Iron Deficiency in Chronic Kidney Disease

REVIEW www.jasn.org Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment Elizabeth Katherine Batchelor,1 Pinelopi Kapitsinou,2,3 Pablo E. Pergola,4 Csaba P. Kovesdy ,5 and Diana I. Jalal6 1Department of Internal Medicine and 6Division of Nephrology, University of Iowa Hospitals and Clinics, Iowa City, Iowa; 2Feinberg Cardiovascular and Renal Research Institute and 3Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, Illinois; 4Renal Associates PA, Division of Nephrology, University of Texas Health Science Center at San Antonio, San Antonio, Texas; and 5Division of Nephrology, University of Tennessee Health Science Center, Memphis, Tennessee ABSTRACT Anemia is a complication that affects a majority of individuals with advanced CKD. which impairs the body’s ability to appro- Although relative deficiency of erythropoietin production is the major driver of ane- priately utilize the iron sequestered in the mia in CKD, iron deficiency stands out among the mechanisms contributing to the tissues.8 Repletion of iron stores is often impaired erythropoiesis in the setting of reduced kidney function. Iron deficiency necessary in patients with CKD for the plays a significant role in anemia in CKD. This may be due to a true paucity of iron treatment of IDA and to maximize the ef- stores (absolute iron deficiency) or a relative (functional) deficiency which prevents ficacy of ESAs. The traditional biomarkers the use of available iron stores. Several risk factors contribute to absolute and func- used to detect iron deficiency in CKD are tional iron deficiency in CKD, including blood losses, impaired iron absorption, and often unreliable, rendering the diagnostic chronic inflammation. The traditional biomarkers used for the diagnosis of iron- and monitoring processes difficult. To deficiency anemia (IDA) in patients with CKD have limitations, leading to persistent best manage IDA in CKD, a thorough un- challenges in the detection and monitoring of IDA in these patients. Here, we review derstanding of its pathophysiology and the pathophysiology and available diagnostic tests for IDA in CKD, we discuss the treatments is necessary. In this text, we literature that has informed the current practice guidelines for the treatment of IDA review the mechanisms of IDA, the poten- in CKD, and we summarize the available oral and intravenous (IV) iron formulations tial aids and pitfalls in the diagnosis of for the treatment of IDA in CKD. Two important issues are addressed, including the IDA, and the available treatment formu- potential risks of a more liberal approach to iron supplementation as well as the lations for IDA in patients with CKD. We potential risks and benefits of IV versus oral iron supplementation in patients furthermore provide an in-depth discus- with CKD. sion of the current literature as it pertains to target levels of Hgb and iron indices. JASN 31: 456–468, 2020. doi: https://doi.org/10.1681/ASN.2019020213 Anemia, defined as a hemoglobin (Hgb) ofanemia inpatientswith CKD (Figure 1). PATHOPHYSIOLOGY OF IDA concentration of ,13 g/dl in men and Several well conducted studies in patients ,12 g/dl in women, is an important with CKD indicate that use of ESAs to Iron metabolism is tightly regulated at complication of CKD.1 The prevalence normalize Hgb in patients with CKD multiple stages of the red blood cell of anemia increases across the advancing mayworsencardiovascular(CV)out- (RBC) life cycle (Figure 2). Although stages of CKD, with estimates anywhere comes.3–6 Thus, the current guidelines from 7% to .50% in the more advanced advise a target Hgb below the definition 2 1 Published online ahead of print. Publication date stages of the disease. Multiple mecha- of normal in patients with CKD. available at www.jasn.org. nisms contribute to the development Many patients with anemia and CKD of anemia in CKD, the most important suffer from iron-deficiency anemia Correspondence: Dr. Diana Jalal, Division of Ne- phrology, Department of Medicine, Carver College fi 1,7 being relative de ciency of erythropoie- (IDA). This is due to both true paucity of Medicine, 200 Hawkins Drive, Iowa City, IA tin (EPO). As such, erythropoiesis- of iron stores (absolute IDA) and relative 52242. Email: [email protected] fi stimulating agents (ESAs) have been (functional) iron de ciency; the latter be- Copyright © 2020 by the American Society of considered a staple for the management ing due to underlying inflammation Nephrology 456 ISSN : 1046-6673/3103-456 JASN 31: 456–468, 2020 www.jasn.org REVIEW recycling, a process influenced by EPO.11 Iron metabolism is further regulated by hepcidin.12 Apeptidehor- mone synthesized predominately in the liver, hepcidin regulates the uptake of iron from the gut and the release of iron from the iron stores.13 Hepcidin production is stimulated by increased iron uptake, inflammation, and infec- tion; it is suppressed in the setting of iron deficiency and hypoxia.12,14 CKD is associated with increased hepcidin levels.15 Hypoxia-inducible factor (HIF) is an important transcription factor in the regulation of erythropoiesis, iron Figure 1. Mechanisms of Anemia in CKD. HIF-PHD, HIF prolyl-hydroxylase do- metabolism, and multiple other main–containing proteins. processes involved in the maintenance of homeostasis.16–19 HIF, a key media- the development of erythroid lineage iron is either transported to the liver tor of cellular adaptation to oxygen from a multipotential myeloid stem and spleen, where it is bound to ferritin deprivation, comprises an oxygen- cell is regulated by EPO, the differenti- for storage, or to the bone marrow sensitive a-subunit (HIF-1a,HIF-2a, ation from erythroblasts into reticulo- where it is used for erythropoiesis.10 Al- or HIF-3a)andastableb-subunit. cytesisaniron-dependentprocess. though dietary intake is typically suffi- HIF heterodimers activate the tran- Hence, iron deficiency will limit re- cient to replace most of the daily losses scription of genes whose promoters sponsiveness to EPO.9 Iron is absorbed of iron, the majority of iron stores are contain hypoxia response elements, in the gastrointestinal tract and bound replenished by macrophage phagocyto- whereas recruitment of coactivators to serum transferrin. Subsequently, sis of the destroyed RBCs and iron such as p300/CREB-binding protein is required in HIF-mediated transcription. HIF-a proteins are regulated by prolyl-4-hydroxylase domain–containing proteins 1–3(PHD1–3), ferrous- and 2- oxoglutarate-dependent oxygenases, whose activity is dependent on oxygen.20 Under normoxic conditions, PHDs hy- droxylate HIF-a at proline residues, al- lowing targeting for ubiquitination by the von Hippel-Lindau (pVHL)-E3- ubiquitin ligase complex and subsequent proteasomal degradation.21 Under hypoxic conditions, HIF-a is sta- bilized and, after nuclear translocation, it dimerizes with the HIF-b subunit, forming heterodimers that activate 100–200 genes, including EPO and other genes involved in iron metabolism. Furthermore, HIF reduces serum levels of hepcidin indirectly through stimulation of EPO-induced erythro- Figure 2. Iron metabolism is a tightly regulated process. Iron is absorbed in the gut and poiesis.22 Compounds that pharmaco- 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 logically inhibit PHDs activate HIF sig- destruction. EPO induces RBC production, leading to the mobilization of iron stores from naling under normoxic conditions and the bone marrow. Hepcidin, which is produced by the liver and often stimulated by in- may represent effective treatments of flammation, leads to decreased iron uptake from the gut and decreased mobilization of anemia in CKD. These concepts are iron stores. Fe-Tf, iron-bound transferrin. summarized in Figure 3. JASN 31: 456–468, 2020 IDA in CKD 457 REVIEW www.jasn.org DIAGNOSIS Biomarkers traditionally used in the diagnosis of IDA include Hgb and he- matocrit, reticulocyte count, mean corpuscular Hgb, and mean corpuscular volume, most of which are decreased in IDA.23 In the setting of absolute iron deficiency, iron studies typically show a decreased iron level, decreased ferritin, elevated transferrin and total iron binding capacity (calculated as transferrin 31.389), and decreased transferrin saturation (TSAT; calculated as serum iron/total iron binding capacity3100). However, there is evidence to indicate that the tra- # Figure 3. Hypoxia signaling controls erythropoiesis by coordinating EPO synthesis with ditional cutoffs of TSAT at 20% and # the expression of genes involved in iron metabolism. Under well oxygenated conditions, serum ferritin at 100 ng/ml are not sen- the three oxygen-labile HIF-a subunits (HIF-1a, HIF-2a, and HIF-3a) are hydroxylated at sitive to detect iron deficiency. In a study specific proline (Pro) residues by PHD enzymes. Prolyl hydroxylation targets HIF-a proteins of 100 patients with CKD (stages 3–5), for ubiquitination by the von Hippel-Lindau (pVHL)-E3-ubiquitin ligase complex with these indices identified only 17% of pa- subsequent proteasomal degradation. Under conditions of reduced PHD activity (for ex- tients with CKD as iron deficient whereas ample hypoxia or pharmacologic inhibition), HIF-a escapes hydroxylation and translocates approximately 50% were iron deficient b to the nucleus, where it forms a heterodimer with the constitutively expressed HIF- based on the gold standard of bone mar- a b subunit. The effective HIF- /HIF- complex activates the transcription genes whose pro- row iron staining.24 Consistent with moters contain hypoxia response elements. The HIF-mediated activation of transcription these findings, patients with iron studies requires the recruitment of coactivators such as p300/CREB-binding protein. An additional fi that are within what is considered the layer of regulation is due to factor-inhibiting HIF (FIH), which hydroxylates a speci cas- “ ” paragine (Asn) residue abrogating transcriptional cofactor recruitment. HIF-a stabilization normal range or at goal, may still results in the activation of genes in diverse biologic processes.

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