New hypothesis: “Six-factor theory of erythropoiesis control” HIF-PH inhibitors correct TNF-α over-induction in ESA-resistant anemia. Atsuo Takemasa, Ajina Tsuchiya Hospital
Abstract
Erythropoiesis-Stimulating agents (ESAs) have made significant contributions to the treatment of renal anemia over the years. Furthermore, many reports have been published on the tissue-protective and anti-inflammatory effects of ESAs.
While the normal EPO receptor is an EPOR homodimer, unlike the hematopoietic effects of ESAs, their tissue protective and anti-inflammatory effects are primarily mediated by a heteroreceptor consisting of EPOR and CD131. The possibility that large doses of ESAs may have adverse effects on the human body and the existence of ESAs-resistant anemia suggest the limitations (paradox) of the conventional treatment model, making it urgent to develop a new theory. Incorporating the pharmacological effects of recently introduced HIF-PH inhibitors (HIF-PHIs), we propose a new hypothesis, the “six-factor theory of erythropoiesis control.” Since proving a theory requires the accumulation of many experiments and observational studies, we will attempt to prove it in a review format. The six factors are EPO, Tumor Necrosis Factor-α (TNF-α), Leptin, Hypoxia-Inducible Factor（HIF）, GATA transcription factor (GATA), and Nuclear Factor-kappa B (NF-κB). The underlying cause of ESAs-resistant anemia is the over-induction of TNF-α by large amounts of ESAs itself. This is corrected by HIF-PHIs. Iron metabolism and hemoglobin synthesis control are downstream of the six factors that regulate the baseline balance between red blood cell production and infection defense.
Iron metabolism is controlled from the upstream by TNF-α and Leptin, which inhibit iron utilization, and by HIF and EPO, which promote iron utilization. Important downstream factors are Transferrin Receptor (TfR) 2, Hepcidin, Erythroferrone, and Fibroblast Growth Factor 23 (FGF23). FGF23, TfR2, and Leptin are at the crossroads of erythropoiesis, iron metabolism, and bone metabolism. Endogenous EPO is reduced by ESA overdose and restored by HIF-PHIs. The pharmacological action of HIF-PHIs, which are highly effective in treating ESAs-resistant anemia, is to produce physiological EPO and improve iron metabolism. Furthermore, HIF-PHIs adjust the imbalance of the six-factor network, creating an environment for efficient red blood cell production. The basis for this is the suppression of TNF-α production by HIF-PHIs. Clinically, if sufficient iron can be replenished to protect the body from the harmful effects of iron deficiency and side effects such as thrombosis can be controlled, HIF-PHIs may become the first choice of standard treatment for renal anemia.
The advent of HIF-PHIs has shed light on previously unknown biological mechanisms, and discussions are likely to progress on fine-tuning the treatment of renal anemia and the combined use of ESAs and HIF-PHIs in small doses.
Keywords:
Erythropoietin, Tumor Necrosis Factor-α, Leptin, Hypoxia-Inducible Factor, GATA Transcription Factor, Nuclear Factor-κB, Erythropoiesis-Stimulating Agent-Resistant Anemia, Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors, Transferrin Receptor 2, Hepcidin, Erythroferrone, Fibroblast Growth Factor 23, Renal Anemia, Chronic Kidney Disease, EPO, CKD