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Vitamin D Therapy in Adults With CKD: A Systematic Review and Meta-analysis

Wing-Chi G. Yeung, MBBS, MMed, Suetonia C. Palmer, MB ChB, PhD, Giovanni

F.M. Strippoli, MD, PhD, Benjamin Talbot, MBBS, Nasir Shah, MSc, MBBS, Carmel
M. Hawley, MBBS, MMedSci, Nigel D. Toussaint, MBBS, PhD, Sunil V. Badve,
MBBS, PhD.

PII: S0272-6386(23)00693-5
DOI: https://doi.org/10.1053/j.ajkd.2023.04.003
Reference: YAJKD 57919

To appear in: American Journal of Kidney Diseases

Received Date: 28 September 2022

Accepted Date: 24 April 2023

Please cite this article as: Yeung WCG, Palmer SC, Strippoli GFM, Talbot B, Shah N, Hawley CM,
Toussaint ND, Badve SV, Vitamin D Therapy in Adults With CKD: A Systematic Review and Meta-
analysis, American Journal of Kidney Diseases (2023), doi: https://doi.org/10.1053/j.ajkd.2023.04.003.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition
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© 2023 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.
Vitamin D Therapy in Adults With CKD: A Systematic Review and Meta-analysis

Wing-Chi G. Yeung1,2,3, MBBS, MMed; Suetonia C. Palmer4, MB ChB, PhD; Giovanni F.M.

Strippoli5,6, MD, PhD; Benjamin Talbot2,3, MBBS; Nasir Shah3, MSc, MBBS; Carmel M.

Hawley7,8,9, MBBS, MMedSci; Nigel D. Toussaint10,11, MBBS, PhD; Sunil V. Badve2,3,12,

MBBS, PhD.

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1 Department of Nephrology, Wollongong Hospital, Sydney, Australia.

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2 The George Institute for Global Health, Sydney, Australia.

3 Faculty of Medicine, University of New South Wales, Sydney, Australia.

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4 Department of Medicine, University of Otago, Christchurch, New Zealand.
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5 Sydney School of Public Health, University of Sydney, Sydney, Australia.

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6 Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.

7 Translational Research Institute, Brisbane, Queensland, Australia.

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8 Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.

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9 Australasian Kidney Trials Network, The University of Queensland, Brisbane, Australia

10 Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia.

11 Department of Medicine, University of Melbourne, Parkville, Australia.

12 Department of Nephrology, St George Hospital, Sydney, New South Wales, Australia.

Corresponding author

Dr Wing Chi Gigi Yeung

Department of Renal Medicine

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3-5 Dudley St, Wollongong NSW 2500, Australia

Email: [email protected]

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Abstract

Rationale & Objective: Vitamin D is widely used to manage chronic kidney disease-mineral

and bone disorder (CKD-MBD). We aimed to evaluate the effects of vitamin D therapy on

mortality, cardiovascular, bone, and kidney outcomes in adults with CKD.

Study Design: Systematic review of randomized controlled trials (RCT) with highly-sensitive

searching of MEDLINE, Embase, and CENTRAL, through 25 February 2023.

Setting & Study Populations: Adults with stage 3, 4, or 5 CKD, including kidney failure treated

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with dialysis. Recipients of a kidney transplant were excluded.

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Selection Criteria for Studies: RCTs with ≥3 months follow-up evaluating a vitamin D

compound.
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Data Extraction: Data were extracted independently by three investigators.
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Analytical Approach: Treatment estimates were summarized using random effects meta-
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analysis. Primary review endpoints were all-cause death, cardiovascular death, and fracture.

Secondary outcomes were major adverse cardiovascular events, hospitalization, bone mineral
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density, parathyroidectomy, progression to kidney failure, proteinuria, estimated glomerular

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filtration rate, hypercalcemia, hyperphosphatemia, biochemical markers of CKD-MBD, and

various intermediate outcome measures of cardiovascular disease. Risk of bias was assessed

using the Cochrane RoB 2 tool. Evidence certainty was adjudicated using GRADE.

Results: Overall, 128 studies involving 11,270 participants were included. Compared to placebo,

vitamin D therapy probably had no effect on all-cause death (relative risk [RR] 1.04; 95% CI

0.84 to 1.24); and uncertain effects on fracture (RR 0.68; 95% CI 0.37 to 1.23) and

cardiovascular death (RR 0.73; 95% CI 0.31 to 1.71). Compared to placebo, vitamin D therapy

lowered serum parathyroid hormone and alkaline phosphatase, but increased serum calcium.

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Limitations: Data were limited by trials with short-term follow-up, small sample size, and the

suboptimal quality.

Conclusions: Vitamin D therapy did not reduce the risk of all-cause death in people with CKD.

Effects on fracture, and cardiovascular, and kidney outcomes were uncertain.

Registration: Registered at PROSPERO with registration number CRD42017057691.

Index words: Chronic kidney disease–mineral and bone disorder, chronic kidney disease, bone

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mineral density, meta-analysis, kidney failure, vitamin D, secondary hyperparathyroidism

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Plain Language Summary

Chronic kidney disease (CKD) is associated with increased risk of death, cardiovascular disease,

and fractures. This excess risk is thought to be related to changes in bone and mineral

metabolism, leading to the development of CKD Mineral and Bone Disorder (CKD-MBD)

which is characterised by vascular calcification and reduced bone quality. Vitamin D is

commonly used in the treatment of this condition. We undertook a review of randomised

controlled trials examining the effect of vitamin D therapy in CKD. We found that vitamin D

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therapy affects serum biomarkers, including an increase in serum calcium. However, it probably

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has no effect on risk of all-cause death in CKD, and the effects on other clinical bone,

cardiovascular, and kidney outcomes are uncertain.

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Introduction

Chronic kidney disease (CKD) (defined as an estimated glomerular filtration rate [eGFR] of

less than 60 ml/min/1.73 m2) poses a significant health burden worldwide, with an estimated

global prevalence ranging between 11-13%.1-3 CKD is associated with increased risks of all-

cause and cardiovascular death. The excess cardiovascular disease burden and mortality in CKD

is largely due to the presence of ‘non-traditional’ risk-factors, and has been associated with

hyperparathyroidism, hyperphosphatemia, and arterial medial calcification, which are highly

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prevalent in CKD patients.4 As kidney function declines, abnormalities of mineral and bone

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metabolism occur due to impaired vitamin D activation and increased parathyroid hormone

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(PTH) levels. These changes lead to the development of CKD-Mineral and Bone Disorder
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(CKD-MBD), which is characterised by reduced bone quality and vascular and soft tissue
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calcification, leading to cardiovascular disease.5

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Vitamin D deficiency (25[OH]D level <25 nmol/L) or insufficiency (25-50 nmol/L) is

common in CKD with only 15-30% patients with CKD stages 3 to 5 having sufficient levels
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greater than 75 nmol/L.6 Low 25(OH)D levels are associated with increased risks of mortality,
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rapid decline of kidney function, and lower bone formation rate and trabecular mineralization

surface with increased fractures in CKD patients.7,8 The risk of fractures increases progressively

as eGFR decreases, with the highest incidence among people with kidney failure treated with

dialysis.9 Compared to the general population, the risk of hip fractures is increased

approximately 14-fold in people with kidney failure, and three-fold in people with CKD stage 3

and 4.10-12 Fractures associated with CKD are linked to excess hospitalization and mortality.13-17

The risk of cardiovascular events also increases as glomerular filtration rate (GFR)

declines.18 Elevated serum phosphate and FGF-23 levels have been associated with vascular

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calcification,19-21 which contributes to arterial stiffness,22 and left ventricular hypertrophy.23,24

Arterial medial calcification is more typically seen in CKD patients,25 and is a strong prognostic

marker of all-cause and cardiovascular death in CKD patients.26

The KDIGO 2017 Clinical Practice Guidelines for CKD-MBD recommend the use of

calcitriol or vitamin D analogs for the management of secondary hyperparathyroidism in patients

with kidney failure treated with dialysis, and severe and progressive hyperparathyroidism in

patients with CKD not receiving dialysis.27 The guideline also recommends correction of

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vitamin D deficiency and insufficiency. A previous meta-analysis of randomized controlled

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trials (RCTs) accumulating evidence through July 2007 showed that vitamin D therapy

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suppressed PTH in people with CKD and incurred hypercalcemia. The effects of vitamin D
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therapy on preventing patient-level outcomes including death and fracture were uncertain.28,29
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We aimed to conduct an updated systematic review of vitamin D therapy in adults with CKD
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with additional cardiovascular and renal outcome.

Methods
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This review updates a previous meta-analysis published in 2007 which examined whether
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vitamin D therapy improves biochemical markers of mineral metabolism and mortality

outcomes.30 In addition, this review also focuses on clinical bone, cardiovascular and kidney

outcomes. The review was conducted according to the Preferred Reporting Items for Systematic

Reviews and Meta-analyses (PRISMA) 2020 statement and review protocol (PROSPERO

CRD42017057691).31

Study selection & eligibility criteria

RCTs that evaluated a vitamin D compound in adults with stage 3, 4 or 5 CKD, including

CKD stage 5D (kidney failure treated with dialysis), were eligible. Trials with a treatment and

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follow-up duration of less than three months were excluded because they are unlikely to detect

treatment-related reduction in fractures or mortality. Trials evaluating vitamin D therapy in

recipients of a kidney transplant were ineligible. Randomized crossover trials were eligible for

inclusion if data from the first crossover period was available. Trials involving children were

excluded as pediatric bone disease is likely a distinct process with different treatment outcomes

such as bony deformities and poor growth.

Information sources, search strategy & selection process

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Relevant trials were identified using highly sensitive electronic searches of MEDLINE,

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Embase, and the Cochrane Central Register of Controlled Trials database (CENTRAL) with an

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English language restriction, from inception to 25 February 2023 (Table S1).
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Titles and abstracts of records retrieved through electronic searching were screened
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independently by two investigators (WCY and BT) for potentially eligible studies. All
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potentially eligible studies were then assessed in full text. Any disagreements were adjudicated

by a third investigator (SB).

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Data collection and risk of bias assessment

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The following data were extracted independently using a standardized form by three

investigators (WCY, BT and NS) including population characteristics, study design, risk of bias

and funding sources and outcomes.

Vitamin D compounds were classified as either nutritional or active, based on whether 1-

alpha-hydroxylation was required for activation in vivo. Of the active compounds, alfacalcidol

and calcitriol were classified as “established” given their long history of use compared to the

other newer synthetic vitamin D analogs (Table S2). Authors were contacted for any missing or

unclear information. The risk of bias of each included study was assessed using the Cochrane

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RoB2 assessment tool, adjudicated independently by at least two investigators.32

Data items

The primary review outcomes were all-cause death, cardiovascular death and fracture as

defined by trial investigators. Secondary review outcomes were major adverse cardiovascular

events (MACE), bone mineral density (BMD), parathyroidectomy, kidney failure requiring

dialysis, proteinuria, estimated glomerular filtration rate (eGFR), systolic blood pressure,

diastolic blood pressure, pulse wave velocity, left ventricular mass, hypercalcemia,

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hyperphosphatemia, surgical parathyroidectomy, biochemical markers of CKD-MBD (calcium,

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phosphate, calcium x phosphate product, PTH, alkaline phosphatase [ALP], bone specific ALP

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[b-ALP], fibroblast growth factor 23 [FGF-23], tartrate-resistant acid phosphatase [TRACP] 5b,
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procollagen type 1 N-terminal propeptide [P1NP]) and vitamin D levels (25-hydroxy-vitamin D
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[25(OH)D], 1,25-dihydroxy-vitamin D [1,25(OH)2D]). Investigator-specified definitions of

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hypercalcemia and hyperphosphatemia were used.

Synthesis methods
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Studies were categorized into five groups based on the interventions compared: (a) vitamin D
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versus placebo or no treatment; (b) vitamin D versus a different vitamin D compound; (c) same

vitamin D compound comparing different routes of administration, dose or frequency; (d)

vitamin D versus calcium; and (e) vitamin D versus cinacalcet.

For dichotomous outcomes, treatment effects were estimated as a risk ratio (RR) with 95%

confidence intervals (CI). For continuous variables, the mean difference in mean treatment

effect from baseline to last measurement between treatment groups was estimated together with

the 95% CI. The mean differences in treatment effects across all studies were summarized as a

mean difference (MD) or a standardized mean difference (SMD) for outcomes where unit

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measurements could not be summarized together with the 95% CI. Summary estimates were

obtained by a random-effects meta-analysis model using the restricted maximum likelihood

(REML) method. The Hartung-Knapp-Sidik-Jonkman (HKSJ) adjustment was used for estimate

of CIs, except in instances where heterogeneity was low and the Wald-type method provided a

more conservative estimate.33 In meta-analyses with two studies, both the HKSJ and Wald-type

distribution CIs are presented. For assessment of between-study variance, the generalized Q

statistic method was used. Heterogeneity in treatment estimates were expressed as I2 statistics

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and 95% CIs, with 75-100% defined as high, 50-75% moderate, and 0-50% low.34

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Where data were available, subgroup analyses were performed, including type of Vitamin D

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compound (nutritional versus active), severity of CKD (dialysis versus non-dialysis), and
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presence of secondary hyperparathyroidism (as defined by investigators) at baseline. We also
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assessed for differences in follow-up by dividing studies into two groups – a) duration 6 months
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or less, and b) greater than 6 months. Tests for subgroup differences were performed using a

random effect meta-regression estimated using REML and HKSJ methods.33 All analyses were
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undertaken using STATA version 15.0 (STATA, College Station, Texas).

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Evidence certainty assessment

Evidence certainty was adjudicated using Grading of Recommendations Assessment,

Development and Evaluation (GRADE).35 GRADE enables adjudication of evidence certainty

based on study risk of bias, imprecision in treatment estimates, inconsistency between study

estimates, indirectness of study results to the research question, and evidence of small study

effects. The evidence certainty was assessed as high, moderate, low, or very low across the

treatment estimate to derive an overall summary of evidence certainty.

Results

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Study selection & characteristics

Overall, 128 trials involving 11,270 participants proved eligible (Figure 1, Table S3). The

median study sample size was 50 participants (range 13-976) and the median follow-up was 24

weeks (range 12-260 weeks). The study mean age was 57.7 years. Eighty-four trials were

conducted in 7,242 participants with kidney failure treated with dialysis and 44 trials were

conducted in 4,028 participants with stage 3-5 CKD not treated with dialysis. A total of 70 trials

(6,339 participants) had an eligibility criterion of secondary hyperparathyroidism as defined by

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the investigators, and 26 trials (3,237 participants) included only those with 25(OH)D deficiency

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at baseline. The definition of this varied from a 25(OH)D level of <10 to <30 ng/mL. The

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primary endpoints in most eligible trials were biochemical endpoints. Characteristics of the 15
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trials excluded due to inadequate data are described in Table S4.
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Risk of bias
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Risk of bias assessment is summarized in Figures S1 and S2. Of the 128 included studies,

22 (18.3%) were deemed to be high risk for missing outcome data. There were some concerns
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(moderate-risk) in the randomization process of 74 studies (61.7%) and outcome measurement in

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51 studies (41.7%).

Study outcomes

All-cause and cardiovascular death

Compared to placebo, vitamin D therapy probably had little or no effect on all-cause death

(RR 1.04 [95% CI 0.84 to 1.24], moderate-certainty evidence) (Figure 2). Meta-regression

analysis revealed that treatment effects did not differ by type of vitamin D (p=0.5), CKD severity

(p=0.3), presence of secondary hyperparathyroidism at baseline (p=0.7) or length of follow-up

(p=0.8) (Table S5). There was no evidence that different routes or schedules of vitamin D

11

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therapy had different effects on all-cause death (Table 1).

Compared with placebo, vitamin D had no significant effect on cardiovascular mortality (RR

0.73 [95% CI 0.31 to 1.71], low-certainty evidence) (Figure 3). Meta-regression analysis

revealed that treatment effects did not differ by type of vitamin D (p=0.9), presence of secondary

hyperparathyroidism at baseline (p=0.5) or duration of follow-up (p=0.5). Other comparisons

are summarized in Table 1.

Fracture

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Compared with placebo, vitamin D therapy had no significant effect on fractures (RR 0.68

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[95% CI 0.37 to 1.23], moderate-certainty evidence) (Figure 4). Meta-regression revealed

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treatment effects did not differ by type of vitamin D (p=0.8). Only two studies reported fracture
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site and only one described the methodology of detecting fractures.36,37 No information was
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provided by any of the trials regarding the nature of the fracture (traumatic versus non-
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traumatic).

MACE
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Compared to placebo, vitamin D therapy had no significant effect on MACE (RR 0.94 [95%
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CI 0.62 to 1.42], moderate-certainty evidence). There was no evidence that type of vitamin D

therapy (p=0.35) or length of follow-up (p=0.49) modified the treatment effect. Results of other

comparisons are summarized in Table 2.

Bone mineral density

Five trials (472 participants) reported change in BMD, as measured by dual-energy x-ray

absorptiometry (DXA). Four trials compared vitamin D to placebo and one trial compared

intravenous to oral calcitriol. In the two trials evaluating active vitamin D, the results showed a

significantly greater increase in femoral and lumbar spine BMD after treatment compared to

12

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placebo. The results are summarized in Table S6. A meta-analysis could not be performed as the

reported outcome measures were different.

Cardiovascular, kidney and other clinical outcomes

Results are summarized in Table 2. Vitamin D had uncertain effects on all surrogate

cardiovascular endpoints. Three studies reported change in median BNP values which could not

be combined into a meta-analysis.38-40 There were no significant between-group differences

reported in any of the three studies.

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Compared to placebo, vitamin D therapy had uncertain effects on risks of kidney failure

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treated with dialysis (RR 0.97 [95% CI 0.48 to 1.98], low-certainty evidence) and eGFR (MD -

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0.81 mL/min [95% CI -1.75 to 0.12], low-certainty evidence). Twelve trials reported the
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outcome of proteinuria (Table S7). Of these, only four were able to be combined into a meta-
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analysis due to differences in outcome measurement and the effect was uncertain (Table 2). The
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effect of vitamin D on surgical parathyroidectomy and hospitalisation were uncertain.

Biochemical markers of CKD-MBD

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Compared to placebo, vitamin D treatment may increase serum calcium (SMD 0.27 [95% CI
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0.12 to 0.41], low-certainty evidence) and calcium X phosphate product (MD 2.85 mg2/dL2 [95%

CI 0.12 to 5.59], low-certainty evidence) (Table S8). Subgroup analysis showed a significant

difference between the effect of nutritional vitamin D (SMD 0.09 [95% -0.03 to 0.22]) and active

vitamin D (SMD 0.52 [95% CI 0.26 to 0.78]) on serum calcium (p=0.002).

Compared to placebo, vitamin D treatment may reduce serum PTH levels (MD -73.02 pg/mL

[95% CI -107.55 to -38.40], low-certainty evidence), and ALP levels (SMD -0.48 [95% CI -0.81

to -0.15], low-certainty evidence). Meta-regression revealed no difference between the

subgroups for effect on PTH (p=0.06) or ALP (p=0.6). In head-to-head trials, active vitamin D

13

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may lead to greater reduction in serum PTH levels than nutritional vitamin D (WMD -23.30

pg/mL [95% CI -45.75 to -0.85]; low-certainty evidence). Results of other comparisons are

summarized in Table S8. The effect of vitamin D on other bone turnover markers was uncertain

(Table S9).

Adverse events

Results are summarized in Table 3. Compared to placebo, vitamin D probably incurred

hypercalcemia (RR 1.75 [95% CI 1.13 to 2.72], moderate-certainty evidence). In the subgroup

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analysis, effect estimates were statistically different between trials involving active and

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nutritional vitamin D (p=0.004). Compared to placebo, active vitamin D probably incurred

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hypercalcemia (RR 2.62 [95% CI 1.76 to 3.90], moderate-certainty evidence), whereas
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nutritional vitamin D did not (RR 0.68 [95% CI 0.39 to 1.19], moderate-certainty evidence)
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(Figure 5). Effect estimates were not affected by CKD severity (p=0.2), presence of SHPT at
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baseline (p=0.6) or duration of follow-up (p=0.5). In head-to-head comparisons, active vitamin

D may have a greater risk of hypercalcemia than nutritional vitamin D (RR 3.48, [95% CI 1.07 to
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11.33], moderate-certainty evidence). Compared to cinacalcet, vitamin D increased the risk of

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hypercalcemia (RR 18.47 [95% CI 3.60 to 94.68], low-certainty evidence).

There was probably no difference in the risk of hyperphosphatemia when comparing vitamin

D and placebo (RR 0.96 [95% CI 0.75 to 1.22], moderate-certainty evidence). In the subgroup

analysis, treatment effect was not modified by type of vitamin D (p=0.9), CKD severity (p=0.8),

SHPT at baseline (p=0.6) or length of follow-up (p=0.8).

Discussion

In this updated systematic review with additional larger trials since 2007, there is now

moderate-certainty evidence that vitamin D therapy may have little or no effect on risks of on all-

14

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cause death in people with CKD. The effects on fracture, cardiovascular death and kidney

failure remain uncertain. Active vitamin D therapy, but not nutritional vitamin D, was associated

with hypercalcemia. There was low-certainty evidence that active vitamin D therapy may be

associated with increased BMD. Similar to findings from previous meta-analyses, this review

showed that vitamin D therapy reduces serum PTH and ALP levels compared to placebo.30,41

This meta-analysis highlights the ongoing paucity of RCTs examining the association

between vitamin D therapy and fracture risk in patients with CKD. Our study confirms the

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results of another recent meta-analysis evaluating the effect of vitamin D on fractures.42

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Although regularly prescribed for bone health in older adults, there is also little evidence that

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vitamin D supplementation reduces fracture risk in the general population.43,44 A recent DOPPS
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study of 41,677 haemodialysis patients found that active vitamin D use was not associated with
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risk of fracture.45
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BMD is closely linked to fracture risk in both the general population and CKD patients.46-48

The KDIGO 2017 Clinical Practice Guideline Update for CKD-MBD suggest the use of BMD
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testing in patients with CKD stages 3-5 to assess fracture risk.27,49 Our study suggests that active
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vitamin D therapy may increase BMD or slow down the rate of BMD loss compared to placebo

in non-dialysis CKD patients. In studies from the general population, eldecalcitol (an active

vitamin D compound) has been associated with a greater reduction in serum b-ALP, lower risk of

vertebral fractures and an increase in BMD compared to placebo.50-53 It is possible that active

vitamin D, which also causes greater PTH suppression in CKD patients compared to nutritional

compounds, could also improve BMD and fracture risk in CKD patients.

There is observational evidence that 25(OH)D levels are associated with mortality in patients

with CKD.54-56 A meta-analysis of 10 prospective studies showed that the relative risk of

15

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mortality per 25 nmol/L increase in serum 25(OH)D was 0.86 (95% CI 0.82 to 0.91).57 Another

meta-analysis of observational studies showed that CKD patients who received vitamin D had

lower mortality compared to those on no treatment (HR 0.74, 95% CI 0.67 to 0.82).58 The

SIMPLIFIED trial (ISRCTN15087616) is an RCT currently underway in the United Kingdom.59

It aims to assess the effect of cholecalciferol 60,000 IU fortnightly in 4200 haemodialysis

patients over 5.5 years, with the primary outcome being all-cause death. Active vitamin D

compounds such as paricalcitol may have a greater effect on mortality. In a cohort study

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involving 67,399 hemodialysis patients, those receiving paricalcitol had a lower mortality rate

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(0.180 per person-year) than those receiving calcitriol (0.223 per person-year).60 In contrast, our

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meta-analysis of RCTs showed no difference in all-cause mortality between vitamin D and
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placebo.
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Apart from its established role in bone metabolism, vitamin D has also been postulated to
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have paracrine effects on vascular function, the renin-angiotensin system and cardiovascular

health.61,62 To date, there have been no other systematic reviews and meta-analyses specifically
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evaluating the effect of vitamin D therapy on cardiovascular outcomes in CKD. One recent
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review examined various interventions for attenuating vascular calcification progression in

CKD,63 and found vitamin D had no effect. In a meta-analysis of RCTs conducted in the general

population, nutritional vitamin D did not have any effect on cardiovascular outcomes or all-cause

mortality.64 Similarly our meta-analysis found uncertain effects on cardiovascular death and

MACE. There have been other meta-analyses of RCTs showing active vitamin D may reduce in

proteinuria in CKD patients,65-67 and more specifically in patients with diabetic kidney

disease,68,69 and IgA nephropathy.70 The selection criteria for these systematic reviews were

different to our current study and included studies of CKD stage 2, paediatric and kidney

16

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transplant patients, as well as studies with a treatment duration of less than 12 weeks.

There are several limitations to this study. The majority of included trials had unclear or high

risk of bias in more than one domain, with relatively small sample sizes and short duration of

follow up. Overall, the quality of evidence was low to moderate. This limited the ability of the

review to assess the true effect of vitamin D. Few trials reported fracture data with limited

information on methodology of detection, fracture site or whether it was traumatic versus non-

traumatic. Some trials reported median serum PTH values which we were unable to include in

of
our meta-analysis. Although we made efforts to contact their respective original authors, we

ro
were unable to obtain any additional data for analysis. This places our review at risk of outcome

-p
reporting bias. There were fifteen trials which met inclusion criteria but were excluded from the
re
analysis due to inadequate data. The majority were of short duration (median 12 weeks) and
lP

none of them reported important clinical outcomes. The exclusion of these trials is unlikely to
na

have affected the results of this review. There were also trials in which vitamin D compounds

were given to both arms as part of standard care which may have masked the effect of vitamin D
ur

on study outcomes. There was significant heterogeneity in investigator-defined thresholds for

Jo

hypercalcemia, hyperphosphatemia and hyperparathyroidism, which may have affected the

validity of the results. A high attrition rate (>20%) observed in some studies may have led to

reduced ability to evaluate true treatment effects. Due to infrastructural constraints, we applied

an English language restriction to our literature search which may have introduced publication

bias.

Since 2007, there have been several meta-analyses on vitamin D compounds in CKD. These

have generally focused on specific outcomes such as PTH,41 FGF-23,71 mortality,72 and

fractures.42 In contrast, this review is much broader and allows a more comprehensive

17

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uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2023. Elsevier Inc. Todos los derechos reservados.
understanding of treatment effects of vitamin D in people with CKD. Importantly, it highlights

the paucity of long-term data on clinically meaningful patient-centered outcomes in this area.

This is slowly changing with trials published in the last five years,73,74 reflecting the growing

recognition of limitations in extrapolating findings from surrogate biochemical endpoints on

clinical practice. This review was the first to systematically stratify the analysis of placebo trials

into nutritional and active vitamin D, demonstrating a clear difference in biochemical effects.

We also performed additional subgroup analysis according to CKD severity and the presence of

of
hyperparathyroidism at baseline. Future research examining the effect of vitamin D compounds

ro
on clinical outcomes in CKD patients with and without hyperparathyroidism is required.

-p
There is no evidence that vitamin D therapy prevents all-cause death, cardiovascular death or
re
fracture in adults with chronic kidney disease. Active vitamin D therapy may increase BMD, but
lP

the effect was uncertain. Vitamin D therapy effectively reduced serum PTH and ALP in patients
na

with CKD, but active compounds increased the risk of hypercalcemia. More RCT data is

required to study the effect on fractures, cardiovascular risk, BMD and hospitalization.
ur
Jo

Supplementary Material
Figure S1. Summary risk of bias
Figure S2. Individual study risk of bias assessed using the Cochrane RoB2 tool
Table S1. Literature search strategy
Table S2. Vitamin D compounds
Table S3. Included trial characteristics
Table S4. Trials excluded due to inadequate data for meta-analysis
Table S5. Subgroup analyses of primary outcomes in trials comparing vitamin D and placebo or
no treatment
Table S6. Summary of bone mineral density results
Table S7. Trials reporting proteinuria
Table S8. Summary of trial results for mean difference in serum calcium, phosphate, calcium
phosphate product, PTH and vitamin D levels after Vitamin D therapy in people with chronic
kidney disease
Table S9. Summary of trial results for mean difference in serum bone turnover markers after
Vitamin D therapy in people with CKD

18

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Article Information
Authors' Contributions: research idea and study design: WY, SB, SP, GS; data acquisition:
WY, BT, NS; data analysis/interpretation: WY, SB, SP, GS; statistical analysis: WY, SP, GS;
supervision or mentorship: CH, NT. Each author contributed important intellectual content
during manuscript drafting or revision and agrees to be personally accountable for the
individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity
of any portion of the work, even one in which the author was not directly involved, are
appropriately investigated and resolved, including with documentation in the literature if
appropriate.
Support: None.
Financial Disclosure: The authors declare that they have no relevant financial interests.
Peer Review: Received September 28, 2022. Evaluated by 2 external peer reviewers, with direct
editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief.

of
Accepted in revised form April 24, 2023.

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Table 1. Summary of primary outcomes – fractures, all-cause and cardiovascular mortality.
Outcome analysed Studies Intervention Control Relative risk (95% CI) I2 Certainty of
(Intervention vs Control) reporting event rate n/N event rate (95% CI) evidence
outcome (n) n/N (GRADE)^
All-cause mortality
Vitamin D vs placebo 26 167/1574 154/1471 1.04 (0.84 to 1.24) 0% (0 to 27) Moderate
- Nutritional vitamin D vs placebo 16 63/677 64/582 0.82 (0.55 to 1.23) 0%
- Active vitamin D vs placebo 10 104/897 90/889 1.12 (0.93 to 1.35) 0%
Active vs nutritional vitamin D 2 1/73 2/73 0.76 (0.05 to 10.81)* 34% (0 to 87) Low
HKSJ CI: 0.76 (0.00 to
2.3e+07)
New vs established active vitamin D 1 2/44 1/47 2.14 (0.20 to 22.74) - Low

f
IV vs PO route 2 2/26 0/25 2.88 (0.32 to 26.01)* 0% (0 to 0) Low

oo
HKSJ CI: (1.73 to 4.79)
High vs low dose 1 1/22 0/21 2.87 (0.12 to 66.75) - Low

r
High vs low frequency 1 1/60 1/60 1.00 (0.06 to 15.62) - Low

-p
Vitamin D vs calcium 2 3/41 1/30 1.19 (0.08 to 17.54)* 46% (0 to 89) Very low
HKSJ CI: (0.00 to 4.4e+07)

re
Vitamin D vs cinacalcet 4 18/482 14/484 1.14 (0.37 to 3.48) 0% (0 to 66) Low
Cardiovascular mortality

lP
Vitamin D vs placebo 5 18/709 26/691 0.73 (0.31 to 1.71) 0% (0 to 64) Low
- Nutritional vitamin D vs 2 10/177 14/172 0.51 (0.08 to 3.42) 66%

na
placebo HKSJ CI: 0.51 (0.00 to
1.1e+05)
- Active vitamin D vs placebo 3 8/532 12/519 0.66 (0.18 to 2.45) 0%
ur
Fractures
Vitamin D vs placebo 8 14/816 23/796 0.68 (0.37 to 1.23) 0% (0 to 32) Moderate
Jo
- Nutritional vitamin D vs 3 2/90 7/90 0.46 (0.01 to 21.32) 18%
placebo
- Active vitamin D vs placebo 5 12/726 16/706 0.74 (0.42 to 1.28) 0%
Abbreviations: IV – intravenous; PO – oral.
* Pooled estimate from random-effects model, with Wald-type distribution CIs. For meta-analyses with 2 studies, both the Wald-type distribution
and Hartung-Knapp-Sidik-Jonkman (HKSJ) CIs are given.
^ GRADE Working Group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there
is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of
effect.

25

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Table 2. Summary of trial results for cardiovascular, kidney and other clinical outcomes after Vitamin D therapy in people
with chronic kidney disease
Outcomes Studies No. of Relative risk or mean p-value I2 Certainty of
reporting participants difference in change score (95% CI) evidence
outcome (n) (n) (95% CI) (GRADE)^
Major cardiovascular events (MACE)
Vitamin D vs placebo 10 1887 RR 0.94 (0.62 to 1.42) 0.8 2% (0 to 54) Moderate
- Nutritional vitamin D vs placebo 5 568 RR 0.86 (0.51 to 1.46) 0.5 0%
- Active vitamin D vs placebo 5 1319 RR 0.46 (0.09 to 2.29) 0.3 44%
Active vs nutritional vitamin D 3 460 RR 0.71 (0.30 to 1.70) 0.2 0% (0 to 27) Very low
New vs established active vitamin D 1 25 RR 0.31 (0.01 to 6.94) 0.5 - Very low

f
Vitamin D vs calcium 1 47 RR 3.13 (0.13 to 73.01) 0.5 - Very low

oo
Vitamin D vs cinacalcet 3 654 RR 0.93 (0.02 to 49.78) 0.9 83% (0 to 95) Very low
Systolic blood pressure (mmHg)

r
Vitamin D vs placebo 10 844 MD -0.50 (-3.31 to 2.31)* 0.7 0% (0 to 0) Low

-p
- Nutritional vitamin D vs placebo 5 369 MD -0.31 (-4.62 to 3.99)* 0.9 0%
- Active vitamin D vs placebo 5 475 MD -0.64 (-4.34 to 3.06)* 0.7 0%

re
Active vs nutritional vitamin D 2 155 MD 0.68 (-6.52 to 7.88)* 0.9 0% (0 to 0) Low
HKSJ CI: (-18.98 to 20.34) 0.7

lP
New vs established active vitamin D 1 80 MD 0.00 (-14.75 to 14.75) 0.9 - Low
Diastolic blood pressure (mmHg)
Vitamin D vs placebo 9 821 MD -0.26 (-2.20 to 1.67)* 0.8 0% (0 to 0) Low

na
- Nutritional vitamin D vs placebo 4 369 MD 0.58 (-2.28 to 3.43)* 0.7 0%
- Active vitamin D vs placebo 3 452 MD -0.97 (-3.59 to 1.66)* 0.5 0%
ur
Active vs nutritional vitamin D 2 155 MD 1.57 (-4.24 to 7.39)* 0.6 0% (0 to 0) Low
HKSJ CI: (-6.36 to 9.50) 0.2
Jo
New vs established active vitamin D 1 80 MD 1.00 (-8.41 to 10.41) 0.8 - Low
Pulse wave velocity (m/s)
Vitamin D vs placebo 7 454 MD -0.55 (-1.59 to 0.49) 0.3 49% (0 to 81) Low
- Nutritional vitamin D vs placebo 4 246 MD -0.79 (-2.29 to 0.72) 0.2 45%
- Active vitamin D vs placebo 3 208 MD -0.05 (-3.29 to 3.19) 0.9 43%
Active vs nutritional vitamin D 1 80 MD -0.40 (-2.48 to 1.68) 0.7 - Low
Left ventricular mass index (g/m2)
Vitamin D vs placebo 7 428 MD 0.41 (-0.33 to 1.15) 0.2 0% (0 to 49) Low
- Nutritional vitamin D vs placebo 4 176 MD -0.06 (-8.07 to 7.95) 0.9 0%
- Active vitamin D vs placebo 3 252 MD 0.42 (-0.04 to 0.89) 0.06 0%
Estimated glomerular filtration rate (mL/min/1.73m2)
Vitamin D vs placebo 15 1406 MD -0.97 (-1.81 to -0.13) 0.03 99% (87 to Low
100)
- Nutritional vitamin D vs placebo 3 245 MD 0.31 (-0.57 to 1.18) 0.3 0%
- Active vitamin D vs placebo 10 1161 MD -1.12 (-2.10 to -0.14) 0.03 99%
Active vs nutritional vitamin D 1 115 MD 0.07 (-0.44 to 0.57) 0.8 - Low

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 New vs established active vitamin D 2 115 MD 0.05 (-0.45 to 0.56)* 0.8 0% (0 to 80) Low
HKSJ CI: (-0.14 to 0.25) 0.2
Urine albumin/creatinine ratio (mg/mmol)
Vitamin D vs placebo 3 132 MD -0.12 (-0.60 to 0.37)* 0.6 0% (0 to 0) Low
- Nutritional vitamin D vs placebo 1 29 MD -0.25 (-1.22 to 0.72)* 0.6 -
- Active vitamin D vs placebo 2 103 MD -0.07 (-0.63 to 0.49)* 0.8 0%
HKSJ CI: (-1.12 to 0.98) 0.6
Active vs nutritional vitamin D 1 40 MD 0.04 (-0.81 to 0.89) 0.9 - Low
Progression to dialysis
Vitamin D vs placebo 5 615 RR 0.97 (0.48 to 1.98) 0.9 0% (0 to 46) Low
- Nutritional vitamin D vs placebo 1 97 RR 0.78 (0.22 to 2.74) 0.8 0%
- Active vitamin D vs placebo 4 518 RR 1.14 (0.36 to 3.63) 0.9 0%

f
Active vs nutritional vitamin D 1 204 RR 0.83 (0.34 to 2.02) 0.7 - Low

oo
Hospitalisation
Vitamin D vs placebo 4 506 0.82 (0.19 to 3.48) 0.7 48% (0 to 84) Low

r
- Nutritional vitamin D vs placebo 3 446 1.28 (0.90 to 1.81) 0.4 0%

-p
- Active vitamin D vs placebo 1 60 0.20 (0.05 to 0.84) 0.03 -
Active vs nutritional vitamin D 1 204 0.30 (0.06 to 1.40) 0.1 - Low

re
Vitamin D vs cinacalcet 1 324 0.56 (0.40 to 0.78) 0.001 - Low
Parathyroidectomy

lP
Vitamin D vs placebo 2 140 0.82 (0.06 to 12.02)* 0.9 63% (0 to 93) Very low
HKSJ CI: (0.00 to 3.0e+07)

na
Vitamin D vs cinacalcet 1 312 2.96 (0.12 to 72.16) 0.5 - Low
Abbreviations: IV – intravenous; PO – oral.
* Pooled estimate from random-effects model, with Wald-type distribution CIs. For meta-analyses with 2 studies, both the Wald-type
ur
distribution and Hartung-Knapp-Sidik-Jonkman (HKSJ) CIs are given.
Jo

27

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Table 3. Summary of trial results for adverse events.
Outcomes Studies No. of Relative risk (95% CI) I2 Certainty of
reporting participants (95% CI) evidence
outcome (n) (n) (GRADE)^
Hypercalcemia
Vitamin D vs placebo 28 3561 1.75 (1.13 to 2.72) 26% (0 to 54) Moderate
- Nutritional vitamin D vs placebo 11 906 0.68 (0.39 to 1.19) 0%
- Active vitamin D vs placebo 17 2655 2.62 (1.76 to 3.90) 0%
Active vs nutritional vitamin D 5 295 3.48 (1.07 to 11.33) 0% (0 to 35) Moderate
New vs established active vitamin D 11 795 0.96 (0.81 to 1.13) 0% (0 to 44) Moderate
IV vs PO route 4 396 0.99 (0.48 to 2.04) 29% (0 to 78) Moderate
High vs low dose 1 43 3.82 (0.91 to 15.95) - Low

f
oo
High vs low frequency 4 234 0.80 (0.21 to 2.95) 22% (0 to 75) Low
Vitamin D vs calcium 1 50 1.50 (0.86 to 2.63) - Low
Vitamin D vs cinacalcet 2 592 18.47 (3.60 to 94.68)* 0% (0 to 0) Moderate

r
HKSJ CI: (4.17 to 81.68)

-p
Hyperphosphatemia
Vitamin D vs placebo 8 1241 0.96 (0.75 to 1.22) 0% (0 to 52) Moderate

re
- Nutritional vitamin D vs placebo 5 567 0.90 (0.77 to 1.06) 0%
- Active vitamin D vs placebo 3 674 1.55 (0.26 to 9.26) 45%

lP
Active vs nutritional vitamin D 1 115 2.04 (0.74 to 5.58) - Low
New vs established active vitamin D 4 526 0.97 (0.77 to 1.22) 0% (0 to 68) Moderate

na
IV vs PO route 2 42 0.75 (0.50 to 1.13) 0% (0 to 67) Moderate
HKSJ CI: (0.09 to 5.96)
High vs low frequency 6 293 0.89 (0.48 to 1.67)* 0% (0 to 7) Low
ur
Vitamin D vs calcium 2 97 3.08 (1.22 to 7.81)* 0% (0 to 0) Low
HKSJ CI: (0.35 to 27.36)
Jo
Vitamin D vs cinacalcet 1 268 4.00 (0.45 to 35.32) - Low
Abbreviations: IV – intravenous; PO – oral.
* Pooled estimate from random-effects model, with Wald-type distribution CIs. For meta-analyses with 2 studies, both the Wald-type
distribution and Hartung-Knapp-Sidik-Jonkman (HKSJ) CIs are given.

28

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Figure 1. PRISMA flow diagram for new systematic reviews which included searches of
databases and registers only.

Figure 2. Forest plot summarising all-cause death in trials comparing vitamin D to placebo or no
treatment.

Figure 3. Forest plot summarising cardiovascular death in trials comparing vitamin D to placebo
or no treatment.

Figure 4. Forest plot summarising fracture outcomes in trials comparing vitamin D to placebo or
no treatment.

Figure 5. Forest plot summarising hypercalcemia in trials comparing vitamin D to placebo or no

treatment.

of
ro
-p
re
lP
na
ur
Jo

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 Identification of studies via databases and registers

Records removed before

screening:
Identification

Duplicate records removed

Records identified from:
(n = 2515)
Databases (n = 4928)
Records marked as ineligible
Registers (n = 769)
by automation tools (n = 0)
Records removed for other
reasons (n = 0)

Records excluded after review of

Records screened
title and abstract
(n = 3182)
(n = 2877)

of
Reports sought for retrieval Reports not retrieved
(n = 305) (n = 0)
Screening

ro
Reports assessed for eligibility
-p
Reports excluded (n = 147):
• Follow-up duration <12 weeks (n = 53)
re
(n = 305)
• Included CKD Stage 1-2 patients (n = 17)
• Data from first period of crossover study not
available (n = 11)
lP

• Paediatric or transplant (n = 14)

• Inadequate data for analysis (n = 15)
• Other (n = 37)
na
ur

Studies included (n = 128):

Reports of included studies a) Vitamin D vs placebo or no treatment (n = 75)
Included

(n = 158) • Nutritional vitamin D vs placebo (n = 39)

Jo

Studies included in review • Active vitamin D vs placebo (n = 36)

(n = 128) b) Vitamin D vs other vitamin D (n = 28)
• Nutritional vs nutritional (n = 1)
• Active vs nutritional (n = 10)
• Active vs active
§ New vs established (n =14)
§ Established vs established (n = 2)
§ New vs new (n = 1)
b) Same vitamin D in different route / dose /
frequency (n = 18)
c) Vitamin D vs calcium (n = 3)
d) Vitamin D vs cinacalcet (n = 4)

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 Control Vitamin Risk Ratio %
Comparison and Study ID n/N D n/N (95% CI) Weight

Nutritional Vitamin D vs Placebo

Morrone 2022 33/143 28/141 1.16 (0.74, 1.82) 20.64
Brimble 2022 4/34 12/31 0.30 (0.11, 0.84) 3.95
Delanaye 2013 6/22 5/21 1.15 (0.41, 3.19) 3.92
Li 2014 10/62 2/34 2.74 (0.64, 11.80) 1.93
Gregorio 2021 2/18 3/14 0.52 (0.10, 2.69) 1.52
Merino 2015 3/47 2/47 1.50 (0.26, 8.57) 1.36
Matuszkiewicz-Rowinska 2022a 1/31 2/31 0.50 (0.05, 5.23) 0.75
Alshahawey 2021 1/30 1/30 1.00 (0.07, 15.26) 0.55
Hewitt 2013 1/30 1/30 1.00 (0.07, 15.26) 0.55
Bhan 2015 1/69 1/36 0.52 (0.03, 8.10) 0.55

f
oo
Barshadoust 2018 0/20 3/20 0.14 (0.01, 2.60) 0.49
Shirazian 2013 0/25 1/25 0.33 (0.01, 7.81) 0.41

r
Massart 2014 0/26 1/29 0.37 (0.02, 8.71) 0.41

-p
Ramirez-Sandoval 2019 0/29 1/29 0.33 (0.01, 7.86) 0.41
Levin 2017b 1/29 0/30 3.10 (0.13, 73.14) 0.41

re
Obi 2020 0/62 1/34 0.19 (0.01, 4.43) 0.41
Subgroup, REML+HKSJ
2
(I = 0.0%, p = 0.6)
63/677 lP 64/582 0.82 (0.55, 1.23) 38.27
na
Active Vitamin D vs Placebo
Shoji 2018 89/488 80/476 1.09 (0.82, 1.43) 54.74
ur

Memmos 1981 3/31 3/33 1.06 (0.23, 4.88) 1.77

Jo

Matuszkiewicz-Rowinska 2022b 3/31 2/31 1.50 (0.27, 8.36) 1.39

Hamdy 1995 4/89 1/87 3.91 (0.45, 34.29) 0.87
Coyne 2006 2/107 1/113 2.11 (0.19, 22.96) 0.72
Karalliedde 2022 1/72 1/68 0.94 (0.06, 14.80) 0.54
Delmez 2000 0/7 1/8 0.38 (0.02, 7.96) 0.44
Moe 2001 1/17 0/15 2.67 (0.12, 60.93) 0.42
Coburn 2004 0/27 1/28 0.35 (0.01, 8.12) 0.41
Levin 2017a 1/28 0/30 3.21 (0.14, 75.61) 0.41
Subgroup, REML+HKSJ 104/897 90/889 1.12 (0.93, 1.35) 61.73
2
(I = 0.0%, p > 0.9)

Heterogeneity between groups: p = 0.138

Overall, REML+HKSJ 167/1574 154/1471 1.04 (0.87, 1.24) 100.00
2
(I = 0.0%, p = 0.9)

.1 1 10
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 Vitamin Control Risk Ratio %
Study ID D n/N n/N (95% CI) Weight

Morrone 2022 9/143 8/141 1.11 (0.44, 2.79) 42.73

of
ro
Shoji 2018 7/488 11/476 0.62 (0.24, 1.59) 41.31

-p
re
lP
Brimble 2022 1/34 6/31 0.15 (0.02, 1.19) 8.58

na
Moe 2001 1/17 0/15 2.67 (0.12, 60.93) 3.72

ur
Jo
Coburn 2004 0/27 1/28 0.35 (0.01, 8.12) 3.65
Overall, REML+HKSJ 18/709 26/691 0.73 (0.31, 1.71) 100.00
2
(I = 0.2%, p = 0.4)

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Comparison Vitamin Control Risk Ratio %
and Study ID D n/N n/N (95% CI) Weight

Nutritional Vitamin D vs Placebo

Brimble 2022 1/34 2/31 0.46 (0.04, 4.78) 7.93
Massart 2014 0/26 5/29 0.10 (0.01, 1.74) 5.40
Hewitt 2013 1/30 0/30 3.00 (0.13, 70.83) 4.38
Subgroup, REML+HKSJ 2/90 7/90 0.46 (0.01, 21.32) 17.71

f
oo
2
(I = 18.0%, p = 0.3)

- pr
re
Active Vitamin D vs Placebo
Shoji 2018 9/488
lP 12/476 0.73 (0.31, 1.72) 59.90
Thadhani 2011 1/115 2/112 0.49 (0.04, 5.29) 7.69
na

Baker 1986 1/38 1/38 1.00 (0.06, 15.41) 5.85

ur

Przedlacki 1995 0/13 1/12 0.31 (0.01, 6.94) 4.53

Jo

Karalliedde 2022 1/72 0/68 2.84 (0.12, 68.44) 4.32

Subgroup, REML+HKSJ 12/726 16/706 0.74 (0.42, 1.28) 82.29
2
(I = 0.0%, p = 0.9)

Heterogeneity between groups: p = 0.607

Overall, REML+HKSJ 14/816 23/796 0.68 (0.37, 1.23) 100.00
2
(I = 0.0%, p = 0.8)

.1 10 100
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 Vitamin Control Risk Ratio %
Comparison and Study ID D n/N n/N (95% CI) Weight

Nutritional Vitamin D vs Placebo

Brimble 2022 4/34 6/31 0.61 (0.19, 1.95) 6.97
Morrone 2022 2/143 8/141 0.25 (0.05, 1.14) 5.00
Popovtzer 1992 3/22 2/19 1.30 (0.24, 6.96) 4.39
Hewitt 2013 3/30 2/30 1.50 (0.27, 8.34) 4.26
Mose 2014 1/32 5/32 0.20 (0.02, 1.62) 3.16
Birkenhager-Frenkel 1995 1/13 3/12 0.31 (0.04, 2.57) 3.08
Bhan 2015 3/69 1/36 1.57 (0.17, 14.51) 2.85
Ramirez-Sandoval 2019 2/29 1/29 2.00 (0.19, 20.86) 2.62
Massart 2014 1/26 1/29 1.12 (0.07, 16.95) 2.04
Gregorio 2021 1/18 0/14 2.37 (0.10, 54.08) 1.59

f
Kumar 2017 0/58 1/59 0.34 (0.01, 8.15) 1.55

oo
Subgroup, REML+HKSJ 21/474 30/432 0.68 (0.39, 1.19) 37.52
2
(I = 0.0%, p = 0.7)

r
-p
Active Vitamin D vs Placebo re
Martin 1998 27/401 14/417 2.01 (1.07, 3.77) 11.37
Przedlacki 1995 5/13 3/12 1.54 (0.46, 5.09) 6.78
lP
Hamdy 1995 14/89 3/87 4.56 (1.36, 15.32) 6.69
Delmez 2000 3/7 3/8 1.14 (0.33, 3.94) 6.53
na

Baker 1986 6/38 2/38 3.00 (0.65, 13.94) 4.98

Moe 2001 4/16 2/15 1.88 (0.40, 8.78) 4.94
Wang 2014 13/30 1/30 13.00 (1.81, 93.22) 3.47
ur

Coburn 2004 1/27 1/28 1.04 (0.07, 15.76) 2.04

Jo

Akizawa 2004 70/150 0/26 25.21 (1.61, 394.90) 2.00

Memmos 1981 16/27 0/30 36.54 (2.30, 581.14) 1.98
Sprague 2016 6/285 0/144 6.59 (0.37, 116.18) 1.86
Thadhani 2011 3/115 0/112 6.82 (0.36, 130.52) 1.77
Zoccali 2014 2/44 0/44 5.00 (0.25, 101.25) 1.71
Coyne 2006 2/107 0/113 5.28 (0.26, 108.68) 1.69
Rix 2004 1/18 0/18 3.00 (0.13, 69.09) 1.58
Ross 2008 1/61 0/26 1.31 (0.05, 31.06) 1.56
Levin 2017a 1/39 0/40 3.08 (0.13, 73.27) 1.55
Subgroup, REML+HKSJ 175/1467 29/1188 2.62 (1.76, 3.90) 62.48
2
(I = 0.0%, p = 0.6)

Heterogeneity between groups: p = 0.000

Overall, REML+HKSJ 196/1941 59/1620 1.75 (1.13, 2.72) 100.00
2
(I = 25.6%, p = 0.1)

.1 1 10
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