Interventions for idiopathic steroid‐resistant nephrotic syndrome in children

Isaac D Liu; Narelle S Willis; Jonathan C Craig; Elisabeth M Hodson

doi:10.1002/14651858.CD003594.pub6

. 2019 Nov 21;2019(11):CD003594. doi: 10.1002/14651858.CD003594.pub6

Interventions for idiopathic steroid‐resistant nephrotic syndrome in children

Isaac D Liu ¹, Narelle S Willis ^2,³, Jonathan C Craig ^3,⁴, Elisabeth M Hodson ^2,^3,^✉

Editor: Cochrane Kidney and Transplant Group

PMCID: PMC6868353 PMID: 31749142

Abstract

Background

The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy. Children who fail to respond to corticosteroids in the first episode of nephrotic syndrome (initial resistance) or develop resistance after one or more responses to corticosteroids (delayed resistance) may be treated with immunosuppressive agents including calcineurin inhibitors (CNI) (cyclosporin or tacrolimus) and with non‐immunosuppressive agents such as angiotensin‐converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). However, response to these agents is limited so newer agents are being assessed for efficacy. This is an update of a review first published in 2004 and updated in 2006, 2010 and 2016.

Objectives

To evaluate the benefits and harms of different interventions used in children with idiopathic nephrotic syndrome, who do not achieve remission following four weeks or more of daily corticosteroid therapy.

Search methods

We searched the Cochrane Kidney and Transplant Register of Studies to 17 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria

Randomised controlled trials (RCTs) and quasi‐RCTs were included if they compared different immunosuppressive agents or non‐immunosuppressive agents with placebo, prednisone or other agent given orally or parenterally in children aged three months to 18 years with steroid‐resistant nephrotic syndrome (SRNS). Studies, which enrolled children and adults but in which paediatric data could not be separated from adult data, were also included.

Data collection and analysis

Two authors independently searched the literature, determined study eligibility, assessed risk of bias and extracted data. For dichotomous outcomes, results were expressed as risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, results were expressed as mean difference (MD) and 95% CI. Data were pooled using the random effects model. The certainty of the evidence was assessed using the GRADE approach.

Main results

Twenty‐five studies (1063 participants) were included. Fourteen studies were at low risk of bias for sequence generation and allocation concealment. Five and 19 studies were at low risk of performance and detection bias. Fourteen, 14 and 13 studies were at low risk of attrition bias, reporting bias and other bias respectively.

Cyclosporin compared with placebo or no treatment may increase the number of participants who achieve complete remission (4 studies, 74 participants: RR 3.50, 95% CI 1.09 to 11.20) or complete or partial remission (4 studies, 74 children: RR 3.15, 95% CI 1.04 to 9.57) by 6 months (low certainty evidence). It is uncertain whether cyclosporin increases the likelihood of worsening hypertension or reduces the likelihood of end‐stage kidney disease (very low certainty evidence).

CNI compared with IV cyclophosphamide (CPA) may increase the number of participants with complete or partial remission at 3 to 6 months (2 studies, 156 children: RR 1.98, 95% CI 1.25 to 3.13) (low certainty evidence) and probably reduces the number with treatment failure (non response, serious infection, persistently elevated creatinine (1 study, 124 participants: RR 0.32, 95% CI 0.18 to 0.58) (moderate certainty evidence) with little or no increase in serious infections (1 study, 131 participants: RR 0.49, 95% CI 0.16 to 1.56) (moderate certainty evidence).

Tacrolimus compared with cyclosporin may make little or no difference to the number who achieve complete or partial remission (2 studies, 58 participants: RR 1.05, 95% CI 0.87 to 1.25) (low certainty evidence) or in the number with worsening hypertension (2 studies, 58 participants: RR 0.41, 95% CI 0.08 to 2.15) (low certainty evidence).

Cyclosporin compared with mycophenolate mofetil (MMF) and dexamethasone probably makes little or no difference to the number who achieve complete or partial remission (1 study, 138 participants: RR 2.14, 95% CI 0.87 to 5.24) (moderate certainty evidence) and makes little or no difference to the number dying (1 study, 138 participants: RR 2.14, 95% CI 0.87 to 5.24) or with 50% reduction in glomerular filtration rate (GFR) (1 study, 138 participants: RR 2.29, 95% CI 0.46 to 11.41) (low certainty evidence).

Among children, who have achieved complete remission, tacrolimus compared with MMF may increase the number of children who maintain complete or partial response for 12 months (1 study, 60 children: RR 2.01, 95% CI 1.32 to 3.07) (low certainty evidence).

Oral CPA with prednisone compared with prednisone alone may make little or no difference to the number who achieve complete remission (2 studies, 84 children: RR 1.06, 95% CI 0.61 to 1.87) (low certainty evidence).

IV CPA compared with oral CPA (2 studies, 61 children: RR 1.58, 95% CI 0.65 to 3.85) and IV compared with oral CPA plus IV dexamethasone (1 study, 49 children: RR 1.13, 95% CI 0.65 to 1.96) may make little or no difference to the number who achieve complete remission (low certainty evidence).

It is uncertain whether rituximab and cyclosporin compared with cyclosporin increases the likelihood of remission because the certainty of the evidence is very low.

It is uncertain whether adalimumab or galactose compared with conservative therapy increases the likelihood of remission because the certainty of the evidence is very low.

Two studies reported that ACEi may reduce proteinuria in children with SRNS. One study reported that the dual angiotensin II and endothelin Type A receptor antagonist, sparsentan, may reduce proteinuria more effectively than the angiotensin receptor blocker, irbesartan.

Authors' conclusions

To date RCTs have demonstrated that CNIs may increase the likelihood of complete or partial remission compared with placebo/no treatment or CPA. For other regimens assessed, it remains uncertain whether the interventions alter outcomes because the certainty of the evidence is low. Further adequately powered, well designed RCTs are needed to evaluate other regimens for children with idiopathic SRNS. Since SRNS represents a spectrum of diseases, future studies should enrol children from better defined groups of patients with SRNS.

Plain language summary

Interventions for idiopathic steroid resistant nephrotic syndrome in children

What is the issue?

Nephrotic syndrome is a condition where the kidneys leak protein from the blood into the urine. Corticosteroids are used in the first instance to achieve remission. Other agents such as calcineurin inhibitors (cyclosporin, tacrolimus) or angiotensin‐converting enzyme inhibitors are required for those children do not respond to corticosteroids in their first episode of nephrotic syndrome (initial resistance) or who develop steroid resistance after one or more responses to corticosteroids (delayed resistance).

What did we do?

We searched Cochrane Kidney and Transplant's Specialised Register (up to 17 September 2019). Randomised controlled trials were included if they compared different immunosuppressive agents or non‐immunosuppressive agents with placebo, prednisone or other agent in children with steroid resistant nephrotic syndrome. Studies of new treatments were included as these included children as well as adults.

What did we find?

This review found that cyclosporin compared with placebo, no treatment or prednisone may increase the number of participants, in whom urine protein disappears (complete remission) or is markedly reduced (partial remission). Calcineurin inhibitors (cyclosporin, tacrolimus) also may increase the number of children, who achieve complete or partial remission compared with intravenous cyclophosphamide. There may be little or no benefit of other immunosuppressive agents studied so far. Angiotensin‐converting enzyme inhibitors may reduce the amount of protein in the urine.

Conclusions

Calcineurin inhibitors may increase the likelihood of complete or partial remission compared with placebo/no treatment or cyclophosphamide. However, the certainty of the evidence is low because the studies were small. It remains uncertain whether other interventions may alter outcomes due to few small studies. Larger and well‐designed randomised controlled trials are needed to evaluate other treatment combinations for children with steroid resistant nephrotic syndrome.

Summary of findings

Background

Description of the condition

Nephrotic syndrome is a condition in which the glomeruli of the kidney leak protein from the blood into the urine. It results in hypoproteinaemia and generalised oedema. Children with untreated nephrotic syndrome are at increased risk of bacterial infection, characteristically resulting in peritonitis, cellulitis or septicaemia, of thromboembolic phenomena and of protein calorie malnutrition with significant reductions in quality of life. Prospective studies of children with newly diagnosed idiopathic nephrotic syndrome identified through Paediatric Surveillance Units in the Netherlands, Australia and New Zealand reported incidences of idiopathic nephrotic syndrome of 1.12 to 1.9 per 100,000 children aged below 16 years (El Bakkali 2011; Sureshkumar 2014; Wong 2007). A literature review of studies from 1946 to 2014 found the average incidence of nephrotic syndrome from retrospective and prospective studies to be 4.7 (range 1.15 to 16.9) per 100,000 children (Chanchlani 2016). The proportion of children with steroid resistance disease varied between 2.1 to 27.3% (average 12.4%).

In clinical studies childhood nephrotic syndrome is classified into steroid‐sensitive nephrotic syndrome (SSNS), steroid‐resistant nephrotic syndrome (SRNS), congenital and infantile nephrotic syndrome (0 to 12 months) and nephrotic syndrome secondary to other diseases including Henoch Schönlein nephritis, systemic lupus erythematosus and hepatitis B nephropathy. Most children with primary nephrotic syndrome respond to corticosteroid therapy within four weeks. In those children who fail to respond to corticosteroids, kidney biopsy is performed to determine pathology. The majority of children with SRNS have focal segmental glomerulosclerosis (FSGS), mesangioproliferative glomerulonephritis (MesPGN) or minimal change disease (MCD). FSGS is a leading cause of end‐stage kidney disease (ESKD) in children. FSGS is a heterogeneous disease with some children having FSGS secondary to immunological factors, some children having FSGS secondary to mutations in the genes coding for podocyte proteins including podocin and nephrin and a few older children having FSGS secondary to hyperfiltration (reduced kidney mass, obesity, diabetes mellitus) (Deegens 2011). A study of 1783 unrelated families found that single gene mutations responsible for SRNS were identified in 29.5% families overall with mutations in 25.3% children aged 1 to 6 years, 17.8% in children aged 7 to 12 years and 10.8% in adolescents aged 13 to 18 years (Sadowski 2015). Few children with FSGS secondary to genetic mutations respond to immunosuppressive agents and in these children, nephrotic syndrome rarely recurs following kidney transplantation (Ding 2014). Children with SRNS may have corticosteroid resistant disease from initial presentation (Initial resistance) or may develop steroid resistance after one or more responses to corticosteroids (delayed resistance); children with delayed steroid resistance do not have disease causing gene mutations (Bierzynska 2017). About one third of children suffer recurrence of nephrotic syndrome following kidney transplantation. Recent data suggest that recurrence of disease post transplant is much more common in children with SRNS and delayed steroid resistance (Ding 2014). These data are consistent with an immunological cause of SRNS in these children.

Description of the intervention

Oral corticosteroids are the first‐line treatment for a child presenting with idiopathic nephrotic syndrome. For children who present with their first episode of nephrotic syndrome, about 90% will achieve remission with corticosteroid therapy (Koskimies 1982). Of those who respond, about 95% will have responded after four weeks of daily corticosteroid therapy and 98% will have responded after eight weeks of corticosteroid therapy (ISKDC 1981a).

Children who fail to respond to corticosteroids are treated with immunosuppressive agents such as calcineurin inhibitors (CNI) (cyclosporin, tacrolimus), cyclophosphamide (CPA), chlorambucil, mycophenolate mofetil (MMF), and the anti CD 20 monoclonal antibody, rituximab. Rates of complete and partial remission with CNI based on observational studies and individual groups in randomised controlled trials (RCTs) vary between 30% and 80% (Choudhry 2009; FSGS‐CT 2011; Niaudet 1994). Remission rates of up to 60% with combinations of intravenous (IV) methylprednisolone and CPA are reported in observational studies (Tune 1996) and of around 50% in individual treatment groups in RCTs (Gulati 2012; ISKDC 1974; ISKDC 1996). Failure to achieve complete or partial remission is associated with progression to ESKD (Gipson 2006). Other non‐immunosuppressive agents including angiotensin‐converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and fish oil have also been used in SRNS.

How the intervention might work

Corticosteroids, immunosuppressive agents and monoclonal antibodies may act by suppressing production of plasma factors by T and B cells since immunological mechanisms are believed to be responsible for some cases of SRNS. Some immunosuppressive medications including dexamethasone, CNI, and rituximab may be effective in nonimmune causes of SRNS by directly targeting podocytes. ACEi and ARB reduce proteinuria and are aimed at reducing progressive glomerulosclerosis (Deegens 2011).

Why it is important to do this review

There is considerable diversity in the use of these agents with differences in treatment modes, combinations and dosage regimens. Optimal combinations with least toxicity remain to be determined. Despite the use of newer immunosuppressive agents, the response rate to therapy remains low. The aims of the update of this systematic review initially published in 2004 and updated in 2006, 2010 and 2016 were to identify new RCTs assessing the benefits and harms of interventions used to treat idiopathic SRNS in children and to incorporate them where appropriate in meta‐analyses to increase the evidence base available on the efficacy of treatment of SRNS in children.

Objectives

Methods

Criteria for considering studies for this review

Types of studies

All RCTs and quasi‐RCTs, in which different agents were used in the treatment of participants including children (aged three months to 18 years) with idiopathic SRNS, were included.

Types of participants

Inclusion criteria

Children aged three months to 18 years with SRNS (i.e. persistence of proteinuria > 3+ on dipstick, urinary protein‐creatinine ratio (UP/C) > 0.2 g/mmol (> 2 g/g) or > 40 mg/m²/h after four weeks or more of daily corticosteroid agent). Where a kidney biopsy was performed, only children with biopsy diagnoses of MCD, MesPGN, IgM nephropathy or FSGS were included. Children with initial steroid resistance and children with delayed steroid resistance were included. Children with disease‐causing genetic mutations associated with FSGS where kidney biopsy was not performed could also be included.

Where studies included adults and children were included and where paediatric data could not be separated, data of all participants in these studies were included in this review.

Exclusion criteria

Children with SSNS, children with congenital nephrotic syndrome and children with other kidney or systemic forms of nephrotic syndrome defined on kidney biopsy, clinical features or serology (e.g. post‐infectious glomerulonephritis, Henoch‐Schönlein nephritis, systemic lupus erythematosus, membranous glomerulopathy or mesangiocapillary glomerulonephritis) were excluded. Children with FSGS secondary to hyperfiltration (obesity, diabetes mellitus, reduced kidney mass) were excluded.

Types of interventions

All interventions were potentially eligible. Interventions considered were as follows.

IV corticosteroid agent versus oral corticosteroid agent, placebo or no intervention
Different doses and/or durations of IV corticosteroid agent
Non‐corticosteroid immunosuppressive agent (with or without concomitant use of corticosteroid agent) versus corticosteroid agent alone, placebo or no treatment
Two different non‐corticosteroid agents (with or without concomitant use of corticosteroid agent)
Different doses, durations and routes of administration of the same non‐corticosteroid agent (with or without concomitant use of corticosteroid agent)
Other non‐immunosuppressive agents such as ACEi or fish oil used with or without corticosteroid or non‐corticosteroid immunosuppressive agents.

Types of outcome measures

Primary outcomes

Number in complete remission during and following therapy (i.e. the child became oedema‐free and urine protein was < 1+ on dipstick, urinary UP/C < 0.02 g/mmol (< 0.2 g/g) or < 4 mg/m²/h for three or more consecutive days)
Number in partial remission with reduction in proteinuria (i.e. proteinuria < 2+, urinary UP/C < 0.2 g/mmol or < 40 mg/m²/h) and an increase in serum albumin levels
Number reaching ESKD.

Secondary outcomes

Changes in kidney function: serum creatinine (SCr); creatinine clearance (CrCl); estimated glomerular filtration rate (eGFR)
Adverse effects of therapy
Duration of remission or partial remission
Reduction in proteinuria.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Register of Studies up to 17 September 2019 through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources.

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

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

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

Searching other resources

No other resources were searched for this update because the scope of the Cochrane Kidney and Transplant Register of Studies covers the most likely sources of studies.

Data collection and analysis

Selection of studies

The search strategy described was used to obtain titles and abstracts of studies that were relevant to the review. The titles and abstracts were screened independently by two authors, who discarded studies that were not applicable. However, studies and reviews that might include relevant data or information on studies were retained initially. Two authors independently assessed retrieved abstracts and, if necessary the full text, of these studies to determine which studies satisfied the inclusion criteria. Disagreements were resolved in consultation with a third author.

Data extraction and management

Data extraction was carried out by the same authors independently using standard data extraction forms. Studies reported in non‐English language journals were translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was used in the analyses. Disagreements were resolved in consultation with a third author.

Assessment of risk of bias in included studies

Studies to be included were assessed independently by two authors without blinding to authorship or journal. Discrepancies were resolved by discussion with a third author.

The following items were assessed using the risk of bias assessment tool (Higgins 2011) (seeAppendix 2).

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

Measures of treatment effect

For dichotomous outcomes (e.g. remission or no remission) results were expressed as risk ratios (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (e.g. protein excretion), the mean difference (MD) was to be used, or the standardised MD (SMD) if different scales were to be used.

Adverse events were reported in the text if they could not be included in meta‐analyses.

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

Any further information required from the original author was requested by written correspondence and any relevant information obtained in this manner was included in the review. 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). A guide to the interpretation of I² values was as follows:

0% to 40%: might not be important;
30% to 60%: may represent moderate heterogeneity;
50% to 90%: may represent substantial heterogeneity;
75% to 100%: considerable heterogeneity.

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

Assessment of reporting biases

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

Data synthesis

Data was pooled using the random effects model but the fixed effects model was analysed to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was planned to explore possible sources of heterogeneity (e.g. participants, treatments and study quality). Heterogeneity among participants could be related to age and renal pathology. Heterogeneity in treatments could be related to prior agent(s) used and the agent, dose and duration of therapy. However, there were insufficient studies of each intervention to allow subgroup analyses.

Sensitivity analysis

Sensitivity analysis was planned to determine the effect of removal of a single study on the results of a meta‐analysis when results of one study differed from other studies in the meta‐analysis. However, there were insufficient studies of each intervention to allow sensitivity analysis.

'Summary of findings' tables

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

Complete remission
Partial remission
Complete or partial remission
Chronic kidney disease
Adverse events.

Results

Description of studies

Results of the search

For the initial 2004 version of the review, of the 1744 titles and abstracts screened, 10 studies were identified; one study was excluded so nine studies (10 reports) were included in the review (Bagga 2004; Chongviriyaphan 1999; Elhence 1994; Garin 1988; ISKDC 1970; ISKDC 1974; ISKDC 1996; Lieberman 1996; Ponticelli 1993a). An update in 2006 identified four additional studies of which two were included (Kleinknecht 1980; Yi 2006) so the 2006 update included 11 studies (13 reports). A second update in 2010 identified three additional studies and the full publication of one study previously available as an abstract (Yi 2006). Therefore 14 studies (18 reports) were included in the 2010 update; 494 children entered the studies and 449 were evaluated.

A further search to 2 March 2016 identified 21 new studies, of which five were included (FSGS‐CT 2011; Gulati 2012; Magnasco 2012; Sinha 2017; Wu 2015). The 2016 update included 19 studies (42 reports) comprising 820 children of whom 773 were evaluated (Figure 1). Although we were not able to obtain separate paediatric data from the authors, we chose to include FSGS‐CT 2011 because it was one of the largest studies looking at interventions for SRNS, 93 (67%) of participants were below 18 years of age and subgroup analyses by study authors showed no differences in outcomes between paediatric and adult participants. We also identified three ongoing studies. The first study evaluated the safety and efficacy of sparsentan (a dual endothelin receptor) in a phase 2 study compared with irbesartan (DUET 2017). The second study is evaluating the 12 month relapse free survival in children with SRNS treated with rituximab or tacrolimus (NCT02382575). The third study is evaluating ofatumumab compared with placebo in children with steroid‐ and CNI‐resistant nephrotic syndrome (NCT02394106).

Flowchart of included and excluded studies

In 2019 we identified four new included studies (FONT I 2009; FONT II 2011; Shah 2017; Valverde 2010), In addition, results from the DUET 2017 study, which had been identified as an ongoing study in the 2016 update, were available. A review of previously excluded studies revealed an eligible study for inclusion (Bhaumik 2002). Four studies included both adult and paediatric participants and separate paediatric data were not available (Bhaumik 2002; DUET 2017; FONT I 2009; FONT II 2011). There were six additional reports of three already included studies (FSGS‐CT 2011; Gulati 2012; Sinha 2017), and one new report of an already excluded study. Two studies (NCT02382575; NCT02394106) listed as ongoing in the 2016 update are continuing. Of three additional ongoing studies, one is evaluating abatacept (Trachtman 2018), one is evaluating ACTH (NCT02972346), and one is evaluating sparsentan in a phase 3 study (DUPLEX 2018) in treatment resistant nephrotic syndrome. The 2019 update included 25 studies (69 reports) with five ongoing studies (Figure 1).

Included studies

The 25 included studies enrolled 1063 participants of which 1012 were evaluated. Study characteristics are shown in Characteristics of included studies.

Four studies compared cyclosporin with placebo, no treatment or methylprednisolone (84 enrolled/74 children and adults evaluated) (Bhaumik 2002; Garin 1988; Lieberman 1996; Ponticelli 1993a). Two studies (Garin 1988; Ponticelli 1993a) included children with MCD and FSGS, while two studies (Bhaumik 2002; Lieberman 1996) included only participants with FSGS. Three studies (Bhaumik 2002; Lieberman 1996; Ponticelli 1993a) included only participants with initial steroid resistance.
Two studies compared oral CNI with IV CPA. APN 2008 (32 children) compared oral cyclosporin with IV CPA in children with initial steroid resistance. Gulati 2012 (124/131 children evaluated) compared oral tacrolimus with IV CPA in children with initial and delayed steroid resistance. Both studies included children with MCD, FSGS and MesPGN.
Two studies (Choudhry 2009 (41 children); Valverde 2010 (17 children)) compared oral cyclosporin with oral tacrolimus. Choudhry 2009 included children with initial or delayed steroid resistance and children with MCD, FSGS and MesPGN. Valverde 2010 did not report whether patients had initial or delayed steroid resistance, and did not state histological types.
FSGS‐CT 2011 (138 participants) compared cyclosporin with MMF and oral dexamethasone in children (93) and adults (45) with biopsy confirmed primary FSGS and initial steroid resistance. Separate paediatric data could not be obtained from the authors.
Wu 2015 (18/22 children evaluated) compared MMF, IV CPA or leflunomide in three groups already receiving prednisone and tacrolimus. The study included children with MCD, FSGS, MesPGN and IgM nephropathy. The authors did not state whether the children had initial or delayed steroid resistance.
Sinha 2017 (60 children) compared tacrolimus with MMF to maintain remission in children with initial or delayed steroid resistance, who had achieved remission with tacrolimus. The study included children with MCD and FSGS.
Two studies (84/93 children evaluated) compared oral CPA and prednisone with prednisone alone in children with initial steroid resistance (ISKDC 1974; ISKDC 1996). ISKDC 1974 included children with MCD, FSGS and MesPGN. ISKDC 1996 only included children with FSGS.
Three studies compared IV with oral CPA in children with initial or delayed steroid resistance (Elhence 1994; Mantan 2008; Shah 2017). In Mantan 2008 (49/52 children evaluated), IV dexamethasone was given to children in the oral CPA group. Elhence 1994 (11/13 children evaluated) only included children with MCD while Mantan 2008 and Shah 2017 (50 children) included children with MCD, FSGS and MesPGN.
Magnasco 2012 (31 children) compared rituximab and standard care (prednisolone and cyclosporin) with standard care alone in children with MCD, FSGS and unknown histology and with initial or delayed steroid resistance.
Kleinknecht 1980 (30 children) compared chlorambucil with indomethacin. This study did not report whether patients had initial or delayed steroid resistance. The study included children with MCD, FSGS and MesPGN.
ISKDC 1970 (31 children) compared azathioprine (AZA) and prednisone with placebo and prednisone in children with MCD, FSGS or MesPGN, who had initial steroid resistance.
Two studies evaluated ACEi. Bagga 2004 (25 children) compared different doses of the ACEi, enalapril in children with MCD, FSGS or MesPGN in a cross‐over study. Yi 2006 (45/57 children evaluated) compared the ACEi, fosinopril, and prednisone with prednisone alone. Both studies included children with initial and delayed steroid resistance.
DUET 2017 (96/109 adults and children evaluated for efficacy; all evaluated for adverse effects) compared the dual angiotensin II and endothelin type A receptor antagonist, sparsentan with the ARB, irbesartan in patients with primary FSGS.
Chongviriyaphan 1999 (5 children) compared fish oil with placebo in children with FSGS or MesPGN in a cross over study; the authors did not state whether the children had initial or delayed resistance.
FONT I 2009 (19/21 adults and children evaluated) compared adalimumab with rosiglitazone in participants with FSGS and initial steroid resistance.
FONT II 2011 (19/21 adults and children evaluated) compared adalimumab, galactose and conservative therapy in participants with therapy resistant primary FSGS.

Excluded studies

23 studies (39 reports) were excluded.

Adeniyi 1979 was excluded because 31/36 included children had nephrotic syndrome considered secondary to Plasmodium malariae.
Nine studies did not include children (Arora 2002; Koshikawa 1993; Kumar 2004a; Li 2006g; Ren 2011; Ren 2013; Saito 2014; Shibasaki 2004; Walker 1990).
Four studies did not include children with nephrotic syndrome (Kano 2003) or included children with an ineligible renal pathology (Buyukcelik 2002; Hari 2018; Saito 2017).
Two studies evaluated interventions in children with SSNS (Hiraoka 2000; Iyengar 2006).
Five studies evaluated interventions in both children with steroid‐resistant and steroid‐dependent disease and the results could not be separated (Jung 1990; Khemani 2016; Tejani 1988; Yi 2008; Zhao 2013a).
In one study, only children with SSNS were randomised; children with SRNS were not randomised (Ahn 2018).
One study was excluded because it was a single arm study (JPRN‐C000000007).

Risk of bias in included studies

See Figure 2; Figure 3.

Methodological quality graph: review authors' judgements about each methodological quality 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 satisfactory in 14 studies (APN 2008; Bagga 2004; Choudhry 2009; DUET 2017; FSGS‐CT 2011; Gulati 2012; ISKDC 1970; Lieberman 1996; Magnasco 2012; Mantan 2008; Ponticelli 1993a; Shah 2017; Sinha 2017; Wu 2015) and unclear in the remaining studies.

Allocation concealment was adequate in 14 studies (APN 2008; Bagga 2004; Choudhry 2009; DUET 2017; FSGS‐CT 2011; Gulati 2012; ISKDC 1970; ISKDC 1996; Lieberman 1996; Magnasco 2012; Mantan 2008; Ponticelli 1993a; Shah 2017; Sinha 2017) and unclear in the remaining studies.

Blinding

Five studies reported that care givers (families, research staff) were blinded to treatment groups (Chongviriyaphan 1999; DUET 2017; ISKDC 1970; Lieberman 1996; Magnasco 2012). In the remaining 20 studies, care givers were not blinded to treatment groups.

Nineteen studies were considered at low risk of detection bias as the outcome was laboratory‐based and unlikely to be influenced by blinding (APN 2008; Bagga 2004; Choudhry 2009; Elhence 1994; FONT I 2009; FONT II 2011; FSGS‐CT 2011; Garin 1988; ISKDC 1970; ISKDC 1996; Lieberman 1996; Ponticelli 1993a; Sinha 2017; Wu 2015; Yi 2006) or the outcome assessors were blinded to treatment groups (Chongviriyaphan 1999; DUET 2017; Gulati 2012; Magnasco 2012). In two studies (ISKDC 1974; Mantan 2008), outcome of proteinuria was measured on dipstick or in a laboratory and it was unclear in how many children the outcome was laboratory‐based. In two studies (Bhaumik 2002; Kleinknecht 1980), no information was provided on how the outcome was assessed. In two studies (Shah 2017; Valverde 2010) there was no blinding and outcome assessment could be influenced by lack of blinding.

Incomplete outcome data

Attrition bias was considered to be present if more than 10% of participants were excluded from analysis. Fourteen studies were considered to have provided complete outcome data (Bagga 2004; Bhaumik 2002; Choudhry 2009; DUET 2017; FONT I 2009; FONT II 2011; FSGS‐CT 2011; Garin 1988; Gulati 2012; ISKDC 1974; Magnasco 2012; Mantan 2008; Shah 2017; Sinha 2017). Nine studies did not provide complete outcome data. In the remaining two studies, available only as abstracts (Kleinknecht 1980; Valverde 2010), it was unclear whether complete outcome data was provided.

Selective reporting

Reporting bias was considered to be present if studies did not report on the number of patients with remission (complete or partial) and on adverse effects and if results of the primary outcome were not reported in a way that allowed inclusion of the data in meta‐analyses. Thirteen studies were considered to be free of selective reporting (APN 2008; Choudhry 2009; DUET 2017; Elhence 1994; FONT II 2011; FSGS‐CT 2011; Garin 1988; Gulati 2012; ISKDC 1996; Lieberman 1996; Mantan 2008; Shah 2017; Yi 2006). Nine studies were considered to have reported outcomes selectively or results for the primary outcome could not be included in meta‐analyses (Bagga 2004; Chongviriyaphan 1999; DUET 2017; FONT I 2009; ISKDC 1970; ISKDC 1974; Magnasco 2012; Ponticelli 1993a; Wu 2015). In the remaining three studies (Bhaumik 2002; Kleinknecht 1980; Valverde 2010), available only as abstracts, it was unclear whether there was selective reporting of outcomes.

Other potential sources of bias

Thirteen studies reported funding by university or government agencies or stated that they did not receive monetary support and were considered free of other potential sources of bias (Chongviriyaphan 1999; Choudhry 2009; FONT I 2009; FONT II 2011; FSGS‐CT 2011; Gulati 2012; ISKDC 1974; ISKDC 1996; Magnasco 2012; Shah 2017; Sinha 2017; Yi 2006; Wu 2015). Four studies reported funding from pharmaceutical companies and were considered at risk of potential bias (APN 2008; DUET 2017; ISKDC 1970; Ponticelli 1993a). Other potential sources of bias were unclear in the remaining eight studies as none reported on support.

The definition of steroid resistance varied between studies.

Nine studies defined steroid resistance as persistent proteinuria of > 4 mg/m²/h or UP/C > 1g/g after four weeks (FONT I 2009; FSGS‐CT 2011; Lieberman 1996; Wu 2015), five weeks (Kleinknecht 1980), six weeks (APN 2008) or eight weeks of daily prednisone (Bagga 2004; ISKDC 1970; ISKDC 1974). One study (FONT II 2011) defined steroid resistance as persistent proteinuria of > 4 mg/m²/h or UP/C > 1g/g “following a standard course of prednisone/prednisolone/methylprednisolone prescribed for FSGS therapy”.
Nine studies defined steroid resistance as persistent proteinuria > 40 mg/m²/h, > 2 g/g or above 1 g/m²/d after four weeks (Choudhry 2009; Gulati 2012; Mantan 2008; Shah 2017; Sinha 2017), five weeks (Ponticelli 1993a), eight weeks (Garin 1988; ISKDC 1996) or six months (Magnasco 2012) of prednisone.
Two studies defined steroid resistance as no response after eight weeks of prednisone (Bhaumik 2002; Yi 2006) but did not define the degree of proteinuria.
Four studies did not define steroid resistance (Chongviriyaphan 1999; DUET 2017; Elhence 1994; Valverde 2010).

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9

Summary of findings for the main comparison. Cyclosporin versus placebo or no treatment for idiopathic steroid‐resistant nephrotic syndrome in children.

Cyclosporin versus placebo/no treatment for idiopathic steroid‐resistant nephrotic syndrome in children
Patient or population: idiopathic steroid‐resistant nephrotic syndrome in children  Setting: paediatric nephrology services  Intervention: cyclosporin  Comparison: placebo/no treatment
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with placebo/no treatment	Risk with cyclosporin	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Complete remission: all renal pathologies	57 per 1,000	200 per 1,000  (62 to 640)	RR 3.50  (1.09 to 11.20)	74 (4)	⊕⊕⊝⊝  LOW ^{1 2}
Complete remission: FSGS	69 per 1,000	217 per 1,000  (67 to 702)	RR 3.14  (0.97 to 10.18)	58 (3)	⊕⊕⊝⊝  LOW ^{1 2}
Complete or partial remission: all renal pathologies	229 per 1,000	720 per 1,000  (238 to 1,000)	RR 3.15  (1.04 to 9.57)	74 (4)	⊕⊕⊝⊝  LOW ^{1 2}
Complete or partial remission: FSGS	333 per 1,000	887 per 1,000  (283 to 1,000)	RR 2.66  (0.85 to 8.31)	49 (2)	⊕⊕⊝⊝  LOW ^{1 2}
Adverse events: worsening of hypertension	167 per 1,000	167 per 1,000  (28 to 997)	RR 1.00  (0.17 to 5.98)	24 (1)	⊕⊝⊝⊝  VERY LOW ^{1 2}
Adverse events: infection	429 per 1,000	300 per 1,000  (86 to 1,000)	RR 0.70  (0.20 to 2.51)	17 (1)	⊕⊝⊝⊝  VERY LOW ^{1 2}
Adverse events: ESKD	333 per 1,000	77 per 1,000  (10 to 597)	RR 0.23  (0.03 to 1.79)	25 (1)	⊕⊝⊝⊝  VERY LOW ^{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; FSGS: focal segmental glomerulosclerosis; ESKD: end‐stage kidney disease
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

Calcineurin inhibitor versus IV cyclophosphamide for idiopathic steroid‐resistant nephrotic syndrome in children
Patient or population: idiopathic steroid‐resistant nephrotic syndrome in children  Setting: paediatric nephrology services  Intervention: calcineurin inhibitor (CNI)  Comparison: IV cyclophosphamide (CPA)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with IV CPA	Risk with CNI	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Treatment response at 3 to 6 months: complete or partial remission	397 per 1,000	787 per 1,000  (497 to 1,000)	RR 1.98  (1.25 to 3.13)	156 (2)	⊕⊕⊝⊝  LOW ^{1 2}
Treatment response at 3 to 6 months: complete remission	128 per 1,000	440 per 1,000  (236 to 822)	RR 3.43  (1.84 to 6.41)	156 (2)	⊕⊕⊝⊝  LOW ^{1 2}
Treatment response at 3 to 6 months: partial remission	269 per 1,000	452 per 1,000  (116 to 1,000)	RR 1.68  (0.43 to 6.56)	156 (2)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
Adverse events: treatment failure at 6 months  (non response, serious infection, persistently elevated creatinine)	541 per 1,000	173 per 1,000  (97 to 314)	RR 0.32  (0.18 to 0.58)	124 (1)	⊕⊕⊕⊝  MODERATE ²
Adverse events: medications ceased due to adverse events	154 per 1,000	31 per 1,000  (6 to 132)	RR 0.20  (0.04 to 0.86)	131 (1)	⊕⊕⊕⊝  MODERATE ²
Adverse events: serious infections	123 per 1,000	60 per 1,000  (20 to 192)	RR 0.49  (0.16 to 1.56)	131 (1)	⊕⊕⊕⊝  MODERATE ²
Adverse events: death	15 per 1,000	5 per 1,000  (0 to 122)	RR 0.33  (0.01 to 7.92)	131 (1)	⊕⊕⊝⊝  LOW ⁴
*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

Tacrolimus versus cyclosporin for idiopathic steroid‐resistant nephrotic syndrome in children
Patient or population: idiopathic steroid‐resistant nephrotic syndrome in children  Setting: Paediatric nephrology services  Intervention: tacrolimus  Comparison: cyclosporin
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with cyclosporin	Risk with tacrolimus	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Treatment response at 6 months: complete remission	500 per 1,000	570 per 1,000  (320 to 1,000)	RR 1.14  (0.64 to 2.03)	41 (1)	⊕⊕⊝⊝  LOW ¹
Treatment response at 6 months: complete and partial remission	750 per 1,000	428 per 1,000  (120 to 1,000)	RR 0.57  (0.16 to 2.08)	41 (1)	⊕⊕⊝⊝  LOW ¹
Treatment response at 12 months: complete remission	500 per 1,000	400 per 1,000  (225 to 710)	RR 0.80  (0.45 to 1.42)	58 (2)	⊕⊕⊝⊝  LOW ²
Treatment response at 12 months: complete and partial remission	833 per 1,000	875 per 1,000  (725 to 1,000)	RR 1.05  (0.87 to 1.25)	58 (2)	⊕⊕⊝⊝  LOW ²
Adverse events: persistent nephrotoxicity	100 per 1,000	48 per 1,000  (5 to 485)	RR 0.48  (0.05 to 4.85)	41 (1)	⊕⊕⊝⊝  LOW ¹
Adverse events: worsening of hypertension	No events	No events	‐	58 (2)	⊕⊕⊝⊝  LOW ^{2 3}
*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

Cyclosporin versus mycophenolate mofetil with pulse dexamethasone for idiopathic steroid‐resistant nephrotic syndrome in children
Patient or population: idiopathic steroid‐resistant nephrotic syndrome in children  Setting: paediatric nephrology services  Intervention: cyclosporin  Comparison: mycophenolate mofetil with pulse dexamethasone (MMF + IV DEXA)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with MMF + IV DEXA	Risk with cyclosporin	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Treatment response at 52 weeks: complete remission (primary outcome 1, 2)	91 per 1,000	195 per 1,000  (79 to 476)	RR 2.14  (0.87 to 5.24)	138 (1)	⊕⊕⊕⊝  MODERATE ¹
Treatment response at 52 weeks: partial remission (primary outcome 3)	242 per 1,000	264 per 1,000  (148 to 468)	RR 1.09  (0.61 to 1.93)	138 (1)	⊕⊕⊕⊝  MODERATE ¹
Sustainable remission between 52 and 78 weeks: complete or partial remission (primary outcome 1, 2, 3)	333 per 1,000	460 per 1,000  (300 to 700)	RR 1.38  (0.90 to 2.10)	138 (1)	⊕⊕⊕⊝  MODERATE ¹
CKD or death: death by 52 weeks	30 per 1,000	5 per 1,000  (0 to 114)	RR 0.18  (0.01 to 3.75)	138 (1)	⊕⊕⊝⊝  LOW ^{1 2}
CKD or death: 50% decline in GFR by 78 weeks	30 per 1,000	69 per 1,000  (14 to 346)	RR 2.29  (0.46 to 11.41)	138 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Adverse events (weeks 0 to 26): serious infection requiring hospitalisation	106 per 1,000	69 per 1,000  (23 to 208)	RR 0.65  (0.22 to 1.96)	138 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Adverse events (weeks 0 to 26): hypertension	91 per 1,000	153 per 1,000  (60 to 390)	RR 1.68  (0.66 to 4.29)	138 (1)	⊕⊕⊝⊝  LOW ^{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

Tacrolimus versus mycophenolate mofetil to maintain remission for idiopathic steroid‐resistant nephrotic syndrome in children
Patient or population: idiopathic steroid‐resistant nephrotic syndrome in children  Setting: paediatric nephrology services  Intervention: tacrolimus to maintain remission  Comparison: mycophenolate mofetil (MMF) to maintain remission
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with MMF to maintain remission	Risk with tacrolimus	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Number with complete or partial response at one year	448 per 1,000	901 per 1,000  (592 to 1,000)	RR 2.01  (1.32 to 3.07)	60 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Number with complete response at one year	414 per 1,000	741 per 1,000  (459 to 1,000)	RR 1.79  (1.11 to 2.90)	60 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Number with partial response at one year	34 per 1,000	161 per 1,000  (20 to 1,000)	RR 4.68  (0.58 to 37.68)	60 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Number with treatment failure by one year	552 per 1,000	99 per 1,000  (33 to 298)	RR 0.18  (0.06 to 0.54)	60 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Number with frequent relapses by one year	345 per 1,000	97 per 1,000  (31 to 317)	RR 0.28  (0.09 to 0.92)	60 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Number with steroid resistance by one year	207 per 1,000	14 per 1,000  (0 to 254)	RR 0.07  (0.00 to 1.23)	60 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Change in GFR	Change in GFR was 13 mL/min higher with tacrolimus (3.71 lower to 29.71 higher) compared to MMF		‐	60 (1)	⊕⊕⊝⊝  LOW ^{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

Oral cyclophosphamide versus prednisone/placebo for idiopathic steroid‐resistant nephrotic syndrome in children
Patient or population: idiopathic steroid‐resistant nephrotic syndrome in children  Setting: paediatric nephrology services  Intervention: oral cyclophosphamide (CPA)  Comparison: prednisone/placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with prednisone/placebo	Risk with oral CPA	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Complete remission: all renal pathologies	353 per 1,000	374 per 1,000  (215 to 660)	RR 1.06  (0.61 to 1.87)	84 (2)	⊕⊕⊝⊝  LOW ^{1 2}
Complete remission: FSGS	250 per 1,000	253 per 1,000  (108 to 593)	RR 1.01  (0.43 to 2.37)	63 (2)	⊕⊕⊝⊝  LOW ^{1 2}
Complete or partial remission	571 per 1,000	503 per 1,000  (303 to 829)	RR 0.88  (0.53 to 1.45)	53 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Complete or partial remission: FSGS	571 per 1,000	503 per 1,000  (303 to 829)	RR 0.88  (0.53 to 1.45)	53 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Treatment failure	360 per 1,000	572 per 1,000  (313 to 1,000)	RR 1.59  (0.87 to 2.88)	60 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Adverse events: death (all causes)	80 per 1,000	86 per 1,000  (15 to 476)	RR 1.07  (0.19 to 5.95)	60 (1)	⊕⊕⊝⊝  LOW ^{1 2}
Adverse events: hypertension with seizures	40 per 1,000	28 per 1,000  (2 to 436)	RR 0.71  (0.05 to 10.89)	60 (1)	⊕⊝⊝⊝  VERY LOW ^{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; FSGS: focal segmental glomerulosclerosis
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

IV versus oral cyclophosphamide for idiopathic steroid‐resistant nephrotic syndrome in children
Patient or population: idiopathic steroid‐resistant nephrotic syndrome in children  Setting: paediatric nephrology services  Intervention: IV cyclophosphamide (CPA)  Comparison: oral CPA
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with oral CPA	Risk with IV CPA	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Complete remission	414 per 1,000	654 per 1,000  (269 to 1,000)	RR 1.58  (0.65 to 3.85)	61 (2)	⊕⊕⊝⊝  LOW ^{1 2}
Partial remission	80 per 1,000	80 per 1,000  (12 to 524)	RR 1.00  (0.15 to 6.55)	50 (1)	⊕⊕⊝⊝  LOW ³
Continuing remission at one year	160 per 1,000	120 per 1,000  (30 to 482)	RR 0.75  (0.19 to 3.01)	50 (1)	⊕⊕⊝⊝  LOW ^{2 3}
Adverse events: renal insufficiency	120 per 1,000	40 per 1,000  (5 to 359)	RR 0.33  (0.04 to 2.99)	50 (1)	⊕⊕⊝⊝  LOW ^{2 3}
Adverse events: bacterial infection	103 per 1,000	106 per 1,000  (10 to 1,000)	RR 1.02  (0.10 to 10.62)	61 (2)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
Adverse events: vomiting	34 per 1,000	82 per 1,000  (12 to 558)	RR 2.38  (0.35 to 16.17)	61 (2)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}
Adverse events: alopecia	80 per 1,000	120 per 1,000  (22 to 658)	RR 1.50  (0.27 to 8.22)	50 (1)	⊕⊕⊝⊝  LOW ^{2 3}
*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

IV cyclophosphamide versus oral cyclophosphamide plus IV dexamethasone for idiopathic steroid‐resistant nephrotic syndrome in children
Patient or population: idiopathic steroid‐resistant nephrotic syndrome in children  Setting: paediatric nephrology services  Intervention: IV cyclophosphamide (CPA)  Comparison: oral CPA plus IV dexamethasone (DEXA)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with oral CPA  plus IV DEXA	Risk with IV CPA	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Treatment response at 6 months: complete remission	478 per 1,000	540 per 1,000  (311 to 937)	RR 1.13  (0.65 to 1.96)	49 (1)	⊕⊕⊝⊝  LOW ¹
Treatment response at 6 months: partial remission	87 per 1,000	77 per 1,000  (12 to 503)	RR 0.88  (0.14 to 5.79)	49 (1)	⊕⊕⊝⊝  LOW ¹
Treatment response at 6 months: complete or partial remission	565 per 1,000	616 per 1,000  (384 to 983)	RR 1.09  (0.68 to 1.74)	49 (1)	⊕⊕⊝⊝  LOW ¹
Treatment response at 18 months: sustained remission/steroid‐sensitive relapses	478 per 1,000	540 per 1,000  (311 to 937)	RR 1.13  (0.65 to 1.96)	49 (1)	⊕⊕⊝⊝  LOW ¹
Treatment response at 18 months: CKD	43 per 1,000	38 per 1,000  (3 to 580)	RR 0.88  (0.06 to 13.35)	49 (1)	⊕⊕⊝⊝  LOW ¹
Adverse events: hypertension	435 per 1,000	17 per 1,000  (0 to 296)	RR 0.04  (0.00 to 0.68)	49 (1)	⊕⊕⊝⊝  LOW ¹
Adverse events: bacterial infections	348 per 1,000	230 per 1,000  (94 to 567)	RR 0.66  (0.27 to 1.63)	49 (1)	⊕⊕⊝⊝  LOW ¹
*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; CKD: chronic kidney disease
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

Rituximab/cyclosporin/prednisolone compared to cyclosporin/prednisolone for idiopathic steroid‐resistant nephrotic syndrome in children
Patient or population: idiopathic steroid‐resistant nephrotic syndrome in children  Setting: paediatric nephrology services  Intervention: rituximab/cyclosporin/prednisolone (RTX/CSA/PRED)  Comparison: CSA/PRED
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Outcomes	Risk with CSA/PRED	Risk with RTX/CSA/PRED	Relative effect  (95% CI)	No. of participants  (studies)	Certainty of the evidence  (GRADE)
Number with complete remission: complete remission in initial steroid resistance	0 per 1,000	0 per 1,000  (0 to 0)	not estimable	16 (1)	⊕⊝⊝⊝  VERY LOW ^{1 2}
Number with complete remission: complete remission in delayed steroid resistance	375 per 1,000	428 per 1,000  (124 to 1,000)	RR 1.14  (0.33 to 3.94)	15 (1)	⊕⊝⊝⊝  VERY LOW ^{1 2}
Number with complete remission: complete remission in all patients	200 per 1,000	188 per 1,000  (44 to 788)	RR 0.94  (0.22 to 3.94)	31 (1)	⊕⊝⊝⊝  VERY LOW ^{1 2}
Adverse events: bronchospasm/treatment discontinued	0 per 1,000	0 per 1,000  (0 to 0)	RR 2.82  (0.12 to 64.39)	31 (1)	⊕⊝⊝⊝  VERY LOW ^{1 2}
Adverse events: hypotension	0 per 1,000	0 per 1,000  (0 to 0)	RR 2.82  (0.12 to 64.39)	31 (1)	⊕⊝⊝⊝  VERY LOW ^{1 2}
Adverse events: skin rash	0 per 1,000	0 per 1,000  (0 to 0)	RR 6.59  (0.37 to 117.77)	31 (1)	⊕⊝⊝⊝  VERY LOW ^{1 2}
Adverse events: mild dyspnoea	0 per 1,000	0 per 1,000  (0 to 0)	RR 4.71  (0.24 to 90.69)	31 (1)	⊕⊝⊝⊝  VERY LOW ^{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

Date	Event	Description
9 October 2019	New citation required but conclusions have not changed	New studies and interventions added
9 October 2019	New search has been performed	New search, new interventions included; types of participants extended to include "Children with disease‐causing genetic mutations associated with FSGS in whom a biopsy is not performed"

Date	Event	Description
6 October 2016	New citation required and conclusions have changed	Five new studies included, new interventions included
6 October 2016	New search has been performed	New search, summary of findings tables incorporated
16 September 2014	New search has been performed	Search strategies updated
29 September 2010	New citation required and conclusions have changed	Four new studies, new comparisons, risk of bias assessment replaces quality assessment and summary of findings tables included.
9 October 2008	Amended	Converted to new review format.

Database	Search terms
CENTRAL	MeSH descriptor: [Nephrotic Syndrome] explode all trees MeSH descriptor: [Nephrosis, Lipoid] explode all trees nephrotic syndrome:ti,ab,kw (Word variations have been searched) lipoid nephrosis:ti,ab,kw (Word variations have been searched) minimal change glomerulonephritis:ti,ab,kw (Word variations have been searched) minimal change nephr*:ti,ab,kw (Word variations have been searched) idiopathic steroid resistant nephrotic syndrome:ti,ab,kw (Word variations have been searched) SRNS:ti,ab,kw (Word variations have been searched) {or #1‐#8}
MEDLINE	Nephrotic Syndrome/ Nephrosis Lipoid/ nephrotic syndrome.tw. lipoid nephrosis.tw. minimal change glomerulonephritis.tw. minimal change nephr$.tw. idiopathic steroid resistant nephrotic syndrome.tw. or/1‐7
EMBASE	Nephrotic Syndrome/ Lipoid Nephrosis/ nephrotic syndrome.tw. lipoid nephrosis.tw. minimal change glomerulonephritis.tw. minimal change nephropathy.tw. idiopathic steroid resistant nephrotic syndrome.tw. or/1‐7

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete remission	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 All renal pathologies	4	74	Risk Ratio (M‐H, Random, 95% CI)	3.50 [1.09, 11.20]
1.2 FSGS	3	58	Risk Ratio (M‐H, Random, 95% CI)	3.14 [0.97, 10.18]
2 Complete or partial remission	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 All renal pathologies	4	74	Risk Ratio (M‐H, Random, 95% CI)	3.15 [1.04, 9.57]
2.2 FSGS	2	49	Risk Ratio (M‐H, Random, 95% CI)	2.66 [0.85, 8.31]
3 Adverse events	3		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1 Worsening of hypertension	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Infection	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 ESKD	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment response at 3 to 6 months	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.1 Complete or partial remission	2	156	Risk Ratio (M‐H, Random, 95% CI)	1.98 [1.25, 3.13]
1.2 Partial remission	2	156	Risk Ratio (M‐H, Random, 95% CI)	1.68 [0.43, 6.56]
1.3 Complete remission	2	156	Risk Ratio (M‐H, Random, 95% CI)	3.43 [1.84, 6.41]
2 Mean time to remission	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
3 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1 Treatment failure (non response, serious infection, persistently elevated creatinine) at 6 months	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Any serious adverse effect	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 Medications ceased due to adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.4 Serious infections	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.5 Death	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.6 Persistent nephrotoxicity	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Treatment response at 6 months	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 Complete remission	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Partial remission	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Complete and partial remission	1		Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Treatment response at 12 months	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
2.1 Complete remission	2	58	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.45, 1.42]
2.2 Partial remission	2	58	Risk Ratio (M‐H, Random, 95% CI)	1.53 [0.92, 2.56]
2.3 Complete and partial remission	2	58	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.87, 1.25]
3 Relapse following complete or partial remission	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Change in eGFR over 12 months	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
5 Adverse events	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
5.1 Persistent nephrotoxicity	1	41	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.05, 4.85]
5.2 Reversible nephrotoxicity	1	41	Risk Ratio (M‐H, Random, 95% CI)	0.67 [0.32, 1.41]
5.3 Worsening of hypertension	2	58	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.08, 2.15]
5.4 Headache	1	41	Risk Ratio (M‐H, Random, 95% CI)	2.86 [0.12, 66.44]
5.5 Paraesthesia	1	41	Risk Ratio (M‐H, Random, 95% CI)	2.86 [0.12, 66.44]
5.6 Hypertrichosis	1	41	Risk Ratio (M‐H, Random, 95% CI)	0.02 [0.00, 0.38]
5.7 Gingival hyperplasia	1	41	Risk Ratio (M‐H, Random, 95% CI)	0.08 [0.01, 0.56]
5.8 Acne or skin infections	1	41	Risk Ratio (M‐H, Random, 95% CI)	0.38 [0.08, 1.74]
5.9 Diarrhoea	1	41	Risk Ratio (M‐H, Random, 95% CI)	5.71 [0.75, 43.36]
5.10 Sepsis/pneumonia	1	41	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.06, 14.22]

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	Statistical method	Effect size
1 Treatment response at 52 weeks	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 Complete remission (primary outcome 1,2)	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Partial remission (primary outcome 3)	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Complete or partial remission (primary outcome 1,2,3)	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Sustainable remission between 52 and 78 weeks	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.1 Complete remission (secondary outcome 1,2)	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Partial remission (secondary outcome 3)	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 No sustainable remission (secondary outcome 4,5)	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 CKD or death	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1 Death by 52 weeks	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 50% decline in GFR by 78 weeks	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3.3 ESKD by 78 weeks	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Adverse events (weeks 0 to 26)	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1 Serious infection requiring hospitalisation	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Total Infections	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.3 Total hospitalisations	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.4 Gastrointestinal adverse effects	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.5 Neuropsychiatric conditions	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.6 Hypertension	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 Number with complete or partial response at one year	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 Complete or partial response	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Complete response	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Partial response	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Number with treatment failure by one year	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.1 Treatment failure	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Frequent relapses	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Steroid resistance	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
3 Relapses per year	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
4 Prednisone dose	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
5 Change in GFR	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
6 Adverse events	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6.1 All serious adverse events	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.2 Serious infections	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
6.3 Hypovolaemia	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Complete remission	2	61	Risk Ratio (M‐H, Random, 95% CI)	1.58 [0.65, 3.85]
2 Partial remission	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Continuing remission at one year	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Time to remission	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
5 Mean duration of remission	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
6 Adverse events	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
6.1 Renal insufficiency	1	50	Risk Ratio (M‐H, Random, 95% CI)	0.33 [0.04, 2.99]
6.2 Bacterial infection	2	61	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.10, 10.62]
6.3 Vomiting	2	61	Risk Ratio (M‐H, Random, 95% CI)	2.38 [0.35, 16.17]
6.4 Alopecia	1	50	Risk Ratio (M‐H, Random, 95% CI)	1.5 [0.27, 8.22]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Number with complete remission	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 Complete remission in initial steroid resistance	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Complete remission in delayed steroid resistance	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 Complete remission in all patients	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 End of study creatinine	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1 Initially resistant patients	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Delayed resistant patients	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 End of study serum albumin	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
3.1 Initially resistant patients	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3.2 Delayed resistant patients	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
4 Adverse events	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1 Abdominal pain	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.2 Bronchospasm/treatment discontinued	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.3 Hypotension	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.4 Skin rash	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4.5 Mild dyspnoea	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 Short‐term response (remission)	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 MMF versus CPA	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 LEF versus MMF	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 LEF versus CPA	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Long‐term response (remission at 12 months)	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.1 MMF versus CPA	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 LEF versus MMF	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 LEF versus CPA	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 Number with reduction in proteinuria & stable GFR	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
1.1 Adalimumab versus conservative therapy	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 Galactose versus conservative therapy	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 Proteinuria	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
1.1 After 4 weeks of treatment	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 After 8 weeks of treatment	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.3 After 12 weeks of treatment	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2 Tubular proteinuria	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
2.1 Retinol binding protein (mg/L)	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Beta 2 microglobulin (mg/L)	1	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
3 Serum albumin	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
4 Systolic blood pressure	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
5 Creatinine clearance	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
6 Serum potassium	1	Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Partial remission (> 40% reduction in UP/C) at 8 weeks	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2 Adverse events	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.1 Any treatment related adverse effect	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.2 Serious adverse effect requiring study withdrawal	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.3 Hypotension	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.4 Peripheral oedema	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2.5 Hyperkalaemia	1	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]

Methods	Study design: parallel RCT Time frame: January 2001 to November 2004 Follow‐up period: 48 weeks for whole study
Participants	Setting: tertiary, multicentre study Countries: Germany, Austria; study by the Arbeitsgemeinschaft fur Pädiatrische Nephrologie SRNS: Initial non‐responder; absence of complete remission (proteinuria < 4 mg/m²/h) 14 days after ≥ 4 weeks of prednisone (60 mg/m²/d) and 3 methylprednisone pulses (500 mg/m²); FSGS (21), MCD (10) or MesPGN (1) on biopsy; normal C3; CrCl > 70 mL/min/1.73 m² Number: CSA group (15; MCD (6), FSGS (8), MesPGN (1)); CPA group (17; (MCD (4), FSGS (13), MesPGN (0)) Mean age ± SD (years): CSA group (6.99 ± 5.48); CPA group (6.84 ± 3.90) Sex (M/F): CSA group (11/4); CPA group (8/9) Exclusion criteria: hereditary, syndromic and secondary nephrotic syndrome; pre‐treatment with immunosuppressive therapy other than prednisone; prednisone regimen other than APN or ISKDC
Interventions	CSA group Oral CSA: 150 mg/m²/d in 2 divided doses aiming for trough levels of 120 to 180 ng/mL for 24 weeks and then CSA to achieve trough level of 80 to 120 ng/mL for 24 weeks CPA group IV CPA: starting at 500 mg/m² over 4 hours every 4 weeks for 7 doses; dose increased or decreased by 250 mg/m² according to WCC; maximum dose 1 g/m² Co‐interventions Tapering dose of alternate day prednisone to week 48
Outcomes	Complete remission (proteinuria < 4 mg/m²/h) within 24 weeks but non‐responder treatment offered from 12 weeks so results only interpretable to 12 weeks Partial remission (resolution of oedema, albumin > 35 g/L, proteinuria 4 to 40 mg/m²/h at 24 weeks) at 12 weeks Adverse events
Notes	Exclusions post randomisation but pre‐intervention: none Stop or end points/s: study to be discontinued if number of patients achieving complete/partial remission by 12 weeks was significantly greater with one treatment; patients failing to respond were offered non‐responder protocol after 12 weeks therapy Additional data requested from authors: none Other: more patients with FSGS in CPA group; 6 patients in CPA group had heterozygous mutations or sequence variations of NPHS2 gene Inclusion criteria allowed inclusion of patients with partial response to prednisone (proteinuria > 4mg/m²/h but < 40 mg/m²/h)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random lists, stratified by centre
Allocation concealment (selection bias)	Low risk	Central allocation by study coordinator
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding of participants or investigators; lack of blinding could influence management
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Laboratory measure of primary outcome unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	High risk	Complete follow‐up to 12 weeks, then non‐responders could be withdrawn to enter non‐responder protocol 5/15 CSA group withdrawn from 12 weeks onwards (4 treated with non‐responder protocol of high dose CSA) 14/17 CPA group withdrawn from 12 weeks onwards (7 treated with non‐responder protocol of pulse methylprednisolone)
Selective reporting (reporting bias)	Low risk	Complete or partial remission, adverse effects reported at 12 weeks
Other bias	High risk	Funded in part by a grant from Novartis Pharma

PERMALINK

Interventions for idiopathic steroid‐resistant nephrotic syndrome in children

Isaac D Liu

Narelle S Willis

Jonathan C Craig

Elisabeth M Hodson

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Inclusion criteria

Exclusion criteria

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

'Summary of findings' tables

Results

Description of studies

Results of the search

1.

Included studies

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. Cyclosporin versus placebo or no treatment for idiopathic steroid‐resistant nephrotic syndrome in children.

Summary of findings 2. Calcineurin inhibitor versus IV cyclophosphamide for idiopathic steroid‐resistant nephrotic syndrome in children.

Summary of findings 3. Tacrolimus versus cyclosporin for idiopathic steroid‐resistant nephrotic syndrome in children.

Summary of findings 4. Cyclosporin versus mycophenolate mofetil with pulse dexamethasone for idiopathic steroid‐resistant nephrotic syndrome in children.

Summary of findings 5. Tacrolimus versus mycophenolate mofetil to maintain remission for idiopathic steroid‐resistant nephrotic syndrome in children.

Summary of findings 6. Oral cyclophosphamide versus prednisone or placebo for idiopathic steroid‐resistant nephrotic syndrome in children.

Summary of findings 7. IV versus oral cyclophosphamide for idiopathic steroid‐resistant nephrotic syndrome in children.

Summary of findings 8. IV cyclophosphamide versus oral cyclophosphamide plus IV dexamethasone for idiopathic steroid‐resistant nephrotic syndrome in children.

Summary of findings 9. Rituximab/cyclosporin/prednisolone versus cyclosporin/prednisolone for idiopathic steroid‐resistant nephrotic syndrome in children.

Cyclosporin versus placebo/prednisone

Remission by six months

1.1. Analysis.

1.2. Analysis.

Adverse events

1.3. Analysis.

Calcineurin inhibitors versus intravenous cyclophosphamide

Remission by three to six months

Methods	Study design: cross‐over RCT Time frame: not reported Follow‐up period: 20 weeks; first part of cross‐over included so outcome at 8 weeks used
Participants	Setting: tertiary centre Country: India SRNS (no remission after 8 weeks of prednisone); patients with initial SRNS (15) or late SRNS (10) following response to prednisone Number (high dose/low dose): 14/11 Mean age, range (months): high dose (78, 60 to 104.7); low dose (96, 80.5 to 136.4) Sex (M/F): high dose (9/5); low dose (9/2) Histology High dose: MCD (3); FSGS (5); MCGN (3); MesPGN (3) Low dose: MCD (1); FSGS (4); MCGN (4) Exclusion criteria: severe hypertension (SBP or DBP > 99th percentile); GFR < 70 mL/min/1.73 m²; secondary nephrotic syndrome (SLE, HSP, Hepatitis B, amyloidosis); single functioning kidney; treatment with daily prednisone, IV steroids, alkylating agents, levamisole, CSA, IV albumin in previous 4 weeks; patients unable to attend 4 weekly visits; age < 1 year or > 16 years
Interventions	High dose enalapril 0.6 mg/kg/d for 8 weeks in 2 doses Low dose enalapril 0.2 mg/kg/d for 8 weeks in 2 doses Co‐interventions Alternate day prednisone Furosemide
Outcomes	Urine albumin/Cr ratio (median, 95% CI) after 8 weeks Urine albumin/Cr reduction (median, 95% CI) after 8 weeks Levels of Cr, albumin, cholesterol, potassium, BP Adverse events: cough
Notes	Exclusions post randomisation but pre‐intervention: 4 (high dose group (1), low dose group (3)) excluded after randomisation and before treatment Stop or end points/s: not reported Additional data requested from authors: Information on allocation concealment, study characteristics and results received from authors
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer generated random numbers
Allocation concealment (selection bias)	Low risk	Sealed opaque envelopes opened by investigator, who did not manage the patients (information from author)
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No blinding of participants or investigators; lack of blinding could influence management
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Laboratory assessment of outcome unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All patients randomised were included and completed the study (information from authors)
Selective reporting (reporting bias)	High risk	Outcomes reported (urinary albumin excretion, kidney function, adverse events) but no results could be included in meta‐analyses
Other bias	Unclear risk	Funding source not reported

Methods	Study design: parallel group RCT Time frame: January 1996 to March 2000 Follow up period: 6 months
Participants	Setting: Tertiary centre Country: India SRNS (biopsy proven primary FSGS); no response to 8 weeks of prednisolone (2 mg/kg/d) Number (group A/group B): 13/12 Age range: 3 to 49 years Sex (M/F): not reported but stated similar between groups Exclusion criteria: SSNS
Interventions	Group A Cyclosporin 1 to 4 mg/kg/day with oral prednisolone for at least 6 months Group B Methylprednisolone 250‐750 mg IV daily for 7 days and then weekly for at least 12 weeks Co‐interventions BP control Dietary protein 0.8 to 1.0 g/kg/d ACE inhibitors Lipid lowering agents
Outcomes	Complete remission Decline in proteinuria & stable creatinine Progression to ESKD Rate of decline in GFR Hospitalisation for therapy related complications
Notes	Abstract‐only publication 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	No blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	No information provided on how outcome was measured
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants accounted for
Selective reporting (reporting bias)	Unclear risk	Abstract‐only publication
Other bias	Unclear risk	Insufficient information to permit judgement

Methods	Study design: parallel RCT (Phase 2) Time frame: April 2014 to April 2016 Follow‐up period: 8 weeks of RCT
Participants	Setting: tertiary centres (USA, Belgium, Czech Republic, Italy). Country: 44 study centres in USA, Europe (European sites could enrol people aged 18 to 75 years) Biopsy proven primary FSGS (idiopathic or identified podocyte mutation), UPC ≤ 1.0 g/g, eGFR > 30 mL/min/1.73 m², BP < 145/96 mm Hg in adults; BP > 90/60 mm Hg and < 95th percentile for age, gender, and height in patients < 18 years, stable immunosuppressive regimens for > 1 month; completed RTX or CPA for > 3 months before study Number: 185 patients screened, 109 patients randomised; 96 evaluated for efficacy/109 evaluated for adverse effects; Sparsentan 62 evaluated for efficacy/73 randomised; irbesartan 32 evaluated for efficacy/36 randomised Age (range): 8 to 75 years Sparsentan group: 13/73 aged ≤ 18 years; Irbesartan group: 10/36 aged ≤ 18 years Sex (M/F): Sparsentan (41/32); irbesartan (19/17) Exclusion criteria: secondary FSGS; diabetes; significant cardiac/cerebrovascular disease; hepatitis; malignancy; transplantation; anaemia; hyperkalaemia; BMI > 40; pregnancy; lactation; other investigational drug in previous 28 days; previous sparsentan; unwilling to comply.
Interventions	Sparsentan groups (dual endothelin and angiotensin inhibitor) 200 mg, 400 mg or 800 mg daily for 8 weeks; data from these groups pooled; participants < 50 kg received half dose in each group Irbestartan group (angiotensin inhibitor) 150 mg daily for first week then 300 mg daily for next 7 weeks; participants < 50 kg received half dose in each group Co‐interventions Immunosuppressives except RTC/CPA: Sparsentan 21/73; irbesartan 13/36
Outcomes	Change in urinary protein/creatinine ratio (UPC) from baseline to 8 weeks (% with 95% CI) % with UPC ≤ 1.5 g/g with > 40% reduction at 8 weeks (FSGS partial remission end point) Changes to baseline albumin, 24‐hour urinary protein, GFR, BP, creatinine, lipid profiles Quality of Life (SF36 in adults; PEDsQL version 4.0 in < 18 years)
Notes	Double‐blind study for 8 weeks then all patients continued on/changed to sparsentan & followed to 144 weeks
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	QUOTE: "At week 0, a computer‐generated randomization sequence, via an interactive Web response system, used to randomise patients (3:1) to receive sparsentan or irbesartan within sequential dose‐escalating, 20‐patient cohorts." Error in computer programme led to 2:1 randomisation
Allocation concealment (selection bias)	Low risk	At week 0, a computer‐generated randomization sequence, via an interactive Web response system, used to randomize patients (3:1) to receive sparsentan or irbesartan
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	QUOTE: "Investigators, participants, caregivers, and the study sponsor were blinded to treatment allocations until database extraction and unblinding at the completion of the 8‐week, double‐blind treatment period". Both medications were encapsulated in grey gelatin capsules
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	QUOTE: "Investigators, participants, caregivers, and the study sponsor were blinded to treatment allocations until database extraction and unblinding at the completion of the 8‐week, double‐blind treatment period"
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Data reported on 96/109 (88%) for efficacy; adverse effects reported for all 109 patients
Selective reporting (reporting bias)	High risk	Primary outcome was reduction in UP/Cr reported as geometric mean +/‐ 95% CI and could not be included in meta‐analysis. A secondary outcome defined by the authors of "FSGS partial remission end point (FPRE) (UP/C:≤ 1.5 g/g and > 40% reduction in proteinuria" and not pre‐specified in the protocol was included in meta‐analyses
Other bias	High risk	Trial organised and supported by Retrophin Inc. (San Diego, CA)

Methods	Study design: parallel RCT (phase 1 study) Time frame: not reported Follow‐up period: 16 weeks
Participants	Setting: multicentre Country: USA Adults and children aged 2 to 41 years with biopsy‐confirmed primary FSGS and initial steroid resistance; steroid resistance (UP/C > 1.0 g/g after 4 weeks of steroid therapy), persistent proteinuria (UP/C > 1.0 g/g) and eGFR > 40 mL/min/1.73 m²; patients were admitted who failed treatment in the FSGS‐CT Study 2011 or were ineligible for FSGS‐CT Study because of previous use of study interventions; patients off all immunosuppressive agents for at least 4 weeks. Inclusion criteria assumed to be the same as FSGS‐CT study. Number (enrolled/completed): adalimumab group (10/9); rosiglitazone group (11/10) Mean age ± SD (years): adalimumab group (16.8 ± 9.0); rosiglitazone group (15.4 ± 6.2) Sex (M/F): adalimumab group (2/8); rosiglitazone group (8/3) Exclusion criteria (assumed to be the same as FSGS‐CT study): secondary FSGS; allergic to the study medications; obesity; ANC < 2000/mm³; HCT < 28%; uncontrolled hypertension; DM; active or serious infection; cirrhosis or chronic active liver disease; history of significant GI disorder; organ transplantation; history of malignancy; participation in another therapeutic trial within 30 days before randomisation; lactation, pregnancy, child‐bearing age and refused birth control
Interventions	Adalimumab group Adalimumab 24 mg/m² subcutaneously (maximum 40 mg/dose) on alternate weeks for 16 weeks for a maximum of 40 mg Rosiglitazone group Rosiglitazone 3 mg/m²/twice daily orally for 16 weeks Co‐interventions ACEi or ARB with unchanged dosage Diuretics Low dose prednisolone Lipid lowering agents
Outcomes	% reduction in proteinuria eGFR and creatinine serum albumin Blood glucose Adverse events
Notes	4/9 participants had reduction in proteinuria of 50% with adalimumab. I adverse effect probably related to adalimumab 2/10 participants had reduction in proteinuria of 40% with rosiglitazone. 3 adverse effects possibly related to rosiglitazone. Data not added to meta‐analysis as outcomes differed between groups. Information on methods/results requested from authors but none received.
*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	Open‐label study
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Primary outcomes were laboratory based and unlikely to be influenced by lack of blinding
Incomplete outcome data (attrition bias)   All outcomes	Low risk	9% did not complete study; 1/11 did not complete rosiglitazone arm; 1/10 did not complete adalimumab arm
Selective reporting (reporting bias)	High risk	Expected outcomes reported but data could not be incorporated into meta‐analyses
Other bias	Low risk	This work was supported by grants from the NIH–NIDDK (5R21‐DK070341), and the GCRC program of the Division of Research Resources, NIH RR00046 (UNC) and NIH RR018535 (North Shore Long Island Jewish Health System)

Study	Reason for exclusion
Adeniyi 1979	Wrong population: children had nephrotic syndrome secondary to Plasmodium malariae (31/36)
Ahn 2018	Wrong study design: children with SRNS were not randomised; only children with FRNS/SDNS were randomised
Arora 2002	Wrong population: adult patients
Buyukcelik 2002	Wrong population: study of gemfibrozil on lipid profiles in children with nephrotic syndrome; ineligible renal pathology as all except one had MPGN
Hari 2018	Mixed population of children with nephrotic syndrome including MPGN, Membranous GN, FSGS and MCD
Hiraoka 2000	Wrong population: SSNS patients
Iyengar 2006	Wrong population: SSNS patients
JPRN‐C000000007	Wrong study design: this study started on 1‐8‐2005 states it is a single arm study on the UMIN‐CTR Clinical Trial Registry. Number on Registry is UMIN‐CTR registry is C000000009
Jung 1990	Mixed population of steroid dependent and steroid resistant patients; unable to separate data
Kano 2003	Wrong population: included patients did not have nephrotic syndrome but moderate proteinuria with normal serum albumin levels
Khemani 2016	Mixed population: includes SDNS and SRNS patients and the data on these cannot be separated. No reply to email to chief investigator
Koshikawa 1993	Wrong population: adult patients
Kumar 2004a	Wrong population: adults patients
Li 2006g	Wrong population: adult patients
Ren 2011	Wrong population: adult patients
Ren 2013	Wrong population: adult patients
Saito 2014	Wrong population: adult patients
Saito 2017	Wrong population: patients with membranous GN
Shibasaki 2004	Wrong population: not clear if paediatric patients were included in study; includes patients with non MCD or FSGS pathology
Tejani 1988	Mixed population: includes SSNS and SRNS patients and the results cannot be separated
Walker 1990	Wrong population: adult patients
Yi 2008	Probably not an RCT: no mention of "random" and group numbers unequal (87 vs 55). Includes largely steroid dependent patients and not steroid resistant patients
Zhao 2013a	Mixed population: includes both steroid‐resistant and steroid‐dependent patients and results cannot be separated

Trial name or title	DUPLEX study
Methods	Open‐label RCT
Participants	Participants aged 8 to 75 years (US) or 18 to 75 years (outside US) with biopsy‐proven FSGS or MCD or FSGS with documented genetic mutation in podocyte protein Up/C ≥ 1.5 g/g at screening & eGFR > 30 mL/min/1.73 m²
Interventions	Sparsentan 400 mg/day titrating to 800 mg/day Irbesartan 150 mg/day titrating to 300 mg/day
Outcomes	Slope of eGFR from week 6 to week 108 Proportion of patients achieving a Up/C ≤ 1.5 g/g and a > 40% reduction from baseline in Up/C at Week 36
Starting date	April 3, 2018
Contact information	Radko Komers, MD, PhD; medinfo@retrophin.com
Notes	NCT03493685. Estimated completion date is December 2022. Other name: 021FSGS16010

Trial name or title	Efficacy and safety of rituximab to that of calcineurin inhibitors in children with steroid resistant nephrotic syndrome
Methods	Open‐label RCT
Participants	Children aged 3 to 16 years with SRNS (MCD, MesPGN or FSGS)
Interventions	Rituximab infusions weekly for 2 to 4 doses over up to 4 weeks compared with oral tacrolimus given until the child has achieved 6 months of relapse free survival
Outcomes	12‐month relapse‐free survival in the ITT population; adverse effects
Starting date	March 2015; estimated enrolment 120 children
Contact information	Dr. Biswanath Basu, Nilratan Sircar Medical College, India (basuv3000@gmail.com)
Notes	Estimated study completion date March 2017 Other study numbers: PednephroRCT/PM/NRSMCH‐33, CTRI/2015/01/005364

Trial name or title	Ofatumumab in children with steroid‐ and calcineurin‐inhibitor‐resistant nephrotic syndrome: a double‐blind randomised, controlled, superiority trial
Methods	RCT
Participants	Children aged 2 to 18 years with SRNS (MCD, MesPGN or FSGS) and resistance to CNI and MMF
Interventions	Single dose of IV Ofatumumab in normal saline versus placebo (normal saline alone); other immunosuppressive therapies will be withdrawn; all children with receive an ACEi
Outcomes	Complete or partial disease remission; adverse events
Starting date	March 2015; estimated enrolment 50 children
Contact information	Dr Gian Marco Ghiggeri, Istituto Giannina Gaslini, Italy (gmarcoghiggeri@ospedale‐gaslini.ge.it)
Notes	Estimated study completion date March 2018

Trial name or title	Availability study of ACTH to treat children SRNS/SDNS
Methods	Open‐label parallel group RCT
Participants	42 children aged 3 to 12 years with SDNS or SRNS & MCD
Interventions	Intervention: ACTH 0.4 U/kg/day (maximum 25 units) for three consecutive days every 4 weeks + routine treatment. Comparator: Routine treatment
Outcomes	24 hr urinary protein excretion. Remission/relapse
Starting date	November 2016. Estimated completion date June 2019
Contact information	Yufeng Li, Ph.D. mieuniversity@hotmail.com. Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
Notes	Availability and Safety Study of ACTH to Treat Children with SRNS/SDNS

Trial name or title	A phase II randomised, placebo‐controlled, double‐blind, parallel arms with switchover, pilot study to evaluate the efficacy and safety of intravenous abatacept in treatment resistant nephrotic syndrome (focal segmental glomerulosclerosis/ minimal change disease)
Methods	Randomised placebo controlled trial (quadruple blind)
Participants	90 patients aged ≥ 6 years with TRNS due to MCD or FSGS (Collapsing FSGS excluded), GFR ≥ 45 mL/min/1.73 m². Patients stratified for age (< 18 and ≥ 18) and APOL1 risk status. Exclusions: Patients with recurrence of disease post transplant, secondary TRNS, DM, CHF, BMI > 40, recent or chronic infections
Interventions	1. 16 week parallel arms comparing IV abatacept and placebo (normal saline) on days 1, 14, 28 and then every 28 days 2. 16 week cross‐over with placebo group receiving abatacept and abatacept group receiving placebo 3. 169 day abatacept extension with all receiving abatacept 4. Weight tiered dose of abatacept from 500 to 1000 mg. Children < 18 years weighing < 75 kg: 10 mg/kg/dose 4. Standard immunosuppression (CNI, MMF, prednisone) unchanged in 1 months, ACEi, ARB
Outcomes	1. Difference in % of participants who achieve a renal response by 113 days (end of first 16 week parallel group study). Renal response defined as a ≥ 50% reduction in Up/C from baseline to day 113 with Up/C < 3g/g and eGFR > 90 mL/min/1.73 m² (if below normal at baseline, remaining ≥ 75% of baseline. 2. Change in proteinuria, GFR, remission, quality of life (PROMIS), adverse events
Starting date	March 1, 2016. Estimated completion date June 2020
Contact information	Anna Greka: agreka@bwh.harvard.edu
Notes	27 study sites. NCT02592798. Sponsor: Bristol‐Myers Squibb