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Concept: Anemia

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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

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BACKGROUND: Use of multivitamin supplements during the pre-HAART era has been found to reduce viral load, enhance immune response, and generally improve clinical outcomes among HIV-infected adults. However, immune reconstitution is incomplete and significant mortality and opportunistic infections occur in spite of HAART. There is insufficient research information on whether multivitamin supplementation may be beneficial as adjunct therapy for HIV-infected individuals taking HAART. We propose to evaluate the efficacy of a single recommended daily allowance (RDA) of micronutrients (including vitamins B-complex, C, and E) in slowing disease progression among HIV-infected adults receiving HAART in Uganda. METHODS: We are using a randomized, double-blind, placebo-controlled trial study design. Eligible patients are HIV-positive adults aged at least 18 years, and are randomized to receive either a placebo; or multivitamins that include a single RDA of the following vitamins: 1.4 mg B1, 1.4 mg B2, 1.9 mg B6, 2.6 mcg B12, 18 mg niacin, 70 mg C, 10 mg E, and 0.4 mg folic acid. Participants are followed for up to 18 months with evaluations at baseline, 6, 12 and 18 months. The study is primarily powered to examine the effects on immune reconstitution, weight gain, and quality of life. In addition, we will examine the effects on other secondary outcomes including the risks of development of new or recurrent disease progression event, including all-cause mortality; ARV regimen change from first- to second-line therapy; and other adverse events as indicated by incident peripheral neuropathy, severe anemia, or diarrhea.DiscussionsThe conduct of this trial provides an opportunity to evaluate the potential benefits of this affordable adjunct therapy (multivitamin supplementation) among HIV-infected adults receiving HAART in a developing country setting.Trial registrationClinical Trial Registration-URL: www.clinicaltrials.gov. Unique identifier: NCT01228578.

Concepts: Antiretroviral drug, HIV, AIDS, Immune system, Dietary supplement, Anemia, Folic acid, Vitamin B12

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Hookworms infect more people than HIV and malaria combined, predominantly in third world countries. Treatment of infection with chemotherapy can have limited efficacy and re-infections after treatment are common. Heavy infection often leads to debilitating diseases. All these factors suggest an urgent need for development of vaccine. In an attempt to develop a vaccine targeting the major human hookworm, Necator americanus, a B-cell peptide epitope was chosen from the apical enzyme in the hemoglobin digestion cascade, the aspartic protease Na-APR-1. The A(291)Y alpha helical epitope is known to induce neutralizing antibodies that inhibit the enzymatic activity of Na-APR-1, thus reducing the capacity for hookworms to digest hemoglobin and obtain nutrients. A(291)Y was engineered such that it was flanked on both termini by a coil-promoting sequence to maintain native conformation, and subsequently incorporated into a Lipid Core Peptide (LCP) self-adjuvanting system. While A(291)Y alone or the chimeric epitope with or without Freund’s adjuvants induced negligible IgG responses, the LCP construct incorporating the chimeric peptide induced a strong IgG response in mice. Antibodies produced were able to bind to and completely inhibit the enzymatic activity of Na-APR-1. The results presented show that the new chimeric LCP construct can induce effective enzyme-neutralising antibodies in mice, without the help of any additional toxic adjuvants. This approach offers promise for the development of vaccines against helminth parasites of humans and their livestock and companion animals.

Concepts: Immune system, Protein, Bacteria, Anemia, Dog, Hookworm, Parasitic worm, Necator

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BACKGROUND Iron deficiency and iron deficiency anaemia are frequent problems in both the primary and the specialist health services. It is important to detect iron deficiency and to determine the causal relationship because iron deficiency may be secondary to a serious disease. The diagnosis of iron deficiency is largely based on biochemical and haematological laboratory findings, but there is no standardisation or consensus on the interpretation of these findings.METHOD Non-systematic search in the PubMed database with a discretionary selection of articles, based on the authors' knowledge of the field.RESULTS Ferritin measurement is the most important analysis in the study of iron deficiency, but there is no consensus on the diagnostic cut-off. It is usual in Norway today to use a ferritin level of < 12 - 20 μg/L, but at this low level the sensitivity for detecting iron deficiency is very low. A number of studies show that if the diagnostic cut-off is increased to the order of 30 μg/L the sensitivity is significantly higher for only a small reduction in specificity.INTERPRETATION When studying iron deficiency as a cause of anaemia, the diagnostic cut-off for detecting deficiency should be higher than that used today. The ferritin level increases with inflammation and ought in practice to be considered in conjunction with the CRP level. The level of transferrin receptor in plasma increases with iron deficiency without being influenced by inflammation and is therefore a good supplement to ferritin measurement. Measurement of iron, transferrin and transferrin saturation provides little information additional to that provided by ferritin in iron deficiency studies.

Concepts: Hemoglobin, Iron, Anemia, Hematology, Iron deficiency anemia, Transferrin, Serum iron, Iron metabolism

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The quantity of circulating reticulocytes is an important indicator of erythropoietic activity in response to a wide range of haematological pathologies. While most modern laboratories use flow cytometry to quantify reticulocytes, most field laboratories still rely on ‘subvital’ staining. The specialist ‘subvital’ stains, New Methylene Blue (NMB) and Brilliant Crésyl Blue are often difficult to procure, toxic, and show inconsistencies between batches. Here we demonstrate the utility of Giemsa’s stain (commonly used microbiology and parasitology) in a ‘subvital’ manner to provide an accurate method to visualize and count reticulocytes in blood samples from normal and malaria-infected individuals.

Concepts: Biology, Red blood cell, Anemia, Hematology, Flow cytometry, Stain, Reticulocyte, New methylene blue

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Red cell distribution width (RDW) is a parameter of the standard full blood count tests, measuring the size variability of erythrocytes. Recently, its elevation has been proven to reliably reflect the extent systematic inflammation, mainly in cardiometabolic diseases. Up to date, its association with solid malignancies has been scarcely investigated.

Concepts: Cancer, Breast cancer, Metastasis, Anemia, Complete blood count, Mean corpuscular volume, Red blood cell distribution width

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Dietary iron absorption is regulated by hepcidin, an iron regulatory protein produced by the liver. Hepcidin production is regulated by iron stores, erythropoiesis and inflammation, but its physiology has not been characterized when repeated blood loss occurs. Hepcidin was measured in plasma samples obtained from 114 first-time/reactivated (no blood donations in prior 2 years) female donors and 34 frequent (≥3 red blood cell donations in prior 12 months) male donors as they were phlebotomized ≥4 or more times over 18-24 months. Hepcidin was compared to ferritin and hemoglobin using multivariable repeated measures regression models. Hepcidin, ferritin and hemoglobin declined with increasing frequency of donation in the first-time/reactivated females. Hepcidin and ferritin correlated well with each other (Spearman correlation of 0.74), but on average hepcidin varied more between donations for a given donor relative to ferritin. In a multivariable repeated measures regression model the predicted inter-donation decline in hemoglobin varied as a function of hepcidin and ferritin; hemoglobin was 0.51 g/dL lower for subjects with low (≤45.7 ng/ml) or decreasing hepcidin and low ferritin (≤26 ng/ml), and was essentially zero for other subjects including those with high (>45.7 ng/ml) or increasing hepcidin and low ferritin (≤26 ng/ml) (p<0.001). Hepcidin rapidly changes in response to dietary iron needed for erythropoiesis. The dynamic regulation of hepcidin in the presence of low ferritin suggests that plasma hepcidin may provide clinically useful information about an individual's iron status (and hence capacity to tolerate repeated blood donations) beyond that of ferritin alone.

Concepts: Hemoglobin, Blood, Red blood cell, Spearman's rank correlation coefficient, Liver, Anemia, Hematology, Iron deficiency anemia

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Abstract Background: Methylmalonic aciduria and homocystinuria type C (cblC), a disorder of vitamin B12 (cobalamin) metabolism caused by mutations in the MMACHC gene, presents with many systemic symptoms, including neurological, cognitive, psychiatric, and thromboembolic events. Retinal phenotypes, including maculopathy, pigmentary retinopathy, and optic atrophy are common in early onset form of the disease but are rare in adult onset forms. Materials and Methods: An adult Hispanic female presented with decreased central vision, bilateral pericentral ring scotomas and bull’s eye-appearing macular lesions at 28 years of age. Her medical history was otherwise unremarkable except for iron deficiency anemia and both urinary tract and kidney infections. Screening of the ABCA4 gene, mutations in which frequently cause bull’s eye maculopathy, was negative. Subsequently, analysis with whole exome sequencing was performed. Results: Whole exome sequencing discovered compound heterozygous mutations in MMACHC, c.G482A:p.Arg161Gln and c.270_271insA:p.Arg91Lysfs*14, which segregated with the disease in the family. The genetic diagnosis was confirmed by biochemical laboratory testing, showing highly elevated urine methylmalonic acid/creatinine and homocysteine levels, and suggesting disease management with hydroxycobalamin injections and carnitine supplementation. Conclusions: In summary, a unique case of an adult patient with bull’s eye macular lesions and no clinically relevant systemic symptoms was diagnosed with cblC by genetic screening and follow-up biochemical laboratory tests.

Concepts: Genetics, Anemia, Folic acid, Vitamin B12, Iron deficiency anemia, Genetic disorders, Methylmalonic acid, Methylmalonic acidemia

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We sought to evaluate the feasibility and efficacy of hybrid transapical closure of paravalvar mitral leaks using a new Occlutech PLD occluder in patients with heart failure and/or haemolytic anaemia.

Concepts: Hemoglobin, Red blood cell, Anemia, Hemolytic anemia, Hemolysis, Hematology