Treatment of anemia in difficult-to-manage patients with chronic kidney disease

Abstract

The management of anemia of chronic kidney disease (CKD) is often challenging. In particular, for patients with underlying inflammation, comorbid type 2 diabetes or cancer, those hospitalized, and recipients of a kidney transplant, the management of anemia may be suboptimal. Responsiveness to iron and/or erythropoiesis-stimulating agents, the mainstay of current therapy, may be reduced and the risk of adverse reactions to treatment is increased in these difficult-to-manage patients with anemia of CKD. This review discusses the unique patient and disease characteristics leading to complications and suboptimal treatment response. New treatment options in clinical development, such as hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, may be particularly useful for difficult-to-treat patients. In clinical studies, HIF-PH inhibitors provided increased hemoglobin levels and improved iron utilization in anemic patients with non-dialysis-dependent and dialysis-dependent CKD, and preliminary data suggest that HIF-PH inhibitors may be equally effective in patients with or without underlying inflammation. The availability of new treatment options, including HIF-PH inhibitors, may improve treatment outcomes in difficult-to-manage patients with anemia of CKD.

Keywords: anemia; cancer; chronic kidney disease; hospitalization; hypoxia-inducible factor-prolyl hydroxylase inhibitor; inflammation; kidney transplantation; type 2 diabetes.

Graphical abstract

Figure 1

Pathophysiological mechanisms of anemia of inflammation. During inflammation, activated immune cells release cytokines that reduce hemoglobin levels through multiple pathophysiological mechanisms: hepatic production of hepcidin is increased that prevents iron (Fe³⁺) egress from macrophages and inhibits dietary iron absorption leading to sequestration of stored iron; erythropoietin (EPO) release from the kidneys is inhibited, which decreases erythropoietic stimulation of the bone marrow; at the same time, bone marrow erythroid proliferation is directly inhibited; hemophagocytosis of red blood cell (RBC) by reticuloendothelial system (RES) macrophages is increased, leading to further RBC loss. IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.

Figure 2

Schematic diagram showing how hypoxia-inducible factor-prolyl hydroxylase inhibitors affect the management of anemia of chronic kidney disease (CKD). Through the pharmacologic action of hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors, HIF-α degradation is suppressed and allowed to dimerize with the β subunit allowing the transcription of genes involved in iron homeostasis and erythropoiesis. HIF-PH inhibitors stimulate erythropoietin (EPO) production in the kidney, and both directly and indirectly increase iron (Fe) availability. Directly, HIF-PH inhibitors increase iron absorption in the duodenum and upregulate transferrin (TF) and TF receptors. Indirectly, erythropoiesis in the bone marrow leads to the inhibition of hepcidin production, increasing iron availability. Black arrows indicate normal physiology; inhibitory and stimulatory effects are shown in blue (erythropoiesis-stimulating agent [ESA]), red (iron), and green (HIF-PH inhibitor) arrows. ERFE, erythroferrone; RBC, red blood cell; RES, reticuloendothelial system.