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American Journal of Kidney Diseases

Recent and Emerging Therapies for Iron Deficiency in Anemia of CKD: A Review

Published:November 07, 2021DOI:https://doi.org/10.1053/j.ajkd.2021.09.017
      Iron deficiency commonly contributes to the anemia affecting individuals with chronic kidney disease. This review describes diagnostic criteria for iron deficiency in chronic kidney disease, as well as mechanisms of functional and absolute iron deficiency and general treatment principles as delineated in the KDIGO (Kidney Disease: Improving Global Outcomes) guideline. Repletion of absolute iron deficits has progressed over time with the addition of better tolerated, more effective oral agents, including ferric citrate, ferric maltol, and sucrosomial iron. This article examines the structural characteristics and trial data enabling regulatory approval of these novel oral agents. Newer intravenous iron therapies, including ferric carboxymaltose and ferric derisomaltose, allow for fewer infusions and decreased risk of serious hypersensitivity reactions. Concerns about adverse effects such as cardiovascular events and infections are discussed. The potential risk of 6H syndrome (high FGF-23, hypophosphatemia, hyperphosphaturia, hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism) due to these intravenous agents is emphasized. The proposed pathophysiology of 6H syndrome and hypophosphatemia is described. Ferric pyrophosphate citrate enables administration of iron for repletion through dialysate. Relative merits, costs, and risks of various iron agents such as hypersensitivity and 6H syndrome/hypophosphatemia are summarized.

      Index Words

      Pathophysiology of Iron Deficiency Anemia

      Normal iron homeostasis depends on adequate absorption of iron from the diet. Absorbed iron replaces losses due to menstruation and sloughing of epithelial cells from the skin and intestines.
      • Beaumont C.
      • Delaby C.
      Recycling iron in normal and pathological states.
      Iron in the body is tightly regulated because there are no natural mechanisms for its excretion. The mechanisms of iron absorption and internal distribution are summarized in Fig 1.
      Figure thumbnail gr1
      Figure 1Direct and indirect regulation of systemic iron homeostasis. Iron (Fe) is provided mainly by reticuloendothelial macrophages that recycle iron from senescent red blood cells (RBCs), with a lesser contribution from dietary absorption and other body stores. Iron circulates in the plasma, predominantly bound to transferrin (TF), and is stored in cells in the form of ferritin. The liver hormone hepcidin controls systemic iron homeostasis by inducing degradation of the iron exporter ferroportin (FPN) to reduce iron entry into plasma from dietary sources and body stores. Iron deficiency and erythropoietic drive suppress hepcidin production to provide adequate iron for erythropoiesis and other essential functions. Iron and inflammation induce hepcidin to prevent iron overload and limit iron availability to pathogens. Iron induces hepcidin transcription by stimulating liver endothelial cells to produce bone morphogenetic proteins (BMPs) BMP2 and BMP6, which bind to the hepatocyte BMP receptor complex and coreceptor hemojuvelin (HJV) to activate SMAD transcription factors. Iron also induces hepcidin via the hepatocyte iron-sensing apparatus involving transferrin receptor 2 (TFR2), transferrin receptor 1 (TFR1), and homeostatic iron regulator protein (HFE). These pathways are all inhibited by iron deficiency, which also increases the activity of transmembrane serine protease 6 (TMPRSS6) to cleave HJV and further suppress hepcidin. Under conditions of accelerated erythropoietic activity, erythropoietin (EPO) induces erythroid progenitor cells to produce erythroferrone (ERFE), which suppresses hepcidin by functioning as a ligand trap to block the BMP signaling pathway. During inflammation, interleukin 6 (IL-6) and other inflammatory cytokines induce hepcidin transcription directly via a signal transducer and activator of transcription 3 (STAT3)–binding element in the hepcidin promoter. Hypoxia-inducible factors (HIFs), which are stabilized by low-oxygen (O2) and low-iron conditions, contribute to iron homeostasis and erythropoiesis by regulating the production of EPO in the kidney, ferrireductase duodenal cytochrome B (DCYTB) and iron transporters FPN and divalent metal transporter 1 (DMT1) in the intestine, and the plasma iron carrier TF. Abbreviations: HEPH, hephaestin; HO, heme oxygenase; HRG, heme transporter HRG1. Image ©2021 Elsevier, Inc; reproduced from Babitt et al
      • Babitt J.L.
      • Eisenga M.F.
      • Haase V.H.
      • et al.
      Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference.
      with permission of the copyright holder.

      Functional Versus Absolute Iron Deficiency

      In patients with chronic kidney disease (CKD), the unavailability of iron for hematopoiesis can be absolute or functional. Absolute iron deficiency occurs when the amount of storage iron in the liver, spleen, and marrow is minimal. This may stem from blood losses related to the dialysis procedure, gastrointestinal bleeding, or poor oral iron intake.
      • Thomas D.W.
      • Hinchliffe R.F.
      • Briggs C.
      • et al.
      Guideline for the laboratory diagnosis of functional iron deficiency.
      The prevalence of iron-deficiency anemia in the United States increased between 1999 and 2018, with the increase estimated to range between 10.5% and 106%, depending on age and sex. This has been attributed to a cultural dietary shift from beef to poultry-based food products over that time period.
      • Sun H.
      • Weaver C.M.
      Decreased iron intake parallels rising iron deficiency anemia and related mortality rates in the US population.
      Functional iron deficiency is characterized by adequate iron stores, the gold standard for which is presence of stainable iron in bone marrow, but usually diagnosed in the clinical setting by blood tests as noted below.
      • Muckenthaler M.U.
      • Rivella S.
      • Hentze M.W.
      • Galy B.
      A red carpet for iron metabolism.
      • Moreb J.
      • Popovtzer M.M.
      • Friedlaender M.M.
      • Konijn A.M.
      • Hershko C.
      Evaluation of iron status in patients on chronic hemodialysis: relative usefulness of bone marrow hemosiderin, serum ferritin, transferrin saturation, mean corpuscular volume and red cell protoporphyrin.
      • Phiri K.S.
      • Calis J.C.
      • Kachala D.
      • et al.
      Improved method for assessing iron stores in the bone marrow.
      Functional iron deficiency represents a supply/demand mismatch for iron to support erythropoiesis. On the supply side, inflammation leads to decreased iron availability primarily due to increased hepcidin concentration in plasma. On the demand side, erythropoiesis-stimulating agents (ESAs) used in patients with CKD accelerate red blood cell production and exceed the ability to sufficiently mobilize iron from stores. Functional iron deficiency due to ESA therapy can often be overcome with therapeutic iron supplementation, whereas anemia of inflammation may be more resistant to this intervention (Box 1).
      • Batchelor E.K.
      • Kapitsinou P.
      • Pergola P.E.
      • Kovesdy C.P.
      • Jalal D.I.
      Iron deficiency in chronic kidney disease: updates on pathophysiology, diagnosis, and treatment.
      Iron Deficiency in Anemia of CKD: Summary
      • Iron deficiency commonly contributes to anemia of chronic kidney disease and is amenable to treatment with newer oral and intravenous therapies
      • Intravenous iron can lead to a number of rare but serious adverse effects, and hypophosphatemia is increasingly recognized as prevalent and potentially serious
      • The choice of iron supplementation should be individualized to the patient and based on convenience, tolerance, cost, and the severity of iron deficiency

      Diagnosis of Iron-Deficiency Anemia

      Absolute iron deficiency in patients with CKD is defined by transferrin saturation (TSAT) <20% and ferritin level <100 ng/mL. Functional iron deficiency is defined by TSAT <20% and ferritin level >100 ng/mL in CKD without kidney replacement therapy (KRT) and >200 ng/mL in patients with CKD treated by dialysis. However, these parameters have been questioned and are an area of active review.
      • Babitt J.L.
      • Eisenga M.F.
      • Haase V.H.
      • et al.
      Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference.
      Because inflammation, which is highly prevalent in CKD, can increase ferritin and decrease transferrin concentrations in plasma, this compromises the applicability of these standard diagnostic tests. Alternative measures such as reticulocyte hemoglobin (Hb) content and percentage of hypochromic red blood cells have been proposed. However, limited availability of these assays has restricted their use in clinical practice, particularly in the United States.
      • Wish J.B.
      Assessing iron status: beyond serum ferritin and transferrin saturation.

      Principles of Management

      The 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline on anemia management in CKD suggests the treatment of anemia with iron supplementation in adults with CKD stage 3-5 when TSAT is <30% and ferritin level is <500 ng/mL.
      Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group
      KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Chapter 2: use of iron to treat anemia in CKD.
      The goal is to balance transfusion avoidance with the risks and side effects of iron therapy. The evidence base for these recommendations in adults is not robust. In pediatric patients with anemia who are not already receiving therapy, treating TSAT <20% and ferritin level <100 ng/mL with iron is recommended in all patients with CKD stage 3-5. The evidence base for this recommendation is stronger than that in adults, but, noting that estimates of response are less likely to be accurate, KDIGO presents as an opinion that intravenous (IV) iron be avoided during active infection.
      Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group
      KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Chapter 2: use of iron to treat anemia in CKD.
      A Cochrane Review of 28 studies with 2,098 participants in which oral and IV iron therapy were compared for patients with CKD
      • Albaramki J.
      • Hodson E.M.
      • Craig J.C.
      • Webster A.C.
      Parenteral versus oral iron therapy for adults and children with chronic kidney disease.
      provided strong evidence that those receiving IV iron have increased ferritin (mean difference, 243.25 [95% CI, 188.74-297.5] ng/mL) and TSAT (mean difference, 10.20% [95% CI, 5.56%-14.83%]). The difference in Hb increase among patients treated with IV iron was also significant (mean difference, 0.90 [95% CI, 0.44-1.37] g/dL). Morbidity and cardiovascular mortality did not differ significantly between the 2 groups, but were reported in few studies. An updated meta-analysis
      • Shepshelovich D.
      • Rozen-Zvi B.
      • Avni T.
      • Gafter U.
      • Gafter-Gvili A.
      Intravenous versus oral iron supplementation for the treatment of anemia in CKD: an updated systematic review and meta-analysis.
      in 2016 showed that patients with stages 3-5 CKD (including those receiving dialysis [stage 5D]) treated with IV iron were more likely to exhibit an Hb increase >1 g/dL (risk ratio, 1.61 [95% CI, 1.39-1.87]) than those treated with oral iron. Safety analysis showed similar rates of mortality and adverse events, although IV iron was associated with a higher risk of hypotension (risk ratio, 3.71 [95% CI, 1.74-7.94]) and lower risk of gastrointestinal adverse events (risk ratio, 0.43 [95% CI, 0.28-0.67]). The meta-analysis authors thus recommended increased use of IV iron for patients with CKD stages 3-5.
      • Shepshelovich D.
      • Rozen-Zvi B.
      • Avni T.
      • Gafter U.
      • Gafter-Gvili A.
      Intravenous versus oral iron supplementation for the treatment of anemia in CKD: an updated systematic review and meta-analysis.
      The KDIGO guideline agrees that IV iron is generally more effective than oral iron for patient receiving hemodialysis (HD), but that oral iron is a reasonable alternative for patients with CKD who are not undergoing HD. For the latter group of patients, the choice between oral and IV iron is more nuanced. KDIGO advises clinicians to “select the route of iron administration based on the severity of iron deficiency, availability of venous access, response to prior oral iron therapy, side effects with prior oral or IV iron therapy, patient compliance, and cost.”
      Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group
      KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Chapter 2: use of iron to treat anemia in CKD.
      Although some studies have noted the potential for serious adverse effects to be greater with IV versus oral iron, considerations of adherence and effectiveness may encourage the use of IV formulations.
      • Agarwal R.
      Iron deficiency anemia in chronic kidney disease: uncertainties and cautions.

      Newer Oral Iron Agents

      Although oral iron has been available for many years, its use has been limited in part by gastrointestinal side effects, including dyspepsia and constipation.
      • Babitt J.L.
      • Eisenga M.F.
      • Haase V.H.
      • et al.
      Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference.
      Some of the dyspepsia is thought to arise from gastric acid interacting with the ferrous form (ie, Fe2+), which is more basic than ferric iron (Fe3+). Conversion of Fe2+ to Fe3+ by gastric acid facilitates its absorption even though the Fe3+ must be reduced back to Fe2+ by ferrireductase (duodenal cytochrome B [DCYTB]) before absorption by the divalent metal transporter 1 (DMT1) channel in the small bowel. That is the rationale for administering Fe2+ supplements on an empty stomach when gastric acid will not be buffered by food. Novel iron formulations use Fe3+, which does not require administration on an empty stomach and causes less dyspepsia, and the bioavailability of which is not decreased by agents that decrease stomach acidity such as H2 blockers and proton pump inhibitors.

      Ferric Citrate

      Ferric citrate is a novel oral iron preparation in which Fe3+ is complexed to a polymer of tricarboxylic acid (citrate) and water. Originally introduced as a phosphate binder, ferric citrate subsequently obtained US Food and Drug Administration (FDA) approval as a treatment for iron-deficiency anemia in patients with CKD without KRT. Ferric citrate was compared with placebo in 232 patients with CKD and iron-deficiency anemia who were not receiving KRT in whom therapy with iron salts such as ferrous sulfate had failed. A substantially higher percentage of those treated with ferric citrate (52.1%) versus placebo (19.1%; P < 0.001) exhibited the primary endpoint of a 1-g/dL increase in Hb level at any time during the 16-week randomization period. There was slightly more gastrointestinal toxicity, both diarrhea (24% vs 19%) and constipation (22% vs 15%), in ferric citrate versus placebo recipients, respectively.
      • Fishbane S.
      • Block G.A.
      • Loram L.
      • et al.
      Effects of ferric citrate in patients with nondialysis-dependent CKD and iron deficiency anemia.
      A pooled analysis of the 232-patient phase 3 trial with a 149-patient phase 2 trial demonstrated that more patients treated with ferric citrate exhibited an Hb level >10 g/dL (47.8% vs 18.6% with placebo). This analysis also identified a higher rate of gastrointestinal side effects in the ferric citrate arm.
      • Chertow G.M.
      • Block G.A.
      • Neylan J.F.
      • Pergola P.E.
      • Uhlig K.
      • Fishbane S.
      Safety and efficacy of ferric citrate in patients with nondialysis-dependent chronic kidney disease.
      A reanalysis of the phase 3 trial showed that patients with more severe iron deficiency experienced a greater increase in Hb level.
      • Pergola P.E.
      • Fishbane S.
      • LeWinter R.D.
      • et al.
      Hemoglobin response to ferric citrate in patients with nondialysis-dependent chronic kidney disease and iron deficiency anemia.
      A randomized trial of 60 patients with CKD who were not receiving KRT found ferric citrate to be more effective in increasing TSAT and ferritin level at 12 weeks. However, the ferric citrate group was prescribed 1,260 mg of elemental iron per day, compared with 195 mg/d in the ferrous sulfate group, so the differences may not be surprising even accounting for the 3- to 4-fold lower bioavailability of ferric iron.
      • Santiago P.
      Ferrous versus ferric oral iron formulations for the treatment of iron deficiency: a clinical overview.
      ,
      • Nagpal J.
      • Choudhury P.
      Iron formulations in pediatric practice.
      Hb levels, as well as a number of other parameters (fibroblast growth factor 23 [FGF-23], intact parathyroid hormone, and erythroferrone), were not significantly different between the 2 groups.
      • Womack R.
      • Berru F.
      • Panwar B.
      • Gutiérrez O.M.
      Effect of ferric citrate versus ferrous sulfate on iron and phosphate parameters in patients with iron deficiency and CKD: a randomized trial.
      In patients with CKD undergoing dialysis, ferric citrate is indicated for phosphate binding but is used on an off-label basis as an iron supplement. A phase 3 randomized controlled trial of ferric citrate versus sevelamer carbonate and/or calcium acetate in 441 prevalent HD recipients over 1 year demonstrated higher median ferritin levels in the ferric citrate arm, with an average mean difference of 282 ng/mL (P < 0.001). TSAT increased in the ferric citrate arm by 9.5% (P < 0.001). ESA dose, IV iron requirements, and Hb level were all favorably affected in the ferric citrate arm to a statistically significant degree, with no increase in adverse events.
      • Lewis J.B.
      • Sika M.
      • Koury M.J.
      • et al.
      Ferric citrate controls phosphorus and delivers iron in patients on dialysis.
      Although the price of ferric citrate is higher than those of other phosphate binders and oral iron therapies, economic analyses suggest that the reduction in ESA and IV iron requirements would result in a net savings by implementing these therapies.
      • Rodby R.
      • Umanath K.
      • Niecestro R.
      • et al.
      Phosphorus binding with ferric citrate is associated with fewer hospitalizations and reduced hospitalization costs.
      ,
      • Rodby R.A.
      • Umanath K.
      • Niecestro R.
      • et al.
      Ferric citrate, an iron-based phosphate binder, reduces health care costs in patients on dialysis based on randomized clinical trial data.
      Ferric citrate reduced serum phosphate levels among patients with CKD without KRT who had increased baseline serum phosphate concentrations (≥4.5 mg/dL) but did not reduce serum phosphate levels among patients with baseline serum phosphate concentrations within the population reference range. Ferric citrate reduced FGF-23 concentrations to a statistically significant degree (P < 0.001) versus placebo.
      • Block G.A.
      • Pergola P.E.
      • Fishbane S.
      • et al.
      Effect of ferric citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis-dependent chronic kidney disease: path analyses.
      A meta-analysis of 16 studies of ferric citrate use in patients with CKD demonstrated significant increases in Hb level, TSAT, and ferritin level versus the comparator.
      • Choi Y.J.
      • Noh Y.
      • Shin S.
      Ferric citrate in the management of hyperphosphataemia and iron deficiency anaemia: a meta-analysis in patients with chronic kidney disease.

      Ferric Maltol

      Ferric maltol consists of one Fe3+ ion complexed to 3 maltol moieties. This structure protects the Fe3+ ion while passing through the stomach and provides high bioavailability when the complex is dissociated at the enterocyte, where Fe3+ is reduced to Fe2+ and then absorbed via DMT1. As such, a lower dose of iron has been shown to be efficacious with this agent: 30 mg twice daily.
      • Pergola P.E.
      • Fishbane S.
      • Ganz T.
      Novel oral iron therapies for iron deficiency anemia in chronic kidney disease.
      In a placebo-controlled study of 168 patients with CKD without KRT studied for 16 weeks, ferric maltol increased Hb level by 0.5 ± 0.122 g/dL, compared with a change of −0.02 ± 0.165 g/dL in the placebo arm (P = 0.0149).

      Pergola PE, Kopyt NP. Oral ferric maltol for the treatment of iron-deficiency anemia in patients with CKD: a randomized trial and open-label extension. Am J Kidney Dis. Published online May 3, 2020. doi:10.1053/j.ajkd.2021.03.020

      In addition to data presented for use in patients with iron-deficiency anemia–secondary inflammatory bowel disease, these results led to US FDA approval in 2019.
      Shield Therapeutics. Accrufer [prescribing information].

      Sucrosomial Iron

      The sucrosome is a novel drug-delivery method that has been applied to oral iron repletion. Sucrose esterified with fatty acids and combined with lecithin forms a phospholipid bilayer encasing ferric pyrophosphate.
      • Gómez-Ramírez S.
      • Brilli E.
      • Tarantino G.
      • Muñoz M.
      Sucrosomial(®) iron: a new generation iron for improving oral supplementation.
      The bilayer is further coated with tricalcium phosphate and starch, permitting it to pass through the stomach acid. Downstream, it is endocytosed through Peyer’s patch microfold cells.
      • Pergola P.E.
      • Fishbane S.
      • Ganz T.
      Novel oral iron therapies for iron deficiency anemia in chronic kidney disease.
      The efficacy of sucrosomial iron 30 mg/d was evaluated in a 3-month open-label randomized controlled trial in 99 patients with CKD without KRT in comparison with IV sodium ferric gluconate 125 mg per week until a total dose of 1,000 mg was administered. At 3 months, the proportions of patients who exhibited increases in Hb level of 0.6 g/dL were 56.2% with sodium ferric gluconate and 43.5% with sucrosomial iron (P < 0.05). Fewer adverse events attributed to treatment were seen in the sucrosomial iron group (3.1% vs 34.5%; P < 0.001).
      • Pergola P.E.
      • Fishbane S.
      • Ganz T.
      Novel oral iron therapies for iron deficiency anemia in chronic kidney disease.
      ,
      • Pisani A.
      • Riccio E.
      • Sabbatini M.
      • Andreucci M.
      • Del Rio A.
      • Visciano B.
      Effect of oral liposomal iron versus intravenous iron for treatment of iron deficiency anaemia in CKD patients: a randomized trial.
      Sucrosomial iron (as SiderAL) is available over the counter in the United States through its manufacturer’s website and other online vendors.

      Summary of Novel Oral Irons

      Each of the novel oral iron agents has improved gastrointestinal tolerability relative to Fe2+ formulations. Sucrosomial iron is a reasonable first choice because of its lower overall cost and availability without a prescription. Ferric maltol is next in cost, and ferric citrate is the costliest but also offers phosphate binding capability (Table 1).
      Table 1Oral Therapies for Iron Repletion in CKD
      CharacteristicFerrous SulfateFerrous FumarateFerrous GluconateFerric CitrateFerric MaltolSucrosomial Iron
      Side effect
       Dyspepsia+++++++++
       Constipation++++++
      Available over the counterYesYesYesNoNoYes
      Phosphate binderNoNoNoYesNoNo
      Approximate minimum annual cost, USD$10.80
      Based on daily iron repletion dose.
      $237.60
      Based on daily iron repletion dose.
      $37.60
      Based on daily iron repletion dose.
      $8,294.40
      Based on recommended dose.
      $7,200.00
      Based on recommended dose.
      $720.00
      Based on recommended dose.
      Based on information from Lexicomp.
      Lexicomp Inc.
      Abbreviation: CKD, chronic kidney disease.
      a Based on daily iron repletion dose.
      b Based on recommended dose.

      Newer IV Iron Agents

      The number of IV iron agents has increased steadily in the past few years. Older agents such as iron dextran (1974), sodium ferric gluconate (1999), and iron sucrose (2000) have been joined by ferumoxytol in 2009 and, more recently, ferric carboxymaltose and ferric derisomaltose (also known as iron isomaltoside). Concerns about oxidative stress induced by rapid iron release,
      • Auerbach M.
      • Coyne D.
      • Ballard H.
      Intravenous iron: from anathema to standard of care.
      ,
      • Goetsch A.T.
      • Moore C.V.
      • Minnich V.
      Observations on the effect of massive doses of iron given intravenously to patients with hypochromic anemia.
      manifested by adverse reactions including cardiovascular events, motivated the development of newer compounds.
      • Rostoker G.
      When should iron supplementation in dialysis patients be avoided, minimized or withdrawn?.
      • Kuo K.L.
      • Hung S.C.
      • Lin Y.P.
      • et al.
      Intravenous ferric chloride hexahydrate supplementation induced endothelial dysfunction and increased cardiovascular risk among hemodialysis patients.
      • Kuragano T.
      • Matsumura O.
      • Matsuda A.
      • et al.
      Association between hemoglobin variability, serum ferritin levels, and adverse events/mortality in maintenance hemodialysis patients.
      • Bailie G.R.
      • Larkina M.
      • Goodkin D.A.
      • et al.
      Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality.
      Modern formulations contain iron enveloped by a carbohydrate moiety that minimizes iron release within the circulation.
      • Babitt J.L.
      • Eisenga M.F.
      • Haase V.H.
      • et al.
      Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference.
      ,
      • Auerbach M.
      • Coyne D.
      • Ballard H.
      Intravenous iron: from anathema to standard of care.
      ,
      • Blumenstein I.
      • Shanbhag S.
      • Langguth P.
      • Kalra P.A.
      • Zoller H.
      • Lim W.
      Newer formulations of intravenous iron: a review of their chemistry and key safety aspects - hypersensitivity, hypophosphatemia, and cardiovascular safety.
      The newer agents have reduced rates of anaphylaxis compared with iron dextran, but ongoing concerns remain surrounding hypersensitivity reactions, cardiovascular events, and hypophosphatemia (Table 2).
      • Blumenstein I.
      • Shanbhag S.
      • Langguth P.
      • Kalra P.A.
      • Zoller H.
      • Lim W.
      Newer formulations of intravenous iron: a review of their chemistry and key safety aspects - hypersensitivity, hypophosphatemia, and cardiovascular safety.
      ,
      • Kalra P.A.
      • Bhandari S.
      Safety of intravenous iron use in chronic kidney disease.
      Table 2Newer (Third-Generation) Intravenous Iron Formulations
      AgentMolecular Weight, DaMaximum Weekly DoseMinimum Infusion Time, min[Fe], mg/mLBlack Box WarningSevere

      Hypersensitivity
      Hypophosphatemia
      Ferumoxytol731,000510 mg1530Yes0.2%0.4%
      Ferric carboxymaltose150,000750 or 1,000 mg1550No1.6%∼40%
      Ferric derisomaltose150,0001,000 mg or 20 mg/kg if <50 kg15100No0.3%3.5%
      No test dose is required for any of the 3 agents. Table based on information from Glaspy et al,
      • Glaspy J.A.
      • Lim-Watson M.Z.
      • Libre M.A.
      • et al.
      Hypophosphatemia associated with intravenous iron therapies for iron deficiency anemia: a systematic literature review.
      Balakrishnan et al,
      • Balakrishnan V.S.
      • Rao M.
      • Kausz A.T.
      • et al.
      Physicochemical properties of ferumoxytol, a new intravenous iron preparation.
      and Lexicomp.
      Lexicomp Inc.

      Ferumoxytol

      Because it was approved more than a decade ago, ferumoxytol is not considered a newer IV iron agent and will not be discussed in detail in this review. However, it is important to point out that ferumoxytol was the first IV iron agent to decrease the incidence of anaphylaxis compared with iron dextran and to decrease the intravascular release of free iron compared with sodium ferric gluconate and iron sucrose. Because the adverse reactions to free iron in the circulation are dose-related, the maximum FDA-approved single dose of sodium ferric gluconate is 125 mg,
      Ferrlecit full prescribing information 2011.
      although it is commonly administered on an off-label basis in doses of 250 mg.
      • Reed B.N.
      • Blair E.A.
      • Thudium E.M.
      • et al.
      Effects of an accelerated intravenous iron regimen in hospitalized patients with advanced heart failure and iron deficiency.
      The maximum FDA-approved single doses of iron sucrose are 100 mg in patients undergoing maintenance dialysis, 200 mg in patients with CKD not treated with KRT, and 300-400 mg in peritoneal dialysis recipients.
      Luitpold Pharmaceuticals
      Venofer (iron sucrose) [prescribing information].
      For patients with CKD without KRT or undergoing home dialysis, such a limitation requires several visits to an infusion center to administer a 1,000-mg repletion dose of IV iron. This also means more venipunctures for those infusions, which puts future vascular access at risk. Ferumoxytol is approved for 510-mg administration by infusion or slow IV push over a period of 15 minutes. It has been reported that 1,020 mg ferumoxytol can be safely administered over a period of 15 minutes, allowing for iron repletion in a single visit.
      • Auerbach M.
      • Strauss W.
      • Auerbach S.
      • Rineer S.
      • Bahrain H.
      Safety and efficacy of total dose infusion of 1,020 mg of ferumoxytol administered over 15 min.
      ,
      • Khan H.
      • May P.
      • Kuo E.
      • et al.
      Safety and efficacy of a single total dose infusion (1020mg)of ferumoxytol.

      Ferric Carboxymaltose

      Initially approved by the FDA in 2013, ferric carboxymaltose is composed of ferric oxyhydroxide surrounded and tightly bound by carboxymaltose
      • Auerbach M.
      • Coyne D.
      • Ballard H.
      Intravenous iron: from anathema to standard of care.
      ,
      • Blumenstein I.
      • Shanbhag S.
      • Langguth P.
      • Kalra P.A.
      • Zoller H.
      • Lim W.
      Newer formulations of intravenous iron: a review of their chemistry and key safety aspects - hypersensitivity, hypophosphatemia, and cardiovascular safety.
      ,
      Injectafer (ferric carboxymaltose) [prescribing information].
      Ferric carboxymaltose is dosed at 15 mg/kg on day 0 and day 7 for individuals ≤50 kg in weight. The original FDA approval was 2 doses of 750 mg for individuals >50 kg in weight, but, in 2021, the FDA approved a single 1,000-mg dose in such individuals as an alternative.
      Injectafer (ferric carboxymaltose) [prescribing information].
      Ferric carboxymaltose was compared in 2 cohorts of patients with iron-deficiency anemia versus other standard iron therapies based on Hb level increase between day 0 and day 35.
      Injectafer (ferric carboxymaltose) [prescribing information].
      ,

      ClinicalTrials.gov. Efficacy and safety of intravenous ferric carboxymaltose (FCM) in patients with iron deficiency anemia (IDA). Updated February 20, 2018. Accessed May 16, 2021. https://clinicaltrials.gov/ct2/show/results/NCT00982007.

      In cohort 1, ferric carboxymaltose 1,500 mg increased Hb level by a mean of 1.57 g/dL, compared with 0.80 g/dL with oral ferrous sulfate (P < 0.001). In cohort 2, ferric carboxymaltose 1,500 mg increased Hb level by a mean of 2.90 g/dL, compared with 2.16 g/dL with IV iron sucrose 1,000 mg (P < 0.001). Serious adverse events were not significantly different with ferric carboxymaltose versus the comparators.
      In the REPAIR-IDA trial, among 2,584 patients with iron-deficiency anemia and CKD without KRT, mean Hb increases at 56 days were 1.13 g/dL in the ferric carboxymaltose (750 mg × 2 doses) group and 0.92 g/dL in the iron sucrose (200 mg × 5 doses) group, meeting criteria for noninferiority (95% CI, 0.13-0.28).
      • Onken J.E.
      • Bregman D.B.
      • Harrington R.A.
      • et al.
      Ferric carboxymaltose in patients with iron-deficiency anemia and impaired renal function: the REPAIR-IDA trial.
      Serious adverse events were similar between groups; ferric carboxymaltose recipients had more hypertensive episodes, whereas iron sucrose recipients had more hypotension. Hypophosphatemia was identified at greater frequency in the ferric carboxymaltose arm.
      • Onken J.E.
      • Bregman D.B.
      • Harrington R.A.
      • et al.
      Ferric carboxymaltose in patients with iron-deficiency anemia and impaired renal function: the REPAIR-IDA trial.
      The FIND-CKD trial studied ferric carboxymaltose for 56 weeks in patients with CKD without KRT, with a primary endpoint of initiation of other anemia intervention (ESA, other iron therapy, or transfusion) or 2 consecutive Hb measurements <10 g/dL.
      • Macdougall I.C.
      • Bock A.H.
      • Carrera F.
      • et al.
      FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia.
      Ferric carboxymaltose treatment was targeted to high ferritin (400-600 ng/mL) or low ferritin (100-200 ng/mL) compared with ferrous sulfate in a 1:1:2 ratio. The percentages of participants who reached the primary outcome were 23.5% in the ferric carboxymaltose high-ferritin arm, 32.2% in the ferric carboxymaltose low-ferritin arm, and 31.8% in the ferrous sulfate arm. The hazard ratio for the primary endpoint was 0.65 (95% CI, 0.44-0.95; P = 0.026) for high-ferritin ferric carboxymaltose versus oral iron. No difference in cardiovascular or infectious adverse events was noted.
      • Macdougall I.C.
      • Bock A.H.
      • Carrera F.
      • et al.
      FIND-CKD: a randomized trial of intravenous ferric carboxymaltose versus oral iron in patients with chronic kidney disease and iron deficiency anaemia.

      Ferric Derisomaltose

      Iron isomaltoside was initially approved in Australia in 2017 and later by the US FDA in 2020 after being renamed ferric derisomaltose. Compositionally, ferric derisomaltose is ferric oxyhydroxide encased in derisomaltose. The FERWON group studied ferric derisomaltose administered as a single 1,000-mg dose versus iron sucrose given in as many as 5 doses of 200 mg over a period of 2 weeks.
      • Auerbach M.
      • Henry D.
      • Derman R.J.
      • Achebe M.M.
      • Thomsen L.L.
      • Glaspy J.
      A prospective, multi-center, randomized comparison of iron isomaltoside 1000 versus iron sucrose in patients with iron deficiency anemia; the FERWON-IDA trial.
      ,
      • Bhandari S.
      • Kalra P.A.
      • Berkowitz M.
      • Belo D.
      • Thomsen L.L.
      • Wolf M.
      Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial.
      FERWON-IDA included 1,512 patients with diverse etiologies of iron-deficiency anemia, whereas FERWON-NEPHRO examined 1,538 patients with CKD without KRT. Both FERWON trials were randomized at a 2:1 ratio of ferric derisomaltose to iron sucrose, with coprimary endpoints of efficacy at increasing Hb level at 8 weeks and serious or severe hypersensitivity reactions. Efficacy was nearly identical between the 2 agents, increasing Hb level by 2.5 g/dL in both arms of FERWON-IDA and by 1.22 g/dL in both arms of FERWON-NEPHRO. Hypersensitivity events were also insignificantly different, with a pooled relative risk difference 0.1% higher with ferric derisomaltose versus iron sucrose. An analysis of 5 of these studies (N = 5,247) noted that the rate of moderate to severe hypersensitivity reactions was low across all current IV iron formulations excluding iron dextran, at 0.2%-1.7%. The differences between agents were small, and confidence intervals overlapped.
      • Achebe M.
      • DeLoughery T.G.
      Clinical data for intravenous iron - debunking the hype around hypersensitivity.
      • Wolf M.
      • Chertow G.M.
      • Macdougall I.C.
      • Kaper R.
      • Krop J.
      • Strauss W.
      Randomized trial of intravenous iron-induced hypophosphatemia.
      • Wolf M.
      • Rubin J.
      • Achebe M.
      • et al.
      Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron-deficiency anemia: two randomized clinical trials.
      Another meta-analysis (N = 8,599) examining the risk of serious hypersensitivity reactions among IV iron recipients showed a low rate overall, but lower rates with ferric derisomaltose than with ferric carboxymaltose or iron sucrose.
      • Pollock R.F.
      • Biggar P.
      Indirect methods of comparison of the safety of ferric derisomaltose, iron sucrose and ferric carboxymaltose in the treatment of iron deficiency anemia.
      The ferric derisomaltose arms in the combined FERWON studies had 63 events in 50 (2.5%) patients versus 48 events in 41 (4.1%) patients in the iron sucrose arms (P = 0.018). Driven by hypertension, congestive heart failure, and atrial fibrillation, the time to first adverse cardiovascular event was also longer with ferric derisomaltose versus iron sucrose (P = 0.014). Although unexpected given the short study duration (8 weeks), this differential could be due to slower mobilization of iron and consequent lesser oxidative stress in the ferric derisomaltose recipients.
      • Blumenstein I.
      • Shanbhag S.
      • Langguth P.
      • Kalra P.A.
      • Zoller H.
      • Lim W.
      Newer formulations of intravenous iron: a review of their chemistry and key safety aspects - hypersensitivity, hypophosphatemia, and cardiovascular safety.
      The PHOSPHARE-IDA paired randomized controlled trials studied ferric carboxymaltose and ferric derisomaltose with respect to hypophosphatemia occurring between baseline and day 35 in patients with iron-deficiency anemia and normal kidney function.
      • Wolf M.
      • Rubin J.
      • Achebe M.
      • et al.
      Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron-deficiency anemia: two randomized clinical trials.
      Serum phosphate level <2.0 mg/dL occurred with both agents, but significantly more often with ferric carboxymaltose than ferric derisomaltose (trial A, 75.0% vs 7.9% [P < 0.001]; trial B, 73.7% vs 8.1% [P < 0.001]). A separate systematic review and meta-analysis showed analogous results for hypophosphatemia (47% in ferric carboxymaltose vs 4% in ferric derisomaltose; P < 0.001). Normal kidney function, low baseline serum ferritin level, and low TSAT were identified as predictors for hypophosphatemia.
      • Schaefer B.
      • Meindl E.
      • Wagner S.
      • Tilg H.
      • Zoller H.
      Intravenous iron supplementation therapy.
      ,
      • Glaspy J.A.
      • Lim-Watson M.Z.
      • Libre M.A.
      • et al.
      Hypophosphatemia associated with intravenous iron therapies for iron deficiency anemia: a systematic literature review.

      6H Syndrome

      The 6H syndrome (high FGF-23, hypophosphatemia, hyperphosphaturia, hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism) seen with various IV iron formulations but most prominent with ferric carboxymaltose is thought to occur as a result of impaired cleavage (inactivation) of the phosphatonin FGF-23.
      • Kassianides X.
      • Bhandari S.
      Hypophosphataemia, fibroblast growth factor 23 and third-generation intravenous iron compounds: a narrative review.
      ,
      • Edmonston D.
      • Wolf M.
      FGF23 at the crossroads of phosphate, iron economy and erythropoiesis.
      Longer-term complications of hypophosphatemic osteomalacia and fractures have also been described (Fig 2).
      • Zoller H.
      • Schaefer B.
      • Glodny B.
      Iron-induced hypophosphatemia: an emerging complication.
      Clinicians will need to weigh the relative risks, costs, and availability of the various IV iron formulations when selecting therapy (Table 3).
      Figure thumbnail gr2
      Figure 26H syndrome (high fibroblast growth factor 23 [FGF-23], hypophosphatemia, hyperphosphaturia, hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism). In the setting of iron deficiency, FGF-23 transcription is increased. Normally, this has no substantial adverse consequences because FGF-23 is cleaved proportionally to synthesis to the inactive form. However, higher levels of intact FGF-23 develop in the presence of certain IV iron formulations. It is speculated that the carbohydrate moieties of the iron formulations inhibit the cleavage of FGF-23. The extent of this apparent inhibition, and consequent hypophosphatemia, appears to be greatest with ferric carboxymaltose (FCM), substantially less with ferric derisomaltose (FDI), lesser still with iron sucrose (IS), and extremely uncommon with ferumoxytol (FER) and iron dextran (ID). Estimates of relative incidence of hypophosphatemia are limited by lack of head-to-head comparisons across agents and heterogeneity among studies in thresholds of hypophosphatemia when reported. Increased FGF-23 leads to enhanced urinary phosphate wasting, lowering serum phosphorus and leading to weakness and fatigue. Increased FGF-23 also reduces 1,25-dihydroxyvitamin D levels, resulting in decreased serum calcium. Low calcium may contribute to weakness and fatigue and, more importantly, causes increased parathyroid hormone. Increased rates of osteomalacia and atypical fractures have been reported principally with ferric carboxymaltose to date. (Based on information from Kassianides et al,
      • Kassianides X.
      • Bhandari S.
      Hypophosphataemia, fibroblast growth factor 23 and third-generation intravenous iron compounds: a narrative review.
      Blumenstein et al,
      • Blumenstein I.
      • Shanbhag S.
      • Langguth P.
      • Kalra P.A.
      • Zoller H.
      • Lim W.
      Newer formulations of intravenous iron: a review of their chemistry and key safety aspects - hypersensitivity, hypophosphatemia, and cardiovascular safety.
      and Glaspy et al.
      • Glaspy J.A.
      • Lim-Watson M.Z.
      • Libre M.A.
      • et al.
      Hypophosphatemia associated with intravenous iron therapies for iron deficiency anemia: a systematic literature review.
      )
      Table 3Pros and Cons of Parenteral Iron Formulations
      AgentProsCons
      Iron dextranLowest cost, can give 1,000 mg in 1 dose (off label), low risk of 6H syndromeHigh rate of hypersensitivity, requires test dose, requires 1.5 h of infusion and observation
      Ferric gluconateLow risk of severe hypersensitivity, low cost, low risk of 6H syndromeTakes 4-8 doses to administer 1,000 mg, administered over 1 h, risk of hypotension
      Iron sucroseLow risk of severe hypersensitivity, low cost, low risk of 6H syndromeTakes 3-5 doses to administer 1,000 mg
      FerumoxytolLow incidence of 6H syndrome, takes 2 doses to administer 1,000 mgHas black box warning for hypersensitivity, higher cost
      Ferric carboxymaltoseHighest total US approved dose (1,500 mg in 2 doses), 1,000 mg in 1 dose also US approved, low risk of severe hypersensitivityHighest incidence of 6H syndrome/hypophosphatemia, higher cost
      Ferric derisomaltose 1,000 mg in 1 dose is US approved, low risk of severe hypersensitivity  Hypophosphatemia (4%), higher cost, limited availability (?)
      Ferric pyrophosphate citrateLow risk of severe hypersensitivity, given through dialysate, low risk of 6H syndromeIn-center hemodialysis patients only; for iron maintenance, not repletion; risk of hypotension
      Abbreviation: 6H syndrome, high fibroblast growth factor 23, hypophosphatemia, hyperphosphaturia, hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism.

      Ferric Pyrophosphate Citrate

      Ferric pyrophosphate citrate offers the option to administer iron directly via dialysate bicarbonate containers or a bicarbonate central delivery system and was FDA-approved for use in patients receiving HD in 2015.
      • Lee K.H.
      • Ho Y.
      • Tarng D.C.
      Iron therapy in chronic kidney disease: days of future past.
      The iron dose administered with each dialysis is 5-7 mg, which approximates the iron loss with each HD treatment. The CRUISE paired trials compared ferric pyrophosphate citrate versus placebo over 48 weeks and found that Hb levels were maintained with ferric pyrophosphate citrate, whereas they decreased by 0.4 g/dL with placebo (P < 0.001).
      • Fishbane S.N.
      • Singh A.K.
      • Cournoyer S.H.
      • et al.
      Ferric pyrophosphate citrate (Triferic™) administration via the dialysate maintains hemoglobin and iron balance in chronic hemodialysis patients.
      Ferritin and TSAT were more stable in the ferric pyrophosphate citrate arm, along with decreased ESA and IV iron requirements. Because some dialysis providers are concerned regarding the infection risk associated with iron in the bicarbonate central delivery system and because some dialysis machines use solid bicarbonate concentrate, an IV form of ferric pyrophosphate citrate was developed and approved by the FDA in 2020. The IV form is infused over the course of the HD treatment (pre- or postmembrane) and provides 6.75 mg iron in a prefilled syringe. Ferric pyrophosphate citrate can be infused using the machine’s heparin pump and, if the patient is receiving heparin, can be safely mixed with the heparin.

      Pratt RD. Ferric pyrophosphate citrate injection: no clinical drug interaction with unfractionated heparin in hemodialysis patients [abstract]. In: Kidney Week 2020 Reimagined Abstracts. American Society of Nephrology; 2020:B6-B7. Abstract PO2631.

      Conclusions

      Functional and absolute iron deficiency often contribute to anemia in patients with CKD, and iron repletion is required for effective Hb synthesis. Newer oral agents may provide increased iron bioavailability and fewer side effects than traditional iron salts, perhaps decreasing the need for IV iron therapy in some patients with CKD without KRT receiving home dialysis. For patients with milder degrees of iron deficiency (eg, TSAT >15% and ferritin >50 ng/mL), we propose starting with an inexpensive oral ferrous salt unless the patient reports previous intolerance to such agents. If the patient does not show a response in 2-3 months or is intolerant of Fe2+, it is reasonable to switch to a newer ferric oral iron supplement or IV iron preparation. If the patient has more severe iron deficiency (TSAT <15% or ferritin <50 ng/mL), we recommend proceeding directly to an IV iron agent. Newer IV iron formulations are associated with fewer anaphylactic reactions than iron dextran and decreased free iron that may contribute to acute reactions and long-term vascular injury. Because these IV iron preparations can be given in larger single doses than ferric gluconate or iron sucrose, they are better suited for patients with CKD without KRT and those receiving home dialysis to decrease visits to infusion centers and venipuncture. Nonetheless, caution with respect to nuanced risks of IV iron formulations remains prudent because of acute reactions and hypophosphatemia. Newer IV iron agents are expensive and may not be approved by some prescription drug plans. In such cases, we prefer to prescribe 1,000 mg of iron dextran in a single infusion than to subject the patient to multiple smaller infusions of sodium ferric gluconate or iron sucrose. It remains to be determined how a shift away from in-center HD for treatment of kidney failure, as well as more effective therapies to slow the rate of CKD progression, as proposed by the Advancing American Kidney Health Initiative, will accelerate the development and uptake of iron therapies designed to decrease patient travel to infusion centers while maintaining or improving tolerance and safety.

      Article Information

      Authors’ Full Names and Academic Degrees

      Jonathan W. Bazeley, MD, and Jay B. Wish, MD.

      Support

      None.

      Financial Disclosure

      Dr Wish has served on advisory boards for AstraZeneca, Akebia, Otsuka, Vifor, and Rockwell Medical and is on speaker’s bureaus for AstraZeneca and Akebia. Dr Bazeley declares that he has no relevant financial interests.

      Peer Review

      Received June 1, 2021, in response to an invitation from the journal. Evaluated by 2 external peer reviewers, with direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form September 3, 2021.

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