Roxadustat – another drug that causes pulmonary hypertension? – first human report

Cygulska, Kamila; Wejner‐Mik, Paulina; Plewka, Michał; Figiel, Łukasz; Chrzanowski, Łukasz; Kasprzak, Jarosław D.

doi:10.20452/pamw.4445

Cited by 11 publications

(9 citation statements)

References 1 publication

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“…Consequently, the safety of roxadustat must be further proved in large‐scale and long‐term studies. It has been shown that HIF‐PHIs can cause hyperkalaemia, 39,40 metabolic acidosis 21 and pulmonary hypertension 41 . However, DD patients are usually prone to the above conditions; therefore, it is not clear whether HIF‐PHIs are the specific causes of these AEs in such patients.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of roxadustat for anaemia in dialysis‐dependent and non‐dialysis‐dependent chronic kidney disease patients: A systematic review and meta‐analysis

Tian

Liu

et al. 2021

Brit J Clinical Pharma

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Aims Renal anaemia is a common complication of chronic kidney disease (CKD). Roxadustat is the first‐in‐class oral hypoxia‐inducible factor prolyl hydroxylase inhibitor for the treatment of anaemia. In this systematic review, we aimed to investigate the efficacy and safety of roxadustat in the treatment of anaemia in CKD patients. Methods PubMed, Cochrane Library, Embase, and http://ClinicalTrials.gov databases were searched from their inception to February 2021 for randomised controlled trials (RCTs) that compared the efficacy and safety of roxadustat to those of an erythropoiesis‐stimulating agent (ESA) or a placebo in treating anaemia in CKD patients. Results Nine RCTs involving 2743 patients were found. The meta‐analysis showed that roxadustat increased haemoglobin (Hb) level by 0.91 g/dL (95% confidence interval [CI]: 0.47–1.34, P < .05), transferrin level by 0.50 mg/dL (95% CI: 0.34–0.65, P < .05), and total iron‐binding capacity by 50.64 μg/dL (95% CI: 36.21–65.07, P < .05) in CKD patients. Decreases in hepcidin (mean difference [MD] = −23.16, 95% CI: −37.12 to −9.19, P < .05) and ferritin (MD = ‐38.35, 95% CI: −67.41 to −9.29, P < .05) levels were also observed. There was no significant difference in the incidence of adverse events (AEs) (OR: 1.12, 95% CI: 0.95–1.32, P = .17) between the roxadustat and control groups; however, the incidence of serious AEs in the roxadustat group was significantly higher than that in the ESA group (OR: 1.33, 95% CI: 1.06–1.68, P < .05). Conclusion Roxadustat can significantly improve renal anaemia in CKD patients by increasing Hb level and iron metabolism. However, attention must be paid to the risk of SAEs during treatment.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of roxadustat for anaemia in dialysis‐dependent and non‐dialysis‐dependent chronic kidney disease patients: A systematic review and meta‐analysis

Tian

Liu

et al. 2021

Brit J Clinical Pharma

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“…The investigators believed that roxadustat stabilized HIF-2α and affected the production of pulmonary hypertension induced by vascular remodeling. Although the association between roxadustat and pulmonary artery was not clear (87). PHI inhibits PHD from a molecular mechanism, then stabilizes HIF-2α to up-regulate Notch3 and transform growth factor β, and promote the conversion of pericytes into myofibroblasts or vascular smooth muscle cells.…”

Section: Safety Of Roxadustat In the Treatment Of Anemiamentioning

confidence: 99%

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

Yan

2020

Front. Med.

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Anemia is a complication of chronic kidney disease (CKD), primarily due to insufficient secretion of erythropoietin (EPO) by the kidney. Erythropoiesis-stimulating agents (ESAs) are used to treat anemia associated with chronic kidney disease. A poor response to ESAs has been associated with inflammation. Inflammation can affect erythrocytes and its production in many ways, but mainly through the inflammatory cytokine IL-6 to stimulate the synthesis of hepcidin in the liver. Hepcidin causes iron insufficiency, which causes erythrocytes to fail to mature normally. In addition, inhibition of bone marrow erythroid precursor cells by inflammatory cytokines such as IL-1 and TNF-α also affects bone marrow hematopoiesis. These cytokines are also important factors leading to EPO resistance. Roxadustat is a new drug for the treatment of renal anemia. In addition to promoting the production of EPO, clinical trials have shown that it can significantly reduce hepcidin and can potentially be used for the treatment of inflammation-induced anemia in CKD.

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“…Identification of the role of PHD2 in the matured vasculature in Phd2 ∆ECi mice is not only necessary for better understanding of pathogenesis of pulmonary vasculopathies, but also important to predict possible long-term side effects of PHD2 inhibitors that have recently entered the clinics for anemia treatment [20,64]. In this respect it is interesting to note that in contrast to severe PAH phenotypes, as one might expect based on previous results [6][7][8], pulmonary and cardiac complications typical for PAH have been reported only in one patient thus far [65]. While our Phd2 ∆ECi model did not recapitulate all PAH pathologies, we did observe progressive vascular resistance and lung damage in aged mice.…”

Section: Discussionmentioning

confidence: 79%

PHD2 deletion in endothelial or arterial smooth muscle cells reveals vascular cell type-specific responses in pulmonary hypertension and fibrosis

et al. 2022

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Hypoxia plays an important regulatory role in the vasculature to adjust blood flow to meet metabolic requirements. At the level of gene transcription, the responses are mediated by hypoxia-inducible factor (HIF) the stability of which is controlled by the HIF prolyl 4-hydroxylase-2 (PHD2). In the lungs hypoxia results in vasoconstriction, however, the pathophysiological relevance of PHD2 in the major arterial cell types; endothelial cells (ECs) and arterial smooth muscle cells (aSMCs) in the adult vasculature is incompletely characterized. Here, we investigated PHD2-dependent vascular homeostasis utilizing inducible deletions of PHD2 either in ECs (Phd2∆ECi) or in aSMCs (Phd2∆aSMC). Cardiovascular function and lung pathologies were studied using echocardiography, Doppler ultrasonography, intraventricular pressure measurement, histological, ultrastructural, and transcriptional methods. Cell intrinsic responses were investigated in hypoxia and in conditions mimicking hypertension-induced hemodynamic stress. Phd2∆ECi resulted in progressive pulmonary disease characterized by a thickened respiratory basement membrane (BM), alveolar fibrosis, increased pulmonary artery pressure, and adaptive hypertrophy of the right ventricle (RV). A low oxygen environment resulted in alterations in cultured ECs similar to those in Phd2∆ECi mice, involving BM components and vascular tone regulators favoring the contraction of SMCs. In contrast, Phd2∆aSMC resulted in elevated RV pressure without alterations in vascular tone regulators. Mechanistically, PHD2 inhibition in aSMCs involved actin polymerization -related tension development via activated cofilin. The results also indicated that hemodynamic stress, rather than PHD2-dependent hypoxia response alone, potentiates structural remodeling of the extracellular matrix in the pulmonary microvasculature and respiratory failure.

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Roxadustat – another drug that causes pulmonary hypertension? – first human report

Cited by 11 publications

References 1 publication

Efficacy and safety of roxadustat for anaemia in dialysis‐dependent and non‐dialysis‐dependent chronic kidney disease patients: A systematic review and meta‐analysis

Efficacy and safety of roxadustat for anaemia in dialysis‐dependent and non‐dialysis‐dependent chronic kidney disease patients: A systematic review and meta‐analysis

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

PHD2 deletion in endothelial or arterial smooth muscle cells reveals vascular cell type-specific responses in pulmonary hypertension and fibrosis

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