**3. Vitamin D metabolism in health and renal disease**

#### **3.1 VD metabolism in healthy subjects**

VD is synthesized predominantly endogenously (approx. to 90% of the total VD in human body). In the skin, the ultraviolet light transforms 7-dehydroxycholesterol (provitamin D) to pre-vitamin D, which under the influence of body temperature spontaneously isomerizes to cholecalciferol (vitamin D3). Approximately, 10% of total body VD is taken orally (vitamin D2, ergocalciferol, and cholecalciferol). VD is transported via VD-binding protein to the liver, where it is hydroxylated to 25VD. The next step in VD activation is hydroxylation of 25VD by the enzyme 1α-hydroxylase (CYP27B1) to 1,25VD, which is the active VD metabolite. The process occurs predominantly in the renal tubules. In addition, non-renal CYP27B1 was detected in skin (basal keratinocytes and hair follicles), lymph nodes (granulomata), colon (epithelial cells and parasympathetic ganglia), pancreas (islets), adrenal medulla, brain (cerebellum and cerebral cortex), prostate epithelial cells, and placenta (decidual and trophoblastic cells) [10], indicating the wider significance of the VD metabolites. Finally, 1,25VD is inactivated by the enzyme 24-hydroxylaze.

1,25VD exerts its effect via the vitamin D receptor (VDR), which is detected in all human organs. 1,25VD binds to VDR, the complex forms a heterodimer with the receptor for retinoid X (RXR) within the nucleus. The 1,25VD-VDR-RXR complex binds to vitamin D reacting elements, modulating gene expression. The highest expression of VDR is detected in bones, small intestines, and parathyroid gland. VDR activation leads to influencing bone metabolism), increase of calcium and phosphate absorption, and PTH secretion suppression. However, due to the wider VDR distribution in human body, its activation is associated with effects beyond influencing calcium-phosphorus metabolism–renin-angiotensin system (RAS) suppression and cardiac hypertrophy prevention (myocardial VDR), diabetes mellitus control (pancreatic VDR), and immune system modulation (VDR in the immune cells).

The above-mentioned stages of VD metabolism form the so called VD axis.

**249**

**Table 1.**

*Vitamin D Deficiency in Renal Disease DOI: http://dx.doi.org/10.5772/intechopen.88928*

All levels of VD metabolism are significantly affected in renal disease.

Even during the initial stages of CKD (eGFR below 60 ml/min/1.73 m<sup>2</sup>

**VD axis Healthy subjects In CKD**

Cholecalciferol/ergocalciferol Skin synthesis from

25-hydroxyvitamin D(25VD) Hepatic synthesis

1,25-dihydroxyvitamin D(1,25VD) Hydroxylation

Vitamin D receptor(VDR) Widely spread

*Vitamin D axis in health and in renal disease.*

*CKD, chronic kidney disease; VDRE, vitamin D reacting elements; UV, ultraviolet.*

reduced phosphate tubular excretion, higher levels of fibroblast growth factor 23 (FGF-23) occur, which suppress CYP27B1 activity. Furthermore, phosphatemia and metabolic acidosis decrease enzyme activity too. In addition, 1,25VD levels in renal disease are reduced because of increased catabolism due to increased FGF-23 levels. Finally, the smaller number of functioning tubules is directly associated with lower

Cholecalciferol synthesis is reduced in uremic skin. In addition, these patients are usually older, with reduced exposure to sunlight, which is additionally associated with poorer skin VD synthesis. What is more, oral VD intake is decreased due

25VD is reduced in CKD due to reduced amount of its precursor, increased loss in nephrotic patients, and 25VD sequestration in adipose tissue due to higher rate of

VDR is affected in CKD too. Low 1,25VD downregulates of VDR expression [13]. In areas of nodular growth in the parathyroid gland reduced VDR content is detected. In uremia, there is significant decrease in VDR-RXR binding to vitamin D reacting elements, as well as reduced RXR content in the parathyroid glands, explaining increased PTH levels without the presence of hypocalcaemia and hyperphosphatemia [14]. Hypocalcaemia in advanced CKD increases the parathyroid levels of calreticulin, a cytosolic protein that binds the DNA-binding domain of nuclear receptors, thus blocking VDR-mediated transactivation. Higher levels of inflammatory cytokines were found to be associated with impaired binding of VDR-RXR to vitamin D

UV light or oral intake

(25-hydroxylase)

in renal tubules (1α-hydroxylase) and other organs

in human body, esp. bone and parathyroid glands (calcium-phosphorus metabolism) In all other organs (pleiotropy)

) due to

• Reduced skin synthesis (age, uremia, reduced UV exposure)

• Reduced amount of its precursor • Increased loss in nephrotic

• 25VD sequestration in adipose

• Reduced synthesis in renal tubules

• Downregulated expression (low 1,25VD, hypocalcaemia) • Impaired binding to VDRE (uremia, inflammatory cytokines,

• Reduced VDR content in parathyroid glands (hypertrophy)

• Reduced oral intake

• Increased catabolism • Suppressed 1α-hydroxylase

in advanced CKD

patients

tissue

activity

etc.)

**3.2 VD metabolism in CKD**

to protein intake reduction.

obesity in CKD patients [11, 12].

1,25VD production in advanced CKD.
