Whole-body iron transport and metabolism: Mechanistic, multi-scale model to improve treatment of anemia in chronic kidney disease

by Joydeep Sarkar, Alka A. Potdar, Gerald M. Saidel Iron plays vital roles in the human body including enzymatic processes, oxygen-transport via hemoglobin and immune response. Iron metabolism is characterized by ~95% recycling and minor replenishment through diet. Anemia of chronic kidney disease (CKD) is characterized by a lack of synthesis of er ythropoietin leading to reduced red blood cell (RBC) formation and aberrant iron recycling. Treatment of CKD anemia aims to normalize RBC count and serum hemoglobin. Clinically, the various fluxes of iron transport and accumulation are not measured so that changes during disease (e.g., CKD) and trea tment are unknown. Unwanted iron accumulation in patients is known to lead to adverse effects. Current whole-body models lack the mechanistic details of iron transport related to RBC maturation, transferrin (Tf and TfR) dynamics and assume passive iron efflux from macrophages. Hence, they are not pr edictive of whole-body iron dynamics and cannot be used to design individualized patient treatment. For prediction, we developed a mechanistic, multi-scale computational model of whole-body iron metabolism incorporating four compartments containing major pools of iron and RBC generation process. The model accounts for multiple forms of ironin vivo, mechanisms involved in iron uptake and release and their regulation. Furthermore, the model is interfaced with drug pharmacokinetics to allow simulation of treatment dynamics. We calibrated our m...
Source: PLoS Computational Biology - Category: Biology Authors: Source Type: research

Related Links:

AbstractBackgroundIron deficiency is a common cause of anemia in pediatric patients with hemodialysis-dependent chronic kidney disease (CKD-5HD). Ferric pyrophosphate citrate (FPC, Triferic ®) donates iron directly to transferrin, bypassing the reticuloendothelial system and avoiding iron sequestration. Administration of FPC via dialysate or intravenously (IV) may provide a suitable therapeutic option to current IV iron preparations for these patients.MethodsThe pharmacokinetics and safety of FPC administered via dialysate and IV to patients aged
Source: Pediatric Nephrology - Category: Urology & Nephrology Source Type: research
AbstractBackground25-Hydroxyvitamin D (25OHD) deficiency is common in children with chronic kidney disease (CKD). It has been associated with an increased risk for anemia in both healthy US children and in adults with CKD. This association has not been explored in children with CKD.MethodsChildren aged 1 –16 enrolled in the Chronic Kidney Disease in Children (CKiD) study with mild to moderate kidney dysfunction, and with 25OHD measured at baseline (n = 580), were included in the analysis. The cross-sectional associations between 25OHD and hemoglobin (g/dL) and anemia were assessed. Anemia was defined as hemoglobin
Source: Pediatric Nephrology - Category: Urology & Nephrology Source Type: research
ConclusionsOur findings support the presence of erythropoiesis inhibitory substances in uremic sera. EPO/EPO-R-dependent mechanisms may play a role in inhibiting erythropoiesis. The in vitro bioassay described herein may serve as an indicator of rHuEPO responsiveness which may encourage further investigation of underlying mechanisms of EPO resistance.
Source: Pediatric Nephrology - Category: Urology & Nephrology Source Type: research
An overview of the treatments for anaemia in chronic kidney disease and the tests needed to prescribe and assess their effectiveness.
Source: Clinical Pharmacist - Category: Drugs & Pharmacology Source Type: research
Z, Tesař V, Vokurka M Abstract Hepcidin is a key regulator of iron metabolism and plays an important role in many pathologies. It is increased by iron administration and by inflammation, while erythropoiesis downregulates its expression. It decreases iron availability and thus contributes to anemia of chronic diseases. The aim of the study was to measure hepcidin as a marker and pathogenic factor in ANCA-associated vasculitis (AAV). Hepcidin plasma concentration was measured by the immunological method in 59 patients with AAV and compared to patients with non-vasculitic etiology of chronic kidney disease, patien...
Source: Physiological Research - Category: Physiology Authors: Tags: Physiol Res Source Type: research
In this study, we further investigated the effects of other protein-bound uremic toxins on HIF-dependent EPO expression using EPO-producing HepG2 cells. We found that indoxyl glucuronide (IG) and IS, but not p-cresyl sulfate, phenyl sulfate, 3-indoleacetic acid or hippuric acid, inhibited hypoxia mimetic cobalt chloride-induced EPO mRNA expression. Furthermore, IG at concentrations similar to the blood levels in CKD patients inhibited the transcriptional activation of HIF induced by both cobalt chloride treatment and hypoxic culture. IG also induced CYP1A1 mRNA expression and nuclear translocation of AHR protein, indicatin...
Source: Biochemical and Biophysical Research communications - Category: Biochemistry Authors: Tags: Biochem Biophys Res Commun Source Type: research
Conclusions: Switching to RetacritTM was non-inferior to continuing ­Epogen® in maintaining hemoglobin levels in patients receiving hemodialysis, when both ESAs were dosed using a specified algorithm (ClinicalTrials.gov, NCT02504294).Am J Nephrol 2018;48:214 –224
Source: American Journal of Nephrology - Category: Neurology Source Type: research
Conclusions: TP0463518 induced dose-dependent EPO production, mainly derived from the liver in HV and CKD patients. These results suggest that TP0463518 is a new strategy for treating anemia in CKD, which can be used regardless of renal functions.Am J Nephrol 2018;48:157 –164
Source: American Journal of Nephrology - Category: Neurology Source Type: research
Authors: Auerbach M, Chertow GM, Rosner M Abstract INTRODUCTION: Ferumoxytol is a superparamagnetic molecule originally developed as a contrast agent for magnetic resonance imaging. Elemental iron is contained within the carbohydrate core and is released slowly after infusion allowing a large dose of iron to be administered in a short period of time. Ferumoxytol, originally approved for iron deficiency in chronic kidney disease, received a broad label for any cause of iron deficiency after oral iron intolerance or in those circumstances when oral iron is ineffective or harmful. AREAS COVERED: The chemistry, pha...
Source: Expert Review of Hematology - Category: Hematology Tags: Expert Rev Hematol Source Type: research
CONCLUSIONS: Switching to RetacritTM was non-inferior to continuing -Epogen® in maintaining hemoglobin levels in patients receiving hemodialysis, when both ESAs were dosed using a specified algorithm (ClinicalTrials.gov, NCT02504294). PMID: 30196301 [PubMed - as supplied by publisher]
Source: American Journal of Nephrology - Category: Urology & Nephrology Authors: Tags: Am J Nephrol Source Type: research
More News: Anemia | Biology | Chronic Kidney Disease | Diets | Iron | Nutrition | Study | Urology & Nephrology