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11 Effects of Natural Vitamin D Supplementation on Non-classic Target Organs

11 Effects of Natural Vitamin D Supplementation on Non-classic Target Organs

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of type 2 muscle fibers [91–93]. It may also increase muscle strength via the release

of intracellular calcium, which facilitates muscular contraction, after stimulating

the intracellular phospholipase C and protein kinase C signaling pathway. The

poor muscular performances associated with lack of vitamin D is also associated

with a significant increase of fat infiltration in muscle [94, 95]. Such lipid infiltration may reduce muscle performances because of an impaired muscle mitochondrial activity and a decreased insulin-mediated glucose uptake, use and glycogen

synthesis [96].

Numerous studies have evidenced that this muscular weakness can regress following natural vitamin D administration [97]. When the levels of vitamin D are

increased from <5 to >16 ng/ml, after vitamin D supplementation (800 IU/day at

least) with calcium, the performance in speed walking and proximal muscle strength

are markedly and progressively improved until obtaining values of 40 ng/ml. The

increased muscle capacity is clinically translated by a significant 22 % decrease in

the risk of fall as demonstrated by the results of a large meta-analysis of five clinical

trials [98, 99].

Muscle wasting and reduction in maximal exercise capacity have been reported

at every CKD stage, their prevalence usually runs parallel with the progression of

renal disease and affects more than half of patients undergoing dialysis therapy

[100]. The clinical signs including sarcopenia, frailty as well as the morphological

changes, which mainly affect type II muscle fibers, correlated with serum 25(OH)D

levels [101]. Actually, vitamin D supplementation significantly improved muscle

performance in the elderly, however, the results are more questionable in CKD

patients and require definitive demonstration by large RCTs.



28.11.2



The Kidney and Nephroprotection



Experimental studies, using a variety of experimental models, including unilateral

ureteral obstruction, anti-thy-1 glomerulonephritis, sub-total nephrectomy and

diabetic nephropathy, have clearly demonstrated that vitamin D can be renoprotective against renal injury. Indeed, vitamin D exerts renal anti-inflammatory and

immunomodulatory effects, inhibits the renin-angiotensin-aldosterone system,

and inhibits the pathways leading to the stimulation of pro-fibrotic factors such as

NF-kB and TGFβ. Vitamin D also decreases the renal expression of markers characteristics of the epithelia-mesenchymal transition, such as TGFβ, resulting in the

attenuation of interstitial and glomerular renal fibrosis, as well as the degree of

proteinuria [102, 103]. In human, most of the anti-proteinuric and renoprotection

studies have been performed with active vitamin D analogs including calcitriol,

22-oxa-calcitriol, and paricalcitol [104–107] and no definitive scientific evidence

exists showing that natural vitamin D2 or D3 could have renoprotection

properties.



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Natural Vitamin D in Chronic Kidney Disease



28.11.3



479



The Cardiovascular System



Vitamin D affects the cardiovascular system via direct effects, since cardiac and

vascular cells express both the VDR and the 1a-hydroxylase, and also via indirect

effects because calcitriol controls insulin secretion and sensitivity, inflammation,

PTH, and renin, and thus blood pressure [108]. The vitamin D system is also linked

to the FGF23-klotho axis, which also mediates left ventricular hypertrophy development. Epidemiological studies have demonstrated that people residing in higher

latitudes and with low serum vitamin D levels have an increased risk of arterial

hypertension and cardiovascular diseases [109]. Intervention studies, as reported

by the results of a large meta-analysis including 18 randomized clinical trials, have

also shown that natural vitamin D supplementation slightly but significantly

decreased the risk of cardiovascular complications [110]. However, convincing

results regarding the potential benefits of natural vitamin D supplementation in

CKD subjects are still lacking. In addition, the recent PRIMO study (Paricalcitol

capsule benefits in renal failure-induced cardiac morbidity) showed that 48-weeks

treatment with paricalcitol did not improve let ventricular hypertrophy (LVH) or

improve diastolic dysfunction in CKD patients [111]. Similarly, another RCT using

paricalcitol was negative in term of cardiovascular endpoints – the OPERA study.

This study failed to show reduction of LVH with paricalcitol in 60 CKD stage 3–5

patients [112].



28.11.4



The Immune System



Briefly summarized, vitamin D stimulates innate immunity with potential protective effects against some infectious diseases. In vitro treatment of monocyte/macrophage cells with natural vitamin D, through the VDR activation and the

stimulation of Toll like 2 receptor, increases the expression of the antimicrobial

molecule cathelicidin [113]. In vivo, only animal studies have demonstrated a protective effect of vitamin D treatment against mammary infection [114]. Although

some trials have shown that, compared to placebo, vitamin D supplementation may

reduce the incidence of some viral infections [115] or their outcomes [116], it

remains to be confirmed in larger studies whether natural vitamin D supplementation reduce the frequency of viral, bacterial and parasite infections in the general

population.

Regarding the adaptive immune system, vitamin D inhibits some part of the

adaptive immunity, especially shifting Th1 and Th17 lymphocytes towards a Th2

and Treg phenotype, with potential protective effects on some autoimmune diseases

[117]. It also suppresses T-cells proliferation, decreases the secretion of IL2 and

IFNγ by TCD4, decreases the cytotoxicity of TCD8 cells. Through all these actions

and the modulation of the acquired immune system, vitamin D has been suggest to



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protect against a variety of diseases such as tuberculosis, osteoarthritis, diabetes,

seasonal flu, multiple sclerosis, and Crohn’s disease [15]. No definitive scientific

evidence exists demonstrating that natural vitamin D2 or D3 could improve immune

response in CKD subjects.



28.12



Cancers



The cancer-protecting effects of vitamin D, in particular colon cancer, may be

explained via its anti-proliferating properties and its pro-differentiating and proapoptotic effects. Vitamin D also inhibits angiogenesis and tumor growth. Moreover,

vitamin D improves cell-to-cell contact, reinforces cell adherence and intercellular

communication, decreasing by this way the risk of cell metastasis [118]. In human,

several groups have reported contradictory findings, the Women’s Health Initiative

(WH) study did not find any cancer protecting effect of daily administration of

400 IU of vitamin D3 [119]. However, another study providing 1,100 IU/day of

vitamin D observed a significant reduction in the risk of any cancer [120]. However,

there is still a need of RCT in CKD demonstrating the anti-cancer effect of natural

vitamin D supplementation.



28.13



Diabetes



There is a large body of experimental evidences demonstrating the protecting of

natural vitamin D against diabetes and metabolic syndrome. Indeed, the VDR and

the 1a-hydroxylase are expressed in pancreatic b-cells, and the insulin gene possesses the VRE in its promoter region. Thus, vitamin D stimulates insulin secretion,

β-cell proliferation, glucose transport, and insulin sensitivity [121]. Epidemiological

studies have found a significant association between low serum vitamin D levels

and the prevalence of type 1 diabetes [122, 123]. However, there has not been clearly

demonstrated that vitamin D supplementation prevents the occurrence of diabetes

and/or improves glucose control in humans.



28.14



Potential Adverse Effects of Natural Vitamin D



As for most medication, some people can present signs of allergic reaction, which

is mainly due to inactive ingredients contained in ergocalciferol formulations. The

other potential side effects are related to calcium and phosphate metabolism and

include hypercalcemia and hyperphosphatemia usually secondary to



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481



hypervitaminosis D, which has become very uncommon nowadays. The first cases

were reported in 1992 from Boston, USA, where eight subjects had clinical and

biological signs of hypervitaminosis D (mean serum 25(OH)D levels of 294 ng/ml)

after having taken excessive vitamin D fortification of dairy milk [124]. Recently,

seven cases of vitamin D intoxication occurred in Turkish children, who unintentionally received an estimated daily intake of vitamin D between 266,000 and

800,000 IU because of an erroneously manufactured vitamin D supplement from

fish oil [125]. Hypervitaminosis D is extremely rare in the general population (<1 %)

with current recommended dose range of 400–4,800 IU/day for up to 1 year [126,

127], and depends on numerous factors including the type of natural vitamin D

compounds, the starting dosage, season, body mass index, baseline concentrations

of 25(OH)D, calcium, and PTH, as well as genetic polymorphisms [126]. Similarly,

oral administration of a dose up to 100,000 IU monthly of cholecalciferol maintained circulating 25(OH)D levels over 30 ng/ml in 90 % of CKD subjects without

hypervitaminosis D. These values reached a plateau after the first 12 weeks of treatment and remained stable for next 3 months without any case of hypercalcemia or

hyperphosphatemia [128].

The renal manifestation of hypervitaminosis D may be an impaired renal function with polyuria, polydipsia, hypercalciuria, reversible azotemia, nauseas,

anorexia, constipation, arterial hypertension, anemia, weight loss, metabolic acidosis, nephrocalcinosis, generalized vascular calcification, irreversible renal failure

and death. Excessive treatment with ergocalciferol has also been associated with the

development of low bone remodeling in case of CKD patients, bone demineralization in adult osteoporotic patients. It has been also associated with a decline in the

average rate of linear growth and an increased bone mineralization in children with

dwarfism. Mental retardation has also been reported incase of hypervitaminosis D.



28.15



Conclusions



Assessment of vitamin D status in CKD patients is presently seen as a step for formulating appropriate treatment of SHPT and CKD-MBD. There is ample biological

and observational data to support the importance of maintaining a normal vitamin D

status in CKD. Ideally, changes in clinical practice should be based on experiments

rather than on observational studies. Accordingly, RCTs with nutritional vitamin D

compounds have demonstrated serum PTH reductions but with a possible increased

risk of hypercalcemia and/or hyperphosphatemia. The size and quality issues of the

existing trials limits conclusions that can be drawn regarding their effects on patientlevel skeletal outcomes, and larger higher quality RCTs focused on skeletal and

survival outcomes are needed, some of them are actually ongoing as listed on

Table 28.2. Furthermore, future studies to further delineate role of bioavailable vitamin D in CKD are also needed.



Country

USA



Italy



USA



Sweden



USA



Clinical trial name

or sponsor

DIVINE



NUTRIVITA-D001



D2D



TILLVAL-D



Melamed M.



NCT01029002



NCT00893451



NCT00535158



NCT01457001



Clinical trial number

NCT00892099



Table 28.2 RCTs focused on skeletal and survival outcomes



Chronic kidney

disease stage 3–4



Chronic kidney

disease stage 3–4



Chronic

hemodialysis

patients



Chronic

hemodialysis

patients



Population

Incident

hemodialysis

patients (HD)



Number of patients not

described. Ergocalciferol (D2)

50,000 units once weekly for

8 weeks then every other week

for 4 weeks versus placebo

24 CKD patients, randomized,

placebo-controlled, single-centre,

two-way cross-over study with

two treatment periods of 10 weeks

separated by a washout period of

6 weeks. Cholecalciferol

3,200 IU/day versus placebo

75 patients with CKD stage 3–4.

Randomized to 50,000 IU/month

of ergocalciferol versus placebo

for 3 months. Then open label

for 3 more months



Number of patients and duration

36 patients treated by 50,000 IU

Ergocalciferol weekly; 33

patients treated by 50,000 IU

Ergocalciferol monthly; 36

patients treated by placebo

Number of patients not described.

Two groups randomized to

natural vitamin D versus placebo



Effect of vitamin D on

albuminuria



Insulin secretion and

insulin sensitivity

determined by

insulin-glucose clamp



Risk of myocardial

infarction, stroke,

sudden death, an death

for other causes

Performance on muscle

function tests



Outcomes

Cathelidicin-infection;

achievement of vitamin

D sufficeincy



2014



2011



2011



2016



Date end

of study

2013



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C. Basile et al.



UK



USA



USA



USA



China



Barts & The London

NHS Trust



The Cleveland

Clinic



POSH-D



Atlanta VA Medical

Center (2)



EVIDENCE



NCT01672047



NCT00427037



NCT00781417



NCT01173848



NCT00882401



Kidney transplant



Chronic kidney

disease stage 3–4



Chronic kidney

disease stage 2–3



Chronic kidney

disease stage 3–4



Chronic kidney

disease stage 3–4



250 patients with CKD stage 3–4

and 100 CKD stage 5.

Randomized to ergocalciferol

according to 25(OH)D level

<12 nmol/L 50,000 IU/week ×

12 week, 12–39 nmol/L

50,000 IU/week × 4 week

then,50,000 IU/month,

40–75 nmol/L 50,000 IU/month,

75–116.75 nmol/L 25,000 IU/

month versus placebo, for 2 years



64 patients with CKD stage 3–4.

Randomized to 50,000 IU/month

of ergocalciferol versus placebo

for 5 months

90 patients with CKD stage 3–4.

Randomized to either

ergocalciferol or cholecalciferol

50,000 IU/week for 3 months

and then every month for 3

additional months

48 patients with CKD stage 2–3.

Randomized to cholecalciferol

50,000 IU once a week for

12 weeks then every other week

for 40 weeks versus placebo

34 patients with CKD stage 3–4.

Randomized to cholecalciferol

50,000 IU once a week for

12 weeks versus placebo

Effect of vitamin D3 on

serum 25(OH)D and

PTH levels and bone

turnover markers (CTX

and C-telopeptide)

Progression of coronary

calcification



Effect of vitamin D3 on

serum 25(OH)D and

PTH levels and on

calciuria



Effect of vitamin D2

and D3 on serum

25(OH)D and PTH

levels



Effects of vitamin D

therapy on endothelial

function



Natural Vitamin D in Chronic Kidney Disease

(continued)



2015



2013



2011



2013



2011



28

483



UK



Japan



USA



USA



CHAMBER



University of

Colorado, Denver



Indiana University



Country

UK



D-FENCE



Clinical trial name

or sponsor

St George’s

University of

London



Table 28.2 (continued)



NCT00749736



NCT02360644



NCT02214563



NCT01532349



Clinical trial number

NCT01323712



Chronic kidney

disease stage 3–4



Chronic kidney

disease stage 2–5



Hemodialysis

patients



Children, between

1 and 21 years old,

with CKD stage

2–5



Population

Chronic kidney

disease stage 3b–4



100 patients with CKD stage3–4,

randomized to 4,000 IU/day of

cholecalciferol or doxercalciferol

for 6 months



120 subjects divided in 5 groups:

30 CKD 1–2, 30 CKD 3, 30

CKD 4–5, and 30 control.

Treated by 5,000 IU/day of

cholecalciferol



Number of patients and duration

50 patients with CKD stage

3b–4. Randomized to

cholecalciferol Cholecalciferol

100,000 Units 6 doses; 0, 4, 8,

12, 24, 42 weeks versus placebo

28 children with CKD stage 2–5.

Randomized to 2,000 IU/day of

cholecalciferol or to

cholecalciferol 400 IU/day for

3 months

90 patients with CKD stage 5D

Impact of vitamin D

supplementation on

serum hepcidin levels

Study of the two major

phase I drug

metabolizing enzymes

(CYP2B6, CYP3A),

and three transporters

[P-gp, MRP2, and

MATE1/2 K]. Also

CYP450s responsible

for vitamin D

metabolism

Change in CD4+/CD8+

ratio, TH1/TH2

cytokine profile, and

conversion from

anergic to reactive skin

testing



Changes in serum

hepcidin levels after

vitamin D

supplementation



Outcomes

Impact of vitamin D

supplementation on

cardiac hypertrophy

and function



2012



2019



2015



2015



Date end

of study

2014



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C. Basile et al.



USA



USA



USA



Canada



University of

Kansas



NEPH-Cal-D



Massachusetts

General Hospital



University of British

Columbia



NCT01247311



NCT01026363



NCT01325610



NCT01835691



Chronic kidney

disease stage 3b–4



Chronic kidney

disease stage 3–4



Chronic

hemodialysis

patients



Chronic kidney

disease stage 3–4



60 subjects divided in 2 groups:

one treated by 50,000 IU/week

of cholecalciferol and the other

with 50,000 IU/week of

ergocalciferol, for 12 weeks

37 hemodialysis patients treated

by 20,000 IU/day of

cholecalciferol. Open lable, for

12 weeks

60 subjects divided in 2 groups:

one treated by 50,000 IU every

other day of calcitriol 0.25 mcg/

day, for 14 days

129 patients with CKD stage

3b–4, randomized to 5,000 IU 3

× week of cholecalciferol or

calcitriol 0.50 mcg 3 × week or

placebo for 3 6 months

Effect of vitamin D on

pulse wave velocity,

blood pressure control.

Change in proteinuria,

FGF23, PTH,

phosphate, calcium and

C-reactive protein



Vitamin D status as

measured by 25(OH)D

levels, and calcium

absorption

Effect on vitamin D on

cathelidicin (hCAP18)

levels



Effect on vitamin D

levels and inflammatory

parameters



2014



2014



2012



2015



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486



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11 Effects of Natural Vitamin D Supplementation on Non-classic Target Organs

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