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


### **Table 2.**

*Vitamin D Deficiency*

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;

The major mechanisms for abnormal VD metabolism and VD deficiency were outlined in the section above. Of particular importance is hyperphosphatemia, caused by initial renal damage, leading to higher FGF-23 levels, which in turn suppresses CYP27B1 activity and increases 1,25VD catabolism. Suboptimal VD levels are the basis of the abnormal calcium-phosphate metabolism in renal disease. Currently, the term CKD-associated mineral bone disorder (CKD-MBD) is used to define the wide spectrum of CKD-related abnormalities in calcium-phosphate

CKD-MBD comprises of three major aspects—biochemical abnormalities, bone

The biochemical abnormalities in CKD-MBD represent the laboratory aspect of the disorder. These include calcium level (ionized or total), phosphate level, PTH, alkaline phosphatase (total or bone specific), and VD status (25VD). Other indicators, such as 1,25VD and FGF-23 are not measured routinely. The earliest changes occur in PTH and VD metabolites—the abnormal values for PTH, 25VD

According to the current guidelines, testing for calcium, phosphate, PTH, and

and phosphate levels are detected in eGFR below 40 and remain stable until

of laboratory evaluation should be based on the rate of CKD progression, the magnitude of abnormalities, and the evaluation of treatment's effectivity. Similarly,

testing depends on baseline values and therapeutic interventions [17]. The timing and frequency suggested by Kidney Disease: Improving Global Outcomes (KDIGO)

Bone involvement in CKD [renal osteodystrophy (ROD)] is of pivotal importance, as it is associated with bone fractures (asymptomatic or symptomatic), bleeding, chronic disability, poorer life quality, and higher mortality in renal disease. In children with CKD, it leads to growth retardation and skeletal

Several types of bone histological changes can be detected in CKD, according to three major histological indicators: turnover, mineralization, and volume. Bone turnover (T) is a parameter, corresponding to bone formation rate. It can be abnormally low, normal, or very high and is best assessed via bone biopsy and tetracycline

alkaline phosphatase should be initiated in eGFR<60 ml/min/1.73 m<sup>2</sup>

25VD should be tested in patients with eGFR<60 ml/min/1.73 m<sup>2</sup>

, whereas abnormal calcium

; the frequency

and frequency of

use of calcimimetics upregulated VDR expression in rat models [16]. The VD axis in health and renal disease is depicted in **Table 1**.

**4. Vitamin D deficiency: clinical implications in renal disease**

metabolism, as their importance spans beyond bone health.

**4.1 CKD-associated mineral bone disorder (CKD-MBD)**

changes, and vascular calcifications [17].

eGFR<20 ml/min/1.73 m2

are summarized in **Table 2**.

deformities [17].

*4.1.2 Bone disorders in CKD-MBD*

*4.1.1 Biochemical abnormalities in CKD-MBD*

and 1,25VD are detected in eGFR<60 ml/min/1.73 m2

[18].

**250**

*Suggested testing for biochemical indicators of CKD-MBD according to CKD stage.*

labeling. Mineralization (M) is the second parameter. Normally, the osteoblasts lay down new collagen and direct mineralization of the matrix. This process is impaired in CKD, leading to thickened osteoid. Mineralization is measured by osteoid maturation time and mineralization lag time. The osteoid maturation time is the osteoid width divided by the distance between labels per day. The mineralization lag time is the osteoid maturation time adjusted for the percentage of osteoid surface that has a tetracycline label. Mineralization is classified as normal and abnormal. Bone volume (V) sums up bone formation and resorption rates. It is generally accepted that bone volume is expressed as bone volume per tissue volume and is classified as low, normal, and high bone volume.

According to the TMV classification of bone histology in CKD, the following ROD categories are recognized [19]:


In addition, age related/postmenopausal osteoporosis can be detected. Measurement of bone mineral density [by using dual-energy X-ray absorptiometry (DXA)] is most informative in CKD stages 1–2; in these cases, low BMD is associated with osteoporosis and treatment is performed as in the general population. Patients with low BMD and CKD stages 3–5 are designated as having CKD-MBD with low BMD. Recent reports demonstrate that BMD testing can predict fracture risk in eGFR<60 ml/min/1.73 m<sup>2</sup> . The current KDIGO guidelines broaden the indications for BMD testing in CKD stages 3–5D to assess fracture risk, if it will have effect on treatment. Finally, normal histology is also possible [17, 20].


*PTH, parathyroid hormone; BAP, bone specific alkaline phosphatase; N, normal;* ↓*, decreased;* ↑*, increased values; OF, osteitis fibrosa; MHPTBD, mild secondary hyperparathyroidism related bone disease; AD, adynamic bone disease; OM, osteomalacia.*

#### **Table 3.**

*Clinical presentation, laboratory, radiologic and histologic findings in low turnover mineral bone disease (LTMBD) and high turnover mineral bone disease (HTMBD).*

It should be noted that histological findings differ according to renal replacement type. In patients on hemodialysis OF and MUO are the most common findings, in peritoneal dialysis–AD is detected in up to 50%, whereas in patients in CKD stages 3–5 not on dialysis the most common findings are OF and MUO. However, in the latter group, the highest percentage of normal histology is detected [20].

Bone biopsy is regarded as the golden standard for the precise diagnosis of the bone changes in CKD-MBD. Indications for bone biopsy are bone fractures, bone pain, unexplained hypercalcemia/hypophosphatemia, evaluation of the type of bone turnover (which may lead to treatment correction), and suspected aluminum toxicity. Planning antiresorptive treatment in eGFR<30 ml/min/1.73 m2 is currently not an indication for bone biopsy, as no evidence exists, linking bisphosphonate use to higher AD prevalence in CKD [17]. The most widely recognized disadvantages

**253**

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

*4.1.3 Vascular calcification in CKD-MBD*

hyperphosphatemia than paricalcitol [29–31].

**4.2 VD pleiotropy in renal disease**

ropy in CKD patients will be presented.

immune and non-immune renal diseases.

*4.2.1 VD pleiotropy in CKD: proteinuria and CKD progression*

of the procedure are pain, laborious procedure, time-consuming, and expensive histological evaluation, as well as insufficient histopathological expertise [21].

These limitations restrict the wide use of bone biopsy. Therefore, markedly elevated PTH and bone-specific alkaline phosphatase can be used in clinical practice to predict bone turnover in CKD-MBD. Thus, two types of mineral bone diseases are defined high turnover mineral bone disease (HTMBD) and low turnover mineral bone disease (LTMBD). In cases, in which clinical and laboratory data are inconclusive of the type of bone turnover, bone biopsy should be considered [17]. The clinical, laboratory, radiological, and histological characteristics of the both entities are summarized in **Table 3**.

Vascular calcification (VC) is deposition of calcium phosphate in vascular tissues. It presents with calcification of arterial media, intima, valves, and rarely with calcific uremic arteriolopathy (calciphylaxis). Normally, this occurs with aging. However, the process is accelerated in CKD and leads to increased mortality and morbidity. Initially, it was regarded as a finding in patients with end-stage renal disease (ESRD), but currently, it is detected in early CKD stages in adults and in

Patients with VC are regarded as having the highest risk for cardiovascular events. The diagnosis is based on abdominal lateral radiograph (vascular calcifications), echocardiogram (valvular calcifications), or computer tomography [17].

The association of VC with VD status in CKD is not well defined as contradicting reports exist. Two report demonstrate, that lower serum 1,25VD is associated with increased risk for and demonstrated that 25VD has no association with VC [23, 24]. As arterial stiffening is regarded as related pathology to VC in CKD, it should be noted that two recent interventional studies demonstrated improvement of endothelial dysfunction in CKD patients after cholecalciferol supplementation [25–27]. Higher serum levels of 1,25VD and high doses of VD supplementation increased the

children with ESRD, thus depicting a more complicated picture [22].

risk for VC [23, 28], thus indicating the dual role of VD in vascular health.

Finally, the type of VD treatment may be important too. Generally, vitamin D analogs (VDA) demonstrate similar effectivity in reduction of PTH levels to calcitriol, with lower toxicity—lower rates of hypercalcemia and hyperphosphatemia, thus suggesting lower risk for supplementation-enhanced VC. Unfortunately, more trails are needed to evaluate the effect of different supplementation types on VC prevalence. In addition, new VDA are being evaluated in the treatment of CKD-MBD, with more expressed cardiac protection and less hypercalcemia and

As mentioned above, the VDR and the enzyme CYP27B1 have wider distribution in the body and are being expressed in organs not involved in calcium-phosphate metabolism. This indicates a greater physiological importance of the VD axis, spanning beyond skeletal physiology. These extraskeletal properties are designated as pleiotropic effects of VD. In this sub-section, the current knowledge of VD pleiot-

Poorer VD status was associated with higher proteinuria and faster progression of CKD. In addition, VDR activation was found to slow CKD progression in

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

*Vitamin D Deficiency*

Clinical presentation

**252**

It should be noted that histological findings differ according to renal replacement type. In patients on hemodialysis OF and MUO are the most common findings, in peritoneal dialysis–AD is detected in up to 50%, whereas in patients in CKD stages 3–5 not on dialysis the most common findings are OF and MUO. However, in the latter group, the highest percentage of normal histology is detected [20].

*Clinical presentation, laboratory, radiologic and histologic findings in low turnover mineral bone disease* 

**HTMBD LTMBD**

Arthralgia Arthralgia Bone pain Bone pain Calciphylaxis Calciphylaxis Bone fractures Bone fractures

Pruritus Pruritus

Aluminum toxicity—anemia,

Vomiting, nausea, hypertension

dementia

(hypercalcemia)

Early stages N/↑ Advanced stages—↑↑

Early stages N/↓ Advanced—↓/↑

Early stages N/↓ Advanced—↓

Early stages N/↓ Advanced stages ↓

Fractures

Muscle weakness, spasms, tetany, paresthesia,

convulsions (hypocalcaemia)

(hypercalcemia)

Myalgia

Serum calcium N in early stages

Serum phosphate N in early stages

BAP N in early stages

PTH N/↑ in early stages

*disease; OM, osteomalacia.*

**Table 3.**

pelvis

*(LTMBD) and high turnover mineral bone disease (HTMBD).*

Vomiting, nausea, hypertension

Laboratory **HTMBD LTMBD**

↓/N/↑ in advanced HTMBD

↑ in advanced HTMBD

↑↑↑ in advanced HTMBD

N to very high in advanced stages

Radiology **HTMBD LTMBD**

Histology HTMBD LTMBD

Subperiosteal erosions—hands, clavicles, and

Vertebral osteosclerosis Looser zones Brown tumors Bone deformities

OF, MHPTBD AD, OM *PTH, parathyroid hormone; BAP, bone specific alkaline phosphatase; N, normal;* ↓*, decreased;* ↑*, increased values; OF, osteitis fibrosa; MHPTBD, mild secondary hyperparathyroidism related bone disease; AD, adynamic bone* 

Extraskeletal calcifications Osteopenia and osteoporosis

Bone biopsy is regarded as the golden standard for the precise diagnosis of the bone changes in CKD-MBD. Indications for bone biopsy are bone fractures, bone pain, unexplained hypercalcemia/hypophosphatemia, evaluation of the type of bone turnover (which may lead to treatment correction), and suspected aluminum

not an indication for bone biopsy, as no evidence exists, linking bisphosphonate use to higher AD prevalence in CKD [17]. The most widely recognized disadvantages

is currently

toxicity. Planning antiresorptive treatment in eGFR<30 ml/min/1.73 m2

of the procedure are pain, laborious procedure, time-consuming, and expensive histological evaluation, as well as insufficient histopathological expertise [21].

These limitations restrict the wide use of bone biopsy. Therefore, markedly elevated PTH and bone-specific alkaline phosphatase can be used in clinical practice to predict bone turnover in CKD-MBD. Thus, two types of mineral bone diseases are defined high turnover mineral bone disease (HTMBD) and low turnover mineral bone disease (LTMBD). In cases, in which clinical and laboratory data are inconclusive of the type of bone turnover, bone biopsy should be considered [17]. The clinical, laboratory, radiological, and histological characteristics of the both entities are summarized in **Table 3**.

### *4.1.3 Vascular calcification in CKD-MBD*

Vascular calcification (VC) is deposition of calcium phosphate in vascular tissues. It presents with calcification of arterial media, intima, valves, and rarely with calcific uremic arteriolopathy (calciphylaxis). Normally, this occurs with aging. However, the process is accelerated in CKD and leads to increased mortality and morbidity. Initially, it was regarded as a finding in patients with end-stage renal disease (ESRD), but currently, it is detected in early CKD stages in adults and in children with ESRD, thus depicting a more complicated picture [22].

Patients with VC are regarded as having the highest risk for cardiovascular events. The diagnosis is based on abdominal lateral radiograph (vascular calcifications), echocardiogram (valvular calcifications), or computer tomography [17].

The association of VC with VD status in CKD is not well defined as contradicting reports exist. Two report demonstrate, that lower serum 1,25VD is associated with increased risk for and demonstrated that 25VD has no association with VC [23, 24]. As arterial stiffening is regarded as related pathology to VC in CKD, it should be noted that two recent interventional studies demonstrated improvement of endothelial dysfunction in CKD patients after cholecalciferol supplementation [25–27]. Higher serum levels of 1,25VD and high doses of VD supplementation increased the risk for VC [23, 28], thus indicating the dual role of VD in vascular health.

Finally, the type of VD treatment may be important too. Generally, vitamin D analogs (VDA) demonstrate similar effectivity in reduction of PTH levels to calcitriol, with lower toxicity—lower rates of hypercalcemia and hyperphosphatemia, thus suggesting lower risk for supplementation-enhanced VC. Unfortunately, more trails are needed to evaluate the effect of different supplementation types on VC prevalence. In addition, new VDA are being evaluated in the treatment of CKD-MBD, with more expressed cardiac protection and less hypercalcemia and hyperphosphatemia than paricalcitol [29–31].

#### **4.2 VD pleiotropy in renal disease**

As mentioned above, the VDR and the enzyme CYP27B1 have wider distribution in the body and are being expressed in organs not involved in calcium-phosphate metabolism. This indicates a greater physiological importance of the VD axis, spanning beyond skeletal physiology. These extraskeletal properties are designated as pleiotropic effects of VD. In this sub-section, the current knowledge of VD pleiotropy in CKD patients will be presented.

#### *4.2.1 VD pleiotropy in CKD: proteinuria and CKD progression*

Poorer VD status was associated with higher proteinuria and faster progression of CKD. In addition, VDR activation was found to slow CKD progression in immune and non-immune renal diseases.

In IgA nephropathy, human studies associated poorer VD status with poorer clinical outcomes [32]. In addition, calcitriol supplementation suppressed proteinuria in IgA patients by activating the VDR and thus influencing cytokine and leukotriene metabolism [33].

Recent studies demonstrated the importance of VD axis in systemic lupus erythematosus (SLE) and lupus nephritis (LN). Poorer VD status correlated with higher SLE activity, whereas poorer VDR expression in renal tissue was linked to higher renal activity and more severe renal lesions in patients with LN [34, 35]. Podocyte autophagy is a key factor in renal involvement in LN. A recent study showed that poorer VD status correlated with higher podocyte autophagy activity and VD effectively suppressed it in LN, thus protecting podocytes from antibodymediated injury [36]. VD and VDR affect autophagy via different mechanisms: activating calcium-dependent intracellular kinases, downregulating mTOR expression, or upregulation of the cyclin-dependent kinase inhibitor *p19INK4D* [37].

However, VD has renoprotective effect in non-immune glomerular diseases too. In diabetic nephropathy (DN), both animal models and clinical trials demonstrate the negative correlation between low VD and the risk for DN and DN progression, as well as the beneficial effect of VD/VD analogs in reducing albuminuria, renal fibrosis, thus retarding disease progression [38, 39]. The effect can be explained with RAS suppression, suppression of inflammatory mediators [nuclear factor-kappa B (NF-κB), transforming growth factor-β(TGF-β)], suppressing the Wnt/β-catenin pathway, which is involved in epithelial to mesenchymal cell transition (EMT) in high glucose milieu, as well as upregulation of nephrin expression [39–41].

The mechanisms mentioned in DN (suppression of RAS, inflammation, EMT) are the basis of renal protection of VD in other renal diseases–in animal models and human clinical trials [33]. Additionally, an inverse correlation between VD status and proteinuria and blood pressure control in autosomal polycystic kidney disease (ADPKD) was reported, as well as reduction of proteinuria and hypertension on treatment with VDR agonist in experimental PKD. However, the findings are to be evaluated prospectively in interventional study in patients with ADPKD [42].

### *4.2.2 VD pleiotropy in CKD: autoimmunity, inflammation, and infection*

The presence of VDR and CYP27B1 has been well recognized in the immune cells, which modulate their differentiation and proliferation. VD suppresses B-cell proliferation, modulates T-helper proliferation, favoring the T-helper type 2 subtype, thus suppressing inflammatory cytokine synthesis (IL17, IL21) and stimulating the production of anti-inflammatory ones (IL10). In addition, VD enhances the production of cathelicidin and β-defensin 2, as well as influences autophagy and apoptosis [33, 43]. All these properties of VD and VDR demonstrate the importance of VD axis in protective and pathological immunity.

### *4.2.2.1 VD and autoimmunity/inflammation*

The role of VD in LN has been already discussed. Other studies, evaluating the VD–SLE association demonstrate that poorer VD is related to higher SLE activity in adults and children [44]. Different supplementation regimens also demonstrated improvement in inflammatory markers, disease activity indices, decrease in T-helpers types 1 and 17 [44]. However, despite the different papers, reporting beneficial effect from VD, a recent study demonstrated increase of SLE activity after exposing patients to UV radiation, despite improvement in VD status [45]. Thus, the SLE-VD correlation still remains to be clarified.

**255**

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

be clarified [50, 51].

*4.2.2.2 VD and infection*

*4.2.3 VD pleiotropy in CKD: neoplasia*

trials and registries [57].

*4.2.3.1 Breast cancer*

data for CKD patients.

*4.2.3.2 Colorectal cancer*

supplementation currently are inconsistent [46, 47].

The rheumatoid arthritis (RA) and the inflammatory bowel disease (IBD) are diseases that influence kidney health by causing AA amyloidosis, which in turn progresses to ESRD. VD status was inversely associated with RA disease activity and RA-associated complications [46]. However, despite some reports, indicating beneficial effect of VD supplementation on T-helper 17 function, the results for VD

Several studies demonstrated lower VD status in patients with more aggressive IBD. However, the findings may be attributed to lower absorption of VD due to the active intestinal inflammation, especially in Crohn's disease [48, 49]. Interventional studies also demonstrated the beneficial effect of VD supplementation in suppressing pro-inflammatory markers in IBD. Yet, the importance of VD in IBD remains to

Infection is a well-recognized leading cause for death in CKD patients, especially those on dialysis. It was already mentioned that the VD axis plays a role in immunity by enhancing cathelicidin production. In dialysis patients, low cathelicidin levels were detected, which were associated with higher risk for infection and also modest correlation to 1,25VD levels was discovered [52]. Interventional studies also demonstrated the decreased risk for infection in dialysis patients. VD supplementation reduced significantly the risk for hospitalization due to acute respiratory infections in hemodialysis (HD) patients; in another study, VD supplementation decreased the risk for peritonitis in patients on peritoneal dialysis (PD) [53, 54]. A more recent study also demonstrated decrease in infection rates in dialysis patients treated with VDR analogs [55]. In contrast to these findings, Yildirim et al. failed to demonstrate a significant relation between VD status and inflammatory markers in CKD patients [56].

An already mentioned paper demonstrated reduced malignancy-associated mortality in VDA-treated dialysis patients. However, the study did not evaluate the specific localization of the neoplasia, nor its histology [55]. Therefore, in this subsection, the most common malignant diseases will be reviewed and their association with VD. Unfortunately, the exact association between VD and neoplasia in CKD patients is not well evaluated, as CKD patients are usually excluded from large

The reports evaluating the association between VD deficiency and breast cancer are inconsistent. The inverse association between breast cancer and VD, detected in several studies was not supported by more recent prospective studies. In addition, a controversy exists about the beneficial effect of VD supplementation on breast cancer risk and survival [44]. Unfortunately, the cited studies did not demonstrate

Several studies demonstrate an inverse correlation between colorectal cancer and 25VD levels [58, 59]. The findings do not correspond to the results of a larger

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

*Vitamin D Deficiency*

leukotriene metabolism [33].

In IgA nephropathy, human studies associated poorer VD status with poorer clinical outcomes [32]. In addition, calcitriol supplementation suppressed proteinuria in IgA patients by activating the VDR and thus influencing cytokine and

Recent studies demonstrated the importance of VD axis in systemic lupus erythematosus (SLE) and lupus nephritis (LN). Poorer VD status correlated with higher SLE activity, whereas poorer VDR expression in renal tissue was linked to higher renal activity and more severe renal lesions in patients with LN [34, 35]. Podocyte autophagy is a key factor in renal involvement in LN. A recent study showed that poorer VD status correlated with higher podocyte autophagy activity and VD effectively suppressed it in LN, thus protecting podocytes from antibodymediated injury [36]. VD and VDR affect autophagy via different mechanisms: activating calcium-dependent intracellular kinases, downregulating mTOR expression,

or upregulation of the cyclin-dependent kinase inhibitor *p19INK4D* [37].

*4.2.2 VD pleiotropy in CKD: autoimmunity, inflammation, and infection*

of VD axis in protective and pathological immunity.

Thus, the SLE-VD correlation still remains to be clarified.

*4.2.2.1 VD and autoimmunity/inflammation*

However, VD has renoprotective effect in non-immune glomerular diseases too. In diabetic nephropathy (DN), both animal models and clinical trials demonstrate the negative correlation between low VD and the risk for DN and DN progression, as well as the beneficial effect of VD/VD analogs in reducing albuminuria, renal fibrosis, thus retarding disease progression [38, 39]. The effect can be explained with RAS suppression, suppression of inflammatory mediators [nuclear factor-kappa B (NF-κB), transforming growth factor-β(TGF-β)], suppressing the Wnt/β-catenin pathway, which is involved in epithelial to mesenchymal cell transition (EMT) in high glucose milieu, as well as upregulation of nephrin expression [39–41].

The mechanisms mentioned in DN (suppression of RAS, inflammation, EMT) are the basis of renal protection of VD in other renal diseases–in animal models and human clinical trials [33]. Additionally, an inverse correlation between VD status and proteinuria and blood pressure control in autosomal polycystic kidney disease (ADPKD) was reported, as well as reduction of proteinuria and hypertension on treatment with VDR agonist in experimental PKD. However, the findings are to be evaluated prospectively in interventional study in patients with ADPKD [42].

The presence of VDR and CYP27B1 has been well recognized in the immune cells, which modulate their differentiation and proliferation. VD suppresses B-cell proliferation, modulates T-helper proliferation, favoring the T-helper type 2 subtype, thus suppressing inflammatory cytokine synthesis (IL17, IL21) and stimulating the production of anti-inflammatory ones (IL10). In addition, VD enhances the production of cathelicidin and β-defensin 2, as well as influences autophagy and apoptosis [33, 43]. All these properties of VD and VDR demonstrate the importance

The role of VD in LN has been already discussed. Other studies, evaluating the VD–SLE association demonstrate that poorer VD is related to higher SLE activity in adults and children [44]. Different supplementation regimens also demonstrated improvement in inflammatory markers, disease activity indices, decrease in T-helpers types 1 and 17 [44]. However, despite the different papers, reporting beneficial effect from VD, a recent study demonstrated increase of SLE activity after exposing patients to UV radiation, despite improvement in VD status [45].

**254**

The rheumatoid arthritis (RA) and the inflammatory bowel disease (IBD) are diseases that influence kidney health by causing AA amyloidosis, which in turn progresses to ESRD. VD status was inversely associated with RA disease activity and RA-associated complications [46]. However, despite some reports, indicating beneficial effect of VD supplementation on T-helper 17 function, the results for VD supplementation currently are inconsistent [46, 47].

Several studies demonstrated lower VD status in patients with more aggressive IBD. However, the findings may be attributed to lower absorption of VD due to the active intestinal inflammation, especially in Crohn's disease [48, 49]. Interventional studies also demonstrated the beneficial effect of VD supplementation in suppressing pro-inflammatory markers in IBD. Yet, the importance of VD in IBD remains to be clarified [50, 51].
