*6.1.2 Treatment with calcitriol and VDA*

Calcitriol is naturally existing 1,25VD, whereas VDA are synthetic derivatives of vitamin D2 (paricalcitol, doxercalciferol) and vitamin D3 (alfacalcidol, falecalcitriol, 22-oxacalcitriol). Despite the existing trials demonstrating positive effect of calcitriol/VDA on biochemical abnormalities, more recent studies do not demonstrate improvement in patient-centered end-points, such as left ventricular mass index and heart function; however, hypercalcemia was observed. Taking into account that modest PTH elevation is a possible adaptive response in CKD, the lack of significant clinical effects and higher risk for hypercalcemia, the use of calcitriol and VDA is not routinely recommended in CKD stages 3–5 not on dialysis. Their use is advocated in cases of severe and progressive secondary hyperparathyroidism and eGFR below 30 ml/min/1.73 m<sup>2</sup> or dialysis patients [17].

The data for hypercalcemia rates in calcitriol and VDA are conflicting. Zand et al. demonstrated lower hypercalcemia prevalence in patients treated with paricalcitol; other reports established no difference in hypercalcemia between calcitriol and paricalcitol [29, 99].

## *6.1.3 Other therapeutic measures*

Other measures, recommended by KDIGO that optimize VD treatment in CKD-MBD are avoidance of hypercalcemia, reduction of phosphate serum levels, including phosphate dietary restriction, limitation of the use of calcium-based phosphate binders, calcium dialysate concentrations within the range of 1.25 and 1.50 mmol/l [17].

### *6.1.4 Novel agents*

#### *6.1.4.1 Calcifediol*

Calcifediol is an oral 25-hydroxyvitamin D3. A study demonstrated reduction in PTH levels without changes in phosphate, calcium, and FGF-23 levels in CKD patients. In this chapter, patient-related outcomes were not assessed [100]. Further trials are needed to clarify the use of calcifediol in renal disease.

### *6.1.4.2 Vitamin K*

Vitamin K plays a crucial role in vascular health. It serves as a cofactor for γ-glutamyl carboxylation, which converts glutamate into γ-carboxyglutamate (Gla). In vitamin K insufficiency, which is common in CKD, higher levels of desphosphorylated-uncarboxylated matrix Gla-protein (MGP) are established, which are associated with VC, as MGP serves as calcification inhibitor. Vitamin K supplementation increases MGP carboxylation. What is more, VD supplementation upregulates MGP synthesis, whereas vitamin K suppressed 1,25VD-associated calcinosis [101, 102].

Therefore, it can be hypothesized that vitamin K supplementation in CKD can be an adjuvant treatment to VD supplementation and will decrease its adverse effects. Further research of the efficacy and safety of vitamin K supplementation in CKD is needed.
