Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD

Abstract

Erythropoiesis-stimulating agents (ESAs) increase hemoglobin levels, reduce transfusion requirements, and have been the standard of treatment for anemia in patients with chronic kidney disease (CKD) since 1989. Many safety concerns have emerged regarding the use of ESAs, including an increased occurrence of cardiovascular events and vascular access thrombosis. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a new class of agents for the treatment of anemia in CKD. These agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease. HIF-PH inhibitors improve iron mobilization to the bone marrow. They are administered orally, which may be a more favorable route for patients not undergoing hemodialysis. By inducing considerably lower but more consistent blood erythropoietin levels than ESAs, HIF-PH inhibitors may be associated with fewer adverse cardiovascular effects at comparable hemoglobin levels, although this has yet to be proved in long-term clinical trials. One significant concern regarding the long-term use of these agents is their possible effect on tumor growth. There are 4 such agents undergoing phase 2 and 3 clinical trials in the United States; this report provides a focused review of HIF-PH inhibitors and their potential clinical utility in the management of anemia of CKD.

Review of WADA Prohibited Substances: Limited Evidence for Performance-Enhancing Effects

“…Small molecule HIFs are in clinical development but have not yet been approved for clinical use. The published clinical studies show that these compounds produce modest increases in erythropoietin in both anaemic patients and healthy volunteers [45, 46], however there are currently no studies evaluating effects on the performance of healthy or trained subjects.…”

An Emerging Treatment Alternative for Anemia in CKD Patients: A Review on Daprodustat

“…When the body is exposed to low oxygen levels, such as at increased altitudes the body stimulates the production of EPO to increase RBCs and restore oxygen balance [3,12]. This mechanism of compensation is initiated through transcription factor, HIF-α, more specifically the isoform HIF-1α which is commonly referred to as HIF-1.…”

“…When HIF-α accumulates it forms a functional dimer with HIF-β, which subsequently translocates to the nucleus where it binds to hypoxia response elements (HREs) on DNA. This results in the induction of gene expression of EPO, which in turn promotes an erythropoietic response and up regulation of iron transport [3,13]. When the body has adequate oxygen levels, HIF-α is degraded and regulated by HIF-PH.…”

“…When the body has adequate oxygen levels, HIF-α is degraded and regulated by HIF-PH. Daprodustat stabilizes HIF-1α by inhibiting HIF-PH, therefore increasing levels of HIF-α, leading to increases in EPO, and decreasing hepcidin, an indirect regulator of iron absorption and utilization [3,12,13].…”

“…As the disease state progresses, patients are at an increased risk of developing anemia. Anemia in CKD patients may be caused by iron deficiency, inflammation, or a disruption in the production of erythropoietin (EPO) [2,3]. Erythropoietin is a hormone that stimulates the production of red blood cells [4].…”