**3.2 VD metabolism in CKD**

*Vitamin D Deficiency*

min/1.73 m<sup>2</sup>

the indicator of VD status in CKD [3].

therefore, they require VD screening [7].

**3.1 VD metabolism in healthy subjects**

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

regarded as a cut-off value for vitamin D sufficiency.

the ratio between free and total 25VD remained unchained; therefore, total 25VD is

Generally, 25VD level has reverse association with parathyroid hormone (PTH) levels. In addition, higher 25VD is associated with higher calcium intestinal reabsorption. However, at 25VD ≥ 75 nmol/l, no reduction in PTH levels and no increase in calcium intestinal reabsorption occurs [4, 5]. Therefore, 25VD ≥ 75 nmol/l is

No generally accepted definition for VD deficiency exists, as authors choose cut-off value either serum 25VD of 25 nmol/L [6] or serum 25VD of 50 nmol/L [7]. However, target levels of 75 nmol/L are recommended, taking into consideration the clinical importance of mild VD insufficiency (25VD between 50 and 74.9 nmol/L) [7, 8]. Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function, present for more than 3 months, with implications for health [one of the following: estimated glomerular filtration rate (eGFR) less than 60 ml/

,presence of proteinuria, structural abnormalities of the kidney

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

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

detected on imaging, pathological findings detected on kidney biopsy, urine sediment pathology, electrolyte abnormalities due to tubular disorders, history of kidney transplantation] [9]. CKD patients are at increased risk for VD deficiency;

**248**

24-hydroxylaze.

the immune cells).

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

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 to protein intake reduction.

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 obesity in CKD patients [11, 12].

Even during the initial stages of CKD (eGFR below 60 ml/min/1.73 m<sup>2</sup> ) due to 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 1,25VD production in advanced CKD.

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


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

#### **Table 1.**

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

reacting elements, contributing to vitamin D resistance in patients on hemodialysis [15]. Finally, hypocalcaemia in CKD suppresses the calcium-sensing receptor (CaSR) in the parathyroid glands, which in turn downregulates parathyroid VDR expression; use of calcimimetics upregulated VDR expression in rat models [16].

The VD axis in health and renal disease is depicted in **Table 1**.
