Iron: a double‐edged sword

Youssef, Lyla A.; Spitalnik, Steven L.

doi:10.1111/trf.14296

Cited by 12 publications

(18 citation statements)

References 31 publications

(55 reference statements)

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“…For NRS, we will only report results descriptively on the primary outcome of infection instead of pooling results due to heterogeneity in clinical conditions, study designs and variations in statistical adjustment. If possible, results will be displayed in a forest plot, with studies sorted according to study design features, and the pooled estimate will be suppressed as recommended by the Cochrane Collaboration 6…”

Section: Methodsmentioning

confidence: 99%

“…Iron is essential for extracellular pathogens as it an ideal redox catalyst for important cellular processes such as respiration and DNA replication 5. Humans are able to withhold free (non-transferrin-bound) iron from invading pathogens through a process termed nutritional immunity in an effort to limit infection 5 6. Intravenous iron administration can lead to increased levels of circulating free iron, which can be detrimental to the host and promote pathogen growth.…”

Section: Introductionmentioning

confidence: 99%

“…Interpreting data on infection from these meta-analyses is challenging because infection is not always defined as a prespecified, standardised outcome measure in RCTs but rather reported as safety outcome. A recent editorial highlighted the need for an adequately powered trial of intravenous iron with infection as a primary outcome 6…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Risk of infection associated with intravenous iron preparations: protocol for updating a systematic review

et al. 2019

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IntroductionThe benefits and risk of intravenous iron have been documented in previous systematic reviews and continue to be the subject of randomised controlled trials (RCTs). An ongoing issue that continues to be raised is the relationship between administering iron and developing infection. This is supported by biological plausibility from animal models. We propose an update of a previously published systematic review and meta-analysis with the primary focus being infection.Methods and analysisWe will include RCTs and non-randomised studies (NRS) in this review update. We will search the relevant electronic databases. Two reviewers will independently extract data. Risk of bias for RCTs and NRS will be assessed using the relevant tools recommended by The Cochrane Collaboration. Data extracted from RCTs and NRS will be analysed and reported separately. Pooled data from RCTs will be analysed using a random effects model. We will also conduct subgroup analyses to identify any patient populations that may be at increased risk of developing infection. We will provide a narrative synthesis on the definitions, sources and responsible pathogens for infection in the included studies. Overall quality of evidence on the safety outcomes of mortality and infection will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach.Ethics and disseminationThis systematic review will only investigate published studies and therefore ethical approval is not required. The results will be broadly distributed through conference presentations and peer-reviewed publications.Trial registration numberPROSPERO (CRD42018096023).

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Risk of infection associated with intravenous iron preparations: protocol for updating a systematic review

et al. 2019

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“…As much as 70% of the total iron in the human body, or 3-5 g, is contained within RBCs, specifically in the heme protoporphyrin rings of hemoglobin (a single RBC contains ∼1.0 billion heme moieties per ∼250 million hemoglobin molecules; Gkouvatsos et al, 2012;Korolnek and Hamza, 2015;Yoshida et al, 2019). Notably, iron is a potent catalyst for generating reactive oxygen species (ROS) via the Fenton reaction, which can quickly lead to systemic toxicity due to the high reactivity of iron when free in the circulation (e.g., upon overload of transferrin, the plasma iron chaperone) (Papanikolaou and Pantopoulos, 2005;Kosman, 2010;Hod et al, 2010;Korolnek and Hamza, 2015;Rapido et al, 2017;Youssef and Spitalnik, 2017a). For this reason, highly specialized mechanisms are required for regulating RBC catabolism and iron recycling.…”

Section: Introductionmentioning

confidence: 99%

“…With ∼2 million RBCs being recycled every second via this mechanism, EP is the largest source of iron flux in the body (Korolnek and Hamza, 2015). Excessive EP by individual macrophages can lead to ferroptosis both in vitro and in vivo (Dixon et al, 2012;Youssef and Spitalnik, 2017a). This form of iron-induced, non-apoptotic cell death is characterized by an overwhelming, iron-dependent accumulation of lethal ROS derived from lipid peroxidation (Dixon et al, 2012;Cao and Dixon, 2016).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Reprogramming of Mouse Bone Marrow Derived Macrophages Following Erythrophagocytosis

et al. 2020

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Reticuloendothelial macrophages engulf ∼0.2 trillion senescent erythrocytes daily in a process called erythrophagocytosis (EP). This critical mechanism preserves systemic heme-iron homeostasis by regulating red blood cell (RBC) catabolism and iron recycling. Although extensive work has demonstrated the various effects on macrophage metabolic reprogramming by stimulation with proinflammatory cytokines, little is known about the impact of EP on the macrophage metabolome and proteome. Thus, we performed mass spectrometry-based metabolomics and proteomics analyses of mouse bone marrow-derived macrophages (BMDMs) before and after EP of IgG-coated RBCs. Further, metabolomics was performed on BMDMs incubated with free IgG to ensure that changes to macrophage metabolism were due to opsonized RBCs and not to free IgG binding. Uniformly labeled tracing experiments were conducted on BMDMs in the presence and absence of IgG-coated RBCs to assess the flux of glucose through the pentose phosphate pathway (PPP). In this study, we demonstrate that EP significantly alters amino acid and fatty acid metabolism, the Krebs cycle, OXPHOS, and arachidonate-linoleate metabolism. Increases in levels of amino acids, lipids and oxylipins, heme products, and RBC-derived proteins are noted in BMDMs following EP. Tracing experiments with U-13 C 6 glucose indicated a slower flux through glycolysis and enhanced PPP activation. Notably, we show that it is fueled by glucose derived from the macrophages themselves or from the extracellular media prior to EP, but not from opsonized RBCs. The PPP-derived NADPH can then fuel the oxidative burst, leading to the generation of reactive oxygen species necessary to promote digestion of phagocytosed RBC proteins via radical attack. Results were confirmed by redox proteomics experiments, demonstrating the oxidation of Cys152 and Cys94 of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and hemoglobin-β, respectively. Significant increases in early Krebs cycle and C 5-branched dibasic acid metabolites

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Risk of Infection Associated With Administration of Intravenous Iron

et al. 2021

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IMPORTANCEIntravenous iron is recommended by many clinical guidelines based largely on its effectiveness in reducing anemia. However, the association with important safety outcomes, such as infection, remains uncertain. OBJECTIVE To examine the risk of infection associated with intravenous iron compared with oral iron or no iron. DATA SOURCES Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized clinical trials (RCTs) from 1966 to January 31, 2021. Ongoing trials were sought from ClinicalTrials.gov, CENTRAL, and the World Health Organization International Clinical Trials Search Registry Platform. STUDY SELECTION Pairs of reviewers identified RCTs that compared intravenous iron with oral iron or no iron across all patient populations, excluding healthy volunteers. Nonrandomized studies published since January 1, 2007, were also included. A total of 312 full-text articles were assessed for eligibility. DATA EXTRACTION AND SYNTHESIS Data extraction and risk of bias assessments were performed according to the Preferred Reporting Items of Systematic Reviews and Meta-analyses (PRISMA) and Cochrane recommendations, and the quality of evidence was assessed using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. Two reviewers extracted data independently. A random-effects model was used to synthesize data from RCTs. A narrative synthesis was performed to characterize the reporting of infection. MAIN OUTCOMES AND MEASURESThe primary outcome was risk of infection. Secondary outcomes included mortality, hospital length of stay, and changes in hemoglobin and red blood cell transfusion requirements. Measures of association were reported as risk ratios (RRs) or mean differences.RESULTS A total of 154 RCTs (32 920 participants) were included in the main analysis. Intravenous iron was associated with an increased risk of infection when compared with oral iron or no iron (RR, 1.17; 95% CI, 1.04-1.31; I 2 = 37%; moderate certainty of evidence). Intravenous iron also was associated with an increase in hemoglobin (mean difference, 0.57 g/dL; 95% CI, 0.50-0.64 g/dL; I 2 = 94%) and a reduction in the risk of requiring a red blood cell transfusion (RR, 0.93; 95% CI, 0.76-0.89; I 2 = 15%) when compared with oral iron or no iron. There was no evidence of an effect on mortality or hospital length of stay. (continued) Key Points Question In patients who require treatment with intravenous iron, what is the evidence that this intervention increases the risk of developing a new infection? Findings In this systematic review and meta-analysis of 154 randomized clinical trials that included 32 920 participants, intravenous iron was associated with an increased risk of infection. Meaning The results of this study suggest that, despite broad advocacy in clinical guidelines, intravenous iron may increase the risk of infection, which must be balanced with the potential benefits of treating anemia and reducing blood transfusion requirements.

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Iron: a double‐edged sword

Cited by 12 publications

References 31 publications

Risk of infection associated with intravenous iron preparations: protocol for updating a systematic review

Risk of infection associated with intravenous iron preparations: protocol for updating a systematic review

Metabolic Reprogramming of Mouse Bone Marrow Derived Macrophages Following Erythrophagocytosis

Risk of Infection Associated With Administration of Intravenous Iron

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