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phlebotomy) there is release of iron from the Fe3+ stores of the I-region of the RES compartment. Your "iron level" is checked before each blood donation to determine if it is safe for you to give blood. The perturbations associated with injections of rhHepc and rEpo require model equations for drug concentrations in plasma and in a generic tissue. This model does not assume a simple gradient approach to all transport processes, which is common in previous models of whole-body iron metabolism [18, 19, 39]. (Code available as supplementary material). Iron from the hemoglobin in senescent RBCs that are phagocytosed by the macrophages of the ISF is delivered as Fe3+ into the intracellular region. Furthermore, the model is interfaced with drug pharmacokinetics to allow simulation of treatment dynamics. Recent studies [2729] propose mathematical models to better predict the dosing strategy of recombinant erythropoietin (rEpo) used to treat anemia in patients with chronic kidney disease (CKD) [3032]. All expressions in the model are based on causal mechanistic understanding of processes and not based on associations or correlations observed in observed data. Hepatocytes in the liver also contain TfR1 receptors, which is yet another means of iron uptake from serum transferrin. This experiment allows calibration of changes in Epo synthesis and secretion in response to changes in serum hemoglobin. Citation: Sarkar J, Potdar AA, Saidel GM (2018) Whole-body iron transport and metabolism: Mechanistic, multi-scale model to improve treatment of anemia in chronic kidney disease. where . Its most critical physiological function is associated with the oxygen carrying capacity of hemoglobin. (69). The Fe3+ from the senescent RBC acts as a source of Fe3+ in the intracellular (I) region. This relation is based on saturation of high affinity Epo receptors of CFUe. Most of the decrease in RBC number density occurs within a year. As explained before, all simulations of the whole-body model, especially the perturbations, start from a set of steady-state which is obtained by simulating the model for a period of time and allowing it to reach a steady-state. Blood loss is the most common cause of iron deficiency. For blood donors, each donation results in the loss of 200 to 250 mg of iron. With this perturbation including plasma volume reduction, the concentration of plasma iron changes as: PLoS Comput Biol 14(4): (27), Here, FPN is the half-life of FPN and is the steady-state concentration of FPN. Changes in concentration of IHepc can be rationalized as representing the dynamics of normalized mRNA expression for Hepc. (32) where kPT and kTP are rate coefficients for transport between plasma (P) and tissue (T) and, is the time constant of drug loss by several processes including metabolism. To reduce the number of parameters to be estimated, we assumed relationships between species transport parameters based on molecular weight MW of each species such as: To estimate the model parameters listed in Table 8, the dynamic model output is fit to the time course of serum drug (rEpo) concentration. The very low binding affinity of transferrin to TfR2 produces significantly different dynamics in this compartment as opposed to assuming the same binding affinity as TfR. are ignored for this model. Iron ingestion increases serum iron levels and Hepc synthesis leading to increased serum Hepc. Because the rate of iron loss and replenishment by intestinal absorption is small, this metabolic model focuses on key aspects of iron recycling in contrast to previous models of iron metabolism [18, 20, 26, 28, 38, 39]. Four different types of arrows are used to connect compartments and species which are explained in the legend drawn inside the figure. For example, the model parameters were estimated by matching the model outputs to steady-state values of clinical markers. For most species, the transport fluxes between M and ISF are governed by passive diffusion: Of special clinical significance is our model simulation of anemia in CKD patients with insufficient erythropoietin and treatments with rEpo and iron dextran infusion. Ceruloplasmin (Cp), a ferroxidase associated with macrophage iron release [912], is essential in intestinal iron transport. This makes the generation of ensemble predictions intractable for the scope of this study and has been avoided. As described above, distinctive values of binding rate constants were obtained for Fe3+Tf and (Fe3+)2Tf to TfR and these were used in the model simulations during the parameter estimation process. The goal is to add enough detail to represent the dose response and dynamics of Hepc to changes in serum iron, which is different from previous models [21]. From the literature, we specified steady-state reference values for initial basic model variables and parameters. (11) About 6 percent of body iron is a component of certain proteins, essential for respiration and energy metabolism, and as a component of enzymes involved in the synthesis of collagen and some neurotransmitters. With this simplification, iron uptake by maturing erythroblasts is represented by a single set of reactions in a single EB compartment. Enough experimental data was available to constrain the model parameters for analysis of the CKD anemia treatment. according to an empirical function [36]: Validation, The model incorporates a constraint such that serum hemoglobin () reaches saturation with long-term repeated doses of rEpo (S5 Fig). Iron diseases are typically characterized by breakdown of such regulatory pathways (e.g. These data show time-course interaction of mono- and di-ferric transferrin to transferrin receptors over a wide range of doses. Iron plays vital roles in the human body including enzymatic processes, oxygen-transport via hemoglobin and immune response. The RBC half-life, which is 4 times less in mice [83], has a great effect on serum iron when rhHepc is injected. Copyright: 2018 Sarkar et al. Yes The value of this parameter was obtained by fitting the model to the data as shown in Supplement S2 Fig. Software, Other causes of genitourinary bleeding and respiratory tract bleeding also increase iron requirements. Here, the mechanism of iron release from Tf and recycling of Tf and TfR has been simplified as a single reaction. For these simulations, changes in two serum markershemoglobin (A) and serum iron (B) are shown along with two measuresferroportin levels in cells of the RES (C) and iron efflux from RES (D), which cannot be easily measured in vivo. https://doi.org/10.1371/journal.pcbi.1006060.t005, https://doi.org/10.1371/journal.pcbi.1006060.t006. The large ensemble of models can then be compared to the training data across all the scenarios using likelihood-based scores. The simulated treatment consists of epoietin-alpha injections (rEpo = 100 ug/Kg) every 2 weeks and IV iron-dextran (1g) every 2 weeks for 12 months. CKD patients have been reported to have blood loss [82]. (54) The dynamics of hepatocyte iron are described in the Liver compartment section. A schematic representation of the recycling process in iron metabolism has been depicted in literature [8]. Phlebotomy produces a loss of blood volume that leads to changes in serum hemoglobin and Epo concentrations. P represents drugs taken orally, SC represents subcutaneous administration, VT represents the volume of the tissue compartment. The modified equations for Epo and Hepc are For example, the CFU section is assumed spatially distributed because a simpler spatially lumped model cannot reproduce the expected responses. Cooking in iron pots can add up to 80 percent more iron to your foods. https://doi.org/10.1371/journal.pcbi.1006060.g002. Ideally, one could generate an ensemble of models generated by varying all the parameters estimated around the best estimated values. We encourage you to discuss any questions or concerns you may have with your provider. where and are the input rates from synthesis of Epo by kidneys and Hepc by liver, which have been discussed in detail later (section on Erythropoietin and Hepcidin Inputs). (49) In the membrane (M) region: In the model, the transcriptional regulation is represented as a Hills function. Writing review & editing, Current address: F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States of America, Affiliation In the simulation of CKD with treatments, only the best calibrated model was used for all simulations. Methodology, In the EB region, iron is taken from (Fe3+)Tf and (Fe3+)2Tf via transferrin receptor (TfR). This experiment performed in mice allows estimation of the half-life of FPN which is crucial for simulation of long-term changes in FPN levels. In plasma, these species include iron-hemoglobin (HbFe), free ferric iron (Fe3+), apo-transferrin (Tf), mono-ferric transferrin (Fe3+Tf), diferric transferrin ((Fe3+)2Tf), ceruloplasmin (Cp), erythropoietin (Epo), and hepcidin (Hepc). (64) Inside the liver compartment of volume VL, the concentrations of some species change as: Since HbFe3+ is not in CFUe its concentration changes according to The metabolic model parameters (kRES,rhHepc,FPN,EPN) were estimated (Table 9) by matching serum iron output using the pharmacokinetic model for rhHepc in conjunction with the whole-body model to the normalized serum iron data. Values for all initial model variables and parameters are listed in tables described later in the document. Future versions of the model may be developed to add further mechanistic detail to iron absorption in the gut and the regulation of hepcidin synthesis as shown in some studies [21]. Mathematical modeling of key experimental data can help provide answers to such complex problems. The iron stores in the I-region of the RES compartment represent the overall iron stores in the model. 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. Then it would be expected that the estimates of accumulation of iron in the RES would be reduced by the amount accumulated in the hepatocytes. (19) The naturally damped oscillations produced as a result are shown by simulation of a longer time period (5 days) for the same variables (D-F). Formal analysis, The CFUe number forming at = 0 from differentiating Burst Forming Unit Erythroids (BFUe) is dependent on the total BFUe number NBFUe available for differentiation and The time course of change of all four variables over time have been plotted from the start of the treatment at time 0. https://doi.org/10.1371/journal.pcbi.1006060.g006. From an age-distributed cell number balance, we obtain This approach requires knowledge of the error rates for each of the different types of measurements used in likelihood scoring and subsequent large-scale simulations. In the liver compartment, we consider the dynamics of binding of iron-transferrin to transferrin receptor 2 (TfR2), internalization and storage of iron inside the liver depicted in Fig 2. rEpo injection affects CFUe dynamics leading to increased hemoglobin in blood. Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, United States of America, Roles Furthermore, the cross-correlation coefficients were estimated, but no significant cross-correlation was observed and hence not reported. (53) (7) If your doctor foresees this, he or she will discuss your options for blood donation. The uptake of iron from the gut lumen to blood also involves more than one transporter [4] and the details of iron uptake from the gut are not included in this model. e1006060. (48) where reflects initial blood loss and are empirical rate parameters [25]. The model simulation of rhHepc injection (Fig 5A) shows that the serum iron drops to its minimum around 8hr and then gradually rises back to normal around 96hr. The model can reproduce varying degrees of anemia of CKD as shown with the reduction in plasma red blood cell density (A), plasma hemoglobin (B), serum iron (C) and transferrin saturation (D). (17) The degradation of Fe3+ refers to non-specific binding of serum Fe3+ to plasma. In order to develop confidence that the parameter estimates are global, a Differential Evolution algorithm [68] was used with multiple restarts to find the best result. The model assumes that iron recycling is 100%. Thus, in this model, Hepc levels are lower than normal in CKD patients. The optimal hemoglobin level needs to be personalized [33]. It is for educational purposes only and is not intended to replace the advice of your doctor or other health care provider. Our multi-scale model of iron metabolism integrates molecular mechanisms with cellular and tissue transport of iron in organ systems of the whole body (Figs 1 & 2). No, Is the Subject Area "Iron deficiency anemia" applicable to this article? (12) (65). Yes The relative affinities of (Fe3+)Tf and (Fe3+)2Tf are known (Table 6). The injection of iron-dextran into the system was carefully simulated to avoid a sudden, large increase in serum iron as reported [33]. This model was calibrated using a variety of experimental mouse and human data. From in vitro experiments [67], the normalized concentration (y) of I125-labelled (Fe3+)2Tf that is internalized can be described by The significant accumulation of iron in the RES system is likely to have additional pathological effects [36, 37]. Furthermore, it integrates data from in vitro cellular experiments, mouse experiments, healthy human volunteer studies, and clinical studies of anemia with chronic kidney disease (CKD). Unwanted iron accumulation in patients is known to lead to adverse effects. Writing review & editing. In the I region, the species j concentrations change according to Such an approach could pave the way for development of effective personalized treatment of CKD anemia. Ferrous sulfate 325 mg, taken orally once a day, and by eating foods high in iron. The remaining parameters were estimated by comparing model outputs in response to perturbations corresponding to experimental time-course data. The dissociation of Fe3+ FPN allows FPN to recycle and Fe3+ to diffuse into the ISF or bind to Tf to form Fe3+Tf in the membrane region. The model output incorporating this perturbation was fit to experimental time-course data for serum iron (), transferrin saturation () and serum hepcidin () [11]. The only information available is the half-life of ferroportin mRNA, but that is known to be significantly smaller than that of the stable transporter protein. (36) From experiments [2, 64], is the mean total serum transferrin. Methodology, https://doi.org/10.1371/journal.pcbi.1006060.t008. The total number of parameters estimated in this model is high, so the requirement of the ensemble size would be very large. This steady-state solution for each of the species is described below in Table 11. https://doi.org/10.1371/journal.pcbi.1006060.t011. At steady state, we obtain Parameters of the model were estimated in stages with estimates from the previous step carried forward for future parameter estimation steps. iron dextran treatment in CKD anemia) the Fe3+ levels increase significantly in the model. UCSF Health medical specialists have reviewed this information. Visualization, This iron can also be released through ferroportin on the cells. The model parameter represents the sensitivity of CFUe maturation to rEpo concentrations. The model also does not incorporate the expression of erythroferrone by the erythroblasts and its inhibitory effect on hepcidin synthesis [81]. While most of iron is recycled (>95%), the loss of iron is usually replenished by uptake of iron from diet [4, 24, 53]. In CKD patients, it has been observed that serum levels of Hepc are often higher than normal even with reduced serum iron [84]. With this perturbation, rEpo acts like endogenous Epo and increases the rate of BFUe differentiation into CFUe as represented by Beyond the effects and mechanisms of CKD anemia, other aspects associated with iron metabolism could be investigated using this model as a platform for the analysis of copper deficiency on iron metabolism through ceruloplasmin or even other iron metabolism related genetic mutations. We incorporated the Hepc blocking of iron transport from RES through degradation of both intracellular and membrane FPN [1517]. However, in the simulation of CKD, the serum concentration of Epo is calibrated to achieve specific levels of serum hemoglobin. While the model does not account for total ferritin stores in the human body, Fe3+ is the closest proxy for ferritin stores in the model, though it likely underestimates the total ferritin content. To predict the dynamics of iron release in the RES, detailed mechanisms that describe the interaction between serum iron, Hepc and iron release are essential. With a multi-scale model, processes that occur at the molecular and cellular levels can be related to observed behaviors at the tissue-, organ- and whole-body levels. The reaction rates for each chemical species j in the three RES regions (RjISF,RjI,RjM) are based on the kinetics as indicated in Fig 2 and described below. Also, the current model is missing the negative regulation of hepcidin expression mediated through erythroferrone, which could be significant due to rhEPO administration. (5) Project administration, (66) Yes The reliability of the estimated parameters was estimated by calculating the coefficient of variation (CV) for each parameter for the specific simulation scenario of the estimation process. (43). 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. The IHepc concentration increases by synthesis at rate RIHepc and decreases by natural mRNA degradation with a characteristic time IHepc: Data Availability: All relevant data are within the paper and its Supporting Information files. (50). In this study, we have developed a multi-scale model of iron metabolism, which integrates intracellular, molecular mechanisms with cellular and tissue transport of iron. A top-down modeling methodology has been used to develop this model providing just enough detail to simulate the inter-tissue iron fluxes and changes during disease and treatment. Where kRBCEB is a differentiation rate coefficient. Model parameters were estimated using experimental data associated with the following perturbations applied to the basic model: https://doi.org/10.1371/journal.pcbi.1006060.t007. While there is a large focus on the multitude of diseases implicated due to iron deficiency, excessive iron is also very toxic [1]. Iron is essential for a wide variety of biological functions. (45) (3) Iron also is needed for proper immune function. here. Writing original draft, Increase in liver intracellular Fe3+ leads to increase in Hepc [50] through increased transcription which is represented in the model as increased synthesis of IHepc [51]. The process of maturation of erythroblasts into mature RBC has been simplified into a lumped model unlike the age-distributed model for maturation of CFU. A detailed schematic of the reactions and transport processes incorporated in the model is presented in Fig 2. serum iron, total iron binding capacity, serum hemoglobin, RBC cell concentration) related to therapy while simultaneously providing output of changes in transport fluxes and intracellular species related to iron metabolism. This is explained by the role of inflammation on Hepc synthesis [85]. Yes where These cells proliferate, but are negligible in bone marrow reaction or transport processes related to iron. To mathematically model iron metabolism in the mouse using information from human iron metabolism, it is necessary to scale the compartmental volumes and RBC half-life in blood. This mechanistic whole-body model can be the basis for future studies that incorporate iron metabolism together with related clinical experiments. Simulated treatments of CDK anemia for patients with a starting Hb~10 mg/dL, 4.6 pM and Epo = 0 are shown in Fig 6. Compared to the basic model equations, the modified plasma concentrations involve this loss in plasma volume, which tends to increase concentration with time. Iron metabolism is characterized by ~95% recycling and minor replenishment through diet. The steady-state CFU number is defined as follows: The hematocrit decreases for the first ten days and rebounds to the initial level over the next 50 days (Fig 3A), while the time course of Epo concentration is the opposite (Fig 3B). The reactions of chemical species are represented by the following kinetics (Fig 2): The internal processes are developed for recycling of transferrin receptors and incorporation of iron into hemoglobin. No, PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US, Corrections, Expressions of Concern, and Retractions, https://doi.org/10.1371/journal.pcbi.1006060, https://pubchem.ncbi.nlm.nih.gov/compound/24393. All species transport between plasma and liver is governed by passive diffusion: During model simulation of iron deficiency (e.g. The current clinical guidelines for treatment of anemia in CKD [33, 34] also include administration of iron dextran to CKD patients where rEpo alone is not enough to improve the hemoglobin levels. (44) Nevertheless, the model simulations correspond well to the data.