Recombinant erythropoietin (EPO), introduced in 1987, represented a therapeutic revolution in the management of anemia in chronic kidney disease (CKD), transforming the quality of life of dialysis patients and improving the mortality and morbidity associated with this severe anemia . It is a pathophysiological treatment because the anemia in CKD is mainly related to a significant decrease in erythropoietin production by the diseased kidneys, as evinced by the sharply decreased levels of circulating erythropoietin during CKD; moreover, there is a parallel between the severity of renal failure and the decrease in circulating erythropoietin levels(Panjeta et al., 2017). Erythropoietin is a growth factor acting on the bone marrow, which is necessary for the early stages of erythropoiesis; EPO thus acts on burst-forming unit-erythroid cells (BFU-E cells), colony-forming unit-erythroid cells (CFU-E cells) and proerythroblasts (Besarab et al., 2009) via a specific receptor. It should be noted that in addition to this early EPO-dependent phase, erythropoiesis has a later phase dependent on the incorporation of iron into the heme nucleus of hemoglobin (Figure 1).

In addition to its primary action on erythropoiesis, EPO is also a pleiotropic growth factor acting during fetal development, not only on erythropoiesis but also on angiogenesis, fetal brain development, and also neuronal, retinal and vascular protection, and wound healing in adulthood (Vaziri & Ateshkadi, 1999). EPO production takes place in the liver during fetal life and in the kidneys from birth. It has recently been shown that during CKD, the liver takes over from the deficient kidneys in the synthesis of erythropoietin, especially as renal function is impaired(Seigneux S et al., 2016).

EPO production occurs in the kidney (and liver) in response to changes in tissue oxygenation or hypoxia(Koury & Haase, 2015) [6]. Hypoxia leads to transcription of the erythropoietin gene in peritubular interstitial fibroblasts and in the liver(Seigneux S et al., 2016) [6]. EPO promotes erythropoiesis in pluripotent bone marrow cells committed to the erythroblastic lineage (BFU-E and CFU-E) and proerythroblasts [6]. The resulting increase in circulating erythrocytes and hemoglobin leads to improved tissue oxygenation [6]. The hypoxia inducible factor (HIF) transcription factor in EPO-producing kidney cells regulates erythropoietin production in a hypoxia-inducible manner (Figure 2)(Koury & Haase, 2015).

The level of HIF-α is regulated by specific enzymes called HIF-prolyl hydroxylase (HIF-PHD) that trigger its degradation at the proteasome. There are three HIF-PHD enzymes in humans that hydroxylate HIF-α and thus regulate its stability: HIF-PHD1, HIF-PHD2, and HIF-PHD3. The enzyme HIF-PHD2 is considered the primary regulator of HIF under normal oxygenation conditions (Locatelli et al., 2017-01-25).

The activation of HIF is a physiological response of the body in the presence of low oxygen levels (hypoxia). Indeed, at normal oxygen levels, HIF-prolyl hydroxylase remains abundant. It causes the degradation of HIF-α and thus prevents the activation of a hypoxic response. In contrast, during periods of hypoxia (low oxygen), HIF-prolyl hydroxylase is inactive, because oxygen is required for the enzymatic reaction, and HIF-α will therefore accumulate. HIF-α then dimerizes with constitutively expressed HIF-β, and the dimer moves to the nucleus, allowing transcription of key genes that manage hypoxia(Locatelli et al., 2017-01-25). Several hundred genes are direct targets of HIF; these genes play a role in cell migration, cell growth and cycle, angiogenesis, vasomotor regulation, glucose metabolism and availability, and barrier functions, as well as EPO synthesis and iron availability for erythropoiesis (Figure 3)(Schödel & Ratcliffe, 2019).

These are small synthetic molecules with very low renal elimination (without dosage adjustment during CKD). They are analogs with an antagonistic effect on 2-oxoglutarate, a natural substrate of HIF-prolyl hydroxylase at the origin of the inhibition of this enzyme. This results in a simulated state of hypoxia, allowing the accumulation of HIF-α in the cells (Vareesangthip et al., 2023)(Locatelli & Del Vecchio, 2022).

Pharmacological inhibition of HIF-prolyl hydroxylase 2 induces transcription of EPO genes and inhibition of hepcidin synthesis, resulting in efficient and coordinated erythropoiesis. The production of erythrocytes follows the conjunction of EPO production and the synthesis of its cellular receptors associated with an increase in iron availability. This optimization of martial metabolism is due to increased intestinal iron absorption and iron release by macrophages and cells of the reticuloendothelial system following the inhibition of hepcidin synthesis and the arrest of degradation of ferroportin, the protein exporting iron from these cells (Vareesangthip et al., 2023)(Locatelli & Del Vecchio, 2022). In an ancillary study of Roxadustat, it was shown that blood erythropoietin concentrations in patients treated with this dustat were close to physiological values, whereas circulating erythropoietin concentrations on Epoetin alfa appeared to be largely supra-physiological (by a factor of 5 to 6) Figure 4) (Provenzano et al., 2016). In the same study, Roxadustat significantly reduced hyperhepcidemia in dialysis patients and increased iron utilization for erythropoiesis, as evinced by the increase in the hemoglobin content of reticulocytes (CHr) (Figure 5) . It should be remembered that the inhibition of hepatic hepcidin under dustat is indirect, due to the medullary production of erythroferrone.

Evrenzo® is the first dustat marketed in Europe. Its clinical development included trials involving 9,600 patients either in advanced renal failure or on dialysis (Figure 6)(Tang et al., 2021) . It has similar efficacy to ESAs in treating CKD anemia (Figure 7) (Tang et al., 2021). The European Medicines Agency’s (EMA) summary of product characteristics states (verbatim), «What is it used for? Evrenzo is a medicine used in adults to treat the symptoms of anemia caused by chronic renal failure. How is Evrenzo used? Patients treated with an ESA and whose haemoglobin levels are stable should not be switched to Evrenzo unless there is clinical justification and expected benefits.»

In other words, according to the summary of product characteristics established by the EMA, Evrenzo® can be given in the first intention in pre-dialysis and dialysis in ESA-naive patients and in the second intention in pre-dialysis and dialysis in case of resistance or intolerance to ESAs (Source Title, n.d.).

The opinion of the Transparency Commission of the French National Authority for Health (HAS) for Evrenzo® dated March 30, 2022 specifies that its (verbatim) «medical service rendered (MSR) is important only in patients not already treated with an erythropoiesis-stimulating agent, not dialyzed or dialyzed for less than 4 months» Table I.[(Source Title, n.d.). Evrenzo® has a level V medical benefit (ISMR V) (Table II.) (Source Title, n.d.).

Currently, Roxadustat is also marketed in other European Union countries and in the United Kingdom in the European AMM indication, as well as in Japan and China in a broader indication (non-dialyzed and dialyzed CKD).

The clinical development of Daprodustat included 8,169 patients either in advanced renal failure or on dialysis (Figure 8)(Fu et al., 2022) . It has similar efficacy to ESAs in treating anemia in CKD (Fu et al., 2022). The decision of the EMA regarding the European AMM of Daprodustat is expected in April or May 2023, and should logically lead to the submission of a reimbursement application to the HAS Transparency Commission (CT) in the fall of 2023. The opinion of the CT should be known at the beginning of 2024, and the marketing of Daprodustat should occur during 2024 after the price has been fixed by the Economic Committee for Health Products.

Vadadustat (Vafseo® from Akebia Therapeutics (Cambridge, Massachusetts, USA) and Otsuka Pharmaceutical (Chiyoda, Tokyo, Japan)) received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) in February 2023, which is a key step in obtaining a European AMM (Source Title, n.d.). Its clinical development has included 8,438 patients on dialysis or with advanced non-dialysis CKD, and it has similar efficacy to ESAs in treating anemia due to renal failure (Xiong et al., 2022).

Despite the real interest in this new therapeutic class in home dialysis, linked to the absence of the cold chain, which is complex to implement in this situation, and to the positive modulation effect of dustats on martial metabolism, which is strongly disrupted in dialyzed CKD, there is a paucity of data. Studies are limited to 2 works on peritoneal dialysis (PD), one involving Roxadustat, the other involving Vadadustat(Akizawa et al., 2019-07-31)(Dasgupta et al., 2022-11) .

The first study was of Roxadustat and involved 56 Japanese patients treated with PD; 13 were ESA-naive and 43 on ESA then converted to this dustat. The follow-up was 24 weeks. Both types of patients were within the 10-12 g/dl target by week 6 and remained within the target during the 24 weeks of the study (Figure 9)(Akizawa et al., 2019-07-31).

The second work dedicated to PD was a pre-specified analysis of the ASCEND-D study (NCT02879305) of Daprodustat in dialysis, which included 340 PD patients randomized (1/1)to either Daprodustat or Darbepoetin alfa. This study, presented at the last American Society of Nephrology (ASN) congress, showed an identical cardiovascular safety and efficacy profile on anemia between Darbepoetin and Daprodustat in PD (Figure 10) (Dasgupta et al., 2022-11).

In recent years, the nephrological community had shown an interest and enthusiasm for the new therapeutic class of dustats (Koury & Haase, 2015)(Locatelli et al., 2017-01-25)(Schödel & Ratcliffe, 2019). However, this has greatly diminished in the last 3 years due to the unfinished nature of the studies on the different molecules, which have been limited to non-inferiority studies. There have not been any superiority studies or specific studies on patients who are hypo-responders or resistant to ESAs, a medical problem that is currently unresolved and is a source of great concern to the nephrologists (Babitt et al., 2021) . Only home dialysis has escaped this negative judgment regarding HIF stabilizers and appeared for Locatelli and Del Veccio, in their recent narrative review published in the Journal of the American Society of Nephrology (JASN) in late 2022, as an elective indication for this new class. This has been due to the HIF stabilizers’ lack of need for the cold chain, their positive impact on martial metabolism, and their oral mode of administration, which have been compared with the difficulties and imperfections of the current treatment of anemia with ESAs and iron derivatives in this patient population (Locatelli & Del Vecchio, 2022).

HIF stabilizers are a new and very promising therapeutic class for anemia in advanced or end-stage renal disease. They seem to be of great interest in home dialysis because of their oral form, the absence of the cold chain and their positive effect on martial metabolism.

Dr. Guy Rostoker reports consulting fees from Astellas (consulting on Roxadustat, 2019-2021, 2023), GlaxoSmithKline (consulting on Daprodustat, 2022-2023), Vifor (consulting on Kapruvia, 2021-2023).

He reports research funding from Amgen, Astellas, Baxter, Hemotech, Gambro Hospal, Nipro, Physidia and Theradial. He also declares speaking fees from Amgen, Aguettant, Astellas, Roche, Sanofi and Vifor.