TRANSLATIONAL CHARACTERIZATION OF ACUTE PHOSPHATE DISPOSITION AS IT RELATES TO BONE AND MINERAL HOMEOSTASIS AND CHRONIC KIDNEY DISEASE

Abstract

Elevated serum phosphate is an independent risk factor for cardiovascular disease (CVD) in the general population, and this elevated risk is most prominent in the setting of chronic kidney disease (CKD). Dysregulation of mineral homeostasis is a hallmark of progressing CKD, however serum phosphate elevates very late in disease progression. This thesis describes a series of translational experiments that address a largely overlooked aspect of phosphate homeostasis, acute phosphate regulation. The overall objective of the research was to characterize the role of acute phosphate homeostasis within long-term homeostasis and it’s importance in pathophysiological settings. This work introduces a clinical tool, termed an oral phosphate tolerance test (OPTT), whereby the acute circulating, hormonal and excretory responses are assessed following the consumption of a phosphate-containing drink. This response was characterized in the setting of both healthy and impaired kidney function in humans, addressing the roles of age, sex and prevailing dietary phosphate. The acute response to an oral phosphate load was also characterized in the context of a rat model of CKD and in a pharmacologically induced model of vascular calcification to assess distribution and acute tissue accrual via phosphate radioisotope tracking. The major findings are: (i) impaired acute phosphate excretion is present in kidney disease prior to chronic elevations in serum phosphate, (ii) calcifying vasculature has a significant role in acute non-renal phosphate clearance following a phosphate challenge such that there is a blunted rise in serum phosphate following acute oral phosphate, (iii) chronic consumption of high dietary phosphate attenuates the hormonal response to an oral load of phosphate, but does not impact the excretion efficiency, and (iv) the OPTT responses differed according to sex, but not age, whereby females excreted more phosphate and calcium in the time period immediately after delivery. The acute non-renal phosphate clearance mediated by calcifying vasculature likely contribute to the initiation and progression of VC. These findings point to the importance of targeting diet-induced phosphate spikes therapeutically to reduce the morbidity linked to the progression of vascular calcification, and other phosphate-driven diseases. The OPTT has potential as a clinical tool for the early identification of impaired phosphate tolerance in populations at risk for CVD.