The Effect of Iron Supplementation on FGF23 in Chronic Kidney Disease Patients: a Systematic Review and Time-Response Meta-Analysis

Abu‐Zaid, Ahmed; Magzoub, Duha; Aldehami, Mohammad Abdulrahman; Behiry, Abdulrahman Adel; Bhagavathula, Akshaya Srikanth; Hajji, Raouf

doi:10.1007/s12011-021-02598-1

Cited by 10 publications

(5 citation statements)

References 23 publications

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“…(55) Further, a meta-analysis of the effect of iron therapy on FGF23 levels in CKD patients showed that iron supplementation significantly reduced FGF23 levels compared with the control arms, and that oral iron was more efficacious at reducing FGF23 than intravenous iron therapy. (56) Finally, in an iron-deficient mouse model of CKD, supplementation with ferric citrate resulted in lower levels of total and intact FGF23, as well as suppressed bone Fgf23 transcription, (49) which are consistent with our in vivo and in vitro results. Collectively, our data support that the lower FGF23 is attributable to reduced FGF23 transcription in bone from increased iron availability to the osteocyte through the actions of HIF-PHI on iron utilization.…”

Section: Discussionsupporting

confidence: 83%

The HIF-PHI BAY 85-3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model

Noonan

Agoro

et al. 2020

Journal of Bone and Mineral Research

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Fibroblast growth factor‐23 (FGF23) is a critical factor in chronic kidney disease (CKD), with elevated levels causing alterations in mineral metabolism and increased odds for mortality. Patients with CKD develop anemia as the kidneys progressively lose the ability to produce erythropoietin (EPO). Anemia is a potent driver of FGF23 secretion; therefore, a hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHI) currently in clinical trials to elevate endogenous EPO to resolve anemia was tested for effects on iron utilization and FGF23‐related parameters in a CKD mouse model. Mice were fed either a casein control diet or an adenine‐containing diet to induce CKD. The CKD mice had markedly elevated iFGF23 and blood urea nitrogen (BUN), hyperphosphatemia, and anemia. Cohorts of mice were then treated with a patient‐equivalent dose of BAY 85‐3934 (BAY; Molidustat), which elevated EPO and completely resolved aberrant complete blood counts (CBCs) in the CKD mice. iFGF23 was elevated in vehicle‐treated CKD mice (120‐fold), whereas circulating iFGF23 was significantly attenuated (>60%) in the BAY‐treated CKD mice. The BAY‐treated mice with CKD also had reduced BUN, but there was no effect on renal vitamin D metabolic enzyme expression. Consistent with increased EPO, bone marrow Erfe, Transferrin receptor (Tfrc), and EpoR mRNAs were increased in BAY‐treated CKD mice, and in vitro hypoxic marrow cultures increased FGF23 with direct EPO treatment. Liver Bmp‐6 and hepcidin expression were downregulated in all BAY‐treated groups. Femur trabecular parameters and cortical porosity were not worsened with BAY administration. In vitro, differentiated osteocyte‐like cells exposed to an iron chelator to simulate iron depletion/hypoxia increased FGF23; repletion with holo‐transferrin completely suppressed FGF23 and normalized Tfrc1. Collectively, these results support that resolving anemia using a HIF‐PHI during CKD was associated with lower BUN and reduced FGF23, potentially through direct restoration of iron utilization, thus providing modifiable outcomes beyond improving anemia for this patient population. © 2021 American Society for Bone and Mineral Research (ASBMR).

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Section: Discussionsupporting

confidence: 83%

The HIF-PHI BAY 85-3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model

Noonan

Agoro

et al. 2020

Journal of Bone and Mineral Research

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“…Moreover, given the short median observation period in the PIVOTAL trial (2.1 years), long-term prognosis and iron accumulation are concerns in Japan where patients require HD for long periods of time [ 24 ]. Intravenous iron supplementation is reported to be associated with increases in intact fibroblast growth factor 23 level and suppression of the action of ESAs [ 25 , 26 ]. The DOPPS study showed that more Japanese patients had low CRP levels compared with their Western counterparts [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Low-Dose Oral Iron Replacement Therapy Is Effective for Many Japanese Hemodialysis Patients: A Retrospective Observational Study

Ogawa¹,

Tsuchiya

Kanemitsu³

et al. 2022

Nutrients

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Western guidelines recommend the use of intravenous iron supplementation for hemodialysis patients. However, in Japanese patients with well-controlled inflammation, iron replacement may be achieved with oral iron supplementation. This study involved 108 courses in 77 outpatient hemodialysis patients who received low-dose oral iron replacement therapy. Data from baseline to week 28 of treatment were analyzed to identify factors associated with effectiveness. Changes over time in erythrocyte- and iron-related parameters and erythropoiesis-stimulating agent (ESA) dose were investigated in the effective group. A total of 84 courses (77.8%) satisfied the effectiveness criteria. Compared with the effective and ineffective groups, only C-reactive protein (CRP) was significantly different (p < 0.01). ROC curve analysis with efficacy as the endpoint showed a CRP cut point value of ≤0.1 mg/dL (area under the curve, 0.69; 95% confidence interval, 0.57–0.81). The relationship between serum ferritin and hemoglobin fluctuation by reducing the ESA dose showed a positive correlation (p < 0.001). In the ESA maintenance group, the serum ferritin gradually increased and then remained constant at about 60 ng/mL. Our data suggest that patients with CRP ≤ 0.1 mg/dL may benefit from low doses of oral iron supplementation. Approximately 60 ng/mL serum ferritin may be sufficient during stable hematopoiesis.

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“…Two studies [5,10] reported a median, range (minimum-maximum), or interquartile range values, and we computed the essential mean and standard deviation values as described previously by Wan et al [21]. One study [10] had two arms (intravenous and topical administration of prophylactic TXA), and we regarded each arm as a stand-alone RCT during meta-analysis, consistent with the published literature [22,23]. We labelled the TXA intravenous arm RCT [10], whereas the TXA topical arm RCT [10].…”

Section: Data Synthesis and Statistical Analysismentioning

confidence: 99%

Prophylactic tranexamic acid to reduce blood loss and related morbidities during hysterectomy: a systematic review and meta-analysis of randomized controlled trials

Abu‐Zaid¹,

Baradwan²,

Badghish³

et al. 2022

Obstet Gynecol Sci

Self Cite

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To perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluated the efficacy and safety of prophylactic tranexamic acid (TXA) versus a control (placebo or no treatment) during hysterectomy for benign conditions. Six databases were screened from inception to January 23, 2022. Eligible studies were assessed for risk of bias. Outcomes were summarized as weighted mean differences and risk ratios with 95% confidence intervals in a random-effects model. Five studies, comprising six arms and 911 patients were included in the study. Two and three studies had an overall unclear and low risk of bias, respectively. Estimated intraoperative blood loss, requirement for postoperative blood transfusion, and requirement for intraoperative topical hemostatic agents were significantly reduced in a prophylactic TXA group when compared with a control group. Moreover, postoperative hemoglobin level was significantly higher in the prophylactic TXA group than in the control group. Conversely, the frequency of self-limiting nausea and vomiting was significantly higher in the prophylactic TXA group than in the control group. There were no significant differences between the groups in terms of surgery duration, hospital stay, and diarrhea rate. All the RCTs reported no incidence of major adverse events in either group, such as mortality, thromboembolic events, visual disturbances, or seizures. There was no publication bias for any outcome, and leave-one-out sensitivity analyses demonstrated stability of the findings. Among patients who underwent hysterectomy for benign conditions, prophylactic TXA appeared largely safe and correlated with substantial reductions in estimated intraoperative blood loss and related morbidities.

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The Effect of Iron Supplementation on FGF23 in Chronic Kidney Disease Patients: a Systematic Review and Time-Response Meta-Analysis

Cited by 10 publications

References 23 publications

The HIF-PHI BAY 85-3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model

The HIF-PHI BAY 85-3934 (Molidustat) Improves Anemia and Is Associated With Reduced Levels of Circulating FGF23 in a CKD Mouse Model

Low-Dose Oral Iron Replacement Therapy Is Effective for Many Japanese Hemodialysis Patients: A Retrospective Observational Study

Prophylactic tranexamic acid to reduce blood loss and related morbidities during hysterectomy: a systematic review and meta-analysis of randomized controlled trials

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