*4.2.4.1 VD and diabetes mellitus*

Basic science studies demonstrated improvement in glucose metabolism due to immunomodulatory effect (especially in diabetes type 1), improvement of β cell function by increase in insulin secretion, and decreasing insulin resistance by stimulating insulin receptor expression via activating the VDR. Other mechanisms such as RAS suppression and anti-inflammatory effect of VD were also taken into consideration. However, observational studies do not establish clear relationship between VD status and DM prevalence, as some studies support the association, whereas others do not [44]. Interventional trials also have conflicting results. Two recent prospective studies showed improvement in glucose metabolism after vitamin D supplementation was applied [67, 68]. Unfortunately, the studies did not evaluate patients with renal disease. Two interventional studies with paricalcitol failed to detect improvement in insulin resistance in patients CKD stages 3 and 4 and in dialysis [69, 70].

### *4.2.4.2 VD and cardiovascular disease (CVD)*

CVD is a leading cause for mortality in CKD. As VDR and 27CYPB1 are expressed in the cells of the cardiovascular system, it could be expected that the VD axis can play a beneficial role in cardio-vascular health. A possible cardioprotection can be explained with RAS suppression and anti-inflammatory effects; VDR activation can improve cardiac muscle cells contractility and modulate their proliferation and growth. In addition, VD can improve peripheral vascular health by affecting endothelial and smooth muscular cells too [71].

**257**

(PTMBD) and VD pleiotropy.

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

*and anemia*

self-monitoring [75].

*4.2.5.1 Muscle health and cognitive function*

*4.2.5.2 Anemia and peritoneal fibrosis*

Even though the association between VD deficiency and CVD has been recognized in the general population and in CKD, large randomized interventional studies failed to demonstrate improvement from VD supplementation in cardiovascular outcomes, cardiac structure, or function in CKD patients [72]. An improvement in blood pressure control and endothelial function (as measured by brachial artery flow-mediated dilatation) was observed after VD supplementation in the general population; however, in CKD patients, no significant antihypertensive effect was detected [73]. Similarly, the results for the effect on VD supplementation on arterial stiffness and endothelial function are conflicting [72, 73]. Therefore, the use of VD in renal disease

in order to improve cardiovascular events is currently not recommended [72].

*4.2.5 VD pleiotropy in CKD: muscle health, cognitive function, peritoneal fibrosis,* 

In hemodialysis (HD) patients, a positive relationship between muscle strength and VD levels was detected, with optimal handgrip strength in 25VD above 30 ng/ ml (75 nmol/L). In ESRD patients, suboptimal VD was associated with lower quadriceps mass and increased risk for falls [74]. In addition, in PD patients, low 25VD was found to be the independent factor for global cognitive impairment due to the antioxidant and neuroprotective role of 1,25VD. This is of crucial importance, as PD is a home-based renal replacement therapy that needs adequate cognition and

Treatment with VDA led to the improvement of anemia in ESRD patients. A possible mechanism is suppression of inflammation and direct stimulation of erythropoiesis. In addition, paricalcitol reduced PD-associated thickening of the peritoneum and prevented peritoneal fibrosis in animal models. However, recent study in PD patients did not detect any benefit from paricalcitol supplementation in preventing peritoneal remodeling. In contrast to these results, Kerschbaum et al. demonstrated protective effect of oral active VD against peritonitis in PD patients [33, 54, 76].

Suboptimal 25VD is a commonly detected problem after kidney transplantation (KT) with prevalence above 80% of the kidney transplant recipients (KTRs). As KTRs are CKD patients, all mentioned factors, predisposing to impaired VD metabolism are valid for this cohort of patients, especially considering the fact that

specific factors influence VD synthesis: sun exposure avoidance due to the increased risk for skin malignancies, use of sun-protecting cosmetics (limiting further UV exposure), proteinuria after KT (increased loss in urine), higher prevalence of obesity after KT (reduced bioavailability), the presence of new onset diabetes after transplantation (NODAT) (by reducing intestinal absorption), use of steroids (increased 1,25VD catabolism), and calcineurin inhibitors (impaired 25VD liver synthesis) [77, 78]. Similarly to CKD in native kidneys, the VD-associated clinical implications after KT are categorized as post-transplant mineral bone disorder

. In addition, transplant-

**5. Vitamin D deficiency after kidney transplantation**

more than 50% of the KTRs have GFR<60 ml/min/1.73 m2

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

*Vitamin D Deficiency*

*4.2.3.3 Other neoplasms*

VD supplementation is applied in MM patients.

*4.2.4.1 VD and diabetes mellitus*

and in dialysis [69, 70].

*4.2.4.2 VD and cardiovascular disease (CVD)*

endothelial and smooth muscular cells too [71].

study, detecting no significant association between colorectal cancer and VD status [60]. Unfortunately, the data from interventional trails with VD supplementation also have conflicting result for the effect of VD on colorectal cancer prevention and survival improvement [44, 61]. Similarly to breast cancer, the data for the associa-

The results about the influence of VD on the risk for other malignancies are controversial. A large study (*n* = 70,563) evaluated the association of 25VD levels on the risk for prostate cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer, and neuroblastoma. 25VD concentrations did not correspond to the risk for any of the mentioned neoplasias. Therefore, the authors do not support the regular VD screening as an attempt for cancer prevention [62]. In addition, a large multicenter study in patients on hemodialysis also did not demonstrate significant association between total cancer prevalence and VD deficiency [63]. Multiple myeloma (MM) is a plasma cell disease that often presents with kidney manifestations. Several studies reported high rates of VD deficiency in MM patients and specific alleles for VDR were associated with higher risk for MM [64, 65]. Lauter and Schmidt-Wolf established that lower VD levels were associated with more expressed plasma cell infiltration of the bone marrow. In this study, VD supplementation improved anemia, led to higher white blood cell and lower platelet count [66]. Yet, the risk for hypercalcemia should be taken into consideration when

tion between colorectal cancer and VD status in renal patients is limited.

*4.2.4 VD pleiotropy in CKD: diabetes mellitus, cardiovascular disease (CVD)*

Basic science studies demonstrated improvement in glucose metabolism due to immunomodulatory effect (especially in diabetes type 1), improvement of β cell function by increase in insulin secretion, and decreasing insulin resistance by stimulating insulin receptor expression via activating the VDR. Other mechanisms such as RAS suppression and anti-inflammatory effect of VD were also taken into consideration. However, observational studies do not establish clear relationship between VD status and DM prevalence, as some studies support the association, whereas others do not [44]. Interventional trials also have conflicting results. Two recent prospective studies showed improvement in glucose metabolism after vitamin D supplementation was applied [67, 68]. Unfortunately, the studies did not evaluate patients with renal disease. Two interventional studies with paricalcitol failed to detect improvement in insulin resistance in patients CKD stages 3 and 4

CVD is a leading cause for mortality in CKD. As VDR and 27CYPB1 are expressed in the cells of the cardiovascular system, it could be expected that the VD axis can play a beneficial role in cardio-vascular health. A possible cardioprotection can be explained with RAS suppression and anti-inflammatory effects; VDR activation can improve cardiac muscle cells contractility and modulate their proliferation and growth. In addition, VD can improve peripheral vascular health by affecting

**256**

Even though the association between VD deficiency and CVD has been recognized in the general population and in CKD, large randomized interventional studies failed to demonstrate improvement from VD supplementation in cardiovascular outcomes, cardiac structure, or function in CKD patients [72]. An improvement in blood pressure control and endothelial function (as measured by brachial artery flow-mediated dilatation) was observed after VD supplementation in the general population; however, in CKD patients, no significant antihypertensive effect was detected [73]. Similarly, the results for the effect on VD supplementation on arterial stiffness and endothelial function are conflicting [72, 73]. Therefore, the use of VD in renal disease in order to improve cardiovascular events is currently not recommended [72].

#### *4.2.5 VD pleiotropy in CKD: muscle health, cognitive function, peritoneal fibrosis, and anemia*

#### *4.2.5.1 Muscle health and cognitive function*

In hemodialysis (HD) patients, a positive relationship between muscle strength and VD levels was detected, with optimal handgrip strength in 25VD above 30 ng/ ml (75 nmol/L). In ESRD patients, suboptimal VD was associated with lower quadriceps mass and increased risk for falls [74]. In addition, in PD patients, low 25VD was found to be the independent factor for global cognitive impairment due to the antioxidant and neuroprotective role of 1,25VD. This is of crucial importance, as PD is a home-based renal replacement therapy that needs adequate cognition and self-monitoring [75].

#### *4.2.5.2 Anemia and peritoneal fibrosis*

Treatment with VDA led to the improvement of anemia in ESRD patients. A possible mechanism is suppression of inflammation and direct stimulation of erythropoiesis. In addition, paricalcitol reduced PD-associated thickening of the peritoneum and prevented peritoneal fibrosis in animal models. However, recent study in PD patients did not detect any benefit from paricalcitol supplementation in preventing peritoneal remodeling. In contrast to these results, Kerschbaum et al. demonstrated protective effect of oral active VD against peritonitis in PD patients [33, 54, 76].
