What are the implications of normal 25-hydroxyvitamin D (25(OH)D) but low 1,25-dihydroxyvitamin D (1,25(OH)2D) levels?

From the Guidelines

Having normal hydroxyvitamin D but low dihydroxyvitamin D suggests a problem with vitamin D activation, which is often related to kidney dysfunction, and may require calcitriol supplementation (0.25-1.0 mcg daily) if kidney disease is present. This condition typically requires medical evaluation to determine the underlying cause, as the kidneys are responsible for converting 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D 1. Other potential causes include hypoparathyroidism, vitamin D-dependent rickets type 1, or certain medications that interfere with vitamin D metabolism. Symptoms may include bone pain, muscle weakness, and increased risk of fractures. Laboratory testing should include calcium, phosphorus, and parathyroid hormone levels to help identify the underlying disorder.

According to the K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease, patients with CKD or those who are dialysis-dependent are much more likely to have low levels of 25(OH)D in comparison to those with no kidney disease 1. The guidelines also suggest that nutritional vitamin D deficiency and insufficiency can both be prevented by supplementation with vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol) in patients with CKD and GFR of 20 to 60 mL/min/1.73 m2. However, if there is evidence of true vitamin D deficiency, this should be treated, and the best available treatment is vitamin D2, although the doses needed are larger.

In patients with GFR 20 mL/min/1.73 m² and those requiring dialysis, there is no evidence that modest supplementation with ergocalciferol to raise serum 25-hydroxyvitamin D levels will increase the plasma levels of 1,25-dihydroxyvitamin D (calcitriol) or lower the elevated serum levels of intact PTH 1. Therefore, calcitriol supplementation is the most appropriate treatment option for patients with normal hydroxyvitamin D but low dihydroxyvitamin D, especially if kidney disease is present.

Some key points to consider in the management of this condition include:

• Medical evaluation to determine the underlying cause of the low dihydroxyvitamin D levels
• Laboratory testing to include calcium, phosphorus, and parathyroid hormone levels
• Consideration of calcitriol supplementation (0.25-1.0 mcg daily) if kidney disease is present
• Prevention of nutritional vitamin D deficiency and insufficiency through supplementation with vitamin D2 or vitamin D3 in patients with CKD and GFR of 20 to 60 mL/min/1.73 m2.

From the FDA Drug Label

Man’s natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol in the skin to vitamin D3 (cholecalciferol). Vitamin D3 must be metabolically activated in the liver and the kidney before it is fully active as a regulator of calcium and phosphorus metabolism at target tissues The initial transformation of vitamin D3 is catalyzed by a vitamin D3-25-hydroxylase enzyme (25-OHase) present in the liver, and the product of this reaction is 25-hydroxyvitamin D3 [25-(OH)D3] Hydroxylation of 25-(OH)D3 occurs in the mitochondria of kidney tissue, activated by the renal 25-hydroxyvitamin D3-1 alpha-hydroxylase (alpha-OHase), to produce 1,25-(OH)2D3 (calcitriol), the active form of vitamin D3

The condition of having normal hydroxyvitamin D but low dihydroxyvitamin D suggests that there is an issue with the conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 (calcitriol) in the kidneys. This could be due to kidney dysfunction or other factors affecting the activity of the renal 25-hydroxyvitamin D3-1 alpha-hydroxylase enzyme.

• Key points:
  • Normal hydroxyvitamin D levels indicate adequate vitamin D intake and liver function.
  • Low dihydroxyvitamin D levels suggest a problem with kidney function or the conversion process.
  • This condition may lead to hypocalcemia and secondary hyperparathyroidism, which can cause metabolic bone disease 2, 2.

From the Research

Normal Hydroxyvitamin D but Low Dihydroxyvitamin D

• The condition of having normal hydroxyvitamin D (25D) but low dihydroxyvitamin D (1,25-dihydroxyvitamin D or calcitriol) levels is associated with chronic kidney disease (CKD) 3, 4, 5, 6.
• In CKD patients, the kidney's ability to convert 25D to calcitriol is impaired, leading to low calcitriol levels despite normal 25D levels 3, 5.
• This impairment can result in secondary hyperparathyroidism, bone loss, cardiovascular disease, and increased mortality 3, 6.
• Studies have shown that supplementation with vitamin D or calcitriol can help improve calcitriol levels and reduce the risk of these complications 4, 5, 6.
• However, the optimal form and dosage of vitamin D supplementation for CKD patients is still unclear, with some studies suggesting that cholecalciferol may be more effective than ergocalciferol in raising 25D levels 7.

Vitamin D Supplementation in CKD

• Vitamin D supplementation is often recommended for CKD patients with low 25D levels, but the benefits and risks of supplementation need to be carefully considered 4, 5.
• Some studies have suggested that selective vitamin D receptor activation may have direct effects on the cardiovascular system and improve survival in CKD patients 6.
• However, more research is needed to determine the optimal vitamin D derivative and dosage for CKD patients, as well as the potential benefits and risks of supplementation 5, 7.

Research Gaps and Future Directions

• Further studies are needed to investigate the effects of vitamin D supplementation on patient-level outcomes, such as mortality and cardiovascular events, in CKD patients 5, 7.
• Research is also needed to determine the optimal form and dosage of vitamin D supplementation for CKD patients, as well as the potential benefits and risks of supplementation 4, 5, 7.