Vitamin D Deficiency and Treatment Versus Risk of Infection in End-Stage Renal Disease Patients Under Dialysis

A Systematic Review and Meta-analysis

Guobin Su; Zhuangzhu Liu; Xindong Qin; Xu Hong; Xusheng Liu; Zehuai Wen; Bengt Lindholm; Juan-Jesus Carrero; David W Johnson; Nele Brusselaers; Cecilia Stålsby Lundborg

Disclosures

Nephrol Dial Transplant. 2019;34(1):146-156. 

In This Article

Materials and Methods

The methods were pre-specifed in a protocol that was registered with the PROSPERO International Prospective Register of Systematic Reviews (Supplementary data, Item 1; http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018084779).

Our systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.[22]

Search Strategy

We performed a systematic literature search to identify all studies evaluating vitamin D status or supplementation of vitamin D or VDRA in relation to infection-related outcomes (any infection, IRH or infection-related death) among patients undergoing dialysis treatment. The search terms included the relevant key terms: 'vitamin D' and 'dialysis' and 'infection' (Supplementary data, Item 2). The search was conducted by two independent researchers (Z.L. and X.Q.) using the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 12), PubMed (Item S2) (1946–December 2017), Embase (Elsevier; 1974–December 2017), Web of Science (1900–December 2017), Chinese National Knowledge Infrastructure (CNKI; 1979–December 2017), China Biology Medicine disc (CBM; 1976–December 2017) and WanFang Data Knowledge Service Platform (WanFang; 1998–December 2017).

Inclusion and Exclusion Criteria

Studies were included if they met the following criteria: (i) intervention studies [non-randomized intervention study or randomized controlled trial (RCT)], cohort study or case–control study; (ii) adult ESKD patients (age ≥18 years) undergoing haemodialysis (HD) or peritoneal dialysis (PD); (iii) reported at least one outcome of interest: risk of any infection, risk of IRH, infection-related mortality; (iv) presented data for different levels of serum 25(OH)D (the major circulating vitamin D metabolite) or (v) for medication studies, the intervention group received either nutritional vitamin D (D2/ergocalciferol and/or D3/cholecalciferol) supplements or a VDRA (paricalcitol, doxercalciferol, calcitriol, alfacalcidol, maxacalcitol and falecalcitriol) while the comparison group received placebo or no treatment. We excluded case reports, case series, editorials and review articles. Since the aim of this analysis was to compare outcomes for patients with high/normal versus low serum 25(OH)D levels, we also excluded studies that solely reported serum 25(OH)D as a continuous variable if original individual data were not accessible to permit categorization of serum 25(OH)D levels. There was no restriction of language or publication year. There was no restriction of sex or duration of follow-up time. In the case of multiple publications covering the same study population, we only included the report with the longer follow-up.

Exposure

The threshold for defining high/normal serum vitamin D levels, the type of vitamin D used (nutrient or activated form), dose and mode of delivery (oral or intravenous) varied among studies. In order to maximize the total study population, we included all formulations, regimens, vitamin D thresholds and dosing schedules.

Outcomes of Interest

The primary outcome was the composite relative risk (RR) of any infection (any non-hospitalized fatal infection, IRH or infection-related death). All infections were included regardless of their source (community-acquired infections or health care–associated infections) or site (respiratory tract infection, genitourinary infections, bloodstream infections or sepsis, abdominal infections, skin and soft tissue infections, cardiovascular infections, musculoskeletal infections, nervous system infections and device- or dialysis-related infections). The secondary outcomes included the RR of each of these individual infection-related outcomes.

Study Selection and Data Extraction

All the systematic search records from different databases were imported in ENDNOTE. After deduplication, eligible studies were listed and assessed independently by two reviewers (X.Q. and Z.L.) using pre-defined inclusion criteria. First, we excluded studies based on their titles and abstracts. Second, we excluded studies based on the inclusion criteria and listed the reasons for exclusion. Two authors (G.S. and Z.L.) used pre-defined forms to extract data from the studies, including information on region, study design, participants, concentration or level used as a cut-point to define vitamin D deficiency, the test methods, intervention details (types of vitamin D, modes of administration, dose, frequency and duration if applicable), comparison, outcomes, covariates, results and follow-up period. For each study, unadjusted RRs, odds ratios (ORs), hazard ratios (HRs) and incidence rate ratios were extracted, as well as risk assessments based on the most fully adjusted models. If different level groups [e.g. tertiles of 25(OH)D] were reported, the most extreme comparison, that is, the lowest versus highest level, was considered for the primary results. If the RR was not available in the studies, the numbers or incidences of the outcomes were extracted to calculate the RRs.

Quality Assessment

Two review authors (X. Q. and Z.L.) independently assessed the risk of bias of each included RCT using the Cochrane Collaboration's tool to assess sequence generation; allocation concealment; blinding of participants, staff and outcome assessors; completeness of outcome data and evidence of selective outcome reporting and other potential threats to validity. Risk of bias in cohort and case–control studies were assessed using the Newcastle–Ottawa Scale (NOS) tool:[23] selection of study participants (scores 0–4), comparability of subjects (scores 0–2) and exposure or outcome (scores 0–3), with the total score ranging from 0 to 9 (quality of study: low < 4; moderate ≥4–<7; high ≥7–<8). In the case of any disagreement, a third author (N.B.) also assessed the study.

Statistical Analyses

For each outcome measure of interest, random effects meta-analysis was conducted to pool RRs for the dichotomous composite outcome (any non-hospitalized fatal infection, IRH, infection-related mortality) in order to determine the effect of different levels of 25(OH)D (high/normal versus low) or according to the use of vitamin D versus placebo/no use.

HRs and RRs were considered interchangeable in the analyses. If studies only reported ORs, these were converted into RRs using the formula RR = OR/[(1 − P0) + (P0 * OR)], in which P0 was the event incidence in the control group.[24] This formula had a limitation of underestimating the variance of the RRs derived from the ORs.[25] Thus we performed a sensitivity analysis that excluded the studies with this transformation.

I 2 was used to measure heterogeneity across studies, which was categorized as low (0–50%), moderate (51–75%) or high (>75%). Heterogeneity was explored through subgroup analyses whereby results were stratified by the type of vitamin D (VDRA and vitamin D supplement), administration of vitamin D (oral, intravenous or mixed), type of dialysis therapy (HD or PD), different outcomes (risk of any infection, IRH or infection-related mortality) and study design. We performed additional empirical Bayes meta-regression models in studies addressing the use of vitamin D as the exposure. These included the type of dialysis therapy (HD or PD), type of administration (oral or intravenous) and study sample size (<500 or ≥500 participants).

The presence of small study effects and publication bias was evaluated by funnel plots and Egger regression asymmetry analysis.[26] All data analyses were performed using Stata 14.0 (StataCorp, College Station, TX, USA).

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