Corticosteroid therapy for nephrotic syndrome in children

Deirdre Hahn; Susan M Samuel; Narelle S Willis; Jonathan C Craig; Elisabeth M Hodson

doi:10.1002/14651858.CD001533.pub6

. 2020 Aug 31;2020(8):CD001533. doi: 10.1002/14651858.CD001533.pub6

Corticosteroid therapy for nephrotic syndrome in children

Deirdre Hahn ¹, Susan M Samuel ², Narelle S Willis ^3,⁴, Jonathan C Craig ^4,⁵, Elisabeth M Hodson ^3,^4,^✉

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC8094227 PMID: 35659203

Abstract

Background

In nephrotic syndrome protein leaks from blood into the urine through the glomeruli resulting in hypoproteinaemia and generalised oedema. While most children with nephrotic syndrome respond to corticosteroids, 80% experience a relapsing course. Corticosteroids have reduced the death rate to around 3%. However, corticosteroids have well recognised potentially serious adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis, and behavioural disturbances. This is an update of a review first published in 2000 and updated in 2002, 2005, 2007, and 2015.

Objectives

The aim of this review was to assess the benefits and harms of different corticosteroid regimens in children with steroid‐sensitive nephrotic syndrome (SSNS). The benefits and harms of therapy were studied in two groups of children 1) children in their initial episode of SSNS, and 2) children who experience a relapsing course of SSNS.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies up to 30 May 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria

Randomised controlled trials (RCTs) performed in children (one to 18 years) in their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent.

Data collection and analysis

Two authors independently assessed risk of bias and extracted data. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).

Main results

In this 2020 review update 16 new included studies were identified providing a total of 48 included studies with 3941 randomised participants.

Risk of bias methodology was often poorly performed with only 25 studies and 22 studies respectively assessed to be at low risk for random sequence generation and allocation concealment. Only nine studies (19%) were at low risk of bias for performance (blinding of participants and personnel) and 11 studies were at low risk of detection bias (blinding of outcome assessment); nine of these studies were placebo‐controlled RCTs. Twenty‐two studies (fewer than 50%) were at low risk for attrition bias and 23 studies were at low risk for reporting bias (selective outcome reporting).

In seven studies, which evaluated children in their initial episode of SSNS and were at low risk of bias for selection bias, there is little or no difference in the number of children with frequent relapses when comparing two months of prednisone with three months or more (RR 0.99, 95% CI 0.82 to 1.19; 585 participants, 4 studies; I² = 0%) or when comparing three months with five to seven months of therapy (RR 0.99, 95% CI 0.74 to 1.33; 376 participants, 3 studies; I² = 35%; high certainty evidence). In analyses of eight studies at low risk of selection bias, there is little or no difference in the number of children with any relapse by 12 to 24 months when comparing two months of prednisone with three months or more (RR 0.91, 95% CI 0.78 to 1.06; 637 participants; 5 studies; I² = 47%) or when comparing three months with five to seven months of therapy (RR 0.88, 95% CI 0.70 to 1.11; 377 participants, 3 studies; I² = 53%). Little or no difference was noted in adverse effects between the different treatment durations.

Among children with relapsing SSNS, two small studies showed that time to remission did not differ between prednisone doses of 1 mg/kg compared with the conventional dose of 2 mg/kg (MD 0.71 days, 95% CI ‐0.43 to 1.86; 79 participants) and that the total prednisone dose administered was lower (MD ‐20.60 mg/kg, 95% CI ‐25.65 to ‐15.55; 20 participants). Two studies found little or no difference in the number with relapse at six months when comparing dosing by weight with dosing by surface area (RR 1.03, 95% CI 0.71 to 1.49; 146 participants). One study found a reduced risk of relapse with low daily dosing compared with alternate daily dosing (MD ‐0.90 number of relapses/year, 95% CI ‐1.33 to ‐0.47). Four studies found that in children with frequently relapsing disease, daily prednisone during viral infections compared with alternate‐day prednisone or no treatment reduced the risk of relapse.

Authors' conclusions

There are now four well designed studies randomising 823 children which have clearly demonstrated that there is no benefit of prolonging prednisone therapy beyond two to three months in the first episode of SSNS. Small studies in children with relapsing disease have identified no differences in the times to remission using half the conventional induction dose of 2 mg/kg or 60 mg/m². It is imperative that a much larger study be carried out to confirm these findings.

Lower dose prednisone therapy administered daily during an upper respiratory infection or other infection reduces the risk of relapse compared with continuing alternate‐day prednisone or no prednisone based on four small studies. The results of a much larger RCT enrolling more than 300 children are awaited to determine the relative efficacies and adverse effects of using alternate‐day compared with daily prednisone to prevent relapse in children with intercurrent infections.

Plain language summary

Corticosteroid therapy for children with nephrotic syndrome

What is the issue?

Nephrotic syndrome is a condition where the kidneys leak protein from the blood into the urine. When untreated, children can suffer from serious infections. In most children with nephrotic syndrome, this protein leak resolves with corticosteroid drugs (prednisone, prednisolone) reducing the risk of serious infection. However, children usually have repeat episodes which are often triggered by viral infections. Corticosteroid drugs can have serious side effects in children so we need to know the best way to use them.

What did we do?

We looked at evidence from 48 studies randomising 3941 children. Fourteen studies, in children with their first episode of nephrotic syndrome, evaluated prednisone for two or three months compared with longer durations. Thirteen studies evaluated different corticosteroid regimens in children with frequently relapsing disease (FRNS). Studies were of variable quality with only about half of the studies at low risk of producing biased results.

What did we find?

In high quality studies, there was no difference in the risk of relapse or in the number of children who relapse frequently between long duration (three to seven months) and shorter durations (two to three months) of prednisone (high certainty evidence). Giving daily rather than alternate‐day prednisone during a viral infection may reduce the number of children who relapse with infection. Two very small studies suggested that lower doses of prednisone can be used to achieve and maintain remission.

Conclusions

Children with their first episode of nephrotic syndrome only need two or three months of prednisone since longer courses do not reduce the risk of relapse or reduce the risk that the child will relapse frequently. We need more information to determine whether giving daily prednisone during an infection reduces the risk of relapse. We need a large study to determine whether we can use lower doses of prednisone to treat a relapse in children with nephrotic syndrome.

Summary of findings

Background

Description of the condition

Nephrotic syndrome is the most common acquired childhood kidney disease. The characteristic features, including oedema, proteinuria and hypoalbuminaemia, result from alterations of the perm‐selectivity barrier of the glomerular capillary wall.

The reported incidence is 2 to 7/100,000 children, with a prevalence of 16/100,000 (Eddy 2003). There are marked differences in the incidence of nephrotic syndrome depending on ethnicity with proportions ranging from 1.15 to 16.9/100,000 children with the highest incidence in children from south Asia (Noone 2018). Most children have minimal change disease, in which changes on light microscopy are minor or absent and respond to corticosteroid agents. The histological variant seen and the response to immunosuppressive treatment varies with ethnicity (Eddy 2003). Steroid‐sensitive nephrotic syndrome (SSNS) is less common in African and African‐American children, and in South Africa only 7.2% of 236 African children had SSNS compared with 62% of 286 Indian children (Bhimma 1997). The pathogenesis of SSNS remains unknown but appears to be related to abnormalities in T‐cell and B‐cell regulation leading to injury of the podocyte, a key component of the glomerular filtration barrier.

About 80% of children who respond to corticosteroids experience a relapsing course with recurrent episodes of oedema and proteinuria (Koskimies 1982; Tarshish 1997). The complications of nephrotic syndrome are related to effects of the disease itself, and to adverse effects related to corticosteroid therapy and to corticosteroid sparing agents. Children with nephrotic syndrome are at increased risk of bacterial infection (characteristically resulting in peritonitis, cellulitis, or septicaemia), thromboembolic phenomena, protein calorie malnutrition, and acute kidney injury. Before antibiotics became available, two thirds of children with nephrotic syndrome died. Death rates fell to 35% with the introduction of sulphonamides and penicillin (Arneil 1971) and fell further with the use of corticosteroid medications (Arneil 1956).

Description of the intervention

Corticosteroids have been used to treat childhood nephrotic syndrome since 1950 when large doses of adrenocorticotrophic hormone (ACTH) and cortisone given for two to three weeks were found to induce diuresis with loss of oedema and proteinuria (Arneil 1956, Arneil 1971). Corticosteroid usage has reduced the death rate in childhood nephrotic syndrome to around 3%, with infection remaining the most important cause of death (ISKDC 1984). Of children who present with their first episode of nephrotic syndrome, approximately 80% will achieve remission with corticosteroid therapy (Koskimies 1982). Because of this dramatic before‐after treatment evidence, oral corticosteroids are the first‐line treatment of a child presenting with idiopathic nephrotic syndrome and no randomised controlled prospective studies of corticosteroids compared to placebo were carried out. The achievement of remission with corticosteroid therapy determines long term prognosis for kidney function irrespective of kidney histology (Niaudet 2009). However, corticosteroids have well documented adverse effects in children. Major complications related to prolonged corticosteroid use in nephrotic syndrome include growth impairment, particularly with steroid therapy administered daily (Hyams 1988), cataracts (Aydin 2019; Ng 2001), arterial hypertension (Aydin 2019) and excessive weight gain or obesity (Ruth 2005). Two studies (Mishra 2010; Neuhaus 2010) highlight the impact of psychological and behavioural abnormalities related to corticosteroid therapy. Anxiety, depression, emotional lability, aggressive behaviour and attention problems had already developed with completion of 12 weeks of therapy (Mishra 2010). Neuhaus 2010 demonstrated that family background, particularly maternal distress, reduced the quality of life and psychosocial adjustment. Patients and families report challenges in living with the disease because the condition is poorly understood and the clinical course is uncertain (Beanlands 2017). Adverse effects are particularly prevalent in those children who relapse frequently and require multiple courses of corticosteroids.

How the intervention might work

Glucocorticoids are potent anti‐inflammatory and immunosuppressant drugs. The effects of glucocorticoids are known to be mediated by both genomic and non‐genomic mechanisms (Schijvens 2019). It is widely believed the main effect is through the regulation of nuclear gene expression via the cytosolic glucocorticoid receptor, which activates genes for anti‐inflammatory cytokines and suppresses genes for pro‐inflammatory cytokines (Kadmiel 2013; Kirshcke 2014; Ponticelli 2018). Glucocorticoids are lipid soluble and can easily pass through cell membranes. This process takes several hours. More recently research had identified corticosteroid effects, which are independent of nuclear gene transcription and occur earlier (Ramamoorthy 2016). These are mediated via interactions of various kinases with cytosolic or membrane‐bound glucocorticoid receptors and do not require protein synthesis. At high glucocorticoid doses, suppression of T‐cell function occurs. Corticosteroids also act directly to stabilise the podocyte cytoskeleton (Guess 2010; Ohashi 2011).

Why it is important to do this review

The original treatment schedules for childhood nephrotic syndrome were developed in an ad hoc manner more than 50 years ago. The International Study of Kidney Disease in Children (ISKDC) was established in 1966 and determined by consensus a regimen of daily corticosteroids for four weeks followed by corticosteroids given on three consecutive days out of seven for four weeks (Arneil 1971). Since then, many physicians have used regimens involving periods of daily followed by alternate‐day or intermittent therapy and RCTs have investigated different durations and total corticosteroid therapy doses in an effort to delineate the optimal doses and durations of corticosteroid therapy balancing efficacy and toxicity. These have been evaluated in previous versions of this systematic review. However, despite these data, there remains no consensus on the most appropriate corticosteroid regimen to achieve and maintain remission with the least adverse effects. Observational data (Raja 2017) and very small RCTs (Borovitz 2020; Sheikh 2019) suggest that children can be successfully treated with smaller doses and durations of corticosteroid therapy. Therefore, the 2020 update of this review has been undertaken to identify whether new RCTs, which evaluate different corticosteroid regimens in the initial episode of SSNS and in relapsing disease, provide additional information on the most effective corticosteroid therapy for steroid sensitive nephrotic syndrome in children.

Objectives

The aim of this review was to assess the benefits and harms of different corticosteroid regimens in children with SSNS. The benefits and harms of therapy were studied in two groups of children:

Children in their initial episode of SSNS
Children who experience a relapsing course of SSNS.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs and quasi‐RCTs were included in which different doses, dose strategies, routes of administration and durations of treatment with prednisone, prednisolone or other corticosteroid agent are compared in the treatment of SSNS in children.

Types of participants

Inclusion criteria

Children aged one to 18 years with SSNS (i.e. become oedema free with urine protein ≤ 1+ on dipstick, urinary protein/creatinine ratio ≤ 20 mg/mmol or ≤ 4 mg/m²/hour for three consecutive days while receiving corticosteroid therapy). A kidney biopsy diagnosis of minimal change disease was not required for inclusion of the study.

Children with initial episode of SSNS
Children with relapsing SSNS

Exclusion criteria

Children with steroid‐resistant nephrotic syndrome (failure to achieve remission following four weeks or more of prednisone at 60 mg/m²/day) or congenital or infantile nephrotic syndrome
Children with other kidney or systemic forms of nephrotic syndrome defined on kidney biopsy, clinical features or serology (e.g. idiopathic membranous glomerulonephritis, mesangiocapillary glomerulonephritis, post‐infectious glomerulonephritis, Henoch‐Schönlein nephritis, systemic lupus erythematosus)

Types of interventions

Prednisone, prednisolone, or other corticosteroid medication given orally or intravenously. The following aspects of the corticosteroid regimens were considered.

Shorter duration compared with two months of corticosteroid treatment
Longer durations compared with three months or more of corticosteroid treatment
Comparisons of different doses of corticosteroid medication given for induction of a remission
Comparisons of other regimens of corticosteroid therapy
Different corticosteroid agents (e.g. deflazacort, methylprednisolone) compared with standard agents (e.g. prednisone, prednisolone)
Comparisons of daily, alternate‐day or intermittent administration of corticosteroid medication. Intermittent administration refers to the administration of corticosteroids on three consecutive days of seven days
Single daily dose compared with divided daily doses of corticosteroid medication.

Types of outcome measures

Primary outcomes

The numbers of children with and without relapse at 12 months or more after completion of treatment.
The number of children who developed frequently relapsing nephrotic syndrome (FRNS).

Secondary outcomes

Mean relapse rates
Serious adverse events including reduced growth rates, hypertension, cataracts/glaucoma, psychological disorders, infections, thromboses and osteoporosis
Cumulative corticosteroid dosage

Search methods for identification of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Register of Studies up to 30 May 2020 through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources.

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Searches of kidney and transplant journals, and the proceedings and abstracts from major kidney and transplant conferences
Searching of the current year of EMBASE OVID SP
Weekly current awareness alerts for selected kidney and transplant journals
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.

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

Searching other resources

Reference lists of review articles, relevant studies, and clinical practice guidelines.
Contacting relevant individuals/organisations seeking information about unpublished or incomplete studies.
Conference proceedings of meetings of the International Pediatric Nephrology Association and European Society for Paediatric Nephrology.

Data collection and analysis

Selection of studies

The initial review was undertaken by four authors. The titles and abstracts were screened by two authors who discarded studies that were not relevant (i.e. studies of lipid lowering agents) although studies and reviews that could have included relevant data or information on studies were retained initially. Three authors independently assessed abstracts, and if necessary, the full text, to determine which studies satisfied the characteristics required for inclusion. Updates in 2003, 2005, 2007 and 2015 were undertaken by three or four authors (DH, EH, NW, JC). The 2020 update was undertaken by three reviewers (DH, SS, EH) with final review by two other reviewers (NW and JC).

Data extraction and management

Data extraction and assessment of risk of bias were performed by two authors using standardised data extraction forms. Studies in languages other than English were translated before data extraction. Where more than one report of a study was identified, data were extracted from all reports. Where there were discrepancies between reports, data from the primary source was used. Study authors were contacted for additional information about studies where possible.

Assessment of risk of bias in included studies

For this update, the following items were assessed independently by two authors using the risk of bias assessment tool (Higgins 2011) (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 a risk of bias?

Measures of treatment effect

For dichotomous outcomes (relapse or no relapse, side effects) the risk ratio (RR) for individual studies were calculated and summary statistics estimated using the random effects model and results compared to those obtained using a fixed effects model. Where continuous scales of measurement were used to assess the effects of treatment (cumulative steroid therapy, relapse rate), these data were analysed as the mean difference (MD) or standardised mean difference (SMD) if different scales had been used. The time to relapse was not included since many children did not experience relapse so the data would be biased.

Unit of analysis issues

Data from cross‐over studies were included in the meta‐analyses if separate data for the first part of the study were available. Otherwise results of cross‐over studies were reported in the text only.

Dealing with missing data

We aimed to analyse available data in meta‐analyses using ITT data. However, where ITT data were not provided, or additional information could not be obtained from authors, available published data were used in the analyses.

Assessment of heterogeneity

We first assessed the heterogeneity by visual inspection of the forest plot. We then quantified 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 is as follows.

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 I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P‐value from the Chi² test, or a confidence interval for I²) (Higgins 2011).

Assessment of reporting biases

The search strategy used aimed to reduce publication bias caused by lack of publication of studies with negative results. Where there were several publications on the same study, all reports were reviewed to ensure that all details of methods and results were included to reduce the risk of selective outcome reporting bias.

Data synthesis

Data were combined using random effects model for dichotomous and continuous data.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was used to investigate between study differences based on risk of bias, differences between definitions of FRNS and different durations of treatment in the experimental group in studies of initial treatment with different durations of prednisone.

Sensitivity analysis

Where a single study differed considerably from the other studies in the meta‐analysis, this study was temporarily excluded to determine whether its removal altered the results of the meta‐analysis.

Summary of findings and assessment of the certainty of the evidence

We presented the main results of the review in 'Summary of findings' tables. These tables present key information concerning the quality of the evidence, the magnitude of the effects of the interventions examined, and the sum of the available data for the main outcomes (Schunemann 2011a). 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 quality 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. The quality of a body of evidence involves consideration of within‐trial risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias (Schunemann 2011b). We presented the following outcomes in the 'Summary of findings' tables.

Outcomes included in Summary of Findings Tables

Number with relapse
Number with frequent relapse (total and stratified for risk of bias)
Adverse effects (psychological disturbances, hypertension, Cushing's Syndrome, eye complications)

Results

Description of studies

Results of the search

Search results are shown in Figure 1.

For the 2020 update, our search (to 30 May 2020) identified 34 new reports. After full‐text review, 14 new included studies were identified (16 reports); one previous ongoing study has now been included. In addition, 12 new reports of six existing studies were identified. Two studies (APN 2006; Zhang 2014), which evaluated non‐corticosteroid agents with prednisone in the initial episode of SSNS, have been transferred to the Cochrane review evaluating non‐corticosteroid agents in SSNS (Larkins 2020) so that this review now only includes studies assessing corticosteroids. No other new excluded studies were identified. Five new ongoing studies were identified (CTRI/2015/11/006345; CTRI/2018/05/013634; CTRI/2018/05/014075; RESTERN 2017; Sinha 2016) and one study (PREDNOS 2 2014) identified in Hahn 2015 is continuing.

For the search results of our previous reviews please see (Hodson 2002; Hodson 2003; Hodson 2005; Hodson 2007; Hahn 2015).

Included studies

The 48 included studies randomised/analysed 3941/3659 children and were divided into groups according to the comparisons of corticosteroid regimens. Most studies used prednisone or prednisolone. For ease of reading, the term "prednisone" has been used in the text for both medications.

Three months or more versus two months therapy in the initial episode of SSNS (13 studies; 1465 randomised children)

Thirteen studies (APN 1993; Bagga 1999; Jayantha 2002a; Ksiazek 1995 (Groups 1 and 3); Moundekhel 2012; Norero 1996; Paul 2014; PREDNOS 2019; PREDNOS PILOT 2019; Satomura 2001; Ueda 1988; Yoshikawa 1998; Yoshikawa 2015) compared durations of two months with three months or more of prednisone therapy. In all of these studies except Satomura 2001, increased duration of treatment resulted in increased total prednisone dose compared with the control group. Satomura 2001 compared three months of treatment with two months using the same total dose of prednisone in each group. In Ksiazek 1995, which compared three different regimens, data from the two month therapy group (Group 3) and the group treated for six months (group 1) were included in the meta‐analysis. Norero 1996 excluded those children who became steroid dependent. In this update, Yoshikawa 1998, which compared two months of prednisone with 4.5 months with both groups received the Chinese herb, Sairei‐to, was included in this analysis on the assumption that the effect of the herb would be the same in both treatment groups. Data from Paul 2014 could not be included in meta‐analyses because of differential loss to follow up, with loss to follow up of 15/47 children (33%) in the 12‐week treatment group compared with 6/46 children (13%) in the 8‐week treatment group.

Five to seven months versus three months therapy in the initial episode of SSNS (nine studies; 992 randomised children)

Nine studies (Al Talhi 2018; Anand 2013; Hiraoka 2003; Ksiazek 1995 (Groups 1 and 2); Mishra 2012, Pecoraro 2003; Sharma 2002; Sinha 2015; Teeninga 2013) compared five to seven months with three months of prednisone therapy. One study including 60 children (Anand 2013) did not report the numbers of children treated in each group so data from only eight studies could be included in the meta‐analyses. Increased duration of prednisone treatment led to increased total prednisone dose compared with the three month group in all studies except Teeninga 2013, who compared three months with six months therapy, using the same total dose of prednisone in both groups. From Ksiazek 1995, data from the experimental groups treated for three months (group 2) and six months (group 1) were included in this analysis. Pecoraro 2003 included three groups ‐ a control group treated for three months and two experimental groups treated for six months with different total doses of prednisone. Only the control group and treatment group 1 (total prednisone dose 5235 mg/m²) were included in the meta‐analysis.

Daily prednisone treatment during viral infections in children with relapsing or initial episode of SSNS (four studies; 224 randomised children)

Three studies (Abeyagunawardena 2008; Gulati 2011; Mattoo 2000) compared daily with alternate‐day prednisone to prevent relapse during viral infections in children with SSNS receiving alternate‐day prednisone. One study (Abeyagunawardena 2014) compared daily prednisone with placebo to prevent relapse during upper respiratory tract viral infections in children not receiving prednisone.

Deflazacort versus prednisone therapy in children with relapsing or initial episode of SSNS (four studies; 118 randomised children)

Four studies explored different regimens of deflazacort versus prednisone.

Agarwal 2010 compared deflazacort with prednisone in children with the initial episode of SSNS but the details of the intervention were not reported
Broyer 1997 compared deflazacort with an equivalent dose of prednisone with reducing doses over 12 months in children with steroid dependent SSNS
Liern 2008 compared deflazacort with methylprednisolone for 12 weeks in children with relapsing SSNS in a cross over study
Singhal 2015 compared deflazacort with prednisone for 12 weeks in children with the initial episode of SSNS

Oral methylprednisolone regimens in children with the initial episode of SSNS (three studies; 113 randomised children)

Three studies compared different regimens of methylprednisolone with prednisone

Imbasciati 1985 compared six months of treatment commencing with methylprednisolone with prednisone with six months of prednisone
Mocan 1999 compared 14 days of high dose methylprednisolone with six months of prednisone
Zhang 2007d compared six months of treatment involving methylprednisolone with six months of prednisone. The details of interventions were not reported.

One month therapy versus two months of therapy in the initial episode of SSNS (one study; 61 randomised children)

APN 1988 compared less than two months of prednisone with two months.

Five months versus 12 months therapy in the initial episode of SSNS (one study; 58 randomised children)

Kleinknecht 1982 compared five months of prednisone with 12 months; the timing of the follow‐up period in relation to the duration of initial therapy was not stated.

Different total doses of prednisone given for three months in the initial episode of SSNS (one study; 68 randomised children)

Hiraoka 2000 compared a higher dose versus a conventional dose of prednisone given for three months.

Alternate‐day therapy versus intermittent therapy in relapsing SSNS (one study; 64 randomised children)

APN 1981 compared an alternate‐day prednisone regimen with three out of seven day regimen to maintain remission.

Daily therapy versus intermittent therapy in relapsing SSNS (one study; 64 randomised children)

ISKDC 1979 compared a daily prednisone regimen with a 3 out of 7 day regimen to maintain remission.

Single daily doses versus multiple daily doses in relapsing nephrotic syndrome (two studies; 150 randomised children)

Ekka 1997 and Li 1994 compared a single daily dose of prednisone with three times/day dosing to achieve remission

Low versus conventional dose prednisone in relapsing nephrotic syndrome (three studies; 130 randomised children)

Borovitz 2020 compared two reduced doses (1 mg/kg/day; 1.5 mg/kg/day) with conventional dose prednisone 2 mg/kg/day to achieve remission
Sheikh 2019 compared reduced dose (1 mg/kg/day) of prednisone with conventional dose (2 mg/kg/day) to achieve remission
Kansal 2019 compared different alternate‐day prednisone doses in the second month of initial treatment to maintain remission

Daily versus alternate‐day prednisone in relapsing nephrotic syndrome (one study; 62 randomised children)

Yadav 2019 compared daily with alternate‐day prednisone for one year in children with frequently relapsing SSNS

Weight‐based versus body surface area‐based dosing of prednisone in the initial episode of SSNS (two studies; 160 randomised children)

Two studies (Basu 2020; Raman 2016) compared weight‐based dosing with body surface area‐based dosing in children with their initial episode of SSNS and with relapse of SSNS.

Alternate‐day prednisone for four weeks versus eight week weaning regimen in relapsing nephrotic syndrome (one study; 126 randomised children)

PROPINE 2018 compared four weeks of alternate‐day prednisone with an eight week weaning regimen using the same cumulative prednisone dose. The authors reported that the probability of remission at one year was similar between groups.

Three months or more versus two months therapy in relapsing nephrotic syndrome (one study; 129 randomised children)

Jayantha 2002b compared two months of prednisone with seven months in children with relapsing nephrotic syndrome.

Addition of cortisol to prednisone regimen compared with no cortisol addition in relapsing nephrotic syndrome (one cross‐over study: 13 randomised children)

Leisti 1978 compared the addition of cortisol supplementation with no cortisol In children with relapsing nephrotic syndrome and a subnormal response to 2 hour ACTH test 1 to 12 days after completing prednisone,

Excluded studies

In the 2015 review (Hahn 2015), we excluded 33 studies (47 reports) after full text assessment for this review. Of these 33 excluded studies, six were not RCTs and 27 were RCTs involving non‐corticosteroid interventions in children with SSNS. In the 2020 review these studies have been removed. In addition, two studies previously included (APN 2006; Zhang 2014) were excluded from this review and transferred to the Cochrane review of "Non‐corticosteroid interventions in children with steroid sensitive nephrotic syndrome" (Larkins 2020).

Risk of bias in included studies

Risk of bias assessments were performed using Cochrane's risk of bias assessment tool (Appendix 2). Summaries of risk of bias assessments are shown in Figure 2; Figure 3.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Random sequence generation was considered at low risk of bias in 25 studies (Abeyagunawardena 2008; Abeyagunawardena 2014; Agarwal 2010; APN 1993; Bagga 1999; Basu 2020; Broyer 1997; Gulati 2011; Hiraoka 2003; Imbasciati 1985; Jayantha 2002a; Jayantha 2002b; Kleinknecht 1982; Liern 2008; Mishra 2012; PREDNOS 2019; PREDNOS PILOT 2019; Raman 2016; Sharma 2002; Singhal 2015; Sinha 2015; Teeninga 2013; Yadav 2019; Yoshikawa 1998; Yoshikawa 2015) and high risk in seven studies (Borovitz 2020; Li 1994; Mattoo 2000; Mocan 1999; Moundekhel 2012; Pecoraro 2003; Satomura 2001). Sequence generation methods was assessed as unclear in the remaining 16 studies.

Allocation concealment was considered to be at low risk of bias in 22 studies (Abeyagunawardena 2008; Abeyagunawardena 2014; Al Talhi 2018; APN 1981; APN 1988; APN 1993; Bagga 1999; Basu 2020; Broyer 1997; Gulati 2011; Hiraoka 2003; Imbasciati 1985; Kleinknecht 1982; Liern 2008; PREDNOS 2019; PREDNOS PILOT 2019; Raman 2016; Sinha 2015; Teeninga 2013; Yadav 2019; Yoshikawa 1998; Yoshikawa 2015) and at high risk of bias in nine studies (Borovitz 2020; Ksiazek 1995; Li 1994; Mattoo 2000; Mocan 1999; Moundekhel 2012; Norero 1996; Pecoraro 2003; Satomura 2001). Ksiazek 1995 stated that parents could influence which treatment group their child was assigned. Allocation concealment methods was assessed as unclear in the remaining 17 studies.

Blinding

Nine studies were considered to be at low risk of performance and detection bias because they were placebo controlled studies (Abeyagunawardena 2008; Abeyagunawardena 2014; Broyer 1997; Leisti 1978; Liern 2008; PREDNOS 2019; PREDNOS PILOT 2019; Sinha 2015; Teeninga 2013). Basu 2020 and Yoshikawa 2015 was open‐label studies so at high risk of performance bias but were at low risk of detection bias. Kansal 2019 was assessed as unclear risk for both performance and detection bias. The remaining studies were at high risk of both performance and detection bias. Most studies reported the primary outcome of relapse using the ISKDC definition of relapse (ISKDC 1970).

Incomplete outcome data

We assessed 22 studies to be at low risk of attrition bias because they reported fewer than 10% of participants lost to follow‐up or excluded from analysis (Al Talhi 2018; APN 1993; Bagga 1999; Basu 2020; Borovitz 2020; Broyer 1997; Hiraoka 2000; Hiraoka 2003; Imbasciati 1985; Ksiazek 1995; Leisti 1978; Mattoo 2000; Mishra 2012; PREDNOS 2019; PREDNOS PILOT 2019; Raman 2016; Sheikh 2019; Singhal 2015; Sinha 2015; Teeninga 2013; Yadav 2019; Yoshikawa 2015). Fifteen studies were considered at high risk of attrition bias because more than 10% of participants were lost to follow‐up or excluded from the analysis (Abeyagunawardena 2008; Abeyagunawardena 2014; APN 1981; APN 1988; Ekka 1997; Gulati 2011; ISKDC 1979; Jayantha 2002a; Jayantha 2002b; Mocan 1999; Norero 1996; Paul 2014; PROPINE 2018; Sharma 2002; Yoshikawa 1998). The remaining 11 studies were considered to be unclear risk of attrition bias.

Selective reporting

Studies were deemed to be at risk of reporting bias if outcome data did not include one or more outcomes of FRNS, relapse rate and adverse events. Studies were also considered to be at high risk of bias if data were provided in a format, which could not be entered into the meta‐analyses. Cross‐over studies were considered to be at high risk of bias if data from the first and second parts of the study were not separable. Twenty‐three studies were at low risk of reporting bias (Al Talhi 2018; APN 1981; APN 1993; Bagga 1999; Basu 2020; Broyer 1997; Ekka 1997; Gulati 2011; Hiraoka 2000; Hiraoka 2003; Imbasciati 1985; Jayantha 2002a; Norero 1996; PREDNOS 2019; PREDNOS PILOT 2019; Sharma 2002; Sheikh 2019; Singhal 2015; Sinha 2015; Teeninga 2013; Yadav 2019; Yoshikawa 2015; Ueda 1988). There were 19 studies at high risk of selective reporting bias (Abeyagunawardena 2008; Abeyagunawardena 2014; APN 1988; Borovitz 2020; ISKDC 1979; Jayantha 2002b; Kleinknecht 1982; Ksiazek 1995; Leisti 1978; Li 1994; Liern 2008; Mattoo 2000; Mocan 1999; Moundekhel 2012; Paul 2014; Pecoraro 2003; PROPINE 2018; Raman 2016; Yoshikawa 1998). The remaining six studies were at unclear risk of selective reporting bias.

Other potential sources of bias

Fifteen studies were considered at low risk of potential bias as they were funded by educational or philanthropic organisations or stated that they received no funding (Abeyagunawardena 2008; APN 1981; APN 1988; Bagga 1999; Basu 2020; Gulati 2011; Leisti 1978; Norero 1996; PREDNOS 2019; PREDNOS PILOT 2019; Sinha 2015; Teeninga 2013; Ueda 1988; Yadav 2019; Yoshikawa 2015). One study was considered to be at high risk of bias as it was funded by industry and no full‐text publication has been identified 10 years after the first conference abstract (Pecoraro 2003). The remaining 32 studies were deemed unclear of other risk of bias as no information on funding sources was provided.

In Ueda 1988 the calculated total protocol dose (4620 mg/m²) exceeded the dose administered (3132 ± 417 mg/m²) suggesting that the protocol was not adhered to in all patients. In three studies (Jayantha 2002a; Ksiazek 1995; Ueda 1988) the numbers of children in the treatment and control groups differed markedly.

Effects of interventions

See: Table 1; Table 2

Summary of findings 1. Steroid therapy in first episode of nephrotic syndrome: 3 months or more versus 2 months of therapy for nephrotic syndrome in children.

Steroid therapy in first episode of nephrotic syndrome: 3 months or more versus 2 months of therapy for nephrotic syndrome in children
Patient or population: children with nephrotic syndrome Setting: paediatric or paediatric nephrology services Intervention: steroid therapy in first episode of nephrotic syndrome: 3 months or more Comparison: 2 months of therapy
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Certainty of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Risk with 2 months of therapy	Risk with 3 months or more of therapy
Number with frequent relapses by 12 to 24 months	450 per 1,000	387 per 1,000 (319 to 477)	RR 0.86 (0.71 to 1.06)	976 (8)	⊕⊕⊕⊝¹ MODERATE
Number of children relapsing by 12 to 24 months	646 per 1,000	497 per 1,000 (407 to 614)	RR 0.77 (0.63 to 0.95)	1309 (12)	⊕⊕⊝⊝^1,2 LOW
Number with frequent relapses by 12 to 24 months stratified by risk of selection bias: Low risk of selection bias	413 per 1,000	409 per 1,000 (339 to 491)	RR 0.99 (0.82 to 1.19)	585 (4)	⊕⊕⊕⊕ HIGH
Number with frequent relapses by 12 to 24 months stratified by risk of selection bias: Unclear or high risk of bias for allocation bias	357 per 1,000	161 per 1,000 (93 to 275)	RR 0.45 (0.26 to 0.77)	220 (3)	⊕⊕⊝⊝ ^1,2 LOW
Adverse events: psychological disorders	470 per 1,000	470 per 1,000 (249 to 894)	RR 1.00 (0.53 to 1.90)	456 (4)	⊕⊕⊝⊝^2,3 LOW
Adverse events: hypertension	50 per 1,000	89 per 1,000 (28 to 287)	RR 1.78 (0.55 to 5.73)	548 (7)	⊕⊕⊕⊝ ¹ MODERATE
Adverse events: Cushing's syndrome	402 per 1,000	450 per 1,000 (305 to 663)	RR 1.12 (0.76 to 1.65)	547 (5)	⊕⊕⊕⊝¹ MODERATE
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: Confidence interval; RR: Risk ratio
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

Date	Event	Description
30 May 2020	New citation required but conclusions have not changed	Conclusions unchanged from previous update
30 May 2020	New search has been performed	16 new studies added to review

Date	Event	Description
16 September 2015	Amended	Minor amendment to forest plot description 2.8.2 ‐ changed from 'Low risk...' to "High risk..."
11 March 2015	New search has been performed	New studies identified
11 March 2015	New citation required and conclusions have changed	10 new studies included
13 May 2009	Amended	Contact details updated.
23 September 2008	Amended	Converted to new review format.
21 August 2007	New citation required and conclusions have changed	Substantive amendment

Database	Search terms
CENTRAL	MeSH descriptor: [Nephrotic Syndrome] this term only MeSH descriptor: [Nephrosis, Lipoid] this term only "nephrotic syndrome" "lipoid nephrosis" #1 or #2 or #3 or #4 child* or infant* boy* or girl* pediatric* or paediatric* #6 or #7 or #8 #5 and #9
MEDLINE	nephrotic syndrome/ nephrosis, lipoid/ nephrotic syndrome.tw. lipoid nephrosis.tw. or/1‐4 exp child/ exp Infant/ child$.tw. infant$.tw. (boy$ or girl$).tw. (pediatric or paediatric).tw. or/7‐12 and/5,12
EMBASE	nephrotic syndrome/ lipoid nephrosis/ nephrotic syndrome.tw. lipoid nephrosis.tw. or/1‐4 exp Child/ child$.tw. infant$.tw. (boy$ or girl$).tw. (pediatric or paediatric).tw or/6‐10 and/5,11

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.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Number with frequent relapses by 12 to 24 months	8	976	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.71, 1.06]
1.2 Number of children relapsing by 12 to 24 months	12	1309	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.63, 0.95]
1.3 Number with frequent relapses by 12 to 24 months stratified by risk of bias for selection bias	7	805	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.59, 1.06]
1.3.1 Low risk of selection bias	4	585	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.82, 1.19]
1.3.2 Unclear or high risk of selection bias	3	220	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.26, 0.77]
1.4 Number of children relapsing by 12 to 24 months stratified by risk of selection bias	11	1108	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.65, 0.95]
1.4.1 Low risk of selection bias	5	637	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.78, 1.06]
1.4.2 Unclear or high risk of selection bias	6	471	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.49, 0.98]
1.5 Adverse events	8		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.5.1 Psychological disorders	4	456	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.53, 1.90]
1.5.2 Hypertension	7	548	Risk Ratio (M‐H, Random, 95% CI)	1.78 [0.55, 5.73]
1.5.3 Cataracts/eye disorders	6	623	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.11, 1.52]
1.5.4 Retarded growth	4	354	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.25, 1.18]
1.5.5 Cushingoid facies	5	547	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.76, 1.65]
1.5.6 Infections	2	172	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.53, 1.17]
1.5.7 Osteoporosis	3	233	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.06, 3.38]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Number with frequent relapses by 12 to 24 months	6	706	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.49, 1.09]
2.2 Number of children relapsing by 12 to 24 months	7	762	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.45, 0.85]
2.3 Number with frequent relapses stratified by risk of selection bias	6	706	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.49, 1.09]
2.3.1 Studies at low risk of selection bias	3	376	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.74, 1.33]
2.3.2 Studies at high or unclear risk of selection bias	3	330	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.32, 0.72]
2.4 Number of children relapsing by 12 to 24 months stratified by risk of selection bias	7	762	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.45, 0.85]
2.4.1 Studies at low risk of selection bias	3	376	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.69, 1.11]
2.4.2 Studies at high or unclear risk of selection bias	4	386	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.34, 0.67]
2.5 Adverse events	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.5.1 Hypertension	6	752	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.71, 1.74]
2.5.2 Eye complications	5	614	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.18, 1.17]
2.5.3 Infections	5	702	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.65, 1.46]
2.5.4 Cushingoid appearance	6	762	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.60, 1.23]
2.5.5 Gastrointestinal bleeding	1	140	Risk Ratio (M‐H, Random, 95% CI)	1.50 [0.26, 8.70]
2.5.6 Addisonian crisis	1	140	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.05, 5.39]
2.5.7 Psychological disorders	4	505	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.05, 1.83]
2.5.8 Growth	3	436	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.36, 1.48]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
3.1 Number of children relapsing by 6 to 12 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.2 Number of children relapsing by 12 to 24 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.3 Number with frequent relapses	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
5.1 Relapse at 12 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.2 Number with FRNS	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.3 Adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.3.1 Hypertension	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.3.2 Psychological disorders	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.3.3 Cushing's Syndrome	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Time to remission	2	38	Mean Difference (IV, Random, 95% CI)	‐5.54 [‐8.46, ‐2.61]
6.2 Number with relapse	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
7.1 Number with relapse with infection	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
7.2 Number of relapses/patient	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
7.2.1 Number of infection‐related relapses/patient/year	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
7.2.2 Total relapses (episodes/patient/1 year)	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
7.3 Number of relapses/patient at 2 years	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 Number with remission	2	67	Risk Ratio (M‐H, Random, 95% CI)	1.08 [0.94, 1.24]
8.2 Number of children with relapse by 9 to 12 months	2	63	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.27, 0.78]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Number of children relapsing during therapy	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9.1.1 Intermittent dose versus alternate‐day therapy (6 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9.1.2 Daily versus intermittent therapy (2 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9.2 Number of children with relapses by 9 to 12 months	4		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9.2.1 Intermittent dose versus alternate‐day therapy (6 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9.2.2 Single versus divided dose therapy (2 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9.2.3 Intravenous versus oral therapy (6 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9.2.4 Prolonged oral versus intermittent therapy (2 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9.3 Mean time to relapse	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
9.3.1 Single versus divided dose therapy (2 months therapy)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
9.3.2 Daily versus intermittent therapy (2 months therapy)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
9.4 Mean relapse rate/patient/year	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
9.4.1 Single versus divided dose therapy (2 months therapy)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
9.4.2 Daily versus intermittent therapy (2 months therapy)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
9.5 Cumulative steroid dose	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
9.6 Mean time to remission	2	138	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.98, 1.06]
9.7 Serious adverse events	2	138	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.18, 0.91]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Time to remission with different prednisone doses	2	79	Mean Difference (IV, Random, 95% CI)	0.71 [‐0.43, 1.86]
10.2 Cumulative prednisone dose to achieve remission	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
10.3 Number with relapse	2	59	Risk Ratio (M‐H, Random, 95% CI)	0.66 [0.16, 2.68]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
11.1 Number of relapses in 12 months	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
11.2 Adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
11.2.1 Cushingoid facies	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
11.2.2 Cataracts	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Relapse at 6 months	2	146	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.71, 1.49]
12.2 Adverse effects	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
12.2.1 Cushingoid features	2	144	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.58, 2.32]
12.2.2 Serious infections	2	144	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.20, 1.66]
12.2.3 Eye changes	1	84	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.05, 5.57]
12.2.4 Hypertension	2	144	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.05, 1.73]
12.3 Prednisone dose	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
12.3.1 Induction dose	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
12.3.2 Cumulative dose over 6 months	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
13.1 Number with relapses	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13.1.1 Relapse by 6 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13.1.2 Relapse by 12 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13.1.3 Relapse by 2 years	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13.1.4 Relapse by 3 years	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13.2 Relapse rate/patient/year	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
13.2.1 Relapse rate at 1 year	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
13.2.2 Relapse rate at 2 years	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
13.2.3 Relapse rate at 3 years	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
13.3 Number with FRNS or SDNS	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13.4 Cumulative steroid dose	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
13.4.1 After 1 year	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
13.4.2 After 2 years	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
13.4.3 After 3 years	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
13.5 Adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13.5.1 Number with hypertension	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13.5.2 Number with growth failure	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

*Study characteristics*
Methods	Study design: cross‐over RCT Time frame: July 2003 to January 2005. Study continued until 40 children had 2 URTIs Duration of follow‐up: until child had 2 URTI
Participants	Country: Sri Lanka Setting: single tertiary referral centre Inclusion criteria: children aged 1 to 16 years with FRNS receiving maintenance low dose (0.1 to 0.6 mg/kg) alternate‐day oral prednisolone Number (analysed/recruited): 40/48; treatment group first (18); control group first (22) Median age (range): 5.3 years (1.5 to 13.2) Sex (M/F): 29/11 Exclusion criteria: glucocorticoid related side effects; frequent relapses requiring steroid sparing agents; did not have two viral infections within study period; sustained remission with disease stability
Interventions	Treatment group Prednisolone: 5 mg daily for 7 days at onset of viral infection. Additional medication given on alternate days to achieve daily prednisone Control group Placebo: alternate days for 7 days at onset of viral infection. Additional medication given on alternate days to achieve placebo administration on alternate days with continuing prednisone on alternate days Randomised at onset of URTI to receive one of the interventions. At next URTI received alternate therapy
Outcomes	Number relapsing during 6 months of therapy and in subsequent 6 months Mean relapse rate during treatment and in subsequent 6 months
Notes	Definitions FRNS: 2+ relapses within 6 months of first response or 4 relapses in any 1 year (ISKDC definition) Relapse: urine protein excretion 3+ or more on urinalysis for 3 consecutive days in patient who had previously been in remission Remission: urinary protein excretion negative or trace on urinalysis for 3 consecutive days URTI: presence of 3 or more of the following criteria ‐ cough, runny nose, sore throat, lethargy, body aches and fever Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomly allocated, sealed envelopes, sequential patients
Allocation concealment (selection bias)	Low risk	Randomly allocated, sealed envelopes
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Investigators and parents blinded to contents of containers
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Investigators and parents blinded to contents of containers
Incomplete outcome data (attrition bias) All outcomes	High risk	8/48 excluded from study (17%) for need for additional immunosuppression (4), no second viral infection (3), number without further relapses (1)
Selective reporting (reporting bias)	High risk	Not all the review's pre‐specified outcomes were recorded; no mention of adverse events
Other bias	Low risk	The study appears to be free of other source of bias

*Study characteristics*
Methods	Study design: double‐blind placebo controlled, cross‐over RCT Time frame: recruited January 2011 to March 2011 Duration of follow‐up: 24 months
Participants	Country: Sri Lanka Setting: tertiary referral university centre Inclusion criteria: children with FRNS off prednisone for 3 months or more Number (analysed/randomised): treatment group first (19/27); control group first (14/21) Mean age ± SD (years): treatment group first (12.0 ± 2.4); control group first (10.0 ± 2.9) Sex (M/F): treatment group first (12/7); control group first (9/5) Exclusion criteria: children with SSNS receiving alternate‐day prednisone
Interventions	Treatment group Prednisolone: 0.5 mg/kg/day for 5 days at start of each URTI for 12 months and then crossed over to control group Control group Placebo for 5 days at start of each URTI for 12 months and then crossed over to treatment group
Outcomes	Number of relapses associated with URTI in each year
Notes	Abstract‐only publication Definitions of SDNS, URTI and relapse not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "At the time of enrolment in the study, the patients were randomised into two groups using the envelope method"
Allocation concealment (selection bias)	Low risk	QUOTE: "At the time of enrolment in the study, the patients were randomised into two groups using the envelope method"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "Group 1 patients were provided a bottle labeled "Drug A" containing 100 5‐mg tablets and group 2 patients received "Drug B" containing 100 5‐mg tablets."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "Group 1 patients were provided a bottle labeled "Drug A" containing 100 5‐mg tablets and group 2 patients received "Drug B" containing 100 5‐mg tablets."
Incomplete outcome data (attrition bias) All outcomes	High risk	15/48 (31%) did not complete both parts of the 2 year cross‐over study
Selective reporting (reporting bias)	High risk	No report of adverse effects; cross‐over study and no separate results available for first part of the study so results could not be included in meta‐analyses
Other bias	Unclear risk	Insufficient information to permit judgement

*Study characteristics*
Methods	Study design: parallel RCT Time frame: not reported Duration of follow‐up: 6 months
Participants	Country: India Setting: single centre Inclusion criteria: children with initial episode of INS Number: treatment group (22); control group (20) Mean age ± SD (years): not reported Gender: not reported Exclusion criteria: not reported
Interventions	Treatment group Deflazacort (dose and duration not reported) Control group Prednisolone (dose and duration not reported)
Outcomes	Remission at 2 and 6 weeks BMD
Notes	Abstract‐only publication
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomisation
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Not all prespecified outcomes mentioned but only abstract available
Other bias	Unclear risk	insufficient information to permit judgement

*Study characteristics*
Methods	Study design: parallel group RCT Time frame: 12 month period starting April 2015, end date May 2016 Follow‐up: 6 months
Participants	Country: India Setting: Single centre renal clinic Inclusion criteria: children with initial episode or IFR SSNS Number (analysed/randomised): treatment group 1 (30/30); treatment group 2 (30/30) Mean age ± SD (years): treatment group 1 (5.77 ± 2.2); treatment group 2 (5.47 ± 2.6) Sex (M/F): treatment group 1 (19/11); treatment group 2 (21/9) Initial episode/infrequently relapsing SSNS: treatment group 1 (11/19); treatment group 2 (15/15) Exclusion criteria: SRNS; secondary nephrotic syndrome; anaemia; leucopenia, thrombocytopenia; abnormal LFT; active chronic infection (HIV, Hepatitis B or C, TB) live vaccination in past month
Interventions	Treatment group 1 (weight‐based dosing) Prednisone 2 mg/kg/day in 3 divided doses for 6 weeks in initial episode or till remission for IFR SSNS Then prednisone 1.5 mg/kg on alternate days for 6 weeks in initial episode and for 4 weeks in IFR SSNS Treatment group 2 (BSA‐based dosing) Prednisone 60 mg/m²/day in three divided doses for 6 weeks in initial episode or till remission in IFR SSNS Then 40 mg/m²/day on alternate days for 6 weeks in initial episode and for 4 weeks in IFR SSNS
Outcomes	Primary outcome: relapse‐free survival at 6 months Secondary outcomes: Cumulative steroid dose to achieve remission. All patients and for initial episode/IFR SSNS Cumulative steroid dose during 6 months. All patients and for initial episode/IFR SSNS Time to remission. All patients and for initial episode/IFR SSNS Adverse events
Notes	Definitions used from Indian Pediatric Nephrology Group, Indian Academy of Pediatrics. Management of steroid sensitive nephrotic syndrome: revised guidelines. Indian Pediatr. 2008;45:203‐14. Trial Registration CTRI/2015/03/005655 Funding source: none reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomisation with variable blocks; stratified for sex, initial episode versus IFR SSNS
Allocation concealment (selection bias)	Low risk	Opaque sealed envelopes Investigators responsible for enrolment, randomisation, group assignment
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Primary outcome was relapse and this was confirmed by laboratory measurement of urinary protein/creatinine ratio, which is unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed 6 months follow up
Selective reporting (reporting bias)	Low risk	All expected outcomes reported on
Other bias	Low risk	Authors stated that they received no external funding for the study

PERMALINK

Corticosteroid therapy for nephrotic syndrome in children

Deirdre Hahn

Susan M Samuel

Narelle S Willis

Jonathan C Craig

Elisabeth M Hodson

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Outcomes included in Summary of Findings Tables

Results

Description of studies

Results of the search

1.

Included studies

Three months or more versus two months therapy in the initial episode of SSNS (13 studies; 1465 randomised children)

Five to seven months versus three months therapy in the initial episode of SSNS (nine studies; 992 randomised children)

Daily prednisone treatment during viral infections in children with relapsing or initial episode of SSNS (four studies; 224 randomised children)

Deflazacort versus prednisone therapy in children with relapsing or initial episode of SSNS (four studies; 118 randomised children)

Oral methylprednisolone regimens in children with the initial episode of SSNS (three studies; 113 randomised children)

One month therapy versus two months of therapy in the initial episode of SSNS (one study; 61 randomised children)

Five months versus 12 months therapy in the initial episode of SSNS (one study; 58 randomised children)

Different total doses of prednisone given for three months in the initial episode of SSNS (one study; 68 randomised children)

Alternate‐day therapy versus intermittent therapy in relapsing SSNS (one study; 64 randomised children)

Daily therapy versus intermittent therapy in relapsing SSNS (one study; 64 randomised children)

Single daily doses versus multiple daily doses in relapsing nephrotic syndrome (two studies; 150 randomised children)

Low versus conventional dose prednisone in relapsing nephrotic syndrome (three studies; 130 randomised children)

Daily versus alternate‐day prednisone in relapsing nephrotic syndrome (one study; 62 randomised children)

Weight‐based versus body surface area‐based dosing of prednisone in the initial episode of SSNS (two studies; 160 randomised children)

Alternate‐day prednisone for four weeks versus eight week weaning regimen in relapsing nephrotic syndrome (one study; 126 randomised children)

Three months or more versus two months therapy in relapsing nephrotic syndrome (one study; 129 randomised children)

Addition of cortisol to prednisone regimen compared with no cortisol addition in relapsing nephrotic syndrome (one cross‐over study: 13 randomised children)

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

*Study characteristics*
Methods	Study design: parallel RCT Time period: not reported Follow‐up: 1 year
Participants	Country: France Setting: multicentre, renal clinics Inclusion criteria: children with SDNS (2+ relapses in 12 months despite alternate‐day prednisone or within 2 months of stopping this regimen). Number: treatment group 1 (20); treatment group 2 (20) Mean age ± SD (years): treatment group 1 (9.2 ± 2.7); treatment group 2 (8.5 ± 4) Sex (M/F): treatment group 1 (15/5); treatment group 2 (17/3) Exclusion criteria: not reported
Interventions	Treatment group 1 Deflazacort: dose equivalent to prednisone of 60 mg/m²/day till in remission for 5 days then 60 mg/m² on alternate days for 6 weeks, taper 6 to 8 weeks then 15 to 20 mg/m² on alternate days for 1 year Treatment group 2 Prednisone given as above
Outcomes	Number relapsing during 1 year of therapy Mean relapse rate/patient Serious adverse events
Notes	Six children in treatment group and 5 in control group also received cyclosporin Definitions Relapse: not reported Remission: not reported Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Blocks of 10 packages containing equal numbers of each intervention in order determined by random code"
Allocation concealment (selection bias)	Low risk	QUOTE: "Block randomisation and sealed packages, lots of 10"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of participants and key study personnel ensured. QUOTE: "Medication in identical bottles and identical tablets"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of outcome assessment ensured. QUOTE: "Blinded until end of study"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawal/lost to follow‐up: 2/40 (loss to follow‐up (1); protocol treatment deviation (1))
Selective reporting (reporting bias)	Low risk	All the review's pre‐specified outcomes have been reported (cannot report on SDNS, as all remained on steroids as per protocol).
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

*Study characteristics*
Methods	Study design: RCT Time frame: March 2014 to July 2015 Follow‐up: 6 months
Participants	Country: India Setting: single centre Inclusion criteria: children with SSNS, treated with prednisone for first time or following relapse (includes frequently and infrequent relapsers) Number (analysed/randomised): treatment group 1 (44/50); treatment group 2 (42/50) Mean age (years): treatment group 1 (5.4 ± 2.9); treatment group 2 (5.2 ± 2.5) Sex (M/F): treatment group 1 (27/13); treatment group (27/13) Exclusion criteria: infants; secondary nephrotic syndrome; children with BSA > 1 m² and weight > 30 kg; active infection
Interventions	Treatment group 1 (Body weight based) Prednisolone: 2 mg/kg daily (maximum 60 mg) in two divided doses for 6 weeks, 1.5 mg/kg (maximum 40 mg) on alternate days for 6 weeks Treatment group 2 (BSA‐based) Prednisolone: 60 mg/m² daily (maximum 60 mg) in 2 divided doses for 6 weeks, 40mg/m² alternate days for 6 weeks,
Outcomes	Time taken for remission Number of relapses Cumulative dose of prednisolone Adverse effects
Notes	CTRI/2014/04/004541 The median cumulative dose of prednisone was 81 mg/kg (IQR 30 to 115) in the BW‐based group and 96 mg/kg (IQR 36 to 130) in the BSA group Funding source: Supported, in part, by institutional and departmental funds
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE "Block randomization using 20 blocks of two block sizes (4 and 6) was generated using random allocation software version 2.0 (Informer Technologies, Inc.) to allocate the enrolled subjects into one of two groups (BW‐based or BSA‐based prednisolone regimen) in an allocation ratio of 1:1 by a person not directly involved with data collection, analysis or interpretation. This randomization list was concealed from the investigators carrying out the study"
Allocation concealment (selection bias)	Low risk	QUOTE: "Allocation was concealed placing individual assignments (folded twice) in serially numbered, sealed opaque envelopes by a person not involved in the trial".
Blinding of participants and personnel (performance bias) All outcomes	High risk	Clinicians not blinded but statistician was blinded to treatment groups
Blinding of outcome assessment (detection bias) All outcomes	High risk	QUOTE: The clinicians were not blinded but "the statistician was blinded to the assigned interventions until initial analysis and preparation of the first draft of manuscript".
Incomplete outcome data (attrition bias) All outcomes	Low risk	44/49 analysed for primary outcome. 7/100 (7%) not analysed
Selective reporting (reporting bias)	High risk	Outcomes presented as medians with ranges and not able to add to meta‐ analyses
Other bias	Unclear risk	Insufficient information to permit judgement

*Study characteristics*
Methods	Study design: quasi‐RCT Study duration: not reported Duration of follow‐up: 1 year
Participants	Country: Japan Setting: multicentre, renal clinics Inclusion criteria: initial episode of SSNS Number: treatment group 1 (37); treatment group 2 (36) Mean age ± SD (years): not reported Sex (M/F): not reported Exclusion criteria: not reported
Interventions	Treatment group 1 (high dose) Prednisolone: 60 mg/m²/day for 4 weeks; 40 mg/m² on alternate days for 4 weeks Total duration: 8 weeks Treatment group 2 (low dose) Prednisolone: 40 mg/m²/day for 4 weeks; 40 mg/kg on alternate days for 8 weeks Total duration: 12 weeks
Outcomes	Number with relapse at 12 months Time to relapse
Notes	Abstract‐only publication No definitions provided Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Patients assigned "alternately"
Allocation concealment (selection bias)	High risk	"Alternation" used
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not reported and the outcome is likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	High risk	Blinding of outcome assessment not reported and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient data to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient data to permit judgement
Other bias	Unclear risk	Insufficient data to permit judgement

*Study characteristics*
Methods	Study design: RCT Time frame: not reported (last follow‐up September 2019) Follow‐up: 12 months
Participants	Country: India Setting: government hospital Inclusion criteria: children aged 1 to 12 years with relapse of SSNS Number: treatment group 1 (30); treatment group 2 (30) Mean age ± SD (years): not reported Sex (M/F): treatment group 1: not reported Exclusion criteria: children with infections; co‐morbidities; other immunosuppression
Interventions	Treatment group 1 (low dose) Prednisolone: 1 mg/kg/day until remission Therapy switched to 2 mg/kg if not in remission by day 15 Total dose: total 3150mg/m² Treatment group 2 (conventional dose) Prednisolone 2 mg/kg/day until day 15 or disease remission
Outcomes	Time to remission Number of relapses in each group
Notes	Abstract‐only publication Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Said to be randomised, insufficient information to permit judgement
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded and outcome is likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not blinded and outcome is likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients appear accounted for
Selective reporting (reporting bias)	Low risk	Pre‐specified outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

*Study characteristics*
Methods	Study design: RCT Time frame: commenced March 2011 Follow‐up: 6 months post initial therapy
Participants	Country: India Setting: single centre Inclusion criteria: children with initial episode of SSNS Number: treatment group 1 (12); treatment group 2 (13) Mean age ± SD (years): treatment group 1 (3.54 ± 1.21); treatment group 2 (5.53 ± 3.73) Sex (M/F): treatment group 1 (7/5); treatment group 2 (7/6) Exclusion criteria: children with nephrotic syndrome secondary to systemic disorder or drugs
Interventions	Treatment group 1 Deflazacort: 2.4 mg/kg daily for 6 weeks in 2‐3 divided doses; 1.8 mg/kg in a single dose alternate days for 6 weeks Total duration: 12 weeks Treatment group 2 Prednisolone: 2 mg/kg daily for 6 weeks; 1.5 mg/kg alternate days for 6 weeks Total duration: 12 weeks
Outcomes	Time taken to induce remission Number of relapses on and off treatment in both groups
Notes	Funding source: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random table
Allocation concealment (selection bias)	Unclear risk	Insufficient data to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded and lack of blinding may influence outcome
Blinding of outcome assessment (detection bias) All outcomes	High risk	Not blinded and lack of blinding may influence outcome
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Low risk	All prespecified outcomes mentioned
Other bias	Unclear risk	Insufficient data to permit judgement

Study	Reason for exclusion
APN 2006	RCT comparing cyclosporin with prednisone. Transferred to Cochrane Review on "Non‐corticosteroid immunosuppressive agents for steroid‐sensitive nephrotic syndrome in children"
Zhang 2014	RCT comparing azithromycin with prednisone. Transferred to Cochrane Review on "Non‐corticosteroid immunosuppressive agents for steroid‐sensitive nephrotic syndrome in children"

Study name	Efficacy of short prednisolone treatment for relapse in children with steroid sensitive nephrotic syndrome: a randomised controlled study
Methods	Parallel RCT
Participants	114 children aged 1 to 16 years with SSNS and relapse
Interventions	Treatment group 1 Prednisolone: 2 mg/kg daily till remission, then 1.5 mg/kg on alternate days for 2 weeks Treatment group 2 Prednisolone: 2 mg/kg daily till remission, then 1.5 mg/kg on alternate days for 4 weeks
Outcomes	Time to first relapse Relapse rates Cumulative dose of steroids Adverse effects of steroids
Starting date	15/12/2015
Contact information	Professor Pankaj Hari; pankajhari@hotmail.com
Notes

Study name	A randomised controlled clinical trial to compare the efficacy of standard dose of steroids vs reduced dose in treating relapses in children with steroid sensitive nephrotic syndrome
Methods	Parallel, open‐label RCT Follow‐up for 6 months
Participants	60 children aged 1 to 18 years. All children with idiopathic nephrotic syndrome on stable immunosuppression (either long‐term alternate‐day steroids, levamisole or MMF) or on no immunosuppression for last 6 months with infrequent relapses defined as < 2 relapses in last 6 months
Interventions	Treatment group Prednisolone: 1 mg/kg every alternate day to treat relapse in children with nephrotic syndrome. Duration unclear. No information on prednisone dose/duration to achieve remission Control group Prednisolone: 1.5 mg/kg every alternate day to treat relapse. Duration unclear but same as experimental group. No information on prednisone dose/duration to achieve remission
Outcomes	Proportion of frequent relapsers on the reduced dose regime as compared to standard regime Number of relapses in children in whom steroid dose is reduced to 1mg/kg on alternate days for 4 weeks instead of the standard 1.5 mg/kg every alternate day in 6 months Cumulative steroid dose in two groups for 6 months
Starting date	1/6/2018
Contact information	Associate Professor Suprita Kalra. kalrasuprita@gmail.com
Notes	Children with SRNS or SSNS commenced on steroid sparing agent in past 6 months because of FRNS or SDNS

Study name	A comparison of two doses of prednisolone for relapses in children with steroid sensitive nephrotic syndrome: a randomised controlled non inferiority trial
Methods	Parallel, open label RCT Follow‐up for 12 months
Participants	60 children aged 1 to 12 years with SSNS presenting with relapse
Interventions	Treatment group Prednisolone: 1mg/kg/day till remission or two weeks whichever is earlier Control group Prednisolone 2mg/kg/day till remission or 2 weeks whichever is earlier
Outcomes	Primary outcome The difference in the mean time to achieve remission between experimental and control groups Secondary outcomes Proportion of children with relapse who achieved remission with 1 mg/kg/day versus 2 mg/kg/day of oral prednisolone within 4 weeks Time to first relapse after treatment of a relapse over 12 months Number of relapses over the subsequent 12 months over 12 months Cumulative dose of steroids Adverse effects
Starting date	01/06/2018
Contact information	Kirtisudha Mishra. kirtisen@gmail.com
Notes	Children receiving non‐corticosteroid immunosuppressive agents are excluded

Study name	Short course daily prednisolone therapy at the time of upper respiratory infection in children with relapsing steroid sensitive nephrotic syndrome: The PREDNOS 2 study
Methods	Parallel RCT
Participants	Subjects aged over 1 to 19 years with relapsing SSNS who have had two or more relapses in the preceding 12 months
Interventions	Standard course therapy Weeks 1 to 4 prednisolone 60 mg/m²/day (max 80 mg), weeks 5 to 8, prednisolone 40 mg/m² on alternate days for 28 days Extended course therapy Weeks 1 to 4 60mg/m²/day, weeks 5 to 16 prednisolone 60 mg/m² on alternate days tapering by 10 mg/m² every 2 weeks
Outcomes	Primary outcome measure Incidence of URTI‐related relapse following the first URTI during the 12 month follow‐up period Secondary outcome measures Rate of URTI‐related relapse of nephrotic syndrome (relapses per year) Rate of relapse (URTI‐related and non URTI‐related) of nephrotic syndrome (relapses per year) Cumulative dose of prednisolone (mg/kg and mg/m2) received over the 12 month study period Incidence of serious adverse events Incidence of adverse effects of prednisolone including assessment of behaviour using the Achenbach Child Behaviour Checklist Incidence of escalation of background immunosuppressive therapy (e.g. addition of cyclosporin, tacrolimus, cyclophosphamide etc.) Incidence of reduction of background immunosuppressive therapy (i.e. cessation of long term maintenance prednisolone therapy) Quality of life using the CHU‐9D, EQ‐5D and PedsQL Cost per relapse of nephrotic syndrome Cost per QALY gained
Starting date	1 November 2010
Contact information	Martin Christian: Martin.Christian@nuh.nhs.uk
Notes