Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment

Abstract

Anemia is a complication that affects a majority of individuals with advanced CKD. Although relative deficiency of erythropoietin production is the major driver of anemia in CKD, iron deficiency stands out among the mechanisms contributing to the impaired erythropoiesis in the setting of reduced kidney function. Iron deficiency plays a significant role in anemia in CKD. This may be due to a true paucity of iron stores (absolute iron deficiency) or a relative (functional) deficiency which prevents the use of available iron stores. Several risk factors contribute to absolute and functional iron deficiency in CKD, including blood losses, impaired iron absorption, and chronic inflammation. The traditional biomarkers used for the diagnosis of iron-deficiency anemia (IDA) in patients with CKD have limitations, leading to persistent challenges in the detection and monitoring of IDA in these patients. Here, we review the pathophysiology and available diagnostic tests for IDA in CKD, we discuss the literature that has informed the current practice guidelines for the treatment of IDA in CKD, and we summarize the available oral and intravenous (IV) iron formulations for the treatment of IDA in CKD. Two important issues are addressed, including the potential risks of a more liberal approach to iron supplementation as well as the potential risks and benefits of IV versus oral iron supplementation in patients with CKD.

Keywords: anemia; chronic kidney disease; iron.

Figure 1.

Mechanisms of Anemia in CKD. HIF-PHD, HIF prolyl-hydroxylase domain–containing proteins.

Figure 2.

Iron metabolism is a tightly regulated process. Iron is absorbed in the gut and bound to soluble transferrin. Iron is then moved to storage in the bone marrow and used for erythropoiesis. Additional stores are repleted by macrophage uptake of iron from RBC destruction. EPO induces RBC production, leading to the mobilization of iron stores from the bone marrow. Hepcidin, which is produced by the liver and often stimulated by inflammation, leads to decreased iron uptake from the gut and decreased mobilization of iron stores. Fe-Tf, iron-bound transferrin.

Figure 3.

Hypoxia signaling controls erythropoiesis by coordinating EPO synthesis with the expression of genes involved in iron metabolism. Under well oxygenated conditions, the three oxygen-labile HIF-α subunits (HIF-1α, HIF-2α, and HIF-3α) are hydroxylated at specific proline (Pro) residues by PHD enzymes. Prolyl hydroxylation targets HIF-α proteins for ubiquitination by the von Hippel-Lindau (pVHL)-E3-ubiquitin ligase complex with subsequent proteasomal degradation. Under conditions of reduced PHD activity (for example hypoxia or pharmacologic inhibition), HIF-α escapes hydroxylation and translocates to the nucleus, where it forms a heterodimer with the constitutively expressed HIF-β subunit. The effective HIF-α/HIF-β complex activates the transcription genes whose promoters contain hypoxia response elements. The HIF-mediated activation of transcription requires the recruitment of coactivators such as p300/CREB-binding protein. An additional layer of regulation is due to factor-inhibiting HIF (FIH), which hydroxylates a specific asparagine (Asn) residue abrogating transcriptional cofactor recruitment. HIF-α stabilization results in the activation of genes in diverse biologic processes. For instance, HIF-2α induces EPO production from renal peritubular fibroblasts and hepatocytes, promoting erythroid progenitors’ cell viability, proliferation, and differentiation through EPO receptor (EPOR) signaling. Genes expressed in duodenum, duodenal cytochrome b reductase (DCYTB) and divalent metal transporter-1 (DMT1) along with ferroportin (FPN) are activated by HIF-2, increasing iron uptake while HIF signaling also controls the expression of iron transport genes transferrin (Tf) and transferrin receptor (TfR). O₂, oxygen; OH, hydroxide.