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

Joydeep Sarkar, Alka A Potdar and Gerald M Saidel

PLOS Computational Biology, 2018, vol. 14, issue 4, 1-34

Abstract: 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 erythropoietin 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 treatment 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 predictive 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 iron in 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 model with experimental and clinical data from peer-reviewed literature to reliably simulate CKD anemia and the effects of current treatment involving combination of epoietin-alpha and iron dextran. This in silico whole-body model of iron metabolism predicts that a year of treatment can potentially lead to 90% downregulation of ferroportin (FPN) levels, 15-fold increase in iron stores with only a 20% increase in iron flux from the reticulo-endothelial system (RES). Model simulations quantified unmeasured iron fluxes, previously unknown effects of treatment on FPN-level and iron stores in the RES. This mechanistic whole-body model can be the basis for future studies that incorporate iron metabolism together with related clinical experiments. Such an approach could pave the way for development of effective personalized treatment of CKD anemia.Author summary: Iron is mostly recycled with very little loss or replenishment. This model simulates the complex regulatory network that maintains iron within healthy limits. Iron diseases are typically characterized by breakdown of such regulatory pathways (e.g. synthesis of erythropoietin, inhibition of iron release by hepcidin, etc.) that lead to pathological lack of iron or deposition of iron. Most iron metabolism research focuses on the specific roles of the regulatory proteins (e.g. HFE, ceruloplasmin), but here we chose to focus on the interplay between ferroportin and hepcidin. The current literature lacks an integrated whole-body view of iron metabolism with key fluxes that are essential for investigating the roles of regulatory protein within feedback networks and molecular pathways. These aspects can be investigated by simulations with our top-down, mechanistic computational model. Our model simulations suggest possible improvements in treatment of anemia of chronic kidney disease. Furthermore, this model can provide a platform for future developments of powerful predictive tools that can be used to accelerate drug development of iron-disorder diseases.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1006060

DOI: 10.1371/journal.pcbi.1006060

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