Objectives
This is a protocol for a Cochrane Review (intervention). The objectives are as follows:
To assess the benefits and harms of adjuvant interventions (anti‐inflammatory or antioxidative) in preventing kidney scarring (detected by DMSA scan) in children with febrile urinary tract infections.
Background
Description of the condition
Urinary tract infection (UTI) is amongst the most common bacterial infections in children [1]. Most febrile UTIs in childhood affect the kidney parenchyma and therefore, are treated as acute pyelonephritis. Permanent kidney damage may occur in people with acute pyelonephritis, which is postulated to be chiefly mediated by acute inflammation in response to uropathogen, rather than a direct bacterial invasion of kidney parenchyma [2, 3, 4, 5]. Kidney scarring can be detected by 99mTc dimercaptosuccinic acid (DMSA) scintigraphy, and may be observed in 10% to 15% of children following the first episode of febrile UTI [6, 7]. Acquired kidney scarring subsequently increases the risk for hypertension and proteinuria, but rarely results in chronic kidney disease [8, 9].
Description of the intervention and how it might work
Antibiotic therapy is the most effective treatment to prevent kidney scarring in children with febrile UTIs, although some children may still develop kidney scarring [10]. Studies in animal models have shown that inflammatory cytokines and cells play a key role in kidney scarring following acute pyelonephritis [11, 12, 13]. Therefore, suppressing acute inflammation may help reduce the risk of acquired kidney scarring in children with febrile UTIs [3, 14]. Previous studies using anti‐inflammatory or antioxidant interventions demonstrated a reduction in the level of urinary cytokines [15]. Clinical trials have examined the efficacy of adjuvant interventions with corticosteroids, vitamin A, carnitine, and ibuprofen, in addition to antibiotic therapy, and have shown benefits in reducing kidney scarring [16, 17, 18, 19]. However, recent studies have shown conflicting results regarding the impact of these anti‐inflammatory interventions on the risk of scarring [20, 21, 22, 23].
Why it is important to do this review
Urinary tract infections (UTIs) are common bacterial infections in childhood, affecting 2% of boys and 7% of girls before the age of six years [1]. UTIs account for almost 5% to 15% of paediatric emergency visits [24]. Therefore, the overall cost and burden of managing UTIs in the paediatric population is considerable. Despite optimal management of febrile UTI with appropriate antimicrobial agents, 10% to 15% of children develop permanent kidney scarring. Hence, interventions to reduce the risk of kidney damage are important [ 6]. Kidney scarring is concerning for both physicians and parents, as it may have long‐term adverse consequences, including proteinuria, hypertension, preeclampsia, and chronic kidney disease [25, 26, 27]. Therefore, this review is crucial for physicians, children, and their parents.
Over the last few years, clinical trials have examined the efficacy of many anti‐inflammatory/antioxidant agents for reducing the risk of kidney scarring, with variable success [16, 19, 21, 23, 28]. A meta‐analysis of three trials, conducted by two of the authors of this review team, with a limited number of participants, showed that adjuvant corticosteroid therapy during febrile UTI reduces the risk of kidney scarring [29]. However, more recent studies have shown conflicting results [20, 22]. While a multicentre trial from North America showed a lower rate of kidney scarring failed to reach statistical significance, a study from Italy concluded that oral steroids could reduce the risk of kidney scarring [18, 20].
Therefore, it is important to synthesise the existing data, using Cochrane review methodology, to provide more reliable, evidence‐based guidance for healthcare professionals and policymakers.
Objectives
To assess the benefits and harms of adjuvant interventions (anti‐inflammatory or antioxidative) in preventing kidney scarring (detected by DMSA scan) in children with febrile urinary tract infections.
Methods
We will follow the Methodological Expectations for Cochrane Intervention Reviews (MECIR) to conduct the review, and PRISMA 2020 to report our findings [30, 31].
Criteria for considering studies for this review
Types of studies
Inclusion criteria
Study design: randomised controlled trials (RCTs)
There will be no language, geographical, or publication year restrictions for including studies.
All studies will be included, regardless of outcomes reported.
Exclusion criteria
Cross‐over RCTs, cluster‐RCTs, quasi‐RCTs, non‐randomised studies, and observational studies
We will exclude cross‐over RCTs, because our primary outcome is assessed four to six months after the intervention has been completed, making a cross‐over design impractical.
Types of participants
Inclusion criteria
Population: children aged < 18 years, with or without primary vesicoureteral reflux (VUR). RCTs, including data from both adults and children, will only be included if they provide separate data for children, or if the children constitute more than 75% of the entire study population.
Urinary tract infection (UTI) definition: based on significant growth from urine culture, and in symptoms suggestive of UTI. Urine specimens for defining UTI should be collected by clean catch, catheterisation, or suprapubic aspiration.
Exclusion criteria
Population: adult population, children with pre‐existing chronic kidney disease (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2)
Children with febrile UTI in the setting of a neurogenic bladder, posterior urethral valve, or any other urological abnormalities, except primary VUR
Studies that define UTIs based on bag specimens
Types of interventions
We will include studies that compare adjuvant anti‐inflammatory interventions, such as corticosteroids, vitamin A, vitamin E, non‐steroidal anti‐inflammatory drugs (NSAIDs), and L‐carnitine with placebo or an active intervention. We will include all studies using these interventions as an adjuvant to antibiotic therapy during the treatment of febrile UTI to prevent kidney scarring, regardless of the type of anti‐inflammatory agent, dose, duration, or route of administration. Studies can use any antibiotic according to local guidelines or sensitivity patterns for treating febrile UTIs.
Comparisons will be based on these intervention groups.
Anti‐inflammatories: corticosteroids (prednisolone, methyprednisolone, dexamethasone)
NSAIDs
Antioxidants: vitamin A, vitamin E
Carnitine
Placebo
Outcome measures
Critical and important outcomes reported in this review are core outcomes for the management of UTI in children.
Critical outcomes
Kidney scarring
Death (any cause), as reported in studies
Serious adverse events, such as bacteraemia and kidney abscess
Important outcomes
Hospitalisation rate
Change in markers of inflammation, such as blood levels of procalcitonin, C‐reactive protein, erythrocyte sedimentation rate, and urinary interleukin‐6 and interleukin‐8
Estimated glomerular filtration rate (eGFR)
Non‐serious adverse events, such as vomiting, diarrhoea, fussiness
All critical outcomes will be measured up to the last follow‐up visit during the study. Of these outcomes, scarring should be assessed by a dimercaptosuccinic acid (DMSA) scan, performed three to six months after the completion of the intervention. Other outcomes should be measured during the acute intervention phase (the duration during which the intended intervention was used, usually four to seven days, but can vary in different studies). We will calculate the relative risk (with a 95% confidence interval (CI)) for all outcomes, except inflammatory markers and eGFR, in which case, we will calculate the mean difference (MD) with a 95% CI. See Table 1 for specific outcome measures for each outcome category.
1. Table 1. Specific outcome measures for each outcome category.
| Broader outcome grouping | Outcome domain | Outcome measures |
| Efficacy | Kidney scarring | Number of participants with abnormality on DMSA scan after febrile UTI |
| Death | Death (all causes) | |
| Inflammatory markers | Change in markers of inflammation, such as blood levels of procalcitonin, C‐reactive protein, erythrocyte sedimentation rate, and urinary interleukin‐6 and interleukin‐8 | |
| Kidney functions | Estimated glomerular filtration rate | Estimated glomerular filtration calculated by Schwartz formulae, using serum creatinine |
| Side‐effects | Bacteraemia | Growth of pathogenic bacteria in blood |
| Kidney abscess | Based on radiological imaging | |
| Non‐serious adverse events | Vomiting, diarrhoea, fussiness |
Search methods for identification of studies
Electronic searches
The Cochrane Kidney and Transplant Information Specialist will search the following databases for RCTs without language, publication year, or publication status restrictions.
Cochrane Kidney and Transplant Specialised Register via MeerKat (a software application built on Microsoft Access, used to manage the database). MeerKat is a study‐based register and is used to store bibliographic and study details, link multiple reports to a single study, link studies to reviews, and track the progress of reviews. (current date)
Cochrane Central Register of Controlled Trials (CENTRAL; current issue), in the Cochrane Library
Ovid MEDLINE(R) ALL (from 1946)
Embase, included in the CENTRAL search (from 1974)
US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (https://www.clinicaltrials.gov), included in the CENTRAL search (current date)
World Health Organization International Clinical Trials Registry Platform (https://trialsearch.who.int), included in the CENTRAL search (current date)
The Information Specialist will model the subject strategies for databases on the search strategy designed for MEDLINE. Where appropriate, they will combine the subject strategy adaptations of the sensitivity and precision‐maximising search strategy designed by Cochrane for identifying RCTs (described in the Cochrane Handbook for Systematic Reviews of Interventions [32]). We present the MEDLINE, Embase, and CENTRAL search strategy in Supplementary material 1.
Searching other resources
We will check the reference lists of included studies and any relevant systematic reviews identified, for further references to relevant studies.
We will check the included studies for retractions and errata via the Retraction Watch Database, and report the search dates in the review (https://retractiondatabase.org).
We will search Epistemonikos for related systematic reviews (https://www.epistemonikos.org).
We may contact the original study authors or funders of included studies for clarification and further data if study reports are unclear.
Data collection and analysis
Selection of studies
Two review authors (JM and JK) will independently screen titles and abstracts identified in the search, using Covidence [33]. We will retrieve full‐text reports for all references coded as 'include' by either review author. The same two review authors will independently screen the full‐text reports and record reasons for exclusion for ineligible reports. We will resolve disagreements through discussion or, if required, by consulting one of the senior authors (PH or AB). If any abstract or article requires translation from another language to determine its eligibility, we will use Google Translate to convert the manuscript into English.
Data extraction and management
Two review authors will independently extract data from the full text of the eligible trials (JM and JK) into the data extraction form in Covidence. This form will be piloted in three studies before final use. Any discrepancy between the two review authors will be resolved through discussion or, if required, with a third review author (PH). We will extract data for the following information: author's name, year of publication, study design, method of randomisation and allocation, number of study participants, age, details of the intervention (dose, route, and duration), outcome, method of measurement of outcomes, and adverse events related to the intervention (e.g. bacteraemia, renal abscess, hospitalisation, death, kidney function impairment). Data for critical and important outcomes, as stated above, will also be retrieved and recorded. In case of missing data from studies, we will contact the study authors for the same. One review author (AS) will transfer study characteristics and risk of bias judgements to the Review Manager (RevMan) file, and two review authors (JM and JK) will check and transfer study data into the analyses.
Risk of bias assessment in included studies
Two review authors (JK and JM) will independently assess the risk of bias using the RoB 2 tool for all outcomes listed in the outcome measures section at the latest follow‐up [34]. Disagreement will be resolved by discussion with two other review authors (AS and PH). We will assess the risk of bias for all RoB 2 domains and judge each domain as having a high risk of bias, raising some concerns, or at low risk of bias, using the responses to the signalling questions and algorithms within the RoB 2 tool. The tool algorithm will be used to reach an overall risk of bias for each outcome. We will quote evidence to support our judgements, or if we disagree with a judgement recommended by the algorithm. We will provide an explicit statement for our judgement. We will manage our risk of bias assessments using the RoB 2 Excel tool. We will contact study authors for any missing information to assess the risk of bias.
We will assess the risk of bias in the following domains:
bias arising from the randomisation process;
bias due to deviations from intended interventions;
bias due to missing outcome data;
bias in measurement of the outcome; and
bias in selection of the reported result.
We will use the effect of the assignment to the intervention. In order to assess the effect of assignment to the intervention, we will consider the randomisation process, deviations from the intended intervention, and other factors that could influence the risk of bias and affect the true effect of the intervention.
Measures of treatment effect
We will analyse the dichotomous data as risk ratio (RR), and continuous data as mean differences (MD), or standardised mean differences (SMD) if the outcome is measured or reported in different units. We will enter data presented as a scale with a consistent direction of effect.
We will pool the data in a meta‐analysis only if it is meaningful (i.e. when treatments, participants, and the underlying clinical question are similar enough for pooling to make sense). We will provide a narrative summary where it is not feasible to perform a meta‐analysis.
Unit of analysis issues
We will analyse data using participants with one or more events as the unit of analysis rather than each kidney as the unit of analysis. For dichotomous outcomes, if it is not clear whether the number of events applied to the entire population or only to those taking the study medication, we will use the total number randomised per group as the denominator. We will perform sensitivity analyses by using the number of participants who used their study medication at least once as the denominator to test this assumption. In the case of multiple‐arm trials, we will include only the relevant arms. If two comparisons (e.g. intervention A versus placebo and intervention B versus placebo) are combined in the same meta‐analysis, we will half the control group to avoid double‐counting.
Dealing with missing data
We will contact the study investigators to obtain missing numerical outcome data when possible. If this is not possible, and when missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by performing a sensitivity analysis.
Reporting bias assessment
If we find more than 10 studies to pool for a single outcome, we will assess publication bias using a funnel plot.
Synthesis methods
We will synthesise all outcomes across different interventions using data in RevMan, and examine between‐study heterogeneity using the I2 statistic. We will use Mantel‐Haenszel random‐effects meta‐analysis to pool the data across studies, with subsequent testing for the robustness of the analysis by applying the fixed‐effect model. For dichotomous outcomes, we will pool studies using the Mantel‐Haenszel risk ratio. For continuous outcomes, such as the concentration of inflammatory markers, we will calculate pooled statistics as mean differences or standardised mean differences, as applicable [30, 35]. Analysis for all outcomes will include all studies that reported that particular outcome, regardless of the risk of bias. For outcomes where pooling of data is not feasible, we will use the Synthesis Without Meta‐analysis (SWiM) guidelines to summarise the data [36]. We will assess heterogeneity across included studies using Cochran's Q statistics and quantify it using I² statistics [37]. We will also take into consideration the variability in participants' profiles and methodological variations in studies to assess the heterogeneity.
Investigation of heterogeneity and subgroup analysis
If sufficient data are available, we will perform subgroup analysis based on the subtype of intervention (for example, corticosteroids: prednisolone, methylprednisolone, and dexamethasone). If data permit, we will also perform subgroup analysis for children with or without primary vesicoureteral reflux (VUR), as the risk of developing kidney scarring is higher in people with primary VUR.
Equity‐related assessment
We will not perform any equity‐related assessment in this review.
Sensitivity analysis
Data permitting, we plan to undertake the following sensitivity analyses for the critical outcomes.
As per the methodological quality (removing studies judged to be at high risk of bias)
Random‐effects model versus fixed‐effect model for meta‐analysis
As per the source of study funding (removing studies funded by pharmaceutical companies)
Excluding studies with missing data thought to introduce serious bias
We will perform sensitivity analyses by using the number of participants who used their study medication at least once as the denominator to test these assumptions.
Certainty of the evidence assessment
We will create a summary of the findings table for critical outcomes (mortality, kidney scarring, kidney abscess) and important outcomes (hospitalisation rate and estimated glomerular filtration rate (GFR)) listed in the outcome measures section. We will create summary of the findings tables for the following comparisons: corticosteroids versus placebo; NSAIDs versus placebo; antioxidants versus placebo. We will use the five GRADE considerations (overall risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of evidence as it relates to the studies that contributed data to meta‐analyses for prespecified outcomes [38]. Two review authors (JM and JK) will independently assess the certainty of the body of evidence, with disagreement being resolved by a third review author (PH). We will use methods and recommendations described in the GRADE Handbook to guide the application of GRADE methodology [39], through the GRADEpro GDT software [40].
Consumer involvement
We will include consumers for readability of the plain language summary, including caregivers from our clinic for this purpose.
Supporting Information
Supplementary materials are available with the online version of this article: 10.1002/14651858.CD016166.
Supplementary materials are published alongside the article and contain additional data and information that support or enhance the article. Supplementary materials may not be subject to the same editorial scrutiny as the content of the article and Cochrane has not copyedited, typeset or proofread these materials. The material in these sections has been supplied by the author(s) for publication under a Licence for Publication and the author(s) are solely responsible for the material. Cochrane accordingly gives no representations or warranties of any kind in relation to, and accepts no liability for any reliance on or use of, such material.
Supplementary material 1 Search strategies
New
Additional information
Acknowledgements
Editorial and peer‐reviewer contributions
Cochrane Kidney & Transplant supported the authors in the development of this protocol.
The following people conducted the editorial process for this article:
Sign‐off Editor (final editorial decision): A Sign‐off Editor made the final editorial decision but chose not to be publicly acknowledged;
Managing Editor (selected peer reviewers, provided editorial guidance to authors, edited the article): Liz Bickerdike, Cochrane Central Editorial Service;
Editorial Assistant (conducted editorial policy checks, collated peer‐reviewer comments and supported editorial team): Jacob Hester, Cochrane Central Editorial Service;
Copy Editor (copy editing and production): Victoria Pennick, Cochrane Central Production Service;
Peer‐reviewers (provided comments and recommended an editorial decision): Bruce J Schlomer MD, University of Texas Southwestern (clinical/content review); Clare Miles, Cochrane Evidence Production and Methods Directorate (methods review); Jo Platt, Central Editorial Information Specialist (search review).
Contributions of authors
JM: conceived the idea of the review, drafted initial protocol
JK: statistical methods, critically reviewed the draft and approved the final version of the protocol
AS: clinical experts, input in drafting the first draft, approved the final version of the protocol
AB: input to eligibility criteria, edited the final version of the protocol
PH: conceived the idea of the review, critically reviewed the draft and approved the final version of the protocol
Declarations of interest
JM, JK, AS, AB and PH: no commercial or non‐commercial conflicts of interest relevant to this review
Sources of support
Internal sources
-
none, Other
no internal sources of support received
External sources
-
none, Other
no external sources of support received
Registration and protocol
Cochrane approved the proposal for this review in April 2024
Data, code and other materials
Data sharing not applicable to this article as it is a protocol, so no datasets were generated or analysed.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary material 1 Search strategies
Data Availability Statement
Data sharing not applicable to this article as it is a protocol, so no datasets were generated or analysed.