Differences in 25-Hydroxyvitamin D Clearance by eGFR and Race: A Pharmacokinetic Study

Abstract

Background: Conversion of 25-hydroxyvitamin D (25[OH]D) to the active form of vitamin D occurs primarily in the kidney. Observational studies suggest 25(OH)D clearance from the circulation differs by kidney function and race. However, these potential variations have not been tested using gold-standard methods.

Methods: We administered intravenous, deuterated 25(OH)D3 (d-25[OH]D3) in a pharmacokinetic study of 87 adults, including 43 with normal eGFR (≥60 ml/min per 1.73 m2), 24 with nondialysis CKD (eGFR <60 ml/min per 1.73 m2), and 20 with ESKD treated with hemodialysis. We measured concentrations of d-25(OH)D3 and deuterated 24,25-dihydroxyvitamin D3 at 5 minutes and 4 hours after administration, and at 1, 4, 7, 14, 21, 28, 42, and 56 days postadministration. We calculated 25(OH)D clearance using noncompartmental analysis of d-25(OH)D3 concentrations over time. We remeasured 25(OH)D clearance in a subset of 18 participants after extended oral vitamin-D3 supplementation.

Results: The mean age of the study cohort was 64 years; 41% were female, and 30% were Black. Mean 25(OH)D clearances were 360 ml/d, 313 ml/d, and 263 ml/d in participants with normal eGFR, CKD, and kidney failure, respectively (P=0.02). After adjustment for age, sex, race, and estimated blood volume, lower eGFR was associated with reduced 25(OH)D clearance (β=-17 ml/d per 10 ml/min per 1.73 m2 lower eGFR; 95% CI, -21 to -12). Black race was associated with higher 25(OH)D clearance in participants with normal eGFR, but not in those with CKD or kidney failure (P for interaction=0.05). Clearance of 25(OH)D before versus after vitamin-D3 supplementation did not differ.

Conclusions: Using direct pharmacokinetic measurements, we show that 25(OH)D clearance is reduced in CKD and may differ by race.

Clinical trial registry name and registration number: Clearance of 25-hydroxyvitamin D in Chronic Kidney Disease (CLEAR), NCT02937350; Clearance of 25-hydroxyvitamin D3 During Vitamin D3 Supplementation (CLEAR-PLUS), NCT03576716.

Keywords: catabolism; chronic kidney disease; clearance; end stage kidney disease; racial differences; vitamin D.

Copyright © 2021 by the American Society of Nephrology.

Figures

Figure 1.

Concentration-time curves of deuterated vitamin D3 metabolites. (A) Healthy controls, (B) participants with CKD, and (C) participants with kidney failure. The dots indicate the mean; the vertical whiskers indicate the SD in each direction.

Figure 2.

25(OH)D clearance by kidney-disease group and race. The center horizontal line in each box indicates the median; top and bottom box borders indicate the first and third quartiles, respectively. The vertical whiskers depict the most extreme observation within 1.5 times the interquartile range of the nearest quartile; dots show all points lying beyond 1.5 times the interquartile range of the nearest quartile.

Figure 3.

25(OH)D clearance with and without vitamin-D3 supplementation in the vitamin D3–supplemented cohort. The center horizontal line in each box indicates the median; top and bottom box borders indicate the first and third quartiles, respectively. The vertical whiskers depict the most extreme observation within 1.5 times the interquartile range of the nearest quartile; dots show all points lying beyond 1.5 times the interquartile range of the nearest quartile. The spaghetti plot lines show individual changes in 25(OH)D clearance compared with without vitamin D3 supplementation.

Figure 4.

Feedback regulation of vitamin-D metabolism. PTH induces the CYP27B1-mediated conversion of 25(OH)D to 1,25(OH)2D, and inhibits the CYP24A1-mediated clearance of 25(OH)D to 24,25(OH)2D. Through classic negative feedback, 1,25(OH)2D suppresses PTH release and promotes CYP24A1-mediated 25(OH)D clearance. FGF-23 is secreted in response to 1,25(OH)2D, and in a feedback loop, inhibits CYP27B1-mediated 1,25(OH)2D synthesis and induces CYP24A1.