Evaluation of responses to vitamin D3 (cholecalciferol) in patients on dialysis: a systematic review and meta-analysis
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* Chen Xu
* Yan-chun Li
* Su-mei Zhao
* Zhong-xin Li

## Abstract

Vitamin D plays a key role in mineral metabolism and its deficiency is often noted in patients on dialysis for end-stage renal disease (ESRD). We evaluated the efficacy and responses to vitamin D3 (cholecalciferol) in patients undergoing dialysis for ESRD. Randomized controlled trials or prospective studies comparing vitamin D3 supplementation to placebo in patients with ESRD on dialysis were searched from medical databases using the terms, ‘Calcitriol/Cholecalciferol, vitamin D, chronic kidney disease, hemodialysis, serum calcium, parathyroid hormones (PTH), phosphorus, 25(OH)D, and 1,25(OH)2D’. The outcomes analyzed were serum calcium, PTH, phosphorus, 25(OH)D, and 1,25(OH) 2D levels. Of the 259 records identified, 9 studies with a total of 368 patients were chosen for the current meta-analysis. The number of patients, age, and gender distribution among the groups were comparable. Results reveal a greater increase in both 25(OH)D (Pooled difference in means=0.434, 95% CI 0.174 to 0.694, p=0.001) and 1,25(OH) 2D (Pooled difference in means=0.978, 95% CI 0.615 to 1.34, p<0.001) in the treatment arm, as compared to the placebo. There was no difference in the serum calcium or PTH among the two groups. However, patients in the treatment arm had a significant increase in phosphorus levels (Pooled difference in means=0.434, 95% CI 0.174 to 0.694, p=0.001). Vitamin D supplementation facilitated the maintenance of increased levels of 25(OH) D and 1,25(OH) 2D in patients undergoing dialysis for ESRD. This increase in vitamin D was not associated with hypercalcemia or significant changes in PTH levels.

*   Vitamin D

### Significance of this study

#### What is already known about this subject?

*   Vitamin D deficiency in patients on hemodialysis is associated with an increased early mortality rate.

*   The major form of circulating vitamin D is 25, hydroxyvitamin D, (25(OH)D or calcidiol), and it reflects the vitamin D storage.

*   Nutritional deficiency of cholecalciferol or vitamin D3 can lead to secondary hyperparathyroidism.

#### What are the new findings?

*   Vitamin D3 supplementation can increase levels of 25(OH) D and 1,25(OH) 2D in patients undergoing dialysis for end-stage renal disease.

*   Vitamin D3 supplementation leads to higher levels of serum phosphate compared to placebo.

*   There is no significant change in either serum calcium or parathyroid hormones (PTH) levels with vitamin D3 supplementation.

#### How might these results change the focus of research or clinical practice?

*   In patients with ESRD undergoing dialysis, giving oral cholecalciferol will not disturb serum calcium or PTH, but serum phosphate may need monitoring.

## Introduction

Vitamin D deficiency is not uncommon in the general population, but it is very frequently seen in patients with end-stage renal disease (ESRD), where the prevalence is reported to be over 80%.1 Low vitamin D levels are correlated with hyperparathyroidism, low calcium and calcitriol serum levels, female gender, obesity and insufficient sunlight exposure.2 Reports indicate that vitamin D deficiency in patients on incident hemodialysis is associated with an increased early mortality rate,3 and vitamin D supplementation significantly improves cardiac dysfunction and survival in patients undergoing dialysis.4

Cholecalciferol or vitamin D3 is synthesized in the body from 7-dehydrocholesterol, while ergocalciferol or vitamin D2 is obtained primarily though diet and dietary supplements. Both vitamin D3 and D2 are converted to its active forms, 25, hydroxyvitamin D (calcidiol) and 1,25, dihydroxyvitamin D (calcitriol) through hydroxylation. The major form of circulating vitamin D is 25(OH)D, the serum levels of which reflect the status of vitamin D storage.2 ,5 The Endocrine Society Clinical Practice Guidelines define vitamin D deficiency as serum 25(OH)D concentration of <20 ng/mL.6 1,25, dihydroxyvitamin D, (1,25, (OH)2D) is the more potent form of vitamin D, which exerts a number of biological effects in a paracrine or autocrine manner, including calcium/phosphate homeostasis, cellular differentiation and cardioprotection.5 ,7 ,8 The enzyme responsible for the conversion of 25(OH)D to 1,25(OH)2D was identified in the kidneys and as the kidney function deteriorates, the production of 1,25(OH)2D decreases.9 Nutritional deficiency of vitamin D3 can lead to secondary hyperparathyroidism, a hallmark of early and advanced ESRD, the pathogenesis of which are attributed to the deficiency in calcitriol, hypocalcemia and hyperphosphatemia.10 Seibert *et al*11 have shown that cholecalciferol supplementation can normalize the levels of 25(OH)D levels without hyperphosphatemia or hypercalcemia.12 Further, replenishing the vitamin D3 can also lead to decreased iPTH levels and reduced bone resorption.13

Oral cholecalciferol supplementation is reported to be an easy and cost-effective therapy to reduce vitamin D deficiency, and provides some control of mineral metabolism in patients undergoing hemodialysis.4 While meta-analyses of prospective, placebo controlled trials on vitamin D supplementation and reduced mortality risk in the general population are available,14 ,15 analyses of the data on the safety and tolerability of vitamin D3 in randomized controlled trials (RCT) in patients undergoing dialysis for ESRD are lacking. Moreover, since the kidney plays a major role in vitamin D activation, the efficacy of nutritional vitamin D3 supplementation has been questioned in patients with ESRD.16 ,17 Therefore, we undertook the present study to review the responses to administration of vitamin D3 (cholecalciferol) in patients with ESRD receiving either peritoneal dialysis or hemodialysis.

## Materials and methods

### Literature search and selection criteria

We performed an updated literature search of the Medline, Cochrane, EMBASE, and Google Scholar databases until September 22, 2015 using the following key words: ‘Calcitriol/Cholecalciferol, vitamin D, chronic kidney disease (CKD), hemodialysis, serum calcium, PTH or parathyroid hormones, phosphorus, 25(OH)D, and 1,25(OH)2D’. In addition, the reference lists of relevant studies were manually searched to identify studies meeting the inclusion criteria. A study was considered eligible for inclusion if it was a randomized controlled trial or a prospective study including patients with end-stage CKD on dialysis (either hemodialysis or peritoneal dialysis) for at least 3 months, and reported at least one quantitative primary or secondary outcome. Patients in the treatment group should have received oral cholecalciferol, while the control group may receive either placebo or no treatment.

We excluded letters, comments, editorials, case reports, proceedings, personal communications, and studies with no reported quantitative outcome or that are non-human studies.

### Study selection and data extraction

Studies were identified by the search strategy by two independent reviewers. Where there was uncertainty regarding eligibility, a third reviewer was consulted. The following data were extracted from studies that met the inclusion criteria, the name of the first author, year of publication, study design, number of participants in each treatment group, participants' age and gender, types of intervention/treatment received, and outcomes reported. A total of nine studies were included in the current meta-analysis (the details of study selection are represented in figure 1A).

![Figure 1](/https://d3hme472k3gd2d.cloudfront.net/content/jim/64/5/1050/F1.medium.gif)

[Figure 1](/content/64/5/1050/F1)

Figure 1 
(A) Flow chart for study selection, and quality assessment of overall (B) and individual studies (C) included in the meta-analysis, using the Cochrane Risk of Bias Tool.

### Outcome measures

The outcomes analyzed included levels of serum calcium, PTH, phosphorus, 25(OH)D, and 1,25(OH)2D.

### Quality assessment

We utilized the Cochrane Risk of Bias tool18 to assess the quality of 9 included RCT. Results are shown in figure 1B, C.

### Statistical analysis

The primary outcomes were serum calcium, PTH, and phosphorus levels. The secondary outcomes were levels of 25(OH)D and 1,25(OH)2D. Standardized difference in the means was used as the index of effect size. Heterogeneity among the studies was assessed by the Cochran Q and the I-square statistic. The Q statistic was defined as the weighted sum of the squared deviations of the estimates of all studies. p<0.10 was considered statistically significant for heterogeneity. For the I-square statistic, which indicated the percentage of the observed between-study variability due to heterogeneity, the suggested ranges are as follows: no heterogeneity (I2=0–25%), moderate heterogeneity (I2=25–50%), large heterogeneity (I2=50–75%) and extreme heterogeneity (I2=75–100%). The random-effect model (DerSimonian–Laird method) was performed to generate pooled estimates across studies for each outcome. A two-sided p value<0.05 was considered statistically significant. The leave-one-out approach was used to assess sensitivity of meta-analysis. All statistical analyses were performed using the statistical software Comprehensive Meta-Analysis, V.2.0 (Biostat, Englewood, New Jersey, USA).

## Results

### Literature search

Two hundred and fifty nine studies were identified through the database and reference list searches, and after removing duplicate records, 166 studies were screened for eligibility. Of those, 118 articles were excluded for lack of relevancy. After assessing 48 articles for full text reviewing, we excluded 39 studies for reasons like no outcome of interest (23), one-arm studies (10), comparison design did not meet inclusion criteria (5), and patients not on dialysis (1). Nine studies were chosen for the meta-analysis. The study selection flow chart is shown in figure 1A.

### Study characteristics

A total of nine RCT were included in the meta-analysis. The number of patients ranged from 19 to 60, with a mean or median age of 46–75 years. All studies recruited a majority of males, ranging from 37.5% to 76.9% (table 1). Detailed study design and selection criteria are listed in tables 1 and 2. The mean values of all primary and secondary outcomes pretreatment and post-treatment are summarized in table 3. The follow-up duration ranged from 6 weeks to 1 year. Patients in the treatment group had significantly higher levels of 25(OH)D and 1,25(OH)2D after treatment with cholecalciferol.

View this table:
[Table 1](/content/64/5/1050/T1)

Table 1 
Summary of basic characteristics of selected studies for meta-analysis

View this table:
[Table 2](/content/64/5/1050/T2)

Table 2 
Details of subject selection criteria of included studies

View this table:
[Table 3](/content/64/5/1050/T3)

Table 3 
Summary of primary and secondary outcomes for selected studies for meta-analysis

### Measures of primary outcomes

The six studies included in the evaluation of the treatment effect on serum calcium showed no heterogeneity among them (Q=2.1, p=0.830, I2=0%). There was no difference between the treatment and placebo groups (Pooled standardized difference in means=0.025, 95% CI=−0.233 to 0.282, p=0.851; figure 2A). For the PTH level, there was moderate heterogeneity across the six included studies (Q=7.6, p=0.179, I2=34.3%). The pooled results showed that the increase in the PTH level in the treatment group did not reach statistical significance, as compared to the placebo (Pooled standardized difference in means=0.021, 95% CI=−0.301 to 0.343, p=0.898; figure 2B). Patients treated with cholecalciferol had a significantly greater increase in the phosphorus level than those in the placebo group (Pooled standardized difference in means=0.299, 95% CI=0.009 to 0.589, p=0.044). No heterogeneity was found among the studies for phosphorus levels (Q=6.2, p=0.291, I2=18.9%; figure 2C).

![Figure 2](/https://d3hme472k3gd2d.cloudfront.net/content/jim/64/5/1050/F2.medium.gif)

[Figure 2](/content/64/5/1050/F2)

Figure 2 
Forest plots of treatment (cholecalciferol vs placebo/control) effects on (A) serum calcium, (B) PTH, and (C) phosphorus levels. PTH, parathyroid hormone.

### Measures of secondary outcomes

Heterogeneity was observed among the eight studies for 25(OH)D levels (Q=29.6, p<0.001, I2=76.4%), and among the seven studies for 1,25(OH)2D levels (Q=12.0, p=0.063, I2=49.8%). A significantly higher increase in 25(OH)D (Pooled standardized difference in means=2.903, 95% CI=2.265 to 3.542, p<0.001) and 1,25(OH)2D levels were observed, as compared to the placebo group (Pooled standardized difference in means=0.978, 95% CI=0.615 to 1.340, p<0.001; figure 3A, B).

### Sensitivity analysis

The leave-one-out sensitivity analyses for primary outcomes are shown in figure 3. Although the direction of association became negative for serum calcium when Marckmann *et al*21 was removed, the point estimate was close to 0 and no significant results were found (figure 4A). For the PTH level, the pooled standardized differences in means with Mose *et al*, Seibert *et al*, and Marckmann *et al* removed one at a time were quite opposite to the overall pooled results with all six RCTs included, but the point estimates were close to 0 and the p values remained statistically insignificant (figure 4B). In addition, Seibert *et al* had mild to moderate influences on the pooled results for phosphorus level, as it yielded a larger point estimate and statistically significant results when removed (figure 4C).

![Figure 3](/https://d3hme472k3gd2d.cloudfront.net/content/jim/64/5/1050/F3.medium.gif)

[Figure 3](/content/64/5/1050/F3)

Figure 3 
Forest plots for treatment (cholecalciferol vs placebo/control) effect on (A) 25(OH)D, and (B) 1,25 (OH) 2D levels.

![Figure 4](/https://d3hme472k3gd2d.cloudfront.net/content/jim/64/5/1050/F4.medium.gif)

[Figure 4](/content/64/5/1050/F4)

Figure 4 
Sensitivity analysis for the treatment effect on (A) serum calcium, (B) PTH, and (C) phosphorus levels. PTH, parathyroid hormone.

### Publication bias

Publication bias analysis was not performed as more than 10 studies were needed to detect a funnel plot asymmetry.24

## Discussion

Deficiency of vitamin D has been associated with an increased risk of cardiovascular mortality and decreased survival in patients with CKD.23 ,25 ,26 Therapeutic vitamin D supplementation is often associated with vitamin D toxicity, characterized by hypercalcemia, hyperphosphatemia, and over suppression of PTH, which might in turn increase the risk of cardiovascular diseases.23 ,27 ,28 We evaluated the efficacy and tolerability of vitamin D3 in patients with ESRD undergoing dialysis.

The current meta-analysis of 9 studies favors vitamin D3 supplementation. The treatment group showed a greater increase in 25(OH)D and 1,25(OH) 2D, as compared to the placebo group (p<0.001; figure 3A, B), without causing an increase in the serum calcium (p=0.851; figure 2A) or parathyroid hormone levels (p=0.896; figure 2B). In addition, patients treated with cholecalciferol had a significantly greater increase in phosphorus level than those in the placebo group (p=0.001; figure 2C). The sensitivity analysis indicates that the direction and magnitude of effect size did not change considerably for serum calcium and phosphorus levels. However, Delanaye *et al*17 and Armas *et al*22 might have influenced the overall results for PTH. The higher phosphate levels observed in our analysis could probably be due to elevated serum phosphate baseline levels, in addition to dietary factors. Nevertheless, the overall results show increases in 25(OH)D 1,25(OH)2D levels in patients with ESRD without any significant adverse events such as, hypercalcemia or changes in parathyroid hormone levels. Furthermore, serum phosphate levels should be carefully monitored in these patients.

A low vitamin D level is associated with increased mortality, secondary to hyperparathyroidism and cardiovascular diseases. In a cross-sectional analysis of 825 patients on consecutive hemodialysis, 78% had vitamin D deficiency, while 18% were considered severely deficient.3 Their results also demonstrated that calcium, phosphorus, and PTH levels correlated poorly with 25D and 1, 25D concentrations. Deficiency of calcitriol caused by impaired renal function is a main factor in the pathogenesis and pathophysiology of secondary hyperparathyroidism.29 There was also a report indicating that oral depot cholecalciferol could induce a significant decrease in the serum iPTH level, without changing the Ca, P, ratio of CaX P or urinary calcium creatinine rate in patients with stage 3 or 4 CKD.30 Conversely, cholecalciferol had been shown to increase the serum 25(OH) D and 1,25 (OH)2 D levels, while the serum calcium, phosphorus and iPTH levels were found to be decreased.4 It has also been found to reduce soluble Klotho levels, a marker of iPTH, while increasing the levels of 1,25 (OH) D levels.13 The current meta-analysis validates the results of the aforementioned studies. Further, vitamin D3 supplementation is found to be safe and efficacious at the doses used in individual studies included in this review.

Likewise, reports elsewhere also reveal that supplementation with cholecalciferol is safe and well tolerated.31 However, only 57% of patients have achieved recommended calcidiol levels, further suggesting dose-finding studies. Jean *et al* suggested that 10–30 µg/day of vitamin D supplementation is sufficient enough to correct most vitamin D deficiencies in patients on hemodialysis, without any evident toxicity.2 In fact, oral administration has several advantages, including significant cost-effectiveness, and optimal compliance over intravenous administration.32 All of the included studies utilized oral administration of vitamin D3; however, the doses varied widely among the studies (6000–200,000 IU/week). Wasse *et al*23 have used a very high dose of 200,000 IU/week of cholecalciferol for 3 weeks and indicated that 90.5% of the subjects achieved serum 25(OH) D concentrations of≥30 ng/mL, whereas a pharmacokinetic analysis revealed that 10,333 IU/week of cholecalciferol produced a steady state of 24 ng/mL of 25(OH) D with no apparent toxicities.22 The Kidney Diseases Outcomes Quality Initiative (KDOQI) guidelines recommend 50,000 IU/month to 50,000 IU/week of vitamin D2 which effectively increase 25(OH) D levels.19 Estimates of the vitamin D supplement required by patients on dialysis to give 25-OH-D levels >30 ng/mL are between 1800 and 5000 IU/day,33 which is within the range used in the studies included in the current review.

There are several studies showing different effects of ergocalciferol or cholecalciferol on the PTH level.34–36 Vitamin D2 (ergocalciferol) has been shown to be safe and sufficient to obtain and maintain optimal serum 25(OH)D concentrations and prevent vitamin D insufficiency in patients with CKD on dialysis.36 Similarly, vitamin D3 or cholecalciferol supplementation showed higher 25(OH)D, 1,25-dihydroxyvitamin D, and albumin levels, while reducing serum calcium and PTH levels in patients on hemodialysis.37 Existing evidence does not support the superiority of one or the other form of vitamin D in maintaining adequate levels of 25 (OH) D levels in patients on dialysis. Thus, natural or active vitamin D therapy plays a key role in reducing the secondary hyperparathyroidism associated with ESRD in patients undergoing long-term dialysis. However, it should be noted that besides raising 25-OH-D and 1,25-OH2-D levels and PTH suppression, cholecalciferol supplementation may have non-calciotriopic effects, as vitamin D receptors are expressed in a wide variety of other tissues, including the colon, breast and prostate.38 Evidences indicate that the extra renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D may have other significant biological roles as well.35

Efficacy of nutritional cholecalciferol in ESRD is often debated, as opposed to the active vitamin D analogs, and a limited number of meta-analysis exists in patients undergoing dialysis. Our current analysis is one of the few updated reviews in this field. Moreover, the strength of this review is that all the included studies were RCT, thus avoiding biases inherent with observational studies. The previously published meta-analyses mostly included prospective, observational studies in patients with CKD, regardless of their dialysis status.16 ,39 Nevertheless, our results are in agreement with other systematic reviews, where vitamin D supplementation has been found to improve clinical and biochemical end points.

There are several limitations to the current review, including the limited number of studies available for inclusion in the meta-analysis along with the small number of subjects enrolled in each study. Two studies20 ,22 did not use vitamin D status as a patient selection criterion. Most studies also excluded patients with hypercalcemia and hyperphosphatemia, but one study, Armas *et al*,22 did not impose such restrictions. While 8 of the 9 included studies used a placebo as a control intervention, Mieczkowski *et al*8 did not provide any treatment to the control group. All studies, except for that of Mieczkowski *et al*, used either radioimmunoassay or chemiluminescence to measure the levels of 1,25(OH)2D or 25(OH)D, while Mieczkowski *et al*8 have used a manual assay system. In addition, there was heterogeneity in the pre-existing active vitamin D use, or the use of phosphate binders and calcimimetics (like cinacalcet), which may be potential confounding factors. Moreover, a majority of the studies either did not adjust the dosage of pre-existing active vitamin D during the study, or totally excluded the patients who used them 3 months prior to the study. However, the limitations set on the use of phosphate binders were rather loose among the included studies. Furthermore, the dosages of cholecalciferol and dosing schedules also varied among studies. It is also possible that some studies might have had patients with secondary hyperparathyroidism due to vitamin D deficiency. Regardless, our results reveal increased 25(OH)D and 1,25(OH)2D levels after vitamin D3 supplementation, and further underscores the therapeutic role of vitamin D in maintaining mineral metabolism, preventing secondary hyperparathyroidism and thereby minimizing the cardiovascular risk in patients with ESRD.

In summary, the current analysis indicates that in patients undergoing dialysis for CKD, supplementation of D3 (cholecalciferol) increases serum levels of phosphorus, 25(OH)D, and 1,25(OH)2D, but did not increase serum levels of calcium and PTH, showing their efficacy in correcting vitamin D deficiency with minimal effects on serum calcium and PTH.

## Footnotes

*   Contributors ZL, SZ and CX are guarantors of integrity for the entire study. ZL and CX were involved in the study concepts and study design. CX and YL were involved in the definition of intellectual content, statistical analysis and data acquisition. ZL, CX and YL were involved in the literature research. ZL, CX and YL were involved in the manuscript preparation. ZL and CX were involved in the manuscript editing. ZL and SZ were involved in the manuscript review.

*   Competing interests None declared.

*   Provenance and peer review Not commissioned; externally peer reviewed.

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