Grant Abstract: Vitamin D Catabolism in Chronic Kidney Disease

Grant Number: 5R01DK099199-05
PI Name: De Boer
Project Title: Vitamin D Catabolism in Chronic Kidney Disease

Abstract: Vitamin D clearance is an important and often overlooked aspect of vitamin D biology that has relevant implications for the clinical assessment and treatment of vitamin D deficiency. The circulating concentration of 25-hydroxyvitamin D [25(OH)D] is the most widely accepted measure of vitamin D status, and vitamin D supplements are often prescribed and titrated based on 25(OH)D concentration. However, circulating concentrations of 25(OH)D are necessarily determined by both 25(OH)D production and 25(OH)D clearance. Therefore, 25(OH)D clearance likely plays an important role in the assessment of vitamin D status and the response to vitamin D supplementation. Our preliminary data suggest that the serum concentration of 24,25- dihydroxyvitamin D3 [24,25(OH)2D3] may be a useful biomarker of 25(OH)D clearance that reflects tissue-level vitamin D activity and helps guide vitamin D assessment and treatment. Our parent study, funded by R01DK099199, aims to define 25(OH)D clearance in the unsupplemented state and how 25(OH)D clearance is affected by race and kidney function. To accomplish this aim, we have developed a unique deuterated 25(OH)D3 probe for intravenous administration. We have begun administering this to parent study participants and have demonstrated safety as well as expected achieved serum deuterated 25(OH)D3 concentrations. Now, in this administrative supplement application, we propose to leverage this unique 25(OH)D3 probe and our parent study population to extend our studies to the setting of vitamin D supplementation. Specifically, for a subset of 20 participants who complete our parent study, we propose to offer an extension in which vitamin D3 supplements (2000 IU daily) are administered for 6 months, during which pharmacokinetic studies are repeated. With this extension, we aim (1) to determine the effects of vitamin D3 supplementation on 25(OH)D3 clearance using gold standard pharmacokinetic studies, and (2) to evaluate serum 24,25(OH)2D3 to 25(OH)D3 ratio as a novel biomarker of response to vitamin D supplementation. The proposed studies are timed to coincide with completion of parent study procedures for the majority of participants. We expect that the new studies will enhance interpretation of available diagnostic tests, inform the results of ongoing large clinical trials of vitamin D supplements, help develop new strategies to target vitamin D to improve health, and support the use of serum 24,25(OH)2D3 as a biomarker of 25(OH)D clearance for use in future studies.

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