 ± 3.69%. The soluble transferrin receptor level increased (27.29 ± 13.60 mg/L to 38.09 ± 12.78 mg/L), while the total iron binding capacity (49.22 ± 11.29 mg/L to 43.91 ± 12.88 mg/L) and ferritin level (171.05 ± 54.75 ng/mL to 140.83 ± 42.03 ng/mL) decreased. Conclusion Therefore, in patients with ESA-resistant anemia who are undergoing hemodialysis, the combination of low-dose roxadustat and rhuEPO effectively improves renal anemia and iron metabolism.
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Affiliation(s)
- Qiaoying Xu
- Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Nephrology Research Institute, Shandong University, Jinan, China
| | - Jingjing Huang
- Emergency Department, Caoxian People’s Hospital, Heze, China
| | - Qingzhen Liu
- Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Nephrology Research Institute, Shandong University, Jinan, China
| | - Xueling Wang
- Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Nephrology Research Institute, Shandong University, Jinan, China
| | - Haiying Liu
- Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Nephrology Research Institute, Shandong University, Jinan, China
| | - Yan Song
- Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Nephrology Research Institute, Shandong University, Jinan, China
| | - Fulin Dou
- Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Nephrology Research Institute, Shandong University, Jinan, China
| | - Shasha Lv
- Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Nephrology Research Institute, Shandong University, Jinan, China
| | - Gang Liu
- Department of Nephrology, Multidisciplinary Innovation Center for Nephrology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Nephrology Research Institute, Shandong University, Jinan, China
- Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, China
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10
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Kang KW. Preoperative consultation for determining the appropriate transfusion strategy. Blood Res 2024; 59:21. [PMID: 38847904 PMCID: PMC11161442 DOI: 10.1007/s44313-024-00021-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 05/31/2024] [Indexed: 06/10/2024] Open
Abstract
Surgical patients are at risk of postoperative complications and mortality, necessitating preoperative patient optimization through the identification and correction of modifiable risk factors. Although preoperative platelet transfusions aim to reduce the risk of bleeding, their efficacy remains uncertain. Similarly, red blood cell transfusion in patients with anemia does not reduce the risk of postoperative mortality and may exacerbate complications. Therefore, developing individualized strategies that focus on correcting preoperative complete blood count abnormalities and minimizing transfusion requirements are essential. This review aimed to examine complete blood count abnormalities and appropriate transfusion strategies to minimize postoperative complications.
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Affiliation(s)
- Ka-Won Kang
- Department of Internal Medicine, Division of Hematology-Oncology, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul, 02841, the Republic of Korea.
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11
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Tsui JC, Willett K, Cohen JB, Yu Y, VanderBeek BL. Erythropoiesis-Stimulating Agents and the Risk of Vision-Threatening Diabetic Retinopathy. Ophthalmic Epidemiol 2024; 31:249-257. [PMID: 37427852 PMCID: PMC10776797 DOI: 10.1080/09286586.2023.2235001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 06/27/2023] [Accepted: 07/03/2023] [Indexed: 07/11/2023]
Abstract
PURPOSE Animal studies have suggested that Erythropoiesis-Stimulating Agents (ESAs) may increase vascular endothelial growth factor (VEGF)-related retinopathies, but this effect is unclear in humans. This study evaluates the risk of vision-threatening diabetic retinopathy (VTDR), defined as either diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR), in patients exposed to an ESA. METHODS Two analyses were performed. First, a retrospective matched-cohort study was designed using a de-identified commercial and Medicare Advantage medical claims database. The ESA cohort of non-proliferative diabetic retinopathy patients who were new users of an ESA from 2000 to 2022 was matched to controls up to a 3:1 ratio. Exclusion criteria included less than 2 years in the plan, history of VTDR or history of other retinopathy. Multivariable Cox proportional hazards regression with inverse proportional treatment weighting (IPTW) was used to assess the hazard of developing VTDR, DME, and PDR. The second analysis was a self-controlled case series (SCCS) evaluating the incidence rate ratios (IRR) of VTDR during 30-day periods before and after initiating an ESA. RESULTS After inclusion of 1502 ESA-exposed patients compared with 2656 controls, IPTW-adjusted hazard ratios found the ESA cohort had an increased hazard of progressing to VTDR (HR = 3.0 95%CI:2.3-3.8;p < .001) and DME (HR = 3.4,95%CI:2.6-4.4,p < .001), but not PDR (HR = 1.0,95%CI:0.5-2.3,p = .95). Similar results were found within the SCCS which demonstrated higher IRRs for VTDR (IRRs = 1.09-1.18;p < .001) and DME (IRRs = 1.16-1.18;p < .001), but not increased IRRs in PDR (IRR = 0.92-0.97,p = .02-0.39). CONCLUSION ESAs are associated with higher risks for VTDR and DME, but not PDR. Those studying ESAs as adjunctive therapy for DR should be cautious of possible unintended effects.
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Affiliation(s)
- Jonathan C. Tsui
- Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Keirnan Willett
- Kittner Eye Center, Department of Ophthalmology, University of North Carolina, Chapel Hill, NC, USA
| | - Jordana B. Cohen
- Renal-Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania. Philadelphia, PA, USA
| | - Yinxi Yu
- Center for Preventative Ophthalmology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Brian L. VanderBeek
- Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Center for Pharmacoepidemiology Research and Training, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Leonard Davis Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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12
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Hamano T, Yamaguchi Y, Goto K, Mizokawa S, Ito Y, Dellanna F, Barratt J, Akizawa T. Risk Factors for Thromboembolic Events in Patients With Dialysis-Dependent CKD: Pooled Analysis of Phase 3 Roxadustat Trials in Japan. Adv Ther 2024; 41:1526-1552. [PMID: 38363463 PMCID: PMC10960897 DOI: 10.1007/s12325-023-02727-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 11/01/2023] [Indexed: 02/17/2024]
Abstract
INTRODUCTION Thromboembolic events have occurred in clinical trials of roxadustat. This post hoc analysis explored potential factors related to thromboembolic events in dialysis-dependent patients treated with roxadustat in four phase 3 clinical trials in Japan. METHODS Thromboembolic events with onset before and after week 12 were evaluated. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses using conditional logistic models with matched pairs of case-control data explored relationships between thromboembolic events and laboratory parameters. RESULTS Of the 444 patients, 56 thromboembolic events were observed in 44 patients during ≤ 52 weeks of treatment. The proportion of venous and arterial thromboembolic events gradually increased after week 12. Baseline risk factors included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), shorter dialysis vintage (< 4 months), and history of thromboembolism. The absence of concomitant intravenous or oral iron therapy (including ferric citrate) was associated with thromboembolic events before week 12 (hazard ratio 11.25; 95% confidence interval [CI] 3.36-37.71; vs presence). Case-control analysis revealed that low average transferrin saturation (< 10%; unadjusted odds ratio [OR] 6.25; 95% CI 1.52-25.62; vs ≥ 20%), high average transferrin level (≥ 2.5 g/L; unadjusted OR 4.36; 95% CI 1.23-15.39; vs < 2.0 g/L), and high average roxadustat dose (≥ 150 mg; unadjusted OR 5.95; 95% CI 1.07-33.16; vs < 50 mg) over the previous 8 weeks before the event onset were associated with thromboembolic events after week 12. However, adjustment for iron status extinguished the significant relationship between roxadustat dose and events. Multivariate case-control analysis showed that increased transferrin from baseline (≥ 1.0 g/L; adjusted OR 7.85; 95% CI 1.82-33.90; vs < 0.5 g/dL) and decreased mean corpuscular volume (< - 2 fL; adjusted OR 5.55; 95% CI 1.73-17.83; vs ≥ 0 fL) were associated with increased risk of thromboembolic events. CONCLUSION In addition to established risk factors, iron deficiency may be related to thromboembolic events. Graphical Abstract available for this article. TRIAL REGISTRATION NCT02780726, NCT02952092, NCT02780141, NCT02779764.
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Affiliation(s)
- Takayuki Hamano
- Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, 1, Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Aichi, 467-8602, Japan.
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13
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Suttichet TB, Chamnanphon M, Pongpanich M, Chokyakorn S, Kupatawintu P, Srichomthong C, Chetruengchai W, Chuntakaruk H, Rungrotmongkol T, Chariyavilaskul P, Shotelersuk V, Praditpornsilpa K. HLA-B*46:01:01:01 and HLA-DRB1*09:01:02:01 are associated with anti-rHuEPO-induced pure red cell aplasia. Sci Rep 2023; 13:22759. [PMID: 38123661 PMCID: PMC10733298 DOI: 10.1038/s41598-023-50211-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 12/16/2023] [Indexed: 12/23/2023] Open
Abstract
Treatment of anemia in patients with chronic kidney disease (CKD) with recombinant human erythropoietin (rHuEPO) can be disrupted by a severe complication, anti-rHuEPO-induced pure red cell aplasia (PRCA). Specific HLA genotypes may have played a role in the high incidence of PRCA in Thai patients (1.7/1,000 patient years vs. 0.03/10,000 patient years in Caucasians). We conducted a case-control study in 157 CKD patients with anti-rHuEPO-induced PRCA and 56 controls. The HLA typing was determined by sequencing using a highly accurate multiplex single-molecule, real-time, long-read sequencing platform. Four analytical models were deployed: Model 1 (additive: accounts for the number of alleles), Model 2 (dominant: accounts for only the presence or absence of alleles), Model 3 (adjusted additive with rHuEPO types) and Model 4 (adjusted dominant with rHuEPO types). HLA-B*46:01:01:01 and DRB1*09:01:02:01 were found to be independent risk markers for anti-rHuEPO-induced PRCA in all models [OR (95%CI), p-values for B*46:01:01:01: 4.58 (1.55-13.51), 0.006; 4.63 (1.56-13.75), 0.006; 5.72 (1.67-19.67), 0.006; and 5.81 (1.68-20.09), 0.005; for DRB1*09:01:02:01: 3.99 (1.28-12.49), 0.017, 4.50 (1.32-15.40), 0.016, 3.42 (1.09-10.74), 0.035, and 3.75 (1.08-13.07), 0.038, in Models 1-4, respectively. HLA-B*46:01:01:01 and DRB1*09:01:02:01 are susceptible alleles for anti-rHuEPO-induced PRCA. These findings support the role of HLA genotyping in helping to monitor patients receiving rHuEPO treatment.
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Affiliation(s)
- Thitima Benjachat Suttichet
- Center of Excellence in Clinical Pharmacokinetics and Pharmacogenomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Monpat Chamnanphon
- Center of Excellence in Clinical Pharmacokinetics and Pharmacogenomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Monnat Pongpanich
- Department of Mathematics and Computer Science, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
- Faculty of Science, Omics Sciences and Bioinformatics Center, Chulalongkorn University, Bangkok, Thailand
| | - Sarun Chokyakorn
- Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | - Chalurmpon Srichomthong
- Department of Pediatrics, Faculty of Medicine, Center of Excellence for Medical Genomics, Chulalongkorn University, Bangkok, Thailand
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
| | - Wanna Chetruengchai
- Department of Pediatrics, Faculty of Medicine, Center of Excellence for Medical Genomics, Chulalongkorn University, Bangkok, Thailand
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
| | - Hathaichanok Chuntakaruk
- Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand
- Department of Biochemistry, Faculty of Science, Center of Excellence in Structural and Computational Biology, Chulalongkorn University, Bangkok, Thailand
| | - Thanyada Rungrotmongkol
- Program in Bioinformatics and Computational Biology, Graduate School, Chulalongkorn University, Bangkok, Thailand
- Department of Biochemistry, Faculty of Science, Center of Excellence in Structural and Computational Biology, Chulalongkorn University, Bangkok, Thailand
| | - Pajaree Chariyavilaskul
- Center of Excellence in Clinical Pharmacokinetics and Pharmacogenomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
- Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
| | - Vorasuk Shotelersuk
- Department of Pediatrics, Faculty of Medicine, Center of Excellence for Medical Genomics, Chulalongkorn University, Bangkok, Thailand
- Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand
| | - Kearkiat Praditpornsilpa
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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14
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Lacquaniti A, Gargano R, Campo S, Casuscelli di Tocco T, Schifilliti S, Monardo P. The Switch from Ferric Gluconate to Ferric Carboxymaltose in Hemodialysis Patients Acts on Iron Metabolism, Erythropoietin, and Costs: A Retrospective Analysis. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:1071. [PMID: 37374275 DOI: 10.3390/medicina59061071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/18/2023] [Accepted: 05/29/2023] [Indexed: 06/29/2023]
Abstract
Background and Objectives: Iron deficiency and anemia characterize patients on chronic hemodialysis (HD). Available intravenous iron agents, such as ferric gluconate (FG) and ferric carboxymaltose (FCM), vary in dosing regimens and safety profiles. The aim of the present study was to analyze the modification of the iron status, the correction of anemia, and the economic implications after the shift from FG to FCM therapy in chronic HD patients. We evaluated, during the study, the variations in iron metabolism, assessing ferritin and transferrin saturation, erythropoietin-stimulating agent (ESA) doses and the number of administrations, the effects on anemic status, and consequent costs. Materials and Methods: A retrospective study was performed with a follow-up period of 24 months, enrolling forty-two HD patients. The enrolment phase started in January 2015, when patients were treated with iv FG, and continued until December 2015, when FG was discontinued, and, after a wash-out period, the same patients were treated with FCM. Results: The iron switch reduced the administered dose of ESA by 1610.500 UI (31% of reduction; p < 0.001) during the entire study period and reduced the erythropoietin resistance index (ERI) (10.1 ± 0.4 vs. 14.8 ± 0.5; p < 0.0001). The FCM group had the highest percentage of patients who did not require ESA treatment during the study period. The FCM patients were characterized by higher levels of iron (p = 0.04), ferritin (p < 0.001), and TSAT levels (p < 0.001) compared to the FG patients. The annual cost during FG infusion was estimated at EUR 105,390.2, while one year of treatment with FCM had a total cost of EUR 84,180.7 (a difference of EUR 21,209.51 (20%), saving EUR 42.1 per patient/month (p < 0.0001). Conclusions: FCM was a more effective treatment option than FG, reducing ESA dose requirements, increasing Hb levels, and improving iron status. The reduced ESA doses and the decreased number of patients needing ESA were the main factors for reducing overall costs.
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Affiliation(s)
| | - Romana Gargano
- Department of Economics, University of Messina, 98100 Messina, Italy
| | - Susanna Campo
- Nephrology and Dialysis Unit, Papardo Hospital, 98158 Messina, Italy
| | | | - Silvia Schifilliti
- Faculty of Pharmacy, Clinical Pharmacy Fellowship, University of Messina Annunziata Campus, 98168 Messina, Italy
| | - Paolo Monardo
- Nephrology and Dialysis Unit, Papardo Hospital, 98158 Messina, Italy
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15
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Kaka N, Sethi Y, Patel N, Kaiwan O, Al-Inaya Y, Manchanda K, Uniyal N. Endocrine manifestations of chronic kidney disease and their evolving management: A systematic review. Dis Mon 2022; 68:101466. [PMID: 35965104 DOI: 10.1016/j.disamonth.2022.101466] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Chronic Kidney Disease (CKD) shows a wide range of renal abnormalities including the excretory, metabolic, endocrine, and homeostatic function of the kidney. The prognostic impact of the 'endocrine manifestations' which are often overlooked by clinicians cannot be overstated. METHODS AND OBJECTIVES A systematic review was attempted to provide a comprehensive overview of all endocrine abnormalities of CKD and their evolving principles of management, searching databases of PubMed, Embase, and Scopus and covering the literature between 2002 and 2022. RESULTS The endocrine derangements in CKD can be attributed to a myriad of pathologic processes, in particular decreased clearance, impaired endogenous hormone production, uremia-induced cellular dysfunction, and activation of systemic inflammatory pathways. The major disorders include anemia, hyperprolactinemia, insulin resistance, reproductive hormone deficiency, thyroid hormone deficiency, and serum FGF (Fibroblast Growth Factor) alteration. Long-term effects of CKD also include malnutrition and increased cardiovascular risk. The recent times have unveiled their detailed pathogenesis and have seen an evolution in the principles of management which necessitates a revision of current guidelines. CONCLUSION Increased advertence regarding the pathology, impact, and management of these endocrine derangements can help in reducing morbidity as well as mortality in the CKD patients by allowing prompt individualized treatment. Moreover, with timely and appropriate intervention, a long-term reduction in complications, as well as an enhanced quality of life, can be achieved in patients with CKD.
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Affiliation(s)
- Nirja Kaka
- GMERS Medical College, Himmatnagar, Gujarat 382007, India
| | - Yashendra Sethi
- Department of Medicine, Government Doon Medical College, Dehradun, Uttarakhand, India
| | - Neil Patel
- GMERS Medical College, Himmatnagar, Gujarat 382007, India.
| | | | | | | | - Nidhi Uniyal
- Department of Medicine, Government Doon Medical College, Dehradun, Uttarakhand, India
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16
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Wu HH, Chinnadurai R. Erythropoietin-Stimulating Agent Hyporesponsiveness in Patients Living with Chronic Kidney Disease. KIDNEY DISEASES (BASEL, SWITZERLAND) 2022; 8:103-114. [PMID: 35527989 PMCID: PMC9021651 DOI: 10.1159/000521162] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 11/22/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Erythropoietin-stimulating agent (ESA) hyporesponsiveness is commonly observed in patients with anemia secondary to chronic kidney disease (CKD). Because of its complexity, a global consensus on how we should define ESA hyporesponsiveness remains unavailable. The reported prevalence and demographic information on ESA hyporesponsiveness within the CKD population are variable with no consensus definition. SUMMARY ESA hyporesponsiveness is defined as having no increase in hemoglobin concentration from baseline after the first month of treatment on appropriate weight-based dosing. The important factors associated with ESA hyporesponsiveness include absolute or functional iron deficiency, inflammation, and uremia. Hepcidin has been demonstrated to play an important role in this process. Mineral bone disease secondary to CKD and non-iron malnutrition among other factors are also associated with ESA hyporesponsiveness. There is continued debate toward determining a gold-standard treatment pathway to manage ESA hyporesponsiveness. The development of hypoxia-inducing factor-stabilizers brings new insights and opportunities in the management of ESA hyporesponsiveness. KEY MESSAGE Management of ESA hyporesponsiveness involves a comprehensive multidisciplinary team approach to address its risk factors. The progression of basic and clinical research on identifying risk factors and management of ESA hyporesponsiveness brings greater hope on finding solutions to eventually tackling one of the most difficult problems in the topic of anemia in CKD.
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Affiliation(s)
- Henry H.L. Wu
- Department of Renal Medicine, Lancashire Teaching Hospitals NHS Foundation Trust, Preston, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Rajkumar Chinnadurai
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom
- Department of Renal Medicine, Northern Care Alliance NHS Foundation Trust, Salford, United Kingdom
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17
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Sepah YJ, Nguyen QD, Yamaguchi Y, Otsuka T, Majikawa Y, Reusch M, Akizawa T. Two Phase 3 Studies on Ophthalmological Effects of Roxadustat versus Darbepoetin. Kidney Int Rep 2022; 7:763-775. [PMID: 35497806 PMCID: PMC9039484 DOI: 10.1016/j.ekir.2022.01.1045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 12/13/2021] [Accepted: 01/10/2022] [Indexed: 12/02/2022] Open
Abstract
Introduction Roxadustat is an orally administered hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor that represents a novel therapeutic option for patients with anemia of chronic kidney disease (CKD). Methods Conducted in Japan, CL-0307 (NCT02952092) and CL-310 (NCT02988973) were phase 3, darbepoetin alfa (DA)-controlled studies conducted in dialysis-dependent (DD) and non–DD (NDD) patients with CKD, respectively, where patients were randomized to receive roxadustat or DA. Ophthalmic imaging and assessments of visual acuity were performed up to week 24 or at study discontinuation. Ophthalmic imaging was centrally evaluated by independent readers masked to the study treatment. Results In CL-0307, 302 patients (roxadustat, n = 150; DA, n = 152) received ≥1 dose of the study drug and were included in this analysis. In CL-0310, 262 patients (roxadustat, n = 131; DA, n = 131) received ≥1 dose of the study drug and were included in this analysis. Proportions of DD patients with new or worsening retinal hemorrhages (RHs) in the roxadustat group and DA group were 32.4% (46 of 142) and 36.6% (53 of 145), respectively. Proportions of NDD patients with CKD with new or worsening RH in the roxadustat and DA groups were 31.4% (38 of 121) and 39.8% (51 of 128), respectively. Similar trends were apparent in subgroup analyses: patients with/without RH at baseline and with/without diabetes mellitus at baseline. In both studies, there were no differences in retinal thickness, visual acuity, presence of hard exudates or cotton wool spots, or presence of intra- and subretinal fluid between groups, at any given time point. Conclusion In these studies, roxadustat, compared with DA, was not associated with an increased risk of adverse ophthalmologic events in these cohorts.
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Affiliation(s)
- Yasir J. Sepah
- Spencer Center for Vision Research, Byers Eye Institute, Stanford School of Medicine, Stanford, California, USA
- Ocular Imaging Research and Reading Center, Sunnyvale, California, USA
- Correspondence: Yasir J. Sepah, Spencer Center for Vision Research, Byers Eye Institute at Stanford University, 2370 Watson Court, Suite 200, Palo Alto, California 94303, USA.
| | - Quan Dong Nguyen
- Spencer Center for Vision Research, Byers Eye Institute, Stanford School of Medicine, Stanford, California, USA
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18
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Yamamoto H, Nobori K, Matsuda Y, Hayashi Y, Hayasaki T, Akizawa T. Molidustat for Renal Anemia in Nondialysis Patients Previously Treated with Erythropoiesis-Stimulating Agents: A Randomized, Open-Label, Phase 3 Study. Am J Nephrol 2021; 52:884-893. [PMID: 34569482 DOI: 10.1159/000518072] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Accepted: 06/10/2021] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Erythropoiesis-stimulating agents (ESAs) are the current standard of care for anemia due to chronic kidney disease (CKD) in patients not undergoing dialysis. Molidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, is being investigated as an alternative treatment for renal anemia. Molidustat was evaluated in five phase 3 studies, the molidustat once daily improves renal anemia by inducing erythropoietin (MIYABI) program. The present study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia not undergoing dialysis and previously treated with ESAs. METHODS This was a 52-week, active-controlled, randomized (1:1), open-label, parallel-group, multicenter, phase 3 study in Japanese patients with anemia due to CKD (stages 3-5). Molidustat was initiated at 25 mg or 50 mg once daily according to previous ESA dose. The ESA darbepoetin alfa (darbepoetin) was initiated at a starting dose in accordance with the previous ESA dose and injected subcutaneously once every 2 or 4 weeks. Doses were regularly titrated to maintain hemoglobin (Hb) levels in the target range of 11.0-13.0 g/dL. The primary efficacy outcome was the mean Hb level and its change from baseline during the evaluation period (weeks 30-36). The safety outcomes included evaluation of all adverse events. RESULTS In total, 164 patients were randomized to receive molidustat (n = 82) or darbepoetin (n = 82). Baseline characteristics were well balanced. Mean (standard deviation) Hb levels at baseline were 11.31 (0.68) g/dL for molidustat and 11.27 (0.64) g/dL for darbepoetin. The mean (95% confidence interval [CI]) for mean Hb levels during the evaluation period for molidustat (11.67 [11.48-11.85] g/dL) and darbepoetin (11.53 [11.31-11.74] g/dL) was within the target range. Based on a noninferiority margin of 1.0 g/dL, molidustat was noninferior to darbepoetin regarding the change in mean Hb level during the evaluation period from baseline, with a least squares mean (95% CI) difference (molidustat-darbepoetin) of 0.13 (-0.15, 0.40) g/dL. The proportion of patients who reported at least 1 treatment-emergent adverse event (TEAE) was 92.7% for molidustat and 96.3% for darbepoetin. TEAEs leading to death were reported in 2 patients (2.4%) in the molidustat group and none in the darbepoetin group; serious TEAEs were reported in 32.9% and 26.8% of patients, respectively. DISCUSSION/CONCLUSION Molidustat was noninferior to darbepoetin and maintained Hb levels in the prespecified target range in patients with renal anemia not undergoing dialysis and previously treated with ESA. Molidustat was well tolerated, and no new safety signal was observed.
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Affiliation(s)
- Hiroyasu Yamamoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kiyoshi Nobori
- Research and Development Japan, Bayer Yakuhin, Ltd., Osaka, Japan
| | - Yoshimi Matsuda
- Research and Development Japan, Bayer Yakuhin, Ltd., Osaka, Japan
| | - Yasuhiro Hayashi
- Medical Affairs and Pharmacovigilance, Bayer Yakuhin, Ltd., Osaka, Japan
| | - Takanori Hayasaki
- Medical Affairs and Pharmacovigilance, Bayer Yakuhin, Ltd., Osaka, Japan
| | - Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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19
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Zhu XW, Zhang CX, Xu TH, Jiang GN, Yao L. Efficacy of roxadustat in treatment of peritoneal dialysis patients with renal anaemia. World J Clin Cases 2021; 9:7682-7692. [PMID: 34621819 PMCID: PMC8462256 DOI: 10.12998/wjcc.v9.i26.7682] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/02/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There are no studies on the use of roxadustat in patients on regular peritoneal dialysis in China.
AIM To observe the efficacy and safety of roxadustat in treating renal anaemia in peritoneal dialysis patients.
METHODS Patients with renal anaemia who were regularly followed at the Peritoneal Dialysis Center of the First Affiliated Hospital of China Medical University from November 1, 2019 to June 30, 2020 were selected. A before-and-after self-control design was performed to retrospectively analyse the treatment effects on anaemia in patients treated with recombinant human erythropoietin (EPO) and roxadustat.
RESULTS A total of 31 patients with renal anaemia on long-term peritoneal dialysis treated with roxadustat were included. Haemoglobin (Hb) levels were maintained or increased in all patients (100%), and no patients had a decrease in Hb compared with the previous phase. Patients had a mean Hb of 86.2 ± 14.8 g/L with Hb compliance (Hb ≥ 110 g/L) of 16.1% during the EPO phase and a mean Hb of 112.4 ± 18.5 g/L with Hb compliance of 67.7% during the roxadustat phase. No major adverse cardiovascular events occurred in any patient.
CONCLUSION The application of roxadustat in peritoneal dialysis patients with renal anaemia can effectively improve the Hb compliance rate.
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Affiliation(s)
- Xin-Wang Zhu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Cong-Xiao Zhang
- Blood Purification Center, The Fourth People’s Hospital of Shenyang, Shenyang 110031, Liaoning Province, China
| | - Tian-Hua Xu
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Guan-Nan Jiang
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li Yao
- Department of Nephrology, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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20
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Borawski B, Malyszko JS, Kwiatkowska M, Malyszko J. Current Status of Renal Anemia Pharmacotherapy-What Can We Offer Today. J Clin Med 2021; 10:jcm10184149. [PMID: 34575261 PMCID: PMC8470821 DOI: 10.3390/jcm10184149] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 08/30/2021] [Accepted: 09/07/2021] [Indexed: 12/19/2022] Open
Abstract
Chronic kidney disease (CKD) is one of the fastest-growing major causes of death internationally. Better treatment of CKD and its complications is crucial to reverse this negative trend. Anemia is a frequent complication of CKD and is associated with unfavorable clinical outcomes. It is a devastating complication of progressive kidney disease, that negatively affects also the quality of life. The prevalence of anemia increases in parallel with CKD progression. The aim of this review is to summarize the current knowledge on therapy of renal anemia. Iron therapy, blood transfusions, and erythropoietin stimulating agents are still the mainstay of renal anemia treatment. There are several novel agents on the horizon that might provide therapeutic opportunities in CKD. The potential therapeutic options target the hepcidin–ferroportin axis, which is the master regulator of iron homeostasis, and the BMP-SMAD pathway, which regulates hepcidin expression in the liver. An inhibition of prolyl hydroxylase is a new therapeutic option becoming available for the treatment of anemia in CKD patients. This new class of drugs stimulates the synthesis of endogenous erythropoietin and increases iron availability. We also summarized the effects of prolyl hydroxylase inhibitors on iron parameters, including hepcidin, as their action on the hematological parameters. They could be of particular interest in the out-patient population with CKD and patients with ESA hyporesponsiveness. However, current knowledge is limited and still awaits clinical validation. One should be aware of the potential risks and benefits of novel, sophisticated therapies.
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Affiliation(s)
- Bartłomiej Borawski
- Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (B.B.); (M.K.)
| | - Jacek Stanislaw Malyszko
- 1st Department of Nephrology and Transplantology, Medical University of Bialystok, 15-540 Bialystok, Poland;
| | - Marlena Kwiatkowska
- Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (B.B.); (M.K.)
| | - Jolanta Malyszko
- Department of Nephrology, Dialysis and Internal Medicine, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland; (B.B.); (M.K.)
- Correspondence:
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21
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Mulvagh SL, Mullen KA, Nerenberg KA, Kirkham AA, Green CR, Dhukai AR, Grewal J, Hardy M, Harvey PJ, Ahmed SB, Hart D, Levinsson AL, Parry M, Foulds HJ, Pacheco C, Dumanski SM, Smith G, Norris CM. The Canadian Women’s Heart Health Alliance Atlas on the Epidemiology, Diagnosis, and Management of Cardiovascular Disease in Women — Chapter 4: Sex- and Gender-Unique Disparities: CVD Across the Lifespan of a Woman. CJC Open 2021; 4:115-132. [PMID: 35198930 PMCID: PMC8843896 DOI: 10.1016/j.cjco.2021.09.013] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 09/13/2021] [Indexed: 02/09/2023] Open
Abstract
Women have unique sex- and gender-related risk factors for cardiovascular disease (CVD) that can present or evolve over their lifespan. Pregnancy-associated conditions, polycystic ovarian syndrome, and menopause can increase a woman’s risk of CVD. Women are at greater risk for autoimmune rheumatic disorders, which play a role in the predisposition and pathogenesis of CVD. The influence of traditional CVD risk factors (eg, smoking, hypertension, diabetes, obesity, physical inactivity, depression, anxiety, and family history) is greater in women than men. Finally, there are sex differences in the response to treatments for CVD risk and comorbid disease processes. In this Atlas chapter we review sex- and gender-unique CVD risk factors that can occur across a woman’s lifespan, with the aim to reduce knowledge gaps and guide the development of optimal strategies for awareness and treatment.
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22
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Akizawa T, Nobori K, Matsuda Y, Taki K, Hayashi Y, Hayasaki T, Yamamoto H. Molidustat for the treatment of anemia in Japanese patients undergoing peritoneal dialysis: a single-arm, open-label, phase 3 study. Ther Apher Dial 2021; 26:368-377. [PMID: 34310049 PMCID: PMC9290504 DOI: 10.1111/1744-9987.13713] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 07/21/2021] [Indexed: 02/06/2023]
Abstract
This 36‐week, open‐label, single‐arm, phase 3 study investigated the safety and efficacy of molidustat in Japanese patients with renal anemia undergoing peritoneal dialysis. Molidustat was titrated every 4 weeks to maintain Hb levels within the target range (≥11.0 and <13.0 g/dL). The primary efficacy outcome was the responder rate, defined as the proportion of patients who met all of the following criteria: (1) mean Hb levels in the target range during the evaluation period (Weeks 30–36); (2) ≥50% of Hb values within the target range during the evaluation period; and (3) no rescue treatment before the end of the evaluation period. Overall, 51 patients received molidustat. The responder rate (95% CI) during the evaluation period was 54.9% (40.3, 68.9). Overall, 98.0% of patients experienced at least 1 adverse event during the study. No deaths were reported. Molidustat maintained Hb levels in the prespecified range in more than half of the patients and was well tolerated.
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Affiliation(s)
- Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Kiyoshi Nobori
- Bayer Yakuhin Ltd, Research & Development Japan, Osaka, Japan
| | - Yoshimi Matsuda
- Bayer Yakuhin Ltd, Research & Development Japan, Osaka, Japan
| | - Kentaro Taki
- Bayer Yakuhin Ltd, Medical Affairs and Pharmacovigilance, Osaka, Japan
| | - Yasuhiro Hayashi
- Bayer Yakuhin Ltd, Medical Affairs and Pharmacovigilance, Osaka, Japan
| | - Takanori Hayasaki
- Bayer Yakuhin Ltd, Medical Affairs and Pharmacovigilance, Osaka, Japan
| | - Hiroyasu Yamamoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
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23
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Zhang L, Hou J, Li J, Su SS, Xue S. Roxadustat for the treatment of anemia in patients with chronic kidney diseases: a meta-analysis. Aging (Albany NY) 2021; 13:17914-17929. [PMID: 34115611 PMCID: PMC8312415 DOI: 10.18632/aging.203143] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 05/17/2021] [Indexed: 12/12/2022]
Abstract
Background: Anemia is a common complication of chronic kidney disease (CKD). Treating renal anemia with erythropoiesis-stimulating agents (ESAs) or erythropoietin analogs is effective but has side effects. Therefore, we performed a meta-analysis to assess the efficacy and safety of roxadustat in treating CKD-induced anemia. Methods: We searched publications online and conducted a meta-analysis and calculated relative risks with 95% confidence intervals (CIs) for dichotomous data and mean differences (MD) with 95% CIs for continuous data. Results: Of 110 articles, nine were included that contained 12 data sets and 11 randomized control trials on roxadustat. In the non-dialysis-dependent (NDD) high-dose/low-dose subgroups, the change in hemoglobin (Hb) levels was significantly higher in the roxadustat group than in the placebo group (P<0.0001, P=0.001, respectively). The Hb response rate of the roxadustat is higher in the NDD subgroup than in the placebo group (P<0.00001, MD=6.92, 95% CI: 4.03, 11.89). However, in the dialysis-dependent subgroup, there was no significant difference in the change in Hb levels or the Hb response rate between the roxadustat and ESA groups. There was no change in the mortality in the roxadustat group compared to that in the placebo/ESA group. Hyperkalemia may be a side effect of roxadustat. Conclusions: Roxadustat elevated the serum Hb levels in a manner similar to that observed for ESAs. Roxadustat raised the Hb levels more significantly than the placebo and showed a higher Hb response rate than the placebo group in NDD patients. Roxadustat is a safe and effective drug for anemia in CKD patients.
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Affiliation(s)
- Li Zhang
- Department of Nephrology, The First Hospital of Jilin University, Jilin Province, China
| | - Jie Hou
- Department of Nephrology, The First Hospital of Jilin University, Jilin Province, China
| | - Jia Li
- Department of Nephrology, The First Hospital of Jilin University, Jilin Province, China
| | - Sen-Sen Su
- Department of Nephrology, The First Hospital of Jilin University, Jilin Province, China
| | - Shuai Xue
- Department of Thyroid Surgery, The First Hospital of Jilin University, Jilin Province, China
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24
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Barratt J, Andric B, Tataradze A, Schömig M, Reusch M, Valluri U, Mariat C. Roxadustat for the treatment of anaemia in chronic kidney disease patients not on dialysis: a phase 3, randomised, open-label, active-controlled study (DOLOMITES). Nephrol Dial Transplant 2021; 36:1616-1628. [PMID: 34077510 PMCID: PMC8396401 DOI: 10.1093/ndt/gfab191] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Indexed: 02/07/2023] Open
Abstract
Background Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor, is being evaluated for treatment of anaemia of chronic kidney disease (CKD). Methods This randomized, open-label, active-controlled Phase 3 study compared roxadustat versus darbepoetin alfa (DA) in non-dialysis-dependent (NDD) CKD patients with anaemia for ≤104 weeks. Doses were titrated to correct and maintain haemoglobin (Hb) within 10.0–12.0 g/dL. The primary endpoint was Hb response in the full analysis set, defined as Hb ≥11.0 g/dL and Hb change from baseline (BL; CFB) ≥1.0 g/dL in patients with BL Hb >8.0 g/dL or CFB ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL during the first 24 weeks of treatment without rescue therapy (non-inferiority margin, −15%). Key secondary endpoints included change in low-density lipoprotein (LDL), time to first intravenous (IV) iron use, change in mean arterial pressure (MAP) and time to hypertension occurrence. Adverse events were assessed. Results Of 616 randomized patients (roxadustat, 323; DA, 293), 424 completed treatment (roxadustat, 215; DA, 209). Hb response with roxadustat was non-inferior to DA (roxadustat: 256/286, 89.5% versus DA: 213/273, 78.0%, difference 11.51%, 95% confidence interval 5.66–17.36%). Roxadustat maintained Hb for up to 2 years. Roxadustat was non-inferior to DA for change in MAP and time to occurrence of hypertension and superior for change in LDL and time to first IV iron use. Safety profiles were comparable between groups. Findings suggest that there was no difference between groups regarding the composite endpoints major adverse cardiovascular events (MACEs) and MACE+ [MACE: 0.81 (0.52–1.25), P = 0.339; MACE+: 0.90 (0.61–1.32), P = 0.583]. Conclusions Roxadustat is a viable option to treat anaemia in NDD CKD patients maintaining Hb levels for up to 104 weeks.
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Affiliation(s)
| | | | | | | | | | - Udaya Valluri
- Astellas Pharma Global Development, Inc., Northbrook, Illinois, USA
| | - Christophe Mariat
- CHU St Etienne, Service Nephrologie Dialyse Transplantation, St Etienne, France
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25
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Yang Q, Wang X. A case report of rhabdomyolysis caused by the use of roxadustat in the treatment caused by renal anaemia. Int J Clin Pract 2021; 75:e14011. [PMID: 33411966 PMCID: PMC8243928 DOI: 10.1111/ijcp.14011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 12/06/2020] [Indexed: 12/18/2022] Open
Abstract
CASE PRESENTATION In this case, we share a case of one of our patients developed rhabdomyolysis after he was administered roxadustat to treat anaemia caused by chronic renal failure. DISCUSSION More than 1.2 million people died from chronic kidney damage (CKD) globally, in 2017. Anaemia is a common complication of CKD. Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Roxadustat is often used to treat anaemia caused by renal failure. Its adverse effects include high blood pressure, myocardial infarction, heart failure, high potassium, and dizziness; however, there are no reports about rhabdomyolysis associated with roxadustat. CONCLUSION Physicians should be alert about the occurrence of rhabdomyolysis when roxadustat is used.
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Affiliation(s)
- Qin Yang
- Department of NephrologyAffiliated Zhongshan Hospital of Dalian UniversityDalianChina
| | - Xin Wang
- Department of NephrologyAffiliated Zhongshan Hospital of Dalian UniversityDalianChina
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26
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Groenendaal-van de Meent D, Kerbusch V, Barroso-Fernandez B, den Adel M, van Dijk J, Golor G, Schaddelee M. Effect of the Phosphate Binders Sevelamer Carbonate and Calcium Acetate on the Pharmacokinetics of Roxadustat After Concomitant or Time-Separated Administration in Healthy Individuals. Clin Ther 2021; 43:1079-1091. [PMID: 33962762 DOI: 10.1016/j.clinthera.2021.03.025] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 03/23/2021] [Accepted: 03/31/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, treats anemia in chronic kidney disease. Hyperphosphatemia, a common complication in chronic kidney disease, is treated with phosphate binders (PBs). This study in healthy individuals investigated the effect of 2 PBs, sevelamer carbonate and calcium acetate, on the pharmacokinetic properties of a single oral dose of roxadustat administered concomitantly or with a time lag. METHODS This 2-part, Phase I study was conducted with an open-label, randomized, 3-way (part 1) or 5-way (part 2) crossover design, with 5-day treatment periods. On day 1 of each period, participants received 200 mg roxadustat administered alone or (1) concomitantly with sevelamer carbonate (2400 mg) or calcium acetate (1900 mg) (part 1) or (2) 1 hour before or 1, 2, or 3 hours after sevelamer carbonate (part 2A) or calcium acetate (part 2B); 5 additional PB doses were administered during 2 days. In both parts, PBs were administered with meals. Primary pharmacokinetic variables were AUC0-∞ and Cmax. FINDINGS: Twenty-four individuals were randomized in part 1; 60 individuals were randomized in part 2 (part 2A, n = 30; part 2B, n = 30). All participants completed the study in part 1; 28 and 27 individuals completed the study in part 2A and part 2B, respectively. Compared with roxadustat alone, concomitant sevelamer carbonate and calcium acetate administration reduced roxadustat's AUC0-∞ by 67% (90% CI, 63.5%-69.3%) and 46% (90% CI, 41.7%-50.9%), respectively, and reduced roxadustat's Cmax by 66% (90% CI, 61.6%-69.4%) and 52% (90% CI, 46.2%-57.2%), respectively. This effect was attenuated when roxadustat and PB administration occurred with a time lag. Roxadustat's AUC0-∞ was reduced by 41% and 22% to 25%, respectively, when roxadustat was administered 1 hour before or 1 to 3 hours after sevelamer carbonate and by 31% and 14% to 18%, respectively, when administered 1 hour before or 1 to 3 hours after calcium acetate. Roxadustat's Cmax was reduced by 26% and 12%, respectively, when roxadustat was administered 1 hour before and 1 hour after sevelamer carbonate; it was reduced by 19% when administered 1 hour before calcium acetate and was not affected when administered 1 hour after. Roxadustat was well tolerated. IMPLICATIONS Concomitant administration of roxadustat with sevelamer carbonate or calcium acetate reduced exposure to roxadustat in healthy individuals. This effect was attenuated when roxadustat was administered ≥1 hour before or after either PB. Results from this study helped inform dosing and administration guidelines aimed at reducing interactions between roxadustat and these PBs. (Clin Ther. 2021;XX:XXX-XXX) © 2021 Elsevier HS Journals, Inc.
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Affiliation(s)
| | | | - Begona Barroso-Fernandez
- Department of Drug Discovery Research and Bioanalysis, Astellas Pharma Europe B.V., Leiden, the Netherlands
| | - Martin den Adel
- Department of Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe B.V., Leiden, the Netherlands
| | - Jan van Dijk
- Department of Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe B.V., Leiden, the Netherlands
| | - Georg Golor
- Department of Clinical Operations, Parexel GmbH, Berlin, Germany
| | - Marloes Schaddelee
- Department of Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe B.V., Leiden, the Netherlands
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Cirillo L, Somma C, Allinovi M, Bagalà A, Ferro G, Di Marcantonio E, Bellelli S, Dallari LA, Ballo P, Dattolo PC. Ferric carboxymaltose vs. ferrous sulfate for the treatment of anemia in advanced chronic kidney disease: an observational retrospective study and cost analysis. Sci Rep 2021; 11:7463. [PMID: 33811227 PMCID: PMC8018957 DOI: 10.1038/s41598-021-86769-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 03/15/2021] [Indexed: 01/02/2023] Open
Abstract
In non-dialysis-dependent chronic kidney disease (NDD-CKD), erythropoiesis-stimulating agents (ESAs) and iron supplementation are essential for anemia management. Ferric carboxymaltose (FCM) is a relatively novel intravenous iron formulation used in different clinical settings, although scarce data exist in NDD-CKD patients. Primary objective of this study was to retrospectively evaluate the efficacy of FCM compared with oral ferrous sulfate for the treatment of iron-deficiency anemia in a cohort of NDD-CKD patients, considering also the treatment costs. This was a monocentric, retrospective observational study reviewing 349 NDD-CKD patients attending an outpatient clinic between June 2013 and December 2016. Patients were treated by either FCM intravenous infusion or oral ferrous sulfate. We collected serum values of hemoglobin, ferritin and transferrin saturation (TSAT) and ESAs doses at 12 and 18 months. The costs related to both treatments were also analysed. 239 patients were treated with FCM intravenous infusion and 110 patients with oral ferrous sulfate. The two groups were not statistically different for age, BMI and eGFR values. At 18 months, hemoglobin, serum ferritin and TSAT values increased significantly from baseline in the FCM group, compared with the ferrous sulfate group. ESAs dose and rate of infusion decreased only in the FCM group. At 18 months, the treatment costs, analysed per week, was higher in the ferrous sulfate group, compared with the FCM group, and this was mostly due to a reduction in ESAs prescription in the FCM group. Routine intravenous FCM treatment in an outpatient clinic of NDD-CKD patients results in better correction of iron-deficiency anemia when compared to ferrous sulfate. In addition to this, treating NDD-CKD patients with FCM leads to a significant reduction of the treatment costs by reducing ESAs use.
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Affiliation(s)
- Luigi Cirillo
- Nephrology and Dialysis Unit, Santa Maria Annunziata Hospital, Bagno a Ripoli, Florence, Italy
| | - Chiara Somma
- Nephrology and Dialysis Unit, Santa Maria Annunziata Hospital, Bagno a Ripoli, Florence, Italy
| | - Marco Allinovi
- Nephrology, Dialysis and Transplant Unit, Careggi University Hospital, Florence, Italy
| | - Alfredo Bagalà
- Nephrology and Dialysis Unit, Santa Maria Annunziata Hospital, Bagno a Ripoli, Florence, Italy
| | - Giuseppe Ferro
- Nephrology and Dialysis Unit, Santa Maria Annunziata Hospital, Bagno a Ripoli, Florence, Italy
| | - Elio Di Marcantonio
- Nephrology and Dialysis Unit, Santa Maria Annunziata Hospital, Bagno a Ripoli, Florence, Italy
| | - Stefania Bellelli
- Health Technology Assessment and Management (HTAM) Research Area, IRES Piemonte, Torino, Italy
| | - Lorenzo Antonio Dallari
- Nephrology and Dialysis Unit, Santa Maria Annunziata Hospital, Bagno a Ripoli, Florence, Italy
| | - Piercarlo Ballo
- Cardiology Unit, Santa Maria Annunziata Hospital, Bagno a Ripoli, Florence, Italy
| | - Pietro Claudio Dattolo
- Nephrology and Dialysis Unit, Santa Maria Annunziata Hospital, Bagno a Ripoli, Florence, Italy.
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A fully human anti-BMP6 antibody reduces the need for erythropoietin in rodent models of the anemia of chronic disease. Blood 2021; 136:1080-1090. [PMID: 32438400 DOI: 10.1182/blood.2019004653] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 04/28/2020] [Indexed: 12/16/2022] Open
Abstract
Recombinant erythropoietin (EPO) and iron substitution are a standard of care for treatment of anemias associated with chronic inflammation, including anemia of chronic kidney disease. A black box warning for EPO therapy and concerns about negative side effects related to high-dose iron supplementation as well as the significant proportion of patients becoming EPO resistant over time explains the medical need to define novel strategies to ameliorate anemia of chronic disease (ACD). As hepcidin is central to the iron-restrictive phenotype in ACD, therapeutic approaches targeting hepcidin were recently developed. We herein report the therapeutic effects of a fully human anti-BMP6 antibody (KY1070) either as monotherapy or in combination with Darbepoetin alfa on iron metabolism and anemia resolution in 2 different, well-established, and clinically relevant rodent models of ACD. In addition to counteracting hepcidin-driven iron limitation for erythropoiesis, we found that the combination of KY1070 and recombinant human EPO improved the erythroid response compared with either monotherapy in a qualitative and quantitative manner. Consequently, the combination of KY1070 and Darbepoetin alfa resulted in an EPO-sparing effect. Moreover, we found that suppression of hepcidin via KY1070 modulates ferroportin expression on erythroid precursor cells, thereby lowering potentially toxic-free intracellular iron levels and by accelerating erythroid output as reflected by increased maturation of erythrocyte progenitors. In summary, we conclude that treatment of ACD, as a highly complex disease, becomes more effective by a multifactorial therapeutic approach upon mobilization of endogenous iron deposits and stimulation of erythropoiesis.
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29
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Onda K, Koyama T, Kobayashi S, Ishii Y, Ohashi K. Management of iron deficiency anemia in hemodialysis patients based on mean corpuscular volume. RENAL REPLACEMENT THERAPY 2021. [DOI: 10.1186/s41100-021-00327-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
To manage the anemic status in hemodialysis (HD) patients, a well-balanced combination therapy based on the use of erythropoiesis-stimulating agents (ESAs) and iron supplementation is essential. Serum ferritin level and transferrin saturation rate (TSAT) are the current standard tests for screening iron deficiency status. However, these are not included in frequently checked regular blood measurements in many HD centers. Other parameters that could predict a hemoglobin (Hb) increase response from iron supplementation have yet to be established. To determine a frequently checked and regularly measured biomarker for predicting iron deficiency status, this study investigated the value of mean corpuscular volume (MCV) as a clinical parameter for HD patients receiving intravenous iron supplementation (Fe-IV) therapy.
Methods and results
One hundred thirty four HD patients, 88 non-HD patients with anemia, and 50 HD patients on Fe-IV therapy from the Nozatomon clinic were assessed. Comparison of MCV values of anemic HD patients and anemic non-chronic kidney disease (CKD) patients showed that anemic HD patients had significantly higher MCV values (93.9 ± 7.3 fL) compared with anemic non-CKD patients (82.8 ± 8.8fL). Fifty HD patients, who received Fe-IV therapy at ten consecutive HD sessions (inclusion criteria: Hb ≤ 12.0 g/dL, TSAT < 20%, and serum ferritin < 100 ng/mL) showed a rapid increase during the Fe-IV period in MCV, Hb, and TSAT levels. After the completion of the Fe-IV therapy, MCV persisted at the increased levels, whereas Hb levels further increased and peaked at 1 month with a gradual decline after, largely influenced by ESA dosage reductions. The 50 patients were divided into three groups according to the MCV levels obtained immediately prior to the Fe-IV therapy (MCV ≤ 85 fL, 85 fL < MCV ≤ 90 fL, MCV > 90 fL), and Hb changes at 50 days after the initiation of the Fe-IV therapy were compared. All the patients in the MCV ≤ 85 fL group and most of the patients in the 85 fL < MCV ≤ 90 fL group showed linear and consistent Hb increase during the 50-day period. In marked contrast, patients in the MCV > 90 fL group showed dispersed trends in their Hb increase. The present study also revealed that successful ESA dosage reduction could be achieved after the Fe-IV therapy in both the MCV ≤ 85 fL and 85 fL < MCV ≤ 90 fL groups.
Conclusions
The present study underscored the value of MCV in perceiving iron deficiency status as well as predicting iron-based therapeutic response in HD patients.
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30
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Akizawa T, Yamaguchi Y, Majikawa Y, Reusch M. Factors affecting the doses of roxadustat vs darbepoetin alfa for anemia treatment in hemodialysis patients. Ther Apher Dial 2020; 25:575-585. [PMID: 33200512 PMCID: PMC8451884 DOI: 10.1111/1744-9987.13609] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/30/2020] [Accepted: 11/13/2020] [Indexed: 12/12/2022]
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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Affiliation(s)
- Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | | | - Yoshikatsu Majikawa
- Japan-Asia Clinical Development 2, Development, Astellas Pharma, Inc., Tokyo, Japan
| | - Michael Reusch
- Development Medical Science, Astellas Pharma Europe B.V., Tokyo, Japan
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Effect of Kidney Function and Dialysis on the Pharmacokinetics and Pharmacodynamics of Roxadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor. Eur J Drug Metab Pharmacokinet 2020; 46:141-153. [PMID: 33165773 PMCID: PMC7811989 DOI: 10.1007/s13318-020-00658-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background and Objectives Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for anemia in chronic kidney disease. The pharmacokinetics, metabolic profile, and pharmacodynamics of roxadustat were investigated in subjects with different degrees of kidney function. Methods This phase 1 open-label study enrolled subjects with normal and severely impaired kidney function, and end-stage renal disease (ESRD) on continuous ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD) or hemodialysis/hemodiafiltration (HD/HDF). All subjects received a single 100-mg dose of oral roxadustat. Within a single-sequence, two-treatment period design (P1/P2), subjects with ESRD on HD/HDF received roxadustat 2 h after (P1) and 2 h before (P2) a dialysis session. Area under the plasma concentration–time curve (AUC) from administration to infinity (AUCinf), maximum concentration (Cmax), and terminal elimination half-life (t1/2) were assessed for roxadustat; AUC and Cmax were assessed for erythropoietin. Results Thirty-four subjects were enrolled and received roxadustat (normal kidney function, n = 12; severely impaired kidney function, n = 9; ESRD on CAPD/APD, n = 1; ESRD on HD/HDF, n = 12). The geometric least-square mean ratio of AUCinf was 223% and 195% in subjects with severely impaired kidney function and ESRD on HD/HDF, respectively, relative to subjects with normal kidney function; Cmax and t1/2 were comparable. The pharmacokinetic profile of roxadustat was not affected by HD/HDF. AUCinf and t1/2 for the metabolites of roxadustat increased in subjects with kidney impairment. The AUC and Cmax of erythropoietin increased in subjects with severely impaired kidney function or ESRD on HD/HDF. Roxadustat was well tolerated. Conclusions Kidney function impairment increased the AUC of roxadustat and its metabolites. The Cmax and t1/2 of roxadustat were comparable among groups. Roxadustat and its metabolites were not cleared by HD/HDF. Clinical Trials Registration Number: NCT02965040. Electronic supplementary material The online version of this article (10.1007/s13318-020-00658-w) contains supplementary material, which is available to authorized users.
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Akizawa T, Iwasaki M, Yamaguchi Y, Majikawa Y, Reusch M. Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan. J Am Soc Nephrol 2020; 31:1628-1639. [PMID: 32493693 PMCID: PMC7350993 DOI: 10.1681/asn.2019060623] [Citation(s) in RCA: 143] [Impact Index Per Article: 28.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 04/01/2020] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia. METHODS This phase 3, 24-week, double-blind, double-dummy study evaluated roxadustat's noninferiority to darbepoetin alfa for hemodialysis-dependent CKD anemia. We randomly assigned Japanese patients to oral roxadustat three times weekly or to darbepoetin alfa injections once weekly, titrating doses to maintain hemoglobin between 10-12 g/dl. The primary end point was change of average hemoglobin from baseline to weeks 18-24 (∆Hb18-24). Secondary end points were average hemoglobin and proportion of patients with hemoglobin between 10-12 g/dl (maintenance rate) at weeks 18-24, and iron parameters. Safety assessments included treatment-emergent adverse events and adjudicated ophthalmologic findings. RESULTS We randomly assigned 303 patients to roxadustat (n=151) or darbepoetin alfa (n=152). The difference between roxadustat and darbepoetin alfa in ∆Hb18-24 was -0.02 g/dl (95% confidence interval, -0.18 to 0.15), confirming roxadustat's noninferiority to darbepoetin alfa. Average hemoglobin at weeks 18-24 with roxadustat was 10.99 g/dl (95% confidence interval: 10.88 to 11.10), confirming its efficacy. Among patients with one or more hemoglobin value during weeks 18-24, the maintenance rate was 95.2% with roxadustat and 91.3% with darbepoetin alfa. Serum iron, ferritin, and transferrin saturation remained clinically stable with roxadustat; transferrin and total iron binding capacity increased through week 4 before stabilizing. Common treatment-emergent adverse events were nasopharyngitis, shunt stenosis, diarrhea, contusion, and vomiting. The proportion of patients with new or worsening retinal hemorrhage was 32.4% with roxadustat and 36.6% with darbepoetin alfa. We observed no clinically meaningful changes in retinal thickness groups. CONCLUSIONS Roxadustat maintained hemoglobin within 10-12 g/dl in patients on hemodialysis and was noninferior to darbepoetin alfa. Treatment-emergent adverse events were consistent with previous reports. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER A Study of Intermittent Oral Dosing of ASP1517 in Hemodialysis Chronic Kidney Disease Patients with Anemia, NCT02952092 (ClinicalTrials.gov).
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Affiliation(s)
- Tadao Akizawa
- Department of Nephrology, Showa University School of Medicine, Tokyo, Japan
| | - Manabu Iwasaki
- Department of Data Science, Yokohama City University, Yokohama, Japan
| | - Yusuke Yamaguchi
- Japan-Asia Data Science, Development, Astellas Pharma, Inc., Tokyo, Japan
| | - Yoshikatsu Majikawa
- Japan-Asia Clinical Development 2, Development, Astellas Pharma, Inc., Tokyo, Japan
| | - Michael Reusch
- Development Medical Science Urology and Nephrology, Astellas Pharma Europe B.V., Leiden, The Netherlands
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Akizawa T, Yamaguchi Y, Otsuka T, Reusch M. A Phase 3, Multicenter, Randomized, Two-Arm, Open-Label Study of Intermittent Oral Dosing of Roxadustat for the Treatment of Anemia in Japanese Erythropoiesis-Stimulating Agent-Naïve Chronic Kidney Disease Patients Not on Dialysis. Nephron Clin Pract 2020; 144:372-382. [PMID: 32580188 DOI: 10.1159/000508100] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 04/20/2020] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved for the treatment of anemia in Japan for patients with dialysis-dependent (DD) chronic kidney disease (CKD). OBJECTIVE Multicenter, randomized, open-label, noncomparative, phase 3 study to evaluate roxadustat for anemia of non-dialysis-dependent (NDD) CKD in Japan. METHODS Erythropoiesis stimulating agent (ESA)-naïve NDD-CKD patients were randomized to roxadustat (initial dose, 50 or 70 mg 3 times weekly), titrated to maintain hemoglobin (Hb) within 10.0-12.0 g/dL, for ≤24 weeks. Patients with either transferrin saturation of ≥5% or serum ferritin of ≥30 ng/mL during the screening period were eligible. Endpoints included response rate (proportion of patients achieving Hb ≥10.0 or ≥10.5 g/dL and Hb increase ≥1.0 g/dL from baseline) at end of treatment; average Hb (weeks 18-24); change of average Hb from baseline to weeks 18-24; maintenance rate (proportion of patients achieving Hb 10.0-12.0 g/dL at weeks 18-24); rate of rise (RoR) of Hb from weeks 0-4, discontinuation, or dose adjustment. Adverse events were monitored throughout the study. RESULTS Of 135 patients who provided informed consent, 100 were randomized and 99 received roxadustat (50 mg, n = 49; 70 mg, n = 50). The mean (SD) dose of roxadustat per intake at week 22 was 36.3 (22.7) mg in the roxadustat 50 mg group and 36.8 (16.0) mg in the roxadustat 70 mg group. Prior medications included oral iron therapy (20.2%) and intravenous iron therapy (1.0%). Overall response rate (95% CI) was 97.0% (91.4, 99.4; Hb ≥10.0 g/dL) and 94.9% (88.6, 98.3; Hb ≥10.5 g/dL). Mean (SD) Hb (weeks 18-24) was 11.17 (0.62) g/dL. Mean (SD) change of Hb from baseline (weeks 18-24) was 1.34 (0.86) g/dL. Maintenance rate (95% CI) was 88.8% (80.3, 94.5) among patients with ≥1 Hb measurement during weeks 18-24. Mean (SD) RoR of Hb was 0.291 (0.197) g/dL/week (50 mg) and 0.373 (0.235) g/dL/week (70 mg). Nasopharyngitis and hypertension were the most common adverse events. CONCLUSION Roxadustat increased and maintained Hb in ESA-naïve, partially iron-depleted NDD-CKD patients with anemia.
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Affiliation(s)
- Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan,
| | | | - Tetsuro Otsuka
- Japan-Asia Clinical Development 2, Development, Astellas Pharma, Inc., Tokyo, Japan
| | - Michael Reusch
- Therapeutic Area Medical Specialties, Astellas Pharma Europe B.V., Leiden, The Netherlands
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Locatelli F, Del Vecchio L. Are we approaching a new era in the treatment of anemia of chronic kidney disease patients? ANNALS OF TRANSLATIONAL MEDICINE 2020; 7:S333. [PMID: 32016051 DOI: 10.21037/atm.2019.09.119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
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Akizawa T, Ueno M, Shiga T, Reusch M. Oral roxadustat three times weekly in ESA-naïve and ESA-converted patients with anemia of chronic kidney disease on hemodialysis: Results from two phase 3 studies. Ther Apher Dial 2020; 24:628-641. [PMID: 31891449 PMCID: PMC7687179 DOI: 10.1111/1744-9987.13468] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 12/17/2019] [Accepted: 12/27/2019] [Indexed: 12/17/2022]
Abstract
Roxadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for anemia of dialysis-dependent chronic kidney disease (CKD). Japanese hemodialysis patients with anemia of CKD previously naïve to, or converted from, erythropoiesis-stimulating agents (ESAs) were enrolled in two open-label, noncomparative studies of titrated oral roxadustat administered three times weekly. ESA-naïve patients (n = 75) were randomized to roxadustat (initial dose, 50 or 70 mg) for 24 weeks; ESA-converted patients (n = 164) were assigned to roxadustat (initial dose, 70 or 100 mg based on prior ESA dose) for 52 weeks. Efficacy outcomes included average hemoglobin (Hb, weeks 18-24 or 46-52), change of Hb from baseline to weeks 18 to 24 (ΔHb18-24 ) or weeks 46 to 52 (ΔHb46-52 ), and maintenance rate (proportion of patients who achieved average Hb of 10.0-12.0 g/dL for weeks 18-24 or weeks 46-52). Treatment-emergent adverse events (TEAEs) were monitored. Mean (SD) Hb was 10.93 (0.79) g/dL (weeks 18-24) (ESA-Naïve Study), and 10.93 (0.69; weeks 18-24) g/dL and 11.11 (0.67; weeks 46-52) g/dL (ESA-Converted Study). Mean (SD) ΔHb18-24 was 2.26 (1.02) g/dL (ESA-Naïve Study) and -0.03 (0.90) g/dL (ESA-Converted Study); mean (SD) ΔHb46-52 was 0.12 (0.83) g/dL (ESA-Converted Study). The overall maintenance rate was 73.0% (54/74) (ESA-Naïve Study) (weeks 18-24), and 79.1% (129/163; weeks 18-24) and 71.2% (116/163; weeks 46-52) (ESA-Converted Study). Nasopharyngitis was the most common TEAE. Two deaths, considered unrelated to roxadustat, occurred in the ESA-Converted Study. Roxadustat effectively corrected and maintained Hb, regardless of previous ESA treatment, in Japanese anemic CKD patients on hemodialysis.
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Affiliation(s)
| | - Mai Ueno
- Astellas Pharma, Inc., Tokyo, Japan
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Li ZL, Tu Y, Liu BC. Treatment of Renal Anemia with Roxadustat: Advantages and Achievement. KIDNEY DISEASES 2020; 6:65-73. [PMID: 32309288 DOI: 10.1159/000504850] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 11/16/2019] [Indexed: 12/12/2022]
Abstract
Background Although renal anemia has attracted widespread attention, a large proportion of chronic kidney disease (CKD) patients with anemia still do not meet the hemoglobin (Hb) targets. The discovery of prolyl hydroxylase domain (PHD) enzymes as regulators of hypoxia-inducible factor (HIF)-dependent erythropoiesis has led to the development of novel therapeutic agents for renal anemia. Roxadustat, the first small-molecule HIF-PHD inhibitor, has completed the phase 3 trials. There are currently more than 15 phase 3 clinical trials worldwide assessing the efficacy and safety of roxadustat in CKD patients with anemia. This review will summarize recent findings of roxadustat in the treatment of renal anemia. Summary Although the administration of erythropoiesis-stimulating agents (ESAs) and iron supplementation are a well-established and highly effective therapeutic approach for renal anemia, there are several safety concerns. Current findings from phase 2 and 3 trials suggest that roxadustat is clinically effective and well tolerated. On the one hand, roxadustat could increase endogenous erythropoietin (EPO) levels within or near physiological range in a titratable manner by inducing HIF pathway activation transiently. On the other hand, roxadustat also improves iron metabolism by decreasing serum hepcidin and increasing intestinal iron absorption, which is beneficial to functional iron deficiency and absolute iron deficiency. More importantly, the erythropoietic response of roxadustat is independent of baseline inflammatory state of CKD patients. Thus, the discovery of roxadustat will revolutionize the treatment strategy for renal anemia. Key Messages Roxadustat is an emerging and promising therapeutic approach against anemia in CKD patients, which differs from those of conventional ESAs. Roxadustat corrects anemia of CKD patients through multiple pathways, beyond elevating EPO levels within physiological range, and also by handling iron metabolism (particularly decreasing the hepcidin levels). Furthermore, the Hb response of roxadustat is independent of the inflammatory microenvironment.
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Affiliation(s)
- Zuo-Lin Li
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Yan Tu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
| | - Bi-Cheng Liu
- Institute of Nephrology, Zhong Da Hospital, Southeast University School of Medicine, Nanjing, China
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Effects of oral iron and calcium supplement on the pharmacokinetics and pharmacodynamics of molidustat: an oral HIF-PH inhibitor for the treatment of renal anaemia. Eur J Clin Pharmacol 2020; 76:185-197. [PMID: 31919558 DOI: 10.1007/s00228-019-02813-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 10/14/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE The present studies assessed the drug-drug interaction of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, with iron and calcium supplements, which are common medications in patients with anaemia due to chronic kidney disease (CKD). METHODS Forty-two healthy men received molidustat alone (fasted or fed) or combined with oral iron(II) or calcium(II), given immediately before or between 4 h before and 1 h after molidustat in three randomized, open-label, crossover studies (12-15 participants per study). Molidustat AUC and Cmax were assessed as the main pharmacokinetic parameters, and endogenous erythropoietin (EPO) was measured to evaluate pharmacodynamics. RESULTS Depending on prandial state, concomitant intake of iron(II) reduced molidustat AUC and Cmax by 50-75% and 46-84%, respectively, and EPO AUC(0-24) and Cmax by 31-44% and 36-48%, respectively. The influence of iron(II) declined with increasing the time interval to the intake of molidustat, with reductions in molidustat AUC and Cmax of 9% and 10%, respectively, when iron(II) intake occurred 4 h before molidustat. Accordingly, effects on endogenous EPO were less pronounced with increased time separation between oral iron(II) and molidustat intake. Calcium(II) reduced molidustat AUC and Cmax by 15% and 47%, respectively, without influence on EPO response. All treatments were well tolerated. CONCLUSIONS In contrast to concomitant oral intake of calcium, the effect of oral iron supplements on molidustat pharmacokinetics and pharmacodynamics should be considered, and the two agents should be administered with an appropriate time separation.
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Lin Y. Preoperative anemia-screening clinics. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2019; 2019:570-576. [PMID: 31808909 PMCID: PMC6913451 DOI: 10.1182/hematology.2019000061] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Preoperative anemia is associated with increased postoperative morbidity and mortality and with increased risk of perioperative transfusion. It is an important and modifiable risk factor for surgical patients. For high-blood-loss surgery, preoperative anemia is defined as hemoglobin <13 g/dL for both male and female patients. Preoperative anemia is common, ranging from 25% to 40% in large observational studies. The most common treatable cause of preoperative anemia is iron-deficiency anemia; the initial laboratory tests should focus on making this diagnosis. Management of iron-deficiency anemia includes iron supplementation with IV iron therapy when oral iron is ineffective or not tolerated, there is severe anemia, and there is insufficient time to surgery (<4 weeks). In other situations, erythropoiesis-stimulating agents may be considered, particularly for those patients with multiple alloantibodies or religious objections to transfusion. To facilitate the diagnosis and management of preoperative anemia, establishment of preoperative anemia-screening clinics is essential. The goals of management of preoperative anemia are to treat anemia, reduce the need for transfusion, and improve patient outcomes.
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Affiliation(s)
- Yulia Lin
- Transfusion Medicine and Tissue Bank, Department of Laboratory Medicine and Pathobiology, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
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Thavarajah S, Choi MJ. The Use of Erythropoiesis-Stimulating Agents in Patients With CKD and Cancer: A Clinical Approach. Am J Kidney Dis 2019; 74:667-674. [DOI: 10.1053/j.ajkd.2019.04.022] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 04/18/2019] [Indexed: 01/13/2023]
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Akizawa T, Macdougall IC, Berns JS, Yamamoto H, Taguchi M, Iekushi K, Bernhardt T. Iron Regulation by Molidustat, a Daily Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor, in Patients with Chronic Kidney Disease. Nephron Clin Pract 2019; 143:243-254. [PMID: 31387097 PMCID: PMC6979436 DOI: 10.1159/000502012] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 07/09/2019] [Accepted: 07/09/2019] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND/AIMS The current treatment for anemia associated with chronic kidney disease (CKD) includes the administration of erythropoiesis stimulating agents (ESAs) combined with iron supplementation. Molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, has potential to treat anemia associated with CKD through increased erythropoietin production and improved iron availability. Here, we report the effect of molidustat on iron metabolism. METHOD Parameters of iron metabolism were monitored in three 16-week, randomized, controlled, phase 2 studies assessing the safety and efficacy of molidustat in the treatment of anemia associated with CKD in different populations: treatment-naïve and previously ESA-treated patients not on dialysis, and previously ESA-treated patients on hemodialysis. Iron supplementation was left at the discretion of the investigator. RESULTS In treatment-naïve patients not on dialysis, transferrin saturation (TSAT), hepcidin, ferritin, and iron concentrations decreased with molidustat, whereas total iron binding capacity (TIBC) increased. Similar results were observed in previously ESA-treated patients not on dialysis, although changes in those parameters were larger in treatment-naïve than in previously ESA-treated patients. In previously ESA-treated patients receiving hemodialysis, hepcidin concentration and TIBC remained stable with molidustat, whereas TSAT and ferritin and iron concentrations increased. Generally, similar trends were observed in secondary analyses of subgroups of patients not receiving iron supplementation. CONCLUSIONS Molidustat is a potential alternative to standard treatment of anemia associated with CKD, with a different mechanism of action. In patients not receiving dialysis, molidustat increases iron availability. In patients receiving hemodialysis, further investigation is required to understand fully the mechanisms underlying iron mobilization associated with molidustat.
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Affiliation(s)
- Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan,
| | - Iain C Macdougall
- Department of Renal Medicine, King's College Hospital, London, United Kingdom
| | - Jeffrey S Berns
- Perelman School of Medicine at the University of Pennsylvania, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hiroyasu Yamamoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
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Akizawa T, Otsuka T, Reusch M, Ueno M. Intermittent Oral Dosing of Roxadustat in Peritoneal Dialysis Chronic Kidney Disease Patients with Anemia: A Randomized, Phase 3, Multicenter, Open-Label Study. Ther Apher Dial 2019; 24:115-125. [PMID: 31222951 PMCID: PMC7079122 DOI: 10.1111/1744-9987.12888] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 06/12/2019] [Accepted: 06/17/2019] [Indexed: 12/14/2022]
Abstract
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor developed to treat anemia in chronic kidney disease (CKD) patients. This Phase 3, randomized, open-label, 24-week study investigated the efficacy and safety of roxadustat in Japanese CKD patients with anemia on peritoneal dialysis (PD) who were previously treated or not treated with erythropoiesis stimulating agents (ESAs). Patients not previously receiving ESA (ESA-Naïve group) were randomized to roxadustat at a starting dose of 50 or 70 mg three times weekly; patients previously receiving ESA (ESA-Converted group) switched from ESA to roxadustat 70 or 100 mg three times weekly depending on the prior ESA dose. Outcomes included maintenance rate of average hemoglobin (Hb) level within 10-12 g/dL at weeks 18-24, cumulative response rate at end of treatment (Hb thresholds, 10.0 g/dL or 10.5 g/dL; Hb increase, ≥1.0 g/dL), and average Hb levels at weeks 18-24. Safety was assessed by occurrence of treatment-emergent adverse events (TEAEs). Fifty-six patients were enrolled (ESA-Naïve, n = 13; ESA-Converted, n = 43). Maintenance rates (weeks 18-24) were 92.3% (95% CI: 64.0-99.8; ESA-Naïve) and 74.4% (95% CI: 58.8-86.5; ESA-Converted). Cumulative response rate was 100.0% in the ESA-Naïve group. Average Hb levels (weeks 18-24) were 11.05 g/dL (95% CI: 10.67-11.42; ESA-Naïve) and 10.93 g/dL (95% CI: 10.73-11.13; ESA-Converted). Common TEAEs included nasopharyngitis and back pain. Roxadustat was well tolerated and effective in maintaining target Hb levels in CKD patients on PD who were previously treated or not treated with ESA.
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Affiliation(s)
| | | | | | - Mai Ueno
- Astellas Pharma, Inc., Tokyo, Japan
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Effect of Multiple Doses of Omeprazole on the Pharmacokinetics, Safety, and Tolerability of Roxadustat in Healthy Subjects. Eur J Drug Metab Pharmacokinet 2019; 43:685-692. [PMID: 29752643 PMCID: PMC6244714 DOI: 10.1007/s13318-018-0480-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVES Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of anemia in chronic kidney disease. This study investigated the effect of multiple daily oral doses of omeprazole on the pharmacokinetics, safety, and tolerability of a single oral dose of roxadustat. METHODS This phase 1, open-label, two-period, one-sequence, crossover study enrolled healthy subjects. During Period 1, subjects received a single oral dose of 100 mg roxadustat. After a ≥ 7-day washout, subjects started Period 2 and received daily oral doses of 40 mg omeprazole on Days 1-9, and a single oral dose of 100 mg roxadustat on Day 7. Roxadustat pharmacokinetics were assessed on Days 1-4 in Period 1 and on Days 7-10 in Period 2. Primary endpoints were area under the concentration-time profile from the time of dosing extrapolated to infinity (AUCinf) and maximum concentration (Cmax). Safety was assessed by vital signs, laboratory tests, electrocardiograms, and nature, frequency, and severity of treatment-emergent adverse events (TEAEs). RESULTS Eighteen subjects were enrolled. The geometric least squares mean ratio for both AUCinf and Cmax of roxadustat (with omeprazole/alone) was 104.5%; 90% confidence intervals were within the no-effect boundaries of 80.0 and 125.0%, indicating no significant effect of omeprazole on the pharmacokinetics of roxadustat. No serious TEAEs were reported. CONCLUSION Multiple daily oral doses of 40 mg omeprazole had no significant effect on the pharmacokinetics of a single oral dose of 100 mg roxadustat. Roxadustat was considered safe and well tolerated when administered alone or in combination with multiple daily oral doses of 40 mg omeprazole in healthy subjects.
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Akizawa T, Macdougall IC, Berns JS, Bernhardt T, Staedtler G, Taguchi M, Iekushi K, Krueger T. Long-Term Efficacy and Safety of Molidustat for Anemia in Chronic Kidney Disease: DIALOGUE Extension Studies. Am J Nephrol 2019; 49:271-280. [PMID: 30852574 DOI: 10.1159/000499111] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Accepted: 02/06/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND Molidustat, a novel hypoxia-inducible factor-prolyl hydroxylase inhibitor, is being investigated for the treatment of anemia associated with chronic kidney disease (CKD). The efficacy and safety of molidustat were recently evaluated in three 16-week phase 2b studies. Here, we report the results of two long-term extension studies of molidustat. METHODS Both studies were parallel-group, open-label, multicenter studies of ≤36 months' duration, in patients with anemia due to CKD, and included an erythropoiesis-stimulating agent as active control. One study enrolled patients not receiving dialysis (n = 164), and the other enrolled patients receiving hemodialysis (n = 88). The primary efficacy variable for both studies was change in blood hemoglobin (Hb) level from baseline to each post-baseline visit, and safety outcomes included adverse events (AEs). RESULTS In patients not on dialysis, the mean ± SD Hb concentrations at baseline were 11.28 ± 0.55 g/dL for molidustat and 11.08 ± 0.51 g/dL for darbepoetin. The mean ± SD blood Hb concentrations throughout the study (defined as mean of each patient's overall study Hb levels) were 11.10 ± 0.508 and 10.98 ± 0.571 g/dL in patients treated with molidustat and darbepoetin, respectively. Similar proportions of patients reported at least one AE in the molidustat (85.6%) and darbepoetin (85.7%) groups. In patients on dialysis, mean ± SD Hb levels at baseline were 10.40 ± 0.70 and 10.52 ± 0.53 g/dL in the molidustat and epoetin groups, respectively. The mean ± SD blood Hb concentrations during the study were 10.37 ± 0.56 g/dL in the molidustat group and 10.52 ± 0.47 g/dL in the epoetin group. Proportions of patients who reported at least one AE were 91.2% in the molidustat group and 93.3% in the epoetin group. CONCLUSIONS Molidustat was well tolerated for up to 36 months and appears to be an effective alternative to darbepoetin and epoetin in the long-term management of anemia associated with CKD.
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Affiliation(s)
- Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan,
| | - Iain C Macdougall
- Department of Renal Medicine, King's College Hospital, London, United Kingdom
| | - Jeffrey S Berns
- Perelman School of Medicine at the University of Pennsylvania, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Thomas Bernhardt
- Research & Development, Pharmaceuticals, Bayer AG, Berlin, Germany
| | - Gerald Staedtler
- Research & Development, Pharmaceuticals, Bayer AG, Berlin, Germany
| | - Megumi Taguchi
- Medical Affairs, Pulmonology & Cardiology, Bayer Yakuhin Ltd., Osaka, Japan
| | - Kazuma Iekushi
- Medical Affairs, Pulmonology & Cardiology, Bayer Yakuhin Ltd., Osaka, Japan
| | - Thilo Krueger
- Research & Development, Pharmaceuticals, Bayer AG, Wuppertal, Germany
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The anaemia control model: Does it help nephrologists in therapeutic decision-making in the management of anaemia? Nefrologia 2018; 38:491-502. [PMID: 29875061 DOI: 10.1016/j.nefro.2018.03.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 12/07/2017] [Accepted: 03/02/2018] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Anaemia is common in haemodialysis patients and treating it with erythropoiesis-stimulating agents (ESAs) is complex due to many factors. OBJECTIVES To assess the usefulness of the Anaemia Control Model (ACM) in the treatment of anaemia in haemodialysis. METHODS ACM is a software that predicts the optimal dose of darbepoetin and iron sucrose to achieve target haemoglobin (Hb) and ferritin levels, and makes prescription suggestions. Study conducted in dialysis clinics lasting 18months with two intervention phases (IPs) with ACM (IP1, n:213; IP2, n:218) separated by a control phase (CP, n:219). The primary outcome was the percentage of Hb in range and the median dose of ESAs, and the secondary outcomes were transfusion, hospitalisation and cardiovascular events. Clinical and patient analyses were performed. Hb variability was assessed by the standard deviation (SD) of the Hb. We also analysed the patients with most of the suggestions confirmed (ACM compliant group). RESULTS ACM increased the percentage of Hb in range: 80.9% in IP2, compared with 72.7% in the CP and reduced the intake of darbepoetin (IP1: 20 [70]; CP 30 [80] μg P=0.032) with less Hb fluctuation (0.91±0.49 in the CP to 0.82±0.37g/dl in IP2, P<0.05), improving in the ACM compliant group. The secondary outcomes decreased with the use of ACM. CONCLUSIONS ACM helps to obtain better anaemia results in haemodialysis patients, minimising the risks of treatment with ESAs and reducing costs.
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Gardiner R, Roshan D, Brennan A, Connolly D, Murray S, Reddan D. Trends in the treatment of chronic kidney disease-associated anaemia in a cohort of haemodialysis patients: the Irish experience. Ir J Med Sci 2018; 188:223-230. [PMID: 29704093 DOI: 10.1007/s11845-018-1823-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 04/17/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND Anaemia among haemodialysis patients is treated with iron and erythropoietin-stimulating agents (ESAs). ESAs reduce requirements for blood transfusions but are also expensive and overzealous use may be associated with adverse outcomes. Recent international trends have been characterised by reduced ESA doses and a greater reliance on intravenous (IV) iron. We determined trends in prescribing patterns of ESAs and IV iron for the treatment of anaemia in two representative Irish dialysis centres and correlated with current guidelines and international trends. METHODS Patient data was accessed from the Kidney Disease Clinical Patient Management System (KDCPMS) for the period 2012 to 2014. We generated reports on ESA and iron doses, lab data (haemoglobin (Hb), transferrin saturation (TSAT) and ferritin) and patient population characteristics. We mapped the trends in ESA, iron dosing and lab parameters achieved. A linear mixed model determined the significance of these trends over time. RESULTS ESA dosing became lower in the second, third and fourth quarters of 2014. Dosing of iron increased throughout but a large increase was seen in the third and fourth quarters of 2014. Ferritin levels decreased and TSAT and haemoglobin levels increased. Changes in iron dosing were significant with p value of < 0.05. CONCLUSIONS Our findings are consistent with recent global trends toward increasing iron use. Such trends may have economic implications given the high cost of ESAs and the relative affordability of iron. In addition, the potential harm of excessive iron dosing may need to be considered.
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Affiliation(s)
- Roisin Gardiner
- School of Medicine, National University of Ireland, Galway, Ireland
| | - Davood Roshan
- School of Mathematics, Statistics, & Applied Mathematics, National University of Ireland, Galway, Ireland
| | | | | | | | - Donal Reddan
- School of Medicine, National University of Ireland, Galway, Ireland.
- Galway University Hospital, Galway, Ireland.
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Suh HY, Bae J, Kim HL, Kim KH, Cha RH, Ahn JY, Youn JI, Park MY. A Case of Acute Generalized Exanthematous Pustulosis after Injection of an Erythropoiesis-Stimulating Agent. Ann Dermatol 2018; 30:100-101. [PMID: 29386844 PMCID: PMC5762459 DOI: 10.5021/ad.2018.30.1.100] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 12/28/2016] [Accepted: 01/05/2017] [Indexed: 11/17/2022] Open
Affiliation(s)
- Hyun Yi Suh
- Department of Dermatology, National Medical Center, Seoul, Korea
| | - Jooyoon Bae
- Department of Dermatology, National Medical Center, Seoul, Korea
| | - Hong Lim Kim
- Department of Dermatology, National Medical Center, Seoul, Korea
| | - Kyung Ho Kim
- Department of Dermatology, National Medical Center, Seoul, Korea
| | - Ran-Hui Cha
- Division of Nephrology, Department of Internal Medicine, National Medical Center, Seoul, Korea
| | - Ji Young Ahn
- Department of Dermatology, National Medical Center, Seoul, Korea
| | - Jai Il Youn
- Department of Dermatology, National Medical Center, Seoul, Korea
| | - Mi Youn Park
- Department of Dermatology, National Medical Center, Seoul, Korea
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Li W, Zhao Y, Fu P. Hypoxia Induced Factor in Chronic Kidney Disease: Friend or Foe? Front Med (Lausanne) 2018; 4:259. [PMID: 29404328 PMCID: PMC5786558 DOI: 10.3389/fmed.2017.00259] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 12/26/2017] [Indexed: 02/05/2023] Open
Abstract
Many studies have shown evidence that erythropoiesis-stimulating agents (ESAs), as a classic treatment for chronic kidney disease (CKD)-related anemia, have several disadvantages and may trigger various adverse events with long-term use. The hypoxia-induced factor (HIF) pathway has been intensively investigated in kidney disease, especially in CKD, as research has shown that HIF-mediated erythropoiesis might work as a potential therapeutic strategy for managing CKD-related anemia. Development of prolyl hydroxylase domain inhibitors (PHIs), as an effective HIF activator, is a valuable step toward finding a replacement for ESAs, which showed an effective erythropoiesis through a comprehensive and physiological approach by promoting erythropoietin production, increasing iron bioavailability and improving chronic inflammatory status. Heretofore no adverse events or obvious off-target effects have been reported in clinical trials of PHIs. Nevertheless, a cautious inspection with extended follow-up period is warranted to validate the safety of prolonged HIF elevation, especially considering its ambiguous role in fibrogenesis and inflammation responses and possible risks in accelerating vascular calcification and tumorigenesis. A weighed dosing strategy might be the key to circumvent the unexpected side-effect brought by pleotropic effects of HIF elevation and achieve a selective augmentation of HIF-mediated signaling pathway. New studies with longer follow-up period and adequate analysis about the risks for proinflammation, vascular calcification and tumorigenesis are needed to ensure the drugs are safe for long-term use before being widely accepted in daily clinical practice.
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Affiliation(s)
- Weiying Li
- Division of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuliang Zhao
- Division of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Ping Fu
- Division of Nephrology, West China Hospital, Sichuan University, Chengdu, China
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Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH). J Hypertens 2017; 35:657-676. [PMID: 28157814 DOI: 10.1097/hjh.0000000000001283] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
In patients with end-stage renal disease treated with hemodialysis or peritoneal dialysis, hypertension is very common and often poorly controlled. Blood pressure (BP) recordings obtained before or after hemodialysis display a J-shaped or U-shaped association with cardiovascular events and survival, but this most likely reflects the low accuracy of these measurements and the peculiar hemodynamic setting related with dialysis treatment. Elevated BP by home or ambulatory BP monitoring is clearly associated with shorter survival. Sodium and volume excess is the prominent mechanism of hypertension in dialysis patients, but other pathways, such as arterial stiffness, activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, endothelial dysfunction, sleep apnea and the use of erythropoietin-stimulating agents may also be involved. Nonpharmacologic interventions targeting sodium and volume excess are fundamental for hypertension control in this population. If BP remains elevated after appropriate treatment of sodium-volume excess, the use of antihypertensive agents is necessary. Drug treatment in the dialysis population should take into consideration the patient's comorbidities and specific characteristics of each agent, such as dialysability. This document is an overview of the diagnosis, epidemiology, pathogenesis and treatment of hypertension in patients on dialysis, aiming to offer the renal physician practical recommendations based on current knowledge and expert opinion and to highlight areas for future research.
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Sarafidis PA, Persu A, Agarwal R, Burnier M, de Leeuw P, Ferro CJ, Halimi JM, Heine GH, Jadoul M, Jarraya F, Kanbay M, Mallamaci F, Mark PB, Ortiz A, Parati G, Pontremoli R, Rossignol P, Ruilope L, Van der Niepen P, Vanholder R, Verhaar MC, Wiecek A, Wuerzner G, London GM, Zoccali C. Hypertension in dialysis patients: a consensus document by the European Renal and Cardiovascular Medicine (EURECA-m) working group of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) and the Hypertension and the Kidney working group of the European Society of Hypertension (ESH). Nephrol Dial Transplant 2017; 32:620-640. [PMID: 28340239 DOI: 10.1093/ndt/gfw433] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 11/14/2016] [Indexed: 01/07/2023] Open
Abstract
In patients with end-stage renal disease (ESRD) treated with haemodialysis or peritoneal dialysis, hypertension is common and often poorly controlled. Blood pressure (BP) recordings obtained before or after haemodialysis display a J- or U-shaped association with cardiovascular events and survival, but this most likely reflects the low accuracy of these measurements and the peculiar haemodynamic setting related to dialysis treatment. Elevated BP detected by home or ambulatory BP monitoring is clearly associated with shorter survival. Sodium and volume excess is the prominent mechanism of hypertension in dialysis patients, but other pathways, such as arterial stiffness, activation of the renin-angiotensin-aldosterone and sympathetic nervous systems, endothelial dysfunction, sleep apnoea and the use of erythropoietin-stimulating agents may also be involved. Non-pharmacologic interventions targeting sodium and volume excess are fundamental for hypertension control in this population. If BP remains elevated after appropriate treatment of sodium and volume excess, the use of antihypertensive agents is necessary. Drug treatment in the dialysis population should take into consideration the patient's comorbidities and specific characteristics of each agent, such as dialysability. This document is an overview of the diagnosis, epidemiology, pathogenesis and treatment of hypertension in patients on dialysis, aiming to offer the renal physician practical recommendations based on current knowledge and expert opinion and to highlight areas for future research.
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Affiliation(s)
- Pantelis A Sarafidis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Alexandre Persu
- Pole of Cardiovascular Research, Institut de Recherche Expérimentale et Clinique, and Division of Cardiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Rajiv Agarwal
- Department of Medicine, Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
| | - Michel Burnier
- Service of Nephrology and Hypertension, Lausanne University Hospital, Lausanne, Switzerland
| | - Peter de Leeuw
- Department of Medicine, Maastricht University Medical Center, Maastricht and Zuyderland Medical Center, Geleen/Heerlen, The Netherlands
| | - Charles J Ferro
- Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Jean-Michel Halimi
- Service de Néphrologie-Immunologie Clinique, Hôpital Bretonneau, François-Rabelais University, Tours, France
| | - Gunnar H Heine
- Saarland University Medical Center, Internal Medicine IV-Nephrology and Hypertension, Homburg, Germany
| | - Michel Jadoul
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Faical Jarraya
- Department of Nephrology, Sfax University Hospital and Research Unit, Faculty of Medicine, Sfax University, Sfax, Tunisia
| | - Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey
| | - Francesca Mallamaci
- CNR-IFC, Clinical Epidemiology and Pathophysiology of Hypertension and Renal Diseases Unit, Ospedali Riuniti, Reggio Calabria, Italy
| | - Patrick B Mark
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Alberto Ortiz
- IIS-Fundacion Jimenez Diaz, School of Medicine, University Autonoma of Madrid, FRIAT and REDINREN, Madrid, Spain
| | - Gianfranco Parati
- Department of Cardiovascular, Neural, and Metabolic Sciences, San Luca Hospital, Istituto Auxologico Italiano and Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Roberto Pontremoli
- Università degli Studi and IRCCS Azienda Ospedaliera Universitaria San Martino-IST, Genova, Italy
| | - Patrick Rossignol
- INSERM, Centre d'Investigations Cliniques Plurithématique 1433, UMR 1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT Cardiovascular and Renal Clinical Trialists, and Association Lorraine de Traitement de l'Insuffisance Rénale, Nancy, France
| | - Luis Ruilope
- Hypertension Unit & Institute of Research i?+?12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Patricia Van der Niepen
- Department of Nephrology and Hypertension, Universitair Ziekenhuis Brussel - VUB, Brussels, Belgium
| | - Raymond Vanholder
- Nephrology Section, Department of Internal Medicine, Ghent University Hospital, Gent, Belgium
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, The Netherlands
| | - Andrzej Wiecek
- Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia in Katowice, Katowice, Poland
| | - Gregoire Wuerzner
- Service of Nephrology and Hypertension, Lausanne University Hospital, Lausanne, Switzerland
| | | | - Carmine Zoccali
- CNR-IFC, Clinical Epidemiology and Pathophysiology of Hypertension and Renal Diseases Unit, Ospedali Riuniti, Reggio Calabria, Italy
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Production of transgenic chickens constitutively expressing human erythropoietin (hEPO): Problems with uncontrollable overexpression of hEPO gene. BIOTECHNOL BIOPROC E 2017. [DOI: 10.1007/s12257-016-0590-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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