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Concept: Ferritin

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Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD. The primary endpoint was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained either a mean hemoglobin level of 11.0 g/dl or more or a mean increase in hemoglobin of 1.2 g/dl or more over the predose average. Significantly, the primary endpoint was met in 54.9% of patients on vadadustat and 10.3% of patients on placebo. Significant increases in both reticulocytes and total iron-binding capacity and significant decreases in both serum hepcidin and ferritin levels were observed in patients on vadadustat compared with placebo. The overall incidence of adverse events was comparable between the 2 groups. Serious adverse events occurred in 23.9% and 15.3% of the vadadustat- and placebo-treated patients, respectively. Three deaths occurred in the vadadustat arm. Thus, this phase 2b study demonstrated that vadadustat raised and maintained hemoglobin levels in a predictable and controlled manner while enhancing iron mobilization in patients with nondialysis-dependent CKD.

Concepts: Hemoglobin, Chronic kidney disease, Kidney, Erythropoietin, Red blood cell, Anemia, Transferrin, Ferritin

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Background Intravenous (i.v.) iron can improve anaemia of chronic disease and response to erythropoiesis-stimulating agents (ESAs), but data on its use in practice and without ESAs are limited. This study evaluated effectiveness and tolerability of ferric carboxymaltose (FCM) in routine treatment of anaemic cancer patients. Patients and methods Of 639 patients enrolled in 68 haematology/oncology practices in Germany, 619 received FCM at the oncologist’s discretion, 420 had eligible baseline haemoglobin (Hb) measurements, and 364 at least one follow-up Hb measurement. Data of transfused patients were censored from analysis before transfusion. Results The median total iron dose was 1000 mg per patient (interquartile range 600-1500 mg). The median Hb increase was comparable in patients receiving FCM alone (1.4 g/dl [0.2-2.3 g/dl; N = 233]) or FCM + ESA (1.6 g/dl [0.7-2.4 g/dl; N = 46]). Patients with baseline Hb up to 11.0 g/dl and serum ferritin up to 500 ng/ml benefited from FCM treatment (stable Hb ≥11.0 g/dl). Also patients with ferritin >500 ng/ml but low transferrin saturation benefited from FCM treatment. FCM was well tolerated, 2.3% of patients reported putative drug-related adverse events. Conclusions The substantial Hb increase and stabilisation at 11-12 g/dl in FCM-treated patients suggest a role for i.v. iron alone in anaemia correction in cancer patients.

Concepts: Hemoglobin, Oncology, Iron, Interquartile range, Anemia, Iron deficiency anemia, Transferrin, Ferritin

28

Anemia often complicates the course of Inflammatory Bowel Disease (IBD). Hepcidin, a liver-produced peptide hormone, is a key mediator of anemia of chronic disease (ACD). We hypothesized that hepcidin is significantly elevated in anemic CD patients and that hepcidin may cause iron restriction and, therefore, mediate ACD. METHODS: We enrolled 17 patients with CD and ACD recruited from the Cedars-Sinai IBD Center. Routine blood tests included hemoglobin (Hgb), hematocrit, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Anemia was defined as hemoglobin <12g/dL and <13.5g/dL, in men and women, respectively. ACD was diagnosed on the basis of a combination of the following: a) normal or elevated ferritin b) lowered serum iron and total iron binding capacity and c) normal percent iron saturation. Serum and urine hepcidin, as well as IL-6 levels were also measured. Patients with documented iron-deficiency anemia were excluded. RESULTS: There was an excellent correlation between urine (expressed as ng/mg of creatinine) and serum hepcidin levels expressed as ng/ml (r=0.853, p<0.001). We also found a strong positive correlation between serum hepcidin and ferritin levels (r=0.723, p=0.0015). There was a positive correlation between serum hepcidin and IL-6 levels (r=0.546, p=0.023). We found a strong negative correlation between serum hepcidin concentrations and Hgb levels (r=0.528, p=0.029). CONCLUSION: We demonstrate that ACD in CD is characterized by high serum IL-6 and hepcidin levels, which negatively correlate with Hgb levels. Our data support the hypothesis that IL-6-driven hepcidin production mediates ACD in patients with CD.

Concepts: Hemoglobin, Red blood cell, Anemia, Inflammatory bowel disease, Iron deficiency anemia, Transferrin, Ferritin, Total iron-binding capacity

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Abstract Objective. The aim of this study was to investigate demographic, clinical and psychosocial factors associated with sleep quality in patients on continuous ambulatory peritoneal dialysis (CAPD). Material and methods. Demographic data, clinical and biochemical parameters of 112 CAPD patients (convenience sample of 52 women and 60 men, mean age 51 ± 15 years) were measured. In the same patients, the Pittsburgh Sleep Quality Index (PSQI) was used for assessing sleep quality, the Beck Depression Inventory (BDI) for severity of depressive symptoms, the International Restless Legs Syndrome Study Group criteria for the diagnosis of restless legs syndrome (RLS), and the Short Form-36 (SF-36) of Medical Outcomes Study questionnaire for quality of life (QoL). Results. Patients with PSQI scores of > 5 (“bad sleepers”) had lower serum albumin (p = 0.008), total cholesterol (p = 0.034), normalized protein equivalent of nitrogen appearance (p = 0.046) and residual renal function (p = 0.012), but higher serum ferritin (p = 0.016) and BDI scores (p < 0.001). No significant correlation could be demonstrated between sleep quality and other demographic and clinical parameters. Although the prevalence of RLS was higher in poor sleepers, the difference did not reach statistical significance (p = 0.067). In multivariate analysis, only elevated BDI was an independent predictor of poor sleep quality (p = 0.031). Compared with good sleepers, poor sleepers had significantly lower QoL scores in all subscales of the SF-36. Conclusions.Although poor sleepers had lower nutritional indices, an elevated BDI was the only independent predictor of poor sleep quality. Poor sleep quality was also associated with lower QoL in patients on CAPD.

Concepts: Chronic kidney disease, Nephrology, Dialysis, Peritoneum, Peritoneal dialysis, Restless legs syndrome, Ferritin, Beck Depression Inventory

27

Alzheimer’s disease (AD) is primarily caused by overproduction/deposition of β-amyloid (Aβ) in the brain. Dysregulation of iron in the brain also contributes to AD. Although iron affects β-amyloid precursor protein (APP) expression and Aβ deposition, detailed role of iron in AD requires further elucidation. Aβ is produced by sequential proteolytic cleavages of APP by β-secretase and γ-secretase. The γ-secretase complex comprises presenilins (PS1 or PS2), Nicastrin, APH-1, and PEN-2. Herein, we find that PEN-2 can interact with ferritin light chain (FTL), an important component of the iron storage protein ferritin. In addition, we show that overexpression of FTL increases the protein levels of PEN-2 and PS1 amino-terminal fragment (NTF) and promotes γ-secretase activity for more production of Aβ and Notch intracellular domain (NICD). Furthermore, iron treatments increase the levels of FTL, PEN-2 and PS1 NTF and promote γ-secretase-mediated NICD production. Moreover, downregulation of FTL decreases the levels of PEN-2 and PS1 NTF. Together, our results suggest that iron can increase γ-secretase activity through promoting the level of FTL that interacts with and stabilizes PEN-2, providing a new molecular link between iron, PEN-2/γ-secretase and Aβ generation in AD.

Concepts: Alzheimer's disease, Proteins, Molecular biology, Gamma secretase, Ferritin, Presenilin, Nicastrin, FTH1

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To investigate the influence of daily oral iron supplementation on changes in hemoglobin mass (Hbmass) and iron parameters after 2-4 weeks of moderate altitude exposure.

Concepts: Iron, Anemia, Iron deficiency anemia, Parameter, Iron supplements, Ferritin, Iron deficiency

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To assess the incidence of iron deficiency (ID), and iron deficient anemia (IDA) within a cohort of highly trained runners and triathletes, and to examine the association of oral iron supplementation history with serum ferritin (sFe) and hemoglobin (Hb) concentrations.

Concepts: Hemoglobin, Iron, Anemia, Iron deficiency anemia, Iron supplements, Ferritin, Iron deficiency, Anemia of chronic disease

5

Monitoring of serum ferritin levels is widely recommended in the management of anemia among patients on dialysis. However, associations between serum ferritin and mortality are unclear and there have been no investigations among patients undergoing peritoneal dialysis (PD).

Concepts: Dialysis, Ferritin

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BackgroundOnly limited data on the prevalence of iron deficiency (ID) and its correlation with clinical parameters are available in cancer. ID frequently contributes to the pathogenesis of anemia in patients with cancer and may lead to several symptoms such as impaired physical function, weakness and fatigue.Patients and methodsParameters of iron status and clinical parameters were evaluated in 1528 patients with cancer who presented consecutively within a four-month period at our center. One thousand fifty-three patients had solid tumors and 475 hematological malignancies.ResultsID [transferrin saturation (TSAT) < 20%] was noted in 645 (42.6%) of the 1513 patients with TSAT tests available and 500 (33.0%) were anemic. ID rates were highest in pancreatic (63.2%), colorectal (51.9%) and lung cancers (50.7%). Of the 409 iron-deficient patients in whom serum ferritin levels were available additionally to TSAT, 335 (81.9%) presented with functional ID (FID) (TSAT < 20%, serum ferritin ≥30 ng/ml) and 74 (18.1%) with absolute ID. In patients with solid tumors, prevalence of ID correlated with cancer stage at diagnosis (P =0.001), disease status (P = 0.001) and ECOG performance status (P = 0.005).ConclusionsID was frequently noted in cancer and was associated with advanced disease, close proximity to cancer therapy, and poor performance status in patients with solid tumors.

Concepts: Cancer, Oncology, Lung cancer, Cancer staging, Anemia, Hematology, Iron deficiency anemia, Ferritin

2

Sleep problems are common among children with attention-deficit/hyperactivity disorder (ADHD). Serum ferritin levels have been associated with the severity of symptoms and sleep disturbances among children with ADHD. This study was conducted to investigate parent-reported sleep problems in a sample of Egyptian children with ADHD and to examine the relationship between their sleep, symptom-ratings, and low serum ferritin levels.

Concepts: Sleep, Sleep deprivation, Sleep disorder, Case-control study, Narcolepsy, Delayed sleep phase syndrome, Ferritin