Interventions for preventing and treating acute kidney injury in children

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

This review aims to look at the benefits and harms of all pharmacological interventions except dialysis for the prevention and treatment of AKI.

Background

Description of the condition

Acute kidney injury (AKI) is characterized by the abrupt decline of kidney function with a decrease in glomerular filtration rate (GFR) and urinary output (oliguria) (KDIGO 2012). AKI affects 30% to 60% of critically ill patients and is associated with high deaths, morbidity and healthcare costs (Pickkers 2021).

Over the years, the global epidemiology of paediatric AKI has changed remarkably due to standardized AKI definitions, the availability of biomarkers and the establishment of collaborative multicentre studies (Raina 2021). Investigators from the multinational AWARE study (Assessment of Worldwide Acute Kidney Injury, Renal Angina, and Epidemiology) reported an AKI incidence of 26.9%, with 11.6% developing severe AKI using the Kidney Disease Improving Global Outcomes (KDIGO) criterion (Kaddourah 2017). The study also reported a high death rate in patients with severe AKI (11.6%) as compared to those without severe AKI (2.5%) (Kaddourah 2017). A recent meta‐analysis including 12 publications showed a 24.4% pooled incidence of AKI in critically ill children who were at risk of AKI (Raina 2021). Further, the odds of death were eight times higher in children with AKI as compared to those without AKI. The incidence of AKI is much higher in children undergoing cardiac surgery, where it varies from 30% to 50%, in neonates with birth asphyxia and in neonates requiring neonatal intensive care.

Several consensus groups have proposed standard definitions for the staging of AKI, including pRIFLE (pediatric Risk, Injury, Failure, End stage) (Akcan‐Arikan 2007), AKIN (Acute Kidney Injury Network) (Mehta 2007) and the KDIGO classification (KDIGO 2012) (Table 1). These classifications are based on serum creatinine (SCr) and urine output criteria.

1. Acute kidney injury staging.

pRIFLE classification			AKIN classification			KDIGO classification
Class	GFR/eCl	Urine output	Stage	SCr	Urine output	Stage	SCr	Urine output
Risk	↓ eCl ≥ 25%	< 0.5 mL/kg/hour for 6 hours	1	↑ SCr ≥ 26.5 μmol/L OR ↑SCr ≥ 150% to 200% from baseline	< 0.5 mL/kg/hour for > 6 hours	1	↑SCr to ≥ 1.5 to 1.9 times baseline OR ≥ 26.5 mmol/L increase	≤ 0.5 mL/kg/hour for 6 to 12 hours
Injury	↓ eCl ≥ 50%	< 0.5 mL/kg/hour for 12 hours	2	↑ SCr > 200% to 300% from baseline	< 0.5 mL/kg/hour for > 6 hours	2	↑SCr to 2.0 to 2.9 times baseline	0.5 mL/kg/hour for ≥ 12 hours
Failure	↓ eCl ≥ 75% OR eCl < 35mL/min/1.73 m²	< 0.3 mL/kg/hour for 24 hours OR anuria for 12 hours	3	↑ SCr > 300% (> 3‐fold) from baseline or if baseline SCr ≥ 353.6 μmol/L ↑SCr ≥ 44.2 μmol/L; also includes patients requiring KRT independent of stage	< 0.3 mL/kg/hour for 24 hours OR anuria for 12 hours	3	↑SCr to 3.0 times baseline OR ↑ SCr to ≥ 353.6 mmol/L OR Initiation of RRT OR In patients ≤ 18 years, ↓ eGFR to ≤ 35 mL/min/1.73 m²	< 0.3 mL/kg/hour for ≥ 24 hours OR anuria for ≥ 12 hours
Loss	Complete loss of kidney function > 4 weeks	‐‐	‐‐	‐‐	‐‐	‐‐	‐‐	‐‐
ESKD	Complete loss of kidney function > 3 months	‐‐	‐‐	‐‐	‐‐	‐‐	‐‐	‐‐

eCl: estimated creatinine clearance; ESKD: end‐stage kidney disease; GFR: glomerular filtration rate; KRT: kidney replacement therapy; SCr: serum creatinine

SCr and urine output are the most commonly used biomarkers for the diagnosis of AKI (Devarajan 2011; Goldstein 2019); however, both of these have limitations as rises in SCr levels may take hours to days to be detected after kidney injury, influenced by muscle mass and fluid status, while urine output is affected by diuretics and the hydration status (Kim 2016). A number of novel urinary and serum biomarkers such as neutrophil gelatinase‐associated lipocalin (NGAL), cystatin C, kidney injury molecule‐1 (KIM‐1), IL‐18, liver‐type fatty acid‐binding protein (L‐FABP), and tissue inhibitor of metalloproteinase‐2/insulin‐like growth factor‐binding protein 7(TIMP‐2/IGFBP‐7) are being increasingly used in the research and clinical settings for the early diagnosis of AKI (Dai 2015; Meersch 2014). A systematic review assessing the diagnostic accuracy of urinary and serum NGAL for predicting AKI in children showed a pooled sensitivity of 76% and 80% and pooled specificity of 83% and 87%, respectively (Filho 2017). A recent meta‐analysis assessing the diagnostic accuracy of the Renal Angina Index (RAI) alone or in combination with other biomarkers showed that a combination of NGAL and RAI improves the predictive value for AKI (Meena 2022).

The management of AKI in children includes both non‐dialytic and dialytic modalities. Non‐dialytic modalities chiefly focus on fluid management, avoidance of nephrotoxic drugs, managing electrolyte imbalance, and treatment of the underlying cause. Dialytic therapy or kidney replacement therapy (KRT) in the form of peritoneal dialysis, haemodialysis, continuous kidney replacement therapy (CKRT) or sustained low efficacy dialysis are required in patients not responding to the above treatment or done for emergent indications.

Description of the intervention

The aetiology of AKI is multifactorial, and therefore optimising the systemic and kidney perfusion are the initial modalities for the prevention of AKI. KRT is required in patients unresponsive to conservative management or for emergent indications such as severe hyperkalaemia, worsening acidosis, pulmonary oedema and uraemic complications (Bhatt 2021; Moore 2018).

Fluid resuscitation has been considered the mainstay of treatment in critically ill children. Recent randomised controlled trials (RCTs) in adults have shown that the use of a balanced fluid during resuscitation decreases the incidence of hyperchloraemia but without a significant change in the incidence of AKI (Verma 2016). A systematic review comparing balanced versus unbalanced fluid for resuscitation in critically ill children found no difference between the two for AKI, hyperchloraemia or KRT (Lehr 2022).

There is sufficient evidence to show the benefits of therapeutic hypothermia in neonates with birth asphyxia (Abate 2021). It has been suggested that therapeutic hypothermia could prevent injury to other organs, including the kidneys. Results from RCTs determining the effects of therapeutic hypothermia on the incidence of AKI in asphyxiated neonates were variable (Akisu 2003; Eicher 2005; Gluckman 2005; Shankaran 2005; Tanigasalam 2016), and most of the RCTs were underpowered for this outcome (van Wincoop 2021).

Furosemide is a commonly used diuretic in critically ill patients (Mehta 2002). A recent trial using furosemide infusion versus placebo in the early stage of AKI utilizing pRIFLE criterion was stopped early for futility, and the authors didn't find any benefit of using furosemide for prevention of progression to higher stages of AKI in children (Abraham 2021).

Theophylline, an adenosine‐antagonist, has been shown to prevent AKI in neonates with severe birth asphyxia (Bakr 2005; Bhat 2006; Eslami 2009; Jenik 2000; Raina 2016). The possible mechanisms of action include inhibition of renal adenosine‐induced vasoconstriction in the setting of renal hypoxia. Similarly, aminophylline has been shown to decrease the incidence of AKI in preterm neonates with asphyxia (Merrikhi 2012). A double‐blind RCT using a single dose of intravenous aminophylline in children one to 18 years of age undergoing cardiac surgery showed no difference in the incidence of AKI between the groups (Axelrod 2016).

Other modalities for the prevention of AKI, such as fenoldopam (Ricci 2011), a dopamine D1 receptor agonist and dexmedetomidine (Xie 2021), a new generation highly selective α2‐adrenergic receptor agonist, have shown no significant difference in the occurrence of AKI in children undergoing cardiopulmonary bypass as compared to placebo or standard treatment.

Acetaminophen has been shown to attenuate AKI in cell‐free haemoglobin‐mediated oxidative damage and, therefore, is more useful in patients with significant intravascular haemolysis (Plewes 2017).

How the intervention might work

Birth asphyxia affects multiple organ systems, including the brain. Tissue hypoxia causes a redistribution of oxygen to vital organs, whereas organs such as the kidney, gastrointestinal system, and liver are under‐perfused, ultimately leading to organ damage (Polglase 2016). The kidneys are more sensitive to these changes resulting in oliguric or non‐oliguric AKI. Therapeutic hypothermia may have a beneficial role by decreasing the metabolic rate, the reduction in kidney blood flow or by reduction of the critical threshold for oxygen therapy by reduction in oxygen demand (Cornette 2012).

Fluid resuscitation with normal saline may result in hypernatraemia, hyperchloraemia, and metabolic acidosis. This can lead to renal vasoconstriction, ultimately causing a decrease in GFR and leading to AKI (Carcillo 2014; El‐Bayoumi 2012). Electrolyte‐balanced solutions, on the other hand, are hypothesized to be physiological since their composition is similar to plasma, thus having some reno‐protective properties. The sodium concentration in a balanced solution is equal to that of the plasma with a lower chloride concentration. For example, PLasmaLyte, a balanced solution, has a sodium concentration equivalent to 140 mEq/L and a chloride concentration of 98 mEq/L (Morgan 2013).

Furosemide acts on the thick ascending limb of the loop of Henle and inhibits the sodium‐potassium‐chloride pump, and reduces renal tubular energy and oxygen demand (Kramer 1980). This mechanism is proposed to be protective for renal tubules, especially in the setting of renal hypoperfusion or injury.

Animal studies have shown that adenosine acts as a vasoconstrictive metabolite in the kidney following hypoxia and thereby causing a fall in GFR (Dai 2015; Okusa 1999). Non‐specific adenosine antagonists (theophylline and aminophylline) may work by inhibiting vasoconstriction.

Paracetamol reduces oxidative stress by removing cell‐free haemoglobin and myoglobin, which promotes lipid peroxidation of proximal tubular cells and renal vasoconstriction. By removing these oxidative stressors, paracetamol is thought to prevent AKI or halt further kidney damage (Plewes 2017).

Why it is important to do this review

The incidence of AKI ranges from 30% to 50% (Kaddourah 2017) in critically ill children and neonates and is associated with adverse medium‐ and long‐term outcomes, including the development of chronic kidney disease (CKD), increased risk of cardiovascular events, frequent hospitalizations, reduced quality of life and increased death (Sawhney 2015). The present evidence for the prevention and treatment of AKI in children is derived from small single‐centre trials with relatively few patients. Previous systematic reviews have focused on selective interventions and populations (Bhatt 2019; van Wincoop 2021). We propose to conduct a comprehensive and up‐to‐date review of all RCTs to examine different pharmacological agents (except dialysis) for the prevention and treatment of AKI in neonates and children.

Objectives

This review aims to look at the benefits and harms of all pharmacological interventions except dialysis for the prevention and treatment of AKI.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) looking at the prevention and/or treatment of AKI will be included. Studies reported as full text and those published as abstracts only shall be included.

Types of participants

Inclusion criteria

Neonates and children (0 to 18 years) at risk of AKI or with AKI will be included. AKI will be defined as per the definitions used in the individual studies.

Exclusion criteria

Children with pre‐existing kidney disease, congenital anomalies of the kidney and urinary tract, and children with coagulopathy or intracranial bleeding will be excluded from the review.

Types of interventions

Inclusion criteria

We will include studies comparing various pharmacological interventions (theophylline, aminophylline, therapeutic hypothermia, fenoldopam, dexmedetomidine, types of fluids) with placebo or standard care for the prevention and treatment of AKI in children and neonates.

Exclusion criteria

Dialysis interventions will not be included.

Types of outcome measures

Primary outcomes

• Development of AKI

• Death

• Need for KRT

Secondary outcomes

• Length of hospital/intensive care unit (ICU) stay

• Kidney function measures (change in SCr, GFR)

• Fluid balance

• Change in AKI biomarkers, including cystatin C and urinary beta‐2 microglobulin

• Adverse events (electrolyte imbalance, central nervous system dysfunction, liver dysfunction, cardiac dysfunction, pulmonary oedema).

Search methods for identification of studies

Electronic searches

We will search the Cochrane Kidney and Transplant Register of Studies through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources.

1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

2. Weekly searches of MEDLINE OVID SP

3. Searches of kidney and transplant journals and the proceedings and abstracts from major kidney and transplant conferences

4. Searching the current year of EMBASE OVID SP

5. Weekly current awareness alerts for selected kidney and transplant journals

6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of search strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available on the Cochrane Kidney and Transplant website under CKT Register of Studies.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

1. Reference lists of review articles, relevant studies and clinical practice guidelines.

2. Contacting relevant individuals/organisations seeking information about unpublished or incomplete studies.

3. Grey literature sources (e.g. abstracts, dissertations and theses), in addition to those already included in the Cochrane Kidney and Transplant Register of Studies, will be searched.

Data collection and analysis

Selection of studies

The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by three authors (GCB, CIE, RRD), who will discard studies that are not suitably matching with our criterion for the review; however, studies and reviews that might include relevant data or information on trials will be retained initially. Two authors will independently assess retrieved abstracts and, if necessary, the full text of these studies to determine which studies satisfy the inclusion criteria. Disagreements will be resolved in consultation with other authors (RR, EH).

Data extraction and management

Data extraction will be carried out independently by three authors (GCB, RRD, CIE) using standard data extraction forms. Disagreements will be resolved in consultation with a fourth author (EH). Studies reported in non‐English language journals will be translated before assessment. Where more than one publication of one study exists, reports will be grouped together, and the publication with the most complete data will be used in the analyses. Where relevant outcomes are only published in earlier versions, these data will be used. Any discrepancy between published versions will be highlighted.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2022) (see Appendix 2).

• Was there adequate sequence generation (selection bias)?

• Was allocation adequately concealed (selection bias)?

• Was knowledge of the allocated interventions adequately prevented during the study?

  • Participants and personnel (performance bias)

  • Outcome assessors (detection bias)

• Were incomplete outcome data adequately addressed (attrition bias)?

• Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

• Was the study apparently free of other problems that could put it at risk of bias?

Measures of treatment effect

For dichotomous outcomes (number developing AKI, death, number needing KRT), results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (length of hospital stay, change in SCr, change in GFR, fluid balance, change in AKI biomarkers such as cystatin C and urinary beta 2 globulin), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used. If standard deviations (SD) are not available from the authors of the studies, we will impute SD using Cochrane methods.

Unit of analysis issues

Data from the first phase of cross‐over studies, if these data are available, will be used. Data that are expressed in different scales will be analysed using the SMD.

Dealing with missing data

Missing data from studies will be reported, including dropouts in individual studies. We will try to find out the reason for the dropouts. In case of missing or incomplete data or where the reasons for dropouts are not reported, we will try to get information from the contact authors. Quantitative analysis will be performed on an Intention‐to‐treat (ITT) basis.

Assessment of heterogeneity

We will first assess the heterogeneity by visual inspection of the forest plot. We will quantify statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values will be as follows (Deeks 2022).

• 0% to 40%: might not be important

• 30% to 60%: may represent moderate heterogeneity*

• 50% to 90%: may represent substantial heterogeneity*

• 75% to 100%: considerable heterogeneity*.

*The importance of the observed value of the I² statistic depends on the magnitude and direction of effects and the strength of evidence for heterogeneity (e.g. P value from the Chi² test, or a CI for the I² statistic: uncertainty in the value of the I² statistic is substantial when the number of studies is small).

Assessment of reporting biases

A detailed electronic search along with a search of trial registers will be done to minimize publication bias. We will use funnel plots to assess the small study bias if 10 or more studies are identified (Higgins 2022). Visual inspection of the funnel plot will be used to identify asymmetry.

Data synthesis

Data for the prevention and treatment of AKI will be pooled separately using the random effects model, but the fixed effects model will also be used to ensure the robustness of the model selected and for susceptibility to outliers. Data from the first phase of the study will be used for cross‐over trials, if available, the data will be expressed as mean difference (MD) with 95% CI in case of continuous data and risk ratio (RR) with 95% CI in case of categorical data

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be used to explore possible sources of heterogeneity. We will use the following pre‐specified subgroup analysis for the primary outcomes:

• Different study populations (neonates and children)

• Different exposures (e.g. infants undergoing cardiac surgery, radiocontrast agents, birth asphyxia, prematurity)

• Type of interventions (whole body cooling versus selective head cooling; different drug dosage; different fluid regimen)

• Prevention or treatment of AKI

• Different study settings (developing versus developed world)

Sensitivity analysis

Sensitivity analysis will be performed in order to investigate the robustness of the estimate and to explore the impact of the following factors on effect size:

• Repeating the analysis, excluding unpublished studies

• Repeating the analysis taking account of the risk of bias, as specified

• Repeating the analysis, excluding any very long or large studies to establish how much they dominate the results

• Repeating the analysis excluding studies using the following filters: diagnostic criteria, the language of publication, source of funding (industry versus other), and country.

Summary of findings and assessment of the certainty of the evidence

We will present the main results of the review in 'Summary of findings' tables. These tables present key information concerning the certainty of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2022a). The 'Summary of findings' tables also include an overall grading of the evidence related to each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach (GRADE 2008; GRADE 2011). The GRADE approach defines the certainty of a body of evidence as the extent to which one can be confident that an estimate of effect or association is close to the true quantity of specific interest. This will be assessed by two authors. The certainty of a body of evidence involves consideration of the within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, the precision of effect estimates and risk of publication bias (Schunemann 2022b). We plan to present the following outcomes in the 'Summary of findings' tables.

• Development of AKI

• Need for RRT or KRT

• Death

• Adverse events

Appendices

Appendix 1. Electronic search strategies

Database	Search terms
CENTRAL	("acute kidney failure" or "acute renal failure"):ti,ab,kw ("acute kidney injury"):ti,ab,kw ("acute kidney insufficiency"):ti,ab,kw ("acute renal insufficiency"):ti,ab,kw {or 1‐4} (infant* or infancy or newborn* or baby or babies or neonat* or preterm or prematur* or postmatur* or child* or schoolchild* or school age* or preschool* or kid or kids or toddler* or adolesc* or teen* or boy* or girl* or minor or minors or pubert* or pubescen* or prepubescen* or paediatric* or pediatric* or nursery school* or kindergar* or primary school* or secondary school* or elementary school* or high school* or highschool*):ti,ab,kw {and 5‐6}
MEDLINE	exp Acute Kidney Injury/ (acute kidney failure or acute renal failure).tw. (acute kidney injur$ or acute renal injur$).tw. (acute kidney insufficie$ or acute renal insufficie$).tw. acute tubular necrosis.tw. (ARI or AKI or AKF or ATN).tw. or/1‐6 exp Infant/ or exp Child/ or Adolescent/ or exp Puberty/ or Pediatrics/ or exp Schools/ (infant* or infancy or newborn* or baby or babies or neonat* or preterm or prematur* or postmatur* or child* or schoolchild* or school age* or preschool* or kid or kids or toddler* or adolesc* or teen* or boy* or girl* or minor or minors or pubert* or pubescen* or prepubescen* or paediatric* or pediatric* or nursery school* or kindergar* or primary school* or secondary school* or elementary school* or high school* or highschool*).tw. or/8‐9 and/7,10
EMBASE	acute kidney failure/ acute kidney tubule necrosis/ (acute kidney failure or acute renal failure).tw. (acute kidney injur$ or acute renal injur$).tw. (acute kidney insufficie$ or acute renal insufficie$).tw. acute tubular necrosis.tw (ARI or AKI or ARF or AKF or ATN).tw or/1‐7 exp child/ or exp infant/ or adolescent/ or exp adolescence/ or school/ or pediatrics/ or child urology/ (infant* or infancy or newborn* or baby or babies or neonat* or preterm or prematur* or postmatur* or child* or schoolchild* or school age* or preschool* or kid or kids or toddler* or adolesc* or teen* or boy* or girl* or minor or minors or pubert* or pubescen* or prepubescen* or paediatric* or pediatric* or nursery school* or kindergar* or primary school* or secondary school* or elementary school* or high school* or highschool*).tw or/9‐10

 

Appendix 2. Risk of bias assessment tool

Potential source of bias	Assessment criteria
Random sequence generation Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence	Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimisation (minimisation may be implemented without a random element, and this is considered to be equivalent to being random).
	High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
	Unclear: Insufficient information about the sequence generation process to permit judgement.
Allocation concealment Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment	Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web‐based, and pharmacy‐controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
	High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non‐opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
	Unclear: Randomisation stated but no information on method used is available.
Blinding of participants and personnel Performance bias due to knowledge of the allocated interventions by participants and personnel during the study	Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Blinding of outcome assessment Detection bias due to knowledge of the allocated interventions by outcome assessors.	Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
	High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
	Unclear: Insufficient information to permit judgement
Incomplete outcome data Attrition bias due to amount, nature or handling of incomplete outcome data.	Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
	High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as‐treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
	Unclear: Insufficient information to permit judgement
Selective reporting Reporting bias due to selective outcome reporting	Low risk of bias: The study protocol is available and all of the study’s pre‐specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre‐specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre‐specified (convincing text of this nature may be uncommon).
	High risk of bias: Not all of the study’s pre‐specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. sub‐scales) that were not pre‐specified; one or more reported primary outcomes were not pre‐specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta‐analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
	Unclear: Insufficient information to permit judgement
Other bias Bias due to problems not covered elsewhere in the table	Low risk of bias: The study appears to be free of other sources of bias.
	High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data‐dependent process (including a formal‐stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
	Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Contributions of authors

1. Draft the protocol: GCB, RRD, CIE, EH, RR

2. Study selection: GCB, RRD, CIE

3. Extract data from studies: GCB, RRD, CE

4. Enter data into RevMan: GCB, RRD, CIE

5. Carry out the analysis: GCB, RRD, CE

6. Interpret the analysis: GCB, EH, RR, RRD, CIE

7. Draft the final review: GCB, RRD, CIE, EH, RR

8. Disagreement resolution: EH, RR

9. Update the review: GCB, RRD

Sources of support

Internal sources

• Division of Pediatric Nephrology, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), India

External sources

• No sources of support provided

Declarations of interest

• Girish C Bhatt: no relevant interests were disclosed

• Christopher I Esezobor: no relevant interests were disclosed

• Rupesh Raina: no relevant interests were disclosed

• Elisabeth M Hodson: no relevant interests were disclosed

• Rashmi R Das: no relevant interests were disclosed

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