A Hypoxia-Inducible Factor Stabilizer Improves Hematopoiesis and Iron Metabolism Early after Administration to Treat Anemia in Hemodialysis Patients.

Chie Ogawa,Ken Tsuchiya,Kunimi Maeda,Naohisa Tomosugi

doi:10.3390/ijms21197153

Abstract

Roxadustat (Rox), a hypoxia-inducible factor (HIF) stabilizer, is now available for the treatment of anemia in hemodialysis (HD) patients. To investigate hematopoietic effect and iron metabolism, this study involved 30 HD patients who were initially treated with darbepoetin (DA), a conventional erythropoietin-stimulating agent, and then switched to Rox. We measured erythrocyte, reticulocyte indices, and iron-related factors at every HD during the first two weeks after the treatment switch (Days 0–14) and again on Days 21 and 28. We measured erythropoietin (EPO) concentration every week and examined their changes from Day-0 values. The same variables were measured in 15 HD patients who continued DA at every HD for one week. Iron-related factors were also measured on Days 14 and 28. In the Rox group, hepcidin significantly decreased from Day 2. The reticulocyte hemoglobin content (CHr) significantly increased on Day 4, but decreased with a significant increase in reticulocyte count from Day 7. Log10(serum ferritin) significantly decreased after Day 11. Log10(EPO concentration) was lower at all time points. Compared with the DA group, the Rox group showed significant differences in all variables except CHr. These results suggest that Rox improves hematopoiesis and iron metabolism early after administration independent of EPO concentration.

Highlights

Anemia associated with impaired kidney function is defined as renal anemia, and its main cause has been established to be impaired erythropoietin (EPO) production in the kidney
In addition to its EPO-stimulating effect, hypoxia-inducible factor (HIF) regulates the expression of hematopoiesis-related genes, especially the genes of molecules involved in iron metabolism and utilization [15,16,17]
We investigated the relationship between Ret count and red blood cell (RBC) count to examine whether the increase of Ret count affects RBC count

Summary

Introduction

Anemia associated with impaired kidney function is defined as renal anemia, and its main cause has been established to be impaired erythropoietin (EPO) production in the kidney. RHuEPO, collectively known as erythropoietin-stimulating agents (ESAs), includes recently developed long-acting products that have demonstrated significant efficacy in improving anemia, preventing complications, and improving patients’ QOL [5,6]. Multiple hypoxia-inducible factor (HIF) stabilizers are being developed as drugs for a new mechanism of action to stimulate endogenous EPO production. HIF was discovered in 1992 as a transcription factor that is hypoxia-inducible and responsible for the regulation of EPO gene expression [14]. Rox stabilize HIF by inhibiting PHD, allowing HIF to act on EPO-producing cells in the kidney and liver to induce endogenous EPO production and subsequent hematopoiesis. In addition to its EPO-stimulating effect, HIF regulates the expression of hematopoiesis-related genes, especially the genes of molecules involved in iron metabolism and utilization [15,16,17]

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