A new insight into the treatment of renal anemia with HIF stabilizer

Yukio Maruyama,Hirokazu Honda,Satoru Kuriyama

doi:10.1186/s41100-020-00311-x

Abstract

The long-term clinical experiences with recombinant human erythropoietin (rHuEPO) and its analog derivatives have clearly proven that correction of anemia with erythropoiesis stimulating agent (ESA) not only reduces blood transfusion and improves patients’ QOL but has multiple benefits for the concurrent complications of CKD such as Cardio-Renal–Anemia (CRA) syndrome and/or malnutrition-inflammation-atherosclerosis (MIA) syndrome.Unlike ESA, the newly available agent, hypoxia-inducible factor (HIF) stabilizer, stimulates endogenous erythropoietin (EPO) by mimicking hypoxia with HIF prolyl hydroxylase domain enzyme (HIF-PHD) inhibition. The phase 2 and 3 clinical studies have shown that HIF stabilizers are as efficacious as ESA in ameliorating renal anemia. Whether the same clinical benefits on CRA and MIA syndrome hold true in patients given HIF stabilizers is a matter for future debate. Given that HIF stabilizers act on the multiple target genes, the use of this novel agent may lead to unwanted adverse events.Launching HIF stabilizers into the treatment of renal anemia provokes a concern about how this alternative treatment will be taken up in the daily clinical practice. However, guideline-oriented strategies on how to use HIF stabilizer is not available at this limited point due to scant clinical information. Nevertheless, this opinion-based review provides a future insight into the management of renal anemia with HIF stabilizer by reference to the past experiences with ESA. HIF stabilizers can preferably be indicated for CRA syndrome at pre-dialysis stage, ESA resistant anemia at advanced CKD stage, and perhaps for dysregulated iron metabolism akin to MIA syndrome in patients on dialysis.

Highlights

The epoch-making recombinant human erythropoietin came into clinical practice for renal anemia in chronic kidney disease (CKD) patients on dialysis in 1990, and its indication was extended to those at predialysis stage in 1994 in Japan
Lagging about 3 decades behind erythropoiesis stimulating agent (ESA) in 2019, the hypoxia inducible factor (HIF) stabilizer which stimulates endogenous erythropoietin (EPO) by mimicking hypoxia with HIF prolyl hydroxylase domain enzyme (HIF-PHD) inhibition was launched for the first time into the clinical practice of renal anemia in Japan
The pharmacological mode of action of HIF stabilizer to stimulate erythropoiesis is totally different from ESA, the phase-2 and phase-3 clinical studies have shown that HIF stabilizers are as efficacious as ESA in ameliorating renal anemia [5–19]

Summary

Introduction

The epoch-making recombinant human erythropoietin (rHuEPO) came into clinical practice for renal anemia in chronic kidney disease (CKD) patients on dialysis in 1990, and its indication was extended to those at predialysis stage in 1994 in Japan. The adverse effects with HIF stabilizers include expanded interpretations of the ESA-based findings and/or the inferences based on animal experiments ESA erythropoiesis stimulating agent, MIA malnutrition-inflammationatherosclerosis, CRA cardiovascular-renal-anemia, ADPKD autosomal dominant polycystic kidney disease putative adverse events Most of these unknown clinical adverse events have not yet been virtually clarified. Such adverse events include thrombosis/ embolism, relapse of the latent cancer, worsening of pulmonary hypertension, autosomal dominant polycystic kidney disease (ADPKD), and diabetic nephropathy et al (Table 2) Clinical information on these fearful adverse effects with HIF stabilizers is scant at this point, since the observation period in the most studies are too short to draw any scientific conclusion. One can accomplish slow and stable supply of both iron and the effective erythropoiesis that will be maximally beneficial for the correction of anemia but for the prevention of CV events and the dysregulation of iron metabolism

Conclusion

Findings

Funding None