Pediatric Heart Failure: Cardiac Ejection Fraction with Cardiomyopathy Decreased to 21% in Iron Deficient from 37% in Iron Sufficient Children

Introduction: The overall aim of our study was to determine if iron deficiency has harmful effects on cardiac function in children with chronic heart failure. Heart failure in children is a complex, heterogeneous disorder leading to a final common pathway of cardiomyocyte dysfunction and attrition. Cellular, animal, and human studies have shown that iron deficiency causes cardiomyocyte dysfunction that can be reversed with iron treatment. Cellular studies of human iron-deficient cardiomyocytes have shown that supplemental iron restores impaired contractility and relaxation. Animal studies have found that cardiomyocyte-specific deletions or alterations of critical iron proteins (transferrin receptor 1, hepcidin, ferroportin) produce cardiomyocyte iron deficiency (without anemia) and result in ultimately fatal cardiac dysfunction that can be rescued with intravenous (IV) iron. Over half of adults with chronic heart failure are iron deficient. Meta-analysis of small randomized clinical trials has shown that IV iron significantly reduces recurrent hospitalization, cardiovascular mortality, and all-cause mortality in iron deficient adults with heart failure. European Society of Cardiology, American College of Cardiology and American Heart Association guidelines recommend consideration of IV iron therapy for adult iron-deficient patients with heart failure. The prevalence and consequences of iron deficiency in children with heart failure have not been established. Previously, two small retrospective studies of children with heart failure have reported that 56% to 96% were iron deficient, with increased morbidity and mortality. The goals of our study of children with heart failure were to determine (i) how often iron status is assessed, (ii) the prevalence of iron deficiency, and (iii) the effects of iron deficiency on cardiac function in patients with cardiomyopathy. Methods: We retrospectively reviewed electronic medical records to identify pediatric patients ages 1-21 years old seen at Columbia University Irving Medical Center Pediatric Heart Failure clinic with absolute iron deficiency during 2010-2020. Heart failure was defined as presence of symptoms or systolic dysfunction by echocardiography. Patients were excluded with a history of heart transplant, isolated diastolic failure, or renal failure requiring dialysis. In adults with heart failure, a transferrin saturation <20% has a sensitivity of 94% and a specificity of 84% in identifying absolute iron deficiency, as determined from a bone marrow aspirate, and iron stores were present in 100% of patients with a transferrin saturation ≥30% (Circ Heart Fail. 2018;11:e0045). In children with heart failure, we used these criteria to define absolute iron deficiency as a transferrin saturation <20% and iron sufficiency as a transferrin saturation ≥30%. Patients with an intermediate transferrin saturation are likely a mixture of absolute and functional iron deficiency, and of iron sufficiency and were excluded from our analysis of cardiomyopathy. Cardiac ejection fraction was evaluated by an echocardiogram performed within 3 months of measurement of transferrin saturation. Results: Of 579 patients with heart failure, only 159 (27%) had any type of laboratory iron studies. Of patients with iron studies, 81 (51%) were evaluated as outpatients; 49% as inpatients. The cause of heart failure was cardiomyopathy (52%), congenital heart disease (34%), acute myocarditis (6%), and other (8%). In the 82 patients with heart failure due to cardiomyopathy, 39 (48%) were iron deficient and 16 (20%) iron sufficient. In the iron deficient children with cardiomyopathy, the left ventricular ejection fraction was lower than in the iron sufficient patients (median 21% vs. 37%; p=0.03 (Mann-Whitney); Figure). The groups did not differ significantly with respect to hemoglobin (Figure), sex, age, or New York Heart Association class. Conclusion: We report a clinically important decrease in cardiac ejection fraction in children with heart failure due to cardiomyopathy who have absolute iron deficiency. Potentially, iron treatment could safely and effectively reverse the harmful effect of iron deficiency on heart function and prospective randomized trials of oral and intravenous iron therapy are urgently needed. Measurement of iron status should routinely be included in the evaluation of children with heart failure. Figure 1 Figure 1. Disclosures Neunert: Novartis: Research Funding.

Iron metabolism in tuberculosis and iron-containing chemotherapeutic drugs for its treatment

This review included the Russian and international articles on the iron metabolism in tuberculosis and the use of iron-containing drugs in the treatment of tuberculosis over the past 20 years. The main topics covered by the researchers include the features of iron metabolism in mycobacteria, the varieties and pathogenesis of anemia that can develop in tuberculosis: iron deficiency (absolute iron deficiency), associated with a chronic disease (relative iron deficiency) or drug-induced anemia (siderohrestic, hemolytic, aplastic). The possible correction of treatment regimens for tuberculosis is analyzed with the introduction of a complex compound of iron with isoniazid in order to reduce undesirable adverse reactions to isoniazid . The literature search for this review was performed using the RSCI, CyberLeninka, Scopus, Web of Science, MedLine, PubMed databases.

The measurement of reticulocyte hemoglobin content: a modern approach to the diagnosis of iron deficiency in children

Iron deficiency is one of the most widely spread types of microelementosis, especially in a growing organism. It is essential to diagnose iron deficiency at an early stage in order to start treatment timely. Diagnostics of iron deficiency can be complicated by concomitant diseases that distort biochemical parameters of iron metabolism, thus making them not informative enough. In this connection, hemoglobin count in reticulocytes (Ret-Hb) and delta-hemoglobin (Delta-He) may be useful indicators as they help to diagnose true iron deficiency at earliest stages and do not depend on concomitant conditions, which is described in reference sources. In this work, Ret-Hb and Delta-He were detected in the structure of blood hematology test performed on hematology analyzers Sysmex XT-4000 and Sysmex XN-9000 (Japan) in 24 children aged 1–18 with absolute iron deficiency; three of these children had absolute iron deficiency manifested as latent deficiency, and 19 children had hypochromic microcytic anemia of mild or medium severity. The parameter was below the normal limit (the average count was 24.2 ± 3.5 pg), while the normal limit is 28 pg, according to the reference sources. After two weeks of treatment, Ret-Hb increased up to 26.0 ± 2.9 pg. Delta-He, being initially as low as 2.9 ± 0.9 pg (with the lower threshold of 4.0 pg) rose up to 6.3 ± 3.4 pg. The results of our research have demonstrated that Ret-Hb and Delta-He may be regarded as informative, economical and affordable diagnostic parameters that do not require collection of additional blood samples. Their dynamics during treatment should be investigated further. This study was approved by the Independent Ethics Committee and the Scientific Council of Saint Petersburg State Pediatric Medical University of Ministry of Healthcare of the Russian Federation.

Hepcidin and GDF-15 are potential biomarkers of Iron Deficiency Anaemia in Chronic Kidney Disease Patients in South Africa

Background Iron deficiency anaemia is a significant cause of morbidity and mortality among chronic kidney disease (CKD) patients. There is a paucity of information on the role of hepcidin and growth differentiation factor-15 (GDF-15) as potential biomarkers of iron deficiency anaemia among non-dialysis CKD patients. This study aimed to determine the utility of hepcidin and GDF-15 as biomarkers of iron deficiency among non-dialysis CKD patients at an academic hospital in Johannesburg, South Africa. Method A cross-sectional study of 312 consecutive consenting non-dialysis CKD patients and 184 controls at Charlotte Maxeke Academic Hospital was conducted from June 2016 to December 2016. Socio-demographic and clinical characteristics were recorded. Plasma hepcidin and GDF-15 were measured using mass spectrometry and ELISA, respectively. Spearman rank correlation, linear and logistic regression and receiver operator curves were utilised to evaluate the predictive and diagnostic/reference values of hepcidin and GDF-15 in absolute and functional iron deficiency anaemia. Results The mean age of participants was 49.7 ±15.8 years, and 50.6% of them were females. The predictive value of diagnosing absolute iron deficiency anaemia among CKD patients using GDF-15 was 74.02% (95% CI: 67.62% - 80.42%) while the predictive value of diagnosing functional iron deficiency anaemia among CKD patients using hepcidin was 70.1% (95% CI: 62.79% - 77.49%).There was a weak negative correlation between hepcidin levels and GFR (r=-0.19, p=0.04) in anaemic CKD patients, and between serum GDF-15 and haemoglobin (r=-0.34, p=0.001). Serum ferritin (β=0.00389, P-value<0.001), was a predictor of log hepcidin. MCHC (β= -0.0220, P-value 0.005) and CKD stage (β=0.4761, P-value <0.001), race (β = 0.3429, P-value = 0.018) were predictors of log GDF-15. Both GDF-15 (adj OR: 1.0003, 95%CI: 1.0001 – 1.0005, P=0.017) and hepcidin (adj OR: 1.003, 95%CI: 1.0004 – 1.0055, P=0.023) were associated with iron deficiency anaemia after multiple linear regression modelling. Subgroup analysis showed that GDF-15 predicted absolute iron deficiency, while hepcidin predicted functional iron deficiency anaemiaConclusion GDF-15 and hepcidin are potential predictors of iron deficiency anaemia among CKD patients.

P0867ANEMIA AND IRON DEFICIENCY IN NON-DIALYISIS CHRONIC KIDNEY DISEASE: A LINK WITH ADVERSE OUTOCOMES?

Background and Aims Anemia is a major complication of Chronic Kidney Disease (CKD). There are few large observational studies analyzing the association between anemia and significant clinical outcomes in non-dialysis dependent CKD (ND-CKD) patients. Our aim was to evaluate the prevalence of anemia and iron deficiency and their association with mortality, cardiovascular events, need for renal replacement therapy and hospitalizations in an outpatient ND-CKD population. Method A patient-level, retrospective, cohort analysis of all adult ND-CKD patients evaluated in an outpatient nephrology clinic between January 2012 to December 2017 with at least one year follow up. Anemia (defined according to the WHO definition - Hemoglobin [Hb] &lt; 13.0 g/dL in men and 12.0g/dL in women), absolute iron deficiency (ferritin &lt; 100 ng/mL), other demographic and clinical data (CKD staging and etiology, comorbidities) were assessed at the first visit through individual consultation of electronic medical records. Results During the 6-year period, 3008 patients were identified (mean age 70.9±14.1 years; 54.5% male; 91.7% white) with a mean follow-up of 3.3±2.0 years. The most frequent cardiovascular comorbidities were arterial hypertension (81.9%), obesity (58%), diabetes mellitus (57.9%) and dyslipidemia (43.9%). The mean Hb was 11.8 ±1.9 g/dL. Anemia was present in 49.9 % of patients, with similar distribution between genders (50.4% in men vs 49.6% in women) and more frequent in white patients (92% vs 8% p= 0.019). Anemia prevalence increased across CKD stages - 12.9%, 25.9%, 57.2%, 72.7% and 86.4% for stages 1 to 5, respectively (p&lt;0,001 for the trend). Anemia was associated with cardiovascular comorbidities, such as diabetes (52% vs 32%, p&lt;0.001), hypertension (86.7% vs 77.7%, p&lt;0.001), obesity (65.5% vs 60.8 %, p=0.012) and dyslipidemia (46% vs 41.2%, p=0.01). Among patients with ferritin levels available (1638), 41.7% had absolute iron deficiency. Anemia was associated with increased mortality (74% vs 26%, p &lt;0,001) and hospitalization (61,8% vs 38.2%, p &lt;0.001). In multivariate logistic regression analysis, anemia (OR 1,923; 95%IC 1,362-2.716; p&lt;0,001) and absolute iron deficiency (OR 0.531 95% IC 0.348-0.809; p=0.003) emerged as independent predictors of death. Cardiovascular events were more prevalent in the group of patients with Hb levels 10-12 g/dL (4.1 vs2.3% 2p=0.006). Conclusion As expected, anemia prevalence increases across CKD stages and, as well as absolute iron deficiency, is independently associated with adverse clinical outcomes in ND-CKD patients, including death. Future studies should be developed to investigate if correction of these factors improves adverse outcomes.

P1753EFFECTIVENESS AND TOLERABILITY OF 500 MG-I.V. FERRIC CARBOXYMALTOSE FOR THE TREATMENT OF IRON DEFICIENCY IN PATIENTS WITH KIDNEY TRANSPLANT

Background and Aims Post transplantation anaemia (PTA) is a common finding in kidney transplant patients, with reported prevalence ranging from 25 to 40%, and it is associated with adverse outcomes for the kidney allograft and the recipient. The pathogenesis of PTA is multifactorial, including iron deficiency, reduced graft function, untoward effects of drugs (immunosuppressants, ACE-I and ARB), folic acid and vitamin B12 deficiency, inflammatory states. Ferric carboxymaltose (FCM) reportedly improved haemoglobin (Hb) levels and replenished depleted iron stores in various populations of patients with iron-deficiency anaemia, but there are few data about its use in PTA. In this study we evaluated the effectiveness and tolerability of high intravenous doses of FCM (500 mg) for the treatment of iron deficiency and anaemia in patients with kidney transplant. Method Absolute iron deficiency was considered as transferrin saturation (TSAT) less than 20% with ferritin levels below 100 µg/L. Anaemia was defined as Hb&lt;13 g/dL in males and Hb&lt;12 g/dL in females. Out of 101 patients with kidney transplant, 56 presented with absolute iron deficiency (59±13 years old, M/F=0.95, 8±4.6 years of transplantation; serum creatinine 1.45±0.64 mg/dL): of these, 40 patients had anaemia (7 were also taking ESAs) and 16 had normal Hb levels. The 16 patients with absolute iron deficiency and normal Hb were not prescribed iron supplements, fearing of causing erythrocytosis, whereas 36 of 40 patients with anaemia and iron deficiency were given FCM 500 mg, as i.v. infusion for 30 minutes. Hb, ferritin and TSAT were assayed either before and 45-60 days after FCM supplementation, which was repeated if Hb levels were less than 0.5 g/dL below the normal value. Data were reported as mean±SD. Results Among the 56 patients with absolute iron deficiency, there were not any significant differences in serum levels of folic acid and vitamin B12 between those with and without anaemia (p=ns). After the first dose of FCM, in 36 patients with iron deficiency and anaemia, ferritin levels increased from 55±69 ng/mL to 111±107 ng/mL (p&lt;0.01), TSAT increased from 12.2±5.9% to 20.4±10.3% (p&lt;0.01) and Hb increased from 10.9±0.9 g/dL to 12.3±1.3 g/dL (p&lt;0.01). Furthermore, 24/36 patients (67%) no longer had absolute iron deficiency and 19/36 (53%) were not anaemic anymore. Out of the 17 patients still showing anaemia after the first FCM dose, 10 had Hb levels less than 0.5 g/dL below the normal value and were given a second dose of FCM. In this subset, Hb level increased on average from 11.4±0.5 g/dL to 12±0.9 g/dL (p&lt;0.01) and became normal in 3 patients. After the FCM course, in 2 out of 7 patients ESAs were discontinued, whereas in 3 patients their doses were reduced and in 2 patients remained unchanged. Only one patient had an adverse effect during FCM infusion, namely, a transient skin flushing on her face during the second dose, which immediately remitted when the infusion was interrupted. Conclusion In patients with PTA and absolute iron deficiency, single or repeated doses of 500 mg of i.v. FCM were effective in improving Hb levels, well tolerated and reduced the need for ESAs. Of 56 patients with kidney transplant and absolute iron deficiency, 16 (28%) had normal Hb levels. We did not treat such subjects, fearing of causing erythrocytosis. However, given that iron deficiency may affect negatively both heart and muscle metabolism, what is the best management of iron deficiency in transplanted patients without anaemia is still an open question.

AB0720 SOLUBLE TRANSFERRIN RECEPTOR IN DIAGNOSIS OF IRON DEFICIENCY ANEMIA IN PATIENTS WITH SPONDYLOARTHRITIS

Background:Anemia is a frequent hematological disorder in patients with rheumatic diseases. The main pathogenetic variants of anemia are anemia of chronic disease (ACD), iron deficiency anemia (IDA), and anemia of chronic disease with iron deficiency (ACD/IDA). The presence of systemic inflammation hinders to diagnose absolute iron deficiency, because standard tests of iron status are affected by it. Soluble transferrin receptors (sTfR) measurement and the calculation of the sTfR/ log ferritin index (sTfR index) are recommended, but data about diagnostically significant levels of these indicators in patients with spondyloarthritis (SpA) is currently limited.Objectives:To assess the diagnostic significance of sTfR and the sTfR index for detecting absolute iron deficiency in patients with SpA and anemia.Methods:Complete blood count, standart iron metabolism parameters, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were evaluated in 68 patients with SpA. Serum concentration of sTfR was measured with enzyme-linked immunosorbent assay (ELISA) using sTfR ELISA kit («Monobind Inc.», USA). The sTfR index was calculated by the formula sTfR/log10ferritin. Anemia was defined using the World Health Organization criteria. Depending on the serum ferritin concentration, transferrin saturation, and CRP level, ACD, IDA, or combined anemia (ACD/IDA) were diagnosed. Disease activity was determined by the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score based on CRP) scales. Receiver operating characteristic (ROC) analysis was performed with MedCalc.Results:Anemia was found in 48 of 68 (70,6%) SpA patients. 16 (33,3%) patients had ACD and 32 (66,7%) had ACD/IDA. Hemoglobin level in ACD was 118 [112; 123] g/L, in ACD/IDA – 110 [106; 120] g/L, in non-anemic patients – 133 [129; 145] g/L (p<0.001 for all groups). CRP and ESR values were higher in ACD compared to ACD/IDA patients (31.5 [20.3; 46.4] mg/L and 27.0 [16.0; 35.5] mm/h versus 9.8 [5.6; 16.9] mg/L and 15.5 [12.0; 22.5] mm/h, respectively [p=0.00 and p=0.038]). No statistically significant difference was found between all groups in BASDAI and ASDAS-CRP scores.ACD/IDA patients had significant increases in serum sTfR levels (1.7 [1.4; 2.2] mg/L) compared to ACD (1.5 [1.1; 1.7] mg/L, p=0,04) and to non-anemic patients (1,3 [1,1; 1,6] mg/L, p=0,003). The sTfR index was significantly higher in ACD/IDA (0.93 [0.82; 1.24]) compared to patients with ACD (0.64 [0.48; 0.75], p<0.001) and without anemia (0.67 [0.56; 0.81], p<0.001).The areas under the curves (AUCs) for distinguishing between ACD/IDA and ACD were 0.85 for sTfR index (p<0,001), 0.72 for sTfR (p<0,001). The sTfR index (cutoff >0.83) and sTfR (cutoff >1.39 mg/L) had sensitivities of 75% and 53%, and specificities of 83% and 81%, respectively.Conclusion:According to obtained data, serum concentration of sTfR >1.39 mg/L and the sTfR index >0.83 point to the presence of iron deficiency component in the structure of anemic syndrome in patients with SpA.References:Management of patients with SpA requires constant monitoring of side effects of therapy, in particular induced by the non-steroidal anti-inflammatory drugs. Use of sTfR and the sTfR index can improve the detection of IDA. A significant advantage of these indicators is their independence from systemic inflammation.Disclosure of Interests:None declared

Iron deficiency is a common disorder in general population and independently predicts all-cause mortality: results from the Gutenberg Health Study

Background Iron deficiency is now accepted as an independent entity beyond anemia. Recently, a new functional definition of iron deficiency was proposed and proved strong efficacy in randomized cardiovascular clinical trials of intravenous iron supplementation. Here, we characterize the impact of iron deficiency on all-cause mortality in the non-anemic general population based on two distinct definitions. Methods The Gutenberg Health Study is a population-based, prospective, single-center cohort study. The 5000 individuals between 35 and 74 years underwent baseline and a planned follow-up visit at year 5. Tested definitions of iron deficiency were (1) functional iron deficiency—ferritin levels below 100 µg/l, or ferritin levels between 100 and 299 µg/l and transferrin saturation below 20%, and (2) absolute iron deficiency—ferritin below 30 µg/l. Results At baseline, a total of 54.5% of participants showed functional iron deficiency at a mean hemoglobin of 14.3 g/dl; while, the rate of absolute iron deficiency was 11.8%, at a mean hemoglobin level of 13.4 g/dl. At year 5, proportion of newly diagnosed subjects was 18.5% and 4.8%, respectively. Rate of all-cause mortality was 7.2% (n = 361); while, median follow-up was 10.1 years. After adjustment for hemoglobin and major cardiovascular risk factors, the hazard ratio with 95% confidence interval of the association of iron deficiency with mortality was 1.3 (1.0–1.6; p = 0.023) for the functional definition, and 1.9 (1.3–2.8; p = 0.002) for absolute iron deficiency. Conclusions Iron deficiency is very common in the apparently healthy general population and independently associated with all-cause mortality in the mid to long term. Graphic abstract

Iron Deficiency in Chronic Kidney Disease: Updates on Pathophysiology, Diagnosis, and Treatment

Anemia is a complication that affects a majority of individuals with advanced CKD. Although relative deficiency of erythropoietin production is the major driver of anemia in CKD, iron deficiency stands out among the mechanisms contributing to the impaired erythropoiesis in the setting of reduced kidney function. Iron deficiency plays a significant role in anemia in CKD. This may be due to a true paucity of iron stores (absolute iron deficiency) or a relative (functional) deficiency which prevents the use of available iron stores. Several risk factors contribute to absolute and functional iron deficiency in CKD, including blood losses, impaired iron absorption, and chronic inflammation. The traditional biomarkers used for the diagnosis of iron-deficiency anemia (IDA) in patients with CKD have limitations, leading to persistent challenges in the detection and monitoring of IDA in these patients. Here, we review the pathophysiology and available diagnostic tests for IDA in CKD, we discuss the literature that has informed the current practice guidelines for the treatment of IDA in CKD, and we summarize the available oral and intravenous (IV) iron formulations for the treatment of IDA in CKD. Two important issues are addressed, including the potential risks of a more liberal approach to iron supplementation as well as the potential risks and benefits of IV versus oral iron supplementation in patients with CKD.