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Vitamin D comprises a group of fat-soluble seco-sterols.1 The two major forms are vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol),1 which are collectively known as nutritional or native vitamin D.2
Native vitamin D can be acquired through both exogenous and endogenous means (Figure 1).3 Ergocalciferol is obtained from food.3 Cholecalciferol is synthesised in the skin during exposure to ultraviolet B (UVB) radiation from the sun.3 It can also be obtained from food.3
Adapted from Moe SM 2008,2 Holick MF 2007,3 Adams JS et al. 20144 and Dusso A et al. 1988.5
Circulating native vitamin D enters the liver, where it is converted into vitamin D prohormone (calcifediol [25-hydroxyvitamin D]), catalysed by the enzyme 25-hydroxylase (CYP2R1).3
Calcifediol can be converted into vitamin D hormone (calcitriol [1,25-dihydroxyvitamin D]) in the kidneys, parathyroid glands, pancreas, breasts, prostate, colon and any other tissue that expresses the catalysing enzyme 1-alpha-hydroxylase (CYP27B1).3,4
Circulating calcitriol can then bind to the vitamin D receptor in target tissues and activate vitamin D-responsive pathways, leading to increased intestinal calcium and phosphate absorption.3
As part of the vitamin D regulation mechanism, calcifediol and calcitriol can be broken down into 24,25-dihydroxyvitamin D and 1,24,25-trihydroxyvitamin D, respectively, by the catabolising enzyme 24-hydroxylase (CYP24A1).2
Low vitamin D levels are common in chronic kidney disease (CKD).6 Vitamin D insufficiency (52.5–72.5 nmol/L [21–29 ng/mL]) and deficiency (<50 nmol/L [<20 ng/mL])7 can develop early in the course of CKD,8,9 with their prevalence increasing with the progressive loss of renal function.6 Up to 71% of stage 3 CKD patients and up to 84% of stage 4 CKD patients have a serum 25(OH)D level that is at least insufficient if not deficient (Figure 2).6
Adapted from Doorenbos CRC et al. 2009.6
CKD is associated with low concentrations of both 25(OH)D and 1,25(OH)2D.8 The resulting vitamin D insufficiency/deficiency can drive the progression of secondary hyperparathyroidism (SHPT) via two key pathways:8
The low levels of 25(OH)D and 1,25(OH)2D in SHPT patients can themselves be exacerbated by:
Serum 25(OH)D was found to be an independent inverse predictor of disease progression and death in patients with stage 2 to 5 CKD (N=168; Figure 3).10
A longitudinal study of 168 pre-dialysis CKD patients that investigated the relationships between vitamin D deficiency, progression to end-stage renal disease and death.
Reproduced from Ravani P et al. 2009.10
As low vitamin D serum levels help to drive progression of SHPT, correction of vitamin D deficiency is an important aspect of SHPT treatment.12 To date, there is no consensus on optimal serum levels of 25(OH)D in CKD,11 and current vitamin D sufficiency definitions are based only on the general population.7,13
Recent evidence indicates that, to suppress PTH in stage 3 to 5 CKD, 25(OH)D levels higher than recommended for the general public are required.11 A US cross-sectional analysis of 14,289 CKD patients demonstrated that progressively higher 25(OH)D levels are (Figure 4):11
Cross-sectional analysis of 14,289 stage 1 to 5 CKD patients to identify a 25(OH)D target level that optimally lowers PTH without increasing hypercalcaemia and hyperphosphataemia.
Reproduced from Ennis JL et al. 2016.11
1,24,25(OH)3D: 1,24,25-trihydroxyvitamin D; 1,25(OH)2D: 1,25-dihydroxyvitamin D; 24,25(OH)2D: 24,25-dihydroxyvitamin D; 25(OH)D: 25-hydroxyvitamin D; CKD: chronic kidney disease; CYP24A1: cytochrome P450 family 24 subfamily A member 1; CYP27B1: cytochrome P450 family 27 subfamily B member 1; CYP2R1: cytochrome P450 family 2 subfamily R member 1; FGF-23: fibroblast growth factor-23; GFR: glomerular filtration rate; PTH: parathyroid hormone; SHPT: secondary hyperparathyroidism.
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