Low serum
1,25-dihydroxyvitamin D (1,25(
OH)2D) in
end-stage renal disease (
ESRD) is considered a consequence of elevated
fibroblast growth factor 23 (FGF23) and concomitant reduced activity of renal 1α-hydroxylase (
CYP27B1). Current
ESRD treatment strategies to increase serum
calcium and suppress
secondary hyperparathyroidism involve supplementation with
vitamin D analogues that circumvent 1α-hydroxylase. This overlooks the potential importance of
25-hydroxyvitamin D (25(
OH)D) deficiency as a contributor to low serum 1,25(
OH)2D. We investigated the effects of
vitamin D (
cholecalciferol) supplementation (40,000 IU for 12 weeks and maintenance dose of 20,000 IU fortnightly), on multiple serum
vitamin D metabolites (25(
OH)D,
1,25(OH)2D3 and 24,25(
OH)2D3) in 55 haemodialysis patients. Baseline and 12 month data were compared using related-samples Wilcoxon signed rank test. All patients remained on active
vitamin D analogues as part of routine
ESRD care.
1,25(OH)2D3 levels were low at baseline (normal range: 60-120 pmol/L).
Cholecalciferol supplementation normalised both serum 25(
OH)D and
1,25(OH)2D3. Median serum 25(
OH)D increased from 35.1 nmol/L (IQR: 23.0-47.5 nmol/L) to 119.9 nmol/L (IQR: 99.5-143.3 nmol/L) (P < 0.001). Median serum
1,25(OH)2D3 and 24,25(
OH)2D3 increased from 48.3 pmol/L (IQR: 35.9-57.9 pmol/L) and 3.8 nmol/L (IQR: 2.3-6.0 nmol/L) to 96.2 pmol/L (IQR: 77.1-130.6 pmol/L) and 12.3 nmol/L (IQR: 9-16.4 nmol/L), respectively (P < 0.001). A non-significant reduction in daily active
vitamin D analogue dose occurred, 0.94 µmcg at baseline to 0.77 µmcg at 12 months (P = 0.73). The ability to synthesise
1,25(OH)2D3 in
ESRD is maintained but is substrate dependent, and serum 25(
OH)D was a limiting factor at baseline. Therefore,
1,25(OH)2D3 deficiency in
ESRD is partly a consequence of 25(
OH)D deficiency, rather than solely due to reduced 1α-hydroxylase activity as suggested by current treatment strategies.