**6.1 Treatment with cholecalciferol, ergocalciferol, calcitriol, VDA**

Supplementation with cholecalciferol (vitamin D3), ergocalciferol (vitamin D2), or treatment with the active vitamin D calcitriol or VDA suppresses PTH in secondary hyperparathyroidism in CKD. As a first step, a correction of hypocalcemia, hyperphosphatemia, and suboptimal 25VD levels should be performed. In more advanced CKD-related secondary hyperparathyroidism calcitriol and VDA can be initiated. It should be noted that over-suppression of the parathyroid gland due to overdose of the VD treatment is a major cause for AD. Therefore PTH, as well as serum phosphate and calcium, should be regularly monitored. It should be noted that the optimal PTH values for dialysis patients are two times up to nine times the upper normal limit, whereas for patients not on dialysis the optimal range is not established. If trend for lowering/rising values is present, changes in treatment should be changed so that the negative trends be reverted [17]. Similarly, in KTRs cholecalciferol/calcitriol/VDA treatment should also take these trends into consideration.

#### *6.1.1 Supplementation with cholecalciferol/ergocalciferol*

In the general adult population, supplementation doses of VD at least 600 IU daily; however, if improvement in VD status is needed, doses of at least

**261**

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

*6.1.2 Treatment with calcitriol and VDA*

eGFR below 30 ml/min/1.73 m<sup>2</sup>

*6.1.3 Other therapeutic measures*

and paricalcitol [29, 99].

*6.1.4 Novel agents*

*6.1.4.1 Calcifediol*

*6.1.4.2 Vitamin K*

declining GFR [17].

1500–2000 IU per day should be prescribed. The maximal dose VD without medical supervision should be 4000 IU daily. Cholecalciferol and ergocalciferol are equally effective [98]. The KDIGO guidelines recommend VD deficiency in CKD patients and in KTRs to be treated as in the general population. It is the initial therapeutic step, together with correction of hypocalcemia and hyperphosphatemia, as it effectively suppresses PTH in CKD stages 3–5 not on dialysis. More aggressive approach is to be avoided as modest PTH elevation is regarded as adaptive mechanism in

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

 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

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].

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

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].

trials are needed to clarify the use of calcifediol in renal disease.

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

*Vitamin D Deficiency*

its association to VD should be analyzed.

*5.2.4 VD pleiotropy after KT: malignancies*

*5.2.5 VD pleiotropy after KT: NODAT*

*5.2.6 VD pleiotropy after KT: cardiovascular disease*

NODAT prevalence [96].

approach should be chosen and the infection risk for specific etiological agent and

Despite the anti-neoplastic properties of VD *in vitro* and in animal models, the evidence for anti-malignancy effect of VD in CKD patients and KTRs is insufficient. Observational studies report conflicting results for the association between posttransplant malignancies and VD status [86]. A recent study in our transplant center showed that VD-deficient KTRs had higher prevalence of non-cutaneous cancers [94]. A single center study established beneficial effect from active VD supplementation on post-transplant neoplasia rates [95]. The larger prospective, multicenter, double-blind, randomized, controlled study VITALE is currently being performed, which will evaluate the effect of cholecalciferol supplementation on malignancy risk after KT [96].

The major risk factors for NODAT are use of steroids and calcineurin inhibitors. The data for VD-NODAT association are insufficient. The trial VITALE is to assess the effect of high and low doses cholecalciferol in VD–insufficient KTRs on

Marchal et al. established a significant association between lower 25VD and vascular calcification after KT [85]. However, a more recent study did not find a relationship between VD status and post-transplant hypertension and major CV events [97]. One of the aims of the already mentioned trial VITALE is to assess the effect of cholecalcif-

Supplementation with cholecalciferol (vitamin D3), ergocalciferol (vitamin D2), or treatment with the active vitamin D calcitriol or VDA suppresses PTH in secondary hyperparathyroidism in CKD. As a first step, a correction of hypocalcemia, hyperphosphatemia, and suboptimal 25VD levels should be performed. In more advanced CKD-related secondary hyperparathyroidism calcitriol and VDA can be initiated. It should be noted that over-suppression of the parathyroid gland due to overdose of the VD treatment is a major cause for AD. Therefore PTH, as well as serum phosphate and calcium, should be regularly monitored. It should be noted that the optimal PTH values for dialysis patients are two times up to nine times the upper normal limit, whereas for patients not on dialysis the optimal range is not established. If trend for lowering/rising values is present, changes in treatment should be changed so that the negative trends be reverted [17]. Similarly, in KTRs cholecalciferol/calcitriol/VDA

erol supplementation on blood pressure control and CVD rates in KTRs [96].

**6. Treatment of vitamin D deficiency in renal disease**

treatment should also take these trends into consideration.

In the general adult population, supplementation doses of VD at least 600 IU daily; however, if improvement in VD status is needed, doses of at least

*6.1.1 Supplementation with cholecalciferol/ergocalciferol*

**6.1 Treatment with cholecalciferol, ergocalciferol, calcitriol, VDA**

**260**

1500–2000 IU per day should be prescribed. The maximal dose VD without medical supervision should be 4000 IU daily. Cholecalciferol and ergocalciferol are equally effective [98]. The KDIGO guidelines recommend VD deficiency in CKD patients and in KTRs to be treated as in the general population. It is the initial therapeutic step, together with correction of hypocalcemia and hyperphosphatemia, as it effectively suppresses PTH in CKD stages 3–5 not on dialysis. More aggressive approach is to be avoided as modest PTH elevation is regarded as adaptive mechanism in declining GFR [17].
