Parenteral iron nutrition: Iron dextran-poloxamer thermosensitive hydrogel for prolonged intramuscular iron supplementation.

The objective of this study was to evaluate the potential of novel poloxamer thermosensitive hydrogels (PTHs) formulations for prolonged release of iron dextran particles (IDP) for intramuscular (IM) injection. The thermosensitive behaviour helps to avoid hepcidin overexpression and toxicity by releasing IDPs without iron accumulation in injection or deposit sites. We hypothesized that novel PTH formulation would prolong iron liberation compared to the commercial iron dextran formulation (FEDEX). PTHs loaded with IDPs were developed with increasing iron content (0.1, 0.2 and 0.4 g of iron/g of poloxamer) and characterized as a prolonged release IM iron supplement. The PTHs had a biocompatible pH for IM injection (6.4) and thermosensitive viscosity, increasing from ∼50 (4 °C) to ∼3000 mPa.s (37 °C). PTHs were successfully injected in the sol state (at 4 °C) into pork meat at 37 °C, transitioning to the gel state in situ (in ∼60-190 s). Structural characterization indicated that there were no PTH-IDP chemical interactions, suggesting that IDP entrapment in PTHs was physical upon gelation. In vitro release studies revealed that iron release from PTH (0.4 g of iron/g of poloxamer) reached 100 % by day 10, whereas 100 % release from FEDEX was complete in 4 h. This novel iron PTH formulation achieved a 60 times long iron release compared to the commercial product. In conclusion, the reported strategy shows adequate IDP entrapment/release properties for prolonged iron release following ex vivo IM injection using biocompatible materials. These results provide a strong basis for future preclinical evaluation to elucidate aspects such as drug release, local irritation, biocompatibility, and efficacy.

Influence of an iron dextran injection in various diseases on hematological blood parameters, including serum ferritin, neonatal dairy calves.

BACKGROUND: Feeding milk substitutes with low iron content or whole milk without iron supplementation is considered a major factor in developing iron-deficiency anemia in neonatal dairy calves. Young calves are often supplemented with iron dextran injections on the first day of life to prevent anemia. However, the effects of preventive treatment and the presence of disease on serum iron (Fe) concentrations, serum ferritin levels, and hematological blood parameters during the early neonatal stages have not been examined in detail. Therefore, we examined and evaluated the effects of iron dextran injections and health status on the development of hematocrit (Ht), red blood cells (RBC), hemoglobin concentration (Hb), erythrocyte indices (mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration), Fe, and serum ferritin concentrations in dairy calves within the first 10 days of life. The suitability of serum ferritin as a reliable indicator of anemia in very young calves was evaluated by correlating ferritin concentrations with known laboratory diagnostic parameters of anemia. RESULTS: Iron supplementation significantly increased Fe levels (P = 0.048) but did not affect serum ferritin levels in neonatal calves. Fe concentrations were significantly lower in diseased than healthy calves (P = 0.0417). Iron supplementation significantly affected the health status, as observed in Ht (Ptreat=0.0057; Phealth=0.0097), RBC (Ptreat=0.0342; Phealth=0.0243), and Hb (Ptreat=0.0170; Phealth=0.0168). Serum ferritin levels did not significantly correlate with Fe levels. Both groups showed marked differences in ferritin levels, with the highest levels measured on day 2. Fe concentrations showed weak negative correlations with Hb and Ht levels on day 3 (ρ=-0.45; P = 0.0034 and ρ=-0.045; P = 0.0032, respectively). RBC count showed strong positive correlations with Hb and Ht levels (ρ = 0.91 and ρ = 0.93; P < 0.001). CONCLUSION: Iron dextran injections increased Fe concentrations but reduced Ht level, RBC count, and Hb level. The presence of diseases led to a reduction in Fe and higher values of Ht, RBC, and Hb in moderate disease than in severe disease. Due to physiological fluctuations during the first 3 days of life, serum ferritin level seems unuseful for evaluating iron storage before day 4 of life.

Effects of natural oral alternatives to parental iron supplementation on haematological and health-related blood parameters of organic piglets.

The most common and efficient iron supply to prevent neonatal anaemia in piglets is the injection of iron dextran or gleptoferron. This treatment is problematic in organic farms because organic specifications strictly limit the use of chemically synthesised allopathic drugs. Based on the observation that piglets raised outdoors rarely develop anaemia, we hypothesised that piglets satisfy their iron needs by ingesting soil from their environment. Therefore, we compared the efficacy of a 100-mg intramuscular iron dextran injection (Iron, 8 litters, n = 98 piglets) at 4 days (d) of age (d4), to a daily ad libitum supply of dried soil (Soil, 8 litters, n = 101) or dried peat-like river silt (Peat, 8 litters, n = 102) from d4 to weaning (at 49 days of age, d49). Pigs were raised according to organic farming rules. Blood was collected on three males and three females per litter on d4, 20, 41, 50 and 69. BW was similar in the three groups on d4, 20, 41, 50 and 69 (P > 0.1). During the experiment, piglets were affected by a severe digestive E. coli episode but litter mortality rate between d4 and d69 did not differ between groups (P > 0.1). Blood haemoglobin concentration (Hb) was similar in all groups on d4, 50 and 69. However, on d20, Hb was higher in Peat and Iron groups than in the Soil group (P < 0.001), and on d41 and d50, Hb was higher in the Peat group than in Iron and Soil groups (P < 0.001). Mean red blood cell volume (RBCV) remained stable over time in the Peat group. In comparison, RBCV dropped in the Soil group on d20 and d41 (P < 0.001), and in the Iron group on d41 (P < 0.001). Soil and Iron group RBCV returned values similar to the Peat group by d69 (P > 0.1). In conclusion, soil supply in the pen was not sufficient to ensure a satisfactory iron intake in piglets, unlike peat-like river silt, which enable to reach haemoglobin concentrations above 80 mg/mL for over 90% of the piglets from d20 and, over 100% of piglets at weaning. The daily supply of the silt proved more efficient than the 100-mg iron injection beyond 20 days.

The Impact of the Combined Effect of Inhalation Anesthetics and Iron Dextran on Rats' Systemic Toxicity.

Disruption of any stage of iron homeostasis, including uptake, utilization, efflux, and storage, can cause progressive damage to peripheral organs. The health hazards associated with occupational exposure to inhalation anesthetics (IA) in combination with chronic iron overload are not well documented. This study aimed to investigate changes in the concentration of essential metals in the peripheral organs of rats after iron overload in combination with IA. The aim was also to determine how iron overload in combination with IA affects tissue metal homeostasis, hepcidin-ferritin levels, and MMP levels according to physiological, functional, and tissue features. According to the obtained results, iron accumulation was most pronounced in the liver (19×), spleen (6.7×), lungs (3.1×), and kidneys (2.5×) compared to control. Iron accumulation is associated with elevated heavy metal levels and impaired essential metal concentrations due to oxidative stress (OS). Notably, the use of IA increases the iron overload toxicity, especially after Isoflurane exposure. The results show that the regulation of iron homeostasis is based on the interaction of hepcidin, ferritin, and other proteins regulated by inflammation, OS, free iron levels, erythropoiesis, and hypoxia. Long-term exposure to IA and iron leads to the development of numerous adaptation mechanisms in response to toxicity, OS, and inflammation. These adaptive mechanisms of iron regulation lead to the inhibition of MMP activity and reduction of oxidative stress, protecting the organism from possible damage.

Intraperitoneal supplementation of iron alleviates dextran sodium sulfate-induced colitis by enhancing intestinal barrier function.

Iron supplementation is necessary for the treatment of anemia, one of the most frequent complications in inflammatory bowel disease (IBD). However, oral iron supplementation leads to an exacerbation of intestinal inflammation. Gut barrier plays a key role in the pathogenesis of IBD. The aim of this study was to characterize the interrelationship between systemic iron, intestinal barrier and the development of intestinal inflammation in a dextran sulfate sodium (DSS) induced experimental colitis mice model. We found that DSS-treated mice developed severe inflammation of colon, but became much healthy when intraperitoneal injection with iron. Iron supplementation alleviated colonic and systemic inflammation by lower histological scores, restorative morphology of colonic villi, and reduced expression of pro-inflammatory cytokines. Moreover, intraperitoneal supplementation of iron enhanced intestinal barrier function by upregulating the colonic expressions of tight junction proteins, restoring intestinal immune homeostasis by regulating immune cell infiltration and T lymphocyte subsets, and increasing mucous secretion of goblet cells in the colon. High-throughput sequencing of fecal 16 S rRNA showed that iron injection significantly increased the relative abundance of Bacteroidetes, which was suppressed in the gut microbiota of DSS-induced colitis mice. These results provided evidences supporting the protective effects of systemic iron repletion by intraperitoneal injection of iron on intestinal barrier functions. The finding highlights a novel approach for the treatment of IBD with iron injection therapy.

A multicenter study evaluating the effectiveness and safety of single-dose low molecular weight iron dextran vs single-dose ferumoxytol for the treatment of iron deficiency.

There are multiple intravenous (IV) iron formulations available, of which several may be administered as single-dose infusions such as low-molecular weight iron dextran (LMWID), ferumoxytol, ferric carboxymaltose, and ferric derisomaltose. However, administration of ferumoxytol as a single-dose infusion is off-label as it is approved as a two-dose series. Previous studies of ferumoxytol alone support the effectiveness and safety of the single-dose regimen, but there is a paucity of data directly comparing single-dose ferumoxytol to other single-dose IV iron formulations. This multicenter cohort study sought to affirm the safety and effectiveness of single-dose ferumoxytol compared to single-dose LMWID. Overall, 906 patients who received single-dose LMWID (n = 439) or ferumoxytol (n = 467) were identified, of whom 351 met criteria for the primary effectiveness endpoint defined as median change in hemoglobin (Hb), hematocrit (Hct), and ferritin 8 to 12 weeks from baseline. All 906 patients were included for the secondary analysis evaluating the incidence of adverse events (AE) and requirement of additional IV iron infusions. Median change in Hb (LMWID 0.5 g/dL; ferumoxytol 0.8 g/dL; P = .24), Hct (LMWID 1.1%; ferumoxytol 1.25%; P = .89), and ferritin (LMWID 87 ng/dL; ferumoxytol 71 ng/dL; P = .47) was not significantly different between groups. Both groups experienced similar rates of AEs (LMWID 2.3%; ferumoxytol 2.8%; P = .63). The LMWID patients more frequently required additional IV iron infusions (LMWID 28.5%; ferumoxtyol 16.1%; P < .001). These findings support that single-dose ferumoxytol is effective and safe, and that patients may require fewer additional infusions compared to patients who received LMWID.

Effects of increasing Fe dosage in newborn pigs on suckling and subsequent nursery performance and hematological and immunological criteria.

A total of 336 newborn pigs (DNA 241 × 600, initially 1.75 ± 0.05 kg bodyweight [BW]) from 28 litters were used in a 63-d study evaluating the effects of increasing injectable Fe dose on suckling and subsequent nursery pig performance and blood Fe status. GleptoForte (Ceva Animal Health, LLC, Lenexa, KS) contains gleptoferron which is an Fe macromolecule complex that is commercially used as an injectable Fe source for suckling piglets. On the day of processing (day 3 after birth), all piglets were weighed and 6 barrows and 6 gilts per litter were allotted within sex to 1 of 6 treatments in a completely randomized design. Treatments consisted of a negative control receiving no Fe injection and increasing injectable Fe to achieve either 50, 100, 150, 200 mg, or 200 mg plus a 100 mg injection on day 11 after birth. Pigs were weaned (~21 d of age) and allotted to nursery pens based on BW and corresponding treatment in a completely randomized design. During lactation, increasing injectable Fe up to 100 mg improved (quadratic; P < 0.05) average daily gain (ADG) and day 21 BW with no further improvement thereafter. There was no evidence of differences (P > 0.10) observed between the 200 mg and 200 mg + 100 mg treatments for growth. For the nursery period, increasing Fe dosage increased (linear; P < 0.05) ADG, average daily feed intake, and day 42 BW. There was no evidence of differences (P > 0.10) between the 200 mg and 200 mg + 100 mg treatments for nursery growth. For blood criteria, significant treatment × day interactions (P = 0.001) were observed for hemoglobin (Hb) and hematocrit (Hct). The interactions occurred because pigs that had <150 mg of injectable Fe had decreased values to day 21 and then increased to day 63 while pigs with 150 or 200 mg of injectable Fe had increased values to day 21 then stayed relatively constant to day 63. In summary, piglet performance during lactation was maximized at 100 mg while nursery growth performance and blood Fe status were maximized with a 200 mg Fe injection at processing. Providing an additional 100 mg of Fe on day 11 of age increased Hb, and Hct values at weaning and 14 d into the nursery but did not provide a growth performance benefit in lactation or nursery. These results indicate that providing 200 mg of injectable Fe provided from GleptoForte is sufficient to optimize lactation and subsequent nursery growth performance and blood Fe status.

Consequences of parenteral iron-dextran loading investigated in minipigs. A new model of transfusional iron overload.

Patients with blood transfusion-dependent anemias develop transfusional iron overload (TIO), which may cause cardiosiderosis. In patients with an ineffective erythropoiesis, such as thalassemia major, common transfusion regimes aim at suppression of erythropoiesis and of enteral iron loading. Recent data suggest that maintaining residual, ineffective erythropoiesis may protect from cardiosiderosis. We investigated the common consequences of TIO, including cardiosiderosis, in a minipig model of iron overload with normal erythropoiesis. TIO was mimicked by long-term, weekly iron-dextran injections. Iron-dextran loading for around one year induced very high liver iron concentrations, but extrahepatic iron loading, and iron-induced toxicities were mild and did not include fibrosis. Iron deposits were primarily in reticuloendothelial cells, and parenchymal cardiac iron loading was mild. Compared to non-thalassemic patients with TIO, comparable cardiosiderosis in minipigs required about 4-fold greater body iron loads. It is suggested that this resistance against extrahepatic iron loading and toxicity in minipigs may at least in part be explained by a protective effect of the normal erythropoiesis, and additionally by a larger total iron storage capacity of RES than in patients with TIO. Parenteral iron-dextran loading of minipigs is a promising and feasible large-animal model of iron overload, that may mimic TIO in non-thalassemic patients.

High Prevalence of Iron Deficiency Despite Standardized High-Dose Iron Supplementation During Recombinant Erythropoietin Therapy in Extremely Low Gestational Age Newborns.

OBJECTIVE: To assess the effects of protocolized recombinant human erythropoietin (r-HuEPO) therapy and standardized high dose iron supplementation on hematologic and iron status measures in a cohort of extremely low gestational age newborns (ELGANs). STUDY DESIGN: Charts of extremely low gestational age newborns admitted from 2006 to 2016 and who had received r-HuEPO per neonatal intensive care unit protocol were reviewed. The r-HuEPO was started at a dose of 900 IU/kg per week after 7 days of age and continued until 35 weeks postmenstrual age. Oral iron supplementation at 6-12 mg/kg per day was used to maintain a transferrin saturation of >20% during r-HuEPO treatment. Data on demographic features, hematologic and iron panel indices, red blood cell transfusions, and clinical outcomes were collected. Quartile groups were created based on serum ferritin levels at the conclusion of the r-HuEPO treatment and the quartiles were compared. RESULTS: The cohort included 116 infants with mean gestational age 25.8 ± 1.5 weeks and birth weight 793 ± 174.1 g. The r-HuEPO promoted erythropoiesis as indicated by increasing hemoglobin, hematocrit, and reticulocyte count. Serum ferritin decreased over time and was ≤75 ng/mL in 60.2% of infants at the conclusion of r-HuEPO therapy; 87% received packed red blood cell transfusions. Transfusion volume, total iron intake, total iron binding capacity, and transferrin concentration differed among infants in the different serum ferritin quartiles (P < .05). CONCLUSIONS: In extremely low gestational age newborns, r-HuEPO therapy promoted erythropoiesis. Despite a biomarker-based standardized high-dose iron supplementation, the majority of infants had evidence of iron deficiency to a degree that is associated with reduced brain function.

Evaluation of the reported rates of hypersensitivity reactions associated with iron dextran and ferric carboxymaltose based on global data from VigiBase™ and IQVIA™ MIDAS® over a ten-year period from 2008 to 2017.

Objectives: It is hypothesized that the risk of hypersensitivity reactions (HSRs) may be lower with ferric carboxymaltose than iron dextran because of its non-dextran carbohydrate moiety. This study compares the risk of HSRs between iron dextran and ferric carboxymaltose.Methods: This was a retrospective pharmacoepidemiological study with a case-population design covering 2008-2017. Global exposure data were estimated using IQVIA™ sales data. Spontaneously reported HSR data were retrieved from the World Health Organization database (VigiBase™) using different search criteria including: the Standardized MedDRA® Query (SMQ) 'Anaphylactic reaction'; type I-IV HSR terms; narrow terms for anaphylactic/anaphylactoid reactions; and cases with a fatal outcome.Results: Total exposure in 100 mg doses was 117.3 million for iron dextran and 84.2 million for ferric carboxymaltose. The relative risk (with 95% confidence interval) for ferric carboxymaltose versus iron dextran was 4.18 (3.88-4.50) for SMQ Anaphylactic reaction; 12.9 (9.90-16.7) for type I-IV HSRs; 1.72 (1.45-2.04) for anaphylactic/anaphylactoid reactions; and 1.92 (1.24-2.99) for death.Conclusion: The risk of spontaneously reported HSRs was consistently higher with ferric carboxy-maltose than with iron dextran over the period 2008-2017. Thus, this study does not support that dextran-free intravenous irons are associated with fewer HSRs than iron dextran.

Comparison of Oral and Parenteral Iron Administration on Iron Homeostasis, Oxidative and Immune Status in Anemic Neonatal Pigs.

The present study was to evaluate the consequences of iron status across oral and parenteral iron administrations in prevention of iron deficiency anemia. A total of 24 one-day-old male neonatal piglets were allocated into three groups given non-iron supplementation (NON), intramuscular iron dextran injection (FeDex), and oral administration of ferrous glycine chelate (FeGly), respectively. At day 8, no significant differences in final body weight, average weight gain, and tissue coefficients were observed among three groups (P > 0.05). Both oral FeGly and FeDex injection significantly increased serum iron, ferritin, hemoglobin, and tissue iron deposition (P < 0.05). However, FeDex-injected supplementation resulted in rapidly rising hepcidin levels and hepatic iron deposition (P < 0.05). In addition, compared to parenteral iron supplementation, greater serum IgA level, SOD, and GSH-Px activities, lower expressions of IL-1ß and TNF-α in the liver, and lower expressions of IL-6 and TNF-α in the spleen were found in oral iron piglets (P < 0.05). According to our results, oral administration of ferrous glycine chelate improved iron homeostasis, and oxidative and immune status in anemic neonatal pigs.

Long-term Effect of Split Iron Dextran/Hemoglobin Supplementation on Erythrocyte and Iron Status, Growth Performance, Carcass Parameters, and Meat Quality of Polish Large White and 990 Line Pigs.

Heme is an efficient dietary iron supplement applied in humans and animals to prevent iron deficiency anemia (IDA). We have recently reported that the use of bovine hemoglobin as a dietary source of heme iron efficiently counteracts the development of IDA in young piglets, which is the common problem in pig industry. Here, we used maternal Polish Large White and terminal sire breed (L990) pigs differing in traits for meat production to evaluate the long-term effect of split supplementation with intramuscularly administered small amount of iron dextran and orally given hemoglobin on hematological indices, iron status, growth performance, slaughter traits, and meat quality at the end of fattening. Results of our study show that in pigs of both breeds split supplementation was effective in maintaining physiological values of RBC and blood plasma iron parameters as well as growth performance, carcass parameters, and meat quality traits. Our results prove the effectiveness of split iron supplementation of piglets in a far-reach perspective.

Iron Accumulates in Retinal Vascular Endothelial Cells But Has Minimal Retinal Penetration After IP Iron Dextran Injection in Mice.

Purpose: Iron supplementation therapy is used for iron-deficiency anemia but has been associated with macular degeneration in a 43-year-old patient. Iron entry into the neurosensory retina (NSR) can be toxic. It is important to determine conditions under which serum iron might cross the blood retinal barrier (BRB) into the NSR. Herein, an established mouse model of systemic iron overload using high-dose intraperitoneal iron dextran (IP FeDex) was studied. In addition, because the NSR expresses the iron regulatory hormone hepcidin, which could limit iron influx into the NSR, we gave retina-specific hepcidin knockout (RS-HepcKO) mice IP FeDex to test this possibility. Methods: Wild-type (WT) and RS-HepcKO mice were given IP FeDex. In vivo retina imaging was performed. Blood and tissues were analyzed for iron levels. Quantitative PCR was used to measure levels of mRNAs encoding iron regulatory and photoreceptor-specific genes. Ferritin and albumin were localized in the retina by immunofluorescence. Results: IP FeDex in both WT and RS-HepcKO mice induced high levels of iron in the liver, serum, retinal vascular endothelial cells (rVECs), and RPE, but not the NSR. The BRB remained intact. Retinal degeneration did not occur. Conclusions: Following injection of high-dose IP FeDex, iron accumulated in the BRB, but not the NSR. Thus, the BRB can shield the NSR from iron delivered in this manner. This ability is not dependent on NSR hepcidin production.

T2 ∗ Relaxation Time Obtained from Magnetic Resonance Imaging of the Liver Is a Useful Parameter for Use in the Construction of a Murine Model of Iron Overload.

Aim: Iron overload is a life-threatening disorder that can increase the risks of cancer, cardiovascular disease, and liver cirrhosis. There is also a risk of iron overload in patients with chronic kidney disease. In patients with renal failure, iron storage is increased due to inadequate iron utilization associated with decreased erythropoiesis and also to the inflammatory status. To evade the risk of iron overload, an accurate and versatile indicator of body iron storage in patients with iron overload is needed. In this study, we aimed to find useful iron-related parameters that could accurately reflect body iron storage in mice in order to construct a murine model of iron overload. Methods: To select an appropriate indicator of body iron status, a variety of parameters involved in iron metabolism were evaluated. Noninvasively measured parameters were R1, R2, and R2 ∗ derived from magnetic resonance imaging (MRI). Invasively measured parameters included serum hepcidin levels, serum ferritin levels, and liver iron contents. Histopathological analysis was also conducted. Results/Conclusion: Among the several parameters evaluated, the MRI T2 ∗ relaxation time was able to detect iron storage in the liver as sensitively as serum ferritin levels. Moreover, it is expected that using an MRI parameter will allow accurate evaluation of body iron storage in mice over time.

An assessment for diagnostic and therapeutic modalities for management of pediatric Iron defficiency Anemia in Saudi Arabia: a crossectional study.

INTRODUCTION: Iron deficiency anemia (IDA) is a global public health issue that affect more than 2 billion individuals worldwide. However evidence for optimal management of IDA is lacking. METHODS: To assess the diagnostic criteria and therapeutic modalities for pediatric IDA employed by physicians in a major public healthcare facility in Riyadh, a validated questionnaire including demographic data and patient case-scenarios related to diagnosis and treatment of IDA was employed. Robust regression analysis was used to identify factors associated with overall score of participants. RESULTS: Of the 166 physicians surveyed 147(88.6%) were included in the study. Wide variability was observed in IDA diagnosis and therapy practises. For nutritional IDA, only 15.6% recommended no other laboratory tests in addition to CBC. The majority preferred treatment with ferrous sulfate (77.6%) divided into two doses (57.1%), but the total daily elemental iron doses varied widely from 2 to 6 mg/kg. For intravenous iron, 42.9% recommended iron dextran, 32.7% iron sucrose, and 13.4% would continue oral iron. Of all assessed factors, median score was significantly highest in pediatric hematologists compared with pediatricians, family medicine specialists and GPs; p = 0.007, and those work in tertiary care compared with those in primary care; p = 0.043. However, in multivariate robust regression analysis, overall score was only significantly associated with professional qualification [pediatric hematologist ß = 13.71,95%CI 2.48-24.95, p = 0.017; pediatrician ß = 1.77,95%C (- 6.05-9.59, p = 0.66; family medicine ß = 2.66,95%CI-4.30-9.58, p = 0.45 compared with general practitioner]. CONCLUSION: Wide variations exist among physicians in diagnosis and treatment of pediatric IDA. Intervention programs and national guidelines are urgently needed.

Intravenous iron supplementation does not increase infectious disease risk in hemodialysis patients: a nationwide cohort-based case-crossover study.

BACKGROUND: Studies have reported conflicting findings on the infection risk posed by intravenous iron supplementation among hemodialysis (HD) patients. We used a novel study design to assess associations between intravenous iron and infectious diseases. METHODS: Patients initiating HD between 1998 and 2008 were extracted from Taiwan's National Health Insurance Research Database. Their first infectious disease in the period between 1.5 years after dialysis initiation and 2010 was identified and defined as the index date. Through the case-crossover design, the odds of exposure to intravenous iron within the 1-month period immediately preceding the index date (i.e., the case period) were compared with iron exposure in three different matched control periods for the same enrollee, thus possibly reducing some unmeasured confounders. RESULTS: A total of 1410 patients who met our enrollment criteria were extracted from incident HD patients. The odds of intravenous iron exposure during the case period versus total control periods exhibited no significant difference (odds ratio: 1.000, 95% confidence interval: 0.75-1.33). In subgroup analyses, this association remained nonsignificant across patients with diabetes mellitus, heart failure, chronic lung disease, venous catheter for HD, and higher iron load. CONCLUSIONS: We found that intravenous iron supplementation did not increase short-term infection risk among HD patients.

Protocol and baseline data for a prospective open-label explorative randomized single-center comparative study to determine the effects of various intravenous iron preparations on markers of oxidative stress and kidney injury in chronic kidney disease (IRON-CKD).

BACKGROUND: Intravenous (IV) iron is frequently used to treat iron deficiency/anemia in patients who are unable to tolerate oral iron or the oral iron is not sufficient toreplete iron requirements. However, safety concerns regarding the potential increase in oxidative stress and other adverse effects persist and it remains unclear whether all iron preparations are equivalent. Indeed, the comparative risk of adverse events with IV iron preparations has not been extensively assessed. We hypothesize that IV iron leads to changes in oxidative stress, endothelial function, and potential renal damage depending on the iron formulation (related to the generation of "free" or catalytic labile iron) and this may result in more tubular and glomerular injury manifested as increased proteinuria and raised neutrophil gelatinase-associated lipocalin (NGAL) levels in patients with chronic kidney disease (CKD). METHODS: IRON-CKD is a prospective, open-label, explorative, randomized, single-center study designed to compare the safety and efficacy of three parenteral iron preparations: low-molecular-weight iron dextran-Cosmofer, iron sucrose-Venofer, and iron isomaltoside-Monofer. The study includes 40 adults who have established CKD stages 3-5 and serum ferritin (SF) of less than 200 µg/L or transferrin saturation (TS) of less than 20% (or both); they were randomly assigned in a 1:1:1:1 ratio to 200 mg iron dextran, 200 mg iron sucrose, 200 mg iron isomaltoside, or 1000 mg iron isomaltoside. After randomization, participants undergo baseline assessments and then an iron infusion. Each participant is followed up at 2 h, day 1, week 1, and months 1 and 3. At each follow-up visit, patients undergo clinical review, measurement of pulse wave velocity (PWV), blood tests for renal function, and collection of serum/plasma samples for oxidative stress and inflammatory markers. The primary outcomes are measures of oxidative stress, inflammatory markers, and markers of acute renal injury in comparison with baseline measures of each iron preparation and between each of the iron preparations. Secondary objectives include effects on hematinic profiles and hemoglobin concentrations, changes in arterial stiffness, incidence of significant side effects, and change in patients' quality of life. RESULTS: Between October 2015 and April 2018, 521 individuals were identified as potential participants; 216 were contacted, 56 expressed an interest, 49 attended a screening visit, and 40 were confirmed to meet the eligibility criteria and were randomly assigned. The mean age was 58.8 (standard error of the mean 2.2) years, and 23 (58%) were male. All patients were white and English-speaking. The mean SF was 68.8 µg/L, TS was 21.4%, and haemoglobin was 122.6 g/L at randomization for the whole group. The mean estimated glomerular filtration rate was 28.2 mL/min/1.73 m2 the urinary protein/ creatinine ratio was 154.2 mg/mmol, and CRP was 7.5 mg/L. DISCUSSION: IRON-CKD will provide important information on the short-term effects of three preparations of IV iron in CKD patients with biochemical functional or absolute iron deficiency on measures of oxidative stress, inflammation, endothelial function, and renal injury. TRIAL REGISTRATION: European Clinical Trials Database (EudraCT) number 2010-020452-64 .

Safety of Intravenous Iron - Cosmofer and Monofer Therapy in Peritoneal Dialysis and Non-Dialysis-Dependent Chronic Kidney Disease Patients.

Safety of parenteral iron therapy is critical and has been demonstrated in several studies, but concerns persist on safety. We performed a retrospective single-center study investigating the safety and efficacy of parenteral iron administration using 2 iron preparations-Monofer and Cosmofer (Pharmacosmos A/S, Holbaek, Denmark)-in patients with chronic kidney disease (CKD), on peritoneal dialysis (PD) and non-dialysis. A database of CKD patients receiving intravenous (IV) iron was analyzed. Side effects were recorded during infusion, post-infusion, and after 48 hours. In a population of CKD patients (non-dialysis and PD), IV iron is safe with few major adverse effects for these 2 IV iron preparations studied with similar dosing schedules. These data provide reassurance on the relative short-term safety of IV iron preparations regarding acute infusion-related hypersensitivity reactions.

Transient power elevation during iron dextran infusion in a patient with a continuous-flow left ventricular assist device.

Anemia is common in patients with mechanical circulatory support and is associated with increased morbidity. Repletion using parenteral iron infusions has been proven to be beneficial in patients with heart failure. In this report, we describe a case of increased power and flows of continuous-flow left ventricular assist device (LVAD) during an iron dextran infusion. We subsequently studied the effects of iron dextran infusion in an in vitro LVAD mock circulatory loop. The observed increase in flow and power was most likely due to drug-patient interaction rather than drug-LVAD interaction. Mock loops and in vivo animal models may be necessary for proactive evaluation of the safety of intravenous (IV) preparations in this patient population.

Treatment of Iron Deficiency Anemia in Pregnancy with Intravenous versus Oral Iron: Systematic Review and Meta-Analysis.

OBJECTIVE: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the benefits of intravenous (IV) iron in pregnancy. STUDY DESIGN: Systematic review was registered with PROSPERO and performed using PRISMA guidelines. PubMed, MEDLINE, Web of Science, ClinicalTrials.gov, Cochrane Library, and Google Scholar were searched. Eleven RCTs, comparing IV to oral iron for treatment of iron-deficiency anemia in pregnancy, were included. Meta-analyses were performed with Stata software (College Station, TX), utilizing random effects model and method of DerSimonian and Laird. Outcomes were assessed by pooled odds ratios (OR) or pooled weighted mean difference (WMD). Sensitivity analyses were performed for heterogeneity. RESULTS: We found that pregnant women receiving IV iron, compared with oral iron, had the following benefits: (1) Achieved target hemoglobin more often, pooled OR 2.66 (95% confidence interval [CI]: 1.71-4.15), p < 0.001; (2) Increased hemoglobin level after 4 weeks, pooled WMD 0.84 g/dL (95% CI: 0.59-1.09), p < 0.001; (3) Decreased adverse reactions, pooled OR 0.35 (95% CI: 0.18-0.67), p = 0.001. Results were unchanged following sensitivity analyses. CONCLUSION: In this meta-analysis, IV iron is superior to oral iron for treatment of iron-deficiency anemia in pregnancy. Women receiving IV iron more often achieve desired hemoglobin targets, faster and with fewer side effects.