Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials

Abstract

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.

Study design: Cross-sectional study.

Setting & participants: 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).

Predictor: eGFR.

Outcome: Circulating 24,25(OH)2D3 concentration.

Measurements: 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.

Limitations: 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.

Keywords: 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.

Figure 1. Vitamin D₃ metabolism

Vitamin D₃ synthesized in the skin or consumed by mouth is metabolized to 25-hydroxyvitamin D₃ (25(OH)D₃), which can then be metabolized to 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃, the active vitamin D hormone) by CYP27B1. Vitamin D₃ catabolism is accomplished predominantly by CYP24A1, which metabolizes 25(OH)D₃ to 24,25-dihydroxyvitamin D₃ (24,25(OH)₂D₃) and 1,25(OH)₂D₃ to 1,24,25-trihydroxyvitamin D₃ (1,24,25(OH)₃D₃). CYP24A1 is induced by 1,25(OH)₂D₃.

Figure 2. Distribution of estimated GFR among 9596 participants in the Diabetes Control and Complications Trial (DCCT), Multi-Ethnic Study of Atherosclerosis (MESA), Cardiovascular Health Study (CHS), Seattle Kidney Study (SKS), and Hemodialysis (HEMO) Study

Box plots demonstrate the 5^th, 25^th, 50^th, 75^th, and 95^th percentiles, with dots representing estimated GFR outside the 5^th – 95^th percentiles. All HEMO Study participants have end-stage renal disease treated with hemodialysis, represented here as an estimated GFR of 10 mL/min/1.73 m².

Figure 3. Relationships of 24,25-dihydroxyvitamin D₃ (24,25(OH)₂D₃) with 25-hydroxyvitamin D₃ (25(OH)D₃) in five cohort studies and clinical trials

The scatter plots display individual values for each participant. Solid lines represent mean 24,25(OH)₂D₃ concentrations estimated using locally-weighted scatterplot smoothing (LOWESS). Broken lines represent linear fit generated using unadjusted linear regression. LOWESS curves were calculated using all available data but truncated below the 2.5% percentile and above the 97.5% percentile of 25(OH)D₃ concentration for presentation. Note that the ranges of the×and y axes vary in each panel. DCCT = Diabetes Control and Complications Trial; MESA = Multi-Ethnic Study of Atherosclerosis; CHS = Cardiovascular Health Study; SKS = Seattle Kidney Study; HEMO = Hemodialysis Study.

Figure 4. Relationships of 24,25-dihydroxyvitamin D₃ (24,25(OH)₂D₃) with 25-hydroxyvitamin D₃ (25(OH)D₃) among 9596 participants in the Diabetes Control and Complications Trial (DCCT), Multi-Ethnic Study of Atherosclerosis (MESA), Cardiovascular Health Study (CHS), Seattle Kidney Study (SKS), and Hemodialysis (HEMO) Study

The scatter plots display individual values for each participant. Solid lines represent mean 24,25(OH)₂D₃ concentrations estimated using locally-weighted scatterplot smoothing (LOWESS) among subgroups defined by cohort (Panel A) or category of estimated GFR (Panel B). LOWESS curves were calculated using all available data but truncated below the 2.5% percentile and above the 97.5% percentile of 25(OH)D₃ concentration for presentation. The X axis was truncated at 60 ng/mL. Estimated GFR is in mL/min/1.73 m².