You are now leaving our website and heading to a third-party website that we do not operate. We are not responsible for the content of the third-party website. You are advised to review its privacy policy as it may differ from ours.

Are you sure you want to leave?

Confirm

Cancel

BACK
vitamin D icon

Vitamin D metabolism and target 25(OH)D levels for SHPT control

Vitamin D metabolism and target 25(OH)D levels for SHPT control

Vitamin D metabolism

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

Figure 1. Steps in vitamin D anabolism and catabolism2–5
graph

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

Vitamin D deficiency in CKD

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

Figure 2. Prevalence of vitamin D insufficiency/deficiency in stage 3 and 4 CKD patients6
graph

Adapted from Doorenbos CRC et al. 2009.6

 

Low vitamin D levels can promote the progression of SHPT via different pathways8

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

  1. Low 25(OH)D levels limit the amount of 1,25(OH)2D that can be synthesised, leading to increased PTH secretion
  2. Low 1,25(OH)2D levels lead to reduced intestinal calcium absorption, resulting in increased PTH secretion

The low levels of 25(OH)D and 1,25(OH)2D in SHPT patients can themselves be exacerbated by:

  • Elevations in fibroblast growth factor-23 (FGF-23), which downregulate 1-alpha-hydroxylase (CYP27B1), the enzyme responsible for 1,25(OH)2D synthesis.8 FGF-23 also upregulates 24-hydroxylase (CYP24A1), the enzyme that catabolises both 25(OH)D and 1,25(OH)2D8  
  • Progressive loss of 1-alpha-hydroxylase in the kidney due to the reduction in functional renal mass caused by CKD8
 

Learn more about SHPT pathogenesis

 

Low vitamin D is associated with an increased risk of mortality10

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

Figure 3. Time to dialysis and death by presence of 25(OH)D deficiency10
graph

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

 

High levels of 25(OH)D are required to control SHPT in CKD11

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 

  • Associated with lower parathyroid hormone (PTH) concentrations 
  • Not associated with increased rates of hypercalcaemia or hyperphosphataemia
Figure 4. PTH by 25(OH)D levels and CKD stage11
graph

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

 

Learn about the risks associated with uncontrolled SHPT

 
Abbreviations and references

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.

  1. Ross AC et al., editors. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium [Internet]. Washington (DC): National Academies Press (US); 2011. Available from: https://www.ncbi.nlm.nih.gov/books/NBK56070/ [cited 2021 March 15].
  2. Moe SM. Prim Care. 2008;35(2):215–37.
  3. Holick MF. N Engl J Med. 2007;357:266–81.
  4. Adams JS et al. J Steroid Biochem Mol Biol. 2014;144PA:22–7.
  5. Dusso A et al. Kidney Int. 1988;34(3):368–75.
  6. Doorenbos CRC et al. Nat Rev Nephr. 2009;5:691–700.
  7. Holick MF et al. J Clin Endocrinol Metab. 2011;96(7):1911–30.
  8. Friedl C et al. Int J Nephrol Renovascular Dis. 2017;10:109–22.
  9. Wolf M. JASN. 2010;21(9):1427–35.
  10. Ravani P et al. Kidney Int. 2009;75:88–95.
  11. Ennis JL et al. J Nephrol. 2016;29:63–70.
  12. Cunningham J et al. Clin J Am Soc Nephrol. 2011;6:913–21.
  13. Ross AC et al. J Clin Endocrinol Metab. 2011;96(1):53–8.