Background Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed regarding th...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1901713?articleTools=true

Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis.

Iron is biologically essential, but also potentially toxic; as such it is tightly controlled at cell and systemic levels to prevent both deficiency and overload. Iron regulatory proteins post-transcriptionally control genes encoding proteins that modulate iron uptake, recycling and storage and are themselves regulated by iron. The master regulator of systemic iron homeostasis is the liver peptide hepcidin, which controls serum iron through degradation of ferroportin in iron-absorptive enterocytes and iron-recycling macrophages. This review emphasizes the most recent findings in iron biology, deregulation of the hepcidin-ferroportin axis in iron disorders and how research results have an impact on clinical disorders. Insufficient hepcidin production is central to iron overload while hepcidin excess leads to iron restriction. Mutations of hemochro-matosis genes result in iron excess by downregulating the liver BMP-SMAD signaling pathway or by causing hepcidin-resistance. In iron-loading anemias, such as β-thalassemia, enhanced albeit ineffective ery-thropoiesis releases erythroferrone, which sequesters BMP receptor ligands, thereby inhibiting hepcidin. In iron-refractory, iron-deficiency ane-mia mutations of the hepcidin inhibitor TMPRSS6 upregulate the BMP-SMAD pathway. Interleukin-6 in acute and chronic inflammation increases hepcidin levels, causing iron-restricted erythropoiesis and ane-mia of inflammation in the presence of iron-replete macrophages. Our improved understanding of iron homeostasis and its regulation is having an impact on the established schedules of oral iron treatment and the choice of oral versus intravenous iron in the management of iron deficiency. Moreover it is leading to the development of targeted therapies for iron overload and inflammation, mainly centered on the manipulation of the hepcidin-ferroportin axis.

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Iron metabolism and iron disorders revisited in the hepcidin era

Under conditions of hypoxia, most eukaryotic cells can shift their primary metabolic strategy from predominantly mitochondrial respiration towards increased glycolysis to maintain ATP levels. This hypoxia-induced reprogramming of metabolism is key to satisfying cellular energetic requirements during acute hypoxic stress. At a transcriptional level, this metabolic switch can be regulated by several pathways including the hypoxia inducible factor-1α (HIF-1α) which induces an increased expression of glycolytic enzymes. While this increase in glycolytic flux is beneficial for maintaining bioenergetic homeostasis during hypoxia, the pathways mediating this increase can also be exploited by cancer cells to promote tumour survival and growth, an area which has been extensively studied. It has recently become appreciated that increased glycolytic metabolism in hypoxia may also have profound effects on cellular physiology in hypoxic immune and endothelial cells. Therefore, understanding the mechanisms central to mediating this reprogramming are of importance from both physiological and pathophysiological standpoints. In this review, we highlight the role of HIF-1α in the regulation of hypoxic glycolysis and its implications for physiological processes such as angiogenesis and immune cell effector function.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP280572

Regulation of glycolysis by the hypoxia-inducible factor (HIF): implications for cellular physiology.

Anemia is a complication that affects a majority of individuals with advanced CKD. Although relative deficiency of erythropoietin production is the major driver of anemia in CKD, iron deficiency stands out among the mechanisms contributing to the impaired erythropoiesis in the setting of reduced kidney function. Iron deficiency plays a significant role in anemia in CKD. This may be due to a true paucity of iron stores (absolute iron deficiency) or a relative (functional) deficiency which prevents the use of available iron stores. Several risk factors contribute to absolute and functional iron deficiency in CKD, including blood losses, impaired iron absorption, and chronic inflammation. The traditional biomarkers used for the diagnosis of iron-deficiency anemia (IDA) in patients with CKD have limitations, leading to persistent challenges in the detection and monitoring of IDA in these patients. Here, we review the pathophysiology and available diagnostic tests for IDA in CKD, we discuss the literature that has informed the current practice guidelines for the treatment of IDA in CKD, and we summarize the available oral and intravenous (IV) iron formulations for the treatment of IDA in CKD. Two important issues are addressed, including the potential risks of a more liberal approach to iron supplementation as well as the potential risks and benefits of IV versus oral iron supplementation in patients with CKD.

Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment.

The pathogenetic mechanism of contrast-induced acute kidney injury (CI-AKI), which is the third most common cause of hospital-acquired AKI, has not been elucidated. Previously, we demonstrated that renal injury and cell apoptosis were attenuated in nlrp3 knockout CI-AKI mice. Here, we investigated the mechanism underlying NLRP3 inhibition-mediated attenuation of apoptosis in CI-AKI. The RNA sequencing analysis of renal cortex revealed that the nlrp3 or casp1 knockout CI-AKI mice exhibited upregulated cellular response to hypoxia, mitochondrial oxidation, and autophagy when compared with the wild-type (WT) CI-AKI mice, which indicated that NLRP3 inflammasome inhibition resulted in the upregulation of hypoxia signaling pathway and mitophagy. The nlrp3 or casp1 knockout CI-AKI mice and iohexol-treated HK-2 cells with MCC950 pretreatment exhibited upregulated levels of HIF1A, BECN1, BNIP3, and LC3B-II, as well as enhanced colocalization of LC3B with BNIP3 and mitochondria, and colocalization of mitochondria with lysosomes. Additionally, roxadustat, a HIF prolyl-hydroxylase inhibitor, protected the renal tubular epithelial cells against iohexol-induced injury through stabilization of HIF1A and activation of downstream BNIP3-mediated mitophagy in vivo and in vitro. Moreover, BNIP3 deficiency markedly decreased mitophagy, and also significantly exacerbated apoptosis and renal injury. This suggested the protective function of BNIP3-mediated mitophagy in CI-AKI. This study elucidated a novel mechanism in which NLRP3 inflammasome inhibition attenuated apoptosis and upregulated HIF1A and BNIP3-mediated mitophagy in CI-AKI. Additionally, this study demonstrated the potential applications of MCC950 and roxadustat in clinical CI-AKI treatment.Abbreviations: BNIP3: BCL2/adenovirus E1B interacting protein 3; Ctrl: control; DAPI: 4',6-diamidino-2-phenylindole dihydrochloride; EGLN2/PHD1: egl-9 family hypoxia-inducible factor 2; HIF1A: hypoxia inducible factor 1, alpha subunit; H-E: hematoxylin and eosin; IL18: interleukin 18; IL1B: interleukin 1 beta; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mRNA: messenger RNA; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; NLRP3: NLR family, pyrin domain containing 3; NS: normal saline; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; PINK1: PTEN induced putative kinase 1; RNA: ribonucleic acid; SEM: standard error of the mean; siRNA: small interfering RNA; TEM: transmission electron microscopy; TUBA/α-tubulin: tubulin, alpha; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; VDAC: voltage-dependent anion channel; WT: wild-type.

Inhibiting NLRP3 inflammasome attenuates apoptosis in contrast-induced acute kidney injury through the upregulation of HIF1A and BNIP3-mediated mitophagy

Background Roxadustat (FG-4592) is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase that stimulates erythropoiesis and regulates iron metabolism. In phase 2 studies i...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1813599

Yunhua Liao

Papers

Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis

Zhang L, Wang F, Wang L, et al. Prevalence of chronic kidney disease in China: a cross-sectional survey