PROJECT SUMMARY/ABSTRACT The components of chronic kidney disease-mineral and bone disorder (CKD-MBD) include calcitriol deficiency, hyperphosphatemia, and excesses of fibroblast growth factor-23 (FGF-23) and parathyroid hormone (PTH), all of which consistently and strongly associate with cardiovascular disease (CVD) in patients with kidney failure on dialysis. Vascular calcifications are present in >80% of these patients and may be a mechanism through which CKD-MBD increases CVD risk. Intravenously-administered (IV) vitamin D receptor agonists (VDRA) are routinely used as first-line therapy for CKD-MBD in kidney failure, supported by experimental and epidemiological evidence that suggest VDRAs improve CVD and survival. However, the long-term risks and benefits of the current treatment approach, which encourages escalating VDRA doses to reduce PTH concentrations towards the normal range, have never been tested by clinical outcomes trials. This approach often leads to high VDRA doses which incur several risks: (1) a dose-dependent rise in FGF-23, a major risk factor for CVD that is associated with monotonically increasing risk of death in kidney failure; (2) hypercalcemia, a key promoter of vascular calcification; (3) low turnover bone disease, which drive calcium and phosphate into the vasculature because they cannot deposit into bone; (4) held doses of VDRA as a result of (2) and (3), which interrupts therapy and deprives patients of its likely health benefits. The goal of this project is to evaluate the safety, efficacy, and feasibility of a low fixed-dose vitamin D strategy to treat CKD-MBD in kidney failure to move the field towards identifying an optimal strategy that balances the risks and benefits of VDRA use. The two Aims proposed will leverage a unique partnership with Northwest Kidney Centers (NKC), the largest provider of dialysis in Seattle, WA. Aim 1 is a 12-month pragmatic randomized clinical trial of 90 NKC patients on hemodialysis that will compare the effects of a low fixed-dose oral calcitriol strategy (intervention) with the current usual care of PTH-titrated IV VDRAs (control) on a comprehensive panel of biomarkers assessing mineral metabolism, bone turnover, and serum calcification propensity, as well as measures of feasibility and acceptability. Aim 2 is a complementary retrospective cohort study using the NKC electronic health records database that will test associations between mean VDRA dose and variability in VDRA doses with CVD event and hospitalization rates. These Aims test whether a low fixed- dose vitamin D strategy has causal effects that improve intermediate outcomes (Aim 1) and associate with improved clinical outcomes (Aim 2), building a foundation for future large-scale clinical outcomes trials. Integrated with this research agenda is a career development plan designed to position me to become a successful independent investigator in the field of disordered mineral metabolism in CKD. This mentored approach to t...