Impact of Vascular Calcification on the Regulation of Circulating Minerals and Hormones in Experimental Chronic Kidney Disease
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Cardiovascular disease (CVD) is a significant concern in chronic kidney disease (CKD) accounting for over half of all mortality. The high CVD prevalence in CKD is not accounted for by traditional Framingham risk factors (e.g. smoking, obesity) and is likely influenced by CKD-mineral bone disorder (CKD-MBD). CKD-MBD consists of abnormalities in circulating calcium, phosphate, vitamin D, and parathyroid hormone (PTH), as well the development of soft tissue calcifications like vascular calcification (VC). CKD-MBD has been well-characterized clinically and experimentally, however, significant knowledge gaps exist pertaining to: treatment targets and modalities, daily variation in minerals/hormones, the impact of the circulating factors versus local factors on VC, and inversely the impact of VC on the circulating mineral/hormonal milieu. A dietary adenine model was used to induce CKD in rats with differing phosphate diets to propagate/mitigate CKD-MBD. In comparison to healthy rats those with CKD displayed a shift for the acute accrual of infused phosphate and calcium into vascular beds instead of the kidneys and bone. VC amplified this preferential vascular accrual. Further, a preceding phosphate pulse amplifies vascular calcium accrual. In experimental CKD rats CKD treated with calcitriol, alteration of neither the bolus dose nor daily dose administered resulted in improvements to any CKD-MBD parameters. Additionally, adhering to guideline-recommended PTH suppression targets did not provide any benefits in CKD-MBD, other than reducing circulating PTH. In CKD rats fed different phosphate diets, it was found that low phosphate mitigated the pathologic increases in circulating minerals/hormones and protects against VC. Fibroblast growth factor-23 was identified as a potential biomarker for VC in CKD as it was significantly elevated in CKD rats with VC, and early elevations during CKD-induction predicted eventual VC. The daily variations in circulating minerals/hormones was characterized in experimental CKD. It was found that kidney dysfunction did not independently impact circulating minerals/hormones, but that VC significantly impacted the daily variation in circulating phosphate. These findings identify critical areas that need further investigation pertaining to CKD-MBD treatment, as well as expand current knowledge of how the circulating CKD milieu impacts the development of VC and in turn how VC impacts the circulating milieu.
URI for this recordhttp://hdl.handle.net/1974/25890
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