Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials.
BACKGROUND
Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25[OH]D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs.


METHODS
Cross-sectional study.


METHODS
9,596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1,193), Multi-Ethnic Study of Atherosclerosis (N=6,470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712).


METHODS
eGFR.


RESULTS
Circulating 24,25(OH)2D3 concentration.


METHODS
GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry.


RESULTS
Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64-0.88). This correlation was weaker with lower eGFRs. Moreover, the increment in 24,25(OH)2D3 concentration associated with higher 25(OH)D3 concentration (slope) was lower with lower eGFRs: 2.06 (95% CI, 2.01-2.10), 1.77 (95% CI, 1.74-1.81), 1.55 (95% CI, 1.48-1.62), 1.17 (95% CI, 1.05-1.29), 0.92 (95% CI, 0.74-1.10), 0.61 (95% CI, 0.22-1.00), and 0.37 (95% CI, 0.35-0.39) ng/mL of 24,25(OH)2D3 per 10 ng/mL of 25(OH)D3 for eGFRs≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2 and end-stage renal disease treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentrations were 2.92 (95% CI, 2.87-2.96), 2.68 (95% CI, 2.64-2.72), 2.35 (95% CI, 2.26-2.45), 1.92 (95% CI, 1.74-2.10), 1.69 (95% CI, 1.43-1.95), 1.14 (95% CI, 0.62-1.66), and 1.04 (95% CI,1.02-1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and circulating parathyroid hormone and fibroblast growth factor 23 concentrations more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3.


CONCLUSIONS
Lack of direct pharmacokinetic measurements of vitamin D catabolism.


CONCLUSIONS
Lower eGFR is associated strongly with reduced vitamin D catabolism, as measured by circulating 24,25(OH)2D3 concentration.
Division of Nephrology, Department of Medicine, Seattle, WA; Kidney Research Institute, Department of Medicine, Seattle, WA; Department of Epidemiology, University of Washington, Seattle, WA. Electronic address: deboer@u.washington.edu.
Ian H
IH
de Boer
Division of Nephrology, Department of Medicine, Seattle, WA; Kidney Research Institute, Department of Medicine, Seattle, WA.
Michael C
MC
Sachs
Division of Nephrology, Department of Medicine, University of Colorado, Denver, CO.
Michel
M
Chonchol
Division of Nephrology, Department of Medicine, Seattle, WA; Kidney Research Institute, Department of Medicine, Seattle, WA.
Jonathan
J
Himmelfarb
Kidney Research Institute, Department of Medicine, Seattle, WA; Department of Laboratory Medicine, University of Washington, Seattle, WA.
Andrew N
AN
Hoofnagle
Division of Nephrology, Department of Medicine, University of California, San Diego, San Diego, CA.
Joachim H
JH
Ix
Kidney Research Institute, Department of Medicine, Seattle, WA; Division of Nephrology, Department of Pediatrics, Seattle Children's Hospital, Seattle, WA.
Robin A
RA
Kremsdorf
Department of Pharmaceutics, Department of Medicine, University of Washington, Seattle, WA.
Yvonne S
YS
Lin
Division of Nephrology, Department of Medicine, Seattle, WA; Kidney Research Institute, Department of Medicine, Seattle, WA.
Rajnish
R
Mehrotra
Division of Nephrology, Department of Medicine, Seattle, WA; Kidney Research Institute, Department of Medicine, Seattle, WA; Department of Epidemiology, University of Washington, Seattle, WA.
Cassianne
C
Robinson-Cohen
Department of Epidemiology, University of Washington, Seattle, WA; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
David S
DS
Siscovick
Department of Laboratory Medicine, University of Minnesota, Minneapolis, MN.
Michael W
MW
Steffes
Department of Pharmaceutics, Department of Medicine, University of Washington, Seattle, WA.
Kenneth E
KE
Thummel
Department of Laboratory Medicine, University of Vermont, Burlington, VT.
Russell P
RP
Tracy
Department of Pharmaceutics, Department of Medicine, University of Washington, Seattle, WA.
Zhican
Z
Wang
Division of Nephrology, Department of Medicine, Seattle, WA; Kidney Research Institute, Department of Medicine, Seattle, WA; Department of Epidemiology, University of Washington, Seattle, WA.
Bryan
B
Kestenbaum
D015650:24,25-Dihydroxyvitamin D 3 / Q000097:blood*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003920:Diabetes Mellitus / Q000097:blood* / Q000175:diagnosis / Q000503:physiopathology*; D005260:Female; D005919:Glomerular Filtration Rate / Q000502:physiology*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000175:diagnosis / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D064887:Observational Studies as Topic / Q000379:methods*; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D055815:Young Adult
D015415:Biomarkers; D015650:24,25-Dihydroxyvitamin D 3
1,25-dihydroxyvitamin D3; 25-hydroxyvitamin D3; Decreased renal function; active vitamin D; biomarker; chronic kidney disease (CKD); low estimated glomerular filtration rate; vitamin D catabolism