Yokota Hiroki, Pires Ana, Raposo João F, Ferreira Hugo G
Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Gene Regul Syst Bio. 2010 Jun 9;4:53-60. doi: 10.4137/grsb.s4880.
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.
利用数学模型和公开领域的临床数据，研究了成纤维细胞生长因子23（FGF23）在慢性肾脏病（CKD）患者钙/磷代谢中的作用机制。我们之前构建了一个生理模型，该模型描述了甲状旁腺激素（PTH）、骨化三醇和FGF23在涉及骨骼、肠道、肾脏和甲状旁腺等器官的矿物质代谢中的相互作用。由于血清中FGF23水平升高是CKD患者的一个特征性症状，我们在此评估针对FGF23的中和抗体给药后潜在的代谢改变。利用从现有临床数据中确定的参数，我们观察到FGF23水平的短暂降低会提高PTH、骨化三醇和磷的血清浓度。该模型还预测，给药会减少磷的尿量。基于模型的这一预测表明，用中和抗体治疗性降低FGF23并不能减轻CKD患者的磷负荷，反而会降低尿磷排泄。因此，预测CKD患者中高FGF23水平是FGF23介导的磷排泄功能障碍。本文结果表明，有必要了解CKD中FGF23水平升高而未有效调节磷的机制。
