Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin

Abstract

Anemia is a frequent comorbidity of chronic kidney disease (CKD) and is associated with a considerable burden because of decreased patient health-related quality of life and increased healthcare resource utilization. Based on observational data, anemia is associated with an increased risk of CKD progression, cardiovascular events, and all-cause mortality. The current standard of care includes oral or intravenous iron supplementation, erythropoiesis-stimulating agents, and red blood cell transfusion. However, each of these therapies has its own set of population-specific patient concerns, including increased risk of cardiovascular disease, thrombosis, and mortality. Patients receiving dialysis or those who have concurrent diabetes or high blood pressure may be at greater risk of developing these complications. In particular, treatment with high doses of erythropoiesis-stimulating agents has been associated with increased rates of hospitalization, cardiovascular events, and mortality. Resistance to erythropoiesis-stimulating agents remains a therapeutic challenge in a subset of patients. Hypoxia-inducible factor transcription factors, which regulate several genes involved in erythropoiesis and iron metabolism, can be stabilized by a new class of drugs that act as inhibitors of hypoxia-inducible factor prolyl-hydroxylase enzymes to promote erythropoiesis and elevate hemoglobin levels. Here, we review the burden of anemia of chronic kidney disease, the shortcomings of current standard of care, and the potential practical advantages of hypoxia-inducible factor prolyl-hydroxylase inhibitors in the treatment of patients with anemia of CKD.

Keywords: Anemia; Burden; Chronic kidney disease; Erythropoietin; Hypoxia-inducible factor; Iron; Nephrology.

Fig. 1

Hypoxia-inducible factor (HIF) pathway biology. Under normoxic conditions, the HIF-α transcription factor subunit undergoes ubiquitination and proteasome degradation after prolyl hydroxylation (left side of figure). Under hypoxic conditions or pharmacologic HIF prolyl-hydroxylase inhibition, HIF-α is stabilized and, after heterodimerization with HIF-β, increases transcription of hypoxia-responsive genes, including those encoding erythropoietin (EPO) and iron metabolism (right side of figure). DCYTB duodenal cytochrome B, DMT1 divalent metal transporter 1, EPO erythropoietin, FPN ferroportin, OH hydroxide, PH prolyl hydroxylase, Ub ubiquitin, VHL von Hippel-Lindau protein

Fig. 2

Actions of erythropoiesis-stimulating agents (ESAs) and hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs). IV intravenous