Iron-related Parameters Research Articles

Impaired pancreatic beta-cell function after a single dose of oral iron: A before-and-after (pre-post) study.

Although in vitro and animal studies have shown that iron loading in pancreatic beta cells impairs insulin secretion, no human studies have documented the acute effects of oral iron on beta-cell insulin secretory capacity. In the present study, we determined beta-cell insulin secretory capacity at baseline and after a single oral dose of iron (ferrous sulphate, 120 mg elemental iron) in healthy male individuals. Fifteen healthy male volunteers underwent an oral glucose tolerance test (OGTT) to document baseline glucose tolerance and insulin secretion kinetics (baseline OGTT). One week later, the same subjects underwent a second OGTT, 2 h after an oral dose of ferrous sulphate (120 mg of elemental iron) (post-iron OGTT). Changes in disposition index, insulin secretion kinetics, glucose tolerance, insulin resistance, insulin clearance and iron-related parameters in serum were determined. Compared to baseline OGTT, the areas under the curve (AUC) for serum iron and transferrin saturation increased by 125% and 118%, respectively, in the post-iron OGTT. The disposition index decreased by 20% (p = 0.009) and the AUC for glucose concentrations increased by 5.7% (p < 0.001) during the post-iron OGTT. The insulin secretion rate was marginally lower during the first hour (-3.5%, p = 0.63), but became significantly higher during the second hour (22%, p = 0.005) of the post-iron OGTT. Insulin resistance and insulin clearance rate were not affected by iron intake. The decrease in disposition index and glucose tolerance observed after the oral dose of iron points to an acute iron-induced impairment in pancreatic beta-cell insulin secretory capacity.

Ferritin Increase in Hemochromatosis Subjects After Discontinuing Their Regular Maintenance Treatment: A Longitudinal Analysis Performed During the COVID-19 Imposed Hospital Lockdown.

Ferritin Increase in Hemochromatosis Subjects After Discontinuing Their Regular Maintenance Treatment: A Longitudinal Analysis Performed During the COVID-19 Imposed Hospital Lockdown.

Safety and effectiveness of sucroferric oxyhydroxide in Spanish patients on dialysis: sub-analysis of the VERIFIE study

Background and aimsIn this study, we show the results of the subset of Spanish patients of the VERIFIE study, the first post-marketing study assessing the long-term safety and effectiveness of sucroferric oxyhydroxide (SFOH) in patients with hyperphosphatemia undergoing dialysis during clinical practice. Patients and methodsPatients undergoing hemodialysis and peritoneal dialysis with indication of SFOH treatment were included. Follow-up duration was 12–36 months after SFOH initiation. Primary safety variables were the incidence of adverse drug reactions (ADRs), medical events of special interest (MESIs), and variations in iron-related parameters. SFOH effectiveness was evaluated by the change in serum phosphorus levels. ResultsA total of 286 patients were recruited and data from 282 were analyzed. Among those 282 patients, 161 (57.1%) withdrew the study prematurely and 52.5% received concomitant treatment with other phosphate binders. ADRs were observed in 35.1% of patients, the most common of which were gastrointestinal disorders (77.1%) and mild/moderate in severity (83.7%). MESIs were reported in 14.2% of patients, and 93.7% were mild/moderate. An increase in ferritin (386.66ng/mL vs 447.55ng/mL; p=0.0013) and transferrin saturation (28.07% vs 30.34%; p=0.043) was observed from baseline to the last visit (p=0.0013). Serum phosphorus levels progressively decreased from 5.69mg/dL at baseline to 4.84mg/dL at the last visit (p<0.0001), increasing by 32.2% the proportion of patients who achieved serum phosphorus levels ≤5.5mg/dL, with a mean daily SFOH dose of 1.98 pills/day. ConclusionsSFOH showed a favorable effectiveness profile, a similar safety profile to that observed in the international study with most adverse events of mild/moderate severity, and a low daily pill burden in Spanish patients in dialysis.

Iron and iron-related proteins in COVID-19.

COVID-19 can cause detrimental effects on health. Vaccines have helped in reducing disease severity and transmission but their long-term effects on health and effectiveness against future viral variants remain unknown. COVID-19 pathogenesis involves alteration in iron homeostasis. Thus, a contextual understanding of iron-related parameters would be very valuable for disease prognosis and therapeutics.Accordingly, we reviewed the status of iron and iron-related proteins in COVID-19. Iron-associated alterations in COVID-19 reported hitherto include anemia of inflammation, low levels of serum iron (hypoferremia), transferrin and transferrin saturation, and high levels of serum ferritin (hyperferritinemia), hepcidin, lipocalin-2, catalytic iron, and soluble transferrin receptor (in ICU patients). Hemoglobin levels can be low or normal, and compromised hemoglobin function has been proposed. Membrane-bound transferrin receptor may facilitate viral entry, so it acts as a potential target for antiviral therapy. Lactoferrin can provide natural defense by preventing viral entry and/or inhibiting viral replication. Serum iron and ferritin levels can predict COVID-19-related hospitalization, severity, and mortality. Serum hepcidin and ferritin/transferrin ratio can predict COVID-19 severity. Here, serum levels of these iron-related parameters are provided, caveats of iron chelation for therapy are discussed and the interplay of these iron-related parameters in COVID-19 is explained.This synopsis is crucial as it clearly presents the iron picture of COVID-19. The information may assist in disease prognosis and/or in formulating iron-related adjunctive strategies that can help reduce infection/inflammation and better manage COVID-19 caused by future variants. Indeed, the current picture will augment as more is revealed about these iron-related parameters in COVID-19.

Effect of Betaine on Blood Parameters Related to the Iron Status in Acrylamide-Treated Rats.

It has been well documented that acrylamide (ACR) is a human carcinogen. One of the consequences of ACR exposure is central and peripheral nervous system damage, which may lead to hallucinations, drowsiness, and numbness in the hands, as well as legs. Betaine (BET) plays an active role in methylation reactions, including DNA methylation, the integrity of cell membranes, and memory development. It has been approved that BET protects the liver from oxidative stress-inducing substances, such as ethanol, and nonalcoholic fatty liver, brain, kidney, stomach, as well as ovaries, in rats. Therefore, this study was designed to investigate how BET influences iron-related blood parameters and biomarkers in acrylamide-treated rats. Twenty adult rats, weighing 180-200 g and aging 6-7 weeks, were randomly divided into four equal groups and given the following treatments every day for 30 days. The control group was identified as G1. Animals in the G2 group were intubated with BET [250 mg/kg body weight (B.W.)]. Animals in the G3 group were intubated with ACR (1 mg/kg B.W.), while animals in the G4 group were intubated with both BET and ACR at the same doses as animals in G2 and G3 groups. At the end of the experiment, blood samples were collected from anesthetized rats using the cardiac puncture technique for measuring white blood cell count, as well as their differential count, red blood cells count, hemoglobin, and their related parameters, including mean corpuscular volume, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, hematocrit, as well as red cell distribution width. Additionally, serum was taken to measure serum iron concentration, ferritin, total iron-binding capacity, and transferrin saturation percentage. The results showed significant changes in some hematological parameters and the iron status correlated with anemia in the G3 group, treated with ACR. Such changes, accompanied by histopathological changes in the spleen oral intubation of BET alone, as well as its combination with ACR, caused the alleviation of anemia through correcting previous parameters. In conclusion, the findings revealed that BET positively influences anemia in rats treated with ACR.

MO519: Ferric Citrate Hydrate Improves Levels of Transferrin Saturation in Hemodialysis Patients With Lower Levels of Transferrin Saturation

Abstract BACKGROUND AND AIMS Iron deficiency identified by transferrin saturation (TSAT) is reported as a risk factor for all-cause mortality and cardiovascular events in non-dialysis dependent (NDD) chronic kidney disease (CKD) [1, 2] and for all-cause mortality in hemodialysis patients [3]. Ferric citrate hydrate (FC, Riona®), an oral iron-based phosphate binder in CKD patients, is also approved as an iron preparation for iron-deficiency anemia (IDA) in Japan in 2021. In the USA, ferric citrate (Auryxia®) is approved as a phosphate binder for dialysis-dependent CKD and an iron replacement product for the treatment of IDA in patients with NDD-CKD. FC or ferric citrate increased TSAT in patients with NDD-CKD and IDA [4]. However, a few data show that whether FC or ferric citrate has the similar effect in hemodialysis patients whose TSAT is &amp;lt;20%. Considering the additional indication of IDA in Japan, we investigated the FC's effect on TSAT by using the data obtained from the ASTRIO study [5], which was conducted in Japanese hemodialysis (HD) patients. METHOD We conducted a retrospective study using the data of ASTRIO study [5], which is a randomized, prospective, open-label, multicenter 24-week study to investigate the FC's effect on anemia management compared with non-iron-based phosphate binders (PBs) in Japanese HD patients with hyperphosphatemia. Ninety-three patients taking non-iron-based PBs were randomized 1:1 to continue PBs (control) or switch to FC. During 24-week study, serum phosphate and hemoglobin were controlled, 3.5–6.0 mg/dL and 10–12 g/dL, respectively. From 93 patients (FC, n = 48; control, n = 45), we extracted 41 patients (FC, n = 21; control, n = 20) whose TSAT at baseline was &amp;lt;20% and compared the levels of TSAT and other iron related parameters between FC group and control group. RESULTS In the ASTRIO study, the mean (SD) levels of TSAT (%) was 14.3 (4.0) at baseline and rapidly increased to 25.0 (11.1) at 4 weeks in the FC group. After that, the levels of TSAT were almost unchanged in the FC group, whereas, in the control group, the mean (SD) levels of TSAT were almost unchanged during the 24-week study. The mean (SD) levels of serum ferritin gradually increased until week 12 and subsequently showed to be stabilized in the FC group, whereas, in the control group, these were almost unchanged during the 24-week study (Table 1). CONCLUSION In Japanese HD patients whose TSAT was &amp;lt;20%, FC rapidly increased TSAT compared with control. We will also investigate the FC's effect on TSAT in HD patients from the post-marketing surveillance study, the prospective, multicenter and observational, up to maximum 2 years treatment.

Effects of ferric citrate and intravenous iron sucrose on markers of mineral, bone, and iron homeostasis in a rat model of CKD-MBD.

Anemia and chronic kidney disease-mineral and bone disorder (CKD-MBD) are common and begin early in CKD. Limited studies have concurrently compared the effects of ferric citrate (FC) versus intravenous (IV) iron on CKD-MBD and iron homeostasis in moderate CKD. We tested the effects of 10 weeks of 2% FC versus IV iron sucrose in rats with moderate CKD (Cy/+ male rat) and untreated normal (NL) littermates. Outcomes included a comprehensive assessment of CKD-MBD, iron homeostasis and oxidative stress. CKD rats had azotemia, elevated phosphorus, parathyroid hormone and fibroblast growth factor-23 (FGF23). Compared with untreated CKD rats, treatment with FC led to lower plasma phosphorus, intact FGF23 and a trend (P=0.07) toward lower C-terminal FGF23. FC and IV iron equally reduced aorta and heart calcifications to levels similar to NL animals. Compared with NL animals, CKD animals had higher bone turnover, lower trabecular volume and no difference in mineralization; these were unaffected by either iron treatment. Rats treated with IV iron had cortical and bone mechanical properties similar to NL animals. FC increased the transferrin saturation rate compared with untreated CKD and NL rats. Neither iron treatment increased oxidative stress above that of untreated CKD. Oral FC improved phosphorus homeostasis, some iron-related parameters and the production and cleavage of FGF23. The intermittent effect of low-dose IV iron sucrose on cardiovascular calcification and bone should be further explored in moderate-advanced CKD.

Clinical parameters among patients in Japan with anemia and non-dialysis-dependent chronic kidney disease with and without diabetes mellitus who received roxadustat

BackgroundRoxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in patients with non-dialysis-dependent (NDD) CKD evaluated disease state–related parameters among patients with and without diabetes mellitus who received roxadustat. In the 1517-CL-0310 study (NCT02988973), roxadustat was noninferior to darbepoetin alfa for change in average hemoglobin levels at Weeks 18–24 from baseline who received roxadustat.MethodsPatients enrolled in the 1517-CL-0310 study who received roxadustat were included in this post hoc analysis. Hematologic (hemoglobin, reticulocyte/erythrocyte ratio, mean corpuscular volume [MCV], and mean corpuscular hemoglobin [MCH]), iron-related (ferritin, total iron-binding capacity, transferrin, ceruloplasmin, and hepcidin), metabolic (HbA1c, glycated albumin, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), and renal (eGFR) parameters were summarized descriptively by visit through Week 52.ResultsAmong 201 included patients, 105 (52.2%) and 96 (47.8%) were in the Diabetes and No Diabetes subgroups, respectively. There were no clinically meaningful differences through Week 52 for most hematologic, iron-related, metabolic, or renal parameters between patients in the Diabetes and No Diabetes subgroups. MCV and MCH remained lower and HbA1c and glycated albumin remained higher in patients in the Diabetes subgroup through Week 52. Both subgroups experienced a similar benefit from roxadustat in maintaining hemoglobin levels in the target range of 10–12 g/dL.ConclusionRoxadustat maintained hemoglobin levels in the target range with similar clinical parameters irrespective of diabetes mellitus presence at baseline.

Safety and effectiveness of ferric citrate hydrate in serum phosphorus management of patients with chronic kidney disease: a long-term, real-world, observational, post-marketing surveillance study

BackgroundFerric citrate hydrate (FC) is an oral iron-based phosphate binder that is used to treat hyperphosphatemia in patients with chronic kidney disease (CKD). This post-marketing surveillance study was performed to investigate the long-term safety and effectiveness of FC.MethodsThis prospective, multicenter, observational post-marketing surveillance study was performed in a real-world setting in Japan. The study involved CKD patients with hyperphosphatemia receiving FC who were undergoing either hemodialysis or peritoneal dialysis or were non-dialysis-dependent. Adverse drug reactions, iron- and erythrocyte-related parameters (i.e., levels of serum ferritin, transferrin saturation, and hemoglobin), and serum levels of phosphorus, corrected calcium, and intact parathyroid hormone were monitored for up to 104 weeks.ResultsSafety was evaluated in 2723 patients. Of these patients, 20.5% discontinued FC because of adverse events, and 3.9% discontinued FC because of unsatisfactory effectiveness. Iron-related parameters gradually increased after the initiation of FC treatment but stabilized after week 36. Effectiveness was analyzed in 2367 patients. Serum phosphorus immediately decreased, and the effect persisted for 104 weeks.ConclusionIn this 104 week surveillance study, no new safety concerns were noted. The safety profile was not obviously different from those in pre-approval clinical trials and the 52 week interim report of this surveillance study. The serum ferritin level of most patients was below the upper limit of the target range, and iron overload risk was not evident. Long-term FC treatment effectively controlled serum phosphorus.

Iron supplementation in plant-based aquafeed: Effects on growth performance, tissue composition, iron-related serum parameters and gene expression in rainbow trout (Oncorhynchus mykiss)

This study evaluated the effects of iron supplementation in plant-based aquafeed on growth performances, feed intake, nutrient composition, digestibility, iron-related serum parameters and gene expression in juvenile rainbow trout (Oncorhynchus mykiss). Triplicate groups of fish were fed for 60 days using incremental levels of iron in a ferrous sulphate heptahydrate form, as follows: 0 (group Fe0); 150 (group Fe150); 300 (group Fe300); 600 (group Fe600) mg iron/kg feed, corresponding to actual iron levels of 132, 273, 403, 741 mg iron/kg feed, respectively. As a further control, a fifth group was fed a commercial feed (CMF; 253 mg iron/kg feed). Growth performances showed that the highest specific growth rate (SGR), condition factor (CF), protein efficacy ratio (PER), feed intake (FI) and lowest feed conversion rate (FCR) were found in Fe150, Fe300 and CMF groups. Final weight and weight gain (WG) were significantly higher in CMF and Fe150 groups, followed by the Fe300, Fe600 and Fe0 groups (P < 0.05). Apparent digestibility coefficients (ADCs) of protein, lipid, ash and iron were over 90% in Fe150 and Fe300 groups, while significantly lower ADCs were observed in Fe0 and Fe600 groups. Intestinal histomorphological measurements of muscular thickness (muscularis externa; ME, inner circular layer; ICL, outer longitudinal layer; OLL) were higher in CMF and Fe150 groups, while villus length was generally similar among groups, with the exception of the Fe0 group. Serum iron levels were significantly higher in Fe150 and Fe300 groups, while total iron-binding capacity (TIBC) was highest in the Fe150 group. No significant differences were observed in either serum ferritin or liver ferritin gene expression among groups, although hepcidin gene expression was highest in the Fe300 group followed by the Fe150 group. Transferrin gene expression was the lowest in the Fe0 group. Appetite-related Leptin A1 gene expression was not affected by iron addition, but Leptin A2 was up-regulated in all groups except for the Fe0 group. In summary, the study showed that the addition of 150 mg/kg feed of iron (equivalent to ~270 mg/kg feed total) improved growth performances and feed utilization in rainbow trout, which aligns well with the iron levels in current commercial feeds.

Iron Related Biomarkers Predict Disease Severity in a Cohort of Portuguese Adult Patients during COVID-19 Acute Infection

Large variability in COVID-19 clinical progression urges the need to find the most relevant biomarkers to predict patients’ outcomes. We evaluated iron metabolism and immune response in 303 patients admitted to the main hospital of the northern region of Portugal with variable clinical pictures, from September to November 2020. One hundred and twenty-seven tested positive for SARS-CoV-2 and 176 tested negative. Iron-related laboratory parameters and cytokines were determined in blood samples collected soon after admission. Demographic data, comorbidities and clinical outcomes were recorded. Patients were assigned into five groups according to severity. Serum iron and transferrin levels at admission were lower in COVID-19-positive than in COVID-19-negative patients. The levels of interleukin (IL)-6 and monocyte chemoattractant protein 1 (MCP-1) were increased in COVID-19-positive patients. The lowest serum iron and transferrin levels at diagnosis were associated with the worst outcomes. Iron levels negatively correlated with IL-6 and higher levels of this cytokine were associated with a worse prognosis. Serum ferritin levels at diagnosis were higher in COVID-19-positive than in COVID-19-negative patients. Serum iron is the simplest laboratory test to be implemented as a predictor of disease progression in COVID-19-positive patients.

Association of fibroblast growth factor 23 and \u03b1-klotho in hemodialysis patients during administration of ferric citrate hydrate: post hoc analysis of ASTRIO study

BackgroundFibroblast growth factor-23 (FGF23) and α-klotho are associated with anemia in patients with chronic kidney disease. In this post hoc analysis of the ASTRIO study (UMIN000019176), we investigated the relationship between FGF23 and α-klotho during treatment with an iron-based phosphate binder, ferric citrate hydrate (FC), compared with non-iron-based phosphate binders in hemodialysis (HD) patients. We examined the effect of iron absorption by FC on the relationship between FGF23 and α-klotho. There have been few clinical studies evaluating these biomarkers simultaneously in HD patients.MethodsThe ASTRIO study was a 24-week, randomized, open-label, multicenter trial. HD patients taking non-iron-based phosphate binder(s) were randomized at a 1:1 ratio to continue other binder(s) (control group) or switch to FC (FC group). Serum phosphate (P) and hemoglobin (Hb) were maintained within 3.5–6.0 mg/dL and 10–12 g/dL, respectively. Plasma levels of intact FGF23 (i-FGF23), C-terminal FGF23 (c-FGF23), and α-klotho were measured, as were iron-related parameters. Association analyses of FGF23 and α-klotho were conducted.ResultsPatients were randomized to FC (n = 48) and control (n = 45) groups. Serum ferritin significantly increased from baseline to end-of-treatment (EOT) in the FC group, compared with the control group (adjusted mean difference [95% confidence interval]: 79.5 [44.7, 114.4] ng/mL; p < 0.001). The mean change from baseline to EOT in c-FGF23 was significantly different between the FC and control groups (mean ± standard deviation (SD): − 0.2 ± 0.8 loge pg/mL vs. 0.2 ± 0.8 loge pg/mL, respectively; p = 0.04). The mean change from baseline to EOT in i-FGF23 and α-klotho were not significantly different between the FC and control groups (mean ± SD: − 0.1 ± 0.8 loge pg/mL vs. 0.1 ± 0.9 loge pg/mL; p = 0.33, and 2.0 ± 91.5 pg/mL vs. − 8.9 ± 145.3; p = 0.58, respectively). However, both forms of FGF23 and α-klotho were not significantly associated with each other in both groups.ConclusionsIron absorbed via FC administration in HD patients did not influence the correlation relationship between plasma levels of FGF23 and α-klotho under the condition of serum P and Hb were maintained.Trial registrationASTRIO study (UMIN000019176, registered at UMIN Clinical Trials Registry on October 1, 2015).

Dietary Iron Increases Expression of Liver Hepcidin Relative to BMP6 By a Mechanism Involving Transferrin Receptor 2 and Specificity of Transferrin Lobe Iron Occupancy

Introduction: Prior studies have identified two iron signals regulating liver hepcidin expression (PMID 21488083, 21480335). One is mediated by liver sinusoidal BMP6 (and BMP2) and is reflective of liver iron concentration (LIC). The other is independent of BMP expression and reflective of transferrin saturation. The mechanism by which TF regulates hepcidin is unclear but appears to involve hepatocellular transferrin receptor 2 (TFR2). We previously generated mice with TF mutations that block iron binding to either N-lobe (Tf N-bl) or C-lobe (Tf C-bl). These mice demonstrated differences in Epo sensitivity and hepcidin regulation (PMID 31434707). To characterize the differential regulation of Hamp1 in these mice we analyzed the effect of dietary iron in juvenile mice. This model advantages a physiologic low iron state with very low basal Hamp1 and Bmp6 expression.Methods: Twelve-day old WT, Tf N-bl, Tf C-bland Tfr2 Y245X (functional knockout) mice were gavaged with 4 mg/kg/d FeSO 4 (or saline) in 2 divided doses for 3 days and sacrificed on the fourth day. The primary outcome was liver Hamp1 relative to Bmp6 expression by RT-PCR. Other iron-related parameters included liver Bmp2, serum and tissue non-heme iron, and TIBC. Erythroid parameters included splenic Fam132b (Erfe gene) expression, kidney Epo, blood packed cell volume (PCV), splenic weight index (SWI).Results: Iron-treated mice demonstrated increased serum iron, TF saturation, LIC, liver Bmp6 in all strains compared to untreated. Liver Hamp1 was increased in all strains with iron-treatment; however, the magnitude was least in the Tf N-bland greatest in the Tf C-bl mice. Splenic Fam132b was unchanged. The iron-treated Tf C-bl had ~16 fold greater Hamp1 compared with iron-treated Tf N-bl mice (P=0.0005), despite similar Bmp6, Bmp2, and splenic Fam132b expression. The iron-treated Tf C-bl mice also had modestly higher splenic index and PCV compared with iron-treated Tf N-bl mice, despite similar kidney Epo. In Tfr2 Y245X mice Hamp1 and Hamp1 indexed to Bmp6 expression was intermediate between Tf N-bland Tf C-bl mice (figure).Conclusion: Iron treatment increased liver Bmp6 expression as well as Bmp6 sensitivity (Hamp:Bmp6), in association with increases in LIC and in TF saturation. The effect of iron on Bmp6 sensitivity is markedly influenced by which TF lobe iron occupies, as well as the presence of TFR2. These observations support a model in which TF modulates the hepcidin response to BMP6 in either direction, via interaction with TFR2. We speculate that iron occupancy of the N-lobe of transferrin confers an upregulatory signal to hepcidin expression in the hepatocyte, and that its absence confers a downregulatory signal to BMP6 sensitivity in the hepatocyte. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Seguridad y efectividad del oxihidróxido sucroférrico en pacientes españoles en diálisis: subanálisis del estudio VERIFIE

Background and aimsIn this study, we show the results of the subset of Spanish patients of the VERIFIE study, the first post-marketing study assessing the long-term safety and effectiveness of sucroferric oxyhydroxide (SFOH) in patients with hyperphosphatemia undergoing dialysis during clinical practice. Patients and methodsPatients undergoing hemodialysis and peritoneal dialysis with indication of SFOH treatment were included. Follow-up duration was 12–36 months after SFOH initiation. Primary safety variables were the incidence of adverse drug reactions, medical events of special interest, and variations in iron-related parameters. SFOH effectiveness was evaluated by the change in serum phosphorus levels. ResultsA total of 286 patients were recruited and data from 282 were analyzed. Among those 282 patients, 161 (57.1%) withdrew the study prematurely and 52.5% received concomitant treatment with other phosphate binders. Adverse drug reactions were observed in 35.1% of patients, the most common of which were gastrointestinal disorders (77.1%) and mild/moderate in severity (83.7%). Medical events of special interest were reported in 14.2% of patients, and 93.7% were mild/moderate. An increase in ferritin (386.66ng/mL vs 447.55ng/mL; P=.0013) and transferrin saturation (28.07% vs 30.34%; P=.043) was observed from baseline to the last visit. Serum phosphorus levels progressively decreased from 5.69mg/dL at baseline to 4.84mg/dL at the last visit (P<.0001), increasing by 32.2% the proportion of patients who achieved serum phosphorus levels≤5.5mg/dL, with a mean daily SFOH dose of 1.98pills/day. ConclusionsSFOH showed a favorable effectiveness profile, a similar safety profile to that observed in the international study with most adverse events of mild/moderate severity, and a low-daily pill burden in Spanish patients in dialysis.

Evidence of dysregulated iron homeostasis in newly diagnosed diabetics, but not in pre-diabetics.

Diabetes mellitus has been reported to be associated with increased serum levels of ferritin. The basis of this association is unclear. It is also not precisely known whether other iron-related parameters, including hepcidin (the central regulator of systemic iron homeostasis), are affected under these circumstances. This study attempted to determine this. Adult men (normoglycemic or newly diagnosed with diabetes or pre-diabetes) were recruited. Anthropometric, metabolic, and hematological and iron-related parameters in blood were measured. Indices of insulin resistance (HOMA-IR) and pancreatic beta cell function (HOMA-β) were calculated. Subjects in the 3 groups were similar in age, and anthropometric and hematological parameters. Serum ferritin and hepcidin levels were higher in diabetics, than in pre-diabetics and in control subjects. These elevations seen were not linked to the presence of inflammation. HOMA-IR was higher in diabetics, and HOMA-β lower in diabetics and pre-diabetics, than in control subjects. HOMA-IR and serum ferritin were positively correlated with one another. Elevated levels of serum ferritin and hepcidin in newly diagnosed diabetics (but not pre-diabetics) indicate dysregulated iron homeostasis, with the former positively associated with insulin resistance in these patients.

Prepregnancy Obesity Does Not Impact Placental Iron Trafficking

BackgroundIron is critical for fetal development. Neonates of obese women may be at risk for poor iron status at birth as a result of maternal inflammation-driven overexpression of hepcidin. ObjectivesThe objective of this study was to determine differences in placental transfer of oral iron (57Fe) and expression of placental transferrin receptor 1 (TFR1) and ferroportin (FPN) mRNA and protein and their association with maternal and neonatal iron-related parameters, including maternal hepcidin, among women with and without prepregnancy (PP) obesity. Methods57Fe ingested during the third trimester of pregnancy was recovered in venous umbilical cord blood among 20 PP obese [BMI (in kg/m2): 30.5–43.9] and 22 nonobese (BMI: 18.5–29.0) women aged 17–39 y. Placental TFR1 and FPN mRNA and protein expression were quantified via qPCR and Western blot. Maternal and neonatal markers of iron status and regulation, as well as inflammation, were measured. Descriptive and inferential statistical tests (e.g., Student t test, Pearson correlation) were used for data analysis. ResultsThere was no difference in cord blood enrichment of 57Fe or placental mRNA or protein expression of TFR1 or FPN among the women with and without PP obesity. Maternal hepcidin was not correlated with cord blood enrichment of 57Fe or placental FPN mRNA or protein expression. Maternal log ferritin (corrected for inflammation) was inversely correlated with log percent enrichment of 57Fe in cord blood (partial r = –0.50; P < 0.01, controlled for marital status) and protein expression of TFR1 (r = –0.43; P = 0.01). ConclusionsPlacental iron trafficking did not differ among women with and without PP obesity. Findings reinforce the importance of maternal iron stores in regulating placental iron trafficking.

Application of FeOOH Nano-Ellipsoids as a Novel Nano-Based Iron Supplement: an In Vivo Study.

The possibility of employing FeOOH nano-ellipsoids as a novel shape nano-based iron supplement was investigated. Ferrous sulfate and nano-ellipsoids were daily administered by gavage at low and high dosages. After 1month of treatment, the hematologic parameters along with serum and organs' iron contents were measured. Liver enzymes, total serum bilirubin, and LDH level were assayed to evaluate any possible toxicity. More investigation was also performed by organ index calculation and also pathologic studies. It was found that nano-ellipsoids are an effective iron supplement to improve iron-related blood parameters. Interestingly, low-dose nano-ellipsoids were even more effective than high-dose ferrous sulfate. Nano-ellipsoids had no considerable impact on the liver enzymes and serum bilirubin. Meanwhile, high-dose ferrous sulfate significantly increases liver enzyme activity. The increased serum LDH was also the only concern in the groups that were treated with high-dose ferrous sulfate and nano-ellipsoids. Pathologic evaluations revealed some signs of liver inflammation after supplementation with high dose nano-ellipsoids and also ferrous sulfate. Overall, these data indicate FeOOH nano-ellipsoids as a novel shape iron supplement to be employed at low dosage but with greater beneficial effects than high-dose ferrous sulfate.

Iron Overload Decreases Engraftment of Mice Receiving Allogeneic or Syngeneic Bone Marrow Transplant

Background:Transfusional iron overload is a poor prognostic factor in patients undergoing hematopoietic stem cell transplantation (HSCT). In multiple clinical studies, elevated serum ferritin correlated with inferior transplant outcomes; however, ferritin is an imperfect marker of iron burden and may not correlate with other markers, such as liver iron content. These studies are also confounded because increased transfusional need often reflects more severe disease, an independent predictor of worse outcome. Thus, it remains unclear whether the correlation between iron status and transplant outcome is due to transfusional iron overload alone, or is more reflective of other comorbidities. We developed a mouse model of parenteral iron overload followed by high dose chemotherapy and allogeneic or syngeneic HSCT to study, in isolation, the effects of iron overload on engraftment and survival after transplant.Methods:Cohorts of female C57BL/6 (H-2Kb) recipients received 0, 5, 25, or 50mg iron dextran, in divided doses over 2 weeks. Mice were then conditioned with busulfan (20mg/kg daily x 5 days) and cyclophosphamide (100mg/kg daily for the last 3 days). Two days later, mice received 30 x 106 bone marrow cells from female BALB/c (H-2Kd) donors (allogeneic HSCT) or 5 x 106 bone marrow cells from female UBC-GFP (H-2Kb) donors (syngeneic HSCT). Mice received enrofloxacin (10mg/kg daily x 5 days) after transplant. Engraftment was evaluated by flow cytometry as the proportion of donor cells in blood or bone marrow. Iron-related parameters were measured at the time of euthanasia (Day +28 post-transplant). Statistical analysis was performed with GraphPad Prism.Results:Our model of iron overload using iron dextran at escalating doses showed a dose-dependent increase in markers of iron load, such as total liver iron (R2=0.86) and ferritin (R2=0.84)(Fig. 1A-B; both P<0.0001 for linear trend). After allogeneic HSCT, there was a statistically significant decrease in overall survival in all groups receiving iron dextran (range: 47-63%), as compared to the saline control (90%)(Fig 1C; P<0.05); this effect was not dose-dependent. Data from 3 pooled experiments (N=30 mice per group) showed an engraftment rate of 59% in the saline group, and 47%, 42%, and 21% in the 5mg, 25mg, and 50mg iron dextran groups, respectively, suggesting a dose-dependent effect of iron overload on engraftment (Fig. 1D). In the syngeneic HSCT model, iron overload prior to transplant similarly resulted in delayed RBC and platelet engraftment and decreased rates of overall engraftment (Fig. 1E,F,G).Conclusions:Iron overload had a dose-dependent negative effect on overall engraftment after allogeneic and syngeneic HSCT. For allogeneic HSCT, there was also a decrease in overall survival in all the groups receiving iron dextran. For syngeneic HSCT, in which graft rejection cannot occur, iron overload still negatively affected post-transplant engraftment, suggesting that this effect is not due solely to potential immunomodulatory effects of excess iron on graft rejection. The mechanism(s) underlying the effects of iron overload on survival and engraftment rates in allogeneic and syngeneic HSCT, along with the potential benefit of chelation therapy, remain to be determined.Figure 1: Effect of iron overload on survival and engraftment. Mean ± S.D. for (A) total liver iron and (B) ferritin for allogeneic HSCT. Kaplan-Meier survival estimates for (C) mortality and (D) percent of mice not engrafting >50% of nucleated cells for allogeneic HSCT (N=10 mice per group per replicate; 30 mice total per group). Mean ± S.D. for (E) percent red cell engraftment over time and (F) percent platelet engraftment of time in syngeneic HSCT. Kaplan-Meier survival estimates for (F) percent of mice not engrafting >50% of red blood cells (N=10 mice per group per replicate; 20 mice total per group). *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 as compared to the saline control or as specified. Arrow denotes day of transplant. [Display omitted] DisclosuresSpitalnik:New Health Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Oral Administration of Ginger-Derived Lipid Nanoparticles and Dmt1 siRNA Potentiates the Effect of Dietary Iron Restriction and Mitigates Pre-Existing Iron Overload in Hamp KO Mice.

Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and >85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40–50%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH.

Associations among erythropoietic, iron-related, and FGF23 parameters in pediatric kidney transplant recipients.

In pediatric kidney transplant recipients, anemia is common and oftentimes multifactorial. Hemoglobin concentrations may be affected by traditional factors, such as kidney function and iron status, as well as novel parameters, such as fibroblast growth factor 23 (FGF23). Here, we evaluated associations among erythropoietic, iron-related, and FGF23 parameters in a cohort of pediatric kidney transplant recipients, hypothesizing that multiple factors are associated with hemoglobin concentrations. In a cross-sectional analysis of 59 pediatric kidney transplant recipients (median (interquartile range) age 16.3 (13.5, 18.6) years, median estimated glomerular filtration rate (eGFR) 67 (54, 87) ml/min/1.73 m2), the median age-related hemoglobin standard deviation score (SDS) was -2.1 (-3.3, -1.1). Hemoglobin SDS was positively associated with eGFR and calcium, and was inversely associated with erythropoietin (EPO), mycophenolate dose, and total, but not intact, FGF23. In multivariable analysis, total FGF23 remained inversely associated with hemoglobin SDS, independent of eGFR, iron parameters, EPO, and inflammatory markers, suggesting a novel FGF23-hemoglobin association in pediatric kidney transplant patients. In a subset of patients with repeat measurements, only delta hepcidin was inversely associated with delta hemoglobin SDS. Also, delta EPO positively correlated with delta erythroferrone (ERFE), and delta ERFE inversely correlated with delta hepcidin, suggesting a possible physiologic role for the EPO-ERFE-hepcidin axis in the setting of chronic kidney disease (CKD). Our study provides further insight into factors potentially associated with erythropoiesis in pediatric kidney transplant recipients. A higher resolution version of the Graphical abstract is available as Supplementary information.