Model-Based Analysis of FGF23 Regulation in Chronic Kidney Disease
Hiroki Yokota1, Ana Pires2, João F. Raposo3 and Hugo G. Ferreira4
1Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA. 2Department of Nephrology, Fernando da Fonseca Hospital, Lisbon, Portugal. 3Endocrinology Department of the Portuguese Cancer Institute, 1099-023 Lisbon, Portugal. 4REQUIMTE, Department of Chemistry, New University of Lisbon, 2829-516 Caparica, Portugal.
Abstract
The mechanism of FGF23 action in calcium/phosphorus metabolism of patients with chronic kidney disease (CKD) was studied using a mathematical model and clinical data in a public domain. We have previously built a physiological model that describes interactions of PTH, calcitriol, and FGF23 in mineral metabolism encompassing organs such as bone, intestine, kidney, and parathyroid glands. Since an elevated FGF23 level in serum is a characteristic symptom of CKD patients, we evaluate herein potential metabolic alterations in response to administration of a neutralizing antibody against FGF23. Using the parameters identified from available clinical data, we observed that a transient decrease in the FGF23 level elevated the serum concentrations of PTH, calcitriol, and phosphorus. The model also predicted that the administration reduced a urinary output of phosphorous. This model-based prediction indicated that the therapeutic reduction of FGF23 by the neutralizing antibody did not reduce phosphorus burden of CKD patients and decreased the urinary phosphorous excretion. Thus, the high FGF23 level in CKD patients was predicted to be a failure of FGF23-mediated phosphorous excretion. The results herein indicate that it is necessary to understand the mechanism in CKD in which the level of FGF23 is elevated without effectively regulating phosphorus.
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