Development of a quantitative systems pharmacology model of chronic kidney disease: metabolic bone disorder

Abstract

Chronic kidney disease mineral bone disorder (CKD-MBD) is a virtually universal complication of kidney diseases, starting early in the course of disease and resulting in devastating clinical consequences ranging from bone fragility to accelerated atherosclerosis and early cardiovascular death. Guidelines for therapeutic goals for CKD-MBD have been published, and achievement of these guidelines is associated with improved survival. However, the incomplete understanding of CKD-MBD and the individual variability in the manifestations of CKD-MBD have made it difficult to achieve these guidelines. We hypothesized that the progression of MBD through all stages of CKD, including end-stage kidney disease, could be represented by a quantitative systems pharmacology/systems biology (QSP) model. To address this hypothesis, we constructed a QSP model of CKD-MBD, building on an open-source model of calcium and phosphorus metabolism. Specifically, we estimated and validated the model using data from 5,496 patients with CKD enrolled in the Chronic Renal Insufficiency Cohort study. Our model accurately predicted changes in markers of mineral metabolism related to progressing CKD. We demonstrated that the incorporation of fibroblast growth factor 23 and the soft tissue compartment is essential for accurate modeling of the changes in calcium, phosphorus, intact parathyroid hormone, and calcitriol in CKD-MBD. We conclude that our systems biology model accurately represents CKD-MBD disease progression and can be used as a test bench for improving therapeutic interventions.