Roxadustat: do we know all the answers?

Abstract

Anemia is a common complication of chronic kidney disease (CKD), and its prevalence rises as the disease progresses. Intravenous or subcutaneous erythropoiesis-stimulating agents (ESAs) are advised to treat CKD-associated anemia, since shortage of erythropoietin (EPO) and iron are the main cause of anemia. However, ESA resistance and safety have spurred a lot of interest in the development of alternate anemia therapies. Roxadustat, an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that increases erythropoiesis and may modulate iron metabolism, was recently licensed in China, Chile, South Korea, Japan and the European Union for the treatment of CKD-related anemia. Despite this, clinical trials have shown a number of adverse effects, including cardiovascular disease, hyperkalemia, and infections. In addition, of concern is roxadustat's possible effects on other organs and systems. In this review, based on clinical evidence, we discuss the potentially detrimental effects of roxadustat to the known biology on systems other than kidney, and the need for long-term follow-up in order for roxadustat to be approved in more countries in the future.

The Role of Oxygen Homeostasis and the HIF-1 Factor in the Development of Neurodegeneration

“…These analogues exhibit greater selectivity toward prolyl hydroxylases (PHDs) and asparaginyl hydroxylases (FIH) than simple iron chelators. Notable examples include 3,4-dihydroxybenzoate (3,4-DHB) and Roxadustat (FG-4592) [156,157]. For instance, 3,4-DHB has shown significant inhibition of FIH, with selectivity over PHDs [157,158].…”

Managing Anemia: Point of Convergence for Heart Failure and Chronic Kidney Disease?

“…Compared to the epoetin alfa group, adverse effects are more common in the roxadustat group (14.2% vs. 10%), with a percentage of 3.5% for vascular and cardiac disorders [ 78 , 79 , 80 ]. Pulmonary arterial hypertension, arteriovenous fistula thrombosis, and vascular disease are several effects of roxadustat treatment shown in clinical trials [ 81 ]. Possible adverse effects of HIF-PH inhibitors include the occurrence of retinal disorders, hypertension or thrombosis, as reported in roxadustat versus darbepoetin alfa in the safety analysis of pooled phase-3 trials in hemodialysis patients.…”

An Overview of Safety and Efficacy Between Hypoxia-Inducible Factor-Prolyl-Hydroxylase Inhibitors and Erythropoietin-Stimulating Agents in Treating Anemia in Chronic Kidney Disease Patients

“…Erythropoietin synthesis occurs in response to hypoxia and is regulated by HIF. Under normal conditions, hypoxia-inducible factor-alpha (HIF-α) is continuously expressed, but hydroxylated by PHD and then degraded by proteasome ubiquitination after binding to von Hippel-Lindau (VHL) protein [10]. During hypoxia, PHD is inhibited, which allows HIF-α to form a complex with hypoxia-inducible factorbeta (HIF-β), thus increasing the expression of the erythropoietin transcription gene and endogenous erythropoietin production [12].…”

“…This pathway also activates multiple target genes related to inflammation, vascular calcification, and angiogenesis [8]. By inhibiting PHD and stabilizing HIF, HIF-PHI increases endogenous erythropoietin production within the physiological range [10]. Figure 2 shows the mechanism of action of HIF-PHI.…”

“…Although ESA significantly improved anemia management and reduced the need for blood transfusions in CKD patients, it is associated with several adverse effects such as hypertension, thromboembolism, cardiovascular disease, and mortality [8]. In addition, ESA requires adequate intravenous (IV) iron supplementation due to increased iron demand for erythropoiesis [9][10][11].…”