A Novel Choice to Correct Inflammation-Induced Anemia in CKD: Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat

Yan, Zhipeng; Xu, Gaosi

doi:10.3389/fmed.2020.00393

Cited by 25 publications

(28 citation statements)

References 94 publications

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“…Another drug, namely Roxadustat, an oral hypoxia-inducible factor inhibitor is currently being tested in clinical trials involving non-del(5q) low-risk MDS patients with low transfusion burden [183]. This drug has already been approved in China for anaemia related to chronic kidney disease, and works by increasing EPO production, reducing hepcidin and promotes erythroblast maturation [184].…”

Section: What Options Are There: Targeting the Mds Hspc-bmme Crosstalkmentioning

confidence: 99%

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

Mian

Bonnet

2021

Cancers

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Myelodysplastic syndrome (MDS) are clonal haematopoietic stem cell (HSC) disorders driven by a complex combination(s) of changes within the genome that result in heterogeneity in both clinical phenotype and disease outcomes. MDS is among the most common of the haematological cancers and its incidence markedly increases with age. Currently available treatments have limited success, with <5% of patients undergoing allogeneic HSC transplantation, a procedure that offers the only possible cure. Critical contributions of the bone marrow microenvironment to the MDS have recently been investigated. Although the better understanding of the underlying biology, particularly genetics of haematopoietic stem cells, has led to better disease and risk classification; however, the role that the bone marrow microenvironment plays in the development of MDS remains largely unclear. This review provides a comprehensive overview of the latest developments in understanding the aetiology of MDS, particularly focussing on understanding how HSCs and the surrounding immune/non-immune bone marrow niche interacts together.

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Section: What Options Are There: Targeting the Mds Hspc-bmme Crosstalkmentioning

confidence: 99%

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

Mian

Bonnet

2021

Cancers

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“…Among them, roxadustat is the world's first orally administered small-molecule HIF-PHI, which has been approved by the National Medical Products Administration (NMPA) in China for the treatment of anemia in NDD-CKD Chen et al (2019b) and DD-CKD Chen et al (2019a) patients, and by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan for the treatment of anemia in NDD-CKD patients (Dhillon, 2019). Roxadustat has been proven to induce RBC production while maintaining the plasma EPO levels within or near the normal physiologic range in multiple subpopulations of CKD patients (including in the presence of inflammation), without extra intravenous iron supplementation (Besarab et al, 2015;Besarab et al, 2016;Yan and Xu, 2020).…”

Section: Introductionmentioning

confidence: 99%

Safe and Effective Treatment for Anemic Patients With Chronic Kidney Disease: An Updated Systematic Review and Meta-Analysis on Roxadustat

et al. 2021

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Background: Roxadustat is a new oral drug for anemia in chronic kidney disease (CKD). This study aimed to synthesize the evidence from randomized controlled trial (RCT)-based studies that estimated the efficacy and safety of roxadustat in anemia patients with non-dialysis-dependent (NDD) and dialysis-dependent (DD) CKD.Methods: We searched the PubMed, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for related published studies. Moreover, we manually searched relevant pharmaceutical company websites and two international clinical trial registers to search for published and unpublished RCTs comparing roxadustat with erythropoietin-stimulating agents (ESAs) or placebo.Results: Fifteen RCTs (seven for DD-CKD patients, eight for NDD-CKD patients) were included in the meta-analysis, with 10,189 patients, 4,810 DD-CKD patients, and 5,379 NDD-CKD patients enrolled. Compared with ESAs (epoetin alfa or darbepoetin alfa) and placebo, roxadustat raised the hemoglobin level [weighted mean difference (WMD): 0.82 g/dL; 95% confidence interval (CI): 0.43–1.21], transferrin level (WMD: 0.5 g/L; 95% CI: 0.34–0.65), and TIBC level (WMD: 41.79 μg/dL; 95% CI: 38.67–44.92) and lowered the hepcidin level (WMD: −37.38 ng/ml; 95% CI: −46.63– −28.12) in both the DD-CKD and NDD-CKD patients with renal anemia. Roxadustat improved hemoglobin response and lowered the ferritin and TAST levels in the NDD-CKD patients but not in the DD-CKD patients. Furthermore, there was no difference between the treatment-emergent adverse events (TEAEs) of roxadustat and that of ESAs or placebo. But the incidence of serious TEAEs in the roxadustat group was significantly higher with NDD-CKD patients (OR: 1.15; 95% CI: 1.02–1.29).Conclusion: This study confirmed that roxadustat therapy could alleviate the anemia of DD-CKD and NDD-CKD patients by raising the hemoglobin level and regulating iron metabolism, but increased serious incidences of treatment-emergent adverse events (TEAEs) in NDD-CKD patients.

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“…HIF-PH inhibitors inhibit a regulatory enzyme of HIF, thereby inhibiting the degradation of the transcription factor HIF-α and activating the HIF pathway. As a result, similar to the erythropoietic response that occurs when the body is exposed to hypoxia, erythropoiesis is stimulated even in normoxic conditions, thus potentially improving anemia by increasing the red blood cell count and hemoglobin concentration [75][76][77][78][79]. In principle, this leads to the activation of HIF-1 and HIF-2 in cells throughout the body; thus,patients consuming this drug in perioperative management may require special care [80].…”

Section: Epo Expression In Response To Hypoxemia and Anemiamentioning

confidence: 99%

Hypoxia-dependent signaling in perioperative and critical care medicine

Hirota

2021

J Anesth

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A critical goal of patient management for anesthesiologists and intensivists is to maintain oxygen homeostasis in patients admitted to operation theaters and intensive care units. For this purpose, it is imperative to understand the strategies of the body against oxygen imbalance—especially oxygen deficiency (hypoxia). Adaptation to hypoxia and maintenance of oxygen homeostasis involve a wide range of responses that occur at different organizational levels in the body. These responses are greatly influenced by perioperative patient management including factors such as perioperative drugs. Herein, the influence of perioperative patient management on the body's response to oxygen imbalance was reviewed with a special emphasis on hypoxia-inducible factors (HIFs), transcription factors whose activity are regulated by the perturbation of oxygen metabolism. The 2019 Nobel Prize in Physiology or Medicine was awarded to three researchers who made outstanding achievements in this field. While previous studies have reported the effect of perioperatively used drugs on hypoxia-induced gene expression mediated by HIFs, this review focused on effects of subacute or chronic hypoxia changes in gene expression that are mediated by the transcriptional regulator HIFs. The clinical implications and perspectives of these findings also will be discussed. Understanding the basic biology of the transcription factor HIF can be informative for us since anesthesiologists manage patients during the perioperative period facing the imbalances the oxygen metabolism in organ and tissue. The clinical implications of hypoxia-dependent signaling in critical illness, including Coronavirus disease (COVID-19), in which disturbances in oxygen metabolism play a major role in its pathogenesis will also be discussed.

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A Novel Choice to Correct Inflammation-Induced Anemia in CKD: Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat

Cited by 25 publications

References 94 publications

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

Safe and Effective Treatment for Anemic Patients With Chronic Kidney Disease: An Updated Systematic Review and Meta-Analysis on Roxadustat

Hypoxia-dependent signaling in perioperative and critical care medicine

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