Recent and Emerging Therapies for Iron Deficiency in Anemia of CKD: A Review
2021; Elsevier BV; Volume: 79; Issue: 6 Linguagem: Inglês
10.1053/j.ajkd.2021.09.017
ISSN1523-6838
AutoresJonathan W. Bazeley, Jay B. Wish,
Tópico(s)Hemoglobinopathies and Related Disorders
ResumoIron 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. 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. 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.1Beaumont C. Delaby C. Recycling iron in normal and pathological states.Semin Hematol. 2009; 46: 328-338https://doi.org/10.1053/j.seminhematol.2009.06.004Crossref PubMed Scopus (59) Google Scholar 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. 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.2Thomas D.W. Hinchliffe R.F. Briggs C. et al.Guideline for the laboratory diagnosis of functional iron deficiency.Br J Haematol. 2013; 161: 639-648https://doi.org/10.1111/bjh.12311Crossref PubMed Scopus (242) Google Scholar 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.3Sun H. Weaver C.M. Decreased iron intake parallels rising iron deficiency anemia and related mortality rates in the US population.J Nutr. 2021; 151: 1947-1955https://doi.org/10.1093/jn/nxab064Crossref PubMed Scopus (26) Google Scholar 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.4Muckenthaler M.U. Rivella S. Hentze M.W. Galy B. A red carpet for iron metabolism.Cell. 2017; 168: 344-361https://doi.org/10.1016/j.cell.2016.12.034Abstract Full Text Full Text PDF PubMed Scopus (617) Google Scholar, 5Moreb 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.Nephron. 1983; 35: 196-200https://doi.org/10.1159/000183074Crossref PubMed Scopus (52) Google Scholar, 6Phiri K.S. Calis J.C. Kachala D. et al.Improved method for assessing iron stores in the bone marrow.J Clin Pathol. 2009; 62: 685-689https://doi.org/10.1136/jcp.2009.064451Crossref PubMed Scopus (45) Google Scholar 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).7Batchelor 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.J Am Soc Nephrol. 2020; 31: 456-468https://doi.org/10.1681/asn.2019020213Crossref PubMed Google ScholarBox 1Iron 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 •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 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 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.8Babitt 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.Kidney Int. 2021; 99: 1280-1295https://doi.org/10.1016/j.kint.2021.03.020Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar 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.9Wish J.B. Assessing iron status: beyond serum ferritin and transferrin saturation.Clin J Am Soc Nephrol. 2006; 1: S4-S8https://doi.org/10.2215/CJN.01490506Crossref PubMed Scopus (419) Google Scholar 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.10Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work GroupKDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Chapter 2: use of iron to treat anemia in CKD.Kidney Int Suppl. 2012; 2: 292-298https://doi.org/10.1038/kisup.2012.34Abstract Full Text Full Text PDF Scopus (23) Google Scholar 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 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 3-5.12Shepshelovich 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.Am J Kidney Dis. 2016; 68: 677-690https://doi.org/10.1053/j.ajkd.2016.04.018Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar 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.”10Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work GroupKDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Chapter 2: use of iron to treat anemia in CKD.Kidney Int Suppl. 2012; 2: 292-298https://doi.org/10.1038/kisup.2012.34Abstract Full Text Full Text PDF Scopus (23) Google Scholar 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.13Agarwal R. Iron deficiency anemia in chronic kidney disease: uncertainties and cautions.Hemodial Int. 2017; 21: S78-S82https://doi.org/10.1111/hdi.12561Crossref PubMed Scopus (15) Google Scholar Although oral iron has been available for many years, its use has been limited in part by gastrointestinal side effects, including dyspepsia and constipation.8Babitt 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.Kidney Int. 2021; 99: 1280-1295https://doi.org/10.1016/j.kint.2021.03.020Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar 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 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.14Fishbane S. Block G.A. Loram L. et al.Effects of ferric citrate in patients with nondialysis-dependent CKD and iron deficiency anemia.J Am Soc Nephrol. 2017; 28: 1851-1858https://doi.org/10.1681/asn.2016101053Crossref PubMed Scopus (0) Google Scholar 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.15Chertow 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.PLoS One. 2017; 12e0188712https://doi.org/10.1371/journal.pone.0188712Crossref Scopus (19) Google Scholar A reanalysis of the phase 3 trial showed that patients with more severe iron deficiency experienced a greater increase in Hb level.16Pergola 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.Am J Hematol. 2018; 93: E154-E156https://doi.org/10.1002/ajh.25088Crossref PubMed Scopus (6) Google Scholar 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.17Santiago P. Ferrous versus ferric oral iron formulations for the treatment of iron deficiency: a clinical overview.ScientificWorldJournal. 2012; 2012: 846824https://doi.org/10.1100/2012/846824Crossref PubMed Scopus (118) Google Scholar,18Nagpal J. Choudhury P. Iron formulations in pediatric practice.Indian Pediatr. 2004; 41: 807-815PubMed Google Scholar 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.19Womack 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.Clin J Am Soc Nephrol. 2020; 15: 1251-1258https://doi.org/10.2215/cjn.15291219Crossref PubMed Google Scholar 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.20Lewis J.B. Sika M. Koury M.J. et al.Ferric citrate controls phosphorus and delivers iron in patients on dialysis.J Am Soc Nephrol. 2015; 26: 493-503https://doi.org/10.1681/asn.2014020212Crossref PubMed Scopus (0) Google Scholar 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.21Rodby R. Umanath K. Niecestro R. et al.Phosphorus binding with ferric citrate is associated with fewer hospitalizations and reduced hospitalization costs.Expert Rev Pharmacoecon Outcomes Res. 2015; 15: 545-550https://doi.org/10.1586/14737167.2015.995169Crossref PubMed Scopus (18) Google Scholar,22Rodby 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.Drugs R D. 2015; 15: 271-279https://doi.org/10.1007/s40268-015-0103-yCrossref PubMed Scopus (10) Google Scholar 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.23Block 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.Nephrol Dial Transplant. 2019; 34: 1115-1124https://doi.org/10.1093/ndt/gfy318Crossref PubMed Scopus (30) Google Scholar 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.24Choi 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.Br J Clin Pharmacol. 2021; 87: 414-426https://doi.org/10.1111/bcp.14396Crossref PubMed Scopus (7) Google Scholar 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.25Pergola P.E. Fishbane S. Ganz T. Novel oral iron therapies for iron deficiency anemia in chronic kidney disease.Adv Chronic Kidney Dis. 2019; 26: 272-291https://doi.org/10.1053/j.ackd.2019.05.002Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar 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).26Pergola 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.2021.03.020Google Scholar 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 2019.27Shield Therapeutics. Accrufer [prescribing information].https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212320Orig1s000lbl.pdfDate: 2019Date accessed: August 29, 2021Google Scholar 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.28Gómez-Ramírez S. Brilli E. Tarantino G. Muñoz M. Sucrosomial(®) iron: a new generation iron for improving oral supplementation.Pharmaceuticals (Basel). 2018; 11: 97https://doi.org/10.3390/ph11040097Crossref Scopus (53) Google Scholar 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.25Pergola P.E. Fishbane S. Ganz T. Novel oral iron therapies for iron deficiency anemia in chronic kidney disease.Adv Chronic Kidney Dis. 2019; 26: 272-291https://doi.org/10.1053/j.ackd.2019.05.002Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar 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).25Pergola P.E. Fishbane S. Ganz T. Novel oral iron therapies for iron deficiency anemia in chronic kidney disease.Adv Chronic Kidney Dis. 2019; 26: 272-291https://doi.org/10.1053/j.ackd.2019.05.002Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar,29Pisani 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.Nephrol Dial Transplant. 2015; 30: 645-652https://doi.org/10.1093/ndt/gfu357Crossref PubMed Scopus (90) Google Scholar Sucrosomial iron (as SiderAL) is available over the counter in the United States through its manufacturer’s website and other online vendors. 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 CKDCharacteristicFerrous SulfateFerrous FumarateFerrous GluconateFerric CitrateFerric MaltolSucrosomial IronSide effect Dyspepsia+++++++++ Constipation++++++Available over the counterYesYesYesNoNoYesPhosphate binderNoNoNoYesNoNoApproximate minimum annual cost, USD$10.80aBased on daily iron repletion dose.$237.60aBased on daily iron repletion dose.$37.60aBased on daily iron repletion dose.$8,294.40bBased on recommended dose.$7,200.00bBased on recommended dose.$720.00bBased on recommended dose.Based on information from Lexicomp.63Lexicomp Inc.http://online.lexi.comDate accessed: August 3, 2021Google Scholar Abbreviation: CKD, chronic kidney disease.a Based on daily iron repletion dose.b Based on recommended dose. Open table in a new tab Based on information from Lexicomp.63Lexicomp Inc.http://online.lexi.comDate accessed: August 3, 2021Google Scholar Abbreviation: CKD, chronic kidney disease. 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,30Auerbach M. Coyne D. Ballard H. Intravenous iron: from anathema to standard of care.Am J Hematol. 2008; 83: 580-588https://doi.org/10.1002/ajh.21154Crossref PubMed Scopus (90) Google Scholar,31Goetsch A.T. Moore C.V. Minnich V. 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Haase V.H. et al.Controversies in optimal anemia management: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Conference.Kidney Int. 2021; 99: 1280-1295https://doi.org/10.1016/j.kint.2021.03.020Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar,30Auerbach M. Coyne D. Ballard H. Intravenous iron: from anathema to standard of care.Am J Hematol. 2008; 83: 580-588https://doi.org/10.1002/ajh.21154Crossref PubMed Scopus (90) Google Scholar,36Blumenstein 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.Expert Opin Drug Saf. 2021; 20: 757-769https://doi.org/10.1080/14740338.2021.1912010Crossref PubMed Scopus (17) Google Scholar 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).36Blumenstein 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.Expert Opin Drug Saf. 2021; 20: 757-769https://doi.org/10.1080/14740338.2021.1912010Crossref PubMed Scopus (17) Google Scholar,37Kalra P.A. Bhandari S. 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