Differences in 25-Hydroxyvitamin D Clearance by eGFR and Race: A Pharmacokinetic Study
Authors: Hsu Simon , Zelnick Leila R. , Lin Yvonne S. , Best Cora M. , Kestenbaum Bryan , Thummel Kenneth E. , Rose Lynn M. , Hoofnagle Andrew N. , de Boer Ian H. 
Published: October 2020

Significance Statement
The pharmacokinetic clearance of 25-hydroxyvitamin D (25[OH]D) is an essential, yet often overlooked, determinant of the concentration of circulating 25(OH)D, the prevailing marker of vitamin-D status. Observational studies have associated markers of low 25(OH)D clearance with poor clinical outcomes and suggest differences in clearance by kidney function and race. In this study, the authors used gold-standard pharmacokinetic methods to show that reduced 25(OH)D clearance is associated with worsening eGFR. They also found that, among participants with normal eGFR, but not among those with CKD or kidney failure, Black participants had higher 25(OH)D clearance compared with White participants. These findings confirm impaired 25(OH)D clearance as a feature of disordered mineral metabolism in kidney disease, and may provide some insight into racial differences in vitamin-D metabolism.

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