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• W2971344488 abstract "Patients with end-stage renal disease on dialysis commonly receive intravenous iron to treat anemia along with erythropoiesis-stimulating agents. While studies of intravenous iron have demonstrated efficacy in raising hemoglobin, the quantity of administered intravenous iron has raised concerns about iron overload leading to long-term toxicities. The goal of this review is to understand recent trends in intravenous iron use, potential mechanisms of iron toxicity, and to evaluate the available evidence in the literature for potential long-term cardiovascular and infectious complications. We include findings from the recently published landmark clinical trial of intravenous iron for patients receiving hemodialysis to contextualize treatment recommendations. Patients with end-stage renal disease on dialysis commonly receive intravenous iron to treat anemia along with erythropoiesis-stimulating agents. While studies of intravenous iron have demonstrated efficacy in raising hemoglobin, the quantity of administered intravenous iron has raised concerns about iron overload leading to long-term toxicities. The goal of this review is to understand recent trends in intravenous iron use, potential mechanisms of iron toxicity, and to evaluate the available evidence in the literature for potential long-term cardiovascular and infectious complications. We include findings from the recently published landmark clinical trial of intravenous iron for patients receiving hemodialysis to contextualize treatment recommendations. Clinical Summary•Intravenous iron is an essential part of anemia management for patients with chronic kidney diseases now and in the foreseeable future.•Because contemporary practice often utilize repeated doses of large quantities of intravenous iron with varied hold parameters, studies have raised concerns about the harmful, long-term effects of labile iron on cardiovascular and infectious disease.•The recently published randomized clinical trial, PIVOTAL, demonstrated that a proactive intravenous iron dosing regimen is both efficacious and safe compared to a reactive dosing regimen.•While PIVOTAL may herald a new, moderate approach anemia management with respect to intravenous iron, additional evidence is needed on the safety and efficacy of aggressive iron dosing approaches commonly used in the United States. •Intravenous iron is an essential part of anemia management for patients with chronic kidney diseases now and in the foreseeable future.•Because contemporary practice often utilize repeated doses of large quantities of intravenous iron with varied hold parameters, studies have raised concerns about the harmful, long-term effects of labile iron on cardiovascular and infectious disease.•The recently published randomized clinical trial, PIVOTAL, demonstrated that a proactive intravenous iron dosing regimen is both efficacious and safe compared to a reactive dosing regimen.•While PIVOTAL may herald a new, moderate approach anemia management with respect to intravenous iron, additional evidence is needed on the safety and efficacy of aggressive iron dosing approaches commonly used in the United States. Anemia is common in individuals with chronic kidney disease (CKD), especially those with end-stage renal disease requiring dialysis. Iron is often considered an adjuvant therapy to erythropoiesis-stimulating agents (ESAs) for anemia management. Yet, iron itself is a necessary component of hemoglobin synthesis, and its use in dialysis patients has grown across the United States over the last decade.1IV iron use. The DOPPS Practice Monitor.https://www.dopps.org/DPM/Date accessed: February 15, 2019Google Scholar Intravenous (IV) iron replacement, rather than oral iron supplementation, has become the standard of care for patients receiving dialysis for a variety of reasons. First, hemodialysis patients have a high intrinsic iron loss from the dialysis procedure,2Sargent J.A. Acchiardo S.R. Iron requirements in hemodialysis.Blood Purif. 2004; 22: 112-123Crossref PubMed Scopus (52) Google Scholar and both hemodialysis and peritoneal dialysis patients may lose additional iron from gastrointestinal bleeding.3Rosenblatt S.G. Drake S. Fadem S. Welch R. Lifschitz M.D. Gastrointestinal blood loss in patients with chronic renal failure.Am J Kidney Dis. 1982; 1: 232-236Abstract Full Text PDF PubMed Scopus (56) Google Scholar Second, iron homeostasis is altered by inflammation such that oral absorption is impaired in patients with late stages of CKD.4Ganz T. Hepcidin and iron regulation, 10 years later.Blood. 2011; 117: 4425-4433Crossref PubMed Scopus (699) Google Scholar, 5Andrews N.C. Forging a field: the golden age of iron biology.Blood. 2008; 112: 219-230Crossref PubMed Scopus (484) Google Scholar Clinical trials have demonstrated the superiority of IV iron to oral iron in raising hemoglobin levels in patients with CKD or receiving peritoneal or hemodialysis.6Shepshelovich 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: 677-690Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Third, with the introduction of capitated reimbursement program for dialysis services,7Centers for Medicare & Medicaid Services (CMS)HHS. Medicare program; end-stage renal disease prospective payment system. Final rule.Fed Regist. 2010; 75: 49029-49214PubMed Google Scholar dialysis organizations may have been incentivized to favor IV iron over more costly ESAs.8Thamer M. Zhang Y. Kaufman J. Kshirsagar O. Cotter D. Hernan M.A. Major declines in epoetin dosing after prospective payment system based on dialysis facility organizational status.Am J Nephrol. 2014; 40: 554-560Crossref PubMed Scopus (13) Google Scholar At the same time, ESAs have come under regulatory scrutiny9Blackbox warning US Food and Drug AdministrationFDA alert. Information for Healthcare Professionals: erythropoiesis stimulating agents (ESA) [Aranesp (darbepoetin), Epogen (epoetin alfa), and Procrit (epoetin alfa)].https://wayback.archive-it.org/7993/20170723113601/Date: 2007https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126481.htmDate accessed: April 30, 2019Google Scholar after the publication of landmark clinical trials that demonstrated either harm or lack of benefit of treating patients to high hemoglobin levels using ESAs.10Singh A.K. Szczech L. Tang K.L. et al.Correction of anemia with epoetin alfa in chronic kidney disease.N Engl J Med. 2006; 355: 2085-2098Crossref PubMed Scopus (2280) Google Scholar, 11Pfeffer M.A. Burdmann E.A. Chen C.Y. et al.A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.N Engl J Med. 2009; 361: 2019-2032Crossref PubMed Scopus (1648) Google Scholar, 12Drueke T.B. Locatelli F. Clyne N. et al.Normalization of hemoglobin level in patients with chronic kidney disease and anemia.N Engl J Med. 2006; 355: 2071-2084Crossref PubMed Scopus (1785) Google Scholar, 13Besarab A. Bolton W.K. Browne J.K. et al.The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.N Engl J Med. 1998; 339: 584-590Crossref PubMed Scopus (1882) Google Scholar Finally, there has been a growing comfort with IV iron formulations as their safety profiles for anaphylaxis have improved.14Wang C. Graham D.J. Kane R.C. et al.Comparative risk of anaphylactic reactions associated with intravenous iron products.JAMA. 2015; 314: 2062-2068Crossref PubMed Scopus (155) Google Scholar In dialysis patients, the decision on dosing approaches—dose, frequency, and duration—of IV iron therapy is based on dynamic laboratory parameters for anemia including hemoglobin and the iron indices, transferrin saturation and serum ferritin, to achieve a target hemoglobin while preventing the development of iron overload. Currently, dialysis clinics rely on dosing protocols that prescribe dosing approaches for IV iron administration according to guidelines from various expert panels. When these laboratory values are low, patients may receive large doses up to 1000 mg of IV iron per month (often called bolus). For hemodialysis patients, it is often given as consecutive doses of 100 mg over 5-10 dialysis sessions (half-bolus and bolus dose, respectively); for peritoneal dialysis patients, it can be 200 mg weekly over 4 weeks. When these laboratory values are high, patients may receive smaller doses of IV iron, or potentially, none. Protocols also factor in patients' evolving clinical characteristics such as the presence of active infection to provide treatment recommendations. Consequently, the treatment dose, frequency, and duration of IV iron are repeatedly adjusted each time updated laboratory test results become available. Guidelines15KDIGO Anemia Work GroupKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int. 2012; 2: 279-335Google Scholar, 16Locattelli F. Barany P. Covic A. et al.Kidney disease: improving global outcomes guidelines on anemia management in chronic kidney disease: a European Renal Best Practice position statement.Nephrol Dial Transpl. 2013; 28: 1346-1359Google Scholar, 17Kliger A.S. Foley R.N. Goldfarb D.S. et al.KDOQI US commentary on the 2012 KDIGO Clinical Practice Guidelines for Anemia in CKD.Am J Kidney Dis. 2012; 62: 849-859Google Scholar, 18Moist L.M. Troyanov S. White C.T. et al.Canadian Society of Nephrology commentary on the 2012 KDIGO Clinical Practice Guidelines for Anemia in CKD.Am J Kidney Dis. 2012; 62: 860-873Google Scholar, 19MacGinley R. Walker R. Irving M. KHA-CARI guideline: use of iron in chronic kidney disease patients.Nephrology (Carlton). 2013; 18: 747-749Google Scholar, 20Padhi S. Glen J. Pordes B.A.J. Thomas M.E. Management of anaemia in chronic kidney disease: summary of updated NICE guidance.BMJ. 2015; 350: h2258Crossref PubMed Scopus (31) Google Scholar about initiation and termination of IV iron therapy for patients receiving dialysis are listed in Table 1. All guidelines recommend initiation of IV iron therapy when iron indices suggest iron deficiency. However, there is no consensus on the upper target limits of transferrin saturation and serum ferritin for IV iron therapy. Treatment recommendations for higher levels of iron indices vary considerably among guidelines, especially for serum ferritin levels between 500 and 1200 ng/mL. Consequently, contemporary dosing approaches that integrate these guidelines differ on the absolute upper limits of iron indices for IV iron therapy. Common practice is the discontinuation of IV iron for transferrin saturation greater than 50% or serum ferritin greater than 800 ng/mL, with some using an absolute upper limit of 1200 ng/mL. There may be additional variation with respect to dosing for potentially the same level of transferrin saturation and serum ferritin among protocols developed by dialysis organizations.21Li X. Cole S.R. Kshirsagar A.V. Fine J.P. Stürmer T. Brookhart M.A. Safety of dynamic intravenous iron administration strategies in hemodialysis patients.Clin J Am Soc Nephrol. 2019; 14: 728-737Crossref PubMed Scopus (22) Google ScholarTable 1Summary of Recommendations for Initiation and Termination of Intravenous Iron Therapy for Patients Receiving DialysisOrganization (Year)Recommended Initiation of IV Iron TherapyRecommended Upper Limit of IV Iron TherapyKidney Disease: Improving Global Outcomes15KDIGO Anemia Work GroupKDIGO clinical practice guideline for anemia in chronic kidney disease.Kidney Int. 2012; 2: 279-335Google Scholar (2012)With or without ESATSAT ≤ 30%Ferritin ≤ 500 ng/mLTSAT > 30%Ferritin > 500 ng/mL∗For selected patients, “a therapeutic trial of additional iron may be undertaken in patients with serum ferritin >500 ng/mL after due consideration of potential acute toxicities and long-term risk.”European Renal Best Practice16Locattelli F. Barany P. Covic A. et al.Kidney disease: improving global outcomes guidelines on anemia management in chronic kidney disease: a European Renal Best Practice position statement.Nephrol Dial Transpl. 2013; 28: 1346-1359Google Scholar (2013)With ESATSAT < 30%Ferritin < 500 ng/mLWithout ESATSAT < 25%Ferritin < 500 ng/mLTSAT > 30%Ferritin > 500 ng/mLKidney Disease Outcomes Quality Initiative17Kliger A.S. Foley R.N. Goldfarb D.S. et al.KDOQI US commentary on the 2012 KDIGO Clinical Practice Guidelines for Anemia in CKD.Am J Kidney Dis. 2012; 62: 849-859Google Scholar (2013)With or without ESATSAT ≤ 30%Ferritin ≤ 500 ng/mLSee comment†Therapeutic trial of IV iron could be considered when TSAT ≤ 30%, even if ferritin > 500 ng/mL. There is insufficient evidence upon which to base a recommendation for an upper ferritin limit above which IV iron must be withheld.Canadian Society of Nephrology18Moist L.M. Troyanov S. White C.T. et al.Canadian Society of Nephrology commentary on the 2012 KDIGO Clinical Practice Guidelines for Anemia in CKD.Am J Kidney Dis. 2012; 62: 860-873Google Scholar (2013)With or without ESATSAT ≤ 30%Ferritin ≤ 500 ng/mLSee comment‡Guide subsequent iron administration in chronic kidney disease patients based on hemoglobin response to recent iron therapy, as well as ongoing blood losses, iron status tests (TSAT and ferritin), hemoglobin concentration, ESA responsiveness, and ESA dose in ESA treated patients, trends in each parameter, and the patient's clinical status.Kidney Health Australia-Caring for Australasians with Renal Impairment19MacGinley R. Walker R. Irving M. KHA-CARI guideline: use of iron in chronic kidney disease patients.Nephrology (Carlton). 2013; 18: 747-749Google Scholar (2013)With ESATSAT < 20%Ferritin < 200 ng/mLWithout ESATSAT < 30%Ferritin < 100 ng/mLTSAT 30%Ferritin > 1200 ng/mLNational Institute for Health and Care Excellence20Padhi S. Glen J. Pordes B.A.J. Thomas M.E. Management of anaemia in chronic kidney disease: summary of updated NICE guidance.BMJ. 2015; 350: h2258Crossref PubMed Scopus (31) Google Scholar (2015)With or without ESATSAT < 20%Ferritin < 100 ng/mLTSAT > 30%Ferritin > 800 ng/mLESA, erythropoiesis-stimulating agents; IV, intravenous; TSAT, transferrin saturation.∗ For selected patients, “a therapeutic trial of additional iron may be undertaken in patients with serum ferritin >500 ng/mL after due consideration of potential acute toxicities and long-term risk.”† Therapeutic trial of IV iron could be considered when TSAT ≤ 30%, even if ferritin > 500 ng/mL. There is insufficient evidence upon which to base a recommendation for an upper ferritin limit above which IV iron must be withheld.‡ Guide subsequent iron administration in chronic kidney disease patients based on hemoglobin response to recent iron therapy, as well as ongoing blood losses, iron status tests (TSAT and ferritin), hemoglobin concentration, ESA responsiveness, and ESA dose in ESA treated patients, trends in each parameter, and the patient's clinical status. Open table in a new tab ESA, erythropoiesis-stimulating agents; IV, intravenous; TSAT, transferrin saturation. All IV iron formulations have a carbohydrate shell surrounding an iron oxyhydroxide core that contains dynamic amounts of ferrous and ferric iron.22Michael B. Fishbane S. Coyne D.W. Agarwal R. Warnock D.G. Drug insight: safety of intravenous iron supplementation with sodium ferric gluconate complex.Nat Clin Pract Nephrol. 2006; 2: 92-100Google Scholar The different formulations—iron dextran, iron sucrose, ferrous gluconate, and others—vary with respect to their half-life and molecular weight.23Geisser P. Burckhardt S. The pharmacokinetics and pharmacodynamics of iron preparations.Pharmaceutics. 2011; 3: 12-33Google Scholar Within the formulations, soluble ferrous iron is in flux with insoluble ferric iron. As a transition metal, iron can readily donate and accept electrons, a property that allows it to be incorporated into many proteins, notably hemoglobin and myoglobin, but also cytochrome proteins, myeloperoxidase, nitric oxide synthase, respiratory complexes, coenzyme Q10, and others that are crucial to many biologic functions.24Zumbrennen-Bullough K. Babitt J.L. The iron cycle in chronic kidney disease (CKD): from genetics and experimental models to CKD patients.Nephrol Dial Transpl. 2014; 29: 263-273Google Scholar Iron can be potentially toxic when it is not bound to proteins. Hydrogen peroxide is produced in a variety of biologically relevant free radical reactions such as respiration.25Slotki I. Cabantchik Z.I. The labile side of iron supplementation in CKD.J Am Soc Nephrol. 2015; 26: 2612-2619Crossref PubMed Scopus (37) Google Scholar Via the Fenton reaction, iron, in the presence of hydrogen peroxide, can catalyze the production of the hydroxyl free radical (·OH)26Winterbourn C.C. Toxicity of iron and hydrogen peroxide: the Fenton reaction.Toxicol Lett. 1995; 82-83: 969-974Crossref PubMed Scopus (886) Google Scholar that is known to oxidize lipids27Aviram M. Review of human studies on oxidative damage and antioxidant protection related to cardiovascular diseases.Free Radic Res. 2000; 33: S85-S97PubMed Google Scholar and DNA.28Imlay J.A. Chin S.M. Linn S. Toxic DNA damage by hydrogen peroxide through the Fenton reaction in vivo and in vitro.Science. 1988; 240: 640-642Crossref PubMed Scopus (1244) Google Scholar In this way, iron may contribute to accelerated atherosclerosis, and eventually clinical cardiovascular disease.29Reis K.A. Guz G. Ozdemir H. et al.Intravenous iron therapy as a possible risk factor for atherosclerosis in end-stage renal disease.Int Heart J. 2005; 46: 255-264Crossref PubMed Scopus (68) Google Scholar, 30Himmelfarb J. Uremic toxicity, oxidative stress, and hemodialysis as renal replacement therapy.Semin Dial. 2009; 22: 636-643Google Scholar Iron is also a necessary cofactor for the growth of bacteria and subsequently infections, and numerous species of gram positive bacteria have evolved proteins that can scavenge small amounts of unbound iron.31Sheldon J.R. Heinrichs D.E. Recent developments in understanding the iron acquisition strategies of gram positive pathogens.FEMS Microbiol Rev. 2015; 39: 592-630Google Scholar, 32Haley K.P. Skaar E.P. A battle for iron: host sequestration and Staphylococcus aureus acquisition.Microbes Infect. 2012; 14: 217-227Crossref PubMed Scopus (115) Google Scholar The human body has evolved mechanisms both to conserve and tightly regulate iron.33Hentze M.W. Muckenthaler M.U. Andrews N.C. Balancing acts: molecular control of mammalian iron metabolism.Cell. 2004; 117: 285-297Abstract Full Text Full Text PDF PubMed Scopus (1398) Google Scholar The majority of 3-5 g of body iron is stored in hemoglobin and myoglobin. About 20-25 mg of iron is shuttled daily among enterocytes, red blood cells, spleen, bone marrow, and liver, and is tightly bound to proteins such as transferrin or stored in tissue bound to ferritin.5Andrews N.C. Forging a field: the golden age of iron biology.Blood. 2008; 112: 219-230Crossref PubMed Scopus (484) Google Scholar Transferrin can bind up to 2 iron molecules in a redox inert state, and approximately 20%-40% of iron binding sites are normally occupied.34Aisen P. Leibman A. Zweier J. Stoichiometric and site characteristics of the binding of iron to human transferrin.J Biol Chem. 1978; 253: 1930-1937Google Scholar A single ferritin molecule can hold up to 4000 iron atoms.35Arosio P. Ingrassia R. Cavadini P. Ferritins: a family of molecules for iron storage, antioxidation and more.Biochim Biophys Acta. 2009; 1790: 589-599Crossref PubMed Scopus (640) Google Scholar Regulatory proteins such as ferroportin, hepcidin, and erythroferrone oversee the transfer of iron across different cells.36Pantopoulos K. Porwal S.K. Tartakoff A. Devireddy L. Mechanisms of mammalian iron homeostasis.Biochemistry. 2012; 51: 5705-5724Crossref PubMed Scopus (368) Google Scholar Ferroportin is a transmembrane efflux channel that allows the transfer of iron from gastrointestinal cells, macrophages, hepatocytes, and placental cells.37Keel S.B. Abkowitz J.L. The microcytic red cell and the anemia of inflammation.N Engl J Med. 2009; 361: 1904-1906Google Scholar Hepcidin, produced in the liver,4Ganz T. Hepcidin and iron regulation, 10 years later.Blood. 2011; 117: 4425-4433Crossref PubMed Scopus (699) Google Scholar controls whether ferroportin is bound to the cell membrane or internalized and degraded.37Keel S.B. Abkowitz J.L. The microcytic red cell and the anemia of inflammation.N Engl J Med. 2009; 361: 1904-1906Google Scholar Erythroferrone is produced by erythroid progenitors in response to acute anemia to suppress hepcidin expression.38Kautz L. Jung G. Valore E.V. Rivella S. Nemeth E. Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism.Nat Genet. 2014; 46: 678-684Crossref PubMed Scopus (745) Google Scholar These 3 main proteins modulate oral absorption, generally limited to 1-2 mg daily, but perhaps even less for patients on dialysis due to high levels of inflammation induced hepcidin.39Uehata T. Tomosugi N. Shoji T. et al.Serum hepcidin-25 levels and anemia in non-dialysis chronic kidney disease patients: a cross-sectional study.Nephrol Dial Transpl. 2012; 27: 1076-1083Crossref PubMed Scopus (50) Google Scholar In contrast, nearly all IV iron regimens for patients receiving dialysis exceed 25 mg per dose. A typical maintenance dose is 50 mg, while bolus dose is 100 mg given for 10 hemodialysis sessions. In an iron deplete state, down regulation of hepcidin would allow for enhanced metabolism of iron, including iron administered intravenously. Yet, in an iron replete state, the potential mismatch between the typical administered dose of iron (50-100 mg) and the homeostatic/binding capabilities (25 mg) has led to concerns about iron overload, and the safety of IV iron dosing for patients on dialysis. Nontransferrin-bound iron or labile plasma iron is found when administered iron exceeds the carrying capacity of transferrin and can participate in a variety of reactions as it is able to permeate cells.40Brissot P. Ropert M. Le Lan C. Loreal O. Non-transferrin bound iron: a key role in iron overload and iron toxicity.Biochim Biophys Acta. 2012; 1820: 403-410Crossref PubMed Scopus (463) Google Scholar The 2 most commonly used forms of IV iron compounds in dialysis, iron sucrose and ferric gluconate, have 2 times the amount of labile iron as other iron compounds41Jahn M.R. Andreasen H.B. Futterer S. et al.A comparative study of the physicochemical properties of iron isomaltoside 1000 (Monofer), a new intravenous iron preparation and its clinical implications.Eur J Pharm Biopharm. 2011; 78: 480-491Crossref PubMed Scopus (191) Google Scholar and accounts for the limit of the single dose of 200-250 mg for these 2 agents compared to some of the newer IV iron agents that allow over 500 mg to be administered at one time. As we assess the evidence regarding long-term risks of IV iron, it is important to review limitations that may prevent us from making firm conclusions. These limitations include our ability to assess iron status, designs of existing studies evaluating long-term safety, as well as the characteristics of patients included in these studies. Currently, laboratory parameters such as transferrin saturation and ferritin are used to estimate levels of iron stores. The levels of both laboratory parameters can be affected by factors other than iron binding. Transferrin is a negative acute phase reactant.42Gkouvatsos K. Papanikolaou G. Pantopoulos K. Regulation of iron transport and the role of transferrin.Biochim Biophys Acta. 2012; 1820: 188-202Crossref PubMed Scopus (311) Google Scholar Serum ferritin is a positive acute phase reactant, and can also be affected by heavy alcohol intake, infection, malignancy, and liver disease.43Wang W. Knovich M.A. Coffman L.G. Torti F.M. Torti S.V. Serum ferritin: past, present and future.Biochim Biophys Acta. 2010; 1800: 760-769Crossref PubMed Scopus (498) Google Scholar Liver iron concentration has often been considered the gold standard of assessing body iron stores. Historically assessed by liver biopsy, liver iron concentration is now routinely assessed by magnetic resonance imaging, a remarkably less invasive technique. Although magnetic resonance imaging can determine total iron content in the liver, it cannot determine whether the iron is deposited in hepatocytes (parenchymal iron) or in the reticuloendothelial system. The precise location of iron deposition matters because parenchymal iron is considered toxic,44Wish J.B. Aronoff G.R. Bacon B.R. et al.Positive iron balance in chronic kidney disease: how much is too much and how to tell?.Am J Nephrol. 2018; 47: 72-83Crossref PubMed Scopus (52) Google Scholar while iron in the reticuloendothelial system is considerably less toxic. Understanding the potential toxicity of IV iron, especially overload, thus can be especially difficult using labs or imaging. Most epidemiological studies have examined short-term risk of IV iron measured in weeks to a few months.45Li X. Kshirsagar A.V. Brookhart M.A. Safety of intravenous iron in hemodialysis patients.Hemodial Int. 2017; 21: S93-S103Google Scholar Over the patient's life course on dialysis, measured in years, clinicians make dynamic decisions about dosing approach of IV therapy repeatedly after each monthly treatment course with respect to dose, frequency, and duration. Studies using an aggregated cumulative exposure over a long time period do not well align with short-term treatment decisions.46Li X. Kshirsagar A.V. Rest easy with intravenous iron for dialysis patients?: high dose IV iron safety.Clin J Am Soc Nephrol. 2018; 13: 363-365Google Scholar, 47Brookhart M.A. Counterpoint: the treatment decision design.Am J Epidemiol. 2015; 182: 840-845Crossref PubMed Scopus (36) Google Scholar Using aggregated cumulative exposure can mask important clinical heterogeneity in patients' treatment and clinical experience, contributing to potential residual confounding in the estimated associations between iron dose and outcomes of interest.46Li X. Kshirsagar A.V. Rest easy with intravenous iron for dialysis patients?: high dose IV iron safety.Clin J Am Soc Nephrol. 2018; 13: 363-365Google Scholar Moreover, the mortality rate in patients receiving dialysis is high. It is challenging to define long-term toxicity in the context of a low 2- or 5-year survival in these patients. Finally, it is important to examine the evolving clinical characteristics of patients assigned to the different doses of IV iron in observational studies of long-term safety. Studies that rely solely on pre-existing patient registries may not have access to all of the factors that have contributed to a treatment choice, such as frailty. Due to the potential presence of unmeasured confounding, the internal validity of estimated effect measures might be violated despite sophisticated statistical modeling, including high dimensional propensity scoring and marginal structural models. Longitudinal data with information on evolving patient characteristics are necessary for valid assessment of long-term effects. Several observational studies have examined the risk of cardiovascular disease from IV iron use; the results have been conflicting. Three large retrospective cohort studies found no association between IV iron use and short-term cardiovascular safety.48Kshirsagar A.V. Freburger J.K. Ellis A.R. Wang L. Winkelmayer W.C. Brookhart M.A. Intravenous iron supplementation practices and short-term risk of cardiovascular events in hemodialysis patients.PLoS One. 2013; 8: e78930Crossref PubMed Scopus (55) Google Scholar, 49Freburger J.K. Ellis A.R. Kshirsagar A.V. Wang L. Brookhart M.A. Comparative short-term safety of bolus versus maintenance iron dosing in hemodialysis patients: a replication study.BMC Nephrol. 2014; 15: 154Crossref PubMed Scopus (11) Google Scholar, 50Tangri N. Miskulin D.C. Zhou J. et al.Effect of intravenous iron use on hospitalizations in patients undergoing hemodialysis: a comparative effectiveness analysis from the DEcIDE-ESRD study.Nephrol Dial Transpl. 2015; 30: 667-675Crossref PubMed Scopus (31) Google Scholar Two of these studies compared bolus (consecutive iron doses of at least 100 mg with the potential to exceed 600 mg within a month) vs maintenance dosing (all other iron doses during a month) and high dose (>200 mg/month) vs low dose (≤200 mg/month),48Kshirsagar A.V. Freburger J.K. Ellis A.R. Wang L. Winkelmayer W.C. Brookhart M.A. Intravenous iron supplementation practices and short-term risk of cardiovascular events in hemodialysis patients.PLoS One. 2013; 8: e78930Crossref PubMed Scopus (55) Google Scholar, 49Freburger J.K. Ellis A.R. Kshirsagar A.V. Wang L. Brookhart M.A. Comparative short-term safety of bolus versus maintenance iron dosing in hemodialysis patients: a replication study.BMC Nephrol. 2014; 15: 154Crossref PubMed Scopus (11) Google Scholar while one study focused on the comparison between high (>350 mg/month), moderate (>150-350 mg/month), low (>0-150 mg/month), and none.50Tangri N. Miskulin D.C. Zhou J. et al.Effect of intravenous iron use on hospitalizations in patients undergoing hemodialysis: a comparative effectiveness analysis from the DEcIDE-ESRD study.Nephrol Dial Transpl. 2015; 30: 667-675Crossref PubMed Scopus (31) Google Scholar Another cohort study with a meaningfully smaller number of participants than the other 3 studies found that IV iron was associated with an increased risk of new cardiovascular events, and that there was a dose response effect using (somewhat arbitrary) categories of administered IV iron over 6 months: none, 40-800 mg, 840-1600 mg, 1640-2400 mg.51Kuo K.L. Hung S.C. Lin Y.P. et al.Intravenous ferric chloride hexahydrate supplementation" @default.
• W2971344488 created "2019-09-05" @default.
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• W2971344488 date "2019-07-01" @default.
• W2971344488 modified "2023-09-27" @default.
• W2971344488 title "Long-Term Risks of Intravenous Iron in End-Stage Renal Disease Patients" @default.
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• W2971344488 doi "https://doi.org/10.1053/j.ackd.2019.05.001" @default.
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