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

Sidebar

Supplementary Item 1

Project Title: Vitamin D status and related treatment and the risk of infection in end stage renal disease patients under dialysis: a systematic review and meta-analysis

Background/Rationale

Infection is the second leading cause of death in patients with chronic kidney disease[1,2]. Due to impaired renal function and 1α-hydroxylase deficiency, vitamin D deficiency is widespread among patients with CKD, particularly in those under dialysis[3]. Observational studies in recent years have attempted to link vitamin D deficiency with the increased risk of infection and the elevated infection-related mortality in dialysis patients [4,5,6]. A potential mechanism of vitamin D in the protection against pathogens is 25-hydroxy vitamin D (25(OH)D) supports induction of antimicrobial peptides in response to both viral and bacterial stimuli[7]. Besides, vitamin D metabolites have also been reported to induce innate antimicrobial effect or mechanisms, including induction of autophagy and synthesis of reactive nitrogen intermediates and reactive oxygen intermediates.[8]

While vitamin D deficiency seems to be associated with higher infection-related outcomes, other observational studies in those under dialysis have also shown that vitamin D users have lower infection-related hospitalization (IRH) and lower infection-mortality than non-users[9,10]. If associations are causal, this opens perspectives for vitamin therapy in this high-risk population. Although several systematic reviews have been done to investigate the effect of vitamin D in dialysis patients [11,12,13,14], none of these have focused on vitamin D on infection-related outcomes in this population.

Here, we evaluate the impact of vitamin D status on infection-related outcomes, and further to explore whether use of vitamin D affect these outcomes in end stage renal disease (ESRD) patients under dialysis by the means of systematic review, to highlight areas where further original research is required if the evidence is inadequate.

AIM

To explore the impact of vitamin D on infection-related outcomes in end stage renal disease patients under dialysis

Objectives and hypothesis

  1. To evaluate whether vitamin D deficiency would be associated with an increased risk of infection, infection-related hospitalization and infection-related mortality in patients under dialysis.

  2. To explore whether vitamin D users would have lower risk of risk of infection, infection-related hospitalization and infection-related mortality in patients under dialysis, compared with non-users.

Methods

1. Eligibility criteria: Studies will be included if they meet the following criteria:

(1) Intervention studies (non-randomized intervention study or randomized controlled trials) or cohort study or case-controlled studies;

& (2) Adult ESRD patients (age≥18 years old) undergoing hemodialysis or peritoneal dialysis;

& (3) Reported at least one outcome of interest: risk of any infection, risk of infection-related hospitalization, risk of infection-related mortality.

& (4) Presented data for measured of serum 25(OH)D; Or if it is a study related to the use of vitamin D, the intervention group received either nutritional vitamin D (D2/ergocalciferol and/or D3/cholecalciferol) supplementation or activated vitamin D (Paricalcitol, Doxercalciferol, Calcitriol, Alfacalcidol, Maxacalcitol, Falecalcitriol); 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 categorisation of serum 25(OH)D levels. There was no restriction of language and publication year. There was no restriction of sex and 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.

2. Information sources: The search will be conducted by 2 independent researchers (ZZL & XDQ), using search the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 12), Pubmed (Appendix 1) (1946 to Dec 31, 2017), EMBASE (Elsevier) (1974 to Dec 31, 2017), Web of Science (1900 to Dec 31, 2017), Chinese National Knowledge Infrastructure (CNKI, Appendix 2) (1979- to Dec 31, 2017), China Biology Medicine disc (CBM 1976- to Dec 31, 2017), Wanfang Data Knowledge Service Platform (WanFang (1998- to Dec 31, 2017).

We will search the trials registries Current Controlled Trials (http://www.controlled-trials.com/), National Research Register (http://www.nihr.ac.uk/), Chinese Clinical Trial Register (http://www.chictr.org), World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (WHO ICTRP) (http://www.who.int/ictrp/en/), and ClinicalTrials.gov (www.clinicaltrials.gov) for completed and ongoing trials. We will backward and forward citation tracking to identify the references lists and citations of the included studies. We will attempt to identify the grey literature by searching reviews, abstracts presented at meetings of the American Society of Nephrology, National Kidney Foundation, World Congress of Nephrology, Asia pacific society of Nephrology in the past 3 years were searched for additional studies and academic degree dissertations. Our search identified relevant studies published until Dec 31, 2017. The searching period will be updated later on.

3. Search strategy: Our search strategy will include the relevant key terms: 'vitamin D', and 'dialysis' and 'infection'. The searching strategies will be based on the published Cochrane review[12]. We will use the key words/MeSH terms in the key papers obtained from pubmed reminder to adapt the searching strategies [10,15–17].

We will use the search strategy described in Appendix 1 (attached at the end) to search MEDLINE. We will adapt the search strategy to search the other databases. The corresponding authors of all identified eligible studies (published and unpublished) will be contacted to provide de-identified data for the purposes of meta-analysis.

4. Study records: All the systematic search records from different database will be imported in ENDNOTE. After deduplication, eligible studies will be listed and assessed independently by 2 reviewers (XDQ and ZZL) using predefined inclusion criteria. Firstly, exclude studies based on their titles and abstracts. Secondly, exclude studies based on the inclusion criteria and list the exclusion reasons. In the case of multiple publications from the same population, we will only include the report with the longer follow-up.

5. Data items: Two authors (GBS and LLZ) will use predefined forms to extract data from the studies, including information on region, study design, participants, how to define vitamin D deficiency and their reference range, the test methods, intervention details (types of vitamin D, dose, modes of administration, frequency, duration), comparison, outcomes, covariates, results, follow-up period in the data extraction form. For each study, relative risk (RR) including odds ratios, hazard ratios, incidences rate ratio will be extracted (if reported), as well as the ones based on the most fully adjusted models. If different level groups (eg, tertiles of 25(OH)D) were reported, the most extreme comparison, that is, lowest versus highest level, was considered for the primary results. If RR was not available in the studies, the number or incidence of the outcomes will be extracted to calculate the RRs.

6. Outcomes and prioritisation

Primary outcomes

The composite outcomes of the relative risk of any infection, infection-related hospitalization and infection-related mortality during study periods.

Secondary outcomes

Relative risk of any infection

Relative risk of specific infections, eg. Respiratory tract infections, urinary tract infections, etc.

Relative risk of infection-related hospitalization

Relative risk of infection-related mortality during study periods

Relative risk (RR) including odds ratios, hazard ratios, incidences rate ratio and their 95% confidence intervals will be reported for the primary outcomes.

7. Risk of bias in individual studies: Two review authors (XDQ, ZZL) will independently assess the risk of bias of each included trial using The Cochrane Collaboration's tool for assessing risk of bias 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-controlled studies will be assessed using the Newcastle-Ottawa Scale tool. Assessment of quality and generalizability will be based on 3 key broad domains considered fundamental for observational studies: selection of study participants, comparability of cohorts on the basis of the design or analysis, and assessment of outcomes. In the case of any disagreement, a third author (NB) will also assess the study. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines will be followed.

8. Data synthesis: For each outcome measure of interest, random-effects meta-analyses will be conducted to pool mean differences for continuous outcomes, relative risks (RRs) for dichotomous outcome, hazard ratio (HR) for risk of infection, infection-related hospitalizations, infection-related mortality in order to determine the effect of different levels of 25(OH)D, use of vitamin D versus placebo/no use.

HRs and RRs were considered interchangeably in analyses. If studies only reported ORs, therse were converted into RRs using the formula RR=OR/[(1-P0)+(P0*OR)], in which P0 was the event incidence in the control group.

The random-effects model will be used to account for statistical heterogeneity. Forest plots will be used to display the mean difference or RR or HR and 95% CI for each study and the pooled summary effect. The I[2] statistic will be used to measure heterogeneity across studies.

Heterogeneity will be explored through subgroup analyses whereby results were stratified by types of vitamin D, type of dialysis therapy (HD or PD), different outcomes (risk of infection, infection-related hospitalizations, infection-related mortality) and study design.

We will perform additional empirical Bayes metaregression models in studies addressing use of vitamin D as the exposure. These included types of dialysis therapy (HD or PD), types of administration (oral or intravenous) and study sample size (<500 or ≥500 participants).

All data analyses will be performed using Stata 14.0 (StataCorp LP).

9. Meta-bias(es): Publication bias will be assessed by funnel plot. The Egger's test will be used to detect publication bias.

10. Confidence in cumulative evidence: Our proposed study will highlight the serum level of 25(OH)D in relation to infection-related outcomes, and further to evaluate whether the use of vitamin D will reduce the risk of these outcomes in dialysis patients.

Our study have strengths in several ways. We will search the database using not only the English database, such as Medline, EMBAZE, but also the Chinese database such as CNKI, CMB, which has not been used in the previous systematic review.

It is anticipated that there might be heterogeneity in our included study, due to different study design, difference in the dialysis vintage (how long patients start dialysis), mode of dialysis (peritoneal dialysis, hemodialysis), sunshine variation (season, locations) influencing the level of vitamin D, different cutoff of vitamin D deficiency, different testing methods of vitamin D, different types of vitamin D medication (nutrient supplement or active supplement), different of follow-up period. We have planned to have subgroup analysis and meta-regression to investigate to these potential reasons for heterogeneity if applicable. Our analysis plan to select the most adjusted RR in the studies, which despite presenting the most conservative risk estimation may result inoutcome reporting bias. Since the role of vitamin D in relation to infection is a relative new area in patients under dialysis, infection might not be the primary outcome in previous RCTs. Some secondary outcomes related to infection might not be available in our included study, such as the severity of infection, the duration of the infection, total number of courses of antibiotics taken for infections during the trial, total number of days off work or school due to symptoms of acute infection during the trial. Observational study might be the majority of our included studies, in which residual or unmeasured confounding could not be eliminated and prone to be bias.

Relevance: The current guidelines only mention vitamin D to treat chronic kidney disease-mineral bone disorder (CKD-MBD) when their intact parathyroid hormone (iPTH) levels is higher than 2 to 9 times the upper normal limit. However, it does not address the role vitamin D in infection related outcomes. For guideline developers, the result of this systematic review will give evidence about whether vitamin D deficiency would have impact on infection-related outcomes and further whether use of vitamin D would reduce risk of these outcomes in dialysis patients, possibly give new indication of vitamin D in this population and change the guidelines. For dialysis patients and clinicians, our result will inform their practice about who will be benefit most if given vitamin D when their level of 25(OH)D reach a certain cut-off.

Supplementary Item 2

Pubmed searching strategy

#1 "Anti-Bacterial Agents"[Mesh] OR "Anti-Bacterial Agents" OR antibiotic*

#2 amoxicillin OR ampicillin* OR bacitracin OR cephalothin OR cefazolin OR cefotaxime OR cefoperazone OR ceftazidime OR ceftriaxone OR cefuroxime OR chloramphenicol OR ciprofloxacin OR clarithromycin OR clindamycin OR cloxacillin OR colistin OR colimycin OR erythromycin OR flucloxacillin OR furazolidone OR "fusidic acid" OR gentamicin OR gramicidin OR imipenem OR "mafenide acetate" OR mupirocin OR natamycin OR neomycin OR nitrofurazone OR oxacillin OR penicillin OR piperacillin OR polymyxin OR rifam* OR "silver nitrate" OR "silver sulfadiazine" OR "sulfacetamide sodium" OR tobramycin OR amphotericin OR tazocin OR teicoplanin OR tetracycline OR trimethopri* OR sulfamethoxazole OR vancomycin

#3 "Infection"[Mesh] OR "Infecti*" OR "infectious" OR "infection-related"

#4 "Catheter-related infection"[Mesh] OR "Peritonitis"[Mesh] OR "Catheter-related infection" OR "Peritonitis"

#5 "sepsis"[Mesh] OR sepsis OR "Systemic Inflammatory Response Syndrome"[Mesh] OR "Systemic Inflammatory Response Syndrome" OR sirs

#6 "Bacterial Infections and Mycoses"[Mesh] OR "Virus Diseases"[Mesh] OR bacterial*

#7 "pneumonia"[Mesh] OR "Respiratory Tract Infections"[Mesh] OR "respiratory tract infection*" OR "respiratory infection*" OR pharyngit* OR tracheit* OR bronchit* OR pneumon* OR "common cold"[Mesh] OR "common cold*" OR coryza OR influenza* OR flu OR "otitis media*" OR sinusit* OR tonsillit* OR laryngit* OR pharyngit* OR bronchit* OR pneumon*

#8 cystitis[Mesh] OR "Urinary Tract Infections"[Mesh] OR pyelonephritis[Mesh] OR "cystitis*" OR "urinary tract infection*" OR "UTI*" OR pyelonephritis

#10 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8) AND #9

#11 "Vitamin D"[Mesh] OR "vitamin D" OR "vitamin d2" OR "vitamin d3"

#12 "Cholecalciferol"[Mesh] OR "Calcitriol"[Mesh] OR "25-Hydroxyvitamin D3 1-alpha-Hydroxylase"[Mesh] OR "Ergocalciferols"[Mesh] OR "Hydroxycholecalciferols"[Mesh]

#13 "25-hydroxyvitamin D" OR "25-hydroxyvitamin d*" OR "1,25-dihydroxy Vitamin D*" OR "1alpha-hydroxy Vitamin D3" OR "19-nor-1,25-dihydroxy Vitamin D*" OR "cholecalciferol*" OR "colecalciferol*" OR "hydroxycholecalciferol*" OR "falecalcitriol*" OR "calcitriol*" OR "alfacalcidol*" OR "alphacalcidol*" OR "calcipotriol*" OR "epicalcitriol*" OR "22-oxa-1alpha, 25-dihydroxy Vitamin D" OR "F6-1alpha, 25-dihydroxy Vitamin D*"

#14 "25-Hydroxyvitamin D 2"[Mesh] OR "Calcifediol"[Mesh] OR Dihydrotachysterol[Mesh] OR "dihydrotachysterol*" OR "1alpha-hydroxyergocalciferol" OR "dihydrotachysterol*" OR "calciferol*" OR "doxercalciferol*" OR "dihydroxyvitamin D*" OR "hydroxyvitamin D*" OR "calcifediol*" OR "ergocalciferol*" OR "calcifediol lactol" OR "calcifediol lactone"

#15 "maxacalcitol*" OR "oxacalcitriol" OR "paricalcitol*" OR "lexacalcitol*" OR "seocalcitol*" OR "VDRA"

#17 (#11 OR #12 OR #13 OR #14 OR #15) AND #16

#18 "Kidney Failure, Chronic"[Mesh])

#19 "Renal Insufficiency, Chronic"[Mesh]

#20 "chronic kidney disease" OR "renal failure*" OR "CRF" OR "kidney failure*" OR "renal insufficien*" OR "kidney dysfunction" OR "renal dysfunction" OR "reduced kidney function" OR "reduced renal function" OR "chronic kidney" OR "chronic renal"

#21 "estimated glomerular filtration rate" OR "eGFR" OR "reduced eGFR"

#22 "end stage renal disease*" OR ESRD OR "End-Stage Kidney Disease" OR "ESKD" OR "CKD" OR "CKF" OR "CRD" OR "CRF" OR "ESKF" OR "ESRF" OR "uremia"[Mesh]

#23 "predialysis" OR "dialysis" OR "haemodialysis" OR "hemodialysis" OR "dialysis*" OR "Renal Replacement Therapy"[Mesh] OR "Renal Dialysis"[Mesh] OR "Hemofiltration"[Mesh] OR "hemodialysis" OR "Hemofiltration" OR hemodiafiltration OR "peritoneal dialysis" OR "continuous renal replacement therapy" OR "CRRT" OR "Hemodialysis, Home"[Mesh] OR "Hemodiafiltration"[Mesh] OR "Hemofiltration"[Mesh] OR "Peritoneal Dialysis"[Mesh] OR "Peritoneal Dialysis, Continuous Ambulatory"[Mesh]

#24 "CAPD" OR "CCPD" OR "APD"

#25 "kidney transplant*" OR "Kidney Transplantation"[Mesh]

#26 "glomerular disease*" OR "glomerular nephritis" OR "nephritis" OR "nephrotic syndrome*" OR "nephropathy" OR "podocyte disease*" OR "Proteinuria" OR "Albuminuria" OR "Proteinuria"[Mesh] OR "Albuminuria"[Mesh]

#28 #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26

#29 #10 AND #17 AND #28

processing....