Corticosteroid therapy for nephrotic syndrome in children

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

doi:10.1002/14651858.CD001533.pub5

. 2015 Mar 18;2015(3):CD001533. doi: 10.1002/14651858.CD001533.pub5

Corticosteroid therapy for nephrotic syndrome in children

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

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC7025788 PMID: 25785660

Abstract

Background

In nephrotic syndrome protein leaks from the blood to 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 mortality rate to around 3%. However corticosteroids have well recognised potentially serious adverse effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis and behavioural disturbances. This is an update of a review first published in 2000 and updated in 2003, 2005 and 2007.

Objectives

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

Search methods

We searched the Cochrane Renal Group's Specialised Register to 26 February 2015 through contact with the Trials Search Co‐ordinator using search terms relevant to this review.

Selection criteria

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

Data collection and analysis

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

Main results

Ten new studies were identified so a total of 34 studies (3033 total participants) were included in the 2015 review update. The risk of bias attributes were frequently poorly performed. Low risk of bias was reported in 18 studies for sequence generation, 16 studies for allocation concealment, seven for performance and detection bias, 15 for incomplete reporting and 16 for selective reporting. Three months or more of prednisone significantly reduced the risk of frequently relapsing nephrotic syndrome (FRNS) (6 studies, 582 children: RR 0.68, 95% CI 0.47 to 1.00) and of relapse by 12 to 24 months (8 studies, 741 children: RR 0.80, 95% CI 0.64 to 1.00) compared with two months. Five or six months of prednisone significantly reduced the risk of relapse (7 studies, 763 children: RR 0.62, 95% CI 0.45 to 0.85) but not FRNS (5 studies, 591 children: RR 0.78, 95% CI 0.50 to 1.22) compared with three months. However there was significant heterogeneity in the analyses. Subgroup analysis stratified by risk of bias for allocation concealment showed that the risk for FRNS did not differ significantly between two or three months of prednisone and three to six months among studies at low risk of bias but was significantly reduced in extended duration studies compared with two or three months in studies at high risk or unclear risk of bias. There were no significant differences in the risk of adverse effects between extended duration and two or three months of prednisone. Four studies found that in children with FRNS, daily prednisone during viral infections compared with alternate‐day prednisone or no treatment significantly reduced the rate of relapse.

Authors' conclusions

In this 2015 update the addition of three well‐designed studies has changed the conclusion of this review. Studies of long versus shorter duration of corticosteroids have heterogeneous treatment effects, with the older high risk of bias studies tending to over‐estimate the effect of longer course therapy, compared with more recently published low risk of bias studies. Among studies at low risk of bias, there was no significant difference in the risk for FRNS between prednisone given for two or three months and longer durations or total dose of therapy indicating that there is no benefit of increasing the duration of prednisone beyond two or three months in the initial episode of SSNS.

The risk of relapse in children with FRNS is reduced by the administration of daily prednisone at onset of an upper respiratory tract or viral infection. Three additional studies have increased the evidence supporting this conclusion. This management strategy may be considered for children with FRNS. A paucity of data on prednisone use in relapsing nephrotic syndrome remains. In particular there are no data from RCTs evaluating the efficacy and safety of prolonged courses of low dose alternate‐day prednisone although this management strategy is recommended in current guidelines.

Plain language summary

Corticosteroid therapy for children with nephrotic syndrome

Nephrotic syndrome is a condition where the kidneys leak protein from the blood into the urine. When it is untreated, children can often die from infections. Most children, with nephrotic syndrome, respond to corticosteroid drugs (prednisone, prednisolone) reducing the risk of serious infection. However they usually have repeat episodes, which are often triggered by viral infections. Corticosteroid drugs can have serious side effects.

We looked at evidence from 34 studies enrolling 3033 children. Fourteen of 21 studies, in children with their first episode of nephrotic syndrome, evaluated prednisone for two or three months compared with longer durations. Thirteen studies evaluated different corticosteroid regimens in children with frequently relapsing disease (FRNS). Studies were of variable methodological quality with only about half of the studies at low risk of bias.

Among studies of long versus shorter duration of prednisone, older studies at high or unclear risk of bias tended to over‐estimate the effect of longer course therapy compared with new studies at low risk of bias. Studies at low risk of bias found no significant differences in the risk of relapse or the development of FRNS between prednisone given for three to six months compared with two or three months. Therefore there is no benefit of increasing the duration of prednisone beyond two or three months in the initial episode of SSNS.

Based on four studies in children with frequently relapsing nephrotic syndrome, prednisone given for five to seven days at the onset of a viral infection reduces the risk of relapse.

This review updates information previously published in 2000, 2003, 2005 and 2007. The addition of three new studies evaluating different durations of prednisone in the first episode of nephrotic syndrome has changed the conclusions expressed in previous versions of this review

Summary of findings

Background

Description of the condition

Nephrotic syndrome is a well‐recognised chronic illness in childhood. The characteristic features, including oedema, proteinuria and hypoalbuminaemia, result from alterations of the perm‐selectivity barrier of the glomerular capillary wall. The reported incidence is 2 to 7/100,000 children, with a prevalence of 16/100,000 (Eddy 2003). Recent prospective studies revealed an incidence of 1.15 to 2.1/100,000 children/year (El Bakkali 2011).The incidence of nephrotic syndrome is higher in Asian (McKinney 2001), African‐American (Srivastava 1999) and Arab children (Elzouki 1984). Most children have minimal change disease, in which changes on light microscopy are minor or absent, and respond to corticosteroid agents. Despite the overall incidence of childhood nephrotic syndrome remaining relatively stable over the last three decades, the histological pattern appears to be changing with an increase in the incidence of focal and segmental glomerulosclerosis (FSGS), even after adjustment for biopsy practices (Bonilla‐Felix 1999; Gulati 1999; Srivastava 1999). The histological variant and response to immunosuppressive treatment may be related to ethnicity (Eddy 2003). Steroid‐sensitive nephrotic syndrome (SSNS) is less common in African and African‐American children, and in South Africa 7.2% of 236 African children had SSNS compared with 62% of 286 Indian children (Bhimma 1997). The pathogenesis of SSNS remains unknown but appears to be related to abnormalities in T‐cell and B‐cell regulation. About 80% of children who respond to corticosteroids experience a relapsing course with recurrent episodes of oedema and proteinuria (Koskimies 1982; Tarshish 1997). The complications of nephrotic syndrome are related to effects of the disease itself, and adverse effects related to corticosteroid therapy and corticosteroid sparing agents. Children with nephrotic syndrome, which is resistant to therapy, are at increased risk of bacterial infection, characteristically resulting in peritonitis, cellulitis or septicaemia, of thromboembolic phenomena and of protein calorie malnutrition. Before antibiotics became available, two thirds of children with nephrotic syndrome died (Arneil 1971).The survivors remitted spontaneously after several months. Mortality rates fell to 35% with the introduction of sulphonamides and penicillin (Arneil 1971) and fell further with the use of corticosteroid medications.

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 1971). Corticosteroid usage has reduced the mortality 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 evidence, oral corticosteroids are the first‐line treatment of a child presenting with idiopathic nephrotic syndrome and no randomised controlled prospective studies of corticosteroids compared to placebo were carried out. The achievement of remission with corticosteroid therapy determines long term prognosis for kidney function irrespective of kidney histology (Niaudet 2009). However corticosteroids have known adverse effects. Major complications related to prolonged corticosteroid use in nephrotic syndrome include growth impairment, particularly with steroid therapy administered daily (Hyams 1988), cataracts (Ng 2001) and excessive weight gain or obesity (Rüth 2005).Two recent studies (Mishra 2010; Neuhaus 2010) highlight the impact of psychological and behavioural abnormalities related to corticosteroid therapy. Anxiety, depression, emotional lability, aggressive behaviour and attention problems had already developed with completion of 12 weeks of therapy (Mishra 2010). Neuhaus 2010 demonstrated family background, particularly maternal distress, reduced quality of life and psychosocial adjustment. Adverse effects are particularly prevalent in those children who relapse frequently and thus require multiple courses of corticosteroids.

How the intervention might work

The pharmacology and pharmacodynamics of corticosteroids in SSNS are not fully understood (Mehls 2011). 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. Glucocorticoids are lipid soluble and can easily pass through cell membranes. This process takes several hours. More recently research had identified corticosteroid effects, which are independent of nuclear gene transcription and occur earlier. At high glucocorticoid doses, suppression of T‐cell function occurs. Corticosteroids also act directly to stabilise the podocyte cytoskeleton.

Why it is important to do this review

The original treatment schedules for childhood nephrotic syndrome were developed in an ad hoc manner. 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 several randomised controlled trials (RCTs) have investigated different durations and total corticosteroid therapy doses in an effort to delineate the optimal doses and durations of corticosteroid therapy that are most beneficial and least harmful. 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. Therefore the 2015 update of this review has been undertaken to identify further RCTs, which compare different corticosteroid regimens in the initial episode of SSNS and in relapsing disease.

Objectives

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

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

Methods

Criteria for considering studies for this review

Types of studies

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

Types of participants

Inclusion criteria

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

Children with initial episode of SSNS
Children with relapsing SSNS

Exclusion criteria

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

Types of interventions

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

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

Types of outcome measures

Primary outcomes

The numbers of children with and without relapse at six months, 12 months and 24 months after completion of treatment.
The number of children who developed frequently relapsing nephrotic syndrome.

Secondary outcomes

The number of children who required other immunosuppressive therapy because of steroid toxicity
Mean relapse rates/patient
Serious adverse events including reduced growth rates, hypertension, cataracts/glaucoma, psychological disorders, infections, thromboses and osteoporosis
Cumulative corticosteroid dosage

Search methods for identification of studies

Electronic searches

We searched the Cochrane Renal Group's Specialised Register up to 26 February 2015 through contact with the Trials Search Co‐ordinator using search terms relevant to this review. The Cochrane Renal Group’s Specialised Register contains studies identified from the following sources.

Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
Weekly searches of MEDLINE OVID SP
Handsearching of renal‐related journals and the proceedings of major renal conferences
Searching of the current year of EMBASE OVID SP
Weekly current awareness alerts for selected renal journals
Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the Cochrane Renal Group.

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

Searching other resources

Reference lists of nephrology textbooks, review articles and relevant studies and CD‐ROMs and abstract books from nephrology meetings.
Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.
Conference proceedings of meetings of the International Pediatric Nephrology Association and European Society for Paediatric Nephrology.

Data collection and analysis

Selection of studies

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

This 2015 update was undertaken by four authors (DH, EH, NW, JC). Potentially relevant studies were initially determined by two authors from titles and abstracts. Full text articles of potentially eligible articles were reviewed for eligibility by two authors.

Data extraction and management

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

Assessment of risk of bias in included studies

For this update, the following items were assessed during the risk of bias assessment tool (Higgins 2011).

Was there adequate sequence generation (selection bias)?
Was allocation adequately concealed (selection bias)?
Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
- Participants and personnel
- Outcome assessors
Were incomplete outcome data adequately addressed (attrition bias)?
Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

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

Unit of analysis issues

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

Dealing with missing data

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

Assessment of heterogeneity

Heterogeneity was analysed using a Chi² test with N‐1 degrees of freedom and an alpha of 0.05 used for statistical significance and with the I² test (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biases

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

Data synthesis

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

Subgroup analysis and investigation of heterogeneity

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

Sensitivity analysis

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

Results

Description of studies

Results of the search

Search results are shown in Figure 1.

For this latest update our search (to 26 February 2015) identified 48 potentially relevant reports. Of these, nine new studies (16 reports) (Abeyagunawardena 2008; Abeyagunawardena 2014; Gulati 2009; Liern 2008; Mishra 2012; Sinha 2014; Teeninga 2013; Yoshikawa 2014; Zhang 2014) were included. One study awaiting assessment (Mocan 1999) was also included. Our search also identified two studies that are underway; no results were yet available to include in our analysis (PREDNOS Study 2013, PREDNOS 2 Study 2014). We also found 12 reports of nine previously included studies (APN 1988; APN 1993; Bagga 1999; Broyer 1997; Ekka 1997; Hiraoka 2000; Norero 1996; Pecoraro 2003; Yoshikawa 1998). This update includes 34 studies (66 reports) that involved a total of 3033 participants.

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

Included studies

The 34 included studies were divided into groups according to 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.

Prednisone treatment in first episode of nephrotic syndrome

Three months or more versus two months of therapy (741 evaluated children)

Seven studies (APN 1993; Bagga 1999; Jayantha 2002a; Ksiazek 1995; Norero 1996; Satomura 2001; Ueda 1988; Yoshikawa 2014) compared therapies of two months duration with regimens of three months or more. In all of these studies except Satomura 2001, increased duration of treatment resulted in increased total prednisone dose compared with the control group. Satomura 2001 compared three months of treatment with two months weeks 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 and the experimental group treated for six months (experimental group 1) were included in the meta‐analysis. Norero 1996 excluded those children who became steroid dependent.

Five to six months versus three months of therapy (763 evaluated children)

Seven studies (Hiraoka 2003; Ksiazek 1995; Mishra 2012, Pecoraro 2003; Sharma 2000; Sinha 2014; Teeninga 2013) compared five or six months of prednisone with three months of therapy. In all studies except Teeninga 2013, increased duration of prednisone resulted in increased total prednisone dose compared with the control group. Teeninga 2013 compared three months with six months therapy, using the same total dose of prednisone in both groups. From Ksiazek 1995, data from the experimental groups treated for three months (experimental group 2) and six months (experimental group 1) were included in this analysis. Pecoraro 2003 had three groups ‐ a control group treated for three months and two experimental groups treated for six months with different total doses of prednisone. Only the control group and treatment group 1 were included in the meta‐analysis.

Less than two months versus two months of therapy (61 evaluated children)

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

12 months versus five months of therapy (58 evaluated children)

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

Different total doses of prednisone (59 evaluated children)

Hiraoka 2000 compared different total doses of prednisone given for three months.

Prednisone and Sairei‐to therapy (171 evaluated children)

Yoshikawa 1998 compared two months of prednisone with 4.5 months but both groups received the Chinese herb, Sairei‐to. The assumption was made that the effect of the herb would be the same in both treatment groups. However because this assumption may not be correct, this study was considered separately from other studies comparing different durations of prednisone.

Prednisone and cyclosporin therapy (104 evaluated children)

APN 1999 compared three months of prednisone plus two months of cyclosporin with three months of prednisone only.

High dose oral methylprednisolone therapy (15 evaluated children)

Mocan 1999 compared high dose oral methylprednisolone given over two weeks with six months of prednisone therapy.

Prednisone and azithromycin therapy (211 evaluated children)

Zhang 2014 compared the addition of azithromycin to prednisone with prednisone alone at initiation of therapy in the first episode of nephrotic syndrome.

Relapsing nephrotic syndrome

Daily prednisone treatment during viral infections (194 evaluated children)

Three studies (Abeyagunawardena 2008; Gulati 2009; Mattoo 2000) compared daily with alternate‐day prednisone to prevent relapse during viral infections in children with SSNS receiving alternate‐day prednisone. One study (Abeyagunawardena 2014) compared daily prednisone with placebo to prevent relapse during upper respiratory tract infections in children with SSNS off prednisone.

Relapsing nephrotic syndrome: other interventions (454 evaluated children)

Nine studies investigated relapsing SSNS (APN 1981; Broyer 1997; Ekka 1997; Imbasciati 1985; ISKDC 1984; Jayantha 2002b; Leisti 1978; Li 1994; Liern 2008). Ekka 1997 and Li 1994 compared single daily with three times/day dosage of prednisone. The remaining studies explored different treatment regimens aimed at inducing remission, maintaining remission or both. Jayantha 2002b excluded children with steroid dependent nephrotic syndrome. Imbasciati 1985 and Jayantha 2002b included children with infrequently and frequently relapsing SSNS.

Excluded studies

In total, we excluded 34 studies (66 reports) after full text assessment for this review. Of the 34 excluded studies, five were not RCTs and 29 were RCTs involving non‐corticosteroid interventions in children with SSNS.

Risk of bias in included studies

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

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

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

Allocation

Sequence generation was considered to be at low risk of bias in 18 studies (Abeyagunawardena 2008; APN 1993; APN 1999; Bagga 1999; Broyer 1997; Gulati 2009; Hiraoka 2003; Imbasciati 1985; Jayantha 2002a; Jayantha 2002b; Kleinknecht 1982; Liern 2008; Mishra 2012; Sharma 2000; Sinha 2014; Teeninga 2013; Yoshikawa 1998; Yoshikawa 2014), and high risk in six studies (Li 1994; Mattoo 2000; Mocan 1999, Pecoraro 2003; Satomura 2001; Zhang 2014). Sequence generation methods was assessed as unclear in the remaining 10 studies.

Allocation concealment was considered to be at low risk of bias in 16 studies (Abeyagunawardena 2008; APN 1981; APN 1988; APN 1993; APN 1999; Broyer 1997; Gulati 2009; Hiraoka 2003; Imbasciati 1985; Kleinknecht 1982; Liern 2008; Sinha 2014; Teeninga 2013; Yoshikawa 1998; Yoshikawa 2014) and at high risk of bias in eight studies (Ksiazek 1995; Li 1994; Mattoo 2000; Mocan 1999; Norero 1996; Pecoraro 2003; Satomura 2001; Zhang 2014). Ksiazek 1995 stated that parents could influence which treatment group their child was assigned. Allocation concealment methods was assessed as unclear in the remaining 10 studies.

Blinding

Seven studies were considered to be at low risk of performance and detection bias because they were placebo controlled studies (Abeyagunawardena 2008; Abeyagunawardena 2014; Broyer 1997; Leisti 1978; Liern 2008; Sinha 2014; Teeninga 2013). Yoshikawa 2014 was an open‐label study but at low risk of detection bias. The remainder 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 14 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 (APN 1993; Bagga 1999; Broyer 1997; Hiraoka 2000; Hiraoka 2003; Imbasciati 1985; Ksiazek 1995; Leisti 1978; Mattoo 2000; Mishra 2012; Sinha 2014; Teeninga 2013; Yoshikawa 2014; Zhang 2014). Fourteen studies considered at high risk of attrition bias because more than 10% of participants were lost to follow‐up or excluded from the analysis (Abeyagunawardena 2008; Abeyagunawardena 2014; APN 1981; APN 1988; APN 1999; Ekka 1997; Gulati 2009; ISKDC 1979; Jayantha 2002a; Jayantha 2002b; Mocan 1999; Norero 1996; Sharma 2000; Yoshikawa 1998). The remaining six 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 frequently relapsing nephrotic syndrome, 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. Sixteen studies were at low risk of reporting bias (APN 1981; APN 1993; Bagga 1999; Broyer 1997; Ekka 1997; Gulati 2009; Hiraoka 2000; Hiraoka 2003; Imbasciati 1985; Jayantha 2002a; Norero 1996; Sharma 2000; Sinha 2014; Teeninga 2013; Ueda 1988; Yoshikawa 2014). There were 16 studies at high risk of selective reporting bias (Abeyagunawardena 2008; Abeyagunawardena 2014; APN 1988; APN 1999; ISKDC 1979; Jayantha 2002b; Kleinknecht 1982; Ksiazek 1995; Leisti 1978; Li 1994; Liern 2008; Mattoo 2000; Mocan 1999; Pecoraro 2003; Yoshikawa 1998; Zhang 2014). Mishra 2012 and Satomura 2001 were assessed to be at unclear risk of selective reporting bias

Other potential sources of bias

Twelve studies were considered at low risk of potential bias as they were funded educational or philanthropic organisations (Abeyagunawardena 2008; APN 1981; APN 1988; Bagga 1999; Gulati 2009; Leisti 1978; Norero 1996; Sinha 2014; Teeninga 2013; Ueda 1988; Yoshikawa 2014; Zhang 2014). One study was considered to be at high risk of bias as it was funded by industry and no full‐text publication has been identified 10 years after the first conference abstract (Pecoraro 2003). The remaining 21 studies were deemed unclear of other risk of bias as no information on funding sources was provided.

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

Effects of interventions

See: Table 1; Table 2

Summary of findings for the main comparison. Steroid therapy in first episode of nephrotic syndrome: three months of more versus two months for nephrotic syndrome in children.

Steroid therapy in first episode of nephrotic syndrome: 3 months of more versus 2 months for nephrotic syndrome in children
Patient or population: patients with nephrotic syndrome in children  Settings:   Intervention: steroid therapy in first episode of nephrotic syndrome: 3 months of more versus 2 months
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Steroid therapy in first episode of nephrotic syndrome: 3 months of more compared with 2 months
Number with frequent relapses by 12 to 24 months	Study population		RR 0.68   (0.47 to 1)	582 (6)	⊕⊕⊝⊝  low^1,2
	358 per 1000	243 per 1000   (168 to 358)
	Moderate
	359 per 1000	244 per 1000   (169 to 359)
Number of children relapsing by 12 to 24 months	Study population		RR 0.8   (0.64 to 1)	741 (8)	⊕⊕⊝⊝  low^1,2
	668 per 1000	535 per 1000   (428 to 668)
	Moderate
	647 per 1000	518 per 1000   (414 to 647)
Number with frequent relapses by 12 to 24 months stratified by risk of bias for allocation concealment: low risk of bias for allocation concealment	Study population		RR 0.92   (0.69 to 1.23)	362 (3)	⊕⊕⊕⊕  high
	359 per 1000	330 per 1000   (247 to 441)
	Moderate
	348 per 1000	320 per 1000   (240 to 428)
Number with frequent relapses by 12 to 24 months stratified by risk of bias for allocation concealment: unclear or high risk of bias for allocation bias	Study population		RR 0.45   (0.26 to 0.77)	220 (3)	⊕⊕⊕⊝  moderate¹
	357 per 1000	161 per 1000   (93 to 275)
	Moderate
	371 per 1000	167 per 1000   (96 to 286)
Adverse events: psychological disorders	Study population		RR 2.18   (0.43 to 11.13)	233 (3)	⊕⊕⊝⊝  low^1,3
	18 per 1000	40 per 1000   (8 to 202)
	Moderate
	0 per 1000	0 per 1000   (0 to 0)
Adverse events: hypertension	Study population		RR 1.79   (0.47 to 6.86)	456 (6)	⊕⊕⊕⊝  moderate¹
	60 per 1000	107 per 1000   (28 to 410)
	Moderate
	0 per 1000	0 per 1000   (0 to 0)
Adverse events: eye complications	Study population		RR 0.32   (0.07 to 1.42)	400 (5)	⊕⊕⊕⊝  moderate¹
	43 per 1000	14 per 1000   (3 to 62)
	Moderate
	0 per 1000	0 per 1000   (0 to 0)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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 quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Study ID	Relapse on therapy (RR (95% CI))	Relapse by 9 months (RR (95% CI))	Relapse by 12 months (RR (95% CI))	Mean relapse rate MD (95% CI))	Mean time to remission (MD (95% CI)	Steroid therapy
APN 1981	0.60 (0.36 to 1.02)		1.20 (0.93 to 1.55)	‐0.20 (‐0.65 to 0.25)		Alternate‐day versus intermittent
Broyer 1997			0.44 (0.25 to 0.78)	‐1.90 (‐2.77 to ‐1.03)		Deflazacort versus prednisone
Ekka 1997		1.07 (0.77 to 1.50)				Daily versus divided dose prednisone
Imbasciati 1985			1.06 (0.75 to 1.52)			IV and oral versus oral prednisone
ISKDC 1979	0.20 (0.05 to 0.82)	1.00 (0.89 to 1.12)		0.54 (‐0.50 to 1.58)		Daily versus intermittent prednisone
Jayantha 2002b			0.43 (0.29 to 0.65)	‐1.78 (‐2.30 to ‐1.26)		7 months prednisone versus standard ISKDC regimen for relapse
Leisti 1978						Cortisol versus placebo in FRNS (cross‐over): 5/13 (38%) on cortisol relapsed versus 12/13 (92%) on placebo
Li 1994					0.04 days (‐0.98 to 1.06)	Daily versus divided dose prednisone
Liern 2008						Time to relapse (cross‐over): deflazacort 105 ± 4.19 days versus methylprednisolone 85 ± 3.8 days

Date	Event	Description
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

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

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

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number with frequent relapses by 12 to 24 months	6	582	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.47, 1.00]
2 Number of children relapsing by 12 to 24 months	8	741	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.64, 1.00]
3 Mean relapse rate/patient/y	4	295	Mean Difference (IV, Random, 95% CI)	‐0.65 [‐1.29, ‐0.00]
4 Cumulative steroid dose	3	245	Mean Difference (IV, Random, 95% CI)	0.71 [‐0.67, 2.09]
5 Number with frequent relapses by 12 to 24 months stratified by definition of FRNS	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.1 FRNS by ISKDC definition	3	435	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.39, 1.20]
5.2 Variation from ISKDC definition of FRNS	3	147	Risk Ratio (M‐H, Random, 95% CI)	0.64 [0.35, 1.19]
6 Number with frequent relapses by 12 to 24 months stratified by risk of bias for allocation concealment	6	582	Risk Ratio (M‐H, Random, 95% CI)	0.68 [0.47, 1.00]
6.1 Low risk of bias for allocation concealment	3	362	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.69, 1.23]
6.2 Unclear or high risk of bias for allocation bias	3	220	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.26, 0.77]
7 Adverse events	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
7.1 Psychological disorders	3	233	Risk Ratio (M‐H, Random, 95% CI)	2.18 [0.43, 11.13]
7.2 Hypertension	6	456	Risk Ratio (M‐H, Random, 95% CI)	1.79 [0.47, 6.86]
7.3 Ophthalmological disorders	5	400	Risk Ratio (M‐H, Random, 95% CI)	0.32 [0.07, 1.42]
7.4 Retarded growth	4	354	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.25, 1.18]
7.5 Cushing's syndrome	3	232	Risk Ratio (M‐H, Random, 95% CI)	1.32 [0.51, 3.39]
7.6 Infections	2	172	Risk Ratio (M‐H, Random, 95% CI)	0.79 [0.53, 1.17]
7.7 Osteoporosis	3	233	Risk Ratio (M‐H, Random, 95% CI)	0.47 [0.06, 3.38]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number with frequent relapses by 12 to 24 months	5	591	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.50, 1.22]
2 Number of children relapsing by 12 to 24 months	7	763	Risk Ratio (M‐H, Random, 95% CI)	0.62 [0.45, 0.85]
3 Mean relapse rate/patient/y	3	460	Mean Difference (IV, Random, 95% CI)	‐0.39 [‐0.64, ‐0.14]
4 Cumulative steroid dose	3	460	Mean Difference (IV, Random, 95% CI)	‐0.47 [‐1.67, 0.73]
5 Number with frequent relapses stratified by definition of FRNS	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.1 FRNS by ISKDC definition	3	377	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.74, 1.34]
5.2 Variation from ISKDC definition of FRNS	2	214	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.18, 0.72]
6 Number with frequent relapses stratified by risk of bias for allocation concealment	5	591	Risk Ratio (M‐H, Random, 95% CI)	0.78 [0.50, 1.22]
6.1 Studies at low risk of bias for allocation concealment	3	377	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.74, 1.34]
6.2 Studies at high or unclear risk of bias for allocation concealment	2	214	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.18, 0.72]
7 Number with frequent relapses stratified by risk of bias for blinding	5	591	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.51, 1.16]
7.1 Low risk of bias for blinding	2	307	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.87, 1.20]
7.2 High or unclear risk of bias for blinding	3	284	Risk Ratio (M‐H, Random, 95% CI)	0.49 [0.30, 0.78]
8 Number with frequent relapses stratified by risk of bias for attrition	5	591	Risk Ratio (M‐H, Random, 95% CI)	0.77 [0.51, 1.16]
8.1 Low risk of bias for attrition	4	451	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.85, 1.16]
8.2 High risk of bias for attrition	1	140	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.16, 0.69]
9 Adverse events	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
9.1 Hypertension	5	636	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.91, 2.05]
9.2 Eye complications	5	614	Risk Ratio (M‐H, Random, 95% CI)	0.46 [0.18, 1.17]
9.3 Infections	4	586	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.79, 1.51]
9.4 Cushingoid appearance	5	646	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.62, 1.36]
9.5 Gastrointestinal bleeding	1	140	Risk Ratio (M‐H, Random, 95% CI)	1.5 [0.26, 8.70]
9.6 Addisonian crisis	1	140	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.39]
9.7 Psychological disorders	3	389	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.03, 4.39]
9.8 Growth	2	320	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.55, 1.82]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Number of children relapsing by 6 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Number of children relapsing by 12 to 24 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Number with frequent relapses	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Cumulative steroid dose	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Relapse at twelve months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Number with frequently relapsing nephrotic syndrome	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1 Hypertension	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Psychological disorders	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 Cushing's Syndrome	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Long prednisone & Sairei‐to versus standard prednisone & Sairei‐to	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 Relapse at 2 years	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Number with frequent relapses at 2 years	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Relapse by 6 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Relapse by 12 months	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Number needing cytotoxic agents	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Serum creatinine at end of study	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Time to first relapse	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
2 Relapse rate	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
3 Time to remission	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Number with relapse with infection	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Number of relapses/patient	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1 Number of infection‐related relapses/patient/year	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Total relapses (episodes/patient/1 year)	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Number of relapses/patient at 2 years	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of children relapsing during therapy	2		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 Intermittent dose versus alternate‐day therapy (6 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Daily versus intermittent therapy (2 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Number of children with further relapses by 9 to 12 months	5		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.1 Intermittent dose versus alternate‐day therapy (6 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Single versus divided dose therapy (2 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Intravenous versus oral therapy (6 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.4 Deflazacort versus prednisone (12 months therapy)	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.5 Prolonged oral versus intermittent therapy (2 months therapy )	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Mean relapse rate/patient/y	3		Mean Difference (IV, Random, 95% CI)	Totals not selected
3.1 Single versus divided dose therapy (2 months therapy)	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Daily versus intermittent therapy (2 months therapy)	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 Deflazacort versus prednisone (12 months therapy)	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4 Mean time to relapse	2		Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1 Single versus divided dose therapy (2 months therapy)	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Daily versus intermittent therapy (2 months therapy)	1		Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5 Cumulative steroid dose	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
6 Mean time to remission	2	138	Mean Difference (IV, Random, 95% CI)	0.04 [‐0.98, 1.06]
7 Serious adverse events	2	138	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.18, 0.91]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Number with relapses	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 Relapse by 6 months	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Relapse by 12 months	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Relapse by 2 years	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.4 Relapse by 3 years	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Relapse rate/patient/y	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1 Relapse rate at 1 year	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Relapse rate at 2 years	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Relapse rate at 3 years	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Number with frequently relapsing or steroid dependent nephrotic syndrome	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Cumulative steroid dose	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1 After 1 year	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 After 2 years	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4.3 After 3 years	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
5 Adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.1 Number with hypertension	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5.2 Number with growth failure	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Methods	Study design: cross‐over RCT Time frame: July 2003 to January 2005. Study continued until 40 children had 2 URTIs Duration of follow‐up: until child had 2 URTI
Participants	Country: Sri Lanka Setting: single tertiary referral centre Inclusion criteria: children aged 1 to 16 y with FRNS receiving maintenance low dose (0.1 to 0.6 mg/kg) alternate‐day oral prednisolone Number: 40 Median age (range): 5.3 years (1.5 to 13.2) Sex (M/F): 29/11 Exclusion criteria: glucocorticoid related side effects; frequent relapses requiring steroid sparing agents, did not have two viral infections within study period, sustained remission with disease stability
Interventions	Treatment group Prednisolone 5 mg daily for 7 days at onset of viral infection Control group Placebo daily for 7 days Randomised at onset of URTI to receive one of the interventions. At next URTI received alternate therapy
Outcomes	Number relapsing during 6 months of therapy and in subsequent 6 months Mean relapse rate during treatment and in subsequent 6 months
Notes	Definitions FRNS: 2+ relapses within 6 months of first response or 4 relapses in any 1 year (ISKDC definition) Relapse: urine protein excretion 3+ or more on urinalysis for 3 consecutive days in patient who had previously been in remission Remission: urinary protein excretion negative or trace on urinalysis for 3 consecutive days URTI: presence of 3 or more of the following criteria ‐ cough, runny nose, sore throat, lethargy, body aches and fever
*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

Methods	Study design: parallel RCT Time frame: not reported Duration of follow‐up: 12 months
Participants	Country: northern Europe Setting: multicentre, renal clinics Inclusion criteria: children with FRNS Number (analysed/randomised): treatment group 1 (23/30); treatment group 2 (25/34) Mean age ± SD (months): treatment group 1 (88.5 ± 33.0); treatment group 2 (101.3 ± 35.1) Sex (M/F): treatment group 1 (15/8); treatment group 2 (18/7) Exclusion criteria: not reported
Interventions	Treatment group 1 (alternate) Prednisone: 60 mg/m²/d till protein free for 3+ days; then 35 mg/m² on alternate days Total duration: 6 months Treatment group 2 Prednisone: 60 mg/m²/d till protein free for 3+ days; then 40 mg/m² given on 3/7 consecutive days Total duration: 6 months
Outcomes	Number relapsing during 6 months of therapy and in subsequent 6 months Mean relapse rate during treatment and in subsequent 6 months
Notes	Definitions FRNS: 2+ relapses within 6 months of first response or 4 relapses in any 1 year (ISKDC definition) Relapse: urine protein > 40 mg/m²/h for 3 consecutive days (ISKDC) Remission: urinary protein < 4 mg/m²/h for 3 consecutive days (ISKDC)
*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. "One opened when patient qualified to enter the study"
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Blinding no 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

Methods	Study design: parallel RCT Time period: not reported Follow‐up: 1 year
Participants	Country: France Setting: multicentre, renal clinics Inclusion criteria: children with SDNS (2+ relapses in 12 months despite alternate‐day prednisone or within 2 months of stopping this regimen). Number: treatment group 1 (20); treatment group 2 (20) Mean age ± SD (years): treatment group 1 (9.2 ± 2.7); treatment group 2 (8.5 ± 4) Sex (M/F): treatment group 1 (15/5); treatment group 2 (17/3) Exclusion criteria: not reported
Interventions	Treatment group 1 Deflazacort: dose equivalent to prednisone of 60 mg/m²/d till in remission for 5 days then 60 mg/m² on alternate days for 6 weeks, taper 6 to 8 weeks then 15 to 20 mg/m² on alternate days for 1 year Treatment group 2 Prednisone given as above
Outcomes	Number relapsing during 1 year of therapy Mean relapse rate/patient Serious adverse events
Notes	Six children in treatment group and 5 in control group also received cyclosporin Definitions Relapse: not reported Remission: not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Blocks of 10 packages containing equal numbers of each intervention in order determined by random code"
Allocation concealment (selection bias)	Low risk	"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. "Medication in identical bottles and identical tablets"
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Blinding of outcome assessment ensured. "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

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

Study	Reason for exclusion
Alatas 1978	RCT; non‐corticosteroid interventions (chlorambucil)
Anonymous 1968	Not RCT
APN 1982	RCT, non‐corticosteroid interventions (cyclophosphamide/chlorambucil)
Arun 2009	RCT; non‐corticosteroid interventions (zinc)
Baluarte 1978	RCT; non‐corticosteroid interventions (chlorambucil)
BAPN 1991	RCT; non‐corticosteroid interventions (levamisole)
Barratt 1970	RCT; non‐corticosteroid interventions (cyclophosphamide)
Barratt 1973	RCT; non‐corticosteroid interventions (cyclophosphamide)
Barratt 1977	RCT; non‐corticosteroid interventions (azathioprine)
Cerkauskiene 2005	RCT; non‐corticosteroid interventions (fusidic acid)
Chiu 1973	RCT; non‐corticosteroid interventions (cyclophosphamide)
Dayal 1994	RCT; non‐corticosteroid interventions (levamisole)
Donia 2005	RCT; non‐corticosteroid interventions (cyclophosphamide/levamisole)
Edefonti 1988	RCT; non‐corticosteroid interventions (cyclosporin/cyclophosphamide)
Grupe 1976	RCT; non‐corticosteroid interventions (chlorambucil)
Hu 2006	Probably RCT; non‐corticosteroid interventions (herbal medicines)
Idczak‐Nowicka 1996	Not RCT
ISKDC 1970	RCT; non‐corticosteroid interventions (azathioprine)
ISKDC 1974	RCT; non‐corticosteroid interventions (cyclophosphamide)
Liu 1995	Non‐corticosteroid interventions (Chinese medicines). Not sure whether it is RCT
Martinelli 2004	Non‐corticosteroid interventions (cyclophosphamide) in children with FSGS. Not sure whether it is RCT
McCrory 1973	RCT; non‐corticosteroid interventions (cyclophosphamide)
Niaudet 1992	RCT; non‐corticosteroid interventions (cyclosporin/chlorambucil)
Prasad 2004	RCT; non‐corticosteroid interventions (cyclophosphamide)
Rashid 1996	RCT; non‐corticosteroid interventions (levamisole)
Sharipov 2007	Not RCT
Ueda 1990	RCT; non‐corticosteroid interventions (cyclophosphamide)
Wang 2005	Possibly RCT; non‐corticosteroid interventions
Weiss 1993	RCT; non‐corticosteroid interventions (levamisole)
Wingen 1990	Not RCT
Yamashita 1971	Not RCT
Yang 2001	Non‐corticosteroid interventions (herbal). Unclear whether RCT
Yoshioka 2000	RCT; non‐corticosteroid interventions (mizoribine)

Trial name or title	Short course daily prednisolone therapy at the time of upper respiratory infection in children with relapsing steroid sensitive nephrotic syndrome: The PREDNOS 2 study
Methods	Parallel RCT
Participants	Subjects aged over 1 year and less than 19 years with relapsing SSNS who have had two or more relapses in the preceding 12 months
Interventions	Standard course therapy: weeks 1 to 4 prednisolone 60 mg/m²/d (max 80 mg), weeks 5 to 8, prednisolone 40 mg/m² on alternate days for 28 days Extended course therapy: weeks 1 to 4 60mg/m²/d, weeks 5 to 16 prednisolone 60 mg/m² on alternate days tapering by 10 mg/m² every 2 weeks
Outcomes	The primary end point will be the incidence of URTI‐related relapse following the first URTI during the 12 month follow‐up period
Starting date
Contact information	Nicholas Webb. nicholas.webb@cmft.nhs.uk
Notes

PERMALINK

Corticosteroid therapy for nephrotic syndrome in children

Deirdre Hahn

Elisabeth M Hodson

Narelle S Willis

Jonathan C Craig

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

Prednisone treatment in first episode of nephrotic syndrome

Three months or more versus two months of therapy (741 evaluated children)

Five to six months versus three months of therapy (763 evaluated children)

Less than two months versus two months of therapy (61 evaluated children)

12 months versus five months of therapy (58 evaluated children)

Different total doses of prednisone (59 evaluated children)

Prednisone and Sairei‐to therapy (171 evaluated children)

Prednisone and cyclosporin therapy (104 evaluated children)

High dose oral methylprednisolone therapy (15 evaluated children)

Prednisone and azithromycin therapy (211 evaluated children)

Relapsing nephrotic syndrome

Daily prednisone treatment during viral infections (194 evaluated children)

Relapsing nephrotic syndrome: other interventions (454 evaluated children)

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Summary of findings for the main comparison. Steroid therapy in first episode of nephrotic syndrome: three months of more versus two months for nephrotic syndrome in children.

Summary of findings 2. Steroid therapy in first episode of nephrotic syndrome: five or six months versus three months for nephrotic syndrome in children.

Outcome of children in their first episode of SSNS

Three months or more versus two months therapy

1.1. Analysis.

Trial name or title	Long‐term tapering versus standard prednisolone (steroid) therapy for the treatment of the initial episode of nephrotic syndrome: national multicentre randomised double blind trial
Methods	Parallel RCT
Participants	Children presenting with first episode of SSNS, over 1 year and less than 1 year
Interventions	Treatment group: children will receive daily prednisolone for 6 days at the onset of URTI at the onset of each URTI during 12 months  Control group: children will continue their current treatment (with placebo to maintain double blind) at the onset of each URTI during 12 months
Outcomes	Time to first relapse. To determine whether an extended course of prednisolone reduces the relapse rate, reduces the proportion of children who develop frequently relapsing or steroid dependent disease, reduces the requirement for a second or third line agent, is associated with an increased incidence of steroid related adverse events including behavioural problems, is more effective than standard course therapy
Starting date
Contact information	nicholas.webb@cmft.nhs.uk
Notes