HIF stabilizers in the management of renal anemia: from bench to bedside to pediatrics

Abstract

Anemia is a common complication of chronic kidney disease (CKD) in adult and pediatric patients. It has traditionally been treated with erythropoietin therapy and iron supplementation, with great success. With the discovery of the major transcription factor hypoxia inducible factor (HIF) for the erythropoietin gene in 1992, molecules were created that inhibit the HIF prolylhydroxylase enzyme. This new class of drug-called HIF stabilizers, or HIF prolyl-hydroxylase inhibitors-prevents the proteasomal degradation of HIF-α, thereby inducing upregulation of the erythropoietin gene. This new strategy for treating CKD anemia is already in phase III clinical trials in adults, and the potential advantages of this therapy are that it is orally active (thereby avoiding injections), and patients are exposed to lower circulating levels of erythropoietin. The long-term safety of this strategy, however, requires elucidation in these trials, particularly since there are many other hypoxia-sensitive genes, notably, angiogenic factors such as vascular endothelial growth factors (VEGF), as well as glycolytic enzymes. As with all new therapies, it is only once a positive benefit: risk profile has been ascertained in adults that the treatment will translate across into pediatrics. Specific issues in the pediatric CKD population are discussed in this review.

Anemia of Inflammation with An Emphasis on Chronic Kidney Disease

“…However, HIFs have roles in other biological pathways, including in the expression of vascular endothelial growth factor (VEGF), which is associated with retinal disease and cancer [142]. Consequently, the long-term safety of HIF-PHIs, and possibly Hif 2α, needs to be elucidated, in particular, for long-term therapy [143].…”

Mechanisms of hypoxia signalling: new implications for nephrology

“…Small molecules that inhibit the activity of the HIF prolyl hydroxylases (PHD inhibitors) effectively activate the HIF pathway and are currently in late-phase clinical trials, or have been licensed for the treatment of renal anaemia. The development of these and other agents that target different components of the HIF system has been described in other reviews [21][22][23][24] , and will not be detailed exhaustively herein. In this Review, we outline the background biology of hypoxia signalling, review new advances in the understanding of the HIF hydroxylase system, and consider outstanding questions regarding the therapeutic manipulation of these pathways in kidney disease.…”

ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription

“…In anemia, a major complication of chronic kidney disease, HIF stabilizers are currently used to restore circulating EPO levels. The long-term safety of this strategy is hindered by the lack of targeting specificity ( Kular and Macdougall, 2019 ). The use of cell transcriptional machinery to produce therapeutic levels of EPO has been put forward to overcome the side effects associated with HIF stabilizers.…”