F32 Childcare Costs Supplement: Assessment of the Vitamin D Metabolite Ratio as a Therapeutic Target in Clinical Practice

PROJECT SUMMARY/ABSTRACT Impaired vitamin D metabolism is associated with increased risks of bone disease, cardiovascular disease (CVD) and death among patients with chronic kidney disease (CKD), a large and growing population in the United States. The clinical evaluation and treatment of abnormal vitamin D status are a major focus of

nephrology clinical care, but are hampered by the lack of reliable measures of vitamin D adequacy and a limited ability to identify individuals who are likely to respond to vitamin D treatment. The two most commonly used markers used to guide clinical decision-making and treatment, 25-hydroxyvitamin D (25(OH)D) and

parathyroid hormone (PTH) concentrations, are imperfect measures of vitamin D adequacy: 25(OH)D is an inactive metabolite with weak correlation with many downstream responses of vitamin D receptor binding, while PTH reflects activity at just one of many target organs and is influenced by factors other than vitamin D

receptor activation. Measures of tissue-level, functional vitamin D activity may more optimally define vitamin D adequacy. The binding of 1,25-dihydroxyvitamin D (1,25(OH)2D, the active vitamin D metabolite) to vitamin D receptors strongly induces the CYP24A1 enzyme to mediate the pharmacokinetic clearance of 25(OH)D

through the key intermediate 24,25-dihydroxyvitamin D (24,25(OH)2D). Thus the 24,25(OH)2D to 25(OH)D ratio, also called the vitamin D metabolite ratio (VDMR), has been proposed as a novel measure of CYP24A1- mediated 25(OH)D clearance and functional vitamin D activity. The overall study objectives are to validate the VDMR as a marker of 25(OH)D clearance (Aim 1), test whether

the VDMR modifies treatment response to vitamin D supplementation (Aim 2) and whether low VDMR is associated with an increased risk of CVD, the prevailing cause of death in CKD (Aim 3). I will leverage 3 complementary community-based, racially/ethnically diverse cohorts with broad ranges of kidney function to

accomplish these objectives: the Clearance of 25-hydroxyvitamin D in Chronic Kidney Disease Study (CLEAR), the largest cohort with gold standard pharmacokinetic measurements of 25(OH)D clearance; a rigorous randomized clinical trial of oral vitamin D3 nested within the Multi-Ethnic Study of Atherosclerosis

(MESA); and the Chronic Renal Insufficiency Cohort (CRIC), the largest and most comprehensively characterized CKD cohort assembled. In totality, this work will evaluate the use of the VDMR in clinical practice and advance a “precision medicine” approach to vitamin D therapy in CKD. This project will be conducted

under the mentorship of investigators from diverse disciplines, within the rich academic environment collectively formed by the University of Washington and the Kidney Research Institute. The structured training plan proposed in this application and the results of this project will serve as a foundation to transition to a

Career Development Award and an eventual career as an independent researcher.