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4 Classical and Non-classical Actions of Vitamin D

4 Classical and Non-classical Actions of Vitamin D

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Which Vitamin D in Chronic Kidney Disease


Studies of the association between 25(OH) vitamin D levels, bone morphology,

bone mineral density and bone fractures in CKD and/or ESRD are limited in number

but very informative. Coen et al. [27] conducted a retrospective study of 104 patients

(61 males, 43 females; mean age 52.9 ± 11.7 years) on maintenance hemodialysis

who were not receiving any vitamin D supplements and underwent transiliac bone

biopsy for histomorphometric analysis. In those with serum 25-OHD levels <15 ng

ml/1, bone formation rate and trabecular mineralization surface were lower, independent of PTH and calcitriol levels, indicating an important role that 25 (OH) vitamin D has in bone health in ESRD patients. Ambrus et al. performed a retrospective

analysis of the association between fracture and vitamin D status in 130 patients on

maintenance hemodialysis [28]. Patients with fractures had significantly lower 25

(OH) vitamin D levels compared with patients without fractures and lower vitamin

D levels were independently associated with increased fracture risk in a multivariable analysis (OR 11.22, 95 % CI 1.33–94.82). The same investigators also described

low 25 (OH) vitamin D levels associated with reduced bone mineral bone density in

maintenance hemodialysis patients. In another cross-sectional study, Mucsi et al.

[29] found that 25 (OH) vitamin D levels were positively associated with radial bone

mineral density in maintenance hemodialysis patients and with significant attenuation on quantitative bone ultrasound. Lower 25 (OH) vitamin levels have been shown

to be associated with increased subperiosteal resorption and also with reduced bone

mineral density at wrist and lumbar spine in patients [30, 31].


Nutritional Vitamin D Supplementation Effects

on Bone and Mineral Metabolism in CKD and ESRD

The use of vitamin D compounds in the setting of renal disease have been reported

as early as the 1950s [32] One of the earliest reports on the role of 25 (OH) vitamin

D in ESRD patients was published by Fournier et al. over three decades ago [33]. In

this non-randomized trial, bone matrix mineralization evaluated by histomorphometry, increased in patients receiving 25 (OH) vitamin D, whereas it did not change

significantly in patients receiving calcitriol.

Kandula et al. [34] recently in their systematic review and meta-analysis of

identified five randomized trials evaluating nutritional vitamin D supplements

(ergocalciferol or cholecalciferol) in CKD and ESRD. In the pooled analyses of

randomized trials, there was a significant increase in serum 25 (OH) vitamin D

levels (mean difference 14 ng ml/1) and an associated decline in PTH levels (mean

decrease 31.5 pg ml/1) with nutritional vitamin D supplements compared with

placebo. A low incidence of mild and reversible hypercalcemia (up to 3 %) and

hyperphosphatemia (up to 7 %) were reported with nutritional vitamin D supplements. However, none of the studies reported patient centered outcomes related to

bone fractures, bone pain or parathyroidectomy and most trials were of low to

moderate quality.



A.L. Negri et al.

Nutritional Vitamin D Deficiency Effects

on Non-classical Actions of Vitamin D

Several investigations have suggested potential beneficial effects of vitamin D on

both cardiac function and immunity. This is particularly relevant to patients with

ESRD as cardiovascular and infectious disease represent the leading causes of morbidity and mortality in this population. The mechanism for how vitamin D may

improve cardiovascular disease outcomes are not completely clear; however, potential hypotheses include the down regulation of the renin-angiotensin-aldosterone system, direct effects on the heart and vasculature or improvement of glycemic control.

Epidemiological Evidence Evaluating Cardiovascular Risk

in Relation to Nutritional Vitamin D Status in the General


Kendrick et al. reported that individuals surveyed in The National Health and

Nutritional Examination Surveys (NHANES) 1988–1994 with vitamin D deficiency (25(OH)D <20 ng/mL) had higher prevalence of self-reported angina,

myocardial infarction and heart failure compared to individuals with higher levels of vitamin D (OR (95 % CI) 1.20 (1.01–1.36)) [35]. Several cardiovascular

risk factors were associated with lower vitamin D status including hypertension,

diabetes, elevated body mass index (>30), elevated triglyceride level and microalbuminuria in NHANES 1988–1994 [36, 37]. In the most recent NHANES

2000–2004 survey, vitamin D deficiency was also associated with increased prevalence of self-reported coronary heart disease, heart failure and peripheral

vascular disease [38].

Prevalence of peripheral arterial disease is also increased comparing lowest

quartile of 25(OH)D to highest quartile of 25(OH)D [39]. Judd et al. determined in

non-hypertensive individuals from NHANES 1988–1994, optimal vitamin D status

(>32 ng/mL) provided a 20 % reduction in the rate of blood pressure rise with age


Melamed et al. examined all-cause mortality by quartile of 25(OH)D and found

that the lowest quartile of 25(OH)D had significantly increased adjusted mortality

rate ratios (MRR (95 % CI) 1.28 (1.11–1.48) compared to individuals with the highest quartile of 25(OH)D [41]. There was a trend towards increased mortality rate in

the lowest quartile of 25(OH)D due to cardiovascular mortality; however, this did

not reach statistical significance (MRR (95 % CI) 1.22 (0.90–1.65)).

Several studies have prospectively evaluated long-term cardiovascular outcomes

in subjects with no previous history of CVD in relation to their baseline vitamin D

status. Men in the Health Professionals Follow-up Study (HPFS) without previous

CVD who had vitamin D deficiency [(25(OH)D <15 ng/mL] exhibited a twofold

increased rate of myocardial infarction during a 10 year follow-up period [42]. In

the Framingham Offspring Study, subjects with no previous history of CVD and

severe vitamin D deficiency [25(OH)D <10 ng/mL] experienced an increased


Which Vitamin D in Chronic Kidney Disease


hazard ratio for developing a first cardiovascular event after 5 years of follow-up

(1.80; 95 % CI, 1.05–3.08) compared to subjects with higher levels of 25(OH)D

(>15 ng/mL) [43].

Other studies have evaluated cardiovascular risk in relation to vitamin D status in

subjects with established cardiovascular disease. In over 3,000 subjects undergoing

coronary angiography, severe vitamin D deficiency [25(OH)D <10 ng/mL] had

three to five times risk of dying from sudden cardiac death or heart failure over a

7 year follow-up period compared to optimal levels of vitamin D [25(OH)D

>30 ng/mL] [44]. Further, in these same subjects, vitamin D deficiency imparted a

50 % increase in fatal stroke [45]. Subjects in the lowest quartile for 25(OH)D had

increased hazard ratios for all cause and cardiovascular mortality compared to subjects in the highest quartile for 25(OH)D [46].

Epidemiological Evidence Evaluating Cardiovascular Risk

in Relation to Nutritional Vitamin D Status in CKD Patients

Similar findings have been reported in subjects with CRF and in incident hemodialysis patients. All cause and cardiovascular mortality was evaluated in a cohort of

444 patients with eGFR <60 mL/min/1.73 m2 from the Ludwigshafen Risk and

Cardiovascular Health Study, during a median follow-up time of 9.4 years [47].

Multivariate adjusted hazard ratios in severely vitamin D-deficient [25(OH)D

<10 ng/mL] compared to vitamin D-sufficient patients [25(OH)D ≥30 ng/mL]

were 3.79 (1.71–8.43) for all-cause and 5.61 (1.89–16.6) for cardiovascular mortality with no significant interaction with serum PTH concentrations. In another

cohort of patients at different CKD stages, the relationship between vitamin D

serum levels, vascular calcification and stiffness, and the mortality risk was determined [48]. Patients with 25(OH)D ≤16.7 ng/ml had a significantly lower survival

rate than patients above that level. Multivariate adjustments for confounders confirmed 25(OH)D level as an independent predictor of all-cause mortality. Low

25(OH)D levels affected mortality independently of vascular calcification and

stiffness, suggesting that 25D may influence survival in CKD patients via additional pathways. In the prospective cohort study of incident dialysis patients in the

Netherlands (the NECOSAD), all patients with measured 25(OH)D at 12 months

after the start of dialysis were selected [49]. In 762 patients the impact of 25(OH)D

levels on short-term (6 months of follow-up) and longer-term mortality (3 years of

follow-up) was assessed. After adjustments for possible confounders, the hazard

ratio for mortality was 2.0 (1.0–3.8) for short-term and 1.5 (1.0–2.1) for longerterm mortality when comparing patients with 25(OH)D levels ≤10 ng/mL with

those presenting with 25(OH)D levels >10 ng/mL. Adjusted hazard ratios for cardiovascular mortality were 2.7 (1.1–6.5) and 1.7 (1.1–2.7) for short- and longerterm mortality, respectively. For non-cardiovascular mortality, there was no

relevant association overall. In these patients, the impact of 25(OH)D levels on

clinical events was modified by PTH status, with low 25(OH)D levels meaningfully affecting outcomes only in patients with PTH levels above the median of

123 pmol/L.


A.L. Negri et al.

Nutritional Vitamin D Supplementation Effects on Non-classical

Actions of Vitamin D

Nutritional Vitamin D supplementation and cardiovascular risk and infection reduction in the general population.

Very few studies have been conducted to evaluate vitamin D supplementation on

risk of cardiovascular mortality. Two studies prospectively examined vitamin D

supplementation on cardiovascular mortality. In the WHI, women randomized to

vitamin D 400 IU daily and 1,000 mg of calcium had no difference in all cause or

cardiovascular mortality [50]. In a European study by Trivedi et al. elderly individuals receiving a daily equivalent dose of 800 IU of vitamin D did not have improved

cardiovascular survival compared to controls [51].

Wang et al. [52] assess whether vitamin D and calcium supplements reduce the

risk for cardiovascular events in adults. They selected 17 prospective studies and

randomized trials that examined vitamin D supplementation, calcium supplementation, or both and subsequent cardiovascular events. Results of secondary analyses in

eight randomized trials showed a slight but statistically non-significant reduction in

CVD risk (pooled relative risk, 0.90 [95 % CI, 0.77–1.05]) with vitamin D supplementation at moderate to high doses (approximately 1,000 IU/day) but not with

calcium supplementation (pooled relative risk, 1.14 [CI, 0.92–1.41]), or a combination of vitamin D and calcium supplementation (pooled relative risk, 1.04 [CI, 0.92–

1.18]) compared with placebo.

In a recent systematic review of vitamin D on cardiometabolic outcomes Pittas

et al. [53] analyzed four trials on the effect of vitamin D supplementation on incident cardiovascular disease. None reported a statistically significant effect of vitamin D supplementation on various cardiovascular outcomes, including myocardial

infarction, stroke and other cardiac and cerebrovascular outcomes.

Enhancing immunity represents another relevant and promising target for vitamin D therapy. Despite encouraging observational data and clear biological rationale, recent interventional studies have been less encouraging.

One study of 322 obese individuals who received either 40,000 or 20,000 IU of

cholecalciferol weekly or placebo over a year found no association between 25(OH)D

and inflammatory markers (such as IL-6 and TNF-α), even after combining the low

and high-dose cholecalciferol groups [54]. Similarly, in the Vitamin D and Acute

Respiratory Infection Study (VIDARIS) in New Zealand, high dose monthly cholecalciferol therapy failed to prevent the development of upper respiratory tract infections, or affect missed work days, duration of symptoms, or severity of illness [55].

Nutritional Vitamin D Supplementation and Cardiovascular

Risk and Infection Reduction in CKD Patients

Although several interventional studies with nutritional vitamin D supplementation

(with cholecalciferol or ergocalciferol) have been performed in CKD patients, none

of them have analyzed CV risk and mortality [56–58]. As we mention previously a


Which Vitamin D in Chronic Kidney Disease


recent systematic review and meta-analysis of observational studies and randomized controlled trials (RCT) on Vitamin D supplementation in chronic kidney disease performed by Kandula et al. included 22 studies, 17 observational and 5 RCTs.

There was a significant improvement in 25-hydroxyvitamin D and an associated

decline in serum PTH levels among observational studies [34]. PTH reduction was

higher in dialysis patients. Among RCTs, there was a significant improvement in

25-hydroxyvitamin D and an associated decline with a low incidence of hypercalcemia and hyperphosphatemia. As with skeletal effects of vitamin D supplementation

no cardiovascular and infectious outcomes were studied.

With respect to infection reduction in CKD with vitamin D supplementation, The

Dialysis Infection and Vitamin D In New England study (DIVINE; NCT00892099)

is randomizing 120 incident hemodialysis patients to one of two ergocalciferol arms

(60,000 IU weekly or 50,000 IU monthly) or to placebo over 12 weeks and following the response in serum 25(OH)D levels. Secondary outcomes include hospitalizations, changes in cytokines and immunologically active proteins such as

cathelicidin [59].



Active Vitamin D

Active Vitamin D Administration Effects on Mineral

and Skeletal Outcomes in CKD

Multiple randomized trials have been conducted to examine the role of active vitamin compounds in CKD and ESRD. Many of these trials were not specifically

designed to evaluate patient centered skeletal outcomes and had multiple methodological limitations including small sample size and short duration of follow-up.

Several trials have shown that intravenous calcitriol is an effective therapy for the

reduction of serum PTH levels in long term studies [60, 61]. Despite this, very few

studies have shown that this treatment reverses biopsy proven bone lesions as osteitis fibrosa in hemodialysis patients [62] (Table 29.2).

Palmer et al. [63] examined the evidence from randomized controlled trials

regarding the efficacy of vitamin D compounds in CKD and ESRD patients. These

investigators conducted a comprehensive literature search and included trials that

investigated different vitamin D compounds including calcitriol, alfacalcidol, doxerecalciferol, maxacalcitol, paricalcitol and falecalcitriol. They noted significant

variation in PTH lowering effects of vitamin D compounds with newer active vitamin D compounds (doxerecalciferol, maxacalcitol, paricalcitol and falecalcitriol)

significantly lowering PTH compared with placebo [64–66] but no significant PTH

reduction was noted with established vitamin D compounds such as calcitriol, alfacalcidol [67–72]. The more recently developed vitamin D analogues were associated with hypercalcemia (relative risk, but not hyperphosphatemia, with significant

reductions in PTH serum levels. For suppression of PTH, intravenous administration

was superior to oral vitamin D, but higher intravenous doses were used. In terms of


A.L. Negri et al.

Table 29.2 Studies evaluating activated vitamin D and skeletal outcomes in CKD patients



Oral calcitriol

(0.25–0.5 μg) vs

no treatment

Oral calcitriol

(0.25 μg) vs no




et al. [67]



Type of population

Prevalent HD


et al. [72]


Hamdy et al.




0.25–1 μg

CKD stage 3–4

Baker et al.



Oral calcitriol

(0.25 μg) vs no


Andress et al.



IV calcitriol

(1.0–2.5 μg three

times weekly)

Prevalent HD without

biochemical or

radiological evidence

of bone disease

Prevalent HD with

refractory SHPT

CKD stage 4–5 not

on dialysis


Prevented the development

of radiological erosions or

reversed minimal erosions

Increase in bone mineral

density in the calcitriol

group in femoral neck and

lumbar spine

Histological indices of

bone turnover significantly

improved in patients given

alfacalcidol vs controls

Calcitriol delays and may

prevent the development of

osteitis fibrosa

Effective in ameliorating

osteitis fibrosa

patient-level skeletal outcomes such as fractures, bone pain, requirement of surgical

parathyroidectomy, no benefit was noted from the administration of vitamin D compounds [73–76] Table 29.2. However, most studies had inadequate power and insufficient follow-up to appropriately ascertain these outcomes. A more recent

meta-analysis focused on paricalcitol in stage 2–5 CKD patients, confirmed that

paricalcitol can effectively suppress PTH but did not address any patient-level outcomes [77].

In the recently published EVOLVE study with cinacalcet; the comparative arm

was standard of care, namely vitamin D analogs. The calcimimetic arm achieved

lower levels of serum calcium compared with standard care (median level 9.8 mgdl/1

vs 9.2 mgdl/1at 4 months) [78]. Although there were no differences between the two

arms in fractures (13 % vs 12 %), the incidence of parathyroidectomy was significantly lower in cinacalcet arm (7 % vs 14 %).


Active Vitamin D Administration Effects

on Non-classical Vitamin D Outcomes

Mineral and bone disorders (MBD) are early and common complications of CKD,

and progress as glomerular filtration rate declines. Kidney Disease: Improving

Global Outcomes has defined chronic kidney disease-mineral and bone disorder

(CKD-MBD) as a systemic syndrome characterized by: (1) abnormalities in serum


Which Vitamin D in Chronic Kidney Disease


calcium, phosphorus and PTH concentration and vitamin D metabolism, (2) abnormalities in bone turnover, but also in bone mass, quality and mineralization; and

finally the presence of vascular calcifications [79]. This syndrome is common

among CKD patients and has been associated with an increased risk of cardiovascular risk and mortality [80]. Multiple factors contribute to the development and maintenance of CKD-MBD, but principally involve phosphate retention and vitamin D

metabolism abnormalities. As the lack of active vitamin D (calcitriol) is the principal vitamin D abnormality, great impetus has been given to explore if administration

of active vitamin D derivatives can decrease cardiovascular and infectious complications in dialysis patients and increase survival.

Oral Calcitriol and Survival in CKD Patients

Three papers have shown that oral calcitriol even in low doses (less than 1 mcg)

reduce overall and cardiovascular mortality in predialysis and hemodialyzed

patients (Table 29.3). Kovesdy et al. [81] examined the association of oral calcitriol

treatment with mortality and the incidence of dialysis in 520 old male US veterans

with CKD stages 3–5 and not yet receiving dialysis with an estimated glomerular

filtration rate of 30.8 ml/min. Associations were adjusted for age, race, and comorbidities. Two hundred fifty-eight of 520 subjects received treatment with calcitriol,

0.25–0.5 ucg/day, for a median duration of 2.1 years (range, 0.06–6.0 years). The

incidence rate ratios for mortality and combined death and dialysis initiation were

significantly lower in treated with oral calcitriol versus the untreated patients

(p < 0.001 for both in the fully adjusted models). A similar study evaluated associations of oral calcitriol use with mortality and dialysis dependence in 1,418 nondialysis patients with CKD and hyperparathyroidism [82]. The authors abstracted

the data from the Northwest Veterans’ Affairs Consumer Health Information and

Performance Sets (CHIPS) database. They focus on calcitriol as this medication is

commonly prescribed in CKD and could be accurately ascertained from pharmacy

records. Incident calcitriol users and nonusers were selected on the basis of stages

3–4 CKD, hyperparathyroidism, and the absence of hypercalcemia before calcitriol use and then were matched by age and estimated kidney function. During a

median follow-up of 1.9 years, 408 (29 %) patients died and 217 (16 %) initiated

long-term dialysis. After adjustment for demographics, comorbidities, estimated

renal function, medications, and baseline levels of PTH, calcium, and phosphorous, oral calcitriol use was associated with a 26 % lower risk for death (95 %

confidence interval 5–42 % lower; p = 0.016) and a 20 % lower risk for death or

dialysis (95 % confidence interval 1–35 % lower; p = 0.038). The association of calcitriol with improved survival was not statistically different across baseline parathyroid hormone levels. The use of calcitriol was associated with a greater risk for

hypercalcemia. The primary limitation of this study was the potential for confounding by indication, although the authors used a number of techniques to

address this problem.


A.L. Negri et al.

Table 29.3 Observational studies examining all cause and cardiovascular associated with

treatment with activated vitamin D vs no treatment in CKD patients



Oral calcitriol vs no


Type of population

CKD stage 2–5 not

on dialysis


Oral calcitriol vs no


CKD stage 3–4

with SHPT


et al. [83]

7,203 vs


Prevalent HD

CORES database

Shoji et al.


Ogawa et al.


Teng et al.



Tentori et al.



Oral active vitamin

D (calcitriol) vs no


Oral alfa calcidiol

vs no treatment

Oral alfa calcidiol

vs no treatment

Any activated IV

vitamin D vs no


Any activated IV

vitamin D vs no




et al. [81]




et al. [82]



Prevalent HD

Prevalent HD

Prevalent HD from

single non-profit

Dialysis chain

Prevalent HD from

single non-profit

Dialysis chain


Lower all-cause

mortality; trend to

lower ESRF

26 % lower risk of

death; 20 % lower risk

of death or dialysis

Lower all-cause

mortality risk

Lower CV similar

all-cause mortality

Lower all-cause and

CV mortality

20 % lower all-cause


Lower all-cause


Finally, a recent paper addressed the use of oral calcitriol use on the survival of

hemodialysis patients [83]. The authors determined the survival benefit of oral

active vitamin D in hemodialysis patients from six Latin America countries (FME

Register(R) as part of the CORES study) followed for a median of 16 months. Timedependent Cox regression models, after adjustment for potential confounders,

showed that the 7,203 patients who received oral active vitamin D had significant

reductions in overall, cardiovascular, infectious and neoplastic mortality compared

to the 8,801 patients that had not received vitamin D. Stratified analyses found a

survival advantage in the group that had received oral active vitamin D in 36 of the

37 strata studied including that with the highest levels of serum calcium, phosphorus and PTH (Table 29.3). Here Multivariable adjusted analyses revealed that

patients who received oral active vitamin D had a significant 45 % (HR 0.55; 95 %

CI 0.49–0.63) lower mortality risk compared to patients who did not receive oral

active vitamin D. Reductions in mortality risk were similar for cardiovascular,

infectious, and neoplastic causes. The survival benefit of oral active vitamin D was

seen in those patients receiving mean daily doses of less than 1 mcg with the highest

reduction associated with the lowest dose (<0.25 mcg). The reduction in mortality

risk was seen even in the lowest PTH tertile, where a tendency to a higher mortality

has been described. Survival benefit was also seen in patients with high serum phosphorus levels, in which mortality have been shown to be higher. Survival results

were consistent in all centers and across countries despite the differences in mortality rates among them. As in the previous study, the risk of confounding by indication

cannot be ruled out.


Which Vitamin D in Chronic Kidney Disease


Effect of Other Oral Active Vitamin D Analogues on Survival

and Cardiovascular Outcomes in CKD Patients

Although alfacalcidol has been used extensively in Europe and Japan, there has

been few communications of survival in hemodialysis using oral active vitamin D

compounds. Shoji et al. [84] found in a small hemodialysis population that patients

on a low-dose oral alfacalcidol had a significantly lower risk for cardiovascular

death than those without vitamin D supplementation. More recently Ogawa et al.

[85] collected demographic and clinical baseline data from 190 prevalent HD

patients in a regional Japanese cohort. A 5-year survival analysis was performed

according to whether the patients were receiving calcitriol analog therapy.

Alfacalcidol therapy at a mean dose of 5.2 ± 1.8 μg/week was performed in 89

(46.8 %) of the 190 patients. Most patients took oral alfacacidol at a dose not higher

than 1 ug per day. They recorded deaths and cardiovascular events during the follow-up period. A Kaplan-Meier analysis demonstrated that the alfacalcidol users

had a significantly lower rate of all-cause mortality and cardiovascular mortality

than the non-users.

Few studies have been performed with Doxercalciferol (1 alfa hydroxi D2) in

predialysis patients for the control of secondary hyperparathyroidism, but without

evidence on its effects on survival [64, 86]. The same has happened with oral paricalcitol, which have shown to produce reduction in albuminuria in patients with

type 2 diabetes [87, 88]. With this agent two studies have tried to analyze its effects

on cardiac structure and function. In the PRIMO study, 196 patients with chronic

kidney disease (GFR 15–60 mL/min), mild to moderate left ventricular hypertrophy, and preserved ejection fraction were randomly assigned to 2 μg of oral paricalcitol or matching placebo for 48 weeks [89]. Over the study period, there was a

significant decrease in left auricular volume although not in left ventricular mass in

the paricalcitol group compared with the placebo group. Paricalcitol also attenuated

the rise in levels of brain natriuretic. The OPERA trial [90] was a prospective,

double-blind, randomized, placebo-controlled trial that tried to determine whether

oral paricalcitol (1 μg) for 52 weeks could reduce left ventricular mass compared to

placebo in patients with stages 3–5 CKD with LV hypertrophy. Change in LV mass

index did not differ significantly between groups.

Effect of Parenteral Active Vitamin D Analogues on Survival

and Cardiovascular Outcomes in CKD Patients

Parenteral vitamin D has been associated with improved survival among long-term

hemodialyzed patients. In a retrospective study, patients who received injectable

vitamin D (either calcitriol or paricalcitol) had a 20–25 % higher survival rate than

those that did not received injectable vitamin D over the same period of time [91].

All-cause mortality, as well as cardiovascular mortality was less in the group receiving injectable vitamin D after adjusting for potential confounders. In another study

Tentori et al. assessed mortality associated with different vitamin D analogs and


A.L. Negri et al.

with the lack of vitamin D therapy in patients who began HD [92]. In unadjusted

models, mortality was lower in patients on doxercalciferol and paricalcitol versus

calcitriol, but in adjusted models, this difference was not statistically significant. In

all models mortality was higher for patients who did not receive vitamin D versus

those who did.


Nutritional Vitamin D: Optimal Levels, Required

Supplementation Dose and Toxicity

There has been a move to alter the definition of vitamin D sufficiency in the general

population, so that it is no longer simply a 25(OH)D level that avoids rickets. This

has led to a progressive rise in the minimum recommended level of 25(OH)D to

30 ng/ml or above to optimize bone density, falls prevention, calcium absorption,

and PTH suppression. Applying this cut-off value to hemodialysis patients, the

prevalence of vitamin D deficiency in very high, ranging from 50 to 98 % [49].

Deficiency appears to be both more severe and more common in peritoneal dialysis

[93]. The K/DOQI and KDIGO guidelines have recommended testing for vitamin D

insufficiency and deficiency in patients with CKD using the cut-off value of the

general population, although there is no consensus on the definition of vitamin D

insufficiency in CKD.

There are conflicting estimates for the dose necessary to achieve 25(OH)D level

of 30 ng/ml (75 nmol/l) in hemodialysis patients. Published data use a variety of

dosing intervals; however, Cholecalciferol given monthly at an oral dose of

100,000 IU during a 15-month period is usually sufficient to raise levels over 30 ng/

ml in around 90 % of the patients without any evident mineral metabolism toxicity

[94]. Saab et al. [95] have given ergocalciferol oral supplementation at 50,000 IU

monthly to hemodialysis patients during for 6 months increasing 25(OH)D >30 ng/

ml in 95 % of the patients, having none >100 ng/ml. In our own study we have found

similar results with higher initial doses of ergocalciferol but lower maintenance

doses [96].

Except in patients with autonomous 1α-hydroxylase activity, there are no compelling reports of vitamin D toxicity at 25(OH)D levels consistent with sun exposure alone (<111 ng/ml) or at doses in of vitamin D up to 10,000 U/day [97]. These

doses generally result in serum 25(OH)D levels remaining below approximately

88 ng/ml (220 mmol/l) [98]. At this serum level 25(OH)D does not have a direct

effect on gut calcium absorption [99] and hence should not by itself, be capable of

causing hypercalcemia. At levels over approximately 120 ng/ml (300 mmol/l),

25(OH)D does directly affect calcium absorption [99]. Theoretically, toxicity could

still occur at lower 25(OH)D if they result in an increase in free or total 1,25(OH)2

D levels. This is less probable because 24-hydroxylation degradation pathways are

induced by 1,25(OH)2D and FGF23 [100–102]. So any rise in free or total

1,25(OH)2D would lead to an acceleration in the rate of degradation for both

25(OH)D and 1,25(OH)2D. As we said before, high levels 25(OH)D stimulate the


Which Vitamin D in Chronic Kidney Disease


vitamin D receptor [99], and the higher levels by itself would lead to protective

acceleration of degradation. This could explain the trend toward a smaller relative

increment in serum 25(OH)D when higher doses of vitamin D are given [103].

FGF23 levels tend to be high in dialysis patients. It has been postulated that FGF23

levels could stimulate 24-hydroxylase activity and explain in part very high prevalence of low 25(OH)D and 1,25(OH)2D levels in dialysis patients. It has been

recently shown that patients with CKD exhibit an decrease ability to increase serum

24,25(OH)2D3 after cholecalciferol therapy, suggesting decreased 24-hydroxylase

activity in CKD [104]. The observed relationship between baseline FGF23 and

increments in 24,25(OH)2D3 further refutes the idea that FGF23 directly contributes to 25(OH)D insufficiency in CKD through stimulation of 24-hydroxylase




In addition to the endocrine effects of the vitamin D axis on bone and mineral

metabolism, studies have demonstrated there is also extrarenal conversion of

25(OH) vitamin D to 1,25(OH)2 vitamin D in multiple cells leading to autocrine

effects. This advance has led to the speculation that CKD patients may also need to

be supplemented with nutritional vitamin D (ergocalciferol or cholecalciferol).

Unfortunately, to date, the majority of interventional studies have focused on biochemical end points. There are no randomized controlled trials demonstrating that

therapy with any formulation of vitamin D results in improved patient level outcomes. Despite the physiologic importance of vitamin D in health and disease, more

research is required to determine which vitamin D derivative is required for optimal

health in CKD patients. Observational studies or even clinical trials in populations

different from the one we are studying may not clearly inform the practicing physician of the correct treatment. Examples of this are hormone replacement therapy in

women or statin use in dialysis patients. The real gold standard for clinical decisionmaking come from randomized clinical trials, conducted in the population we want

to treat and with clinically meaningful end points. Unfortunately, this level of evidence does not exist for vitamin D therapy in CKD. There are no randomized controlled trials demonstrating that therapy with any formulation of vitamin D results

in improved patient level outcomes. Without randomized clinical trials, causation

cannot be inferred from observational studies. Because well designed clinical trials

are expensive, evidence from animal studies, observational studies, and small pilot

randomized trials with surrogate outcomes are needed to evaluate which therapies

have the most potential for success to be tested in definitive clinical trials.

Multiple observational studies suggest an important role of vitamin D in patients

with CKD and ESRD and potentially in the general population. There could be

potentially different roles for nutritional and active vitamin D compounds, having

nutritional vitamin D a preferred role in infections and cancer prevention, whereas

active vitamin D compounds may play more of a role bone disease and mortality.

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