Ferric citrate is a safe and digestible source of iron in broilers and piglets

Background Iron (Fe) is traditionally supplemented in poultry and swine diets using inorganic forms (e.g. sulfates, oxides). However, research suggests that organic sources are more beneficial due to greater bioavailability. In this paper, we present results from four studies aimed at assessing ferric citrate (CI-FER™, Akeso Biomedical Inc., Burlington, MA, USA) as a safe and effective source of Fe for broilers and piglets. Methods A total of four studies were performed in Germany following standard farming practices for each species. One study in day-old broiler chicks and one study in weaned piglets were designed as target animal safety studies where animals were randomly allocated to one of three treatment groups: a negative control group, the proposed dose group and a multifold dose group. Broilers and pigs were fed the experimental diets for 35 and 42 days, respectively. In each study, average daily feed intake, average daily weight gain and feed conversion ratio were measured, and blood samples were taken at study end for routine biochemistry and haematology. The other two studies were designed to evaluate different sources of dietary Fe for weaned piglets bred and managed under standard farm conditions. All piglets received routine Fe injections (200 mg Fe dextran, intramuscular) on day 3 of age, as well as the experimental diets for 42 days. In both studies, performance parameters were measured. In one study, Fe digestibility and serum Fe, superoxide dismutase and haptoglobin were also measured. In all studies, the general health status of the animals was monitored daily and all culls and mortality recorded. Each study followed a complete randomised block design. Results In broilers, ferric citrate was well tolerated up to 2,000 mg/kg feed (×10 the recommended inclusion rate) and no adverse effects on growth, blood parameters or mortality were observed. In piglets, ferric citrate was well tolerated up to 5,000 mg/kg feed (×10 the recommended inclusion rate) with no adverse effects on growth, blood parameters or mortality. In addition, piglets fed ferric citrate performed significantly better than animals fed the negative control diet (containing only endogenous Fe) and those fed inorganic forms of Fe. Moreover, piglets fed ferric citrate demonstrated improved Fe digestibility and improved oxidative status. Altogether, these findings show that ferric citrate is a safe and easily digestible source of dietary Fe for broilers and piglets.

Ferric Citrate Uptake is a Virulence Factor in Uropathogenic Escherichia coli

More than half of women will experience a urinary tract infection (UTI) with uropathogenic Escherichia coli (UPEC) causing ~80% of uncomplicated cases. Iron acquisition systems are essential for uropathogenesis, and UPEC encode functionally redundant iron acquisition systems, underlining their importance. However, a recent UPEC clinical isolate, HM7 lacks this functional redundancy and instead encodes a sole siderophore, enterobactin. To determine if E. coli HM7 possesses unidentified iron acquisition systems, we performed RNA-sequencing under iron-limiting conditions and demonstrated that the ferric citrate uptake system (fecABCDE and fecIR) was highly upregulated. Importantly, there are high levels of citrate within urine, some of which is bound to iron, and the fec system is highly enriched in UPEC isolates compared to environmental or fecal strains. Therefore, we hypothesized that HM7 and other similar strains use the fec system to acquire iron in the host. Deletion of both enterobactin biosynthesis and ferric citrate uptake (ΔentB/ΔfecA) abrogates use of ferric citrate as an iron source and fecA provides an advantage in human urine in absence of enterobactin. However, in a UTI mouse model, fecA is a fitness factor independent of enterobactin production, likely due to the action of host Lipocalin-2 chelating ferrienterobactin. These findings indicate that ferric citrate uptake is used as an iron source when siderophore efficacy is limited, such as in the host during UTI. Defining these novel compensatory mechanisms and understanding the nutritional hierarchy of preferred iron sources within the urinary tract are important in the search for new approaches to combat UTI.

Ferric Citrate Dosing in Iron Deficiency Anemia in Nondialysis-Dependent Chronic Kidney Disease

<b><i>Introduction:</i></b> Ferric citrate (FC) is indicated as an oral iron replacement for iron deficiency anemia in adult patients with chronic kidney disease (CKD) not on dialysis. The recommended starting dose is one 1-g tablet three times daily (TID). This study investigated long-term efficacy and safety of different FC dosing regimens for treating anemia in nondialysis-dependent CKD (NDD-CKD). <b><i>Methods:</i></b> In this phase 4, randomized, open-label, multicenter study, patients with anemia with NDD-CKD (estimated glomerular filtration rate, ≥20 mL/min and &#x3c;60 mL/min) were randomized 1:1 to one FC tablet (1-g equivalent to 210 mg ferric iron) TID (3 g/day) or 2 tablets twice daily (BID; 4 g/day). At week 12, dosage was increased to 2 tablets TID (6 g/day) or 3 tablets BID (6 g/day) in patients whose hemoglobin (Hb) levels increased &#x3c;0.5 g/dL or were &#x3c;10 g/dL. Primary endpoint was mean change in Hb from baseline to week 24. <b><i>Results:</i></b> Of 484 patients screened, 206 were randomized and 205 received FC. Mean (standard deviation) changes from baseline in Hb at week 24 were 0.77 (0.84) g/dL with FC TID 3 g/day and 0.70 (0.98) g/dL with FC BID 4 g/day. <b><i>Discussion/Conclusions:</i></b> FC administered BID and TID for 48 weeks was safe and effective for treating anemia in this population, supporting potentially increased dosing flexibility.

Phosphate Control: The Next Frontier in Dialysis Cardiovascular Mortality

<b><i>Background:</i></b> Cardiovascular disease (CVD) is a major cause of death in patients with chronic kidney disease (CKD) on dialysis. Mortality rates are still unacceptably high even though they have fallen in the past 2 decades. Hyperphosphatemia (elevated serum phosphate levels) is seen in almost all patients with advanced CKD and is by far the largest remaining modifiable contributor to CKD mortality. <b><i>Summary:</i></b> Phosphate retention drives multiple physiological mechanisms linked to increased risk of CVD. Fibroblast growth factor 23 and parathyroid hormone (PTH) levels, both of which have been suggested to have direct pathogenic CV effects, increase in response to phosphate retention. Phosphate, calcium, and PTH levels are linked in a progressively worsening cycle. Maladaptive upregulation of phosphate absorption is also likely to occur further exacerbating hyperphosphatemia. Even higher phosphate levels within the normal range may be a risk factor for vascular calcification and, thus, CV morbidity and mortality. A greater degree of phosphate control is important to reduce the risk of CV morbidity and mortality. Improved phosphate control and regular monitoring of phosphate levels are guideline-recommended, established clinical practices. There are several challenges with the current phosphate management approaches in patients with CKD on dialysis. Dietary restriction of phosphate and thrice-weekly dialysis alone are insufficient/unreliable to reduce phosphate to &#x3c;5.5 mg/dL. Even with the addition of phosphate binders, the only pharmacological treatment currently indicated for hyperphosphatemia, the majority of patients are unable to achieve and maintain phosphate levels &#x3c;5.5 mg/dL (or more normal levels) [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information), 2011, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information), 2020, RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Phosphate binders do not target the primary pathway of phosphate absorption (paracellular), have limited binding capacity, and bind nonspecifically [PhosLo® gelcaps (calcium acetate): 667 mg (prescribing information). 2013, VELPHORO®: (Sucroferric oxyhydroxide) (prescribing information), 2013, FOSRENAL®: (Lanthanum carbonate) (prescribing information), 2016, AURYXIA®: (Ferric citrate) tablets (prescribing information), 2017, RENVELA®: (Sevelamer carbonate) (prescribing information) 2020]. <b><i>Key Messages:</i></b> Despite current phosphate management strategies, most patients on dialysis are unable to consistently achieve target phosphate levels, indicating a need for therapeutic innovations [RealWorld dynamix. Dialysis US: Spherix Global Insights, 2019]. Given a growing evidence base that the dominant mechanism of phosphate absorption is the intestinal paracellular pathway, new therapies are investigating ways to reduce phosphate levels by blocking absorption through the paracellular pathway.