Managing Iron Deficiency Anemia of CKD With IV Iron

Abstract and Introduction

Abstract

A prevalent complication of chronic kidney disease (CKD), especially in dialysis patients, iron deficiency anemia (IDA) continues to be underdiagnosed and undertreated. The main causes of IDA in this population are reduced intake and impaired intestinal absorption of dietary iron, blood losses, chronic inflammation, and increased iron requirements during therapy with erythropoiesis-stimulating agents (ESAs). The addition of IV iron can relieve iron-restricted erythropoiesis and improve ESA response, as well as balance the risks of ESA therapy. Clinical guidelines for anemia of CKD include recommendations for the use of IV iron. There are a number of factors to consider when managing anemia of CKD, and the various forms of iron are not identical.

Introduction

A prevalent complication of chronic kidney disease (CKD), particularly in dialysis patients, iron deficiency anemia (IDA) remains underdiagnosed and undertreated. This article presents an update on the diagnosis of IDA and the management of IDA with various forms of IV iron.

The World Health Organization defines anemia as a hemoglobin (Hgb) level of <13 g/dL in men and <12 g/dL in women.^[1] In the United States, iron deficiency is the most common cause of anemia. A deficiency of iron in RBCs reduces tissue oxygen delivery, increases cardiac output, and may result in ventricular dilation and hypertrophy, if left untreated.^[2] The main causes of iron deficiency are increased demand for iron, iron loss, and—frequently the case in CKD—decreased iron stores, reduced iron absorption, or inflammatory iron block.

Anemia of CKD may be due to insufficient production of erythropoietin by diseased kidneys, diminished RBC survival, iron or vitamin deficiencies, bleeding diathesis, hyperparathyroidism, chronic inflammation, or comorbidities.^[2,3] Iron deficiency also can develop in hemodialysis (HD) patients receiving erythropoiesis-stimulating agents (ESAs), which cause an increased demand for iron; blood loss from dialysis is another cause of iron deficiency.^[4] Diabetic patients are at increased risk for anemia, and anemia itself is an independent risk factor for CKD.^[5,6]

Symptoms of iron deficiency include fatigue, weakness, anorexia, insomnia, angina, tachycardia, dyspnea, decreased mental and physical performance, and possibly heart failure. Although anemia correction in CKD has been shown to slow the progression of renal disease and improve overall quality of life, IDA remains underdiagnosed and undertreated.^[2,7,8]

Because both early-stage CKD and anemia are usually asymptomatic, renal and hematologic laboratory values should be monitored annually in patients at risk.^[2,3,8] As glomerular filtration rate (GFR) decreases with progressive CKD, the risk of anemia increases from approximately 27% in stage 1 CKD to 76% in stage 5 (GFR <15 mL/min).^[5,9]

Table 1. Laboratory Tests for IDA
Test	Significance	Target Range
Hgb	Oxygen-carrying component of blood	11.0–12.0 g/dL (max 13.0 g/dL)
Fe	Amount available for Hgb synthesis	>30 mcg/dL
TIBC	Amount of Fe to which transferrin is capable of binding	<400 mcg/dL
TSAT^a	Amount immediately available for Hgb synthesis	≥20%
Ferritin	Encapsulated protein core containing Fe; indirect measure of total body Fe stores	200–799 ng/mL (HDD); 100–799 ng/mL (NDD)
CHr	Content of Hgb in reticulocytes; adequacy of Fe for erythropoiesis	>29 pg/cell
Hepcidin	Master regulator of Fe metabolism; decreased in Fe deficiency; increased in state of inflammation; blocks Fe absorption in the gut and macrophage release of Fe	Not defined to date

^aTSAT = Fe/TIBC×100%.
CHr: complete hematologic response; Fe: iron; HDD: hemodialysis-dependent; Hgb: hemoglobin; IDA: iron deficiency anemia; max: maximum; NDD: non–dialysis-dependent; TIBC: total iron-binding capacity; TSAT: transferrin saturation.
Source: References 5, 11.

Table 2. IV Iron Products: A Comparisona
Drug Name/Manufacturer/Approval Year	Concentration	Indication	Test Dose Needed	Dosage/Rate	TDI	Pediatric Patients^b	Postdose Observation Needed	Notes
HMW-ID (DexFerrum), American Regent, 1954	50 mg/mL	General IDA	Yes	Undiluted: 100 mg/day over 2 min until TD reached. Infusion: off-label	Yes (off-label), 4–6 h	Wt 5–15 kg	Yes (60 min after test dose, 30 min after actual dose)	Anaphylactic-type reactions and fatalities reported; resuscitation equipment and trained personnel necessary
LMW-ID (InFed), Watson, 1992	50 mg/mL	General IDA	Yes	Undiluted: 100 mg/day over 2 min until TD reached. Infusion: off-label	Yes (off-label), 4–6 h	Wt 5–15 kg	Yes (60 min after test dose, 30 min after actual dose)	Anaphylactic-type reactions and fatalities reported; resuscitation equipment and trained personnel necessary
Ferric gluconate (Ferrlecit, Nulecit), Sanofi-Aventis (Ferrlecit), Watson (Nulecit), 1999	12.5 mg/mL	HDD	No	Undiluted: 125 mg over 10 min × 8 HD sessions. Infusion: 125 mg/100 mL NS over 1 h	No	>6 y (HDD receiving ESA)	Yes (30 min)	Reactions to benzyl alcohol ingredient
Iron sucrose (Venofer), American Regent, 2000	20 mg/mL	NDD, HDD, PDD	No	Undiluted: HDD—100 mg 2–5 min × 10 HD sessions; NDD—200 mg 2–5 min × 5 over 14 days. Infusion: HD—100 mg/100 mL NS over 15 min; NDD: 200 mg/100 mL NS over 15 min OR limited experience 500 mg/250 mL NS over 3.5–4 h. PDD—days 1, 14: 300 mg/250 mL NS (1.5 h); day 28: 400 mg/250 mL NS (2.5 h)	No	>2 y (NDD, PDD, HDD)	Yes (30 min)	7-day stability; anaphylactoid reactions
Ferumoxytol (Feraheme), AMAG, 2009	30 mg/mL	NDD, HDD	No	Undiluted: 510 mg over 17 sec, repeated in 3–8 days. Infusion: Infusion: off-label	No	Not recommended	Yes (30 min)	MRI interaction for up to 3 mo; resuscitation equipment and trained personnel necessary. Anaphylactic-type reactions presenting with cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, and unresponsiveness reported postmarketing

^aUp to 1,000 mg recommended for initial repletion; treatment may be repeated. Hypersensitivity and life-threatening reactions reported with all formulations. See PIs for more detail. Injectafer, newly FDA approved, not included in this comparison. ^bSee PIs for pediatric dosing. ESA: erythropoiesisstimulating agent; HD: hemodialysis; HDD: hemodialysis-dependent; HMW-ID: high-molecular-weight iron dextran; IDA: iron deficiency anemia; LMW-ID: low-molecular-weight iron dextran; min: minute; NDD: non–dialysis-dependent; NS: normal saline (0.9% sodium chloride); PDD: peritoneal dialysis–dependent; PI: package insert; TD: total dose; TDI: total dose infusion; wt: weight. Source: References 21, 23, 24, 28, 29, 33.