Repurposing cinacalcet suppresses multidrug-resistant Staphylococcus aureus by disruption of cell membrane and inhibits biofilm by targeting IcaR.

BACKGROUND: MDR Staphylococcus aureus infections, along with the severity of biofilm-associated infections, continue to threaten human health to a great extent. It necessitates the urgent development of novel antimicrobial and antibiofilm agents. OBJECTIVES: To reveal the mechanism and target of cinacalcet as an antibacterial and antimicrobial agent for S. aureus. METHODS: Screening of non-antibiotic drugs for antibacterial and antibiofilm properties was conducted using a small-molecule drug library. In vivo efficacy was assessed through animal models, and the antibacterial mechanism was studied using quantitative proteomics, biochemical assays, LiP-SMap, BLI detection and gene knockout techniques. RESULTS: Cinacalcet, an FDA-approved drug, demonstrated antibacterial and antibiofilm activity against S. aureus, with less observed development of bacterial resistance. Importantly, cinacalcet significantly improved survival in a pneumonia model and bacterial clearance in a biofilm infection model. Moreover, the antibacterial mechanism of cinacalcet mainly involves the destruction of membrane-targeted structures, alteration of energy metabolism, and production of reactive oxygen species (ROS). Cinacalcet was found to target IcaR, inhibiting biofilm formation through the negative regulation of IcaADBC. CONCLUSIONS: The findings suggest that cinacalcet has potential for repurposing as a therapeutic agent for MDR S. aureus infections and associated biofilms, warranting further investigation.

A Synopsis of Guidance for Allergic Rhinitis Diagnosis and Management From ICAR 2023.

An updated edition of the International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR) has recently been published. This consensus document, which included the participation of 87 primary authors and 40 additional consultant authors, who critically appraised evidence on 144 individual topics concerning allergic rhinitis, provides guidance for health care providers using the evidence-based review with recommendations (EBRR) methodology. This synopsis highlights topical areas including pathophysiology, epidemiology, disease burden, risk and protective factors, evaluation and diagnosis, aeroallergen avoidance and environmental controls, single and combination pharmacotherapy options, allergen immunotherapy (subcutaneous, sublingual, rush, cluster), pediatric considerations, alternative and emerging therapies, and unmet needs. Based on the EBRR methodology, ICAR:AR includes strong recommendations for the treatment of allergic rhinitis: (1) for the use of newer generation antihistamines compared with first-generation alternatives, intranasal corticosteroid, intranasal saline, combination therapy with intranasal corticosteroid plus intranasal antihistamine for patients not responding to monotherapy, and subcutaneous immunotherapy and sublingual tablet immunotherapy in properly selected patients; (2) against the use of oral decongestant monotherapy and routine use of oral corticosteroids.

Outbreak of Ichthyophthirius multifiliis associated with Aeromonas hydrophila in Pangasianodon hypophthalmus: The role of turmeric oil in enhancing immunity and inducing resistance against co-infection.

Ichthyophthirius multifiliis, a ciliated parasite causing ichthyophthiriasis (white spot disease) in freshwater fishes, results in significant economic loss to the aquaculture sector. One of the important predisposing factors for ichthyophthiriasis is low water temperature (i.e., below 20°C), which affects the health and makes freshwater fishes more susceptible to parasitic infections. During ichthyophthiriasis, fishes are stressed and acute immune reactions are compromised, which enables the aquatic bacterial pathogens to simultaneously infect the host and increase the severity of disease. In the present work, we aimed to understand the parasite-bacteria co-infection mechanism in fish. Later, Curcuma longa (turmeric) essential oil was used as a promising management strategy to improve immunity and control co-infections in fish. A natural outbreak of I. multifiliis was reported (validated by 16S rRNA PCR and sequencing method) in Pangasianodon hypophthalmus from a culture facility of ICAR-CIFRI, India. The fish showed clinical signs including hemorrhage, ulcer, discoloration, and redness in the body surface. Further microbiological analysis revealed that Aeromonas hydrophila was associated (validated by 16S rRNA PCR and sequencing method) with the infection and mortality of P. hypophthalmus, confirmed by hemolysin and survival assay. This created a scenario of co-infections, where both infectious agents are active together, causing ichthyophthiriasis and motile Aeromonas septicemia (MAS) in P. hypophthalmus. Interestingly, turmeric oil supplementation induced protective immunity in P. hypophthalmus against the co-infection condition. The study showed that P. hypophthalmus fingerlings supplemented with turmeric oil, at an optimum concentration (10 ppm), exhibited significantly increased survival against co-infection. The optimum concentration induced anti-stress and antioxidative response in fingerlings, marked by a significant decrease in cortisol and elevated levels of superoxide dismutase (SOD) and catalase (CAT) in treated animals as compared with the controls. Furthermore, the study indicated that supplementation of turmeric oil increases both non-specific and specific immune response, and significantly higher values of immune genes (interleukin-1ß, transferrin, and C3), HSP70, HSP90, and IgM were observed in P. hypophthalmus treatment groups. Our findings suggest that C. longa (turmeric) oil modulates stress, antioxidant, and immunological responses, probably contributing to enhanced protection in P. hypophthalmus. Hence, the application of turmeric oil treatment in aquaculture might become a management strategy to control co-infections in fishes. However, this hypothesis needs further validation.

Iron chelation suppresses secondary bleeding after intracerebral hemorrhage in angiotensin II-infused mice.

AIMS: Secondary bleeding and further hematoma expansion (HE) aggravate brain injury after intracerebral hemorrhage (ICH). The majority of HE results from hypertensive ICH. Previous study reported higher iron content in the brains of hypertensive patients. Iron overload exacerbates the risk of hemorrhagic transformation in thromboembolic stroke mice. Whether iron overload during the process of hypertension participates in secondary bleeding of hypertensive ICH remains unclear. METHODS: Hypertension was induced by continuous infusion of angiotensin II (Ang II) with an osmotic pump into C57BL/6 mice. ICH was simulated by intrastriatal injection of the liquid polymer Onyx-18. Iron chelation and iron overload was achieved by deferoxamine mesylate or iron dextran injection. Secondary bleeding was quantified by measuring the hemoglobin content in the ipsilateral brain hemisphere. RESULTS: Ang II-induced hypertensive mice showed increased iron accumulation in the brain and expanded secondary hemorrhage after ICH modeling. Moreover, iron chelation suppressed while iron overload aggravated secondary bleeding. Mechanistically, iron exacerbated the loss of contractile cerebral vascular smooth muscle cells (VSMCs), aggravated blood-brain barrier (BBB) leakage in Ang II-induced hypertensive mice, and increased glial and MMP9 accumulation after ICH. CONCLUSION: Iron overload plays a key role in secondary bleeding after ICH in Ang II-induced hypertensive mice. Iron chelation during the process of Ang II-induced hypertension suppresses secondary bleeding after ICH.

Intravenous iron infusion and newer non-dextran formulations.

There are several newer intravenous iron formulations to treat iron deficiency and its anaemia. Its use in the primary care setting has been infrequent compared to tertiary centres, due to historical concerns such as anaphylaxis. There is a lack of overall comparison among the intravenous formulations of iron. Compared to oral iron therapy, the newer intravenous formulations, which allow a complete or near-complete replacement in a single sitting of 15-30 minutes, have an improved safety profile with better tolerability, efficacy and effectiveness. They are suited for administration in the primary care setting. The four non-dextran formulations (ferric carboxymaltose, iron sucrose, iron isomaltoside and ferumoxytol) share an equal or near equal efficacy and safety profile. This article also outlines how to provide iron infusion safely and effectively in the community.

Correcting iron deficiency anemia with iron dextran alters the serum metabolomic profile of the infant Rhesus Monkey.

BACKGROUND: The effects of infantile iron deficiency anemia (IDA) extend beyond hematological indices and include short- and long-term adverse effects on multiple cells and tissues. IDA is associated with an abnormal serum metabolomic profile, characterized by altered hepatic metabolism, lowered NAD flux, increased nucleoside levels, and a reduction in circulating dopamine levels. OBJECTIVES: The objective of this study was to determine whether the serum metabolomic profile is normalized after rapid correction of IDA using iron dextran injections. METHODS: Blood was collected from iron-sufficient (IS; n = 10) and IDA (n = 12) rhesus infants at 6 months of age. IDA infants were then administered iron dextran and vitamin B via intramuscular injections at weekly intervals for 2 to 8 weeks. Their hematological and metabolomic statuses were evaluated following treatment and compared with baseline and a separate group of age-matched IS infants (n = 5). RESULTS: Serum metabolomic profiles assessed at baseline and after treatment via HPLC/MS using isobaric standards identified 654 quantifiable metabolites. At baseline, 53 metabolites differed between IS and IDA infants. Iron treatment restored traditional hematological indices, including hemoglobin and mean corpuscular volume, into the normal range, but the metabolite profile in the IDA group after iron treatment was markedly altered, with 323 metabolites differentially expressed when compared with an infant's own baseline profile. CONCLUSIONS: Rapid correction of IDA with iron dextran resulted in extensive metabolic changes across biochemical pathways indexing the liver function, bile acid release, essential fatty acid production, nucleoside release, and several neurologically important metabolites. The results highlight the importance of a cautious approach when developing a route and regimen of iron repletion to treat infantile IDA.

Trends in Anemia, Iron, Therapy, and Transfusion in Hospitalized Pediatric Patients with Inflammatory Bowel Disease.

OBJECTIVE: To evaluate trends in diagnosis and management of iron deficiency anemia using a large national children's hospital database in pediatric patients admitted with inflammatory bowel disease (IBD). STUDY DESIGN: In this retrospective multicenter cohort study, we used the Pediatric Health Information System de-identified administrative database. Patients age <21 years with ≥2 admissions with International Classification of Disease, Ninth Revision and Tenth Revision codes for Crohn's disease or ulcerative colitis from 2012 to 2018 were included. We extracted data regarding diagnoses of anemia and/or iron deficiency, and receipt of oral iron, intravenous (IV) iron, and/or blood transfusion. Data were analyzed descriptively. RESULTS: We identified 8007 unique patients meeting study criteria for a total of 28 260 admissions. The median age at admission was 15.4 years. A diagnosis of anemia was documented in 29.8% of admissions and iron studies were performed in 12.6%. IV iron was given in 6.3% of admissions and blood transfusions in 7.4%. The prevalence of the diagnosis of anemia among IBD admissions increased from 24.6% in 2012 to 32.4% in 2018 (P < .0001). There was a steady increase in the proportion of IBD admissions that used IV iron, from 3.5% in 2012 to 10.4% in 2018 (P < .0001), and the proportion of admissions with red cell transfusions decreased over time from 9.4% to 4.4% (P < .0001). CONCLUSIONS: Iron deficiency anemia is prevalent among pediatric patients with IBD admitted to US children's hospitals. From 2012 to 2018, there was an increase in the use of inpatient IV iron for the treatment of iron deficiency anemia and a decrease in transfusions.

Efficacy and tolerability of intravenous iron for patients with restless legs syndrome: evidence from randomized trials and observational studies.

OBJECTIVE: Restless legs syndrome (RLS) is a common neurological disorder of unclear pathophysiology that appears to involve an iron deficiency in the brain. Some studies, but not others, suggest that intravenous injection of iron can reduce RLS severity. METHOD: The databases Web of Science, PubMed, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed were searched for randomized controlled trials, cohort studies and case-control studies of intravenous iron therapy to treat RLS. Eligible studies were meta-analyzed using Stata 12.0. RESULTS: This analysis indicated that IV iron was more efficacious than placebo in treating RLS (OR: 4.71,95%CI 4.21-5.21,p < 0.0001). According to sub-group analysis, either IV ferric carboxymaltose (FCM) or iron sucrose was more efficacious than placebo in treating RLS. Adverse events did not differ significantly between patients receiving intravenous iron or placebo (OR 1.68, 95%CI 0.92-3.07, p = 0.093). The present study also indicated after accepting IV iron treatment the IRLS score in RLS patients decreased (OR = 6.75,95%CI 4.02-9.49, p < 0.0001). The subgroup analysis showed that IV iron dextran, iron sucrose, and FCM could alleviate the IRLS score. CONCLUSION: The available evidence suggests that intravenous iron is effective and tolerable for patients with RLS regardless of peripheral iron status.

Donor Iron Deficiency Study (DIDS): protocol of a study to test whether iron deficiency in blood donors affects red blood cell recovery after transfusion.

BACKGROUND: Despite fulfilling all requirements for blood donation, a large proportion of regular blood donors are iron deficient. Red blood cells (RBC) from iron-deficient donors may be particularly susceptible to damage induced by standard refrigerated storage. Herein, we present a study protocol for testing whether correcting iron deficiency in donors with iron-deficient erythropoiesis will improve the quality of their refrigerator-stored RBC. MATERIALS AND METHODS: This is a randomised, controlled, double-blind clinical trial. Sixty healthy regular donors who meet donation standards, while exhibiting iron-deficient erythropoiesis by laboratory testing criteria, will donate a single standard RBC unit that will be leucoreduced and stored in a refrigerator under standard conditions for 40-42 days. A 51Cr-radiolabelled 24-hour RBC recovery study will be performed and then these donors will be randomised to receive, in a double-blinded fashion, either intravenous saline, as a control, or low-molecular weight iron dextran (1 g), to provide total iron repletion. Four to six months later, they will donate a second RBC unit, which will be similarly stored, and autologous 51Cr-labelled 24-hour post-transfusion RBC recovery will again be determined. RESULTS: The primary endpoint will be the change in 24-hour post-transfusion recovery from the first to the second donation. The primary outcome will be the group mean difference in the primary endpoints between the group receiving intravenous saline and the group receiving intravenous iron dextran. Secondary outcomes will be quality of life, fatigue, and emotional health, assessed by surveys. CONCLUSION: This study will provide definitive evidence as to whether donor iron deficiency affects the quality of the blood supply and will assess the severity of symptoms affecting iron-deficient blood donors.

Whole-body iron transport and metabolism: Mechanistic, multi-scale model to improve treatment of anemia in chronic kidney disease.

Iron plays vital roles in the human body including enzymatic processes, oxygen-transport via hemoglobin and immune response. Iron metabolism is characterized by ~95% recycling and minor replenishment through diet. Anemia of chronic kidney disease (CKD) is characterized by a lack of synthesis of erythropoietin leading to reduced red blood cell (RBC) formation and aberrant iron recycling. Treatment of CKD anemia aims to normalize RBC count and serum hemoglobin. Clinically, the various fluxes of iron transport and accumulation are not measured so that changes during disease (e.g., CKD) and treatment are unknown. Unwanted iron accumulation in patients is known to lead to adverse effects. Current whole-body models lack the mechanistic details of iron transport related to RBC maturation, transferrin (Tf and TfR) dynamics and assume passive iron efflux from macrophages. Hence, they are not predictive of whole-body iron dynamics and cannot be used to design individualized patient treatment. For prediction, we developed a mechanistic, multi-scale computational model of whole-body iron metabolism incorporating four compartments containing major pools of iron and RBC generation process. The model accounts for multiple forms of iron in vivo, mechanisms involved in iron uptake and release and their regulation. Furthermore, the model is interfaced with drug pharmacokinetics to allow simulation of treatment dynamics. We calibrated our model with experimental and clinical data from peer-reviewed literature to reliably simulate CKD anemia and the effects of current treatment involving combination of epoietin-alpha and iron dextran. This in silico whole-body model of iron metabolism predicts that a year of treatment can potentially lead to 90% downregulation of ferroportin (FPN) levels, 15-fold increase in iron stores with only a 20% increase in iron flux from the reticulo-endothelial system (RES). Model simulations quantified unmeasured iron fluxes, previously unknown effects of treatment on FPN-level and iron stores in the RES. This mechanistic whole-body model can be the basis for future studies that incorporate iron metabolism together with related clinical experiments. Such an approach could pave the way for development of effective personalized treatment of CKD anemia.

Evaluation of the safety of iron dextran with parenteral nutrition in the paediatric inpatient setting.

AIM: Practitioners often avoid administering iron dextran in parenteral nutrition (PN) for hospitalised children because of the concern for anaphylaxis. The primary aim of the present study was to determine the risk of anaphylaxis associated with exposure to PN containing iron dextran in the inpatient setting. METHODS: Charts were reviewed for all children admitted to The Children's Hospital of Philadelphia from January 1, 2011 to December 30, 2013 who received PN containing low molecular weight (LMW) iron dextran. Subject characteristics, primary diagnoses and PN orders were evaluated. The pharmacy adverse events database was queried for adverse drug reactions. RESULTS: Over three years, 89 subjects received PN containing a maintenance dose of LMW iron dextran with a total of 2774 days of exposure. Subjects ranged from two months to 21 years of age and received between 1 and 196 days of PN containing iron dextran. The mean dose of iron dextran in children decreased as the weight category increased from <5 kg (0.21 ± 0.05 mg/kg/day) to ≥40 kg (1.9 ± 0.5 mg/day; P-value for trend <0.005). No anaphylactic reactions occurred in any subjects. CONCLUSIONS: PN containing a maintenance dose of LMW iron dextran can be safely administered to hospitalised children, and further studies are need to evaluate the potential to prevent iron deficiency anaemia and the need for additional IV iron infusions.

Distinct in vitro Complement Activation by Various Intravenous Iron Preparations.

BACKGROUND: Intravenous (IV) iron preparations are widely used in the treatment of anemia in patients undergoing hemodialysis (HD). All IV iron preparations carry a risk of causing hypersensitivity reactions. However, the pathophysiological mechanism is poorly understood. We hypothesize that a relevant number of these reactions are mediated by complement activation, resulting in a pseudo-anaphylactic clinical picture known as complement activation-related pseudo allergy (CARPA). METHODS: First, the in-vitro complement-activating capacity was determined for 5 commonly used IV iron preparations using functional complement assays for the 3 pathways. Additionally, the preparations were tested in an ex-vivo model using the whole blood of healthy volunteers and HD patients. Lastly, in-vivo complement activation was tested for one preparation in HD patients. RESULTS: In the in-vitro assays, iron dextran, and ferric carboxymaltose caused complement activation, which was only possible under alternative pathway conditions. Iron sucrose may interact with complement proteins, but did not activate complement in-vitro. In the ex-vivo assay, iron dextran significantly induced complement activation in the blood of healthy volunteers and HD patients. Furthermore, in the ex-vivo assay, ferric carboxymaltose and iron sucrose only caused significant complement activation in the blood of HD patients. No in-vitro or ex-vivo complement activation was found for ferumoxytol and iron isomaltoside. IV iron therapy with ferric carboxymaltose in HD patients did not lead to significant in-vivo complement activation. CONCLUSION: This study provides evidence that iron dextran and ferric carboxymaltose have complement-activating capacities in-vitro, and hypersensitivity reactions to these drugs could be CARPA-mediated.

Interventions for chronic kidney disease-associated restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) is defined as the spontaneous movement of the limbs (mainly legs) associated with unpleasant, sometimes painful sensation which is relieved by moving the affected limb. Prevalence of RLS among people on dialysis has been estimated between 6.6% and 80%. RLS symptoms contribute to impaired quality of life and people with RLS are shown to have increased cardiovascular morbidity and mortality.Various pharmacological and non-pharmacological interventions have been used to treat primary RLS. However, the evidence for use of these interventions in people with chronic kidney disease (CKD) is not well established. The agents used in the treatment of primary RLS may be limited by the side effects in people with CKD due to increased comorbidity and altered drug pharmacokinetics. OBJECTIVES: The aim of this review was to critically look at the benefits, efficacy and safety of various treatment options used in the treatment of RLS in people with CKD and those undergoing renal replacement therapy (RRT). We aimed to define different group characteristics based on CKD stage to assess the applicability of a particular intervention to an individual patient. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register to 12 January 2016 through contact with the Information Specialist using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCT) and quasi-RCTs that assessed the efficacy of an intervention for RLS in adults with CKD were eligible for inclusion. Studies investigating idiopathic RLS or RLS secondary to other causes were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility and conducted risk of bias evaluation. Results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. MAIN RESULTS: We included nine studies enrolling 220 dialysis participants. Seven studies were deemed to have moderate to high risk of bias. All studies were small in size and had a short follow-up period (two to six months). Studies evaluated the effects of six different interventions against placebo or standard treatment. The interventions studied included aerobic resistance exercise, gabapentin, ropinirole, levodopa, iron dextran, and vitamins C and E (individually and in combination).Aerobic resistance exercise showed a significant reduction in severity of RLS compared to no exercise (2 studies, 48 participants: MD -7.56, 95% CI -14.20 to -0.93; I2 = 65%), and when compared to exercise with no resistance (1 study, 24 participants: MD -11.10, 95% CI -17.11 to -5.09), however there was no significant reduction when compared to ropinirole (1 study, 22 participants): MD -0.55, 95% CI -6.41 to 5.31). There were no significant differences between aerobic resistance exercise and either no exercise or ropinirole in the physical or mental component summary scores (using the SF-36 form). Improvement in sleep quality varied. There was no significant difference in subjective sleep quality between exercise and no exercise; however one study reported a significant improvement with ropinirole compared to resistance exercise (MD 3.71, 95% CI 0.89 to 6.53). Using the Epworth Sleepiness Scale there were no significant differences between resistance exercise and no exercise, ropinirole, or exercise with no resistance. Two studies reported there were no adverse events and one study did not mention if there were any adverse events. In one study, one patient in each group dropped out but the reason for dropout was not reported. Two studies reported no adverse events and one study did not report adverse events.Gabapentin was associated with reduced RLS severity when compared to placebo or levodopa, and there was a significant improvement in sleep quality, latency and disturbance reported in one study when compared to levodopa. Three patients dropped out due to lethargy (2 patients), and drowsiness, syncope and fatigue (1 patient).Because of a short duration of action, rebound and augmentation were noted with levodopa treatment even though it conferred some benefit in reducing the symptoms of RLS. Reported adverse events were severe vomiting, agitation after caffeine intake, headaches, dry mouth, and gastrointestinal symptoms.One study (25 participants) reported iron dextran reduced the severity of RLS at weeks one and two, but not at week four. Vitamins C, E and C plus E (1 study, 60 participants) helped the symptoms of RLS with minimal side effects (nausea and dyspepsia) but more evidence is needed before any conclusions can be drawn. AUTHORS' CONCLUSIONS: Given the small size of the studies and short follow-up, it can only be concluded that pharmacological interventions and intra-dialytic exercise programs have uncertain effects on RLS in haemodialysis patients. There have been no studies performed in non-dialysis CKD, peritoneal dialysis patients, or kidney transplant recipients. Further studies are warranted before any conclusions can be drawn. Aerobic resistance exercise and ropinirole may be suitable interventions for further evaluation.

Combination with intravenous iron supplementation or doubling erythropoietin dose for patients with chemotherapy-induced anaemia inadequately responsive to initial erythropoietin treatment alone: study protocol for a randomised controlled trial.

INTRODUCTION: Erythropoietin (EPO) is a commonly used option in the treatment of chemotherapy-induced anaemia (CIA). However, ∼30-50% of patients fail to achieve an adequate response after initial treatment. Prior studies have demonstrated that intravenous iron might synergistically improve therapeutic response to EPO treatment in this patient population. METHODS AND ANALYSIS: We will perform this multicentre, randomised, open-label, parallel-group, active controlled non-inferiority study to compare the two combination therapies of EPO plus intravenous iron regimen versus doubling the dose of EPO in patients with CIA who have an inadequate response to initial EPO treatment at a routine dose. A total of 603 patients with an increase in haemoglobin (Hb) <1 g/dL will be enrolled and randomised to one of the three study treatment groups at a 1:1:1 ratio Group 1: EPO treatment at the original dose plus intravenous iron dextran 200 mg every 3 weeks (Q3W) for 15 weeks; Group 2: EPO treatment at the original dose plus intravenous iron dextran 100 mg, twice a week for 5 weeks; Group 3: the control group, doubling the EPO dose without preplanned iron supplementation. The primary outcome measure to compare is the Hb response rate at week 15 and the secondary end points involve therapeutic blood transfusions. Time-to-progression, adverse events and quality of life will also be evaluated. ETHICS AND DISSEMINATION: All participants will provide informed consent; the study protocol has been approved by the independent ethics committee of Shanghai East Hospital. This study would clearly demonstrate the potential benefit of combining epoetin treatment with intravenous iron supplementation. Findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of CIA in China. TRIAL REGISTRATION NUMBER: NCT02731378.

Iron Treatment Strategies in Dialysis-Dependent CKD.

Iron deficiency is common in patients on chronic dialysis, and most require iron-replacement therapy. In addition to absolute iron deficiency, many patients have functional iron deficiency as shown by a suboptimal response to the use of erythropoietin-stimulating agents. Both absolute and functional iron-deficiency anemia have been shown to respond to intravenous (IV) iron replacement. Although parenteral iron is an efficacious method and superior to standard doses of oral iron in patients on hemodialysis, there are ongoing safety concerns about repeated exposure potentially enhancing infection risk and cardiovascular disease. Each IV iron product is composed of an iron core with a carbohydrate shell. The avidity of iron binding and the type of carbohydrate shell play roles in the safe maximal dose and the frequency and severity of acute infusion reactions. All IV iron products are taken up into the reticuloendothelial system where the shell is metabolized and the iron is stored within tissue ferritin or exported to circulating transferrin. IV iron can be given as large intermittent doses (loading therapy) or in smaller doses at frequent intervals (maintenance dosing regimen). Limited trial data and observational data suggest that a maintenance dosing regimen is more efficacious and possibly safer than loading therapy. There is no consensus regarding the preferred method of iron repletion in patients on peritoneal dialysis, although small studies comparing oral and parenteral iron regimens in these patients have shown the latter to be more efficacious. Use of IV iron in virtually all hemodialysis and many peritoneal dialysis patients remains the standard of care.

How we diagnose and treat iron deficiency anemia.

It is estimated that one-third of the world's population is anemic, the majority being due to iron deficiency (ID). In adults, ID is associated with fatigue in the absence of anemia, restless legs syndrome, pica and, in neonates, delayed growth and development. In adolescents, ID is associated with decrements in learning and behavioral abnormalities. In the absence of a clear cause, search for a source of bleeding is indicated. No single test is diagnostic of ID unless the serum ferritin is low or the percent transferrin saturation is low with an elevated total iron binding capacity. Oral iron is considered front line therapy except for conditions such as gastric bypass, heavy uterine bleeding, inflammatory bowel disease, and hereditary hemorrhagic telangiectasia. Oral iron has many unpleasant side effects, resulting in low patient adherence. For patients intolerant of, or unresponsive to, oral iron, intravenous (IV) administration is the preferred route. While early formulations were associated with a high incidence of serious adverse events (SAEs), newer formulations are much safer with SAEs occurring very infrequently. Full replacement doses can be administered in a matter of minutes to a few hours. Nevertheless, there remains a reluctance to use IV iron due to a misunderstanding of the safety of the available formulations. IV iron is safe and effective in all clinical circumstances including pregnancy. The preponderance of published evidence suggests IV iron therapy is underutilized and we believe that IV iron should be moved forward in the treatment of ID and iron deficiency anemia (IDA).

Correction of iron deficiency anaemia using IV CosmoFer in CKD patients with asthma: a prospective study.

BACKGROUND: Intravenous (IV) iron is commonly used for correcting iron deficiency anaemia in patients with chronic kidney disease (CKD). There remains a concern for its use in patients with asthma as it may trigger an acute exacerbation. Pre-treatment with a single dose of parenteral hydrocortisone may obviate this risk. METHOD: We carried out a prospective study of known asthmatic patients with CKD requiring single-dose iron repletion therapy. We analysed the efficacy and safety of IV CosmoFer (low molecular weight iron dextran). Twenty non-dialysis CKD patients with iron deficiency anaemia and a history of asthma were enrolled. Severity of asthma and level of control were recorded as per British Thoracic Society Guidelines and Royal Collage of Physician questionnaire, respectively. All patients received IV hydrocortisone 30 min before the test dose of CosmoFer followed by the remaining total dose. Patients were monitored for adverse reactions. Haemoglobin, serum ferritin levels and estimated glomerular filtration rate were measured pre and 6-weeks post-infusion. All patients were followed up until 6 weeks to assess the control of their asthma. RESULTS: All 20 patients completed the study. No patient experienced acute hypersensitivity or infusion reactions. At 6 weeks follow-up, no patient reported worsening of their asthma. There was an increase in mean haemoglobin from 10.1 to 11.1 g/dl and mean ferritin from 93.5 to 302.6 ng/ml. CONCLUSIONS: This study demonstrates that IV CosmoFer may be administered safely in asthmatics by administering a single 50 mg dose of hydrocortisone pre-infusion.