Iron Repletion Research Articles

Abstract 4119891: Risk Factors of Anemia in Pulmonary Arterial Hypertension Patients with Endothelin Receptor Antagonists Administration and Related Treatment

Background: Endothelin receptor antagonists (ERAs) demonstrated significant efficiency in delaying clinical deterioration and improving survival of patients with pulmonary arterial hypertension (PAH). However, the frequent occurrence of anemia after ERAs administration has gained clinical attention currently, whereas the etiology of anemia is unclear. The risk factors of ERAs associated anemia remained undefined. Therefore, we aim to investigate risk factors of developing anemia after ERAs treatment and whether iron supplement could correct anemia. Method: A retrospective cohort study was performed among patients with PAH who received ERAs between January, 2017 and December, 2019 in Fuwai hospital. The primary outcome was development of anemia after ERAs therapy and secondary outcome was correction of anemia after iron supplement. Results: A total of 120 patients with PAH were included in the study and 28 patients developed anemia during follow up . Distinctively, all the patients who developed anemia were female. After ERAs administration, iron metabolism (Ferritin 95.29±144.79 μg/L versus 69.9±118.25 μg/L, P <0.001) and hemoglobin (154.21±23.80 g/L versus 136.12±28.61 g/L, P <0.001) reduced significantly in the total cohort with patients who developed anemia more significant. Baseline iron metabolism (Ferritin: HR 0.98, 95%CI 0.96-0.99, P =0.02) was independently associated with development of anemia after ERAs administration. Compared with patients with iron replete, patients with iron deficiency had over 9-fold risk of developing anemia after receiving ERAs (HR = 9.59, 95%CI 3.62-25.41, P < 0.01). Iron supplement could effectively correct anemia. Conclusion: It is advised that patients receiving ERAs monitor iron metabolism and hemoglobin regularly, especially females and those with low hemoglobin level and compromised iron homeostasis before ERAs administration, which facilitates prevention and early detection of anemia. ERAs-related anemia is mostly mild, oral iron supplement could effectively reverse anemia and aberrant iron metabolism.

Ferric derisomaltose versus usual care in patients with heart failure, reduced ejection fraction, and iron deficiency: a short-term UK cost-utility analysis based on the IRONMAN RCT

Abstract Background In the IRONMAN trial, patients with heart failure (HF), a reduced ejection fraction and iron deficiency who were randomly assigned to ferric derisomaltose (FDI), rather than usual care, had a lower rate of the composite of hospitalization for heart failure (HHF) and cardiovascular (CV) death (rate ratio, RR, 0.82; 95% CI 0.66 to 1.02; p=0.07). A COVID-19 sensitivity analysis, censoring data at 1 year of follow-up showed a greater magnitude of treatment effect (RR 0.66; 95% CI 0.48 to 0.91; p=0.011). Purpose Patient-level data from IRONMAN were used to evaluate the effectiveness and cost-utility of FDI compared to usual care for patients with a current or recent HHF, or raised plasma natriuretic peptide concentrations, from a UK National Health Service (NHS) perspective. Methods A cost-utility analysis (CUA) was conducted covering the first year after randomization. Numbers-needed-to-treat (NNTs) were calculated for the primary endpoint censored at 1 year. In the CUA model, patient survival and rates of (re)hospitalization due to HF, other CV events, infections, respiratory conditions, and other non-CV events were modeled based directly on data from the IRONMAN RCT. UK-specific costs were obtained from the national schedule of NHS costs. Quality of life was estimated based on EQ-5D-5L data collected from patients included in the IRONMAN RCT. Results were undiscounted and reported as absolute and incremental costs in 2023 pounds sterling, and quality-adjusted life expectancy in quality-adjusted life years (QALYs). A willingness-to-pay threshold of £20,000 per QALY was adopted to allow calculation of a net monetary benefit (NMB), a summary measure of the overall value of FDI in monetary terms, capturing changes in both cost and QALY outcomes. Results The NNT analysis showed that 9 patients would need to be treated with FDI to avoid one composite primary endpoint event (CV death and HHF) over 1 year. Relative to usual care, FDI was associated with an improvement of 0.01 QALYs per patient over 1 year (0.58 versus 0.57 QALYs). Total average costs per-patient were £1,672 for FDI, versus £1,975 for usual care, leading to a saving of £302 per patient with FDI. The cost of iron procurement was more than offset by reductions in costs of (re)hospitalizations (Figure). FDI was therefore dominant over usual care, yielding an NMB of £483 over 1 year. Conclusions This short-term, within-trial CUA suggests that FDI both improves QALYs and reduces healthcare expenditure versus usual care when administered to patients with HF and iron deficiency in the UK. Iron repletion with FDI may be a prudent allocation of healthcare resources in this patient population.Breakdown of costs

Myocardial performance improvement after iron replacement in heart failure patients with LVEF <50% and TSAT <20%: The IRON-PATH II echo-substudy

Abstract Background Iron deficiency (ID) is a prevalent comorbidity in patients with heart failure (HF) and left ventricular ejection fraction (LVEF) <50%. ID leads to impaired myocardial global function. Some echocardiographic parameters have demonstrated an additive value in advanced assessment of cardiac performance, like global longitudinal strain (GLS), myocardial work (MW) and its derivatives constructive work (CW), wasted work (WW) and work efficiency (WE). The usual definition of ID may have limitations in rightly identifying systemic iron status, especially those with isolated hypoferritinemia. However, the impact on cardiac function measured by echocardiography after intravenous iron replacement according to TSAT values has never been explored. Purpose Describe the myocardial performance associated with systemic ID defined as TSAT <20% in patients with HF compared to patients with HF without ID (TSAT ≥20%). Afterwards, we aimed to explore changes in myocardial function after iron replacement by echocardiography. Methods The IRON-PATH II was a multicenter, prospective, observational study. The total number of patients to be recruited was 210 in 7 centers across Spain and Portugal. Patients with HF and LVEF ≤50%, without signs of fluid overload or low cardiac output, and haemoglobin ≥11 g/dL were included. The IRON-PATH II echo-substudy included 100 patients who undergone a specific pilot evaluation of echocardiographic. All patients undergone an echocardiography at baseline, ID-patients received a second echocardiography three months after ID replenishment. Results The final study cohort included in the echo-substudy consisted of 98 patients, 41 (42%) were classified in the ID group (TSAT <20%). Regarding the usual definition of ID, 7 patients (15%) in the ID group had TSAT ≥20%, while 4 (7%) in the non-ID group showed TSAT <20%. Mean age was 72±10 years, 22 (22%) were women and most were in NYHA functional class II (71%). Ischemic was the main etiology of HF (50%). The ID group presented worse LV function expressed by LVEF (34% vs. 38%), WW (302[235.5-439,75] mmHg% vs. 209.5[136-297.25] mmHg%) and WE (74±10% vs. 80±10%) (Figure 1). Right ventricle function was also worse in the ID group when measured by fractional area change (FAC) (41.76[33.26-50.33] % vs 46.79[39.23 – 54.94] %) and RV coupling ratio (0.52±0.21 vs 0.64±0.24) but not by TAPSE. Strikingly, no differences were observed in any echocardiographic parameter of myocardial function between the non-ID patients compared with the ID-patients after iron replenishment (Table 1). Conclusions TSAT <20% identified ID status that causes impaired myocardial performance in HF patients. This can be reversed with intravenous iron repletion. This reversible damage to cardiac function can be detected by advanced echocardiographic parameters, both for LV (GLS, WE, MW, WW) and for RV (RVFW strain, RV coupling), but not by LVEF or TAPSE.Figure 1Table 1

Safety of an Accelerated Ferric Gluconate Inpatient Infusion Regimen

Background: Inpatient use of intravenous iron has been increasing. Ferric gluconate is traditionally given once daily. Twice-daily dosing provides faster iron repletion, but there are limited data to support the safety of twice-daily dosing. Objective: The aim of this study was to investigate the safety of twice-daily dosing for ferric gluconate compared with daily dosing. Methods: This was an institutional review board-approved retrospective observational study of hospitalized adult patients who received intravenous ferric gluconate 250 mg daily or twice daily between January 1 and April 3, 2022. The primary composite safety outcome included hypotension, infusion reaction, rapid response alert, or escalation in level of care. Secondary outcomes included total amount of iron received, hospital length of stay, and changes in laboratory values. Results: A total of 126 patients were included in this study, with 63 patients in each group. The primary outcome occurred in 29 patients (46%) in the twice-daily group compared with 36 patients (57.1%) in the daily group (relative risk = 0.81; 95% CI, 0.57-1.13; P = 0.212). Changes in iron, hemoglobin, and transferrin saturation were similar between the 2 groups. Median length of stay was statistically shorter in the twice-daily group (7.79 days) compared with the daily group (12.9 days; p = 0.006). Conclusions: In this retrospective single-center study of hospitalized adult patients, those who received intravenous ferric gluconate twice daily did not experience an increased rate of a composite safety outcome of hypotension, infusion reactions, or escalation in level of care compared with those with daily dosing.

Associations between non-anaemic iron deficiency and outcomes following elective surgery for colorectal cancer: a prospective cohort study.

Iron deficiency is present in up to 75% of patients presenting for colorectal cancer surgery. It is unclear whether iron deficiency without anaemia is associated with worse postoperative outcomes. We hypothesised that, in adults without anaemia undergoing surgery for colorectal cancer, iron deficiency would be associated with worse postoperative outcomes relative to an iron-replete state. We performed a prospective, observational study, recruiting adults (aged ≥ 18 y) without anaemia who were undergoing surgery for colorectal cancer in 16 hospitals across Australia and Aotearoa/New Zealand. Anaemia was defined as a haemoglobin concentration < 130 g.l-1 for men and < 120 g.l-1 for women. Iron deficiency was defined primarily as transferrin saturation < 20%. The primary endpoint was days alive and at home on postoperative day 90. The primary endpoint analysis was adjusted for surgical risk based on recruiting institution; sex; Charlson comorbidity index; CR-POSSUM score; surgical approach; and requirement for neoadjuvant therapy. Of 420 patients, 170 were iron deficient and 250 were iron replete. The median (IQR [range]) days alive and at home in the iron-deficient group was 84.0 (80.7-85.9 [0-88.2]) days and in the iron-replete group was 83.1 (78.7-85.1 [0-88.9]) days. The unadjusted difference in medians between groups was 0.9 (95%CI 0-1.8, p = 0.047) days and the adjusted difference was 0.9 (95%CI 0-1.80, p = 0.042) days, favouring the iron-deficient group. In adult patients without anaemia undergoing surgery for colorectal cancer, iron deficiency defined by transferrin saturation < 20% was not associated with worse patient outcomes and appeared to be associated with more days alive and at home on postoperative day 90.

Effects of iron supplements and iron-containing micronutrient powders on the gut microbiome in Bangladeshi infants: a randomized controlled trial

Anemia is highly prevalent globally, especially in young children in low-income countries, where it often overlaps with a high burden of diarrheal disease. Distribution of iron interventions (as supplements or iron-containing multiple micronutrient powders, MNPs) is a key anemia reduction strategy. Small studies in Africa indicate iron may reprofile the gut microbiome towards pathogenic species. We seek to evaluate the safety of iron and MNPs based on their effects on diversity, composition, and function of the gut microbiome in children in rural Bangladesh as part of a large placebo-controlled randomized controlled trial of iron or MNPs given for 3 months (ACTRN12617000660381). In 923 infants, we evaluate the microbiome before, immediately following, and nine months after interventions, using 16S rRNA gene sequencing and shotgun metagenomics in a subset. We identify no increase in diarrhea with either treatment. In our primary analysis, neither iron nor MNPs alter gut microbiome diversity or composition. However, when not adjusting for multiple comparisons, compared to placebo, children receiving iron and MNPs exhibit reductions in commensal species (e.g., Bifidobacterium, Lactobacillus) and increases in potential pathogens, including Clostridium. These increases are most evident in children with baseline iron repletion and are further supported by trend-based statistical analyses.

A-159 Re-evaluating Ferritin Cutoffs for the Diagnosis of Iron Deficiency and Iron Deficiency Anemia

Abstract Background Iron deficiency (ID) is the most common nutrient deficiency in the world and iron deficiency anemia (IDA) is estimated to affect 1.24 billion people. Serum ferritin is an iron storage protein commonly used as a biomarker for ID and IDA. The ferritin lower limit of normal (LLN) defined in many clinical laboratories is lower than evidence-based cutoffs and may not detect ID and IDA with adequate sensitivity, particularly when sex-based reference intervals (RIs) are used. This may be due in part to the use of asymptomatic, iron-depleted individuals for RI studies. Recent efforts have been made to increase the LLN for ferritin to at least 30 ng/mL and re-evaluate sex based RIs to improve diagnosis of ID and IDA. In this study, we aimed to investigate LLN ferritin cutoffs for ID and IDA in our patient population. Methods Patient data from June 2022-May 2023 were collected with approval from the Institutional Review Board (IRB), including age, sex, and values for ferritin, iron, transferrin saturation, and hemoglobin. Patients were classified as iron replete (IR), ID, or IDA based on measurements for iron, transferrin saturation, and hemoglobin. IR patients were defined as having iron and transferrin saturation values within current RIs, while those below the cutoff were grouped as ID. ID and IDA were further classified based on hemoglobin values. A range of ferritin concentrations between 1 and 100 ng/mL were used to calculate true and false positive rates (TPR and FPR) and diagnostic accuracy (DA). Receiver operator characteristic (ROC) curve and J index analysis were used to define optimal ferritin cutoffs for ID and IDA. Results Data from 26,455 patients (65% female) were used in this study. Conclusions These findings highlight the need to re-examine ferritin RIs in the context of ID/IDA, especially for those patients assigned female at birth.

Differential Effects of Iron Overload and Iron Repletion on Bone and Mineral Metabolism in Growing Mice

Differential Effects of Iron Overload and Iron Repletion on Bone and Mineral Metabolism in Growing Mice

Annotation of DOM metabolomes with an ultrahigh resolution mass spectrometry molecular formula library

Increased accessibility of liquid chromatography mass spectrometry (LC-MS) metabolomics instrumentation and software have expanded their use in studies of dissolved organic matter (DOM) and exometabolites released by microbes. Current strategies to annotate metabolomes generally rely on matching tandem MS/MS spectra to databases of authentic standards. However, spectral matching approaches typically have low annotation rates for DOM. An alternative approach is to annotate molecular formula based on accurate mass and isotopic fine structure measurements that can be obtained from state-of-the-art ultrahigh resolution Fourier Transform Ion Cyclotron Resonance mass spectrometry (FT-ICR MS), but instrument accessibility for large metabolomic studies is generally limited. Here, we describe a strategy to annotate exometabolomes obtained from lower resolution LC-MS systems by matching metabolomic features to a molecular formula library generated for a representative sample analyzed by LC 21T- FT-ICR MS. The molecular formula library approach successfully annotated 53% of exometabolome features of the marine diatom Phaeodactylum tricornutum – a nearly ten-fold increase over the 6% annotation rate achieved using a conventional MS/MS approach. There was 94% agreement between assigned formula that were annotated with both approaches, and mass error analysis of the discrepancies suggested that the FT-ICR MS formula assignments were more reliable. Differences in the exometabolome of P. tricornutum grown under iron replete and iron limited conditions revealed 668 significant metabolites, including a suite of peptide-like molecules released by P. tricornutum in response to iron deficiency. These findings demonstrate the utility of FT-ICR MS formula libraries for extending the accuracy and comprehensiveness of metabolome annotations.

An Electrolytic Elemental Iron Powder Effectively Regenerates Hemoglobin in Anemic Rats and Is Relatively Well Absorbed When Compared to Ferrous Sulfate Monohydrate.

Elemental iron powders are used as food fortificants to reduce the incidence of iron deficiency anemia. However, many commercially available iron powders are relatively untested in vivo. The purpose of this study was to determine the hemoglobin regeneration efficiency (HRE) and relative iron bioavailability (RBV) of an electrolytic elemental iron powder (EIP), by treating anemic rats with 14 d iron repletion diets fortified with four different concentrations (12, 24, 36, or 48 mg iron/kg diet) of EIP and bakery-grade ferrous sulfate monohydrate (FS; FeSO4•H2O), or no added iron (control); n = 9-12/group. The HRE of FS was significantly higher (p ≤ 0.05) than EIP at each concentration of dietary iron tested. For EIP, the HREs (ratios) of diets containing 12, 24, 36, and 48 mg iron/kg were 0.356, 0.205, 0.197, and 0.163, respectively. For both EIP and FS, HRE was inversely associated with increasing dietary iron. The RBVs (%) of iron from EIP in diets at 12, 24, 36, and 48 mg iron/kg as compared to FS were 64.5, 59.1, 50.6, and 54.3%, respectively. Overall, findings show that at the concentrations of iron tested, EIP has RBVs greater than 50% and is an effective fortification agent to replenish hemoglobin and correct iron deficiency anemia.

Thrombocytopenia following iron repletion with ferrous gluconate.

Immune thrombocytopenia (ITP) is an autoimmune disorder marked by low platelet counts that puts patients at risk for spontaneous bleeding. A rare trigger for ITP is iron repletion, which has only been reported in a few cases. In this article, we present a unique case of a 54-year-old male with a history of recurrent ITP who experienced rapid thrombocytopenia following iron repletion with ferrous gluconate. Discontinuation of ferrous medications resulted in platelet counts returning to the normal baseline. Following more than 30 years of the patient's clinical timeline, this case demonstrates the chronic nature of ITP and the complexity of its causes. Further studies are needed to determine the prevalence of iron repletion-induced thrombocytopenia and its underlying mechanisms.

Iron Deficiency in Pulmonary Hypertension.

Pulmonary hypertension (PH) is a complex cardiovascular condition that is characterized by elevated pulmonary arterial pressure, which leads to significant morbidity and mortality. Among the various factors that influence the pathophysiology and progression of PH, iron deficiency has become a critical, yet often overlooked, element. In this review, the prevalence, implications, and therapeutic potential of addressing iron deficiency in patients with PH are elucidated.Iron deficiency, which is prevalent in a significant proportion of patients with PH, has been associated with worsened clinical outcomes, including diminished exercise capacity, impaired oxygen transport and utilization, and compromised right ventricular function. The pathophysiological linkages between iron deficiency and PH are multifaceted and involve alterations in oxygen sensing, endothelial function, and metabolic disturbances.In this review, the evidence from recent clinical trials and studies that assess the impact of iron supplementation, both oral and intravenous, on PH outcomes is critically analyzed. Although some studies suggest improvements in exercise capacity and hemodynamic parameters following iron repletion, the responses appear variable and are not universally beneficial. This review highlights the complexities of iron metabolism in PH and the challenges in effectively diagnosing and treating iron deficiency in this patient population.Furthermore, the potential mechanisms through which iron supplementation might influence pulmonary vascular and right ventricular function, emphasizing the need for personalized treatment approaches are discussed. In this review, the importance of recognizing iron deficiency in the management of patients with PH is highlighted, and further research is warranted to establish comprehensive, evidence-based guidelines for iron supplementation in this unique patient cohort. The ultimate goal of this review is to improve clinical outcomes and quality of life for patients suffering from this debilitating condition.

Iron and cardiovascular health: A review.

Iron is an essential element for the biological processes of living organisms, including the production of crucial oxygen-carrying proteins, formation of heme enzymes, and playing roles in electron transfer and oxidation-reduction reactions. It plays a significant role in various cardiovascular functions, including bioenergetics, electrical activity, and programmed cell death. Minor deficiencies of iron have been found to have negative impact on cardiovascular function in patients with heart failure (HF). The contractility of human cardiomyocytes is impaired by iron deficiency (ID), which results in reduced mitochondrial function and lower energy production, ultimately leading to cardiac function impairment, contributing to significant morbidity and mortality in patients with HF. This review discusses iron homeostasis within the human body, as well as ID pathophysiology and its role in HF. Focusing on therapeutic approaches including iron supplementation and/or repletion in patients with ID and HF, comparing results from recent clinical trials. Intravenous (IV) iron therapy has shown promising results in treating ID in HF patients. Large, randomized trials and meta-analysis, like Ferinject Assessment in patients with ID and chronic HF, AFFIRM-AHF, IRONMAN, and HEART-FID have demonstrated the efficacy of IV iron supplementation with IV ferric carboxymaltose or IV ferric derisomaltose in reducing hospitalizations and improving quality of life in patients with Heart Failure with reduced ejection fraction (HFrEF), New York Heart Association (NYHA) II-III. However, survival and mortality have demonstrated no improvement during acute exacerbations of HF or in outpatient management. The potential benefits of IV iron across the entire HF spectrum and its interaction with other HF therapies remain areas of interest for further research.

Hemoglobin Regeneration Efficiency and Relative Iron Bioavailability of Four Elemental Iron Powders in Rats.

Effective food fortification strategies using elemental iron powders (EIPs) are needed to combat iron deficiency anemia. The purpose of this study was to determine hemoglobin regeneration efficiency (HRE) and relative iron bioavailability (RBV) of four food-grade EIPs (El-Lyte (EL), Hi-Sol (HS), H-325 (H3), and A-131 (A1)) by treating anemic rats with 14 d iron repletion diets (uncooked and cooked), fortified with a 12, 24, or 36 mg iron/kg diet of the EIPs, ferrous sulfate monohydrate (FS, FeSO4•H2O), or no added iron (control), n = 9-12/group. The ability of EL and HS to maintain hemoglobin for 6 weeks on the 6 mg iron/kg diet was also studied. The dissolution rate of iron from the EIPs was measured in hydrochloric acid at pH 1.0. Compared to FS, the EL, HS, and A1 EIPs had >50% overall RBV, with the following order: HS > A1 > EL > H3 (p ≤ 0.05); the effect of cooking was not significant (p > 0.05). Dissolution testing revealed that the mean RBV of the EIPs was positively associated with the percentage of iron solubility. In the 6-week maintenance study, EL and HS maintained hemoglobin as well as FS. Overall, the findings show that at the concentrations of iron tested, these EIPs are effective fortification agents to replenish hemoglobin and correct iron deficiency anemia.

The impact of hematology electronic consultations on the management of iron deficiency.

Delays in the evaluation and treatment of iron deficiency can lead to increased disease-related morbidity and mortality. Electronic consultation (e-consult) is a referral modality that allows providers quicker access to recommendations from a specialist based on electronic chart review. While the use of e-consult is expanding in classical hematology, gaps exist in the understanding of patient outcomes related to its use for iron deficiency. We randomly selected 200 e-consults and 200 traditional referrals from 3,336 hematology referrals for iron deficiency at a single center. The primary outcomes of the retrospective analysis were: time to completion of the referral, and time to treatment with intravenous iron. Secondary outcomes included recurrence of iron deficiency, need for repeat e-consult, conversion to in-person evaluation, and assessment of whether the etiology of iron deficiency was addressed. E-consults significantly reduced the time from referral to intravenous iron repletion (e-consult, 33 days; traditional referral, 68 days; p < .05). Assessment of the underlying etiology occurred in 70.7% of the e-consult encounters compared to 92.5% of traditional referrals (p < .05). These findings highlight advantages of e-consults in improving care delivery in iron deficiency, and identifying gaps that can be improved through practice standardization to ensure equitable, high-value care.

Leading with dysphagia… An unusual view of a common symptom.

Plummer-Vinson syndrome (PVS) is characterized by the classic triad of post-cricoid dysphagia, iron-deficiency anemia and esophageal webs. PVS is commonly found in women of middle age especially in the fourth and fifth decade of life. The prevalence of PVS has decreased due to early detection of iron deficiency and repletion of iron stores. We report a case of a 81-year-old female patient who had a classic presentation of PVS, treated successfully with endoscopic procedure. To our knowledge, the current case is the fourth case of dysphagia related to Plummer-Vinson syndrome reported in an octogenarian in the literature so far. Iron supplementation can resolve dysphagia in many patients, but dilation of esophageal webs may sometimes be required. PVS should be part of the differential diagnosis of sideropenic dysphagia, especially due the risk of pharyngeal and esophageal epidermoid neoplasia.

Iron homeostasis, recycling and vulnerability in the stressed kidney: A neglected dimension of iron-deficient heart failure.

The available evidence suggests that the kidney may contribute importantly to the development of an iron deficiency state in patients with heart failure and may be injured by therapeutic efforts to achieve iron repletion. The exceptional workload of the proximal renal tubule requires substantial quantities of iron for ATP synthesis, which it derives from Fe3+ bound to transferrin in the bloodstream. Following ferrireduction, Fe2+ is conveyed by divalent transporters (e.g. DMT1) out of the endosome of the proximal renal tubule, and highly reactive Fe2+ can be directed to the mitochondria, sequestered safely in a ferritin nanocage or exported through the actions of hepcidin-inhibitable ferroportin. The actions of ferroportin, together with transferrin endocytosis and DMT1-mediated transport, play a key role in the recycling of iron from the tubular fluid into the bloodstream and preventing the loss of filtered iron in the urine. Activation of endogenous neurohormonal systems and proinflammatory signalling in heart failure decrease megalin-mediated uptake and DMT1 expression, and increase hepcidin-mediated suppression of ferroportin, promoting the loss of iron in the urine and contributing to the development of an iron deficiency state. Furthermore, the failure of ferroportin-mediated efflux at the basolateral membrane heightens the susceptibility of the renal tubules to cytosolic excesses of Fe2+, causing lipid peroxidation and synchronized cell death (ferroptosis) through the iron-dependent free radical theft of electrons from lipids in the cell membrane. Ferroptosis is a central mechanism to most disorders that can cause acute and chronic kidney disease. Short-term bolus administration of intravenous iron can cause oxidative stress and is accompanied by markers of renal injury. Experimentally, long-term maintenance of an iron-replete state is accompanied by accelerated loss of nephrons, oxidative stress, inflammation and fibrosis. Intravenous iron therapy increases glomerular filtration rate rapidly in patients with heart failure (perhaps because of a haemodynamic effect) but not in patients with chronic kidney disease, and the effects of intravenous iron on the progression of renal dysfunction in the long-term trials - AFFIRM-AHF, IRONMAN and HEART-FID - have not yet been reported. Given the potential role of dysregulated renal iron homeostasis in the pathogenesis of iron deficiency and the known vulnerability of the kidney to intravenous iron, the appropriate level of iron repletion with respect to the risk of acute and chronic kidney injury in patients with heart failure requires further study.

Critical re-evaluation of the identification of iron deficiency states and effective iron repletion strategies in patients with chronic heart failure.

According to current guidelines, iron deficiency is defined by a serum ferritin level <100 ng/ml or a transferrin saturation (TSAT) <20% if the serum ferritin level is 100-299 μg/L. These criteria were developed to encourage the use of intravenous iron as an adjunct to erythropoiesis-stimulating agents in the treatment of renal anaemia. However, in patients with heart failure, these criteria are not supported by any pathophysiological or clinical evidence that they identify an absolute or functional iron deficiency state. A low baseline TSAT-but not serum ferritin level-appears to be a reliable indicator of the effect of intravenous iron to reduce major heart failure events. In randomized controlled trials, intravenous iron decreased the risk of cardiovascular death or total heart failure hospitalization in patients with a TSAT <20% (risk ratio 0.67 [0.49-0.92]) but not in patients with a TSAT ≥20% (risk ratio 0.99 [0.74-1.30]), with the magnitude of the risk reduction being proportional to the severity of hypoferraemia. Patients who were enrolled in clinical trials solely because they had a serum ferritin level <100 μg/L showed no significant benefit on heart failure outcomes, and it is noteworthy that serum ferritin levels of 20-300 μg/L lie entirely within the range of normal values for healthy adults. Current guidelines reflect the eligibility criteria of clinical trials, which inadvertently adopted unvalidated criteria to define iron deficiency. Reliance on these guidelines would lead to the treatment of many patients who are not iron deficient (serum ferritin level <100 μg/L but normal TSAT) and ignores the possibility of iron deficiency in patients with a low TSAT but with serum ferritin level of >300 μg/L. Importantly, analyses of benefit based on trial eligibility-driven guidelines substantially underestimate the magnitude of heart-failure-event risk reduction with intravenous iron in patients who are truly iron deficient. Based on all available data, we recommend a new mechanism-based and trial-tested approach that reflects the totality of evidence more faithfully than the historical process adopted by clinical investigators and by the guidelines. Until additional evidence is forthcoming, an iron deficiency state in patients with heart failure should be defined by a TSAT <20% (as long as the serum ferritin level is <400 μg/L), and furthermore, the use of a serum ferritin level <100 μg/L alone as a diagnostic criterion should be discarded.

Clinical Usefulness of the serum-Soluble Transferrin Receptor in Iron Dysregulation Associated with long-Term Hemodialysis

Background: Soluble transferrin receptor (sTfR) was reported to be a valuable diagnostic marker for iron dysregulation (ID). Hepcidin, which is a key regulator of iron metabolism, has been shown to have increased values in patients undergoing hemodialysis (HD). Either treatment with erythropoietin stimulating agent（ESA） or iron repletion therapy（IRT）had been reported to induce controversial effect on serum levels between sTfR and hepcidin. Thus, we measured serum levels both of sTfR and hepcidin in 97 HD patients and investigated the clinical value of these measures. Methods: We used a commercial enzyme-linked immunosorbent assay kit to measure serum levels both of hepcidin and sTfR. Results: Although serum sTfR levels did not clearly increase, both sTfR levels and its index value correlated with the saturation of transferrin, erythropoietin-stimulating agent dosage, and erythropoietin resistance index (ERI). In addition, a strong negative correlation was found for sTfR and log serum hepcidin values. Conclusions: Serum sTfR levels and the sTfR index were acceptable markers for iron dysregulation (ID) and ERI even in patients undergoing HD whose serum levels of hepcidin increased.

WCN24-1211 To determine the effectiveness of Lactoferrin in improving Anemia in iron replete CKD patients

WCN24-1211 To determine the effectiveness of Lactoferrin in improving Anemia in iron replete CKD patients