Corticosteroid therapy for nephrotic syndrome in children

Abstract

Background

In nephrotic syndrome, protein leaks from the 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 events such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis, cataracts, glaucoma and behavioural disturbances. This is an update of a review first published in 2000 and updated in 2002, 2005, 2007, 2015 and 2020.

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 contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 9 July 2024 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 Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov.

Selection criteria

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

Data collection and analysis

Summary estimates of effects were obtained using a random‐effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Main results

In this 2024 update, we included five new studies, resulting in 54 studies randomising 4670 children.

Risk of bias methodology was often poorly performed, with only 31 studies and 28 studies respectively assessed to be at low risk for random sequence generation and allocation concealment. Ten studies were at low risk of performance bias (blinding of participants and personnel), and 12 studies were at low risk of detection bias (blinding of outcome assessment); nine of these studies were placebo‐controlled RCTs. Twenty‐seven studies (fewer than 50%) were at low risk for attrition bias, and 26 studies were at low risk for reporting bias (selective outcome reporting).

In studies at low risk of selection bias evaluating children in their initial episode of SSNS, 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 0.96, 95% CI 0.83 to 1.10; 755 children, 5 studies; I² = 0%; high certainty evidence) or when comparing three months with five to seven months of therapy (RR 0.99, 95% CI 0.74 to 1.33; 376 children, 3 studies; I² = 35%; high certainty evidence). In analyses of 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 0.93, 95% CI 0.81 to 1.06; 808 children; 6 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 children, 3 studies; I² = 53%). Little or no difference was noted in adverse events between the different treatment durations.

Amongst children with relapsing SSNS, four small studies (177 children) utilising lower doses of prednisone compared with standard regimens found little or no differences between groups in the numbers with relapse (RR 1.01, 95% CI 0.85 to 1.20; I² = 0%). A fifth study (117 children) reported little or no difference between two weeks and four weeks of alternate‐day prednisone after remission with daily prednisone.

A recent large, well‐designed study with 271 children found that administering daily prednisone compared with alternate‐day prednisone or no prednisone during viral infection did not reduce the risk of relapse. In contrast, four previous small studies in children with frequently relapsing disease had reported that daily prednisone during viral infections compared with alternate‐day prednisone or no treatment reduced the risk of relapse.

Authors' conclusions

There are four well‐designed studies randomising 823 children, which have 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 efficacy using lower induction doses or shorter durations of prednisone therapy. Large, well‐designed studies are required to confirm these findings. While previous small studies had suggested that changing from alternate‐day to daily prednisone therapy at the onset of infection reduced the likelihood of relapse, a much larger and well‐designed study found no reduction in the number relapsing when administering daily prednisone at the onset of infection.

Plain language summary

What are the benefits and risks of using steroids for treating nephrotic syndrome in children?

Key messages

• Nephrotic syndrome (a condition where the kidneys leak protein from the blood into the urine) is usually treated with steroid medication (powerful anti‐inflammatory medicines).

• Children experiencing nephrotic syndrome for the first time only need two to three months of prednisone (a type of steroid medication), as longer durations do not reduce the risk of a repeat episode or reduce the risk that the child will have frequent repeat episodes.

• Although the risk of side effects may be low, many of the studies did not report information that we could analyse.

What is nephrotic syndrome, and why should you treat it with steroids?

Nephrotic syndrome is a condition where the kidneys leak protein from the blood into the urine. When left untreated, children can suffer from serious infections. In most children with nephrotic syndrome, this protein leak is stopped with steroid therapy. Steroids are powerful anti‐inflammatory medicines and can be used for a wide range of conditions, but they can also have serious side effects. These side effects can include depression and anxiety, high blood pressure, eye disorders such as cataracts, increased risk of infection, weight gain and reduced growth. Children can also have repeat episodes of nephrotic syndrome, which is often triggered by viral infection.

What did we want to find out?

We wanted to find out the best treatment options for children with nephrotic syndrome to stop the leaking of protein from the blood into the urine and to avoid the harmful side effects of steroids.

What did we do?

We searched for all studies that compared the benefits and harms of randomly allocating steroid medicines to:

• children who experience nephrotic syndrome for the first time; or

• children who have frequent repeat episodes of nephrotic syndrome.

We compared and summarised the studies' results and rated our confidence in the information based on factors such as study methods and sizes.

What did we find?

We found 54 studies randomising 4670 children looking at a wide variety of steroid treatment options. Studies were conducted in countries around the world, and most were done in South Asia (23 studies). Twenty‐three studies compared giving the steroid prednisone for two or three months with longer durations (three to seven months) to children who experience nephrotic syndrome for the first time. The remaining studies looked at children who had frequent repeat episodes of nephrotic syndrome.

We found longer durations of prednisone (three to seven months) made little to no difference in the risk of children experiencing repeat episodes of nephrotic syndrome or in the number of children who have frequent repeat episodes compared to shorter durations of prednisone (two to three months). There may be no differences in the type and number of side effects with either longer or shorter durations of steroids; however, these were often not reported by the studies.

What are the limitations of the evidence?

We are confident that children experiencing nephrotic syndrome for the first time only need two to three months of prednisone, as longer durations do not reduce the risk of a repeat episode or reduce the risk that the child will have frequent repeat episodes.

We are less confident in the risk of side effects because many of the studies did not report information that we could use.

How up‐to‐date is the evidence?

The evidence is current to July 2024.

Summary of findings

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

Steroid therapy for the first episode of nephrotic syndrome in children: 3 months or more versus 2 months of therapy
Patient or population: children with nephrotic syndrome Setting: paediatric or paediatric nephrology services Intervention: 3 months or more of steroid therapy Comparison: 2 months of steroid therapy
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Risk with 2 months of therapy	Risk with 3 months or more of therapy
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
Relapsing by 12 to 24 months	637 per 1,000	509 per 1,000 (433 to 611)	RR 0.80 (0.68 to 0.96)	1279 (12)	⊕⊕⊝⊝1,2 LOW
Frequent relapses by 12 to 24 months: low risk of selection bias	480 per 1,000	461 per 1,000 (339 to 528)	RR 0.96 (0.83 to 1.10)	756 (5)	⊕⊕⊕⊕ HIGH
Number with frequent relapses by 12 to 24 months: unclear or high risk of selection bias	333 per 1,000	150 per 1,000 (87 to 257)	RR 0.45 (0.26 to 0.77)	220 (3)	⊕⊕⊝⊝ 1,2 LOW
Adverse events: psychological disorders Median follow up: 2 years	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 Median follow up: 1.5 years	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: Cushingoid facies Median follow up: 2 years	402 per 1,000	450 per 1,000 (305 to 663)	RR 1.12 (0.76 to 1.65)	547 (5)	⊕⊕⊕⊝1 MODERATE
Adverse events: eye disorders Median follow up: 2 years	32 per 1,000	13 per 1,000 (3 to 48)	RR 0.41 (0.11 to 1.52)	623 (6)	⊕⊕⊝⊝2,3 LOW
Adverse events: infections Median follow up: 1.75 years	408 per 1,000	323 per 1,000 (216 to 478)	RR 0.79 (0.53 to 1.17)	172 (2)	⊕⊕⊝⊝2,3 LOW
*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

¹ Significant heterogeneity between studies

² Some studies at high or unclear risk of bias

³ Few studies/events included in analyses

Summary of findings 2. Steroid therapy for the first episode of nephrotic syndrome in children: 5 to 7 months versus 3 months of therapy.

Steroid therapy for the first episode of nephrotic syndrome in children: 5 to 7 months versus 3 months of therapy
Patient or population: nephrotic syndrome in children Setting: paediatric or paediatric nephrology services Intervention: 5 to 7 months of steroid therapy Comparison: 3 months of steroid therapy
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	No. of participants (RCTs)	Certainty of the evidence (GRADE)
	Risk with 3 months	Risk with 5 to 7 months
Number with frequent relapses by 12 to 24 months	387 per 1,000	282 per 1,000 (190 to 422)	RR 0.73 (0.49 to 1.09)	706 (6)	⊕⊕⊕⊝ Moderate 1
Number relapsing by 12 to 24 months	738 per 1,000	472 per 1,000 (369 to 598)	RR 0.64 (0.50 to 0.81)	912 (8)	⊕⊕⊝⊝ Low 1 2
Number relapsing by 12 to 24 months: low risk of selection bias	679 per 1,000	598 per 1,000 (469 to 754)	RR 0.88 (0.69 to 1.11)	376 (3)	⊕⊕⊕⊕ High
Number of children relapsing by 12 to 24 months: unclear of high risk of selection bias	778 per 1,000	412 per 1,000 (319 to 537)	RR 0.53 (0.41 to 0.69)	536 (5)	⊕⊕⊝⊝ Low 1 2
Adverse events: psychological disorders Median follow up: 2 years	53 per 1,000	16 per 1,000 (3 to 96)	RR 0.30 (0.05 to 1.83)	505 (4)	⊕⊕⊕⊝ Moderate 1
Adverse events: hypertension Median follow up: 1.75 years	126 per 1,000	140 per 1,000 (90 to 220)	RR 1.11 (0.71 to 1.74)	752 (6)	⊕⊕⊕⊝ Moderate 2
Adverse events: Cushingoid appearance Median follow up: 1.75 years	375 per 1,000	323 per 1,000 (225 to 461)	RR 0.86 (0.60 to 1.23)	762 (6)	⊕⊕⊕⊝ Moderate 1
Adverse events: eye complications Median follow up: 1.5 years	36 per 1,000	17 per 1,000 (6 to 42)	RR 0.46 (0.18 to 1.17)	614 (5)	⊕⊕⊕⊝ Moderate 2
Adverse events: infections Median follow up: 1.5 years	185 per 1,000	181 per 1,000 (120 to 270)	RR 0.98 (0.65 to 1.46)	702 (5)	⊕⊕⊕⊝ Moderate 1 2
*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

¹ Significant heterogeneity between studies

² Some studies at high or unclear risk of bias

Background

Description of the condition

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

Based on a comprehensive meta‐analysis of 27 studies, the overall incidence of idiopathic nephrotic syndrome was 2.92 (95% confidence intervals (CI) 0.00 to 6.51) per 100,000 children per year (Veltkamp 2021), with no significant variation in incidence between 1945 and 2011. 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 seen 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. Steroid‐sensitive nephrotic syndrome (SSNS) is less common in African and African‐American children, and in South Africa, only 6.7% of 236 African children had SSNS compared with 65% 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.

Many children who respond to corticosteroids experience a relapsing course with recurrent episodes of oedema and proteinuria (Koskimies 1982; Tarshish 1997). While the incidence of idiopathic nephrotic syndrome has not changed, the risk of relapse between 1945 and 2011 has fallen from 87.4% to 66.2% based on the meta‐analysis of 54 studies (Veltkamp 2021). The complications of nephrotic syndrome are related to the effects of the disease itself and to adverse effects related to corticosteroid therapy and corticosteroid‐sparing agents. Children with nephrotic syndrome with frequent relapses, steroid dependence, or late resistance to therapy are at increased risk of bacterial infection (characteristically resulting in peritonitis, cellulitis, or septicaemia), thromboembolic phenomena 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 trials (RCTs) 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 the completion of 12 weeks of therapy (Mishra 2010). Neuhaus 2010 demonstrated that family background, particularly maternal distress, reduced the quality of life (QoL) 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 has 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 small RCTs (Borovitz 2020; Kansal 2019; Kainth 2021; Sheikh 2019; Tu 2022) suggest that children can be successfully treated with smaller doses and durations of corticosteroid therapy. Therefore, this 2024 update was 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 regimens for SSNS 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:

1. Children in their initial episode of SSNS

2. Children who experience a relapsing course of SSNS.

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) were included in which different doses, dose strategies, routes of administration and durations of treatment with prednisone, prednisolone or other corticosteroid agents 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 (UPCR) ≤ 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 in the study.

• Children with an initial episode of SSNS

• Children with relapsing SSNS.

Exclusion criteria

• Children with steroid‐resistant nephrotic syndrome (SRNS) (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, IgA vasculitis, systemic lupus erythematosus).

Types of interventions

Prednisone, prednisolone, or other corticosteroid medication given orally or intravenously (IV) without additional non‐corticosteroid medications, including but not limited to alkylating agents, calcineurin inhibitors, mycophenolic acid derivatives, levamisole, Chinese medications, montelukast and monoclonal Anti‐CD20 antibodies.

The following aspects of the corticosteroid regimens were considered.

• Shorter durations compared with two months or more of corticosteroid treatment

• Longer durations compared with two months or less 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 out of seven days

• Single daily dose compared with divided daily doses of corticosteroid medication.

Types of outcome measures

Primary outcomes

1. The numbers of children with and without relapse at six to 24 months or more after completion of treatment.

2. The number of children who developed frequently relapsing nephrotic syndrome (FRNS) or steroid‐dependent nephrotic syndrome (SDNS).

Secondary outcomes

1. Mean relapse rates

2. Serious adverse events, including psychological disturbances, hypertension, Cushing's Syndrome, eye complications (e.g. cataracts, glaucoma), infections, reduced growth rates, thromboses and osteoporosis

3. Cumulative corticosteroid dosage.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Register of Studies up to 9 July 2024 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 of the current year of EMBASE OVID SP

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

6. Monthly searches of the International Clinical Trials Registry Platform (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

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. 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 authors (DH, SS, EH), with a final review by two other authors (NW and JC). This 2024 update was undertaken by three authors (EH, DH, NW), with a final review by two authors (SS, JC).

Data extraction and management

Two authors used standardised data extraction forms to extract data and assess the risk of bias. 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 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)

• Was 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 (e.g. relapse or no relapse, adverse events), the risk ratio (RR) for individual studies was calculated with 95% CI. Where continuous scales of measurement were used to assess the effects of treatment (e.g. cumulative steroid therapy, relapse rate), these data were analysed as mean differences (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, the 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 intention‐to‐treat (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). The following is a guide to the interpretation of I² values.

• 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 95% CI for I²) (Higgins 2022).

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 of 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 the 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 the 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, it was temporarily excluded to determine whether its removal altered the meta‐analysis's results.

Summary of findings and assessment of the certainty of the evidence

We have 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 (Schünemann 2022a). The summary of findings tables also include an overall grading of the evidence related to each of the main outcomes using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) 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 (Schünemann 2022b). We presented the following outcomes in the 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, infections).

Results

Description of studies

The following section contains broad descriptions of the studies considered in this review. For further details on each individual study, see, Characteristics of included studies, Characteristics of excluded studies and Characteristics of ongoing studies.

Results of the search

For this update, we searched the Cochrane Kidney and Transplant Register of Studies (up to 9 July 2024) and identified 21 new reports. Four new studies (five reports) were included, and eight studies (eight reports) were excluded. We also identified two new reports of two existing included studies and one report of an existing ongoing study. We reassessed and reclassified two ongoing studies (five new reports) as included studies (Kainth 2021; PREDNOS 2 2022).

A total of 54 studies were included (103 reports, 4670 randomised children), 10 studies were excluded, and there are four ongoing studies.

Search results are shown in Figure 1.

1.

Flow diagram for 2024 review update study selection

Included studies

The majority of the studies were performed in South Asia (23 studies), Europe (14 studies), Asia (9 studies), and other regions, including the Middle East, South America and the USA (8 studies).

The number of children randomised ranged from 11 to 271 (median number: 66).

The 54 included studies 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 of therapy in the initial episode of SSNS

Thirteen studies (1465 randomised children) compared durations of two months with three months or more of prednisone therapy (APN 1993; Bagga 1999; Jayantha 2000; 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). Except for Satomura 2001, all these studies increased the duration of treatment, resulting in an 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 children who became steroid‐dependent. In this update, Yoshikawa 1998, which compared two months of prednisone with 4.5 months with both groups receiving 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 eight‐week treatment group.

Five to seven months versus three months of therapy in the initial episode of SSNS

Ten studies (1142 randomised children) compared five to seven months with three months of prednisone therapy (Al Talhi 2018; Anand 2013; Hiraoka 2003; Jamshaid 2022; Ksiazek 1995 (groups 1 and 2); Mishra 2012; Pecoraro 2003; Sharma 2002; Sinha 2015; Teeninga 2013). Anand 2013 (60 children) did not report the number of children treated in each group, so data from only nine 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 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 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 SSNS

Five studies (503 randomised children) evaluated the effect of daily prednisone for five to seven days at the onset of infection to prevent relapse (Abeyagunawardena 2008; Abeyagunawardena 2017; Gulati 2011; Mattoo 2000; PREDNOS 2 2022). Three studies (Abeyagunawardena 2008; Gulati 2011; Mattoo 2000) compared daily with alternate‐day prednisone to prevent relapse during viral infections in children with SSNS. Abeyagunawardena 2017 compared daily prednisone with a placebo to prevent relapse during viral upper respiratory tract infections (URTI) in children not receiving prednisone. PREDNOS 2 2022 included four groups of children with SSNS, as shown below.

• Not on alternate‐day prednisone

• Receiving alternate‐day prednisone

• Receiving alternate‐day prednisone and other immunosuppressive agents

• Receiving other immunosuppressive agents but not alternate‐day prednisone.

Deflazacort versus prednisone therapy in children with relapsing or an initial episode of SSNS

Four studies (118 randomised children) explored different deflazacort regimens 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) compared different regimens of methylprednisolone with prednisone.

• Imbasciati 1985 compared six months of treatment commencing with methylprednisolone and then 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 versus two months of therapy in the initial episode of SSNS

APN 1988 (61 randomised children) compared less than two months of prednisone with two months.

Five versus 12 months of therapy in the initial episode of SSNS

Kleinknecht 1982 (58 randomised children) 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 reported.

Different total doses of prednisone given for three months in the initial episode of SSNS

Hiraoka 2000 (68 randomised children) compared a higher dose of prednisone given for three months with a conventional dose.

Alternate‐day versus intermittent therapy in relapsing SSNS

APN 1981 (64 randomised children) compared an alternate‐day prednisone regimen with a three out of seven‐day regimen to maintain remission.

Daily versus intermittent therapy in relapsing SSNS

ISKDC 1979 (64 randomised children) compared a daily prednisone regimen with a three out of seven‐day regimen to maintain remission.

Intravenous then oral therapy versus oral therapy alone

Imbasciati 1985 (64 children) compared IV methylprednisolone for three days, then oral prednisone (daily for four weeks, then alternate‐day for four months) with oral prednisone alone.

Single versus multiple daily doses in relapsing nephrotic syndrome

Ekka 1997, Khan 2023, Li 1994 and Weerasooriya 2023 (314 randomised children) compared a single daily dose of prednisone with two or three times/day dosing to achieve remission.

Low versus conventional dose prednisone in relapsing nephrotic syndrome

Five studies (303 randomised children) compared low versus conventional dose prednisone in relapsing nephrotic syndrome.

• Borovitz 2020 compared two reduced daily doses (1 mg/kg/day; 1.5 mg/kg/day) with conventional daily dose of prednisone (2 mg/kg/day) to achieve remission.

• Sheikh 2019 compared a reduced daily dose (1 mg/kg/day) of prednisone with a conventional daily dose (2 mg/kg/day) to achieve remission.

• Tu 2022 compared a reduced daily dose (30 mg/m²/day) of prednisone with a conventional daily dose of prednisone (60 mg/m²/day) to achieve remission.

• Kansal 2019 compared different alternate‐day prednisone doses in the second month of initial treatment to maintain remission.

• Kainth 2021 compared two weeks of alternate‐day prednisone (40 mg/m²) with four weeks after participants achieved remission with a conventional daily dose of prednisone (60 mg/m²/day).

Daily versus alternate‐day prednisone in relapsing nephrotic syndrome

Yadav 2019 (62 randomised children) 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) compared weight‐based dosing with body surface area (BSA)‐based dosing in children with their initial episode of SSNS and with a relapse of SSNS (Basu 2020; Raman 2016).

Alternate‐day prednisone for four weeks versus an eight‐week weaning regimen in relapsing nephrotic syndrome

PROPINE 2020 (78 randomised children) compared 18 doses of prednisone (40 mg/m²) given on alternate days over 36 days with a tapering dose (36 doses) over 72 days using the same cumulative prednisone dose in each group.

Three months or more versus two months of therapy in relapsing nephrotic syndrome

Jayantha 2002b (129 randomised children) compared two months of prednisone with seven months in children with relapsing nephrotic syndrome.

Cortisol addition to prednisone regimen versus no cortisol addition in relapsing nephrotic syndrome

Leisti 1978 (13 randomised children) compared the addition of cortisol supplementation with no cortisol in children with relapsing nephrotic syndrome and a subnormal response to a 2‐hour ACTH test one to 12 days after completing prednisone.

Excluded studies

In this update, eight (eight reports) new studies were excluded. One study (Xu 2020b) was abandoned due to a lack of funding. Five studies investigated prednisone therapy together with Chinese medications (Hou 2021; Wu 2022; Yang 2022a), montelukast (Javidi 2021) or vitamin D (Zhou 2021). Two studies (Zhang 2021b; Zhu 2021a) used intensive regimens in difficult‐to‐manage children, including children with SRNS.

In total, 10 studies were excluded (APN 2006; Hou 2021; Javidi 2021; Wu 2022; Xu 2020b; Yang 2022a; Zhang 2014; Zhang 2021b; Zhou 2021; Zhu 2021a).

Ongoing studies

There are four ongoing studies.

• CTRI/2018/05/013634 will compare alternate‐day prednisone (1 mg/kg versus 1.5 mg/kg) for relapse in children with nephrotic syndrome.

• CTRI/2018/05/014075 will compare 1 mg/kg/day versus 2 mg/kg/day till remission in children with SSNS presenting with relapse.

• RESTERN 2017 will compare daily prednisone till remission, then alternate days for two weeks versus six weeks in children with SSNS presenting with relapse.

• Sinha 2016 will compare tapering prednisone over 12 weeks versus stop therapy in children initially treated with standard therapy for 12 weeks.

Risk of bias in included studies

Risk of bias assessments were performed using Cochrane's risk of bias assessment tool (Appendix 2). Figure 2 summarises the overall risks of bias in the studies, and Figure 3 reports the risks of bias in each individual study.

2.

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

3.

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

Allocation

Randon sequence generation

Random sequence generation was considered at low risk of bias in 31 studies (Abeyagunawardena 2008; Abeyagunawardena 2017; Agarwal 2010; APN 1993; Bagga 1999; Basu 2020; Broyer 1997; Gulati 2011; Hiraoka 2003; Imbasciati 1985; Jayantha 2000; Jayantha 2002b; Kainth 2021; Khan 2023; Kleinknecht 1982; Liern 2008; Mishra 2012; PREDNOS 2019; PREDNOS PILOT 2019; PREDNOS 2 2022; PROPINE 2020; Raman 2016; Sharma 2002; Sheikh 2019; Singhal 2015; Sinha 2015; Teeninga 2013; Weerasooriya 2023; 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 were assessed as unclear in the remaining 16 studies.

Allocation concealment

Allocation concealment was considered to be at low risk of bias in 28 studies (Abeyagunawardena 2008; Abeyagunawardena 2017; Al Talhi 2018; APN 1981; APN 1988; APN 1993; Bagga 1999; Basu 2020; Broyer 1997; Gulati 2011; Hiraoka 2003; Imbasciati 1985; Kainth 2021; Khan 2023; Kleinknecht 1982; Liern 2008; PREDNOS 2019; PREDNOS PILOT 2019; PREDNOS 2 2022; PROPINE 2020; Raman 2016; Sheikh 2019; Sinha 2015; Teeninga 2013; Weerasooriya 2023; 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 were assessed as unclear in the remaining 17 studies.

Blinding

Ten studies were considered to be at low risk of performance bias because they were placebo‐controlled studies (Abeyagunawardena 2008; Abeyagunawardena 2017; Broyer 1997; Leisti 1978; Liern 2008; PREDNOS 2019; PREDNOS PILOT 2019; PREDNOS 2 2022; Sinha 2015; Teeninga 2013). These ten studies, together with Basu 2020 and Yoshikawa 2015 were at low risk of detection bias. Basu 2020 and Yoshikawa 2015 were open‐label studies, so they were at high risk of performance bias but were at low risk of detection bias. For Kansal 2019, the risk for both performance and detection bias was unclear. 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 27 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; Kainth 2021; Khan 2023; Ksiazek 1995; Leisti 1978; Mattoo 2000; Mishra 2012; PREDNOS 2019; PREDNOS 2 2022; PREDNOS PILOT 2019; PROPINE 2020; Raman 2016; Sheikh 2019; Singhal 2015; Sinha 2015; Teeninga 2013; Tu 2022; Yadav 2019; Yoshikawa 2015). Fourteen studies were considered at high risk of attrition bias because 10% or more of participants were lost to follow‐up or excluded from the analysis (Abeyagunawardena 2008; Abeyagunawardena 2017; APN 1981; APN 1988; Ekka 1997; Gulati 2011; ISKDC 1979; Jayantha 2000; Jayantha 2002b; Mocan 1999; Norero 1996; Paul 2014; Sharma 2002; Yoshikawa 1998). The remaining 13 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‐six 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 2000; Kainth 2021; Norero 1996; PREDNOS 2019; PREDNOS 2 2022; PREDNOS PILOT 2019; PROPINE 2020; Sharma 2002; Singhal 2015; Sinha 2015; Teeninga 2013; Tu 2022; Yadav 2019; Yoshikawa 2015; Ueda 1988). There were 22 studies at high risk of selective reporting bias (Abeyagunawardena 2008; Abeyagunawardena 2017; APN 1988; Borovitz 2020; ISKDC 1979; Jamshaid 2022; Jayantha 2002b; Khan 2023; Kleinknecht 1982; Ksiazek 1995; Leisti 1978; Li 1994; Liern 2008; Mattoo 2000; Mocan 1999; Moundekhel 2012; Paul 2014; Pecoraro 2003; Raman 2016; Sheikh 2019; Weerasooriya 2023; Yoshikawa 1998). The remaining six studies were at unclear risk of selective reporting bias.

Other potential sources of bias

Nineteen 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; Kainth 2021; Khan 2023; Leisti 1978; Norero 1996; PREDNOS 2019; PREDNOS 2 2022; PREDNOS PILOT 2019; PROPINE 2020; 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 was identified 10 years after the first conference abstract (Pecoraro 2003). The remaining 34 studies were deemed unclear of other risks 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 2000; Ksiazek 1995; Ueda 1988), the numbers of children in the treatment and control groups differed markedly.

Effects of interventions

See: Table 1; Table 2

Three months or more versus two months of therapy in the initial episode of SSNS

• Therapy for three months or more probably makes little or no difference to the number of children with frequent relapses by 12 to 24 months compared to two months of therapy (Analysis 1.1: RR 0.86, 95% CI 0.71 to 1.06; 976 children, 8 studies; I² = 33%; moderate certainty evidence).

• Therapy for three months or more may reduce the number of children relapsing by 12 to 24 months (Analysis 1.2: RR 0.80, 95% CI 0.68 to 0.96; 1279 children, 12 studies; I² = 70%; low certainty evidence).

  • In subgroup analysis of studies at low risk of selection bias, there is little or no difference in the number with frequent relapses between the two groups (Analysis 1.3.1: RR 0.96, 95% CI 0.83 to 1.10; 755 children; 5 studies; I² = 0%) or the number of children relapsing by 12 to 24 months (Analysis 1.4.1: RR 0.93, 95% CI 0.81 to 1.06; 808 children; 6 studies; I² = 36%) (high certainty evidence) (Figure 4).

  • In contrast, in subgroup analysis of studies at unclear or high risk of selection bias, longer duration of prednisone therapy probably reduces the number of children with frequent relapses (Analysis 1.3.2: RR 0.45, 95% CI 0.26 to 0.77; 220 children, 3 studies; I² = 0%) (moderate certainty evidence) and the number of children relapsing by 12 to 24 months (Analysis 1.4.2: RR 0.69, 95% CI 0.49 to 0.98; 471 children, 6 studies; I² = 72%).

  • Similar differences in results were shown when data were stratified according to risk of bias for detection and performance bias or for attrition bias (data not shown).

• There may be little or no difference in adverse events between the two groups (Analysis 1.5) (low or moderate certainty evidence). In Yoshikawa 2015, results were reported as events, not patients, so they could not be included in the meta‐analyses. The authors reported that the frequency and severity of adverse events were similar in both groups.

1.1. Analysis.

Comparison 1: Steroid therapy in first episode: ≥ 3 months versus 2 months, Outcome 1: Number with frequent relapses by 12 to 24 months

1.2. Analysis.

Comparison 1: Steroid therapy in first episode: ≥ 3 months versus 2 months, Outcome 2: Number relapsing by 12 to 24 months

1.3. Analysis.

Comparison 1: Steroid therapy in first episode: ≥ 3 months versus 2 months, Outcome 3: Number with frequent relapses by 12 to 24 months: stratified by risk of selection bias

1.4. Analysis.

Comparison 1: Steroid therapy in first episode: ≥ 3 months versus 2 months, Outcome 4: Number relapsing by 12 to 24 months: stratified by risk of selection bias

4.

Forest plot of comparison: 1 Steroid therapy in first episode: ≥ 3 months versus 2 months therapy, outcome: 1.3 Number with frequent relapses by 12 to 24 months stratified by risk of bias for selection bias.

1.5. Analysis.

Comparison 1: Steroid therapy in first episode: ≥ 3 months versus 2 months, Outcome 5: Adverse events

Results were downgraded for medium to high levels of heterogeneity between studies and for risk of bias issues (Table 1). The heterogeneity between studies was explained by the risk of bias issues (Analysis 1.3.1; Analysis 1.3.2; Analysis 1.4.1; Analysis 1.4.2) but not by the inclusion or exclusion of patients with steroid‐dependent disease, different durations of prednisone (two months versus three months or more) or different definitions of FRNS (ISKDC definition compared with other definitions) (data not shown).

Five to seven months versus three months of therapy in the initial episode of SSNS

• Five to seven months of therapy probably makes little or no difference to the number of children with frequent relapses by 12 to 24 months compared to three months of therapy (Analysis 2.1: RR 0.73, 95% CI 0.49 to 1.09; 707 children, 6 studies; I² = 68%; moderate certainty evidence).

• Five to seven months of therapy may reduce the number of children relapsing by 12 to 24 months compared to three months of therapy (Analysis 2.2: (RR 0.64, 95% CI 0.50 to 0.81; 912 children; 8 studies; I² = 80%; low certainty evidence).

  • In subgroup analysis of studies at low risk of selection bias, there is little or no difference in the number with frequent relapses (Analysis 2.3.1: RR 0.99, 95% CI 0.74 to 1.33; 376 children, 3 studies; I² = 35%; high certainty evidence) or in the number relapsing by 12 to 24 months (Analysis 2.4.1: RR 0.88, 95% CI 0.69 to 1.11; 376 children, 3 studies; I² = 53%) (Figure 5).

  • In contrast, in subgroups of studies at high or unclear risk of selection bias, five to seven months of therapy probably reduces the risk of FRNS (Analysis 2.3.2: RR 0.48, 95% CI 0.32 to 0.72; 330 children, 3 studies; I² = 0% moderate certainty evidence) and the number relapsing by 12 to 24 months (Analysis 2.4.2: RR 0.53, 95% CI 0.41 to 0.69; 536 children; 5 studies; I² = 60%).

  • Similar differences in results were shown when data were stratified according to risk of bias for detection and performance bias or for attrition bias (data not shown).

• There may be little or no difference in adverse events, including psychological disorders, growth retardation, hypertension, cataracts/glaucoma, osteoporosis, infections or Cushingoid features (Analysis 2.5; low or moderate certainty evidence).

• Anand 2013 reported that the number relapsing at 12 months was lower with six months of prednisone compared with three months. Data could not be included in the meta‐analysis as the numbers in each group were not provided.

2.1. Analysis.

Comparison 2: Steroid therapy in first episode: 5 to 7 months versus 3 months, Outcome 1: Number with frequent relapses by 12 to 24 months

2.2. Analysis.

Comparison 2: Steroid therapy in first episode: 5 to 7 months versus 3 months, Outcome 2: Number relapsing by 12 to 24 months

2.3. Analysis.

Comparison 2: Steroid therapy in first episode: 5 to 7 months versus 3 months, Outcome 3: Number with frequent relapses: stratified by risk of selection bias

2.4. Analysis.

Comparison 2: Steroid therapy in first episode: 5 to 7 months versus 3 months, Outcome 4: Number relapsing by 12 to 24 months: stratified by risk of selection bias

5.

Forest plot of comparison: 2 Steroid therapy in first episode: 5 to 7 months versus 3 months, outcome: 2.3 Number with frequent relapses stratified by risk of selection bias.

2.5. Analysis.

Comparison 2: Steroid therapy in first episode: 5 to 7 months versus 3 months, Outcome 5: Adverse events

Results were downgraded for medium to high levels of heterogeneity between studies and for risk of bias issues (Table 2). The heterogeneity between studies was explained by the risk of bias issues (Analysis 2.3.1; Analysis 2.3.2; Analysis 2.4.1; Analysis 2.4.2) but not by inclusion or exclusion of patients with steroid‐dependent disease, different durations of prednisone (three months versus five to seven months), or different definitions of FRNS (ISKDC definition compared with other definitions) (Data not shown).

One versus two months of therapy in the initial episode of SSNS

• APN 1988 reported two months of therapy compared to one month may reduce the risk of relapse at six to 12 months (Analysis 3.1: RR 1.60, 95% CI 1.01 to 2.54; 61 children) and 12 to 24 months (Analysis 3.2: RR 1.46, 95% CI 1.01 to 2.12; 60 children).

• APN 1988 reported two months of therapy compared to one month had uncertain effects on the number of children with frequent relapses (Analysis 3.3: RR 1.48, 95%CI 0.85 to 2.59; 61 children).

3.1. Analysis.

Comparison 3: Steroid therapy in the first episode: 1 month versus 2 months, Outcome 1: Number relapsing by 6 to 12 months

3.2. Analysis.

Comparison 3: Steroid therapy in the first episode: 1 month versus 2 months, Outcome 2: Number relapsing by 12 to 24 months

3.3. Analysis.

Comparison 3: Steroid therapy in the first episode: 1 month versus 2 months, Outcome 3: Number with frequent relapses

Twelve versus five months of therapy in the initial episode of SSNS

• Ksiazek 1995 reported that 12 months of therapy compared to five months had uncertain effects on the number of children relapsing (Analysis 4.1: RR 0.76, 95% CI 0.51 to 1.13; 58 children).

4.1. Analysis.

Comparison 4: Steroid therapy in the first episode: 12 months versus 5 months, Outcome 1: Number with relapse

Different total doses of prednisone given for three months in the initial episode of SSNS

• Hiraoka 2000 reported a higher dose may reduce the number of children relapsing by 12 months (Analysis 5.1: RR 0.65, 95% CI 0.43 to 0.98; 60 children) but may make little or no difference to the number with frequent relapses (Analysis 5.2: RR 0.69, 95% CI 0.35 to 1.37; 60 children).

• Hiraoka 2000 reported psychological disorders, hypertension, and Cushing's Syndrome may not differ between the groups (Analysis 5.3).

5.1. Analysis.

Comparison 5: Steroid therapy in the first episode: different total doses given over the same duration, Outcome 1: Relapse at 12 months

5.2. Analysis.

Comparison 5: Steroid therapy in the first episode: different total doses given over the same duration, Outcome 2: Number with FRNS

5.3. Analysis.

Comparison 5: Steroid therapy in the first episode: different total doses given over the same duration, Outcome 3: Adverse events

Oral methylprednisolone in children with relapsing or initial episodes of SSNS

• Methylprednisolone, compared with prednisolone, may reduce the time to remission (Analysis 6.1: MD ‐5.54 days, 95% CI ‐8.46 to ‐2.61; 38 children, 2 studies; I² = 0%).

• Imbasciati 1985 reported methylprednisolone, compared with prednisolone, may make little or no difference to the number of children who relapse (Analysis 6.2: RR 1.00, 95% CI 0.75 to 1.52; 62 children).

6.1. Analysis.

Comparison 6: Steroid therapy in first episode: methylprednisone versus prednisolone, Outcome 1: Time to remission [days]

6.2. Analysis.

Comparison 6: Steroid therapy in first episode: methylprednisone versus prednisolone, Outcome 2: Number with relapse

Daily prednisone treatment during viral infections in children with relapsing or initial episodes of SSNS

• Daily prednisone at the onset of URTI compared with placebo probably makes little or no difference to the risk of relapse (Analysis 7.1.1: RR 0.81, 95% CI 0.44 to 1.49; 310 children; 2 studies; I² = 45%) (moderate certainty evidence).

• Subgroup analyses

  • PREDNOS 2 2022 reported that in those not initially receiving any prednisone, administering daily prednisone at the onset of URTI may make little or no difference to the risk of relapse (Analysis 7.1.2: RR 1.11, 95% CI 0.72 to 1.71; 60 children).

  • In children receiving alternate‐day prednisone, changing to daily prednisone at the onset of URTI may make little or no difference to the risk of relapse (Analysis 7.1.3: RR 0.75, 95% CI 0.47 to 1.19; 110 children; 2 studies; I² = 0%).

  • PREDNOS 2 2022 reported that in those receiving alternate‐day prednisone and other immunosuppressive agents, changing to daily prednisone at the onset of URTI may make little or no difference to the risk of relapse (Analysis 7.1.4: RR 0.86, 95% CI 0.50 to 1.50; 89 children).

  • PREDNOS 2 2022 reported that in those receiving other immunosuppressive agents without prednisone, commencing daily prednisone at the onset of URTI may make little or no difference to the risk of relapse (Analysis 7.1.5: RR 1.01, 95% CI 0.44 to 2.28; 43 children).

• Gulati 2011 reported daily prednisone therapy, administered at the onset of URTI, may reduce the infection‐related relapses/patient‐years (Analysis 7.2.1: MD ‐0.70, 95% CI ‐0.87 to ‐0.53; 95 children) and the total number of relapses/patient/year (Analysis 7.2.2: MD ‐0.90, 95% CI ‐1.08 to ‐0.72; 95 children).

• Mattoo 2000 reported daily prednisone, administered at the onset of URTI, may reduce total relapse episodes/patient at two years compared with alternate‐day prednisone (Analysis 7.3: MD ‐3.30, 95% CI ‐4.03 to ‐2.57; 36 children).

• In a cross‐over study in children who had not received alternate‐day prednisone for at least three months, Abeyagunawardena 2017 reported daily prednisone administered at the onset of URTI resulted in 11 relapses associated with 115 episodes of URTI in 33 children compared with 25 relapses associated with 101 episodes of URTI in 33 children completing two years.

7.1. Analysis.

Comparison 7: Daily prednisolone treatment during viral infections, Outcome 1: Number with relapse with infection

7.2. Analysis.

Comparison 7: Daily prednisolone treatment during viral infections, Outcome 2: Number of relapses/patient

7.3. Analysis.

Comparison 7: Daily prednisolone treatment during viral infections, Outcome 3: Number of relapses/patient at 2 years

Deflazacort versus prednisone therapy in children with relapsing or initial episodes of SSNS

• Deflazacort, compared with prednisone, may make little or no difference to the number of children achieving remission (Analysis 8.1: RR 1.08, 95% CI 0.94 to 1.24; 67 children, 2 studies; I² = 0%).

• Deflazacort, compared with prednisone, may reduce the number of children with relapses by nine to 12 months (Analysis 8.2: RR 0.46, 95% CI 0.27 to 0.78; 63 children, 2 studies; I² = 0%).

• No differences in time to remission or time to relapse in 11 children treated with deflazacort or methylprednisolone were found in a cross‐over study by Liern 2008.

8.1. Analysis.

Comparison 8: Deflazacort versus prednisolone, Outcome 1: Number with remission

8.2. Analysis.

Comparison 8: Deflazacort versus prednisolone, Outcome 2: Number with relapse by 9 to 12 months

Alternate‐day or daily therapy versus intermittent therapy in relapsing SSNS

• Number relapsing during therapy.

  • APN 1981 reported uncertain effects between alternate‐day therapy and intermittent therapy on the number of children relapsing during therapy (Analysis 9.1.1: RR 0.60, 95% CI 0.36 to 1.02; 48 children).

  • ISKDC 1979 reported daily therapy may reduce the number of children relapsing during therapy compared to intermittent therapy (Analysis 9.1.2: RR 0.20, 95% CI 0.05 to 0.82; 50 children)

• Number with relapses by nine to 12 months.

  • APN 1981 reported little or no difference in the number of children with relapses by nine to 12 months between alternate‐day and intermittent therapy (Analysis 9.2.1: RR 1.20, 95% CI 0.93 to 1.55; 48 children).

  • ISKDC 1979 reported little or no difference in the number of children with relapses by nine to 12 months between daily and intermittent therapy (Analysis 9.2.2: RR 1.00, 95% CI 0.89 to 1.12; 50 children).

9.1. Analysis.

Comparison 9: Alternate‐day or daily steroid regimens versus intermittent dosing to prevent relapse, Outcome 1: Number relapsing during therapy

9.2. Analysis.

Comparison 9: Alternate‐day or daily steroid regimens versus intermittent dosing to prevent relapse, Outcome 2: Number with relapses by 9 to 12 months

Intravenous then oral therapy versus oral therapy alone

• Imbasciati 1985 reported little or no difference in the number of children relapsing by six months between IV then oral therapy and oral therapy alone (Analysis 10.1: RR 1.06, 95% CI 0.75 to 1.52; 64 children).

10.1. Analysis.

Comparison 10: Intravenous then oral therapy versus oral therapy alone, Outcome 1: Relapse by 6 months

Single versus multiple daily doses in relapsing nephrotic syndrome

• There may be little or no difference between single daily doses versus divided daily dosing in the number with relapse (Analysis 11.1: RR 1.05, 95% CI 0.77 to 1.42; 151 children; 2 studies; I² = 0%)

• Ekka 1997 reported little or no difference between single daily doses versus divided daily dosing in the mean relapse rate (Analysis 11.2: MD ‐0.20, 95% CI ‐0.64 to 0.24; 94 children).

• There may be little or no difference in the mean time to remission between single daily doses and divided daily dosing (Analysis 11.3: MD 0.70 days, 95% CI ‐0.56 to 1.96; 242 children; 3 studies; I² = 60%).

• There may be little or no difference in the mean time to remission between single daily and divided daily dosing according to age group (Analysis 11.4)

• Serious adverse events may be less common with single daily doses compared with divided daily dosing (Analysis 11.5: RR 0.41, 95% CI 0.18 to 0.91; 138 children, 2 studies; I² = 0%).

• Ekka 1997 reported no differences in the cumulative steroid dose between single daily doses versus divided daily dosing (Analysis 11.6: MD ‐0.05 mg/kg, 95% CI ‐0.68 to 0.58; 94 children).

• Khan 2023 reported that the number of children with HPA suppression did not differ between groups (Analysis 11.7)

11.1. Analysis.

Comparison 11: Single versus divided daily doses of prednisone to prevent relapse, Outcome 1: Number with relapse

11.2. Analysis.

Comparison 11: Single versus divided daily doses of prednisone to prevent relapse, Outcome 2: Mean relapse rate

11.3. Analysis.

Comparison 11: Single versus divided daily doses of prednisone to prevent relapse, Outcome 3: Number of days to remission

11.4. Analysis.

Comparison 11: Single versus divided daily doses of prednisone to prevent relapse, Outcome 4: Number of days to remission according to age group

11.5. Analysis.

Comparison 11: Single versus divided daily doses of prednisone to prevent relapse, Outcome 5: Serious adverse events

11.6. Analysis.

Comparison 11: Single versus divided daily doses of prednisone to prevent relapse, Outcome 6: Cumulative steroid dose [mg/kg]

11.7. Analysis.

Comparison 11: Single versus divided daily doses of prednisone to prevent relapse, Outcome 7: Number with HPA suppression

Reduced versus standard prednisone doses in relapsing nephrotic syndrome

• There may be little or no difference in time to remission between reduced (1 mg/kg) and standard prednisone doses (2 mg/kg) (Analysis 12.1: MD 0.72 days, 95% CI ‐0.43 to 1.88; 75 children; 2 studies; I² = 11%).

• There may be little or no difference in the number relapsing between reduced and standard prednisone doses (Analysis 12.2: RR 1.01, 95% CI 0.85 to 1.20; 177 children; 4 studies; I² = 0%).

• Kainth 2021 reported there may be little or no difference in the number developing FRNS or SDNS between reduced duration (two weeks) and standard duration (four weeks) of alternate‐day prednisone (Analysis 12.3: RR 0.97, 95% CI 0.49 to 1.91; 117 children).

• Borovitz 2020 reported that compared to a dose of 2 mg/kg/day, the cumulative dose of prednisone to achieve remission may be less in children treated with a dose of 1 mg/kg/day (Analysis 12.4: MD ‐20.60 mg/kg, 95% CI ‐25.65 to ‐15.55; 20 children).

• Adverse events

  • Tu 2022 reported that there may be no difference in growth or steroid adverse events with low versus conventional dose prednisone (Analysis 12.5).

  • Borovitz 2020 reported that none of the included children had treatment‐related complications.

  • Kansal 2019 reported that prednisone adverse events were more common in the standard dose group compared with the low dose group.

  • Kainth 2021 identified no differences in the number of days to relapse or in steroid adverse effects between reduced duration and standard duration of alternate‐day prednisone.

  • Sheikh 2019 did not provide any information on adverse effects.

12.1. Analysis.

Comparison 12: Reduced versus standard steroid doses to prevent relapse, Outcome 1: Time to remission

12.2. Analysis.

Comparison 12: Reduced versus standard steroid doses to prevent relapse, Outcome 2: Number with relapse

12.3. Analysis.

Comparison 12: Reduced versus standard steroid doses to prevent relapse, Outcome 3: Number with FRNS or SDNS at 12 months

12.4. Analysis.

Comparison 12: Reduced versus standard steroid doses to prevent relapse, Outcome 4: Cumulative prednisone dose to achieve remission [mg/kg]

12.5. Analysis.

Comparison 12: Reduced versus standard steroid doses to prevent relapse, Outcome 5: Adverse events

Daily versus alternate‐day prednisone in relapsing nephrotic syndrome

• Yadav 2019 reported daily, compared with alternate‐day prednisone, may reduce the number of relapses during 12 months of therapy (Analysis 13.1: MD ‐0.90 relapses/year, 95% CI ‐1.33 to ‐0.47; 62 children).

• Yadav 2019 reported there may be little or no difference in the frequency of Cushingoid facies or cataracts (Analysis 13.2).

13.1. Analysis.

Comparison 13: Daily versus alternate‐day prednisone to prevent relapse, Outcome 1: Number of relapses in 12 months [number/year]

13.2. Analysis.

Comparison 13: Daily versus alternate‐day prednisone to prevent relapse, Outcome 2: Adverse events

Short‐duration alternate‐day prednisone without taper of dose versus long‐duration alternate‐day prednisone with tapering dose in relapsing nephrotic syndrome

• PROPINE 2020 reported administering alternate‐day prednisone for 36 days compared with a tapering dose given over 72 days using the same cumulative prednisone dose in each group may make little or no difference to the risk of relapsing during treatment (Analysis 14.1: RR 0.07, 95% CI 0.00 to 1.19; 78 children) or at six months (Analysis 14.2: RR 0.73, 95% CI 0.46 to 1.16; 78 children).

• PROPINE 2020 reported there may be little or no difference in the frequency of viral infection, bacterial infection, or urticaria (Analysis 14.3).

14.1. Analysis.

Comparison 14: Short (36 days) versus long (72 days) duration alternate‐day prednisone to prevent relapse, Outcome 1: Number with relapse during treatment

14.2. Analysis.

Comparison 14: Short (36 days) versus long (72 days) duration alternate‐day prednisone to prevent relapse, Outcome 2: Number with relapse by 6 months

14.3. Analysis.

Comparison 14: Short (36 days) versus long (72 days) duration alternate‐day prednisone to prevent relapse, Outcome 3: Adverse events

Weight‐based versus body surface area‐based dosing of prednisone in relapsing nephrotic syndrome

• Weight‐based dosing may make little or no difference to the number relapsing at six months compared to BSA‐based dosing (Analysis 15.1: RR 1.03, 95% CI 0.71 to 1.49; 146 children; 2 studies; I² = 0%).

• Weight‐based dosing may make little or no difference to the risk of adverse events compared to BSA‐based dosing (Cushingoid features, serious infections, eye changes, hypertension) (Analysis 15.2: 144 children; 2 studies).

• Basu 2020 reported that the mean prednisone dose for both the induction dose over six months and the cumulative dose over six months was lower in the weight‐based dosing group compared with the BSA‐based dosing group (Analysis 15.3.1: ‐32.00 g/kg, 95% CI ‐57.21 to ‐6.79; Analysis 15.3.2: ‐30.00 g/kg, 95% CI ‐54.34 to ‐5.66).

15.1. Analysis.

Comparison 15: Weight‐based versus body surface area (BSA)‐based dosing of prednisolone, Outcome 1: Relapse at 6 months

15.2. Analysis.

Comparison 15: Weight‐based versus body surface area (BSA)‐based dosing of prednisolone, Outcome 2: Adverse events

15.3. Analysis.

Comparison 15: Weight‐based versus body surface area (BSA)‐based dosing of prednisolone, Outcome 3: Prednisone dose

Prolonged steroid therapy for children with relapsing SSNS

• Jayantha 2002b reported seven months of prednisone may reduce the number of relapses at six months (Analysis 16.1.1: RR 0.04, 95% CI 0.01 to 0.25; 90 children), 12 months (Analysis 16.1.2: RR 0.43, 95% CI 0.29 to 0.65; 76 children) and 24 months (Analysis 16.1.3: RR 0.60, 95% CI 0.45 to 0.80; 64 children) compared to two months of therapy.

• Jayantha 2002b reported the relapse rate/patient/year was lower with seven months of prednisone compared to two months at 12 months (Analysis 16.2.1: MD ‐1.78, 95% CI ‐2.30 to ‐1.26; 72 children), 24 months (Analysis 16.2.2: MD ‐1.79, 95% CI ‐2.39 to ‐1.19; 55 children), and 36 months (Analysis 16.2.3: ‐RR 1.74, 95% CI ‐2.39 to ‐1.09; 41 children).

• Jayantha 2002b reported the number with FRNS or SDNS was lower with seven months of prednisone (Analysis 16.3: RR 0.43, 95% CI 0.19 to 0.95; 72 children) compared to two months of prednisone.

• Jayantha 2002b reported the cumulative prednisone dose was lower at one year with two months of treatment (Analysis 16.4.1: MD 0.59 g/kg, 95% CI 0.02 to 1.16; 72 children), but there was little or no difference at two years (Analysis 16.4.2: MD ‐0.32 g/kg, 95% CI ‐1.52 to 0.88; 55 children) or three years (Analysis 16.4.3: MD ‐1.13, 95% CI ‐3.08 to 0.82; 41 children) compared to seven months of prednisone.

• Jayantha 2002b reported there may be little or no difference in hypertension or growth failure between seven months and two months of prednisone (Analysis 16.5).

16.1. Analysis.

Comparison 16: Prolonged steroid therapy (7 months) for relapsing nephrotic syndrome, Outcome 1: Number with relapses

16.2. Analysis.

Comparison 16: Prolonged steroid therapy (7 months) for relapsing nephrotic syndrome, Outcome 2: Relapse rate/patient/year

16.3. Analysis.

Comparison 16: Prolonged steroid therapy (7 months) for relapsing nephrotic syndrome, Outcome 3: Number with FRNS or SDNS

16.4. Analysis.

Comparison 16: Prolonged steroid therapy (7 months) for relapsing nephrotic syndrome, Outcome 4: Cumulative steroid dose

16.5. Analysis.

Comparison 16: Prolonged steroid therapy (7 months) for relapsing nephrotic syndrome, Outcome 5: Adverse events

Cortisol supplementation in children with relapsing nephrotic syndrome and adrenocortical suppression

In a cross‐over study by Leisti 1978, cortisol substitution may result in fewer children with post‐prednisone adrenocortical suppression relapsing during a six‐month period. After three months of treatment, 5/13 children (38%) receiving cortisol had relapsed compared with 12/13 receiving placebo (92%) (Chi² = 4.0, P = 0.05), and at six months, 9/13 children receiving cortisol had relapsed compared with 12/13 receiving placebo.

Discussion

Summary of main results

We have added five new included studies to this 2024 update, bringing the total number of included studies to 54, which randomised 4670 children.

Prednisone in the first episode of SSNS

In earlier iterations of this review (2000 to 2007), we concluded that prednisone administered for longer durations compared with two or three months reduced the risk of relapse and of FRNS in the initial episode of SSNS. In practice, considerable variation exists amongst paediatric nephrologists in the duration of prednisone used in the initial episode of nephrotic syndrome, reflecting in part the poor quality of the evidence from earlier RCTs (MacHardy 2009; Samuel 2013). The 2015 update of this review (Hahn 2015) included three well‐designed and adequately powered studies (Sinha 2015; Teeninga 2013; Yoshikawa 2015), which clearly demonstrated that there was no benefit of prolonging prednisone therapy beyond two or three months. In the 2020 update (Hahn 2020) a further well‐designed study (PREDNOS 2019) also concluded that there was no benefit of prolonging prednisone therapy beyond two months. In our analysis of factors which might account for the differences in results, we concluded that, in studies at low risk of selection or performance bias, we could identify no benefit of extending prednisone therapy beyond eight or 12 weeks. In contrast, studies at high risk for these biases found a benefit of longer durations of therapy. In the 2020 update we included four studies (Al Talhi 2018; Anand 2013; Moundekhel 2012; Paul 2014) which evaluated longer durations of prednisone compared with two or three months. All four studies concluded that there was a benefit from a longer duration of prednisone therapy. All four studies were at high risk of selection and performance bias. In this 2024 update, an additional study (Jamshaid 2022) also found that longer‐duration prednisone reduced the risk of relapse, but this study was at high risk of bias (selection bias, performance bias). Since there are already four well‐designed studies randomising 823 children with nephrotic syndrome, which clearly demonstrate that there is no benefit for durations of prednisone exceeding two or three months, resources should not be wasted on further studies to evaluate different durations of prednisone in the initial episode of SSNS.

Prednisone in relapsing SSNS

Four studies enrolling 204 children found that daily prednisone, administered at the onset of viral infections, compared with alternate‐day prednisone therapy, reduced the rate of relapse. However, a much larger study (PREDNOS 2 2022) involving 271 children, including both children already on alternate‐day and those not on alternate‐day prednisone, did not support this finding. This study was at low risk of bias for all attributes in contrast to the earlier studies (Figure 6), which were at high risk of bias and showed a benefit of changing to daily prednisone therapy at the onset of URTI. Studies at high risk of bias may overestimate the benefit of the intervention (Moher 1998; Schulz 1995). Although PREDNOS 2 2022 does not support changing from alternate to daily prednisone at the onset of a viral infection, such an approach might be considered in children with relapsing SSNS who are already taking low‐dose alternate‐day prednisone or considered to be at a greater risk of a URTI triggering relapse (IPNA 2023).

6.

Forest plot of comparison: 7 Daily prednisolone treatment during viral infections, outcome: 7.2 Number of relapses/patient.

In the 2020 update, nine small studies evaluated different interventions using prednisone in relapsing disease. Yadav 2019 (62 children) found that daily prednisone, compared with alternate‐day prednisone in children with FRNS, was associated with a reduced risk of relapse. Both the KDIGO 2012 and the KDIGO 2021 guidelines suggest that alternate‐day prednisone rather than daily prednisone should be used. Two studies (Basu 2020; Raman 2016) found no difference in the risk for relapse between weight‐based and surface area‐based dosing of prednisone. Two studies (Ekka 1997; Khan 2023) found no difference in time to remission using a single daily dose or multiple daily doses of prednisone. Many clinicians have tapered the dose of prednisone before discontinuing it. PROPINE 2020 found no differences in the risk for relapse or in adverse events in children managed without tapering of the dose of alternate‐day prednisone compared with slow tapering of the dose. The KDIGO 2021 and IPNA 2023 guidelines on SSNS in children conclude that tapering the alternate‐day dose before cessation of prednisone is not necessary and that prednisone can be given as a single daily dose.

Five small studies (Borovitz 2020; Kainth 2021; Kansal 2019; Sheikh 2019; Tu 2022) evaluated regimens using lower doses or shorter durations of prednisone for relapsing SSNS and suggested that smaller doses or shorter durations were as effective as the conventional regimen for relapse of prednisone 60 mg/m²/day till remission followed by four weeks of alternate‐day prednisone at 40 mg/m². Much larger studies are needed to confirm these findings.

Overall completeness and applicability of evidence

Four well‐designed studies randomising 823 children in their first episode of SSNS have confirmed that the optimum duration of prednisone therapy is two or three months, with no additional benefit found with a longer duration of therapy in reducing the number of relapses. Now that we have these data, there is no requirement for further RCTs evaluating the duration of prednisone therapy involving children of all ages with their first episode of SSNS. However, post hoc analyses in two studies (PREDNOS 2019; Sinha 2015) suggested that the benefit of longer‐duration therapy in young children has not been completely excluded, and this is being assessed in an ongoing study enrolling children below four years of age (Sinha 2016). There are currently no RCTs assessing whether lower doses and/or shorter durations of prednisone can be used in the first episode of SSNS.

Four small studies (Abeyagunawardena 2008; Abeyagunawardena 2017; Gulati 2011; Mattoo 2000) reported that daily prednisone initiated at the onset of infection reduced the risk of relapse associated with infective episodes. However, a new, large, and well‐designed study (PREDNOS 2 2022) has not confirmed these findings. Based on these new data, the IPNA 2023 guidelines do not recommend the routine use of daily prednisone at the onset of infection.

Five small studies (Borovitz 2020; Kainth 2021; Kansal 2019; Sheikh 2019; Tu 2022) are the first randomised studies to examine whether lower total doses of prednisone can be used to treat relapsing nephrotic syndrome. It is imperative that a large study is undertaken to confirm that lower doses of prednisone are as effective in achieving and maintaining remission as the conventional dose regimens, which have been used for 50 years; otherwise, there is a risk that clinicians will try using smaller doses of prednisone in relapsing nephrotic syndrome without data from adequately powered RCTs to support such a change in management.

Although adverse effects of medications were reported in more detail in the four recent high‐quality studies (PREDNOS 2019; Sinha 2015; Teeninga 2013; Yoshikawa 2015), generally, there was limited reporting of adverse effects. Amongst 23 studies evaluating increased duration or dose in the initial episode of SSNS, hypertension, ophthalmological disorders and Cushing's syndrome were reported in 14, 11 and 12 studies, respectively. Prednisone therapy is known to be associated with significant behavioural and psychological adverse effects (Mishra 2010; Neuhaus 2010). However, only eight studies reported this outcome. In PREDNOS 2019, a detailed analysis of quantitative data collected using the Achenbach child behaviour checklist found no differences in behaviour scores between the two durations of prednisone, although parents reported more poor behaviour in children treated for two months. No studies have reported on the burden of having a chronic kidney condition on the child or their family (Beanlands 2017).

The studies included the major ethnic groups, but there are no separable data on efficacy and safety for African‐American or African children. These groups of children, who are known to have a higher incidence of initial and late SRNS (Gipson 2011; Kim 2005), may show different responses in studies of increased dose or duration of prednisone. The four recent high‐quality studies were carried out in Europe, Japan, and India, so few African children were included in the studies.

Quality of the evidence

Of the 54 included studies, only 31 (57%) and 28 (52%) studies reported adequate random sequence generation and allocation concealment, respectively.

Only 10 studies (19%) were at low risk of bias for performance bias (blinding of participants and personnel) and 12 for detection bias (blinding of outcome assessment) since these studies were placebo‐controlled studies. Yoshikawa 2015 was an open‐label study and was at high risk of performance bias, but this study was at low risk of detection bias. The remaining studies were at high risk of bias for both performance and detection bias. Studies without blinding are considered at high risk of bias because knowledge of treatment groups could influence both patient management and reporting of remission and relapse (Moher 1998; Schulz 1995).

Fewer than 50% of studies were at low risk for both attrition bias (incomplete reporting of outcome data) and reporting bias (selective outcome reporting). Nineteen studies were considered at low risk of other potential biases as they were funded by educational or philanthropic organisations.

In the summary of findings tables (Table 1; Table 2), the certainty of the evidence was considered moderate or low for efficacy outcomes related to risk of bias and heterogeneity between studies. When studies were separated into subgroups according to the risk of selection bias, the certainty of the evidence was assessed as high for the primary efficacy outcomes of FRNS in seven well‐designed studies, while the certainty of the evidence was judged low or moderate for these outcomes in studies at high or uncertain risk of selection bias. The quality of studies for the adverse effects was considered moderate or low because of the inclusion of some studies at high risk of bias, and few included studies.

Only 18 of the 54 studies were included in the summary of findings tables and all compared treatment regimens in the first episode of nephrotic syndrome. The remaining studies were mostly single studies of an intervention or data were reported differently for each study, so they could not be included in the meta‐analyses. There were four small studies which evaluated the number of relapses after lower prednisone doses compared to standard doses for relapsing nephrotic syndrome. However, these studies only included 177 children, so a summary of the findings table was not created for this limited dataset.

Potential biases in the review process

A detailed search using the Cochrane Kidney and Transplant Register of Studies was last undertaken in July 2024. The Cochrane Kidney and Transplant Register of Studies contains conference abstracts as well as published studies, and there is no language restriction. This minimised the risk that eligible studies were omitted, although more recently published eligible studies and eligible studies in some congress proceedings not searched could have been missed. There were 10 (19%) included studies that were only available in abstract form with limited information on study methods and outcomes. Failure to include these studies could result in an overestimation of treatment effects, since it is known that negative studies are less likely to be published or may be published later than positive studies (Hopewell 2007). Alternately, some authors have argued that the inclusion of these studies could result in overestimation of treatment effect through selective outcome reporting and incomplete reporting of the number of patients completing follow‐up (Egger 2001).

Many studies were small and had incomplete information related to study methodology and results, and further information, particularly from older studies, could not be obtained despite contacting authors. Of the 54 included studies, 16 were published in or before 2000 ‐ before the CONSORT checklist was first published in 1996 would be likely to influence study methodology and reporting (Moher 2001).

This is an extensive review; each step was completed independently by at least two authors, thus minimising the risks of errors in determining study eligibility, data extraction, risk of bias assessment, and data synthesis.

Agreements and disagreements with other studies or reviews

Studies at low risk of bias included in this review indicate that there is no benefit in prolonging the corticosteroid treatment of all children for more than eight to 12 weeks in the initial episode of SSNS. These data have been incorporated into recent guidelines from KDIGO (KDIGO Executive Conclusions 2019; KDIGO 2021) and IPNA (IPNA 2023), which recommend that daily prednisone be given for four or six weeks followed by alternate‐day prednisone for four or six weeks. Since there are no RCTs comparing an eight‐week regimen with a 12‐week regimen, these guidelines have included both regimens.

This review identified four older studies reporting that increasing prednisone administration from alternate‐day to daily or giving prednisone to children not on prednisone at the onset of an intercurrent viral infection reduced the risk of relapse. However, a much larger study (PREDNOS 2 2022) involving 271 children, including both children already on alternate‐day prednisone and children not on alternate‐day prednisone, did not support this finding. IPNA 2023 does not recommend the routine use of daily prednisone at the onset of URTI.

Current guidelines (Gipson 2009; IPNA 2023; IPNG‐IAP 2008; KDIGO 2021) recommend that alternate‐day prednisone therapy be used to reduce the risk of relapse in children with FRNS. However, a small study (Yadav 2019) showed that the number of relapses was lower in children treated with low‐dose daily prednisone compared with alternate‐day dosing, with the total dose/48 hours not differing between treatment groups. There were no differences in adverse events. The IPNA 2023 guidelines recommend that the initial treatment of children with FRNS should be with either alternate‐day or daily prednisone. Guidelines also recommend that children be dosed with prednisone according to BSA rather than weight in children weighing less than 30 kg because the calculation of dose by weight results in a lower dose compared with a calculation based on BSA. However, two studies (Basu 2020; Raman 2016) found no differences in the number of relapses or adverse events between the two dosing schedules. IPNA 2023 guidelines suggest that the dose of prednisone can be calculated using either weight or BSA.

The listed guidelines emphasise the use of non‐corticosteroid immunosuppressive medications in children with FRNS or SDNS. These medications are the subject of another Cochrane systematic review (Larkins 2020).

Authors' conclusions

Implications for practice.

Prolongation of prednisone therapy beyond two to three months in the initial episode of SSNS does not reduce the risk of relapse, as demonstrated in four large, well‐designed studies at low risk of bias (PREDNOS 2019; Sinha 2015; Teeninga 2013; Yoshikawa 2015).

Older studies undertaken in lower‐middle income countries found that daily prednisone therapy during a URTI or other infection reduced the risk of relapse compared with continuing alternate‐day prednisone or no prednisone (Abeyagunawardena 2008; Abeyagunawardena 2017; Gulati 2011; Mattoo 2000). However, a newly published and large study, which assessed this intervention in European children, where the pattern of intercurrent infections may be different, found no benefit of changing to daily prednisone at the onset of infection in reducing the risk of relapse (PREDNOS 2 2022). Therefore, the most recent guidelines (IPNA 2023) do not recommend that prednisone dosing be changed routinely from alternate daily to daily at the onset of infection.

The most important question to be answered currently is whether a lower dose of prednisone is as effective in achieving remission compared with the conventional dose of 60 mg/m²/day (2 mg/kg/day). This study should assess the time to remission, time to relapse and the number of relapses to determine if children with SSNS can be safely and effectively treated with lower doses of prednisone. Initially, such a study should be carried out in children with the relapsing disease before lower doses of prednisone are evaluated in new‐onset disease.

Implications for research.

Four studies randomising 823 children have demonstrated that there is no benefit from prolonging prednisone therapy beyond two to three months in the first episode of SSNS. Therefore, no further studies are required to evaluate the duration of therapy, so scarce resources for RCTs should not be used to look further at the duration of treatment. However, all studies evaluating the duration of prednisone have used similar daily and alternate daily doses of prednisone based on the empirical regimens established by ISDKC and Arbeitsgemeinschaft für Pädiatrische Nephrologie in the 1970s and 1980s, so we still do not know whether the same results could be obtained with lower total doses of prednisone. Five small studies included in the review update examined lower doses or shorter durations of prednisone with the currently recommended doses and found no differences in efficacy or adverse effects. Therefore, the most important question to be answered is whether a lower dose of prednisone is as effective in achieving remission compared with the conventional dose of 60 mg/m²/day (2 mg/kg/day). This study should assess the time to remission, time to relapse and the number of relapses to determine if children with SSNS can be safely and effectively treated with lower doses of prednisone. Initially, such a study should be carried out in children with the relapsing disease before lower doses of prednisone are evaluated in new‐onset disease.

Adverse events, including hypertension, ophthalmological disorders and behavioural or psychological effects, were not reported in all studies. Recently published studies have provided additional information on adverse effects. PREDNOS 2019 identified no differences in behavioural effects between different treatment durations but found that extended‐duration therapy resulted in a small improvement in QoL. PREDNOS 2 2022 found no differences in behavioural effects or in the QoL scores between different treatment groups. All new studies should include evaluations of the QoL for the child and their family.

Current guidelines recommend that children with FRNS receive prolonged treatment with alternate‐day prednisone, although there is no RCT data to support this recommendation. A small RCT shows that low‐dose daily prednisone reduced the number of relapses compared with alternate‐day therapy during a one‐year follow‐up (Yadav 2019). Further RCTs with longer periods of follow‐up are required to evaluate the relative efficacy and safety of using alternate‐day compared with daily prednisone to prevent relapse.

Limited evidence from a small cross‐over study (Leisti 1978) suggests that children with SSNS may suffer post‐prednisone adrenal insufficiency and that this state may predispose them to relapse. Our review of the four well‐designed RCTs (PREDNOS 2019; Sinha 2015; Teeninga 2013; Yoshikawa 2015) identified a single report of adrenal insufficiency. The frequency of adrenal insufficiency and the efficacy of cortisol substitution in such children require examination in further RCTs.

What's new

Date	Event	Description
21 August 2024	New search has been performed	New studies added
21 August 2024	New citation required but conclusions have not changed	Conclusions unchanged from previous update

History

Protocol first published: Issue 2, 1999
Review first published: Issue 4, 2000

Date	Event	Description
30 May 2020	New search has been performed	16 new studies added to review
16 September 2015	Amended	Minor amendment to forest plot description 2.8.2 ‐ changed from 'Low risk...' to "High risk..."
11 March 2015	New citation required and conclusions have changed	10 new studies included
11 March 2015	New search has been performed	New studies identified
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

Appendices

Appendix 1. Electronic search strategies

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

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 standardised 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.

Data and analyses

Comparison 1. Steroid therapy in first episode: ≥ 3 months versus 2 months.

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 relapsing by 12 to 24 months	12	1279	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.68, 0.96]
1.3 Number with frequent relapses by 12 to 24 months: stratified by risk of selection bias	8	976	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.71, 1.06]
1.3.1 Low risk of selection bias	5	756	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.83, 1.10]
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 relapsing by 12 to 24 months: stratified by risk of selection bias	12	1279	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.68, 0.96]
1.4.1 Low risk of selection bias	6	808	Risk Ratio (M‐H, Random, 95% CI)	0.93 [0.81, 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 Cushingoid facies	5	547	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.76, 1.65]
1.5.4 Cataracts/eye disorders	6	623	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.11, 1.52]
1.5.5 Infections	2	172	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.53, 1.17]
1.5.6 Retarded growth	4	354	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.25, 1.18]
1.5.7 Osteoporosis	3	233	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.06, 3.38]

Comparison 2. Steroid therapy in first episode: 5 to 7 months versus 3 months.

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 relapsing by 12 to 24 months	8	912	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.50, 0.81]
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 Low risk of selection bias	3	376	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.74, 1.33]
2.3.2 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 relapsing by 12 to 24 months: stratified by risk of selection bias	8	912	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.50, 0.81]
2.4.1 Low risk of selection bias	3	376	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.69, 1.11]
2.4.2 High or unclear risk of selection bias	5	536	Risk Ratio (M‐H, Random, 95% CI)	0.53 [0.41, 0.69]
2.5 Adverse events	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.5.1 Psychological disorders	4	505	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.05, 1.83]
2.5.2 Hypertension	6	752	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.71, 1.74]
2.5.3 Cushingoid appearance	6	762	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.60, 1.23]
2.5.4 Eye complications	5	614	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.18, 1.17]
2.5.5 Infections	5	702	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.65, 1.46]
2.5.6 Growth	3	436	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.36, 1.48]
2.5.7 Addisonian crisis	1	140	Risk Ratio (M‐H, Random, 95% CI)	0.50 [0.05, 5.39]
2.5.8 Gastrointestinal bleeding	1	140	Risk Ratio (M‐H, Random, 95% CI)	1.50 [0.26, 8.70]

Comparison 3. Steroid therapy in the first episode: 1 month versus 2 months.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Number relapsing by 6 to 12 months	1	61	Risk Ratio (M‐H, Random, 95% CI)	1.60 [1.01, 2.54]
3.2 Number relapsing by 12 to 24 months	1	60	Risk Ratio (M‐H, Random, 95% CI)	1.46 [1.01, 2.12]
3.3 Number with frequent relapses	1	61	Risk Ratio (M‐H, Random, 95% CI)	1.48 [0.85, 2.59]

Comparison 4. Steroid therapy in the first episode: 12 months versus 5 months.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Number with relapse	1	58	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.51, 1.13]

Comparison 5. Steroid therapy in the first episode: different total doses given over the same duration.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 Relapse at 12 months	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.43, 0.98]
5.2 Number with FRNS	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.35, 1.37]
5.3 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.3.1 Psychological disorders	1	60	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.33, 27.23]
5.3.2 Hypertension	1	60	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.33, 5.45]
5.3.3 Cushing's Syndrome	1	60	Risk Ratio (M‐H, Random, 95% CI)	3.00 [0.90, 10.01]

Comparison 6. Steroid therapy in first episode: methylprednisone versus prednisolone.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Time to remission [days]	2	38	Mean Difference (IV, Random, 95% CI)	‐5.54 [‐8.46, ‐2.61]
6.2 Number with relapse	1	64	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.75, 1.52]

Comparison 7. Daily prednisolone treatment during viral infections.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Number with relapse with infection	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1.1 All children	2	310	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.44, 1.49]
7.1.2 Subgroup analysis: children not on alternate‐day prednisone	1	60	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.72, 1.71]
7.1.3 Subgroup analysis: children receiving alternate‐day prednisone	2	110	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.47, 1.19]
7.1.4 Subgroup analysis: children receiving alternate‐day prednisone and other immunosuppression	1	89	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.50, 1.50]
7.1.5 Subgroup analysis: children receiving other immunosuppression without alternate‐day prednisone	1	43	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.44, 2.28]
7.2 Number of relapses/patient	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
7.2.1 Number of infection‐related relapses/patient‐years	1	95	Mean Difference (IV, Random, 95% CI)	‐0.70 [‐0.87, ‐0.53]
7.2.2 Total relapses (episodes/patient/year)	1	95	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.08, ‐0.72]
7.3 Number of relapses/patient at 2 years	1	36	Mean Difference (IV, Random, 95% CI)	‐3.30 [‐4.03, ‐2.57]

Comparison 8. Deflazacort versus prednisolone.

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 with relapse by 9 to 12 months	2	63	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.27, 0.78]

Comparison 9. Alternate‐day or daily steroid regimens versus intermittent dosing to prevent relapse.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Number relapsing during therapy	2	98	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.14, 1.25]
9.1.1 Alternate‐day versus intermittent therapy (6 months therapy)	1	48	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.36, 1.02]
9.1.2 Daily versus intermittent therapy (2 months therapy)	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.05, 0.82]
9.2 Number with relapses by 9 to 12 months	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
9.2.1 Alternate‐day therapy versus intermittent dose therapy (6 months therapy)	1	48	Risk Ratio (M‐H, Random, 95% CI)	1.20 [0.93, 1.55]
9.2.2 Daily versus intermittent therapy (2 months therapy)	1	50	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.89, 1.12]
9.3 Mean relapse rate/patient/year	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
9.3.1 Daily versus intermittent therapy (2 months therapy)	1	50	Mean Difference (IV, Random, 95% CI)	0.54 [‐0.50, 1.58]

9.3. Analysis.

Comparison 9: Alternate‐day or daily steroid regimens versus intermittent dosing to prevent relapse, Outcome 3: Mean relapse rate/patient/year

Comparison 10. Intravenous then oral therapy versus oral therapy alone.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Relapse by 6 months	1	64	Risk Ratio (M‐H, Random, 95% CI)	1.06 [0.75, 1.52]

Comparison 11. Single versus divided daily doses of prednisone to prevent relapse.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Number with relapse	2	151	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.77, 1.42]
11.2 Mean relapse rate	1	94	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.64, 0.24]
11.3 Number of days to remission	3	242	Mean Difference (IV, Random, 95% CI)	0.70 [‐0.56, 1.96]
11.4 Number of days to remission according to age group	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
11.4.1 Children aged 1 to 5 years	1	42	Mean Difference (IV, Random, 95% CI)	2.45 [0.59, 4.31]
11.4.2 Children aged 5 to 10 years	1	27	Mean Difference (IV, Random, 95% CI)	0.12 [‐1.04, 1.28]
11.4.3 Children aged 10 to 14 years	1	35	Mean Difference (IV, Random, 95% CI)	1.88 [0.03, 3.73]
11.5 Serious adverse events	2	138	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.18, 0.91]
11.6 Cumulative steroid dose [mg/kg]	1	94	Mean Difference (IV, Random, 95% CI)	‐0.05 [‐0.68, 0.58]
11.7 Number with HPA suppression	1	56	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.70, 0.99]

Comparison 12. Reduced versus standard steroid doses to prevent relapse.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 Time to remission	2	75	Mean Difference (IV, Random, 95% CI)	0.72 [‐0.43, 1.88]
12.2 Number with relapse	4	177	Risk Ratio (M‐H, Random, 95% CI)	1.01 [0.85, 1.20]
12.3 Number with FRNS or SDNS at 12 months	1	117	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.49, 1.91]
12.4 Cumulative prednisone dose to achieve remission [mg/kg]	1	19	Mean Difference (IV, Random, 95% CI)	‐20.60 [‐25.87, ‐15.33]
12.5 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
12.5.1 Reduced growth in height	1	38	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.36, 4.22]
12.5.2 Steroid adverse events	1	38	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.47, 1.72]

Comparison 13. Daily versus alternate‐day prednisone to prevent relapse.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Number of relapses in 12 months [number/year]	1	62	Mean Difference (IV, Random, 95% CI)	‐0.90 [‐1.33, ‐0.47]
13.2 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
13.2.1 Cushingoid facies	1	62	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.69, 1.45]
13.2.2 Cataracts	1	62	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 4.00]

Comparison 14. Short (36 days) versus long (72 days) duration alternate‐day prednisone to prevent relapse.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
14.1 Number with relapse during treatment	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.07 [0.00, 1.19]
14.2 Number with relapse by 6 months	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.46, 1.16]
14.3 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
14.3.1 Viral infection	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.04, 3.23]
14.3.2 Bacterial infection	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.01, 8.35]
14.3.3 Urticaria	1	78	Risk Ratio (M‐H, Random, 95% CI)	0.35 [0.01, 8.35]

Comparison 15. Weight‐based versus body surface area (BSA)‐based dosing of prednisolone.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
15.1 Relapse at 6 months	2	146	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.71, 1.49]
15.2 Adverse events	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
15.2.1 Hypertension	2	144	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.05, 1.73]
15.2.2 Cushingoid features	2	144	Risk Ratio (M‐H, Random, 95% CI)	1.16 [0.58, 2.32]
15.2.3 Eye changes	1	84	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.05, 5.57]
15.2.4 Serious infections	2	144	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.20, 1.66]
15.3 Prednisone dose	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
15.3.1 Induction dose	1	60	Mean Difference (IV, Random, 95% CI)	‐32.00 [‐57.21, ‐6.79]
15.3.2 Cumulative dose over 6 months	1	60	Mean Difference (IV, Random, 95% CI)	‐30.00 [‐54.34, ‐5.66]

Comparison 16. Prolonged steroid therapy (7 months) for relapsing nephrotic syndrome.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
16.1 Number with relapses	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
16.1.1 Relapse by 6 months	1	90	Risk Ratio (M‐H, Random, 95% CI)	0.04 [0.01, 0.25]
16.1.2 Relapse by 12 months	1	76	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.29, 0.65]
16.1.3 Relapse by 2 years	1	64	Risk Ratio (M‐H, Random, 95% CI)	0.60 [0.45, 0.80]
16.1.4 Relapse by 3 years	1	53	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.56, 0.90]
16.2 Relapse rate/patient/year	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
16.2.1 Relapse rate at 1 year	1	72	Mean Difference (IV, Random, 95% CI)	‐1.78 [‐2.30, ‐1.26]
16.2.2 Relapse rate at 2 years	1	56	Mean Difference (IV, Random, 95% CI)	‐1.79 [‐2.39, ‐1.19]
16.2.3 Relapse rate at 3 years	1	41	Mean Difference (IV, Random, 95% CI)	‐1.74 [‐2.39, ‐1.09]
16.3 Number with FRNS or SDNS	1	72	Risk Ratio (M‐H, Random, 95% CI)	0.43 [0.19, 0.95]
16.4 Cumulative steroid dose	1		Mean Difference (IV, Random, 95% CI)	Subtotals only
16.4.1 After 1 year	1	72	Mean Difference (IV, Random, 95% CI)	0.59 [0.02, 1.16]
16.4.2 After 2 years	1	56	Mean Difference (IV, Random, 95% CI)	‐0.32 [‐1.52, 0.88]
16.4.3 After 3 years	1	41	Mean Difference (IV, Random, 95% CI)	‐1.13 [‐3.08, 0.82]
16.5 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
16.5.1 Hypertension	1	72	Risk Ratio (M‐H, Random, 95% CI)	2.40 [0.86, 6.73]
16.5.2 Growth failure	1	72	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.62, 2.50]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Abeyagunawardena 2008.

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 the child had 2 URTI Country: Sri Lanka Setting: single tertiary centre
Participants	Study characteristics 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 Exclusion criteria: glucocorticoid‐related side effects; frequent relapses requiring steroid‐sparing agents; did not have two viral infections within the study period; sustained remission with disease stability Baseline characteristics Number (analysed/recruited): 40/48; intervention group first (18); control group first (22) Median age (range): 5.3 years (1.5 to 13.2) Sex (M/F): 29/11
Interventions	Intervention group Prednisolone: 5 mg/day for 7 days at onset of viral infection. Additional medication given on alternate days to achieve daily prednisone dosing 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	Outcomes relevant to the review Number relapsing during 6 months of therapy and in subsequent 6 months Mean relapse rate during treatment and in subsequent 6 months
Notes	Additional information 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 children 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

Abeyagunawardena 2017.

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 Country: Sri Lanka Setting: single tertiary centre
Participants	Study characteristics Inclusion criteria: children with FRNS off prednisone for 3 months or more Exclusion criteria: children with SSNS receiving alternate‐day prednisone Baseline characteristics Number (analysed/randomised): intervention group first (19/27); control group first (14/21) Mean age ± SD (years): intervention group first (12.0 ± 2.4); control group first (10.0 ± 2.9) Sex (M/F): intervention group first (12/7); control group first (9/5)
Interventions	Intervention group Prednisolone: 0.5 mg/kg/day for 5 days at start of each URTI for 12 months and then crossed over to the control group Control group Placebo for 5 days at start of each URTI for 12 months and then crossed over to the intervention group
Outcomes	Outcomes relevant to this review Number of relapses associated with URTI each year
Notes	Additional information 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

Agarwal 2010.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Duration of follow‐up: 6 months Country: India Setting: single centre
Participants	Study characteristics Inclusion criteria: children with initial episode of INS Exclusion criteria: not reported Baseline characteristics Number: intervention group (22); control group (20) Mean age ± SD (years): not reported Gender: not reported
Interventions	Intervention group Deflazacort (dose and duration not reported) Control group Prednisolone (dose and duration not reported)
Outcomes	Outcomes relevant to this review Remission at 2 and 6 weeks BMD
Notes	Additional information 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

Al Talhi 2018.

Study characteristics
Methods	Study design Parallel RCT Time frame: 1 January 2011 to 31 December 2014 Duration of follow‐up: 2 years Country: Saudi Arabia Setting: single centre
Participants	Study characteristics Inclusion criteria: children with the initial episode of nephrotic syndrome; age range 1 to 12 years; no prior therapy with steroids or immunosuppressive therapy; informed consent Exclusion criteria: congenital nephrotic syndrome/ infantile nephrotic syndrome; prior history of poor compliance with medical therapy; known allergy to prednisolone; persistent hypertension or gross haematuria; family history of known genetic causes of nephrotic syndrome Baseline characteristics Number (analysed/randomised): intervention group 1 (58/60); intervention group 2 (58/60) Mean age ± SD (years): intervention group 1 (5 ± 2); intervention group 2 (5.2 ± 1.8) Sex (M:F) ratio: intervention group 1 (1.9:1); intervention group 2 (2:1)
Interventions	Intervention group 1 Prednisolone: 60 mg/m2, single dose daily for 6 weeks; then 40 mg/m2 alternate daily for 6 weeks; then 20 mg/m2 alternate daily for 1 week and then 10 mg/m2 alternate daily for 1 week Total duration: 3.5 months Total dose: 620 (140) mg/m2/month Intervention group 2 Prednisolone: 60 mg/m2 single daily dose for 4 weeks; 40 mg/m2 on alternate days for 2 months; 30 mg/m2 alternate daily for 2 months; 20 mg/m2 alternate daily for 2 months Total duration: 7 months Total dose: 550 (107) mg/m2/month
Outcomes	Outcomes relevant to this review Time to initial relapse Mean relapse rate, number with FRNS but no report of number who relapsed overall Adverse events Incidence of psychological changes
Notes	Additional information Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised; method of randomisation not reported
Allocation concealment (selection bias)	Low risk	Sealed envelopes provided to each centre QUOTE: "One opened when patient qualified to enter the study"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients appear accounted for; 4 patients (3%) lost to follow‐up
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Unclear risk	Insufficient information to permit judgement

Anand 2013.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Duration of follow‐up: 12 months Country: India Setting: single centre
Participants	Study characteristics Inclusion criteria: children with initial episode of SSNS Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): 60 randomised (numbers per group not reported) Age range: 1 to 12 years Sex (M/F): not reported
Interventions	Intervention group 1 Prednisolone: 4 weeks daily; then alternate‐day and tapered over 5 months. Daily dose not provided Total dose: 126.5 mg/kg over 6 months Total duration: 6 months Intervention group 2 Prednisolone: 6 weeks daily then 6 weeks alternate days. Daily doses not provided Total dose: 123.8 mg/kg over 3 months Total duration: 3 months
Outcomes	Outcomes relevant to this review Relapse rate by 12 months: 20% (treatment group 1) vs 76.7% (treatment group 2) Adverse effects
Notes	Additional information Abstract‐only publication: numbers of patients in each group not provided so data could not be included in the meta‐analysis Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised; method of randomisation not reported
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Relapse defined by urinalysis done by family/staff
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

APN 1981.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Duration of follow‐up: 12 months Country: Germany and Switzerland Setting: multicentre (11 sites)
Participants	Study characteristics Inclusion criteria: children with FRNS Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): intervention group 1 (23/30); intervention group 2 (25/34) Mean age ± SD (months): intervention group 1 (88.5 ± 33.0); intervention group 2 (101.3 ± 35.1) Sex (M/F): intervention group 1 (15/8); intervention group 2 (18/7)
Interventions	Intervention group 1 (alternate) Prednisone: 60 mg/m2/day till protein free for 3+ days; then 35 mg/m2 on alternate days Total duration: 6 months Intervention group 2 Prednisone: 60 mg/m2/day till protein free for 3+ days; then 40 mg/m2 given on 3/7 consecutive days Total duration: 6 months
Outcomes	Outcomes relevant to this review Number relapsing during 6 months of therapy and in subsequent 6 months Mean relapse rate during treatment and in subsequent 6 months
Notes	Additional information Definitions FRNS: 2+ relapses within 6 months of first response or 4 relapses in any 1 year (ISKDC definition) Relapse: urine protein > 40 mg/m2/h for 3 consecutive days (ISKDC) Remission: urinary protein < 4 mg/m2/h for 3 consecutive days (ISKDC) Funding source: supported by grants from the VW Foundation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information about sequence generation to permit judgement
Allocation concealment (selection bias)	Low risk	Sealed envelopes provided to each centre QUOTE: "One opened when patient qualified to enter the study"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	16/64 withdrawn: steroid toxicity (8); incorrect treatment or uncooperative parents (6); late non‐response (1); one patient unaccounted for in the text
Selective reporting (reporting bias)	Low risk	Recorded the review's pre‐specified outcomes (number with relapse, frequency of relapses, adverse events)
Other bias	Low risk	Supported by grants from the VW Foundation

APN 1988.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Duration of follow‐up: 2 years Country: northern Europe Setting: multicentre (number of sites not reported)
Participants	Study characteristics Inclusion criteria: children with initial episode SSNS Exclusion criteria: previous treatment with corticosteroids or immunosuppressive agents; any contraindications to corticosteroid therapy Baseline characteristics Number: intervention group 1 (32); intervention group 2 (29) Age range: 2 to 16 years Sex (M/F): not reported
Interventions	Intervention group 1 (4 weeks) Prednisone: 60 mg/m2/day till urine protein‐free for 3 days, then 40 mg/m2 on alternate days till albumin > 35 g/L Total duration: about 1 month Intervention group 2 (8 weeks) Prednisone: 60 mg/m2/day for 4 weeks and then 40 mg/m2 on alternate days for 4 weeks Total duration: 2 months
Outcomes	Outcomes relevant to this review Number of patients with/without relapse at 6 months and 1 year after completing daily prednisone Number of relapses/patient/year Time to first relapse Number becoming frequent relapsing patients Number with serious adverse events
Notes	Additional information Complete one‐year follow‐up Definitions FRNS using ISKDC definition Relapse: ISKDC definition Remission: ISKDC definition with albumin ≥ 35 g/L Supported by grant Ez.1‐34844 from the VW‐Foundation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information about sequence generation to permit judgement
Allocation concealment (selection bias)	Low risk	QUOTE: "Central random allocation"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	QUOTE: "77 patients were initially recruited into the trial, but 16 had to be removed at an early stage due to steroid resistance (8), or early deviations from the treatment protocol (8)" QUOTE: "34 patients completed the study for the full 2 years. Data for the other 27 patients were included for the period that they remained in the study protocol. Of the 27, 5 patients of the short‐course group and 4 from the standard group were removed when they required other immunosuppressive agents; 2 patients from each group left the country during the course of the study; 7 children from the short‐course group, and 3 from the standard group, were lost to follow‐up due to failure of continuous parental cooperation; and late treatment faults were observed in 3 cases after short‐course treatment, and in 1 patient after standard therapy. The full course was completed by 15 patients receiving the short course and by 19 receiving standard treatment."
Selective reporting (reporting bias)	High risk	Did not report all the review's pre‐specified outcomes. No report on number of FRNS
Other bias	Low risk	Supported by grants from the VW Foundation

APN 1993.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Duration of follow‐up: 2 years Country: northern Europe Setting: multicentre (number of sites not reported)
Participants	Study characteristics Inclusion criteria: children with initial episode SSNS Exclusion criteria: previous treatment with corticosteroids or immunosuppressive agents; contraindications to corticosteroid therapy Baseline characteristics Number: intervention group 1 (34); intervention group 2 (37) Median age, range (years): intervention group 1 (3.9, 1.5 to 8); intervention group 2 (4.4, 1.5 to 14) Sex (M/F): not reported
Interventions	Intervention group 1 (3 months) Prednisone: 60 mg/m2/day for 6 weeks and then 40 mg/m2 on alternate days for 6 weeks Total duration: 3 months Intervention group 2 (2 months) Prednisone: 60 mg/m2/day for 4 weeks and then 40 mg/m2 on alternate days for 4 weeks Total duration: 2 months
Outcomes	Outcomes relevant to this review Number of patients with/without relapse by 6 and 12 months after completing daily and alternate‐day prednisone Number becoming frequent relapsers Number of serious adverse events
Notes	Additional information Complete one‐year follow‐up Definitions FRNS: ISKDC definition Relapse: ISKDC definition Remission: ISKDC definition Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central random allocation
Allocation concealment (selection bias)	Low risk	Central random allocation
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	7.7% excluded for protocol violation. This proportion of missing outcomes are not sufficient to impact results
Selective reporting (reporting bias)	Low risk	Reported the review's pre‐specified outcomes
Other bias	Unclear risk	Insufficient information to permit judgement

Bagga 1999.

Study characteristics
Methods	Study design Parallel RCT Time frame: September 1992 to June 1995 Follow‐up: minimum of 1 year from completion of initial therapy Country: India Setting: single centre
Participants	Study characteristics Inclusion criteria: children aged 1 to 12 years with first episode SSNS Exclusion criteria: received corticosteroids or immunosuppressive agents; showing features of an underlying systemic disease (e.g., systemic lupus erythematosus, HSP, amyloidosis, vasculitis, and hereditary glomerular diseases); haematuria (> 5 red cells/high‐power field of a centrifuged specimen); persistent hypertension (blood pressure more than the 95th percentile for height for age on 3 or more occasions); CrCl < 80 mL/min/1.73 m2 Baseline characteristics Number (analysed/randomised): intervention group 1 (22/24); intervention group 2 (23/27) Mean age ± SD (years): not reported Sex (M/F): not reported
Interventions	Intervention group 1 (4 months) Prednisolone: 2 mg/kg/day for 4 weeks, 1.5 mg/kg/day for 4 weeks, then 1.5 mg/kg alternate days for 4 weeks, 1 mg/kg alternate days for 4 weeks Total duration: 4 months Intervention group 2 (2 months) Prednisolone: 2 mg/kg/day for 4 weeks, then 1.5 mg/kg on alternate days for 4 weeks Total 2 months
Outcomes	Outcomes relevant to this review Number of patients with/without relapse by 6 and 12 months after completing daily and alternate‐day prednisolone Number becoming frequent relapsers Relapse rate/patient/year; mean time to first relapse Number of serious adverse events Cumulative steroid dose
Notes	Additional information Complete one‐year follow‐up Definitions FRNS: 2+ relapses in 6 months or 3+ within 12 months of initial episode Relapse: 3+ protein on dipstick for 3 consecutive days Remission: nil or trace of protein on dipstick for 3+ consecutive days Funding source: Research grant from the All India Institute of Medical Sciences, New Delhi, India
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Information from author that sequence generation was random
Allocation concealment (selection bias)	Low risk	Information from author that allocation occurred after child had entered study
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawal/lost to follow‐up: 6/51; steroid resistance (4); poor compliance (2)
Selective reporting (reporting bias)	Low risk	All the review's pre‐specified outcomes have been reported
Other bias	Low risk	Research grant from the All India Institute of Medical Sciences, New Delhi, India The study appears to be free of other source of bias

Basu 2020.

Study characteristics
Methods	Study design Parallel RCT Time frame: 12‐month period starting April 2015, end date May 2016 Follow‐up: 6 months Country: India Setting: single centre
Participants	Study characteristics Inclusion criteria: children with initial episode or IFR SSNS Exclusion criteria: SRNS; secondary nephrotic syndrome; anaemia; leucopenia, thrombocytopenia; abnormal LFT; active chronic infection (HIV, Hepatitis B or C, TB) live vaccination in the past month Baseline characteristics Number (analysed/randomised): intervention group 1 (30/30); intervention group 2 (30/30) Initial episode/infrequently relapsing SSNS: intervention group 1 (11/19); intervention group 2 (15/15) Mean age ± SD (years): intervention group 1 (5.77 ± 2.2); intervention group 2 (5.47 ± 2.6) Sex (M/F): treatment group 1 (19/11); treatment group 2 (21/9)
Interventions	Intervention 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 the initial episode and for 4 weeks in IFR SSNS Intervention 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 the initial episode and for 4 weeks in IFR SSNS
Outcomes	Outcomes relevant to this review 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	Additional information 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. 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
Other bias	Low risk	Authors stated that they received no external funding for the study

Borovitz 2020.

Study characteristics
Methods	Study design Parallel RCT Time frame: August 2014 to December 2016 Follow‐up: 3 months Country: Israel Setting: single centre
Participants	Study characteristics Inclusion criteria: children with relapse of SSNS Exclusion criteria: Initial episode of SSNS; SRNS; children on prednisone or other immunosuppressive agents at relapse Baseline characteristics Number: intervention group 1 (9); intervention group 2 (11); intervention group 3 (10) Mean age ± SD (years): intervention group 1 (6.14 ± 3.6); intervention group 2 (6.4 ± 3.3); intervention group 3 (5.9 ± 2.1) Sex (M/F): intervention group 1 (4/5); intervention group 2 (7/4); intervention group 3 (7/3)
Interventions	Intervention group 1 Prednisone: 1 mg/kg/day; on remission, dose reduced to 1 mg/kg on alternate days for 2 weeks, then reduced in 10 mg increments every 2 weeks till dose of 10 to 15 mg on alternate days. Then 5 mg on alternate days for 2 weeks Total dose: 24.9 ± 7.4 mg/kg Average duration: 8 to 10 weeks Intervention group 2 Prednisone: 1.5 mg/kg/day; on remission, dose reduced to 1 mg/kg on alternate days for 2 weeks, then reduced in 10 mg increments every 2 weeks till dose of 10 to 15 mg on alternate days. Then 5 mg on alternate days for 2 weeks Total dose: 42.7 ± 25.9 mg/kg Average duration: 8 to 10 weeks Intervention group 3 Prednisone: 2 mg/kg/day: on remission, dose reduced to 1.5 mg/kg on alternate days for 2 weeks, then reduced in 10 mg increments every 2 weeks till dose of 10 to 15 mg on alternate days. Then 5 mg on alternate days for 2 weeks Total dose: 45.5 ± 3.4 mg/kg Average duration: 10 to 12 weeks
Outcomes	Outcomes relevant to this review Primary outcome: cumulative dose of prednisone in each group Secondary outcomes Mean time to remission Number achieving remission Relapse by 3 months
Notes	Additional information Definition of remission: negative/trace protein on urine dipstick test for 3 consecutive days Definition of relapse: proteinuria on dipstick test (> 3+) accompanied by protein/creatinine ratio > 2 mg/mg and/or serum albumin < 3 g/dL and/or oedema Only comparison of group 1 (1 mg/kg dose) and group 3 (2 mg/kg/dose) were included in the meta‐analysis Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	QUOTE: "Patients were divided into three prednisone treatment groups in running order of enrolment, as follows: first patient, 2 mg/kg/day; second, 1.5 mg/kg/day; third, 1 mg/kg; and so forth. Patients and clinicians were informed about prednisone dose only after randomization"
Allocation concealment (selection bias)	High risk	QUOTE: "Patients were divided into three prednisone treatment groups in running order of enrolment, as follows: first patient, 2 mg/kg/day; second, 1.5 mg/kg/day; third, 1 mg/kg; and so forth. Patients and clinicians were informed about prednisone dose only after randomization"
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding and lack of blinding could influence patient management
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding and lack of blinding could influence assessment of time to remission
Incomplete outcome data (attrition bias) All outcomes	Low risk	All reported participants accounted for
Selective reporting (reporting bias)	High risk	No report of adverse events
Other bias	Unclear risk	Insufficient information to permit judgement

Broyer 1997.

Study characteristics
Methods	Study design Parallel RCT Time period: not reported Follow‐up: 1 year Country: France Setting: single centre
Participants	Study characteristics Inclusion criteria: children with SDNS (2+ relapses in 12 months despite alternate‐day prednisone or within 2 months of stopping this regimen) Exclusion criteria: not reported Baseline characteristics Number: intervention group 1 (20); intervention group 2 (20) Mean age ± SD (years): intervention group 1 (9.2 ± 2.7); intervention group 2 (8.5 ± 4) Sex (M/F): intervention group 1 (15/5); intervention group 2 (17/3)
Interventions	Intervention 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 Intervention group 2 Prednisone given as above
Outcomes	Outcomes relevant to this review Number relapsing during 1 year of therapy Mean relapse rate/patient Serious adverse events
Notes	Additional information Six children in group 1 and 5 in group 2 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

Ekka 1997.

Study characteristics
Methods	Study design Parallel RCT Time frame: December 1993 to June 1995 Follow‐up: 9 months Country: India Setting: single centre
Participants	Study characteristics Inclusion criteria: children aged 1.3 to 17 years with relapsing SSNS Exclusion criteria: received corticosteroids or other immunosuppressive drugs for treatment of the current relapse; steroid resistance or dependence Baseline characteristics Number (analysed/randomised): intervention group 1 (47/52); intervention group 2 (48/54) Mean age ± SD (years): intervention group 1 (5.6 ± 2.8); intervention group 2 (6.6 ± 3.4) Sex (M/F): intervention group 1 (32/15); intervention group 2 (31/16)
Interventions	Intervention group 1 (single dose) Prednisolone: 2 mg/kg/day for 2 to 4 weeks given as a single morning dose till remission and then 1.5 mg/kg on alternate days for 4 weeks Intervention group 2 (divided dose) Prednisolone: 2 mg/kg/day for 2 to 4 weeks given as 3 divided doses and then 1.5 mg/kg on alternate days for 4 weeks
Outcomes	Outcomes relevant to this review Number with/without relapse at 9 months Time to remission Duration of remission
Notes	Additional information Definitions Relapse: urine protein 2+ on dipstick for 3 consecutive days Remission: absence of proteinuria for 3 consecutive days Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomised " insufficient information about sequence generation process 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	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	Withdrawal/lost to follow‐up: 12/106; did not report for follow‐up (11); steroid resistant (1)
Selective reporting (reporting bias)	Low risk	All the review's pre‐specified outcomes have been reported.
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Gulati 2011.

Study characteristics
Methods	Study design Parallel RCT Time frame: September 2006 to October 2009 Duration of follow‐up: 24 months Country: India Setting: single tertiary centre
Participants	Study characteristics Inclusion criteria: children aged 1 to 16 years with FRNS, eligible for prednisone therapy ± levamisole; levamisole given to those requiring > 1 mg/kg prednisolone on alternate days, who had ≥ 1 feature of steroid toxicity Exclusion criteria: impaired kidney function (SCr > 1.2 mg/dL), immunosuppressives other than oral prednisone in the preceding 6 months; steroid threshold > 1 mg/kg on alternate days to maintain remission with more than one feature of steroid toxicity, e.g. cataracts; BMI > 95th percentile for age; stage 2 hypertension Baseline characteristics Number (analysed/randomised): intervention group 1 (49/50); intervention group 2 (46/50) Mean age ± SD (months): intervention group 1 (78.5 ± 35.6); intervention group 2 (81.7 ± 38.7) Sex (M/F): intervention group 1 (35/15); intervention group 2 (32/18)
Interventions	Intervention group 1 Existing prednisolone alternate‐day dose increased to a daily dose for 7 days at the onset of viral infection Intervention group 2 Prednisolone continued at the same alternate‐day dose at onset of viral infection
Outcomes	Outcomes relevant to this review Rates of infection‐associated relapses expressed as episodes/patient‐year Total number of relapses/patient‐year Frequency and types of infection Cumulative dose of prednisone received in both groups
Notes	Additional comments Definitions FRNS: at least 2 relapses in 6 months, or > 3 relapses in 12 months Viral infection: one or more of: fever, rhinorrhoea or cough, diarrhoea Infection‐related relapse: presence of 3+ to 4+ proteinuria for 3 consecutive days occurring in the week after 7 days of onset of an infective illness Remission: trace/negative protein for 3 consecutive days Funding source: Funded by the Indian Council of Medical Research
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Block randomisation. "randomised by stratified randomisation" on basis of therapy with or without levamisole
Allocation concealment (selection bias)	Low risk	QUOTE: "allocation was concealed with opaque sealed envelopes opened at inclusion"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	11/100 (11%) patients excluded or lost to follow‐up; lost to follow‐up (5), discontinued treatment (6)
Selective reporting (reporting bias)	Low risk	All the review's pre‐specified outcomes have been reported
Other bias	Low risk	Funded by the Indian Council of Medical Research

Hiraoka 2000.

Study characteristics
Methods	Study design Parallel RCT Time frame: December 1993 to August 1996 Follow‐up: 2 years Country: Japan Setting: multicentre (number of sites not reported)
Participants	Study characteristics Inclusion criteria: children with initial episode of SSNS; 8 excluded because steroid‐resistant Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): intervention group 1 (30/34); intervention group 2 (29/34) Mean age ± SD (years): intervention group 1 (6.4 ± 3.4); intervention group 2 (7.1 ± 4.0) Sex (M/F): intervention group 1 (21/13); intervention group 2 (21/13)
Interventions	Intervention group 1 (high dose) Prednisolone: 60 mg/m2/day (max 80 mg) for 6 weeks, 40 mg/m2 on alternate days for 6 weeks Total duration: 3 months Intervention group 2 (standard) Prednisolone: 40 mg/m2/day (max 60 mg) for 6 weeks, 40 mg/m2 on alternate days for 6 weeks Total duration: 3 months
Outcomes	Outcomes relevant to this review Number relapsing at 6 months and 12 months Number with frequent relapses Adverse effects
Notes	Additional information Definitions Relapse: urine protein 2+ for 3 days Remission: urine protein < 4 mg/h/m2 for 3 days or more Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomly allocated " ‐ insufficient information about sequence generation process to permit judgement
Allocation concealment (selection bias)	Unclear risk	Randomisation stated but no information on method used is available
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data Withdrawal/lost to follow‐up: 8/68 excluded for steroid resistance
Selective reporting (reporting bias)	Low risk	All the review's pre‐specified outcomes have been reported
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Hiraoka 2003.

Study characteristics
Methods	Study design Parallel RCT Time frame: August 1996 and May 1999 Follow‐up: 2 years Country: Japan Setting: multicentre (number of sites not reported)
Participants	Study characteristics Inclusion criteria: children with initial episode of SSNS Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): intervention group 1 (36/38); intervention group 2 (34/35) Mean age ± SD (years): intervention group 1 (7.6 ± 4.5); intervention group 2 (7.4 ± 4.4) Sex (M/F): intervention group 1 (25/13); intervention group 2 (22/13)
Interventions	Intervention group 1 (7 months) Prednisolone: 60 mg/m2/day (max 80 mg) for 4 weeks; 60 mg/m2 (max 80 mg) on alternate days for 4 weeks and reducing by 10 mg/m2 each month Total duration: 7 months Total calculated dose: 4620 mg/m2 Intervention group 2 (3 months) Prednisolone: 60 mg/m2/day for 6 weeks (max 80 mg); 40 mg/m2 (max 60 mg) on alternate days for 6 weeks Total duration: 3 months Total calculated dose: 3360 mg/m2
Outcomes	Outcomes relevant to this review Number relapsing at 6, 12 and 24 months Number with FRNS Adverse effects
Notes	Additional information Definitions Relapse: urine protein 2+ for 3 days Remission: urine protein < 4 mg/h/m2 for 3 days or more Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"randomly allocated" ‐ sealed envelopes
Allocation concealment (selection bias)	Low risk	QUOTE: "Simple randomisation using sealed envelopes"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawal/ lost to follow‐up: 3/73; steroid resistance (3)
Selective reporting (reporting bias)	Low risk	All the review's pre‐specified outcomes have been reported
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Imbasciati 1985.

Study characteristics
Methods	Study design Parallel RCT Time frame: June 1980 to June 1983 Follow‐up: 12 to 24 months Country: Italy Setting: multicentre (number of sites not reported)
Participants	Study characteristics Inclusion criteria: children aged 2 to 14 years with either initial episode of SSNS or no relapse in previous year Exclusion criteria: evidence of underlying systemic disease, neoplasia, viral hepatitis, or exposure to drugs or toxic agents known to induce nephrotic syndrome; treated with steroids or cytotoxic agents within one year before admission Baseline characteristics Number (adults/children): 22/67; intervention group (33/11); intervention group 2 (34/11) Children (analysed/randomised): intervention group 1 (31/33); intervention group 2 (33/34) Median age, range (years): intervention group 1 (9, 2 to 54); intervention group 2 (8, 2 to 56) Sex (M/F): intervention group 1 (29/15); intervention group 2 (31/14)
Interventions	Intervention group 1 Methylprednisolone: 20 mg/kg IV for 3 days, prednisone 20 mg/m2/day for 4 weeks, 20 mg/m2 on alternate days for 4 weeks, then 20 mg/m2 on alternate days for 4 months Total duration: 6 months Intervention group 2 Prednisone: 60 mg/m2/day for 4 weeks, 40 mg/m2 on alternate days for 4 weeks and 20 mg/m2 on alternate days for 4 months Total duration: 6 months
Outcomes	Outcomes relevant to this review Number with/without relapse during 12 to 24 months follow‐up Mean relapse rate/patient/year
Notes	Additional information Adults also in study. Some endpoints not separated for children, so not examined Definitions Relapse: ISKDC Remission: ISKDC Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Randomly assigned from a table with random numbers"
Allocation concealment (selection bias)	Low risk	Central randomisation centre
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data. All 89 randomised patients followed for 12‐24 months
Selective reporting (reporting bias)	Low risk	All the review's pre‐specified outcomes have been reported.
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

ISKDC 1979.

Study characteristics
Methods	Study design Parallel RCT Time frame: 20 September 1973 to 26 August 1976 Follow‐up: at least 8 months Country: USA and Northern Europe Setting: multicentre (number of sites not reported)
Participants	Study characteristics Inclusion criteria: children aged 3 months to 15 years with SSNS with relapse within 6 months of their initial response to steroid therapy Exclusion criteria: proteinuria ≤ 40 mg/h/m2; hypoalbuminaemia ≥ 2.5 g/dL at the onset of disease; prior treatment with steroids or other cytotoxic immunosuppressant agents; evidence of underlying systemic disease or exposure to agents associated with nephrotic syndrome Baseline characteristics Number (analysed/randomised): intervention group (25/32); control group (25/32) Mean age ± SD (years): not reported Sex (M/F): not reported
Interventions	Intervention group Prednisone: 60 mg/m2/day for 4 weeks and tapered daily dose for 4 weeks Control group Prednisone: 60 mg/m2/day till remission and 40 mg/m2 on 3/7 consecutive days for 4 weeks
Outcomes	Outcomes relevant to this review Number relapsing during treatment and within 12 months Mean time to next relapse Mean relapse rate/patient
Notes	Additional information Definitions Relapse: ISKDC definition Remission: ISKDC definition 10 patients (4 from group 1 and 6 from group 2) were excluded from the analysis because of protocol violations 3 patients (2 from group 1 and 1 from group 2) were lost to follow‐up and one patient was treated incorrectly so the data on these 4 patients were excluded from analyses
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomly allocated " ‐ insufficient information about sequence generation process to permit judgement
Allocation concealment (selection bias)	Unclear risk	Randomisation stated but no information on method used is available
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	14/64 (22%) not included in analyses because of protocol violations or loss to follow up
Selective reporting (reporting bias)	High risk	Not all of the review's pre‐specified primary outcomes have been reported. Adverse events not reported
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Jamshaid 2022.

Study characteristics
Methods	Study design Parallel RCT Time frame: 1 November 2019 to 31 October 2020 Duration of study: follow‐up 12 months Country: Pakistan Setting: single tertiary centre
Participants	Study characteristics Inclusion criteria: children with initial episode of SSNS Exclusion criteria: Relapse of SSNS; steroid‐resistant patients; poor compliance; congenital and secondary nephrotic syndrome Baseline characteristics Number: intervention group 1 (75); intervention group 2 (75) Mean age, mean ± SD (years): intervention group 1 (4.45 ± 1.68); intervention group 2 (4.2 ± 1.68) Sex (M/F): intervention group 1 (35/40); intervention group 2 (23/52)
Interventions	Intervention group 1 Prednisone: 2 mg/kg/day for 4 weeks (maximum dose: 60mg) followed by 1.5 mg/kg/day on alternate days for 8 weeks (maximum dose 40 mg) Total duration: 12 weeks Intervention group 2 Prednisone: 2 mg/kg/day for 4 weeks (maximum dose: 60 mg), 1.5 mg/kg/day every other day for 4 weeks, followed by 5 mg decrements every 2 weeks and then discontinued gradually Total duration: 16 to 24 weeks Co‐interventions None reported
Outcomes	Outcomes relevant to this review Number with one or more relapses Relapse rate/year
Notes	Additional information Remission: absence of oedema with urine protein ≤ 1+ on dipstick, UPCR ≤ 20 mg/mmol or ≤ 4 mg/m2/hour for 3 consecutive days Relapse: presence of oedema with urine protein ≥ 3+ on dipstick for 3 consecutive days
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: “These children were allocated into short‐ and long‐term therapy groups, randomly”
Allocation concealment (selection bias)	Unclear risk	QUOTE: “These children were allocated into short‐ and long‐term therapy groups, randomly”
Blinding of participants and personnel (performance bias) All outcomes	High risk	No blinding
Blinding of outcome assessment (detection bias) All outcomes	High risk	No blinding of outcome assessment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All reported participants accounted for but unclear whether the study reported on all participants included
Selective reporting (reporting bias)	High risk	Incomplete reporting on relapse rates and no report of adverse effects
Other bias	Unclear risk	Unclear what this statement in report means "This Quasi‐experimental study was conducted in the Department of Paediatric Nephrology at the Children’s Hospital Lahore"

Jayantha 2000.

Study characteristics
Methods	Study design Parallel RCT Time frame: September 1994 to 2001 Follow‐up: 2 years Country: Sri Lanka Setting: single centre
Participants	Study characteristics Inclusion criteria: 1 to 11.7 years with initial episode of SSNS Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): intervention group (48/48); intervention group 2 (70/74) Mean age ± SD (years): not reported Sex (M/F): intervention group 1 (28/20); intervention group 2 (52/22)
Interventions	Intervention group 1 (7 months) Prednisolone: 60 mg/m2/day for 4 weeks, 60 mg/m2 on alternate days; reducing alternate day‐dose by 10 mg/m2 every 4 weeks Total duration: 7 months Intervention group 2 (ISKDC) ISKDC regimen: prednisolone 60 mg/m2/day for 4 weeks; 40 mg/m2 on alternate days for 4 weeks Total duration: 2 months
Outcomes	Outcomes relevant to this review Number relapsing by 12 and 24 months Relapse rate/patient/year Number with frequent relapses at 1 year Cumulative dose of steroid Adverse effects
Notes	Additional information Abstract‐only publication; data from author Definitions ISKDC (relapse): proteinuria ≥ 2+ for 5+ days Remission: oedema‐free and urine protein negative/trace FRNS and SDNS: ISKDC and APN definitions
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Random allocation table" ‐ notes received from author
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	Withdrawal/loss to follow‐up: 46/135 (34%) lost to follow‐up at 2 years
Selective reporting (reporting bias)	Low risk	Reported on all of review's pre‐specified outcomes
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Jayantha 2002b.

Study characteristics
Methods	Study design Parallel RCT Time frame: September 1994 to September 2002 Follow‐up: 6 months Country: Sri Lanka Setting: single centre
Participants	Study characteristics Inclusion criteria: children with relapsing SSNS; children with SDNS Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): intervention group 1 (46/69); intervention group 2 (44/60) Age range: 1 to 11.1 years Sex (M/F): 50/45
Interventions	Intervention group 1 (7 months) Prednisolone: 60 mg/m2/day for 4 weeks, then 60 mg/m2 on alternate days. Reducing alternate‐day dose by 10 mg/m2 every 4 weeks Total duration: 7 months Intervention group 2 (2 months) ISKDC regimen: prednisolone 60 mg/m2/day till urine protein‐free for 3 days, then 40 mg/m2 on alternate days for 4 weeks Total duration: 2 months
Outcomes	Outcomes relevant to this review Number relapsing by 6, 12 and 24 months Relapse rate/patient/year Number with frequent relapses, steroid dependence at 1 year Cumulative dose of steroid Adverse effects
Notes	Additional information Abstract‐only publication; data from author Definitions ISKDC‐relapse: proteinuria ≥ 2+ for 5+ days Remission: oedema‐free and urine protein negative/trace FRNS, SSNS and SDNS: ISKDC and APN definitions Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"random allocation table". Information from author
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding not mentioned 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 mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	High risk	24% lost to follow‐up at 1 year (23/95)
Selective reporting (reporting bias)	High risk	Not all the review's pre‐specified outcomes have been reported. No report on adverse effects
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Kainth 2021.

Study characteristics
Methods	Study design Parallel RCT Time frame: August 2015 to July 2017 Follow‐up: 12 months Country: India Setting: single tertiary centre
Participants	Study characteristics Inclusion criteria: children with infrequently relapsing SSNS (< 2 relapses in 6 months and < 4 relapses in 12 months); children randomised at remission Exclusion criteria: FRNS or SDNS; SRNS (failure to remit in current relapse despite 4 weeks of steroid therapy); known secondary cause of nephrotic syndrome; inadequately treated initial episode of SSNS within 12 months of enrolment; receiving alternate immunosuppression within 6 months of enrolment; not receiving prednisolone 60 mg/m2 for at least 7 days for current relapse Baseline characteristics Number (analysed/randomised): intervention group 1 (55); intervention group 2 (62) Median age, IQR (years): intervention group 1 (8, 6 to 11); intervention group 2 (9, 6 to 12) Sex (M/F): intervention group 1 (42/13); intervention group 2 (49/13)
Interventions	Intervention group 1 (short duration) Prednisolone: 60 mg/m2 (maximum dose 60 mg) till remission, then 40 mg/m2 (maximum dose 40 mg) on alternate days for 2 weeks Intervention group 2 (standard duration) Prednisolone: 60 mg/m2 (maximum dose 60 mg) till remission, then 40 mg/m2 (maximum dose 40 mg) on alternate days for 4 weeks
Outcomes	Outcomes relevant to this review Primary outcome: proportion developing FRNS or SDNS by 12 months Secondary outcomes: time to first relapse, relapse rate, cumulative dose of steroids, adverse effects
Notes	Additional information Definitions Relapse: > 3+ protein for 3 days on urinalysis Remission: nil or trace for 3 days on urinalysis
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: “Random numbers were computer generated for 1:1 assignment using variable block size (4 or 6)" QUOTE: "Stratified for FRNS/SDNS before IFR course & for age <4 yrs"
Allocation concealment (selection bias)	Low risk	QUOTE: "Sequentially numbered, opaque, sealed envelopes were designed to ensure allocation concealment. Preparation and safekeeping of the randomization list were ensured by staff not involved in study"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Patients and investigators were not blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Patients and investigators were not blinded. Urine protein diary provided by patient. Dipstick to confirm at follow‐up
Incomplete outcome data (attrition bias) All outcomes	Low risk	6/117 (5.2%) did not complete the study
Selective reporting (reporting bias)	Low risk	Expected outcomes reported though some could not be included in analyses as reported as IQR
Other bias	Low risk	Funded by Dept of Biotech, Gov of India N BT/PR11030/MED/97/1644/2016

Kansal 2019.

Study characteristics
Methods	Study design Parallel RCT Time frame: March 2018 to March 2019 Follow‐up: 3 months after ceasing therapy Country: India Setting: single tertiary centre
Participants	Study characteristics Inclusion criteria: children with relapsing SSNS Exclusion criteria: children with serious infections or on stress dose steroids excluded Baseline characteristics Number (analysed/randomised): intervention group 1 (20/20); intervention group 2 (20/20) Mean age: 7.5 years Sex (M/F): not reported
Interventions	Intervention group 1 Prednisolone: 2 mg/kg until remission, followed by 1 mg/kg alternate daily for 4 weeks Intervention group 2 Prednisolone: 2 mg/kg until remission, followed by 1.5 mg/kg alternate daily for 4 weeks
Outcomes	Outcomes relevant to this review Number achieving remission Number with relapse
Notes	Additional information Abstract‐only publication Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	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	Unclear risk	Blinding not mentioned and the outcome is likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessment not mentioned and outcome measurement likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	insufficient information to permit judgement
Other bias	Unclear risk	insufficient information to permit judgement

Khan 2023.

Study characteristics
Methods	Study design Parallel RCT Time frame: December 2021 to September 2022 Follow‐up: 6 months after ceasing therapy (completed January 2023 Country: India Setting: single tertiary centre
Participants	Study characteristics Inclusion criteria: children aged 1 to 17 years with first episode of SSNS Exclusion criteria: secondary nephrotic syndrome, infection at time of recruitment; previous history of nephrotic syndrome (SSNS or SRNS); already on corticosteroids; allergy to egg or egg components; < 1 or > 12 years Baseline characteristics Number (analysed/randomised): intervention group 1 (29/30); intervention group 2 (27/30) Mean age, IQR (months): intervention group 1 (42, 29 to 60); intervention group 2 (41, 25 to 54) Sex (M/F): intervention group 1 (18/11); intervention group 2 (17/10)
Interventions	Intervention group 1 Prednisolone: 2 mg/kg as a single morning dose for 6 weeks followed by 1.5 mg/kg alternate daily for 6 weeks Intervention group 2 Prednisolone: 2 mg/kg divided into 2 doses for 6 weeks followed by 1.5 mg/kg alternate daily for 6 weeks
Outcomes	Outcomes relevant to this review Number with relapse by 6 months Time to remission (days and IQR) Time to first relapse (days and IQR) Results of Short Synacthen Test at completion of daily prednisolone to assess HPA axis suppression
Notes	Additional information No funding
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated randomisation (reported in trial registration)
Allocation concealment (selection bias)	Low risk	Sequentially numbered, sealed, opaque envelopes (reported in trial registration)
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study (reported in trial registration)
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study (reported in trial registration)
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants accounted for according to abstract
Selective reporting (reporting bias)	High risk	Outcomes reported as medians and IQR, unable to meta‐analyse
Other bias	Low risk	Study apppears free of other biases

Kleinknecht 1982.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Follow‐up: 15 months Country: France Setting: multicentre (number of sites not reported)
Participants	Study characteristics Inclusion criteria: children with initial episode SSNS Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): intervention group 1 (29/29); intervention group 2 (29/29) Mean age ± SD (years): not reported Sex (M/F): not reported
Interventions	Intervention group 1 (13 months) Prednisone: 2 mg/kg/day for 4 weeks and then tapering dose on alternate days for 12 months Intervention group 2 (6 months) Prednisone: 2 mg/kg/day for 4 weeks and then tapering dose on alternate days for 5 months
Outcomes	Outcomes relevant to this review Number relapsing by 6, 12 and 15 months or more
Notes	Additional information Abstract‐only publication Authors confirmed adequate allocation but unable to supply further study information Definitions of FRNS/SSNS/relapse/remission: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Sealed closed number envelopes in series of ten" Information obtained from author
Allocation concealment (selection bias)	Low risk	Central randomisation
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 information to permit judgement
Selective reporting (reporting bias)	High risk	Not all review's pre‐specified outcomes have been reported No data on adverse effect
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Ksiazek 1995.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Follow‐up: 2 years Country: Poland Setting: single centre
Participants	Study characteristics Inclusion criteria: children with initial episode SSNS Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): intervention group 1 (72/72); intervention group 2 (68/68); intervention group 3 (44/44) Mean age (range): 3.6 years (13 months to 11 years) Sex (M/F): 113/71
Interventions	Intervention group 1 (6 months) Prednisone: 1 to 2 mg/kg/day for 4 weeks, 1 mg/kg on alternate days for 4 weeks and taper by 25% each month for 4 months Total duration: 6 months Total calculated steroid dose: 2922 mg/m2 Intervention group 2 (3 months) Prednisone: 1 to 2 mg/kg/day for 4 weeks, 1 mg/kg on alternate days for 4 weeks and taper by 25%/week for 4 weeks. Total duration: 3 months Total calculated steroid dose: 2410 mg/m2 Intervention group 3 (2 months) Prednisone: 4 weeks each of 1 to 2 mg/kg/day and 1 mg/kg on alternate days Total duration: 2 months
Outcomes	Outcomes relevant to this review Number relapsing by 6 months and 2 years after completing daily and alternate‐day prednisone Relapse rate/patient/year
Notes	Additional information Unequal numbers in groups Only intervention group 2 was used in the analyses Definitions FRNS: ISKDC definition Relapse: ISKDC definition Remission: ISKDC definition
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"randomly assigned", insufficient information about sequence generation to permit judgement
Allocation concealment (selection bias)	High risk	QUOTE: "Parents had an influence on assignment, favouring Protocol C"
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	Low risk	All patients followed for 2 years
Selective reporting (reporting bias)	High risk	Not all review's pre‐specified outcomes have been reported No data on numbers with FRNS
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Leisti 1978.

Study characteristics
Methods	Study design Cross‐over RCT Time frame: not reported Follow‐up: 2.4 years Country: Finland Setting: single centre
Participants	Study characteristics Inclusion criteria: children with relapsing SSNS and subnormal response to 2‐hour ACTH test 1 to 12 days after completing prednisone Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): 13/13 Age range: 4.7 to 14.6 years Sex (M/F): 8/5
Interventions	Intervention 15 mg cortisol/day in ≥ 30 kg and 7.5 mg/day in < 30 kg for 6 months or till relapse Treated for 6 months or till relapse. After next relapse treated and post‐steroid adrenal suppression confirmed, patient was given alternate therapy The dose of either medication doubled for 3 days when proteinuria or infection developed Group 1 Cortisol then placebo Group 2 Placebo then cortisol
Outcomes	Outcomes relevant to this review Number with relapse during cortisol or placebo at 3 months and 6 months
Notes	Additional information Data for 2 periods combined Definitions Remission and relapse: ISKDC definitions Further information requested from authors but not received Funding source: Sigrid Juselius Foundation financial support
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"allotted". No other information
Allocation concealment (selection bias)	Unclear risk	Randomisation stated but no information on allocation concealment provided
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All participants and personnel blinded. Tablets were of identical taste and appearance
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All participants and personnel blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants completed study
Selective reporting (reporting bias)	High risk	Not all review's pre‐specified outcomes have been reported No data on adverse events
Other bias	Low risk	Sigrid Juselius Foundation financial support, Medica OY, Helsenki drug preparations

Li 1994.

Study characteristics
Methods	Study design Parallel RCT Time frame: 1990 to December 1992 Follow‐up period: unclear; at least 6 months Country: China Setting: single tertiary centre
Participants	Study characteristics Inclusion criteria: SSNS Exclusion criteria: not reported Baseline characteristics Number: intervention group 1 (19); intervention group 2 (25) Mean age ± SD (years): intervention group 1 (7.21 ± 3.52); intervention group 2 (7.54 ± 4.24) Sex (M/F): intervention group 1 (14/5); intervention group 2 (18/7)
Interventions	Intervention group 1 (single dose) Prednisone: 2 mg/kg/day as a single morning dose for 4 weeks; prednisone 2 mg/kg on alternate days for 5 weeks, then gradually reduced till 6 months Intervention group 2 (divided dose) Prednisone: 2 mg/kg/day given as three divided doses for 4 weeks; prednisone 2 mg/kg on alternate days for 5 weeks, then gradually reduced till 6 months
Outcomes	Outcomes relevant to this review Time to remission Toxicities
Notes	Additional comments Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Patients allocated by alternation
Allocation concealment (selection bias)	High risk	Patients allocated by alternation
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)	High risk	Not all review's pre‐specified outcomes have been reported No data on frequent relapses
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Liern 2008.

Study characteristics
Methods	Study design Cross‐over RCT Time frame: not reported Follow‐up period: not reported Country: Argentina Setting: single centre
Participants	Study characteristics Inclusion criteria: children with SSNS enrolled after first relapse Exclusion criteria: not reported Baseline characteristics Number: 11 Mean age (range): 48 months (16 to 52) Sex (M/F): not reported
Interventions	Intervention group 1 Methylprednisolone: 48 mg/m2/day for 6 weeks (maximum dose not reported), followed by 2/3 of the dose on alternate days for 6 weeks Intervention group 2 Deflazacort: 72 mg/m2/day for 6 weeks (maximum dose 90 mg), followed by 2/3 of the dose on alternate days for 6 weeks
Outcomes	Outcomes relevant to this review Mean time to remission Mean time to relapse Total IgG and its subclasses Adverse effects
Notes	Additional information Additional data requested from authors and received Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomised by computer generated table (information received from author)
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Double blind to patients and medical caregivers
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double blind to patients and medical caregivers
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear if all patients completed both arms of the study
Selective reporting (reporting bias)	High risk	Not all review's pre‐specified outcomes have been reported No data on relapse, frequent relapses and minimal data on adverse effects
Other bias	Unclear risk	Insufficient information to permit judgement

Mattoo 2000.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Follow‐up period: 2 years Country: Saudi Arabia Setting: single tertiary centre
Participants	Study information Inclusion criteria: children with relapsing SSNS receiving prednisone 0.5 mg/kg on alternate days for frequent relapses or following CPA Exclusion criteria: children who were not compliant or lost to follow‐up were excluded from the analysis Baseline characteristics Number (analysed/randomised): intervention group 1 (18/18); intervention group 2 (18/18) Mean age ± SD (years): intervention group 1 (7.2 ± 3.3); intervention group 2 (6.8 ± 3.6) Sex (M/F): intervention group 1 (10/8); intervention group 2 (12/6)
Interventions	Intervention group 1 Prednisone: daily (0.5 mg/kg) for 5 days during URTI Intervention group 2 Prednisone: 0.5 mg/kg on alternate days continued during URTI
Outcomes	Outcomes relevant to this review Mean relapse rate/patient during 2 year follow‐up
Notes	Additional information Definitions Relapse and remission: ISKDC Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Data received from authors; alternate patients allocated to groups
Allocation concealment (selection bias)	High risk	QUOTE: "alternate patients allocated to groups"
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	Low risk	Each patient was followed for a period of two years
Selective reporting (reporting bias)	High risk	Not all review's pre‐specified outcomes have been reported No data on adverse events. Only steroid dependent patients included
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Mishra 2012.

Study characteristics
Methods	Study design Parallel RCT Time frame: July 2007 to June 2009 Follow‐up period: 12 months Country: India Setting: single tertiary centre
Participants	Study characteristics Inclusion criteria: children with first episode of SSNS, aged 1 to 10 years; no systemic disease Exclusion criteria: < and > 10 years; persistent hypertension (> 95th percentile for age, gender on 3 occasions); gross haematuria; CrCl < 80 mL/min/1.73 m2; azotaemia; failure to achieve remission by end of 4 weeks prednisone Baseline characteristics Number (analysed/randomised): intervention group 1 (37/40); intervention group 2 (37/40) Mean age ± SD (years): intervention group 1 (4.4 ± 3.0); intervention group 2 (5.3 ± 3.1) Sex (M/F): intervention group 1 (25/12); intervention group 2 (27/10)
Interventions	Intervention group 1 (prolonged treatment) Prednisolone: 2 mg/kg/day for 6 weeks followed by 1.5 mg/kg on alternate days for 6 weeks, 1 mg/kg for 4 weeks, 0.5 mg/kg on alternate days for 4 weeks Total duration: 20 weeks Calculated total dose: 3990 mg/m2 Intervention group 2 (standard treatment) Prednisone: 2 mg/kg/day for 6 weeks, followed by 1.5 mg/kg on alternate days for 6 weeks Total duration: 12 weeks Calculated total dose: 3360 mg/m2
Outcomes	Outcomes relevant to this review Mean relapse rate/patient during 2‐year follow‐up Number with FRNS Adverse effects
Notes	Additional information Definitions Relapse and remission: ISKDC No definition of FRNS provided Children who did not complete treatment or were not followed for 12 months after treatment completion were excluded from the study Additional data requested from authors and received Funding source: none
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated
Allocation concealment (selection bias)	Unclear risk	Insufficient information to permit judgement
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	Low risk	5/80 (6.3%) lost to follow‐up
Selective reporting (reporting bias)	Unclear risk	Did not reported on all of review's pre‐specified outcomes The number of patients with at least one relapse is unclear
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Mocan 1999.

Study characteristics
Methods	Study design Parallel RCT Time frame: March 1990 to April 1996 Follow‐up period: 38 to 42 months Country: Turkey Setting: single tertiary centre
Participants	Study characteristics Inclusion criteria: initial episode of SSNS Exclusion criteria: not reported Baseline characteristics Number: intervention group 1 (8); intervention group 2 (7) Mean age ± SE (years): intervention group 1 (3.6 ± 2.2); intervention group 2 (4.0 ± 1.7) Sex (M/F): intervention group 1 (7/1); intervention group 2 (5/2)
Interventions	Intervention group 1 (high dose group) Methylprednisolone: 30 mg/kg for 3 days; 20 mg/kg for four days; 10 mg/kg for one week Total duration: 14 days Intervention group 2 (standard therapy) Prednisolone: 60 mg/m2 for 4 weeks, followed by 45, 30, 20,10 and 5 mg/m2 on alternate days for a further 5 months Total duration: 6 months
Outcomes	Outcomes relevant to this review Time to remission Time to first relapse Mean relapse rate during study Adverse effects
Notes	Additional information Definitions of relapse and remission not provided Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	QUOTE: "Children arbitrarily randomised into two groups"
Allocation concealment (selection bias)	High risk	QUOTE: "Children arbitrarily randomised into two groups"
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	High risk	6/21 excluded; 4/21 (21%) lost to follow‐up and this could influence results; 2/21 SRNS
Selective reporting (reporting bias)	High risk	Reported on adverse events, relapse rate but not number with FRNS
Other bias	Unclear risk	Insufficient information to assess whether an important risk of bias exists

Moundekhel 2012.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Duration of follow‐up: 12 months Country: Saudi Arabia Setting: single centre
Participants	Study characteristics Inclusion criteria: children with initial episode SSNS or with infrequently relapsing SSNS Exclusion criteria: FRNS, SDNS, SRNS, secondary nephrotic syndrome Baseline characteristics Number: intervention group 1 (46); intervention group 2 (46) Mean age ± SD (years): intervention group 1 (5.76 ± 3.03); intervention group 2 (5.97 ± 2.56) Sex (M/F): intervention group 1 (26/18); intervention group 2 (31/15)
Interventions	Intervention group 1 (3 months) Prednisolone: 6 weeks each of 60 mg/m2/day and 40 mg/m2 on alternate days Total duration: 12 weeks Total dose: 3020 mg/m2 Intervention group 2 (2 months) Prednisolone: 4 weeks each of 60 mg/m2/day and 40 mg/m2 on alternate days Total duration: 8 weeks Total dose: 2070 mg/m2
Outcomes	Outcomes relevant to this review Relapse by 6 months and 12 months Adverse effects
Notes	Additional information Number of males and females in intervention group 1 doesn't add up to 46 Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Patients said to be "randomly divided"; equal numbers in each group suggests that alternation used
Allocation concealment (selection bias)	High risk	Patients said to be "randomly divided"; equal numbers in each group suggests that alternation used
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	High risk	No report of blinding of outcome assessment
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Unclear if all included patients were reported
Selective reporting (reporting bias)	High risk	No report of FRNS/SDNS & limited report of adverse effects
Other bias	Unclear risk	Insufficient information to permit judgement

Norero 1996.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Duration of follow‐up: 18 months Country: Chile Setting: multicentre (11 sites)
Participants	Study characteristics Inclusion criteria: children with initial episode SSNS Exclusion criteria: secondary INS; initially or became SRNS or SDNS; deviations from therapeutic scheme; release 3 months before end of therapy; biopsy showing different histology to minimal changes Baseline characteristics Number: intervention group 1 (29); intervention group 2 (27) Mean age, range (months): intervention group 1 (25.5, 11 to 156); intervention group 2 (26, 16 to 144) Sex (M/F): not reported
Interventions	Intervention group 1 (3 months) Prednisolone: 6 weeks each of 60 mg/m2/day and 40 mg/m2 on alternate days Total duration: 12 weeks Total dose: 3600 mg/m2 Intervention group 2 (2 months) Prednisolone: 4 weeks each of 60 mg/m2/day and 40 mg/m2 on alternate days Total duration: 8 weeks Total dose: 2400 mg/m2
Outcomes	Outcomes relevant to this review Number with relapse by 12 months and 18 months Mean relapse rate/patient in 18 months Number with frequent relapses Adverse effects
Notes	Additional information Children with SDNS (relapse on reducing dose of steroids) were excluded Renal biopsy showing minimal change disease required for study entry Definitions: FRNS: 2 + relapses in 6 months or 3 + in 1 year Relapse: urinary protein 100 mg/kg/day or 40 mg/m2/hours or UPCR > 1 or 3 + on dipstick for > 3 days Remission: urine protein < 150 mg/day for 3 consecutive days Time to 1st relapse: not reported Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study described as randomised; method of randomisation not reported
Allocation concealment (selection bias)	High risk	Patients allocated by odd or even numbers
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	High risk	Number excluded or lost to follow‐up: 56/96 completed follow‐up. Of 40 excluded patients, 19 had SRNS. Remaining 21 excluded inappropriately: SDNS (5); deviation from protocol (3); duration of follow‐up insufficient (11); loss to follow‐up (2)
Selective reporting (reporting bias)	Low risk	Reported on all of review's pre‐specified outcomes
Other bias	Low risk	Grant No 1940506 from FONDECYT (National Scientific and Technology Foundation)

Paul 2014.

Study characteristics
Methods	Study design Parallel RCT Time frame: January 2006 to May 2008 Follow‐up: 12 months Country: Bangladesh Setting: single centre
Participants	Study characteristics Inclusion criteria: children with initial episode of SSNS; aged 1 to 15 years Exclusion criteria: SRNS; secondary nephrotic syndrome; requiring methylprednisolone; impaired kidney function Baseline characteristics Number (analysed/randomised): intervention group 1 (47/50); intervention group 2 (46/50) Mean age ± SD (months): intervention group 1 (55.2 ± 35.1); intervention group 2 (59.3 ± 37.0) Sex (M/F): ratio 4:3
Interventions	Intervention group 1 (12 weeks) Prednisolone: 60 mg/m2 daily for 6 weeks, then 40 mg/m2 alternate days for 6 weeks Duration 12 weeks Total cumulative dose: 2146.1 ± 708.1 mg/m2 Intervention group 2 (8 weeks) Prednisolone: 60 mg/m2 daily for 4 weeks, then 40 mg/m2 for 4 weeks Duration: 8 weeks Total cumulative dose: 1573.4 ± 450 mg/m2
Outcomes	Outcomes relevant to this review Time from cessation of prednisolone to first relapse Number with relapse at 6 months Cumulative prednisone dose Adverse effects at 12 months available in 41 and 31 patients
Notes	Additional information Definitions FRNS: 2 + relapses in 6 months or 3 + in 1 year SDNS: 2 relapses while on steroids or within 2 weeks of ceasing Relapse: 3+ proteinuria for 3 days (urinary spot protein/creatinine ratio > 2 mg/mg) Remission: Urine protein nil or trace for 3 consecutive days Differential loss to follow up by 12 months: 15 of 47 (33%) in intervention group 1 versus 6 of 46 (13%) in intervention group 2, so data have not been included in 12 to 24‐month analyses. At 6 months, 18/47 in intervention group 1 versus 22/46 in intervention group 2 had relapsed Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "Lottery method"
Allocation concealment (selection bias)	Unclear risk	QUOTE: "Lottery method"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	High risk	No report of blinding of outcome assessment
Incomplete outcome data (attrition bias) All outcomes	High risk	7/93 (7.5%) excluded from 6‐month analysis (2 died, 3 deviated from protocol, 3 lost to follow‐up). 72 (77%) completed 1 year follow‐up and reported data on number (%) with relapse and FRNS refers to 72 who completed 12 months
Selective reporting (reporting bias)	High risk	Expected outcomes of relapse, FRNS, steroid dose and adverse effects reported but only for patients completing 12 months
Other bias	Unclear risk	No information provided

Pecoraro 2003.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Follow‐up: 12 months Country: Italy Setting: single centre
Participants	Study characteristics Inclusion criteria: children with an initial episode of SSNS Exclusion criteria: not reported Baseline characteristics Number: intervention group 1 (16); intervention group 2 (16); intervention group 3 (16) Mean age ± SD (years): not reported Sex (M/F): not reported
Interventions	Intervention group 1 Prednisone: 2 mg/kg/day for 6 weeks; 2 mg/kg on alternate days for 6 weeks, reduced by 0.25 mg/week Total duration: 26 weeks Total calculated dose: 5235 mg/m2 Intervention group 2 IV methylprednisolone: 20 mg/kg/day for 3 days; 1 mg/kg/day for 6 weeks; 1 mg/kg on alternate days for 6 weeks; reduced by 0.25 mg/week to 4 weeks Total duration: 26 weeks Intervention group 3 Prednisone: 2 mg/kg/day for 4 weeks; 2 mg/kg on alternate days for 4 weeks; decreased by 0.25 mg/week Total duration: 12 weeks Total calculated dose: 2362 mg/m2
Outcomes	Outcomes relevant to this review Number with relapse at 1 year and 2 years Adverse effects Cumulative steroid dose
Notes	Additional information No definitions provided Abstract‐only publications Funding source: educational grant from Fresenius
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Information from authors suggests "alternation" was used
Allocation concealment (selection bias)	High risk	'Alternation" was 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	Said that all patients completed follow‐up but unclear whether any patients had been excluded
Selective reporting (reporting bias)	High risk	Not all review's pre‐specified outcomes have been reported No data on frequent relapses
Other bias	High risk	Educational grant from Fresenius

PREDNOS 2 2022.

Study characteristics
Methods	Study design Parallel RCT Time frame: 1 February 2013 to 31 January 2020 Follow‐up: 12 months Country: UK Setting: multicentre (91 sites)
Participants	Study characteristics Inclusion criteria: 1 to 18 years; relapsing SSNS and 2 or more relapses in the preceding 12 months Exclusion criteria: SRNS; receiving or within 3 months of completing a course of CPA or rituximab; receiving daily prednisolone therapy; receiving an alternate‐day prednisolone dose > 15 mg/m2 Baseline characteristics Number (analysed/randomised for primary outcome): intervention group (131/134); control group (131/137) Mean age ± SD (years): intervention group (7.7 ± 3.6); control group (7.5 ± 3.5) Sex (M/F): intervention group (83/51); placebo group (91/46) Ethnicity: intervention group (South Asian: 30; White: 96; other: 8); control group (South Asian: 28; White: 92; other: 17)
Interventions	Intervention group Children not receiving prednisolone at study entry received prednisolone 15 mg/m2/day (maximum dose 40 mg) for 6 days at the development of URTI Children on alternate‐day prednisolone at study entry received daily prednisolone 15 mg/m2/day for 6 days if their alternate‐day prednisolone dose was ≤ 15 mg/m2/day, or they received their current alternate‐day dose given daily for 6 days if that had previously exceeded 15 mg/m2/alternate day Control group Placebo tablets given using same regimens
Outcomes	Outcomes relevant to this review Number with URTI‐related relapses following the first URTI during the 12‐month follow‐up period Number with any relapse (URTI‐related and non URTI‐related) of nephrotic syndrome (relapses per year) Number needing to increase background non‐corticosteroid immunosuppression during follow‐up (e.g. addition of CSA, TAC, CPA) Number able to decrease background non‐corticosteroid immunosuppression during follow‐up (e.g. cessation of long‐term maintenance prednisolone therapy) Incidence of serious adverse events Assessment of behaviour using Achenbach Child Behaviour Checklist Assessment of QoL using the PedsQL Subgroup analyses for primary outcome measure according to background treatment regimens
Notes	Additional information This project was funded by grant HTA 11/129/261 from the NIHR Health Technology Assessment Programme (Dr Webb)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Children were randomized in a 1:1 ratio, minimized by background therapy at recruitment, using a secure 24‐hour internet‐based randomization service or by a telephone call to the University of Birmingham Clinical Trials Unit."
Allocation concealment (selection bias)	Low risk	QUOTE: "Children were randomized in a 1:1 ratio, minimized by background therapy at recruitment, using a secure 24‐hour internet‐based randomization service or by a telephone call to the University of Birmingham Clinical Trials Unit."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: “Both families and the clinical investigation teams were blinded to the allocation of the trial medication”.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "Parents were provided with written information as well as a fridge magnet aide‐memoire for this definition (URTI) and a tympanometric electronic thermometer to accurately record their child’s temperature. They were asked to contact their local research team shortly after commencing treatment" Relapse: the diagnosis of relapse was based on a standard definition of proteinuria (3+) for 3 days based on home urine testing and was not confirmed by a hospital visit
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants were accounted for. Numbers lost to follow‐up were reported. Numbers included in each analysis varied but were reported
Selective reporting (reporting bias)	Low risk	Expected outcomes were reported
Other bias	Low risk	Project funded by NIHR Health Technology Assessment Programme

PREDNOS 2019.

Study characteristics
Methods	Study design Parallel RCT Time frame: July 2011 to October 2014 Follow‐up: 24 months Country: UK Setting: multicentre (86 sites)
Participants	Study characteristics Inclusion criteria: children with initial episode of SSNS Exclusion criteria: biopsy showing changes other than minimal change disease; history of poor adherence; allergy to prednisolone; failed to respond to prednisolone Baseline characteristics Number (analysed/randomised): intervention group 1 (114/119); intervention group 2 (109/118) Mean age ± SD (years): intervention group 1 (5.1 ± 3.2); intervention group 2 (4.7 ± 2.9) Sex (M/F): intervention group 1 (68/31); intervention group 2 (78/36) Ethnicity: intervention group 1 (South Asian: 23; White: 75; other: 16); intervention group 2 (South Asian: 21; White: 73; other: 15)
Interventions	Intervention group 1 Prednisolone: 60 mg/m2 (max. 80 mg) daily for 4 weeks; 12 weeks of prednisolone (alternate day) starting at 60 mg/m2 (max. 80 mg) and tapering by 10 mg/m2 every two weeks Total duration: 16 weeks of prednisolone Total dose: total 3150 mg/m2 Intervention group 2 Prednisolone: 60 mg/m2 (maximum 80 mg) daily for 4 weeks; 4 weeks of prednisolone 40 mg/m2 (max. 60 mg); matching placebo from weeks 9 to 16 Total duration: 8 weeks of prednisolone Total dose: total 2240mg/m2
Outcomes	Outcomes relevant to this review Time to first relapse Number with relapse Number with FRNS and SDNS Adverse effects
Notes	Additional information Funding source: "The PREDNOS study was funded by an investigator led grant from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (HTA grant reference No08/53/31)."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Randomisation online via a secure 24 hour internet based randomisation service or by a telephone call to the Birmingham Clinical Trials Unit." 1:1 ratio using minimisation algorithm to balance ethnicity (South Asian, White, Other) and age (≤ 5, ≥ 6 years). Randomisation took place when child considered to be in remission
Allocation concealment (selection bias)	Low risk	QUOTE: "Randomisation online via a secure 24 hour internet based randomisation service or by a telephone call to the Birmingham Clinical Trials Unit"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Treatment was open‐label for first 4 weeks. Then blinded for participants/personnel for 12 weeks with matching placebo in the control group. Blinded trial drugs were dispensed from a central pharmacy in blister packs
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of participants/personnel for 12 weeks after initial 4 weeks of therapy. Parents tested urine and when relapse occurred, they commenced treatment and informed the trial co‐ordinators
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Low risk	Expected outcomes (relapse, FRNS, adverse effects) reported
Other bias	Low risk	National Institute of Health Research's Health Technology Assessment programme

PREDNOS PILOT 2019.

Study characteristics
Methods	Study design Parallel RCT Time frame: August 2006 to March 2007 Follow‐up: 12 months Country: UK Setting: multicentre (37 sites)
Participants	Study characteristics Inclusion criteria: children with initial episode of SSNS Exclusion criteria: biopsy showing changes other than minimal change disease; history of poor adherence; allergy to prednisolone; failed to respond to prednisolone Baseline characteristics Number: intervention group 1 (25); intervention group 2 (27) Mean age ± SD (years): intervention group 1 (6.5 ± 3.1); intervention group 2 (6.1 ± 3.0) Sex (M/F): intervention group 1 (15/10); intervention group 2 (16/11) Ethnicity: White (38); South Asian (10); other (4)
Interventions	Intervention group 1 Prednisolone: 60 mg/m2 (max. 80 mg) daily for 4 weeks; 12 weeks of prednisolone (alternate day) starting at 60 mg/m2 (max. 80 mg) and tapering by 10 mg/m2 every two weeks Total duration: 16 weeks of prednisolone Total dose: total 3150 mg/m2 Intervention group 2 Prednisolone: 60 mg/m2 (max. 80 mg) daily for 4 weeks; 4 weeks of prednisolone 40 mg/m2 (max. 60 mg); placebo from weeks 9 to 16 Total duration: 8 weeks of prednisolone Total dose: total 2240 mg/m2
Outcomes	Outcomes relevant to this review Time to first relapse Number with relapse Adverse effects
Notes	Additional information Pilot study for PREDNOS 2019 Funding source: sponsored by Great Ormond Street Hospital for Children NHS Foundation Trust (reference number 03/NU/13)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Randomisation online via a secure 24 hour Internet based randomisation service or by a telephone call to the Birmingham Clinical Trials Unit" 1:1 ratio using minimisation algorithm to balance ethnicity (South Asian, White, Other) and age (≤ 5, ≥ 6 years). Randomisation took place when child considered to be in remission
Allocation concealment (selection bias)	Low risk	QUOTE: "Randomisation online via a secure 24 hour Internet based randomisation service or by a telephone call to the Birmingham Clinical Trials Unit"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Treatment was open‐label for first 4 weeks. Then blinded for participants/personnel for 12 weeks with matching placebo in the control group. Blinded trial drugs were dispensed from a central pharmacy in blister packs
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of participants/personnel for 12 weeks after initial 4 weeks of therapy
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients accounted for
Selective reporting (reporting bias)	Low risk	Expected outcomes (relapse, FRNS, adverse effects) reported
Other bias	Low risk	Kidney Research UK and Kid’s Kidney Research

PROPINE 2020.

Study characteristics
Methods	Study design Parallel RCT Time frame: March 2013 to November 2018 Follow‐up: 12 months Country: Italy Setting: multicentre (10 sites)
Participants	Study characteristics Inclusion criteria: 3 to 17 years; had not received a steroid‐sparing agent in the previous year and had experienced at least 1 relapse; CrCl > 90 mL/min/1.73m2, in remission at enrolment and receiving maintenance prednisone or prednisolone ≤15 mg/m2. In April 2014, protocol adapted to allow enrolment after initial diagnosis so a participant could be treated at first relapse; participants randomised on development of relapse Exclusion criteria: co‐morbidities not related to nephrotic syndrome; remission occurred > 21 days after last relapse; relapse on > 30 mg/m2/alternate days, receiving non‐corticosteroid agents or antihypertensive medications Baseline characteristics Number: intervention group 1 (38); intervention group 2 (40) Median age ± IQR (years): intervention group 1 (7.1, 4.8 to 10.9); intervention group 2 (6.3, 3.9 to 8.6) Sex (M/F): intervention group 1 (24/14); intervention group 2 (23/17)
Interventions	Both groups received 60 mg/m2 (maximum dose 60 mg) till remission for 5 days and then randomised Intervention group 1 (short) Prednisone/prednisolone: 40 mg/m2 alternate daily (maximum dose 50 mg) for 18 doses given on alternate days over 36 days (5.1 weeks) Intervention group 2 (long) Prednisone/prednisolone: tapering schedule on alternate days (starting dose 40 mg/m2 (maximum dose 50 mg) over 72 days with same cumulative dose of prednisone as group 1. Dose reduced to 75%, 50%, 37.5%, 25%, 12.5% and then ceased. Each reduction made after 6 doses on alternate days (12 days between dose changes) Total duration 72 days (10.3 weeks)
Outcomes	Outcomes relevant to this review Relapse rate at 6 months differing by 30% between groups Number with relapse at 6 months Time to first relapse Adverse effects
Notes	Additional information Funding source: Italian Medicines agency Only data for primary study included in review. Secondary study comprised a cross‐over study of 40 participants previously enrolled in primary study Note: 128 entered the observation period, 7 were excluded and 78 entered the study. The remaining 43, who were observed, did not relapse, so did not enter the study
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "Patients were randomized by blocks, using a block size of 6. The randomization protocol was stratified per center and for the prescription of PDN maintenance therapy. An online, encrypted, password‐protected case report form was generated on the Phebo platform (GPI SpA, Trento, Italy), a commercial e‐health platform specializing in remote monitoring of biometric parameters. Patients were randomized after communicating the relapse to the coordinating center"
Allocation concealment (selection bias)	Low risk	QUOTE: "Patients were randomized by blocks, using a block size of 6. The randomization protocol was stratified per center and for the prescription of PDN maintenance therapy. An online, encrypted, password‐protected case report form was generated on the Phebo platform (GPI SpA, Trento, Italy), a commercial e‐health platform specializing in remote monitoring of biometric parameters. Patients were randomized after communicating the relapse to the coordinating center"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study and outcomes could be influenced by lack of blinding Patients measured urinary albumin and reported to physicians who made changes if required
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study and outcomes could be influenced by lack of blinding Patients measured urinary albumin and reported to physicians who made changes if required
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants accounted for
Selective reporting (reporting bias)	Low risk	Primary data presented as absolute numbers; expected outcomes reported
Other bias	Low risk	Funding source: Italian Medicines agency

Raman 2016.

Study characteristics
Methods	Study design Parallel RCT Time frame: March 2014 to July 2015 Follow‐up: 6 months Country: India Setting: single centre
Participants	Study characteristics Inclusion criteria: children with SSNS, treated with prednisone for first time or following relapse (includes frequent and infrequent relapsers) Exclusion criteria: infants; secondary nephrotic syndrome; children with BSA > 1 m2 and weight > 30 kg; active infection Baseline characteristics Number (analysed/randomised): intervention group 1 (44/50); intervention group 2 (42/50) Mean age (years): intervention group 1 (5.4 ± 2.9); intervention group 2 (5.2 ± 2.5) Sex (M/F): intervention group 1 (27/13); intervention group (27/13)
Interventions	Intervention group 1 (Body weight‐based) Prednisolone: 2 mg/kg/day (maximum 60 mg) in two divided doses for 6 weeks, 1.5 mg/kg (maximum 40 mg) on alternate days for 6 weeks Intervention group 2 (BSA‐based) Prednisolone: 60 mg/m2/day (maximum 60 mg) in 2 divided doses for 6 weeks, 40 mg/m2 alternate days for 6 weeks
Outcomes	Outcomes relevant to this review Time taken for remission Number of relapses Cumulative dose of prednisolone Adverse effects
Notes	Additional information The median cumulative dose of prednisone was 81 mg/kg (IQR 30 to 115) in the body weight‐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

Satomura 2001.

Study characteristics
Methods	Study design Quasi‐RCT Study duration: not reported Duration of follow‐up: 1 year Country: Japan Setting: multicentre (number of sites not reported)
Participants	Study characteristics Inclusion criteria: initial episode of SSNS Exclusion criteria: not reported Baseline characteristics Number: intervention group 1 (37); intervention group 2 (36) Mean age ± SD (years): not reported Sex (M/F): not reported
Interventions	Intervention 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 Intervention 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	Outcomes relevant to this review Number with relapse at 12 months Time to relapse
Notes	Additional information 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

Sharma 2002.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Duration of follow‐up: at least 1 year Country: India Setting: single tertiary centre
Participants	Study characteristics Inclusion criteria: initial episode of SSNS Exclusion criteria: not reported Baseline characteristics Number: intervention group 1 (70); intervention group 2 (70) Mean age ± SD: 8.9 ± 6.8 years Sex (M/F): not reported
Interventions	Intervention group 1 (6 months) Prednisolone: 60 mg/m2/day for 6 weeks; 40 mg/m2 on alternate days for 6 weeks; taper by 10 mg/m2 each month for 3 months Total duration: 6 months Total dose: 4200 mg/m2 Intervention group 2 (3 months) Prednisolone: 60 mg/m2/day for 6 weeks; 40 mg/m2 on alternate days for 6 weeks; abrupt cessation at 12 weeks without tapering Total duration: 3 months Total calculated dose: 3360 mg/m2
Outcomes	Outcomes relevant to this review Number with relapse by 6 and 12 months Mean relapse rate Number with FRNS Cumulative steroid dose Adverse events
Notes	Additional information 156 enrolled in the study, and 140 evaluated Definitions Remission and relapse: ISKDC FRNS: 2+ in 6 months or 6+ in 18 months SDNS: APN definition Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "table of random numbers". Randomisation at 12 weeks after the beginning of initial therapy. Information provided by authors
Allocation concealment (selection bias)	Unclear risk	QUOTE: "table of random numbers"
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	High risk	16/156 excluded (10.3%); 160 consecutive patients, 4 refused consent. Of 156 entered, 10 were non‐compliant and 6 lost to follow‐up and their results were excluded from analysis
Selective reporting (reporting bias)	Low risk	All the reviews pre‐specified outcomes have been reported
Other bias	Unclear risk	Insufficient information to permit judgement

Sheikh 2019.

Study characteristics
Methods	Study design Parallel RCT Time frame: May 2018 to November 2019 Follow‐up: 12 months: intervention group 1 (10.38 ± 3.5); intervention group 2 (9.95 ± 4.3) Country: India Setting: single centre
Participants	Study characteristics Inclusion criteria: 1 to 12 years with relapse of SSNS Exclusion criteria: concurrent infections requiring hospitalisation; those with associated co‐morbidities; receiving or within 3 months of receiving non‐corticosteroid immunosuppression; failure to achieve remission by 14 days Baseline characteristics Number: intervention group 1 (30); intervention group 2 (30) Mean age ± SD (months): intervention group 1 (65.6 ± 28.4); intervention group 2 (62.5 ± 27.4) Sex (M/F): intervention group 1 (17/13); intervention group 2 (17/13)
Interventions	Intervention 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 3150 mg/m2 Intervention group 2 (conventional dose) Prednisolone 2 mg/kg/day until remission or day 15 if not in remission
Outcomes	Outcomes relevant to this review Achieving remission within 14 days Number of relapses in each group
Notes	Additional information Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "A computer‐generated block randomization sequence of varying block sizes (2 2 2 4 8 4 2 2 2 8 4 4 8 4 4; seed 2384) was created by a physician not involved in the study”
Allocation concealment (selection bias)	Low risk	QUOTE: “Allocation concealment was achieved by sequentially numbered, opaque, sealed envelopes, which were opened after taking informed consent from the attendants of the enrolled patients.”
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study. Not blinded and outcome is likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	High risk	Open‐label study. 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)	High risk	None
Other bias	Unclear risk	Insufficient information to permit judgement. No report on funding

Singhal 2015.

Study characteristics
Methods	Study design Parallel RCT Time frame: commenced March 2011 Follow‐up: 6 months post‐initial therapy Country: India Setting: single centre
Participants	Study characteristics Inclusion criteria: children with initial episode of SSNS Exclusion criteria: children with nephrotic syndrome secondary to systemic disorder or drugs Baseline characteristics Number: intervention group 1 (12); intervention group 2 (13) Mean age ± SD (years): intervention group 1 (3.54 ± 1.21); intervention group 2 (5.53 ± 3.73) Sex (M/F): intervention group 1 (7/5); intervention group 2 (7/6)
Interventions	Intervention 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 Intervention group 2 Prednisolone: 2 mg/kg daily for 6 weeks; 1.5 mg/kg alternate days for 6 weeks Total duration: 12 weeks
Outcomes	Outcomes relevant to this review Time taken to induce remission Number of relapses on and off treatment in both groups
Notes	Additional information 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

Sinha 2015.

Study characteristics
Methods	Study design Parallel RCT Time frame: July 2010 to May 2012 Follow‐up: 1 year Country: India Setting: multicentre (5 sites)
Participants	Study characteristics Inclusion criteria: aged 1 to 12 years with first episode of SSNS; 3 to 4+ proteinuria or UPCR ≥ 2 mg/mg; albumin < 2.5 g/dL; oedema Exclusion criteria: eGFR < 60 mL/min/1.73 m2; known secondary cause (HSP, SLE, hepatitis B or haematuria); residence > 200 km away; previous steroid therapy Baseline characteristics Number (analysed/randomised): intervention group 1 (92/92); intervention group 2 (88/89) Median age, IQR (months): intervention group 1 (44.2, 34.2 to 74.4); intervention group 2 (42.4, 30.0 to 70.5) Sex (M/F): intervention group 1 (56/36); intervention group 2 (59/30)
Interventions	Intervention group 1 (3 months) Prednisolone: 2 mg/kg/day for 6 weeks (maximum daily dose not specified), then 1.5 mg/kg on alternate days for 6 weeks. Then, matching placebo for 12 weeks Actual total dose: 2791.7 ± 286.6 mg/m2 Intervention group 2 (6 months) Prednisolone: 2 mg/kg/day for 6 weeks, 1.5 mg/kg on alternate days for 6 weeks, 1 mg/kg, 0.75 mg/kg, and 0.5 mg/kg on alternate days for 4 weeks each Actual total dose: 3529.7 ± 398.7 mg/m2 Co‐interventions Patients on long‐term steroids received daily supplements of calcium (250 to 500 mg) and vitamin D (200 to 400 U) Hypertension was treated with amlodipine or enalapril
Outcomes	Outcomes relevant to this review Number of steroid‐sensitive relapses during 12 months of follow‐up Proportion with FRNS at 12 and 24 months Cumulative steroid dose mg/m2/year from randomisation to 12 and 24 months Need for steroid‐sparing therapies at 12 and 24 months Mean relapse rate at 12 and 24 months Frequency and type of serious adverse events
Notes	Additional information Funded by the Indian Council of Medical Research Definitions Relapse, remission, FRNS: ISKDC
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated. Randomly assigned 1:1 in permuted blocks of four
Allocation concealment (selection bias)	Low risk	QUOTE: "Procedures for randomisation and packing and distribution were conducted at this centre by individuals, who were not involved in trial implementation"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	QUOTE: "External pharmacy manufactured identical‐appearing sugar coated tablets of prednisolone and placebo, packaged in matching blister packs of 10 tablets each"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "Investigators, patients and outcome assessors were blinded to randomisation schedule. Masking was maintained during data analysis, following which the randomisation code was broken"
Incomplete outcome data (attrition bias) All outcomes	Low risk	6/181 (3%) excluded (SRNS 1, loss to follow‐up 5)
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported
Other bias	Low risk	Funded by Indian Council of Medical Research

Teeninga 2013.

Study characteristics
Methods	Study design Parallel RCT Time frame: February 2005 to December 2009 Duration of study: up to 5 years; minimum follow‐up 18 months Countries: the Netherlands, Belgium Setting: multicentre (69 sites)
Participants	Study characteristics Inclusion criteria: aged 9 months to 7 years with initial episode of SSNS Exclusion criteria: secondary nephrotic syndrome; SRNS Baseline characteristics Number (analysed/randomised): intervention group 1 (62/74); intervention group 2 (64/76) Median age, IQR (years): intervention group 1 (4.7, 3.2 to 6.2); intervention group 2 (3.8, 3.2 to 6.4) Sex (M/F): intervention group 1 (39/23); intervention group 2 (47/27)
Interventions	Intervention group 1 (3 months) Prednisolone: 60 mg/m2/day for 6 weeks (maximum dose not specified); 40 mg/m2 on alternate days for 6 weeks; placebo on alternate days for 12 weeks Cumulative dose: 3360 mg/m2 Total duration: 12 weeks Median duration of follow‐up: 47 months (IQR 32 to 60) Intervention group 2 (6 months) Prednisolone: 60 mg/m2/day for 10 days; 50 mg/m2/day till 6 weeks; 40 mg/m2 on alternate days till end week 10; 30 mg/m2 till end week 14, 10 mg/m2 on alternate days till end week 24 Total duration: 24 weeks Cumulative dose 3320 to 3710 mg/m2 Median duration of follow‐up: 47 months (IQR 37 to 60)
Outcomes	Outcomes relevant to this review FRNS Cumulative incidences of first relapse, steroid dependence Number of relapses/patient‐year Cumulative steroid dose Adverse events
Notes	Additional information Definitions Nephrotic syndrome: > 200 mg protein/mmol creatinine in urine and albumin < 25 g/L in serum Remission: urinary protein excretion < 20mg/L or negative/trace on dipstick analysis on 3 consecutive days Relapse: proteinuria ≥ 2+ on dipstick analysis or > 200 mg protein/mmol creatinine for 3 consecutive days after previously achieved remission FRNS: "Strict" definition: a) 2 or more relapses in 6 months after completing initial therapy; b) 4 relapses within any 12‐month period, including relapses during initial treatment FRNS: "Clinical" definition: frequently relapsing nephrotic syndrome based on clinically relevant decision that included additional treatment of prednisolone maintenance therapy(> 3 months) or other immunosuppressive agents SDNS: 2 or more consecutive relapses either during or within 2 weeks after cessation of prednisolone (APN definition) Funding source: This study was funded by Dutch Kidney Foundation Grant C03.2072 and the Vrienden van het Sophia Foundation
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central pharmacy with a computer generated random number table
Allocation concealment (selection bias)	Low risk	Central pharmacy, controlled allocation concealment with a computer generated random number table. Provided prepackaged medications, with fixed and blinded dose
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants, health care providers, data collectors and researchers were blinded to group allocation. Identical tasteless capsules containing prednisolone or placebo
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants, health care providers, data collectors and researchers were blinded to group allocation. Randomisation code broken September 2011
Incomplete outcome data (attrition bias) All outcomes	Low risk	All patients with consent and not SRNS were included and followed up (13 withdrew consent, 11 steroid resistant)
Selective reporting (reporting bias)	Low risk	All the review's pre‐specified outcomes have been reported
Other bias	Low risk	No disclosures. Trial registered Netherlands Trial Registry number 255. Funded by Dutch Kidney Foundation Grant C03 and by Vrienden van het Sophia Foundation

Tu 2022.

Study characteristics
Methods	Study design Parallel RCT Time frame: November 2017 to December 2019 Duration of study: follow‐up 6 months Country: China Setting: single centre
Participants	Study characteristics Inclusion criteria: children hospitalised with relapse of SSNS Exclusion criteria: initial episode of SSNS, SRNS Baseline characteristics Number (analysed/randomised): intervention group 1 (29/32); intervention group 2 (33/35) Mean age, mean ± SD (years): intervention group 1 ( 6 ± 4 years); intervention group 2 (7 ± 4 years) Sex (M/F): intervention group 1 (25/7); intervention group 2 (24/11)
Interventions	Intervention group 1 (moderate dose of prednisolone) Prednisone: 30 mg/m2/day (maximum dose 30 mg) till urinalysis negative for protein for one week Prednisone: 1.5 mg/kg on alternate days for 4 weeks, then prednisone reduced every 2 to 4 weeks by 2.5 to 5 mg/alternate days until the medication discontinued Intervention group 2 (full dose of prednisolone) Prednisone: 60 mg/m2/day (maximum dose 60 mg) till urinalysis negative for protein for one week Prednisone: 1.5 mg/kg on alternate days for 4 weeks, then prednisone reduced every 2 to 4 weeks by 2.5 to 5 mg/alternate days until the medication discontinued
Outcomes	Outcomes relevant to this review Number with remission Number with relapse by 6 months Adverse events
Notes	Additional information Three participants withdrew from intervention group 1 and two participants withdrew from intervention group 2 before randomisation Reasons for withdrawal: 4 not in remission, 1 with severe oedema
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: “They were randomly divided into a moderate‐dose GC group (32 children) and a full‐dose GC group (35 children).”
Allocation concealment (selection bias)	Unclear risk	QUOTE: “They were randomly divided into a moderate‐dose GC group (32 children) and a full‐dose GC group (35 children).”
Blinding of participants and personnel (performance bias) All outcomes	High risk	No report of blinding so open label presumed
Blinding of outcome assessment (detection bias) All outcomes	High risk	No report of blinding so open label presumed
Incomplete outcome data (attrition bias) All outcomes	Low risk	Exclusions occurred before randomisation, all randomised patients were included in analyses
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Unclear risk	No information provided about monetary support

Ueda 1988.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Duration of follow‐up: 1 year Country: Japan Setting: single tertiary centre
Participants	Study characteristics Inclusion criteria: aged 12 weeks to 16 years with first episode SSNS; severe proteinuria, ≥ 40 mg/h/m2; hypoalbuminaemia, ≤ 2.5 g/dL Exclusion criteria: prior treatment with steroids or cytotoxic agents; evidence of underlying systemic illness; exposure to agents known to be associated with nephrotic syndrome Baseline characteristics Number: intervention group 1 (17); intervention group 2 (29) Mean age ± SD (years): intervention group 1 (5.6 ± 3.2); intervention group 2 (7.2 ± 3.2) Sex (M/F): intervention group 1 (10/7); intervention group 2 (23/6)
Interventions	Intervention group 1 (prolonged) Prednisolone: 60 mg/m2/day for 4 weeks, 60 mg/m2 on alternate days for 4 weeks and tapered by 10 mg/m2/month Total duration: 7 months Intervention group 2 (standard) Prednisolone: 60 mg/m2/day for 4 weeks and 40 mg/m2 on 3/7 days for 4 weeks Total duration: 2 months
Outcomes	Outcomes relevant to this review Number relapsing by 6 and 12 months after completing daily and alternate‐day prednisolone Relapse rate/patient/year FRNS Adverse effects
Notes	Additional information Unequal numbers in groups Definitions FRNS: any relapse occurring within 2 months after ceasing prednisone Relapse: ISKDC Remission: ISKDC Funding source: supported by a grant from the Ministry of Health and Welfare in Japan
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	QUOTE: "allocated randomly", insufficient information about the sequence generation process to permit judgement
Allocation concealment (selection bias)	Unclear risk	Not mentioned, randomisation stated but no information on method used available
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	Unclear risk	Unclear whether any patients, who were randomised, were not included in analysis; complete 1 year follow‐up
Selective reporting (reporting bias)	Low risk	The pre‐specified outcomes of the review have been reported
Other bias	Low risk	Supported by a grant from the Ministry of Health and Welfare in Japan

Weerasooriya 2023.

Study characteristics
Methods	Study design Parallel RCT Time frame: September 2019 to February 2020 Follow‐up: treatment continued till remission achieved Country: Sri Lanka Setting: single centre
Participants	Study characteristics Inclusion criteria: aged 1 to 15 years; admitted for relapse of SSNS Exclusion criteria: started treatment before admission; deranged kidney function; not fulfilling criteria for a relapse; other associated co‐morbidities Baseline characteristics Number (analysed/randomised): intervention group 1 (55/55); intervention group 2 (49/49) Mean age ± SD (years): not reported Sex (M/F): intervention group 1 (34/21); intervention group 2 (24/25)
Interventions	Intervention group 1 Prednisolone (oral): 60 mg/m2 as a single morning dose Continued until remission was achieved, then switched to 60 mg/m2 on alternate mornings Intervention group 2 Prednisolone (oral): 40 mg/m2 in the morning and 20 mg/m2 in the evening Continued until remission was achieved, then switched to 60 mg/m2 on alternate mornings
Outcomes	Outcomes relevant to this review Days to remission Adverse events (mood changes, behavioural changes, increase in appetite, dyspeptic syndromes, new‐onset hypertension, sepsis)
Notes	Additional information Funding: not reported Remission: 3 consecutive days of nil or trace proteinuria
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "grouped and randomised according to a computer‐generated system"
Allocation concealment (selection bias)	Low risk	QUOTE: "grouped and randomised according to a computer‐generated system"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Not blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Assessment of remission based on urinalysis
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All patients accounted for
Selective reporting (reporting bias)	High risk	Not all relvant outcomes reported
Other bias	Unclear risk	Funding source not reported

Yadav 2019.

Study characteristics
Methods	Study design Parallel RCT Time frame: September 2013 to November 2015 Follow‐up: 1 year Country: India Setting: single centre
Participants	Study characteristics Inclusion criteria: children with relapsing SSNS Exclusion criteria: steroid toxicity (BMI > 2 SD, cataract, glaucoma, stage 2 hypertension); levamisole, CPA or CNI or rituximab in previous 6 months Baseline characteristics Number (analysed/randomised): intervention group 1 (30/31); intervention group 2 (31/31) Mean age ± SD (months): intervention group 1 (40.2 ± 32.1); intervention group 2 (39.6 ± 21.8) Sex (M/F): intervention group 1 (22/9); intervention group 2 (20/11)
Interventions	Intervention group 1 Prednisone: 0.2 to 0.3 mg/kg/day for 12 months Intervention group 2 Prednisone: 0.5 to 0.7 mg/kg alternate days for 12 months All patients received daily supplements Calcium carbonate: 250 to 500 mg Vitamin D: 200 to 40 IU
Outcomes	Outcomes relevant to this review Number of relapses Number with sustained remission Time to first relapse Time to treatment failure Adverse effects
Notes	Additional information One patient did not return for follow‐up Funding source: Indian Council of Medical Research (No 5/5/1090/2013‐RHN)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Permutated block randomisation; stratified for steroid dependence. Computer generated allocation Consecutive patients enrolled
Allocation concealment (selection bias)	Low risk	Allocation was concealed in sequentially numbered sealed, opaque envelopes, by personnel not involved in the randomisation process; envelopes were opened following informed written parental consent
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
Blinding of outcome assessment (detection bias) All outcomes	High risk	Assessment of relapse based on urinalysis
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants accounted for
Selective reporting (reporting bias)	Low risk	The pre‐specified outcomes of the review have been reported
Other bias	Low risk	Funding by Indian Council of Medical Research (No 5/5/1090/2013‐RHN)

Yoshikawa 1998.

Study characteristics
Methods	Study design Parallel RCT Time frame: January 1990 to December 1992 Follow‐up: 2 years Country: Japan Setting: multicentre (35 sites)
Participants	Study characteristics Inclusion criteria: children with first episode of SSNS Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): intervention group 1 (83/96); intervention group 2 (88/98) Mean age ± SD (years): intervention group 1 (7.1 ± 3.7); intervention group 2 (8.0 ± 4.1) Sex (males): intervention group 1 (66%); intervention group 2 (71%)
Interventions	Intervention group 1 (prolonged) Prednisolone: 2 mg/kg/day for 4 weeks, 2 mg/kg on alternate days for 8 weeks, 1.5 mg/kg on alternate days for 2 weeks, 1 mg/kg on alternate days for 2 weeks, 0.5 mg/kg on alternate days for 2 weeks Total duration: 18 weeks Intervention group 2 (standard) Prednisone: 2 mg/kg/day for 4 weeks, 1.3 mg/kg on alternate days for 4 weeks Total duration: 8 weeks Co‐interventions Both groups given Chinese herb Sairei‐to: > 40 kg (8.1 g/day); 20 to 40 kg (5.4 g/day); < 20 kg (2.7 g/day)
Outcomes	Outcomes relevant to this review Number relapsing by 2 years Number of patients with FRNS
Notes	Additional information Definitions Relapse, FRNS: ISKDC Funding source: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: 'randomly assigned, concealed envelopes'
Allocation concealment (selection bias)	Low risk	QUOTE: 'randomly assigned, concealed envelopes'
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label study
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	High risk	25/196 (13%) did not complete study
Selective reporting (reporting bias)	High risk	Not all the reviews, pre‐specified outcomes were reported. No reports of adverse effects of steroids
Other bias	Unclear risk	Insufficient data to permit judgment

Yoshikawa 2015.

Study characteristics
Methods	Study design Parallel RCT Time frame: 6 September 2007 to 9 February 2013 Follow‐up: 2 years Country: Japan Setting: multicentre (90 sites)
Participants	Study characteristics Inclusion criteria: aged 1 to 15 years with first episode of INS with remission within 3 weeks Exclusion criteria: secondary nephrotic syndrome; renal insufficiency defined as CrCl ≤ 60 mL/min/1.73 m2; active infections; poorly controlled hypertension; severe liver dysfunction; pregnancy or a history of immunosuppressant medication Baseline characteristics Number (analysed/randomised): intervention group 1 (122/127); intervention group 2 (124/128) Mean age ± SD (years): intervention group 1 (6.3 ± 4.1); intervention group 2 (6.7 ± 4.1) Sex (M/F): intervention group 1 (87/35); intervention group 2 (89/35)
Interventions	Intervention group 1 (6 months) Prednisolone: 60 mg/m2 (max 80 mg) weeks 1 to 4 in 3 divided doses/day, 60 mg/m2 (max 80 mg) on alternate days weeks 5 to 8, 45 mg/m2 (max 60 mg) on alternate days for weeks 9 to 12, 30 mg/m2 (max 40 mg) on alternate days for 13 to 16 weeks, 15 mg/m2 on alternate days for weeks 17 to 20, 7.5 mg/m2 (max 10 mg) on alternate days for 21 to 24 weeks Intervention group 2 (2 months) Prednisolone 60 mg/m2 (max 80 mg) weeks 1 to 4, in 3 divided doses/day, 40 mg/m2 (max 50 mg) on alternate days for weeks 5 to 8
Outcomes	Outcomes relevant to this review Number relapsing by 2 years Number of patients with frequent relapses at 2 years Number needing steroid‐sparing agents at 2 years Number of relapses/patient‐year Adverse events
Notes	Additional information Grant from the Ministry of Health, Labour and Welfare, Japan Definitions Relapse, FRNS: ISKDC Diagnosis of nephrotic syndrome and remission: ISKDC Funding source: Grant from the Ministry of Health, Labour and Welfare, Japan
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated sequence in 1:1 ratio, stratified for age (1 to 10 years or 11 to 15 years), sex and institution
Allocation concealment (selection bias)	Low risk	QUOTE: "Patients were randomly assigned....at the Japan Clinical Research Support Unit"
Blinding of participants and personnel (performance bias) All outcomes	High risk	Open‐label, study patients, guardians, treating physicians and individuals were data were not blinded to treatment groups
Blinding of outcome assessment (detection bias) All outcomes	Low risk	QUOTE: "Apart from trial statistician and data monitoring committee, all treating physicians and other investigators remained blinded to the trial results until follow up was completed"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Excluded 9/255 (3%): early relapses after remission (5), 3 no follow‐up data available (3), withdrew consent before allocated study medication (1)
Selective reporting (reporting bias)	Low risk	All studies pre‐specified outcomes mentioned
Other bias	Low risk	Grant from the Ministry of Health, Labour and Welfare, Japan

Zhang 2007d.

Study characteristics
Methods	Study design Parallel RCT Time frame: not reported Follow‐up: 3 months Country: China Setting: single centre
Participants	Study characteristics Inclusion criteria: children with SSNS Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): 23/31; intervention group 1 (9); intervention group 2 (14) Mean age ± SD (years): not reported Sex (M/F): not reported
Interventions	Intervention group 1 (3 months) Pulse methylprednisolone: no details on dosing provided Intervention group 2 (2 months) Prednisone: no details on dosing provided
Outcomes	Outcomes relevant to this review Time to remission Relapse rate by 3 months Adverse effects
Notes	Additional information 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	No evidence that study was blinded
Blinding of outcome assessment (detection bias) All outcomes	High risk	Clinical outcomes could be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Insufficient information to permit judgement
Selective reporting (reporting bias)	Unclear risk	Insufficient information to permit judgement
Other bias	Unclear risk	Insufficient information to permit judgement

APN: Arbetsgemeinschaft für Pädiatrische Nephrologie; BMD: bone mineral density; BMI: body mass index; BSA: body surface area; CNI: calcineurin inhibitors; CPA: cyclophosphamide; CrCl: creatinine clearance; CPA: cyclophosphamide; CSA: cyclosporin; eGFR: estimated glomerular filtration rate; FRNS: frequently relapsing steroid‐sensitive nephrotic syndrome; HIV: human immunodeficiency virus; HSP: Henoch‐Schönlein purpura; IFR: infrequently relapsing; INS: idiopathic nephrotic syndrome; IQR: interquartile range; ISKDC: International Study of Kidney Disease in Children; LFT: liver function test/s; M/F: male/female; PedsQL: Pediatric Quality of Life Inventory; QoL: quality of life; RCT: randomised controlled trial; SCr: serum creatinine; SD: standard deviation; SDNS: steroid‐dependent nephrotic syndrome; SSNS: steroid‐sensitive nephrotic syndrome; SRNS: steroid‐resistant nephrotic syndrome; TB: tuberculosis; UPCR: urinary protein/creatinine ratio; URTI: upper respiratory tract infection

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
APN 2006	Wrong intervention: RCT comparing cyclosporin with prednisone. Transferred to Cochrane Review on "Non‐corticosteroid immunosuppressive agents for steroid‐sensitive nephrotic syndrome in children"
Hou 2021	Wrong intervention: evaluating Chinese herbal medicine with prednisolone in children with primary nephrotic syndrome
Javidi 2021	Wrong intervention: combination therapy of monteleukast with prednisolone
Wu 2022	Wrong intervention: RCT evaluating Chinese herbal medicine and corticosteroids in children with SSNS
Xu 2020b	Study withdrawn: placebo‐controlled RCT planned to compare 6 months with 3 months of prednisolone in the first episode of SSNS in children aged 1‐6 years. Withdrawn because of lack of funding
Yang 2022a	Wrong intervention: evaluating Chinese medicine with nursing care
Zhang 2014	Wrong intervention: RCT comparing azithromycin with prednisone. Transferred to Cochrane Review on "Non‐corticosteroid immunosuppressive agents for steroid‐sensitive nephrotic syndrome in children"
Zhang 2021b	Wrong population: SRNS
Zhou 2021	Wrong intervention: combination of prednisolone and vitamin D
Zhu 2021a	Wrong intervention: multiple medications used

RCT: randomised controlled trial; SRNS: steroid‐resistant nephrotic syndrome; SSNS: steroid‐sensitive nephrotic syndrome

Characteristics of ongoing studies [ordered by study ID]

CTRI/2018/05/013634.

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	Study design Parallel, open‐label RCT Follow‐up: 6 months
Participants	Study characteristics 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 the last 6 months with infrequent relapses defined as < 2 relapses in the last 6 months
Interventions	Intervention 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 intervention group No information on prednisone dose/duration to achieve remission
Outcomes	Planned 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 Email: kalrasuprita@gmail.com
Notes	Children with SRNS or SSNS commenced on steroid sparing agent in past 6 months because of FRNS or SDNS

CTRI/2018/05/014075.

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	Study design Parallel, open‐label RCT Follow‐up: 12 months
Participants	Study characteristics 60 children aged 1 to 12 years with SSNS presenting with relapse
Interventions	Intervention group Prednisolone: 1 mg/kg/day till remission or two weeks, whichever is earlier Control group Prednisolone 2 mg/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 Email: kirtisen@gmail.com
Notes	Children receiving non‐corticosteroid immunosuppressive agents are excluded

RESTERN 2017.

Study name	Steroid treatment reduction in relapsing childhood nephrotic syndrome: a new nationwide randomised controlled trial in the Netherlands ‐ the RESTERN study
Methods	Study design Double‐blind, placebo‐controlled RCT Follow‐up: 2 years
Participants	Study characteristics 144 children aged 1 to 18 years with relapse of SSNS
Interventions	Intervention group 1 Prednisolone: daily till remission, then alternate days for 2 weeks; placebo for 4 weeks Intervention group 2 Prednisolone: daily till remission, then alternate days for 6 weeks
Outcomes	Planned outcomes Time to first relapse Number of relapses Progression to FRNS or SDNS Cumulative dose of prednisolone
Starting date	December 2016
Contact information	Dr Anne Schijivens, Radboudume Amalia Children's Hospital, Nijmegen, The Netherlands Email: anne.schijvens@radboudumc.nl
Notes

Sinha 2016.

Study name	Randomised controlled trial to compare efficacy of 3‐months versus 6‐months therapy with prednisolone for the first episode of idiopathic nephrotic syndrome in children <4‐yr‐old
Methods	Study design Parallel, open‐label RCT Time frame: July 2015 to August 2019 Follow‐up: 1 year Country: India, USA Setting: multicentre (4); academic centres, one India; 3 centres USA
Participants	Study characteristics Inclusion criteria: children aged 1 year up to 4 years with new‐onset, idiopathic nephrotic syndrome Exclusion criteria: nephrotic syndrome known to be secondary to a systemic disorder, therapy with corticosteroids in the past three months, patients with initial steroid resistance, Patients who show relapse during the first 3 months of pre‐randomisation corticosteroid therapy for nephrotic syndrome, prednisolone therapy for prior episodes of nephrotic syndrome Baseline characteristics Number: intervention group 1 (79); intervention group 2 (81) Mean age ± SD (months): intervention group 1 (32 ± 11); intervention group 2 (35 ± 9) Sex (M/F): not reported
Interventions	Initial treatment 12 weeks of standard therapy: prednisolone 60 mg/m2/day for 6 weeks followed by 40 mg/m2/day every other day for 6 weeks Intervention group 1 Prednisolone: tapering dose over 12 weeks Intervention group 2 Stop therapy: no therapy for 12 weeks
Outcomes	Planned outcomes Proportions of patients with relapse Frequency of relapses Proportions of sustained remission Adverse effects
Starting date	July 2015
Contact information	Dr Aditi Sinha Email: aditisinhaaiims@gmail.com
Notes

FRNS: frequently relapsing nephrotic syndrome; MMF: mycophenolate mofetil; RCT: randomised controlled trial; SDNS: steroid‐dependent nephrotic syndrome; SSNS: steroid‐sensitive nephrotic syndrome; URTI: upper respiratory tract infection

Differences between protocol and review

Risk of bias assessment tool has replaced the quality assessment checklist list used in the previous versions of this review.

Contributions of authors

• Deirdre Hahn: Study selection, quality appraisal, data extraction, data analysis, writing review, updating review.

• Susan Samuel: Study selection, data extraction, updating review

• Narelle Willis: Literature search, obtaining articles, organising translation, data extraction, data analysis, data display, updating review.

• Jonathan Craig: Data analysis, writing review, updating review.

• Elisabeth Hodson: Study selection, quality appraisal, data extraction, data analysis, writing review, updating review.

Sources of support

Internal sources

• No sources of support provided

External sources

• No sources of support provided

Declarations of interest

• Deirdre Hahn: No relevant interests were disclosed

• Susan Samuel: No relevant interests were disclosed

• Narelle Willis: No relevant interests were disclosed

• Jonathan Craig: No relevant interests were disclosed

• Elisabeth Hodson: No relevant interests were disclosed

New search for studies and content updated (no change to conclusions)