Ferric Citrate Research Articles

Preparation and Characteristics of Biomass Gel Foam with High Foaming and Film-Forming Properties for Preventing Coal Spontaneous Combustion

ABSTRACT To overcome the problem of poor biocompatibility of inorganic gel foam, a biomass gel foam was prepared using carboxymethyl chitosan, tannic acid, and ammonium ferric citrate as raw materials. The results indicated that the gel foam exhibited optimal comprehensive performance when the mass concentrations of foaming agent, stabilizer, gelling agent, and crosslinking agent were 0.8, 0.2, 0.9, and 0.6 wt%, respectively. At this point, the foaming multiple was up to 8 and the half-life was 7.79 days. Compared to pure foam, the gel foam demonstrated excellent water retention and film-forming properties. After continuous heating at 80°C for 10 hours, its water retention rate remained as high as 49.34%. The foam film formed after 120 hours of room temperature drying reached a thickness of 1 cm without any liquid separation phenomenon. The gel foam exhibited a good inhibition effect on the spontaneous combustion and oxidation process of coal. The CO inhibition rate reached 67.43% at 100°C, and the cross-point temperature was effectively delayed by 18.2°C. Moreover, the gel foam exhibited excellent burn resistance properties.

Ferric citrate and apo-transferrin enable erythroblast maturation with β-globin from hemogenic endothelium

Red blood cell (RBC) generation from human pluripotent stem cells (PSCs) offers potential for innovative cell therapy in regenerative medicine as well as developmental studies. Ex vivo erythropoiesis from PSCs is currently limited by the low efficiency of functional RBCs with β-globin expression in culture systems. During induction of β-globin expression, the absence of a physiological microenvironment, such as a bone marrow niche, may impair cell maturation and lineage specification. Here, we describe a simple and reproducible culture system that can be used to generate erythroblasts with β-globin expression. We prepared a two-dimensional defined culture with ferric citrate treatment based on definitive hemogenic endothelium (HE). Floating erythroblasts derived from HE cells were primarily CD45+CD71+CD235a+ cells, and their number increased remarkably upon Fe treatment. Upon maturation, the erythroblasts cultured in the presence of ferric citrate showed high transcriptional levels of β-globin and enrichment of genes associated with heme synthesis and cell cycle regulation, indicating functionality. The rapid maturation of these erythroblasts into RBCs was observed when injected in vivo, suggesting the development of RBCs that were ready to grow. Hence, induction of β-globin expression may be explained by the effects of ferric citrate that promote cell maturation by binding with soluble transferrin and entering the cells.Taken together, upon treatment with Fe, erythroblasts showed advanced maturity with a high transcription of β-globin. These findings can help devise a stable protocol for the generation of clinically applicable RBCs.

Cardamonin protects against iron overload induced arthritis by attenuating ROS production and NLRP3 inflammasome activation via the SIRT1/p38MAPK signaling pathway

Iron homeostasis plays an essential role in joint health, while iron overload can cause damage and death of cartilage cells. Cardamonin (CAR) is a substance found in the fruit of the chasteberry plant and has anti-inflammatory and anti-tumor activities. We first administered iron dextran (500 mg/kg) intraperitoneally to establish an iron overload mouse model and surgically induced osteoarthritis. The extent of OA and iron deposition were assessed using Micro-ct, Safranin-O/fast green staining, H&E staining, and Prussian Blue 10 weeks later. We administered primary chondrocytes with Ferric Ammonium Citrate (FAC) to evaluate the chondrocyte changes. Chondrocytes were identified in vitro by toluidine blue staining, and chondrocyte viability was evaluated by CCK-8. The rate of apoptosis was determined by Annexin V-FITC/PI assay. The mechanism of action of CAR was verified by adding the SIRT1 inhibitor EX527, and the expression of SIRT1 and MAPK signaling pathways was detected by Western blot. Iron overload also promoted chondrocyte apoptosis, a process that was reversed by CAR. In addition, CAR reduced NLRP3 inflammasome production via the SIRT1-MAPK pathway, and the SIRT1 inhibitor EX527 inhibited the treatment of OA by CAR.CAR inhibited cartilage degeneration induced by iron overload both in vivo and in vitro. Besides, our study showed that iron overload not only inhibited type II collagen expression but also induced MMP expression by catalyzing the generation of NLRP3 inflammasome. Our results suggest that CAR can treat KOA by promoting SIRT1 expression and inhibiting p38MAPK pathway expression to reduce the production of NLRP3 inflammasome vesicles.

Comparative Efficacy and Acceptability of 12 Phosphorus-Lowering Drugs in Adults with Hyperphosphatemia and Chronic Kidney Disease: A Systematic Review and Network Meta-Analysis

Background: Hyperphosphatemia is associated with cardiovascular morbidity and mortality in adults with chronic kidney disease (CKD). Drug therapy has an irreplaceable role in the management of hyperphosphatemia. Objectives: We aimed to compare and rank phosphorus-lowering drugs, including phosphate binder and nonphosphate binder, in hyperphosphatemia adults with CKD. Methods: We did a systematic review and frequentist random-effect network meta-analysis. We searched in PubMed, Cochrane Library, Web of Science, and Embase from inception to February 1, 2023, for randomized controlled trials of 12 phosphorus-lowering drugs in adults with hyperphosphatemia and CKD. Primary outcomes were efficacy (changes in serum phosphorus) and acceptability (treatment withdrawals due to any cause). We ranked each drug according to the value of surface under the cumulative ranking curve. We applied the Confidence in Network Meta-Analysis frameworks to rate the certainty of evidence. This study was registered with PROSPERO, number CRD42022322270. Results: We identified 2,174 citations, and of these, we included 94 trials comprising 14,459 participants and comparing 13 drugs or placebo. In terms of efficacy, except for niacinamide, all drugs lowered the level of serum phosphorus compared with placebo, with mean difference ranging between −1.61 (95% credible interval [CrI], −2.60 to −0.62) mg/dL for magnesium carbonate and −0.85 (−1.66 to −0.05) mg/dL for bixalomer. Only ferric citrate with odds ratios 0.56 (95% CrI: 0.36–0.89) was significantly associated with fewer dropouts for acceptability. Of the 94 trials, 43 (46%), 7 (7%), and 44 (47%) trials were rated as high, moderate, and low risk of bias, respectively, the certainty of the evidence was moderate to very low. Conclusions: Magnesium carbonate has the best phosphorus-lowering effect in hyperphosphatemia adults with CKD; considering efficacy and acceptability, ferric citrate shows evidence to be the most appropriate drug with or without dialysis.

The role of ferric citrate in a sample of Iraqi patients on hemodialysis- A randomized controlled clinical trial

Background: Uncontrolled hyperphosphatemia is the main difficulty facing staff treating patients with end-stage renal disease on hemodialysis. Sevelamer and calcium-containing phosphate binders have been associated with cost burden and tissue calcification, respectively. Therefore, the current trial was targeted to investigate the efficacy of a new phosphate binder, ferric citrate, in a sample of Iraqi patients with end-stage renal disease on hemodialysis. Keywords: Ferric citrate, Hemodialysis Phosphate binder

A light-responsive wound dressing hydrogel: Gelatin based self-healing interpenetrated network with metal-ligand interaction by ferric citrate.

Interpenetrated network (IPN) hydrogels with desired mechanical properties were prepared based on gelatin. A copolymer of dimethyl aminoethyl methacrylate (DMAEMA) with 2-Acrylamido-2-methylpropane sulfonic acid (AMPS) in gelatin was chemically cross-linked with methylene bis acrylamide (MBA) to form a semi-IPN hydrogel. Also, IPN hydrogel is fabricated from the AMPS-co-DMAEMA and gelatin in the presence of ferric ions with both chemical and physical cross-linkers. According to the compression test, the metal-ligand interaction has a remarkable impact on the mechanical strength of hydrogel. Ferric ions caused a decrease in the pores size confirmed by the SEM images of hydrogels, resulting in preserving its mechanical stability during the swelling test due to a more robust structure of hydrogel. Ferric to ferrous ions reduction is observed under visible light irradiation, which results in a light-sensitive hydrogel with a higher rate of biodegradation compared to semi-IPN hydrogels. MTT assay results implied that the synthesized hydrogels are non-toxic for the L-929 cell line. Also, for more detailed investigations, histological studies are conducted as in vivo tests. With regards to the improvements of mechanical properties harnessed in IPN hydrogels by ferric ions along with the extraordinary self-healing capability, IPNs would be considered an appropriate option for tissue engineering.

Synergistic Amplification of Ferroptosis with Liposomal Oxidation Catalyst and Gpx4 Inhibitor for Enhanced Cancer Therapy.

As a distinctly different way from apoptosis, ferroptosis can cause cell death through excessive accumulation of lipid peroxide (LPO) and show great potential for cancer therapy. However, efficient strategies for ferroptosis therapy are still facing great challenges, mainly due to insufficient endogenous H2 O2 or relatively high pH value for Fenton reaction-dependent ferroptosis, and the high redox level of tumor cells attenuates the oxidation therapy. Herein, an efficient lipid-based delivery system to load oxidation catalyst and glutathione peroxidase 4 (Gpx4) inhibitor is orchestrated, intending to amplify Fenton reaction-independent ferroptosis by bidirectional regulation of LPO accumulation. Ferric ammonium citrate (FAC), Gpx4 inhibitor sorafenib (SF), and unsaturated lipids are constructed into mPEG2K -DSPE-modified liposomes (Lip@SF&FAC). Influenced by the high level of intratumoral glutathione, FAC can be converted into Fe2+ , and subsequently the formed iron redox pair (Fe2+ /Fe3+ ) catalyzes unsaturated phospholipids of liposomes into LPO via a Fenton reaction-independent manner. Meanwhile, SF can downregulate LPO reduction by inhibiting Gpx4 activation. In vitro and in vivo antitumor experiments show that Lip@SF&FAC induces massive LPO accumulation in tumor cells and ultimately exhibits strong tumor-killing ability with negligible side effect. Consequently, this two-pronged approach provides a new ferroptosis strategy for predominant LPO accumulation and enhanced cancer therapy.

Plasma non-transferrin-bound iron uptake by the small intestine leads to intestinal injury and intestinal flora dysbiosis in an iron overload mouse model and Caco-2 cells.

Iron overload often occurs during blood transfusion and iron supplementation, resulting in the presence of non-transferrin-bound iron (NTBI) in host plasma and damage to multiple organs, but effects on the intestine have rarely been reported. In this study, an iron overload mouse model with plasma NTBI was established by intraperitoneal injection of iron dextran. We found that plasma NTBI damaged intestinal morphology, caused intestinal oxidative stress injury and reactive oxygen species (ROS) accumulation, and induced intestinal epithelial cell apoptosis. In addition, plasma NTBI increased the relative abundance of Ileibacterium and Desulfovibrio in the cecum, while the relative abundance of Faecalibaculum and Romboutsia was reduced. Ileibacterium may be a potential microbial biomarker of plasma NTBI. Based on the function prediction analysis, plasma NTBI led to the weakening of intestinal microbiota function, significantly reducing the function of the extracellular structure. Further investigation into the mechanism of injury showed that iron absorption in the small intestine significantly increased in the iron group. Caco-2 cell monolayers were used as a model of the intestinal epithelium to study the mechanism of iron transport. By adding ferric ammonium citrate (FAC, plasma NTBI in physiological form) to the basolateral side, the apparent permeability coefficient (Papp) values from the basolateral to the apical side were greater than 3×10-6 cm s-1. Intracellular ferritin level and apical iron concentration significantly increased, and SLC39A8 (ZIP8) and SLC39A14 (ZIP14) were highly expressed in the FAC group. Short hairpin RNA (shRNA) was used to knock down ZIP8 and ZIP14 in Caco-2 cells. Transfection with ZIP14-specific shRNA decreased intracellular ferritin level and inhibited iron uptake. These results revealed that plasma NTBI may cause intestinal injury and intestinal flora dysbiosis due to the uptake of plasma NTBI from the basolateral side into the small intestine, which is probably mediated by ZIP14.

Consideration of the Characteristics of Oral Iron Preparations from the Viewpoint of the Mechanism of Nausea and Vomiting

The nausea and vomiting that occur as a result of oral iron administration for the treatment of iron-deficiency anemia (IDA) can cause significant physical and emotional stress in patients. Because iron is absorbed from the intestine as ferrous iron, the most widely used treatment for IDA is oral ferrous agents. However, ferrous forms are more toxic than ferric forms because ferrous forms readily generate free radicals. A randomized, double-blind, active-controlled, multicenter non-inferiority study conducted in Japan showed that ferric citrate hydrate (FC) was just as effective as sodium ferrous citrate (SF) in the treatment of IDA, with a lower incidence of adverse reactions such as nausea and vomiting compared with SF. Animal studies have shown that chemotherapy-induced nausea and vomiting (CINV) involves the release of 5-hydroxytryptamine from enterochromaffin cells by free radicals, and that some chemotherapeutic agents cause hyperplasia of these cells. Enterochromaffin cells also contain substance P, which is known to be also closely related to CINV. We found that administration of SF to rats causes hyperplasia of enterochromaffin cells in the small intestine, whereas FC has no effect on enterochromaffin cells. Oral iron agents may induce nausea and vomiting via the effect of ferrous iron on reactive oxygen species production in the intestine and subsequent enterochromaffin cell hyperplasia. Further research to elucidate the detailed mechanism of enterochromaffin cell hyperplasia induced by ferrous iron preparations is needed to develop a treatment for iron deficiency anemia that causes less gastrointestinal damage.

Iron deficiency is related to lower muscle mass in community-dwelling individuals and impairs myoblast proliferation.

Loss of muscle mass is linked with impaired quality of life and an increased risk of morbidity and premature mortality. Iron is essential for cellular processes such as energy metabolism, nucleotide synthesis and numerous enzymatic reactions. As the effects of iron deficiency (ID) on muscle mass and function are largely unknown, we aimed to assess the relation between ID and muscle mass in a large population-based cohort, and subsequently studied effects of ID on cultured skeletal myoblasts and differentiated myocytes. In a population-based cohort of 8592 adults, iron status was assessed by plasma ferritin and transferrin saturation, and muscle mass was estimated using 24-h urinary creatinine excretion rate (CER). The relationships of ferritin and transferrin saturation with CER were assessed by multivariable logistic regression. Furthermore, mouse C2C12 skeletal myoblasts and differentiated myocytes were subjected to deferoxamine with or without ferric citrate. Myoblast proliferation was measured with a colorimetric 5-bromo-2'-deoxy-uridine ELISA assay. Myocyte differentiation was assessed using Myh7-stainings. Myocyte energy metabolism, oxygen consumption rate and extracellular acidification rate were assessed using Seahorse mitochondrial flux analysis, and apoptosis rate with fluorescence-activated cell sorting. RNA sequencing (RNAseq) was used to identify ID-related gene and pathway enrichment in myoblasts and myocytes. Participants in the lowest age- and sex-specific quintile of plasma ferritin (OR vs middle quintile 1.62, 95% CI 1.25-2.10, P<0.001) or transferrin saturation (OR 1.34, 95% CI 1.03-1.75, P=0.03) had a significantly higher risk of being in the lowest age- and sex-specific quintile of CER, independent of body mass index, estimated GFR, haemoglobin, hs-CRP, urinary urea excretion, alcohol consumption and smoking status. In C2C12 myoblasts, deferoxamine-induced ID reduced myoblast proliferation rate (P-trend <0.001) but did not affect differentiation. In myocytes, deferoxamine reduced myoglobin protein expression (-52%, P<0.001) and tended to reduce mitochondrial oxygen consumption capacity (-28%, P=0.10). Deferoxamine induced gene expression of cellular atrophy markers Trim63 (+20%, P=0.002) and Fbxo32 (+27%, P=0.048), which was reversed by ferric citrate (-31%, P=0.04 and -26%, P=0.004, respectively). RNAseq indicated that both in myoblasts and myocytes, ID predominantly affected genes involved in glycolytic energy metabolism, cell cycle regulation and apoptosis; co-treatment with ferric citrate reversed these effects. In population-dwelling individuals, ID is related to lower muscle mass, independent of haemoglobin levels and potential confounders. ID impaired myoblast proliferation and aerobic glycolytic capacity, and induced markers of myocyte atrophy and apoptosis. These findings suggest that ID contributes to loss of muscle mass.

High Phosphate-Binding Capacity of Oxylanthanum Carbonate with a Low Medication Volume: Comparison with Commercially Available Phosphate Binders

Background: A key focus for chronic kidney disease management is phosphate control, but currently available binders have suboptimal phosphate-binding capacity, and their characteristics result in low adherence and poor phosphate regulation. Oxylanthanum carbonate, a novel compound that uses proprietary nanoparticle technology to deliver lanthanum, has the potential to combine high phosphate-binding capacity with good intake convenience, thus improving adherence and patient quality of life. The goal of this study was to assess the volume of oxylanthanum Carbonate required to bind 1 g of phosphate and compare it with other currently available phosphate binders to determine which binder allows for the highest normalized potency with the lowest daily medication volume. Methods: Six phosphate binders were assessed: ferric citrate, calcium acetate, lanthanum carbonate, sevelamer carbonate, sucroferric oxyhydroxide, and oxylanthanum carbonate. Table volume measurements were taken using fluid displacement in corn oil or water. Mean daily dose volume to bind 1 g of phosphate was calculated as volume per tablet multiplied by the mean number of tablets taken per day. Volume to bind 1 g of phosphate was calculated by dividing the volume per tablet by its in vivo binding capacity. Results: Oxylanthanum carbonate had the lowest mean volume, daily phosphate binder dose volume, and equivalent phosphate-binding dose volume (volume to bind 1 g of phosphate for each binder). Conclusions: Oxylanthanum carbonate has the lowest daily phosphate binder dose volume and the smallest volume required to bind 1 g of phosphate compared to all other commercially available phosphate binders. A randomized trial that compares gastrointestinal tolerability across binders would be warranted to demonstrate acceptability and adherence in the target population.

5-Aminolevulinic acid bypasses mitochondrial complex I deficiency and corrects physiological dysfunctions in Drosophila.

Complex I (CI) deficiency in mitochondrial oxidative phosphorylation (OXPHOS) is the most common cause of mitochondrial diseases, and limited evidence-based treatment options exist. Although CI provides the most electrons to OXPHOS, complex II (CII) is another entry point of electrons. Enhancement of this pathway may compensate for a loss of CI; however, the effects of boosting CII activity on CI deficiency are unclear at the animal level. 5-Aminolevulinic acid (5-ALA) is a crucial precursor of heme, which is essential for CII, complex III, complex IV (CIV) and cytochrome c activities. Here, we show that feeding a combination of 5-ALA hydrochloride and sodium ferrous citrate (5-ALA-HCl + SFC) increases ATP production and suppresses defective phenotypes in Drosophila with CI deficiency. Knockdown of sicily, a Drosophila homolog of the critical CI assembly protein NDUFAF6, caused CI deficiency, accumulation of lactate and pyruvate and detrimental phenotypes such as abnormal neuromuscular junction development, locomotor dysfunctions and premature death. 5-ALA-HCl + SFC feeding increased ATP levels without recovery of CI activity. The activities of CII and CIV were upregulated, and accumulation of lactate and pyruvate was suppressed. 5-ALA-HCl + SFC feeding improved neuromuscular junction development and locomotor functions in sicily-knockdown flies. These results suggest that 5-ALA-HCl + SFC shifts metabolic programs to cope with CI deficiency. Bullet outline 5-Aminolevulinic acid (5-ALA-HCl + SFC) increases ATP production in flies with complex I deficiency.5-ALA-HCl + SFC increases the activities of complexes II and IV.5-ALA-HCl + SFC corrects metabolic abnormalities and suppresses the detrimental phenotypes caused by complex I deficiency.

Efficacy and Safety of 5-Aminolevulinic Acid Combined with Iron on Skeletal Muscle Mass Index and Physical Performance of Patients with Sarcopenia: A Multicenter, Double-Blinded, Randomized-Controlled Trial (ALADDIN Study).

Sarcopenia is a geriatric syndrome characterized by decreased physical performance, muscle mass, and strength. Since the intake of 5-aminolevulinic acid (ALA) with iron can increase muscle mass and mitochondria in mice and elevate physical exercise performance in humans, the beneficial effects of ALA in patients with sarcopenia are expected, but this remains unexplored in the literature. This study aimed to assess the efficacy and dose dependency of ALA combined with iron in sarcopenia by measuring skeletal muscle mass index (SMI). Subjects with sarcopenia were enrolled and randomized into the ALA and sodium ferrous citrate (SFC) intake groups (ALA50/SFC29, ALA100/SFC29, ALA150/SFC29, ALA 100/SFC57, and ALA0/SFC29 placebo) and ingested the assigned study food for 12 weeks. The primary endpoint, the change in SMI from baseline to week 12, did not differ significantly between the groups. Hand grip significantly increased or tended to increase from baseline after 12 weeks with all doses of ALA or SFC compared with the placebo group. No consistent changes were observed in the other endpoints, including calf circumference, physical function, or quality of life (QOL). Although this study suggests safe administration and the possibility of ALA improving hand grip strength in patients with sarcopenia, further investigation is required.

A disulfide chaperone knockout facilitates spin labeling and pulse EPR spectroscopy of outer membrane transporters.

Pulse EPR measurements provide information on distances and distance distributions in proteins but require the incorporation of pairs of spin labels that are usually attached to engineered cysteine residues. In previous work, we demonstrated that efficient in vivo labeling of the Escherichia coli outer membrane vitamin B12 transporter, BtuB, could only be achieved using strains defective in the periplasmic disulfide bond formation (Dsb) system. Here, we extend these in vivo measurements to FecA, the E. coli ferric citrate transporter. As seen for BtuB, pairs of cysteines cannot be labeled when the protein is present in a standard expression strain. However, incorporating plasmids that permit an arabinose induced expression of FecA into a strain defective in the thiol disulfide oxidoreductase, DsbA, enables efficient spin-labeling and pulse EPR of FecA in cells. A comparison of the measurements made on FecA in cells with measurements made in reconstituted phospholipid bilayers suggests that the cellular environment alters the behavior of the extracellular loops of FecA. In addition to these in situ EPR measurements, the use of a DsbA minus strain for the expression of BtuB improves the EPR signals and pulse EPR data obtained in vitro from BtuB that is labeled, purified, and reconstituted into phospholipid bilayers. The in vitro data also indicate the presence of intermolecular BtuB-BtuB interactions, which had not previously been observed in a reconstituted bilayer system. This result suggests that in vitro EPR measurements on other outer membrane proteins would benefit from protein expression in a DsbA minus strain.

Nitrogen and iron co-doped carbon quantum dots/MnO2 nanowire composites for flexible solid-state supercapacitors with high areal capacitance

Herein, the synthesis of MnO2 nanowires decorated with transition metal-doped carbon quantum dots (MCQDs) is described for use as binder-free flexible solid-state supercapacitors. In particular, the water-soluble Fe and N co-doped MCQDs prepared by amidation reaction with ferric ammonium citrate and urea had ultrafine particle morphologies and showed super-hydrophilicity in aqueous solution, which greatly improved the contact probability between the electrode and the electrolyte. In addition, the co-doped MCQDs increased both the electrical conductivity and specific capacitance of the MnO2/carbon-based nanocomposites and limited the collapse and exfoliation of the MnO2 structure during extended cycling. Compared with pristine MnO2 electrode, the MCQDs/MnO2 composite electrode exhibited faster charge-discharge rate and improved cycle stability with increased specific capacitance. The flexible symmetric supercapacitor constructed from the MCQDs/MnO2 composite had a capacitance retention of 85.6 % after 10,000 charge/discharge cycles at a current density of 2 mA cm−2. In addition, the device showed a maximum power density of 4.8 W cm−2 at an energy density of 2.3 mW h cm−2, and a maximum energy density of 11.16 mW h cm−2 at a power density of 311.6 mW cm−2. Data Availability StatementThe data that support the findings of this study are available from the corresponding author upon reasonable request.

Aquatic Ferrous Solutions of Prebiotic Mineral Salts as Strong UV Protectants and Possible Loci of Life Origin.

Liposomes are lipid-bilayer vesicles that spontaneously self-assemble from fatty acids (or other amphiphiles) in water by encapsulating surrounding aqueous media. After British scientist Alec Bangham described this phenomenon in the early 1960s, they became a prominent participant in the hypotheses on life origin, particularly in the Lipid World model. A novel scenario of self-sustained Darwinian liposome evolution is based on ever-present natural phenomena of cyclic day/night solar UV radiation and gravitational submersion of liposomes in the Archean aqueous media. One of the assumptions of the hypothesis is the UV-shielding ability of the Archean waters that could protect the submerged liposomes from the damaging solar UV radiation. To corroborate the idea, we measured UV absorption in aquatic solutions of several ferrous mineral salts assumed to be present in Archean pools. Single-agent solutions of simple salts such as FeCl2-iron dichloride, FeCl3-iron trichoride, Fe(NO3)3-ferric nitride, NH4Fe(SO4)2-ferric ammonium sulfate, and (NH4)5[Fe(C6H4O7)2]-ferric ammonium citrate were tested. These direct measurements of UV light absorption supplement and reinforce the proposed hypothesis.

Dietary iron regulates intestinal goblet cell function and alleviates Salmonella typhimurium invasion in mice.

Iron is an important micronutrient that plays a vital role in host defenses and bacterial pathogenicity. As iron treatments increase the risk of infection by stimulating the growth and virulence of bacterial pathogens, their roles in anti-infection immunity have frequently been underestimated. To estimate whether adequate dietary iron intake would help defend against pathogenic bacterial infection, mice were fed iron-deficient (2 mg kg-1 feed), iron-sufficient (35 mg kg-1 feed), or iron-enriched diet (350 mg kg-1 feed) for 12 weeks, followed by oral infection with Salmonella typhimurium. Our results revealed that dietary iron intake improved mucus layer function and decelerated the invasion of the pathogenic bacteria, Salmonella typhimurium. Positive correlations between serum iron and the number of goblet cells and mucin2 were found in response to total iron intake in mice. Unabsorbed iron in the intestinal tract affected the gut microbiota composition, and the abundance of Bacteroidales, family Muribaculaceae, was positively correlated with their mucin2 expression. However, the results from antibiotic-treated mice showed that the dietary iron-regulated mucin layer function was not microbial-dependent. Furthermore, in vitro studies revealed that ferric citrate directly induced mucin2 expression and promoted the proliferation of goblet cells in both ileal and colonic organoids. Thus, dietary iron intake improves serum iron levels, regulates goblet cell regeneration and mucin layer function, and plays a positive role in the prevention of pathogenic bacteria.

#3775 PHOSPHATE BINDERS FOR PATIENTS WITH CHRONIC KIDNEY DISEASE UNDERGOING DIALYSIS: A NETWORK META-ANALYSIS OF RANDOMISED CONTROLLED TRIALS

Abstract Background and Aims Phosphate binders (PBs) are essential for proper serum phosphorus control in patients with chronic kidney disease (CKD) requiring dialysis along with adequate dialysis and phosphorus restriction. To evaluate the clinical efficacy and safety of each PBs, we conducted a systematic review (SR) using a network meta-analysis (NMA) of randomised controlled trials (RCTs). Method We searched published RCTs in MEDLINE, EMBASE, the Cochrane Register of Controlled Trials (CENTRAL), and Clinical trial.gov databases using the search terms and text words relevant to this SR. We included RCTs involving adults (18 years and older) with at least 8 weeks of follow-up. Interventions and controls were the following: sevelamer-, bixalomer-, tenapanor-, iron- (ferric citrate, sucroferric oxyhydroxide), calcium-, magnesium-, lanthanum-, aluminium-, nicotinic acid-, and standard treatment or placebo). The outcomes were all-cause mortality, gastrointestinal adverse events (AEs), coronary artery calcium score (CACS), and serum calcium, phosphorus, and bicarbonate concentrations. Summary estimates were expressed as relative risk (RR) for binary outcomes and mean difference (MD) or standardised mean difference (SMD) for continuous outcomes, respectively, with 95% confidence intervals (CI). The protocol of this study is registered in PROSPERO: CRD42022328388. Results All-cause mortality was identified and analysed in 29 trials involving 12,622 participants. Compared with calcium-containing PBs, sevelamer reduced the risk of all-cause mortality (RR 0.65, 95%CI 0.45 to 0.96). The risk of gastrointestinal AEs was higher for nicotinic acid (RR 3.79, 95%CI 1.29 to 11.12), sucroferric oxyhydroxide (RR 1.96, 95%CI 1.47 to 2.63), sevelamer (RR 1.47, 95%CI 1.14 to 1.88), and lanthanum (RR 1.36, 95%CI 1.14 to 1.64) than calcium-containing PBs. Lanthanum had an inhibitory effect on CACS progression compared to calcium-containing PBs (SMD -0.63, 95% CI -1.05 to -0.22). Serum calcium was lower than calcium-containing PBs in the following order: magnesium (MD -0.67, 95% CI -1.12 to -0.22), placebo (MD -0.64, 95% CI -1.22 to -0.67), nicotinic acid (MD -0.56, 95% CI -1.11 to -0.005), sevelamer (MD -0.35, 95% CI -0.47 to -0.23), and lanthanum (MD -0.24, 95% CI -0.38 to -0.095). No significant difference was observed in serum phosphorus decrease between any PBs and calcium-containing PBs. Serum bicarbonate concentration increased with ferric citrate (MD 1.16, 95% CI 0.36 to 1.96) and sucroferric oxyhydroxide (MD 1.06, 95% CI 0.29 to 1.82) but decreased with sevelamer (MD -1.24, 95% CI -1.71 to -0.77). Conclusion Our findings from SR based on NMA suggest that lanthanum may attenuate CACS and sevelamer may reduce the risk of all-cause mortality compared to calcium-containing PBs in patients with CKD requiring dialysis.

#6606 MEDICATION VOLUME COMPARISON TO BIND PHOSPHATE

Abstract Background and Aims Elevated phosphate concentrations are associated with a significantly increased risk of cardiovascular disease and overall mortality in patients with chronic kidney disease. Current Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend lowering elevated serum phosphorus concentrations toward the normal range in patients with end-stage kidney disease on dialysis through restriction of dietary phosphorus intake, increase in clearance by dialysis, and the use of phosphate binders. However, ∼75% of dialysis patients are not achieving normal phosphate concentrations, potentially due to low adherence and/or binders’ insufficient phosphate binding capacity to match dietary intake. A phosphate binder with a higher phosphate binding capacity could improve phosphate control and potentially clinical outcomes. This study evaluated the medication volume of various phosphate binders to bind 1 gram of phosphorus. Methods Five phosphate binders were assessed: ferric citrate (210 mg ferric iron), calcium acetate (667 mg calcium acetate), lanthanum carbonate (500 and 1,000 mg lanthanum), sevelamer carbonate (800 mg sevelamer carbonate), and lanthanum dioxycarbonate (500 and 1,000 mg lanthanum). The mean daily dose volume to bind 1 g of phosphate was calculated as volume per tablet multiplied by the mean number of tablets taken per day. The volume to bind 1 g of phosphate was calculated by dividing the volume per tablet by its in vivo binding capacity, based on NIH DailyMed website. Results Binding to 1 g of phosphate required 5.6 cm3 of lanthanum dioxycarbonate compared with lanthanum carbonate (19.8 cm3), calcium acetate binders (25.0 cm3), ferric citrate (46.5 cm3), and sevelamer carbonate (73.4 cm3) (Figure 1). Conclusion The study found that lanthanum dioxycarbonate had the lowest volume to bind the same amount of phosphate compared to other binders. With a low medication volume and high phosphate binding capacity, lanthanum dioxycarbonate, a novel investigational nanotechnology product, can be a welcoming choice for patients to manage their hyperphosphatemia. The drug's decreased pill size (making it easy to swallow) and its tolerability have the potential to increase medication adherence and improve phosphate control.

#5517 IN CHRONIC KIDNEY DISEASE, IRON DEFICIENCY-INDUCED ANEMIA IS ASSOCIATED WITH HIGHER LEVELS OF FGF23 THAT ARE NOT REDUCED BY IRON ADMINISTRATION

Abstract Background and Aims Iron (Fe) deficiency significantly contributes to anemia in chronic kidney disease (CKD). High FGF23 levels, commonly found in CKD, are related to adverse outcomes in patients. In the normal setting, an association between Fe deficiency and FGF23 has been observed. However, it is unknown whether Fe deficiency-induced anemia might contribute to the excessive FGF23 levels in CKD. Thus, this study was intended to evaluate the interplay between Fe deficiency, CKD, and FGF23. Method Male Wistar rats with normal renal function received either standard (40 ppm Fe) or Fe-deficient (4 ppm Fe) diets for 6 weeks to induce anemia. Then, several normal and all the anemic rats were switched to an adenine-enriched (0.6%) diet to induce renal damage. Groups of anemic-uremic animals were treated with oral (ferric citrate, FC and ferrous sulfate, FS) or intravenous (ferric carboxymaltose, FCx) Fe at a dose of 9 mg/kg for 5 weeks. Hematological and mineral metabolism parameters were determined at sacrifice. All experimental protocols were approved by the Ethics Committee for Animal Research of the University of Córdoba. Results Plasma and serum biochemistries are shown in Table 1. CKD per se was associated with derangements in hematological parameters. The presence of Fe deficiency-induced anemia further decreased these parameters, being statistically significant in the case of serum Fe (P = 0.003). Iron therapy improved hematocrit, hemoglobin, and Fe levels, although statistical significance for all of them was only reached when FC was administered (P = 0.012, P = 0.038, and P = 0.002, respectively). As expected, CKD rats exhibited disturbances in mineral metabolism. Interestingly, uremic and anemic rats showed higher intact (P = 0.039) and c-terminal (P = 0.048) FGF23 levels when compared with CKD group. Despite normalization of serum Fe, intact FGF23 further increased following administration of FS (P = 0.022), and same trend was observed with all the compounds. However, cFGF23 levels remained unchanged in all the Fe-treated groups. Conclusion The presence of Fe-induced anemia in an experimental model of CKD is associated with further increases in the levels of both intact and c-terminal FGF23. Thus, other factors distinct than serum Fe might influence FGF23 levels. Our results support the need for investigating the precise mechanisms underlying the relationship between Fe and FGF23 to optimize the clinical management of anemia, particularly in the context of renal dysfunction.