The metabolism of 1,25(OH)2D3 in clinical and experimental kidney disease

Abstract

Chronic kidney disease (CKD) results in calcitriol deficiency and altered vitamin D metabolism. The objective of this study was to assess the 24-hydroxylation-mediated metabolism of 25(OH)D₃ and 1,25(OH)₂D₃ in a cross-sectional analysis of participants with a range of kidney function assessed by precise measured GFR (mGFR) (N = 143) and in rats with the induction and progression of experimental kidney disease. Vitamin D metabolites were assessed with LC-MS/MS. Circulating measures of 24-hydroxylation of 25(OH)D₃ (24,25(OH)₂D₃:25(OH)D₃) precisely decreased according to mGFR in humans and progressively in rats with developing CKD. In contrast, the 1,24,25(OH)3D3: 1,25(OH)₂D₃ vitamin D metabolite ratio increased in humans as the mGFR decreased and in rats with the induction and progression of CKD. Human participants taking cholecalciferol had higher circulating 1,24,25(OH)₃D₃, despite no increase of 1,25(OH)₂D₃. This first report of circulating 1,24,25(OH)₃D₃ in the setting of CKD provides novel insight into the uniquely altered vitamin D metabolism in this setting. A better understanding of the uniquely dysfunctional catabolic vitamin D profile in CKD may guide more effective treatment strategies. The potential that 24-hydroxylated products have biological activity of is an important area of future research.

Figure 1

Vitamin D metabolites and 24-hydroxylation ratios in participants delineated by GFR measured by iohexol/inulin clearance. (A) 25(OH)D₃, (B) 24,25(OH)₂D₃, (C) 25-VMR 24,25(OH)₂D₃:25(OH)D₃, (D) 1,25(OH)₂D₃, (E) 1,24,25(OH)₃D₃, (F) 1,25-VMR 1,24,25(OH)₃D₃:1,25(OH)₂D₃. Dotted lines on (A) indicate cut offs for insufficiency and deficiency. One-way ANOVA with post hoc test for linear trend between mGFR categories, if mGFR categories were a significant source of variation, pairwise comparisons were performed with Fishers LSD test for (A–F). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Box plot indicates medial, IQR and range. Participants reporting cholecalcierfol use excluded from graphs and analysis (> 90 N = 109; 90–75 N = 33; 75–60 N = 19; 60–45 N = 12; 45–30 N = 8; 30–15 N = 20; < 15 N = 9).

Figure 2

Vitamin D metabolites separated by cholecalciferol use delineated by measured GFR. (A) 25(OH)D₃, (B) 24,25(OH)₂D₃, (C) 25-VMR: 24,25(OH)₂D₃:25(OH)D₃, (D) 1,25(OH)₂D₃, (E) 1,24,25(OH)₃D₃, (F) 1,25-VMR: 1,24,25(OH)₃D₃:1,25(OH)₂D₃, Two-way ANOVA. Mean SD. P-value indicates whether cholecalciferol use was a significant source of variation. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 3

Longitudinal vitamin D measurements from a rat model of CKD mirrors human 1,24,25(OH)₃D₃ profile. (A) Experimental design and longitudinal elevation in serum creatinine in CKD rats compared to control. Mean/SD. (B) 25(OH)D₃, (C) 24,25(OH)₂D₃, (D) 25-VMR 24,25(OH)₂D₃:25(OH)D₃, (E) 1,25(OH)₂D₃, (F) 1,24,25(OH)₃D₃, (G) 1,25-VMR 1,24,25(OH)₃D₃:1,25(OH)₂D₃. For (B–G) Repeated measures one-way ANOVA with post hoc test for differences between adjacent time points (0–2, 2–4, 4–5 weeks).