Coupling between phosphate and calcium homeostasis: a mathematical model

Abstract

We developed a mathematical model of calcium (Ca) and phosphate (PO) homeostasis in the rat to elucidate the hormonal mechanisms that underlie the regulation of Ca and PO balance. The model represents the exchanges of Ca and PO between the intestine, plasma, kidneys, bone, and the intracellular compartment, and the formation of Ca-PO-fetuin-A complexes. It accounts for the regulation of these fluxes by parathyroid hormone (PTH), vitamin D, fibroblast growth factor 23, and Ca-sensing receptors. Our results suggest that the Ca and PO homeostatic systems are robust enough to handle small perturbations in the production rate of either PTH or vitamin D The model predicts that large perturbations in PTH or vitamin D synthesis have a greater impact on the plasma concentration of Ca ([Ca]) than on that of PO ([PO]); due to negative feedback loops, [PO] does not consistently increase when the production rate of PTH or vitamin D is decreased. Our results also suggest that, following a large PO infusion, the rapidly exchangeable pool in bone acts as a fast, transient storage PO compartment (on the order of minutes), whereas the intracellular pool is able to store greater amounts of PO over several hours. Moreover, a large PO infusion rapidly lowers [Ca] owing to the formation of CaPO complexes. A large Ca infusion, however, has a small impact on [PO], since a significant fraction of Ca binds to albumin. This mathematical model is the first to include all major regulatory factors of Ca and PO homeostasis.

Strategies for Phosphate Control in Patients With CKD

“…Finally, because serum FGF23 increases early in the course of CKD as an adaptive response to prevent phosphate overload, the hypothesis was made that it might be a valuable surrogate marker for long-term serum phosphate fluctuations, like HbA1C for serum glucose, and might provide guidance for clinical interventions. This hypothesis had to be given up with the subsequent advances in our understanding of the numerous mechanisms other than phosphate that play a role in the regulation of FGF23 secretion, such as calcium, PTH, vitamin D, and iron, as well as inflammation 133, 134. In keeping with this knowledge, calcium-based and calcium-free phosphate binders exert different actions on FGF23 secretion despite comparable phosphate-lowering effects 132, 135, 136…”

Calcium fluxes at the bone/plasma interface: Acute effects of parathyroid hormone (PTH) and targeted deletion of PTH/PTH-related peptide (PTHrP) receptor in the osteocytes

“…Models proposed by Neuman (27), Talmage (15, 28), Bronner (17, 29) and Parfitt (13, 18) support the concept of a dynamic bone/plasma Ca 2+ dis/equilibrium possibly modulated by the saturation level of hydroxyapatite solubility and/or access to Ca 2+ binding sites. Novel mathematical models have also been developed to integrate this fast component in the slow-reacting Ca 2+ homeostasis (30–32), but its hormonal regulation remains unsettled despite its importance in the overall plasma Ca 2+ homeostasis. Experiments and models addressed to assess the contribution of PTH [see (13, 15, 18) for reviews] have suggested that the level of blood/bone equilibrium might vary with the level of PTH, but the direct experimental evidence for the PTH effect at the bone surface in eliciting a fast homeostatic response is lacking.…”

Risk factors and antihypertensive medications for mortality in elderly hospitalized hemodialysis patients: a multicenter retrospective study in China

“…Elderly hemodialysis patients often suffer from decreased bone synthesis and reabsorption, and PTH secretion is inhibited [11]. They have degenerative function of hormone secretion and activity, decrease expression of anti-aging Klotho gene and uremic toxins [12].The intake of phosphorus decreases and hypophosphatemia develops, causing a decrease in PTH levels.The specific mechanism of low transport bone disease in elderly hemodialysis patients remains to be further explored [13].There is a positive correlation between serum PTH levels and serum albumin, creatinineand total cholesterol concentrations in elderly hemodialysis patients [14]. The main therapeutic goal of low-transplant renal bone disease is to reduce calcium ion and vitamin D load, avoid excessive inhibition of PTH, maintain PTH activity and improve the quality of life of hemodialysis patients [15].…”