Iron Deficiency Research Articles

Iron deficiency in new onset heart failure: association with clinical factors and quality of life.

The prevalence of iron deficiency (ID) in newly diagnosed heart failure (HF) and the progression of ID in patients after initiation of HF therapy are unknown. We aimed to describe the natural trajectory of ID in patients with new onset HF during the first year after HF diagnosis, assessing associations between ID, clinical factors, and quality of life (QoL). A prospective cohort of patients with new onset HF in hospitals or outpatient clinics at five major hospitals in Stockholm, Sweden, during 2015-2018 were analysed with clinical assessment, electrocardiogram, blood samples including iron levels, Minnesota living with heart failure questionnaire (MLHFQ), and echocardiogram at baseline and after 12months. Of 547 patients with new-onset HF, 482 (88%) had complete iron data at baseline. Mean age was 70years (interquartile range 61-77) and 311 (65%) were men; 55% of patients had ejection fraction (EF)≤40%, 19% had EF 41-49%, and 26% had HF with preserved EF (HFpEF). At baseline, 163 patients (34%) had ID defined as ferritin <100μg/L or ferritin 100-299μg/L and transferrin saturation <20%. After 12months of follow-up, 119 (32%) had ID of the 368 patients who had complete iron data both at baseline and after 12months and did not receive intravenous (i.v.) iron during follow-up. During the first year after HF diagnosis, 19% had persistent ID, 13% developed ID, 11% resolved ID, and 57% never had ID, consequently 24% changed their classification. Anaemia at baseline was the strongest independent predictor of ID 1year after diagnosis [odds ratio (OR) 3.91, 95% confidence interval (CI) 1.88-8.13, P<0.001], followed by HF hospitalization (OR 2.21, 95% CI 1.24-3.95, P<0.01), female sex (OR 2.04, 95% CI 1.25-3.32, P<0.01), HFpEF (OR 1.96, 95% CI 1.13-3.39, P<0.05), and diabetes mellitus (OR 1.92, 95% CI 1.06-3.48, P<0.05). ID was associated with low QoL at baseline (MLHFQ score mean difference 7.4 points, 95% CI 3.1-11.7, P<0.001), but not at follow-up. About one third of patients with new onset HF had ID both at the time of HF diagnosis and after 1year, though a quarter of the patients changed their ID status. Patients with anaemia, HF hospitalization, female gender, HFpEF, or diabetes mellitus at baseline were more likely to have ID after 1year implying that these should be carefully screened for ID to find those in need of i.v. iron treatment.

Physiologically based trimester-specific serum ferritin thresholds for iron deficiency in US pregnant women

AbstractSerum ferritin (SF) concentration is the most widely used indicator for iron deficiency (ID). During pregnancy, the World Health Organization recently recommended SF thresholds for ID of <15 μg/L for the first trimester of pregnancy, based on expert opinion, and made no recommendations for the second and third trimesters. We examined the relationship of SF with 2 independent indicators of the onset of iron-deficient erythropoiesis, hemoglobin and soluble transferrin receptor 1, in cross-sectional data from US National Health and Nutrition Examination Survey for 1999 to 2010 and 2015 to 2018. We included 1288 pregnant women aged 15 to 49 years and excluded women with inflammation or potential liver disease. We used restricted cubic spline (RCS) regression analysis to determine SF thresholds for iron-deficient erythropoiesis. SF decreased during pregnancy; geometric mean SF was higher during the first and lower during the second and third trimesters. Using RCS analysis, the SF thresholds identified during pregnancy were <25.8 μg/L (18.1-28.5) during first trimester, <18.3 μg/L (16.3-22.9) during second trimester, and <19.0 μg/L (14.4- 26.1) during third trimester. These SF threshold levels track concentrations of hepcidin, the iron-regulatory hormone controlling the mobilization of iron stores. An SF concentration of <15 μg/L as the criterion for ID may underestimate the true prevalence of ID throughout pregnancy. In our study, an additional 1 of every 10 pregnant women would be recognized as iron deficient by using the physiologically based thresholds at SF of ∼25 μg/L during the first and ∼20 μg/L during the second and third trimesters.

Enteral Nutrition in Operated-On Gastric Cancer Patients: An Update.

It is well established that the preoperative nutritional status of gastric cancer (GC) patients significantly affects the prognosis of the operated patients, their overall survival, as well as the disease-specific survival. Existing data support that preoperative assessment of nutritional status and early correction of nutritional deficiencies exert a favorable effect on early postoperative outcomes. A variety of relevant indices are used to assess the nutritional status of GC patients who are candidates for surgery. The guidelines of almost all international organizations recommend the use of oral enteral nutrition (EN). Oncologically acceptable types of gastrectomy and methods of patient rehabilitation should take into account the expected postoperative nutritional status. The majority of data support that perioperative EN reduces complications and hospital stay, but not mortality. Oral EN in the postoperative period, albeit in small amounts, helps to reduce the weight loss that is a consequence of gastrectomy. Iron deficiency with or without anemia and low serum levels of vitamin B12 are common metabolic sequelae after gastrectomy and should be restored. EN also significantly helps patients undergoing neoadjuvant or adjuvant antineoplastic therapy. The occurrence of the so-called "postgastrectomy syndromes" requires dietary modifications and drug support. This review attempts to highlight the benefits of EN in GC patients undergoing gastrectomy and to emphasize the type of necessary nutritional management, based on current literature data.

Advance in Iron Metabolism, Oxidative Stress and Cellular Dysfunction in Experimental and Human Kidney Diseases.

Kidney diseases pose a significant global health issue, frequently resulting in the gradual decline of renal function and eventually leading to end-stage renal failure. Abnormal iron metabolism and oxidative stress-mediated cellular dysfunction facilitates the advancement of kidney diseases. Iron homeostasis is strictly regulated in the body, and disturbance in this regulatory system results in abnormal iron accumulation or deficiency, both of which are associated with the pathogenesis of kidney diseases. Iron overload promotes the production of reactive oxygen species (ROS) through the Fenton reaction, resulting in oxidative damage to cellular molecules and impaired cellular function. Increased oxidative stress can also influence iron metabolism through upregulation of iron regulatory proteins and altering the expression and activity of key iron transport and storage proteins. This creates a harmful cycle in which abnormal iron metabolism and oxidative stress perpetuate each other, ultimately contributing to the advancement of kidney diseases. The crosstalk of iron metabolism and oxidative stress involves multiple signaling pathways, such as hypoxia-inducible factor (HIF) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. This review delves into the functions and mechanisms of iron metabolism and oxidative stress, along with the intricate relationship between these two factors in the context of kidney diseases. Understanding the underlying mechanisms should help to identify potential therapeutic targets and develop novel and effective therapeutic strategies to combat the burden of kidney diseases.

Interactions between the nitrogen-fixing cyanobacterium Trichodesmium and siderophore-producing cyanobacterium Synechococcus under iron limitation.

As diazotrophic cyanobacteria of tremendous biomass, Trichodesmium continuously provide a nitrogen source for carbon-fixing cyanobacteria and drive the generation of primary productivity in marine environments. However, ocean iron deficiencies limit growth and metabolism of Trichodesmium. Recent studies have shown the co-occurrence of Trichodesmium and siderophore-producing Synechococcus in iron-deficient oceans, but whether siderophores secreted by Synechococcus can be used by Trichodesmium to adapt to iron deficiency is not clear. We constructed a mutant Synechococcus strain unable to produce siderophores to explore this issue. Synechococcus filtrates with or without siderophores were added into a Trichodesmium microbial consortium consisting of Trichodesmium erythraeum IMS 101 as the dominant microbe with chronic iron deficiency. By analyzing the physiological phenotype, metagenome, and metatranscriptome, we investigated the interactions between the nitrogen-fixing cyanobacterium Tricodesmium and siderophore-producing cyanobacterium Synechococcus under conditions of iron deficiency. The results indicated that siderophores secreted by Synechococcus are likely to chelate with free iron in the culture medium of the Trichodesmium consortium, reducing the concentration of bioavailable iron and posing greater challenges to the absorption of iron by Trichodesmium. These findings revealed the characteristics of iron-competitive utilization between diazotrophic cyanobacteria and siderophore-producing cyanobacteria, as well as potential interactions, and provide a scientific basis for understanding the regulatory effects of nutrient limitation on marine primary productivity.

Mitochondrial iron deficiency triggers cytosolic iron overload in PKAN hiPS-derived astrocytes

Disease models of neurodegeneration with brain iron accumulation (NBIA) offer the possibility to explore the relationship between iron dyshomeostasis and neurodegeneration. We analyzed hiPS-derived astrocytes from PANK2-associated neurodegeneration (PKAN), an NBIA disease characterized by progressive neurodegeneration and high iron accumulation in the globus pallidus. Previous data indicated that PKAN astrocytes exhibit alterations in iron metabolism, general impairment of constitutive endosomal trafficking, mitochondrial dysfunction and acquired neurotoxic features. Here, we performed a more in-depth analysis of the interactions between endocytic vesicles and mitochondria via superresolution microscopy experiments. A significantly lower number of transferrin-enriched vesicles were in contact with mitochondria in PKAN cells than in control cells, confirming the impaired intracellular fate of cargo endosomes. The investigation of cytosolic and mitochondrial iron parameters indicated that mitochondrial iron availability was substantially lower in PKAN cells compared to that in the controls. In addition, PKAN astrocytes exhibited defects in tubulin acetylation/phosphorylation, which might be responsible for unregulated vesicular dynamics and inappropriate iron delivery to mitochondria. Thus, the impairment of iron incorporation into these organelles seems to be the cause of cell iron delocalization, resulting in cytosolic iron overload and mitochondrial iron deficiency, triggering mitochondrial dysfunction. Overall, the data elucidate the mechanism of iron accumulation in CoA deficiency, highlighting the importance of mitochondrial iron deficiency in the pathogenesis of disease.

Hyperspectal imaging technology for phenotyping iron and boron deficiency in Brassica napus under greenhouse conditions

IntroductionThe micronutrient deficiency of iron and boron is a common issue affecting the growth of rapeseed (Brassica napus). In this study, a non-destructive diagnosis method for iron and boron deficiency in Brassica napus (genotype: Zhongshuang 11) using hyperspectral imaging technology was established.MethodsThe recognition accuracy was compared using the Fisher Linear Discriminant Analysis (LDA) and Support Vector Machine (SVM) recognition models. Recognition results showed that Multiple Scattering Correction (MSC) could be applied for the full band hyperspectral data processing, while the LDA models presented better performance on establishing the leaf iron and boron deficiency symptom recognition than the SVM models.ResultsThe recognition accuracy of the training set reached 96.67%, and the recognition rate of the prediction set could be 91.67%. To improve the model accuracy, the Competitive Adaptive Reweighted Sampling algorithm (CARS) was added to construct the MSC-CARS-LDA model. 33 featured wavelengths were selected via CARS. The recognition accuracy of the MSC-CARS-LDA training set was 100%, while the recognition accuracy of the MSC-CARS-LDA prediction set was 95.00%.DiscussionThis study indicates that, it is capable to identify the iron and boron deficiency in rapeseed using hyperspectral imaging technology.

Management of iron deficiency anemia during pregnancy: a midwife-led continuity of care model

BackgroundGlobally, 36.5% of pregnancies are affected by anemia, particularly in low-and middle-income countries, posing significant risks to maternal and perinatal health. In rural Pakistan, 44.3% of pregnant women suffer from iron deficiency, contributing to the high prevalence of anemia. Limited accessibility to antenatal care exacerbates the challenge, necessitating innovative solutions. This study assessed a midwife-led continuity of care model, utilizing intravenous (IV) iron therapy for the management of anemia in Karachi, Pakistan.MethodsWe performed a retrospective analysis of data from a prospective cohort study conducted in two primary healthcare facilities, which employed a community midwife (CMW)-led continuity of care model for antenatal care, including IV iron therapy. We extracted data from February 2021 to March 2022 for women who were diagnosed with anemia based on hemoglobin (Hb) levels, categorized as mild (10.0 to 10.9 g/dL), moderate (7.0 to 9.9 g/dL), or severe (less than 7.0 g/dL). Assessment occurred at the initial antenatal care (ANC) visit to establish baseline anemia severity, and approximately 2 weeks after intravenous (IV) iron therapy administration to evaluate post-treatment changes were considered.ResultsWe enrolled 114 pregnant women, where the majority presented with moderate (88.6%) anemia. After IV iron treatment, 48.5% improved to normal-mild levels, while 50% remained unchanged. Severe anemia affected 10.5% at baseline; 42% shifted to moderate and 50% to normal-mild post-treatment, with one remaining unchanged (p &amp;lt; 0.001). Among women enrolled in the first and second trimesters, severe anemia improved to normal-mild (50%) and moderate levels (50%) (pre-treatment: n = 10, post-treatment: n = 0), and moderate anemia decreased by 48% (pre-treatment: n = 92, post-treatment: n = 47).ConclusionOur midwife-led model of care demonstrated an improvement in iron levels among pregnant women. The model addressed the challenges of anemia prevalence in Pakistan and underscored the significance of empowering front-line healthcare providers, such as community midwives (CMWs) for managing these common conditions.

Sleep disorders in chronic kidney disease.

Sleep disorders are highly prevalent in chronic kidney disease (CKD) but are often under-recognized. Restless legs syndrome, which is common in CKD owing to issues with dopamine metabolism and is exacerbated by iron deficiency and uraemia, can lead to poor sleep quality and increased daytime fatigue. Insomnia is also prevalent in CKD, particularly in patients requiring dialysis, with increased sleep latency and sleep fragmentation being reported. The cause of insomnia in CKD is multifactorial - poor sleep habits and frequent napping during dialysis, uraemia, medications and mood disorders have all been suggested as potential contributing factors. Sleep apnoea and CKD are also now recognized as having a bi-directional relationship. Sleep apnoea is a risk factor for accelerated progression of CKD, and fluid overload, which is associated with kidney failure, can lead to both obstructive and central sleep apnoea. The presence of obstructive sleep apnoea in CKD can exacerbate the already heightened cardiovascular morbidity and mortality in these patients, as well as leading to daytime fatigue and reduced quality of life. Increased awareness, timely diagnosis and appropriate therapeutic interventions are essential to reduce the negative impact of sleep disorders in patients with kidney disease.

Efficacy and safety of Ferrous iron on the prevention of Vascular cOgnitive impaiRment among patients with cerebral Infarction/TIA (FAVORITE): rationale and design of a multicentre randomised trial

BackgroundThe incidence of vascular cognitive impairment (VCI) is high in patients suffering from ischaemic stroke or transient ischaemic attack (TIA) or with vascular risk factors. Effective prevention strategies for VCI...

Chronic autoimmune gastritis and its relation to megaloblastic anemia – Main histopathological and pathophysiological characteristics

Chronic autoimmune gastritis is a sustained inflammation of the stomach, characterized by being immunologically mediated against intrinsic factor-producing parietal cells, leading to nutritional deficiencies that may result in anemia. This study investigates the prevalence and underlying mechanism of anemia in patients with chronic autoimmune gastritis, focusing on iron deficiency anemia and megaloblastic anemia due to vitamin B12 deficiency. A bibliographic review was carried out on the subject, in databases of scientific relevance and verified by peers, whose inclusion criteria allowed only studies relevant to the subject, published in the last five years, which establish a relationship with chronic autoimmune gastritis and anemia. Thus, the exclusion criteria left out studies on chronic gastritis due to other etiologies, those cases not related to anemia, or other studies not relevant to the general objective. In the pathophysiological framework, there is an autoimmune destruction of gastric parietal cells, which leads to a reduction in the secretion of hydrochloric acid and intrinsic factor, essential for the absorption of vitamin B12 and iron, predisposing to iron deficiency and megaloblastic anemia. Histological examination reveals gastric atrophy with loss of glands, lymphocytic infiltration, and presence of plasma cells. Symptoms include dyspepsia, loss of appetite and loss of appetite.

The temporal trends of prevalence and years lived with disability of anaemia in China, Japan, and South Korea, from 1990 to 2021: Results from the Global Burden of Disease Study 2021.

Studies have shown that the disease burden of anaemia varies globally, yet they have not yet determined its exact extent in East Asian countries specifically. We thus aimed to investigate the prevalence and years lived with disability (YLDs) due to anaemia from 1990 to 2021 in China, Japan, and South Korea. We extracted the prevalence and YLDs with their age-standardised rates (ASRs) in China, Japan, and South Korea from the Global Burden of Disease Study 2021, stratified by sex, age, and causes. We then examined the temporal trend of anaemia burden from 1990 to 2021 using joinpoint analysis and the association of anaemia burden with the Human Development Index and Universal Health Index through Spearman's correlation analysis. In 2021, anaemia affected 136 million people in China (95% uncertainty interval (UI) = 131, 141), with ASRs of prevalence of 8.9% (95% UI = 8.6, 9.3), and accounted for 3.0 million YLDs (95% UI = 2.0, 4.4). It affected 13.6 million people in Japan (95% UI = 11.8, 16.0), with ASRs of prevalence of 7.4% (95% UI = 6.1, 9.0), and caused 181 thousand YLDs (95% UI = 108, 282). It also affected 2.7 million individuals in South Korea (95% UI = 2.4, 3.0), with ASRs of prevalence of 5.2% (95% UI = 4.6, 5.7), and led to 34 thousand YLDs (95% UI = 22, 55). We observed a significant gender discrepancy in the anaemia burden in these three countries, with the prevalence and YLD rates in women being almost twice as high as those in men. Moreover, the peak age of the anaemia burden shifted toward higher age groups in all three countries, particularly in Japan. Chronic kidney disease was responsible for a growing share of anaemia cases and YLDs, especially in adults aged more than 60 years in Japan and South Korea. Haemoglobinopathies were another noticeable cause of anaemia in China, though dietary iron deficiency remained the leading cause. Both socioeconomic development and essential health service coverage showed negative associations with the anaemia burden in the three countries in the past three decades, though with differential patterns. Anaemia remains a major public health issue in China, Japan, and South Korea; targeted surveillance and interventions are recommended for high-risk populations and cause-specific anaemia.

#1078 Prevalence of iron deficiency in patients admitted to a geriatric unit: analysis according to the stages of chronic kidney disease

Abstract Background and Aims Iron deficiency (ID) is a poor prognostic factor in chronic diseases such as chronic kidney disease (CKD). Indeed, independently of anemia, ID is associated with more rapid clinical worsening of CKD and is a risk factor for mortality in this condition. In older patients, CKD is common and often associated with other comorbidities. Method The CARENFER PA study is a national multicenter study designed to evaluate ID in older patients (&amp;gt;75 years) newly hospitalized in a geriatric unit. The primary endpoint was the prevalence of ID, defined as serum ferritin &amp;lt; 100 µg/L and/or transferrin saturation coefficient (TSAT) &amp;lt;20%. Absolute ID was defined as serum ferritin &amp;lt; 100 µg/L and functional ID as serum ferritin ≥ 100 µg/L and TSAT &amp;lt; 20%. In this analysis, we explored ID prevalence according to the degree of CKD. The Short Physical Performance Battery (SPPB) test was used to identify older patients at high risk of adverse events (e.g., disability, falls, hospitalization, death). Results 888 patients (mean age, 85.2 years; women, 63.5%) from 16 French centers were analyzed. Stages of CKD were: stage I, 3.8%; II, 53.2%; IIIa, 22.3%; IIIb, 13.3%; IV, 6.0% and V, 1.4%. ID prevalence in the entire cohort was 57.6% (495/859). When present, ID was absolute in 56.2% (278/495) of cases and functional in 43.8% (217/495). ID prevalence was 54.3% (265/488) in patients with stages I-II, and 61.9% (227/367) in patients with stages III-V (p = 0.0271). In the subgroup of anemic patients, ID prevalence was 58.9% (112/190) and 65.9% (147/223), respectively (p = 0.14). We assessed, according to the stages of CKD, various factors likely to affect or be associated with ID. Thus, in patients with at least three comorbidities, ID prevalence was 56.9% (74/130) in patients with stages I-II and 64.8% (142/219) with stages III-V (p = 0.14); in patients with heart failure, ID was present in 63.2% (36/57) and 60.3% (76/126), respectively (p = 0.71). If patients received treatments with possible effect on ID/anemia (e.g., anticoagulant, proton pump inhibitors, platelet antiaggregant), ID prevalence was 58.4% (192/329) for stages I-II and 62.7% (188/300) for stages III-V (p = 0.27). In patients with CRP ≥ 12 mg/L, ID prevalence was 73.8% (96/130) and 72.2% (117/162), respectively (p = 0.76). In univariate analysis of the entire cohort, degree of CKD (stages III-V vs. I-II), at least three comorbidities, CRP ≥ 12 mg/L, anemia and low serum albumin were significantly associated with ID. In multivariate analysis, CRP ≥ 12 mg was the only independent predictor of ID (odds ratio, 2.78; 95% CI, 1.92–4.08; p &amp;lt; 0.0001). In patients with stages I-II, physical performances were poor (SPPB score 0-6) in 44.5% (77/173) of patients without ID and 57.5% (119/207) with ID; in patients with stages III-V, SPPB scores were low in 55.6% (60/108) of patients without ID and 63.5% (106/167) with ID. Conclusion ID prevalence is high (over half of patients) in older patients admitted to a geriatric unit—particularly those with CKD—and is associated with inflammation and a low SPPB score. These new data underline the importance of more systematic screening for ID in older patients. Future randomized controlled trials should evaluate the efficacy of iron supplementation on the outcome of older patients with ID.

#686 The impact of Ferric Derisomaltose (FDI) on role physical functioning in iron deficient but not anaemic patients with chronic kidney disease

Abstract Background and Aims Chronic kidney disease (CKD) is a progressive disorder affecting physiological function, specifically iron deficiency. Iron is crucial for red blood cell production, oxygen transport, mitochondrial function, and cardiac function. Iron deficiency in patients with CKD results from decreased absorption and mobilization, which leads to anaemia, reduced functional capacity, increased cardiac risk, and poorer quality of life. The Iron and the Heart Trial investigated whether correcting iron deficiency in CKD patients (using a single dose of 1000 mg of intravenous (IV) ferric derisomaltose (FDI)) improved functional capacity, as measured by the six-minute walk test, and health-related quality of life (HRQoL) outcomes, including Physical and Mental Health. The SF-36v2 Health Survey tool was used to quantify HRQoL outcomes. Patients identify that whilst clinical outcomes such as survival and functional capacity are important; HRQoL and the symptoms associated with disease burden are far more debilitating. Currently research on how Role Physical functioning, which assesses limitations in routine activities, affects QoL in people with CKD and iron deficiency is limited. This study aimed to explore if correcting iron deficiency in people with CKD without anaemia using IV FDI, improved Role Physical outcomes compared to a placebo group post-infusion at 3 months from the Iron and Heart Trial. Method The Iron and the Heart Trial was a multicentre double blinded randomised study in which non-anaemic CKD patients with iron deficiency were given 1000 mg of IV iron (FDI), compared to a placebo infusion at baseline, and assessed at 1 month and 3-months post-infusion, to evaluate the impact on exercise capacity. Secondary objectives of the trial included impact of iron therapy on QoL. This analysis focused on “Role Physical” as a QoL parameter in the trial participants. A total of 54 CKD patients with iron deficiency but no anaemia (Group 1) were enrolled in the trial and randomly assigned in a 1:1 ratio to either the FDI or placebo group. Within the 54 patients, 26 patients received FDI, and 28 patients received placebo. 10 CKD patients without anaemia or iron deficiency (Group 2) were also included, they did not receive any treatment and were followed up at the same time points as Group 1. Each group completed the Role Physical parameter of the SF-36v2 survey which assessed if participants had cut down the amount of time spent on activities, accomplished less, were limited, or performed tasks with more difficulty because of their condition. The collected responses were categorical variables that were summarised using number (%) and then normalised and summarised using mean (standard deviations). All analyses were undertaken using Microsoft Excel. Results At baseline the Role Physical means (SD) were as follows: placebo 42.8 ± 11.9, FDI 42.1 ± 11.0, Group 2 45.9 ± 9.4. Prior to any intervention, mean Role Physical outcomes were numerically poorer in those with CKD and iron deficiency (placebo and FDI) compared to those with CKD and no iron deficiency (Group 2) (Fig. 1a). Following intervention at 3 months the mean (SD) scores for each group were—placebo 37.5 ± 14.6, FDI 40.9 ± 11.4, Group 2 44.0 ± 13.2. The placebo group experienced a decrease of 12.3% in the mean score for Role Physical outcomes in comparison to their baseline whilst, FDI group only experienced a 3% decrease. For Group 2, there was a decrease of 4% from baseline to 3 months (Fig. 1b). Conclusion Our study showed that while FDI may not improve QoL outcomes, Role Physical functioning, in individuals with CKD and iron deficiency, it may still play a role in slowing the deterioration of these outcomes. Caution must be exercised when interpreting our findings due to the limitations of our study, and further research with sufficient power is needed to extend the findings of the study with a larger sample size to be able to make treatment recommendations for individuals with CKD and iron deficiency.

#2437 Association between iron deficiency and risk of major events in chronic kidney disease—CKD-REIN Cohort

Abstract Background and Aims Iron deficiency (ID) is common in patients with chronic kidney disease (CKD) but remains under-diagnosed and its prognosis poorly documented in the absence of anemia. Data from CKDopps showed low TSAT levels were associated with increased risk of all-cause mortality and incidence of major cardiovascular events in patients with moderate to advanced CKD, an effect that was not modified by the presence of anemia [1]. Additionally, patients with both low TSAT and high ferritin levels displayed the highest risk of all-cause mortality. The aim of the study was to assess the relationship between ID and the risk of major adverse outcomes in patients with CKD in France. Method Using data from the French CKD-REIN cohort which included and followed over 5 years, 3,033 nephrology outpatients with CKD stage 2 to 5 CKD [2], we estimated the prevalence of ID, defined by a ferritin level &amp;lt; 100 mg/L and/or a transferrin saturation (TSAT) &amp;lt; 20%, and associated hazard ratios (HR) of kidney failure with replacement therapy, kidney failure defined by an eGFR &amp;lt; 15 ml/min per 1.73 m2 or initiation of kidney replacement therapy, all-cause mortality, all-cause hospitalization and death or hospitalization for heart failure. The analysis was conducted using a Cox model in which ID was included as a time-dependent variable and adjusted for identified confounders (socio-demographic characteristics, comorbidities, and biological measures) and hemoglobin level. Results A total of 2 914 patients with at least one ferritin or TSAT measurement at baseline or during follow-up were included in the analysis. The majority were men (66%), with a mean age of 67 ± 13 years; 49.6%, 41.2%, and 9.2%, had CKD stage 2/3, 4, and 5, respectively. Baseline prevalence of ID in the cohort was 50% [48-52]. Mean hemoglobin was 13 ± 1.7 g/dL, and only 31% of patients with ID also had a hemoglobin &amp;lt; 12 g/dL. Of the 2 914 patients included in the analysis, 627 (22%) required dialysis or transplantation, and 382 (13%) died before kidney replacement therapy. The incidence rate of kidney failure with replacement therapy was 6.76 versus 3.53 per 100 person-years in patients with and without ID. ID was associated with significant increased risk of kidney failure with replacement therapy, with adjusted HRs for confounders and hemoglobin level of 1.51 [1.24-1.82] (Fig. 1). A total of 836 patients (29%) progressed to kidney failure during the study period, and 341 (12%) died before this stage. The incidence rate of kidney failure was 8.66 versus 6.43 per 100 person-years in patients with and without ID. ID was associated with significant increased risk of kidney failure, with adjusted HRs for confounders and hemoglobin level of 1.19 [1.02-1.38] (Fig. 1). Adjusted HRs for all-cause mortality, for all-cause hospitalization, and for hospitalization or death for heart failure, were 1.31 [1.04-1.66], 1.04 [0.93-1.15], and 1.38 [1.07-1.80], respectively (Fig. 2). Conclusion This study confirms that ID is common in patients with CKD and shows that ID is significantly associated with the risk for kidney failure, all-cause mortality, and heart failure, independent of the presence of anemia. An intervention trial would be needed to assess whether correction of this ID in CKD patients is associated with a reduction in associated risks.

#1546 Mitochondrial oxidative phosphorylation in human proximal tubular epithelial cells is impaired by iron deficiency

Abstract Background and Aims We recently reported that iron deficiency may precede decline in renal function in patients with diabetes who had normal renal function at baseline but had a subsequent annual rate of eGFR decline of 3.3% or more (J Diabetes Investig. 2023;14:874-882.). Mitochondria contain many mitochondrial respiratory chain (MRC) enzymes that require iron as an active center, and consequently iron deficiency is known to impair mitochondrial function. Since the proximal tubular epithelial cells (PTECs) of the kidney are the cells with the greatest number of mitochondria in the body, we investigated whether iron deficiency impairs the mitochondrial capacity of the PTECs. Method Human cultured PTECs were analyzed in ‘control group’, ‘iron-deficient group ‘(co-cultured with deferiprone (DFP), an iron chelator), and ‘rescue group’ (co-cultured with DFP and FeCl3 which saturates the chelating ability of DFP), each with n ≥ 4 (MRC activities n = 4-5, others n ≥ 5). All analyses were performed after 24 hours of incubation. Values are shown as averages ± SEM. Results A Seahorse Extracellular Flux Analyzer showed that the basal oxygen consumption rates (OCRs) of control, iron-deficiency and rescue groups were 30.5 ± 1.2 pmol/min, 11.5 ± 0.7 pmol/min, and 31.1 ± 1.2 pmol/min, respectively, which revealed that basal OCRs of PTECs significantly decreased in the iron-deficient group. In addition, the analyzer also revealed that the activities of MRC for complexes I, II, and III, which have iron-sulfur clusters as their active centers, were significantly decreased in citrate synthase ratio to 77.6 ± 6.2%, 75.1 ± 6.4%, and 72.8 ± 9.3% of the control group, respectively, while complex IV was not significantly different at 84.9% of the control group. These reductions in MRC activities were not observed in the rescue group. Western blotting results also revealed that complex I, II, and III subunit proteins, NDUF9, SDHA, and UQCR2, were significantly reduced in the iron-deficient group (reduced to 38 ± 5.8%, 87 ± 8.8%, and 55 ± 5.7% of the control group, respectively). On the other hand, lactate concentrations in the culture medium of control group, iron-deficient group and rescue group were 1.73 ± 0.13 mmol, 3.01 ± 0.15 mmol and 1.61 ± 0.12 mmol, which revealed that glycolytic system was increased in the iron-deficient group, presumably to compensate for decreased oxidative phosphorylation. In response to intracellular iron deficiency, the iron regulatory protein 2 (IRP2) was shown in Western blotting to be unchanged in the rescue group (123 ± 4.0% of the control group), but increased in the iron-deficient group (170 ± 20% of the control group). The qRT-PCR analyses showed that mRNA expression of iron-sulfur cluster assembly enzyme (ISCU) was significantly decreased in the iron-deficiency group compared with the control group (41.8%), but not in the rescue group (95.1%), which is presumed that IRP2 suppressed ISCU expression, as has been proved previously. These results should indicate that iron deficiency suppressed iron utilization in the mitochondria of PTECs. The number of viable PTECs in the iron-deficient group after 24 hours was 1.99 ± 0.09 × 10^5 cells/well, which was significantly lower than that of the control (3.15 ± 0.15 × 10^5 cells/well) and rescue (2.68 ± 0.18 × 10^5 cells/well) groups. On the other hand, the number of dead PTECs was 0.042 ± 0.019 × 10^5 cells in the iron-deficient group, which was not significantly different from the control (0.023 ± 0.005 × 10^5 cells) and the rescue (0.020 ± 0.011 × 10^5 cells) groups. These data suggest that cell growth should be suppressed by iron deficiency. Conclusion Mitochondrial oxidative phosphorylation through the MRC was impaired by iron deficiency in PTECs. This impairment of mitochondrial capacity in PTECs may lead to PTECs dysfunction, potentially inducing renal damage such as cell death and interstitial injury. Further analysis of the effects of this mitochondrial dysfunction on ATP production capacity and reactive oxygen species production is needed.

#2264 Efficacy and safety of oral iron supplementation with liposomal iron in non-dialysis chronic kidney disease patients with iron deficiency

Abstract Background and Aims Iron deficiency (ID) is very common in patients with non-dialysis dependent chronic kidney disease (NDD-CKD). In these patients, oral iron supplementation is recommended as first-line treatment for ID. However, the efficacy of oral iron supplementation is frequently impaired by a higher incidence of adverse gastrointestinal side effects. Liposomal iron is a compound with ferric pyrophosphate enclosed in a phospholipid nucleus, providing high gastrointestinal absorption and bioavailability and a lower incidence of side effects. However, few data are available on its efficacy in patients with NDD-CKD. Method This single-arm pilot study was carried out in in patients with NDD-CKD stages 1-5 and ID, defined as serum ferritin (SF)&amp;lt;100 ng/mL and/or transferrin saturation (TSAT)&amp;lt; 20%, consecutively seen in two Nephrology units (Naples and Bari) from 01/12/2022 to 01/04/2023. We assessed the efficacy of six months of liposomal iron therapy in correcting ID across three visits after baseline (month 1, 3 and 6). All patients received liposomal iron (30 mg/day twice daily for the first month followed by 30 mg daily for the remaining five months). The primary endpoints were the achievement of SF ≥100 ng/mL and TSAT ≥20%. Secondary outcomes were hemoglobin (Hb) changes and safety of liposomal iron; adherence to the iron supplementation was assessed by monthly pill counting. Changes of continuous variables during the study were analyzed by linear mixed models assuming an unstructured covariance matrix; this was done to take into account the correlation between repeated measures and missing points for patients not completing the study. Change of prevalence of corrected SF and TSAT values from baseline to month 1, 3 and 6 was analyzed by McNemar test. Results 38 patients (65.3 ± 15.2 years, 52.6% males, 35.1% diabetes, eGFR 38.5 ± 28.8 mL/min/1.73 m2) received at least one dose of liposomal iron (safety population). Efficacy population included 34 patients with at least one control visit after baseline. Clinical characteristics of patients enrolled in the two clinics did not differ. In efficacy population, baseline SF was 44 (IQR 19-82) ng/mL and TSAT 14.3 ± 5.9%, corresponding to a percentage of SF&amp;lt;100 ng/mL of 78.9%, and TSAT&amp;lt;20% in 89.5%; 64.7% had both parameters below the cut-offs. Anemia (defined as Hb&amp;lt;12 g/dL in women and &amp;lt;13 g/dL in men) was detected in 22/34 patients. Liposomal iron induced a progressive increase of TSAT from 14.3 ± 5.9%, at baseline to 20.0 ± 7.6% at month-6 (P = 0.009) whereas no difference was detected for SF (Fig. 1A and 1C). Accordingly, at the end of study, the prevalence of TSAT&amp;gt;20% significantly increased from 11.8% to 50.0% (P = 0.002) while correction of SF, mildly improved (from 23.5% to 30.0%, P = 0.214, Fig. 1B and 1D). When patients were stratified by anemia, a significant improvement of TSAT was observed in anemic patients (from 13.3 ± 5.8% to 20.2 ± 8.1%, P = 0.012), whereas no significant improvement was found in patients without anemia (P = 0.093). Adherence to iron supplementation was 100% in patients completing the study. Hb values did not significantly increase at month-6 in either anemic (+0.60 ± 1.39 g/dL, P = 0.258) or non-anemic (+0.08 ± 0.78 g/dL, P = 1.0) patients. In safety population (n = 38), 7 patients dropped out (18.4%). In particular, treatment was discontinued in 4 patients in the first month (2 for diarrhea, 1 for dyspepsia and constipation, and 1 for death), 1 patient after 3 months (switch to intravenous iron for symptomatic anemia), and 2 after five months (1 for dyspepsia and 1 for death). Conclusion The use of liposomal iron in patients with NDD-CKD is associated with a partial correction of functional ID (TSAT&amp;lt;20%), with no significant effect on iron storage. The small sample size prevents any causative conclusion, though it may provide some insights into using these compounds in patients with CKD.

#1881 Association of circulating autoantibodies to erythropoietin receptor with anaemia in patients with type 2 diabetes and chronic kidney disease

Abstract Background and Aims Anaemia is a risk factor for cardiovascular and kidney prognosis in patients with type 2 diabetes and it is important to identify patients at high risk of anemia. We have previously reported that autoantibodies to erythropoietin receptor (anti-EPOR antibodies) may functionally neutralize the activity of erythropoietin and are associated with haemoglobin (Hb) in patients with lupus nephritis, and hypo responsiveness to erythropoiesis-stimulating agents (ESAs) in patients undergoing haemodialysis. This study assessed the association between anti-EPOR antibodies and anaemia in patients with type 2 diabetes and chronic kidney disease. Method This cohort study included patients with type 2 diabetes and chronic kidney disease who were diagnosed between 1989 and 2014 at our hospital. The presence of anti-EPOR antibodies at baseline were assessed by ELISA in stocked serum. To investigate the association between anti-EPOR antibodies and anaemia, odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression analysis adjusted for multiple covariates. We then estimated hazard ratios (HR) and 95% CIs using Cox regression models to investigate the association between anti-EPOR antibodies and the risk of iron deficiency, defined as transferrin saturation below 20% in those with follow-up measurements of iron metabolism. Results The mean age was 63 years, the mean eGFR was 42 ml/min/1.73 m2 and the median urinary protein to creatinine ratio (UPCR) was 1.8 g/gCr. Anti-EPOR antibodies were detected in 26 out of 110 patients (24%). At baseline, most patients with anti-EPOR antibodies had anaemia (n=24, 92%) and severe anaemia with Hb&amp;lt;10 g/dl (n=16, 62%) and used ESAs (n=16, 62%). The presence of anti-EPOR antibodies was independently associated with severe anaemia (OR 9.3; 1.2-70.1, p=0.03) after adjustment for baseline covariates including HbA1c, eGFR, UPCR, iron, and CRP. During a mean follow-up of 6.5 years, 6 of 10 patients (60%) developed iron deficiency in anti-EPOR antibodies positive patients, while 3 of 20 patients (15%) in negative patients. Patients with anti-EPOR antibodies were associated with an higher risk of iron deficiency compared to those without (HR 76.0; 95% CI 1.2-4721.7, p=0.04). Conclusion In patients with type 2 diabetes and chronic kidney disease, the presence of anti-EPOR antibodies was associated with a risk of severe anaemia and iron deficiency independently of kidney function. These results suggest that anti-EPOR antibodies may be useful in predicting the risk of anaemia and establishing therapeutic strategies of anaemia in people with type 2 diabetes.

#1275 Post-transplant renal anaemia: a call to action from a national study in routine clinical practice

Abstract Background and Aims Post-transplant anaemia (PTA) is common, frequently unnoticed and carries associated risks. Current guidelines consider the same treatment recommendations and goals for these patients as for chronic kidney disease-non dialysis (CKD-NDD). Previous reports demonstrated low awareness and management that could improve. Aims: To describe current anaemia management, goals, and adherence to guidelines in a representative sample of kidney transplant (KT) recipients. Method Retrospective nationwide multicentre study including patients from 8 KT hospitals. Nephrologists collected demographics, comorbidities, KT data and immunosuppressive therapy and data related to anaemia management (laboratory values, previously prescribed treatments, and subsequent adjustments) from electronic medical records. We classified as early anaemia that within the first 6 months. The European statement on KDIGO guidelines was the reference for definitions, drug prescriptions and targets. Results We included 297 recipients with PTA aged 62.8 y (SD 13.6) and 60% male. They had received a graft from donors after cardiac death or brain death) (61.6%. 31.1% respectively) a median of 2.5 years [0.5-8.7] before. A total of 158 patients were on treatment with erythropoietin stimulating agents (ESAs) and the distribution of haemoglobin (Hb) and iron are summarized in Table 1. Among 110 patients on ESA treatment but without iron prescription, 44 had an indication to receive iron and 30 of them had absolute iron deficiency (ID). Only 39/158 patients exceeded the ESA resistance index (ERI) limit, and this condition was more frequent in early PTA (26.1 vs 9.2%). Absolute or functional ID accounted for the majority of ESA resistance (28.2 vs 17.1; p &amp;lt; 0.001). Conclusion Hemoglobin levels in these patients are within the upper KDIGO. Iron therapy continues to be underused (especially intravenous), while iron deficiency and prior events explain most of ESA hyporesponsiveness. We identify missed opportunities for accurate prescription targeting and adherence to guidelines.

#653 Changes in iron markers and D-dimer levels during enarodustat treatment depends on different iron prescription patterns in hemodialysis patients

Abstract Background and Aims Iron preparations are commonly administered with erythropoiesis-stimulating agents or hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PH inhibitors) in hemodialysis patients to promote hematopoiesis and prevent iron deficiency. A recent study highlighted the causal relationship between thrombosis and upregulated serum transferrin levels due to iron deficiency. Additionally, rapid increase of hemoglobin (Hb) during HIF-PH inhibitor use is also considered a risk factor for the development of thromboembolism. Therefore, monitoring iron parameters and Hb is essential for managing anemia and thrombosis risk. We investigated the impact of practice patterns of iron supplementation on iron metabolism in patients receiving a HIF-PH inhibitor enarodustat. Changes in D-dimer levels, a thrombosis-related factor, were also assessed. Method We performed a post-hoc analysis using pooled data from two phase 3 clinical studies of enarodustat in Japanese maintenance hemodialysis patients, SYMPHONY HD and SYMPHONY HD-Long studies. We divided the subjects into three groups according to practice patterns of iron administration: subjects who did not receive iron at all during the enarodustat administration period (Non-Iron Group), subjects who received intravenous iron at least once (IV Iron Group), and subjects who continuously received oral iron-containing preparations including ferric citrate (Oral Iron Group). The time courses of transferrin saturation (TSAT), serum ferritin, and D-dimer levels were compared across these three groups using mixed effects models for repeated measures (MMRM) (with an unstructured covariance structure for the dependent variables). Results The Non-Iron Group, IV Iron Group, and Oral Iron Group consisted of 60, 69, and 73 cases, respectively. Figures show the time courses of TSAT, serum ferritin levels, and changes in D-dimer levels for each practice pattern. MMRM analysis revealed that TSAT levels in the Non-Iron Group and IV Iron Group during the enarodustat administration period were significantly lower than those in the Oral Iron Group (p &amp;lt; 0.01 and p &amp;lt; 0.01, respectively). Similar results were observed for serum ferritin levels (p &amp;lt; 0.01 and p &amp;lt; 0.01, respectively). Moreover, the rate of D-dimer increase in the Non-Iron Group was significantly higher than in the Oral Iron Group (p = 0.029). There was a trend toward a higher rate of D-dimer increase in IV Iron Groups compared to the Oral Iron Group (p = 0.11). Conclusion These findings suggest the superiority of continuous oral iron supplementation over intermittent IV iron supplementation or no iron supplementation during HIF-PH inhibitor administration in terms of preventing thrombosis through maintaining TSAT levels. The association between iron-related parameters and the occurrence of thrombosis needs to be analyzed.