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Cochrane Database of Systematic Reviews Review - Intervention

Non‐corticosteroid immunosuppressive medications for steroid‐sensitive nephrotic syndrome in children

Authors' declarations of interest

Version published: 29 October 2013 Version history

https://doi.org/10.1002/14651858.CD002290.pub4

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Abstract

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Background

About 80% to 90% of children with steroid‐sensitive nephrotic syndrome (SSNS) have relapses. Of these children, around half relapse frequently, and are at risk of adverse effects from corticosteroids. Non‐corticosteroid immunosuppressive medications are used to prolong periods of remission in these children; however, these medications have significant potential adverse effects. Currently, there is no consensus about the most appropriate second line agent in children who are steroid sensitive, but who continue to relapse. This is the third update of a review first published in 2001 and updated in 2005 and 2008.

Objectives

To evaluate the benefits and harms of non‐corticosteroid immunosuppressive medications in relapsing SSNS in children.

Search methods

For this update we searched the Cochrane Renal Group's Specialised Register to June 2013.

Selection criteria

Randomised controlled trials (RCTs) or quasi‐RCTs were included if they compared non‐corticosteroid immunosuppressive medications with placebo, prednisone or no treatment, different non‐corticosteroid immunosuppressive medications and different doses, durations or routes of administration of the same non‐corticosteroid immunosuppressive medication.

Data collection and analysis

Two authors independently assessed the risk of bias of the included studies and extracted data. Statistical analyses were performed using a random‐effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).

Main results

We identified 32 studies (1443 children) of which one study is still ongoing. In the 31 studies with data, risk of bias assessment indicated that 11 (37%) and 16 (53%) studies were at low risk of bias for sequence generation and allocation concealment respectively. Six (29%) studies were at low risk of performance and detection bias. Twenty seven (87%) and 19 (60%) studies were at low risk of incomplete and selective reporting respectively. Alkylating agents (cyclophosphamide and chlorambucil) significantly reduced the risk of relapse at six to 12 months (RR 0.43, 95% CI 0.31 to 0.60) and 12 to 24 months (RR 0.20, 95% CI 0.09 to 0.46) compared with prednisone alone. There was no significant difference in relapse risk at two years between chlorambucil and cyclophosphamide (RR 1.31, 95% CI 0.80 to 2.13). There was no significant difference at one year between intravenous and oral cyclophosphamide (RR 0.99, 95% CI 0.76 to 1.29). Cyclosporin was as effective as cyclophosphamide (RR 1.07, 95% CI 0.48 to 2.35) and chlorambucil (RR 0.82, 95% CI 0.44 to 1.53) at the end of therapy while levamisole (RR 0.47, 95% CI 0.24 to 0.89) was more effective than steroids alone. However the effects of cyclosporin and levamisole were not sustained once treatment was stopped. In one small study cyclosporin significantly reduced the relapse rate compared with mycophenolate mofetil (MD 0.75, 95% CI 0.01 to 1.49). Limited data from a cross‐over study suggested that cyclosporin was more effective than mycophenolate mofetil in maintaining remission. In steroid‐ and cyclosporin‐dependent disease, rituximab significantly reduced the risk of relapse at three months compared with conventional therapy. Mizoribine and azathioprine were no more effective than placebo or prednisone alone in maintaining remission.

Authors' conclusions

Eight‐week courses of cyclophosphamide or chlorambucil and prolonged courses of cyclosporin and levamisole reduce the risk of relapse in children with relapsing SSNS compared with corticosteroids alone. Limited data indicate that mycophenolate mofetil and rituximab are valuable additional medications for relapsing SSNS. However clinically important differences in efficacy are possible and further comparative studies are still needed.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Plain language summary

available in

Non‐corticosteroid treatment for nephrotic syndrome in children

Children with nephrotic syndrome lose excessive amounts of protein from their bloodstream into their urine, causing swelling, especially in the face, stomach and legs. The risk of infection also increases because important proteins used by children's immune systems have been lost. Corticosteroid drugs, such as prednisone, can stop protein loss, but often happens again (relapse). Giving children further corticosteroids can lead to poor growth, cataracts, osteoporosis and high blood pressure.

To find out if there was evidence about non‐corticosteroid drugs for children with nephrotic syndrome, and to assess what the benefits and harms of these drugs were, we analysed 32 studies that enrolled 1443 children. The studies compared several drugs and found that cyclophosphamide, chlorambucil, cyclosporin, levamisole and rituximab reduced the risk of relapse in children with frequently relapsing steroid‐sensitive nephrotic syndrome.

We found that more studies are needed that compare different drug treatments to determine how these medicines should be used in children with nephrotic syndrome.

Authors' conclusions

Implications for practice

This systematic review of RCTs showed that oral or intravenous cyclophosphamide, oral chlorambucil and levamisole substantially reduce the incidence of relapse in children with relapsing SSNS. Cyclosporin appears to be as effective as alkylating agents during therapy. However, relapse commonly occurs when cyclosporin therapy is terminated, while remission is generally maintained following completion of a course of alkylating agents. There were insufficient data to determine the relative efficacies of cyclosporin and MMF. While tacrolimus is widely used, there were no studies comparing it with cyclosporin. Currently, there are inadequate data on efficacy and harms available from RCTs to determine which medication should be preferred initially. Thus, the decision as to which medication should be used in a child with frequently relapsing or steroid‐dependent SSNS will largely depend on patient and physician preference following discussion of the need for prolonged courses of cyclosporin or levamisole compared with eight to 12 week courses of the alkylating agents to maintain remission, the possible side effects, and the costs of courses of alkylating agents, and those of prolonged courses of cyclosporin or levamisole.

Implications for research

Further adequately powered RCTs are needed to identify clinically important differences in efficacy among the non‐corticosteroid immunosuppressive drugs in widespread use. Such RCTs would assist clinicians in determining which non‐corticosteroid medication should be preferred in the initial treatment of relapsing SSNS. Before‐after studies have demonstrated that cyclosporin and MMF are effective in relapsing nephrotic syndrome so comparisons of these medications with prednisone are unlikely to be performed. Suggested studies include:

  • MMF versus cyclosporin or tacrolimus

  • levamisole or MMF versus cyclophosphamide.

  • tacrolimus versus cyclosporin particularly in terms of adverse effects.

In these studies patients should be stratified according to whether they are frequent relapsers or steroid‐dependent to determine the relative efficacies of medications in the patients groups. Such a study would be:

  • rituximab with calcineurin inhibitors and prednisone versus those medications alone in steroid‐ and calcineurin‐dependent SSNS.

Summary of findings

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Summary of findings for the main comparison. Alkylating agents versus steroids or placebo or both for steroid‐sensitive nephrotic syndrome in children

Alkylating agents versus steroids or placebo or both for steroid‐sensitive nephrotic syndrome in children

Patient or population: children with steroid‐sensitive nephrotic syndrome
Intervention: alkylating agents versus steroids or placebo or both

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Alkylating agents versus prednisone/placebo

Relapse at 6‐12 months

Study population

RR 0.42
(0.28 to 0.62)

189 (6)

⊕⊕⊕⊝
moderate1

763 per 1000

320 per 1000
(214 to 473)

Moderate

844 per 1000

354 per 1000
(236 to 523)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Only two studies had adequate allocation concealment. None were blinded.

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Summary of findings 2. Intravenous versus oral cyclophosphamide for steroid‐sensitive nephrotic syndrome in children

Intravenous versus oral cyclophosphamide for steroid‐sensitive nephrotic syndrome in children

Patient or population: children with steroid‐sensitive nephrotic syndrome
Intervention: intravenous versus oral cyclophosphamide

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Intravenous versus oral cyclophosphamide

Relapse at 6 months

Study population

RR 0.54
(0.34 to 0.88)

83 (2)

⊕⊕⊝⊝
low¹,²

524 per 1000

283 per 1000
(178 to 461)

Moderate

524 per 1000

283 per 1000
(178 to 461)

Relapse at end of study

Study population

RR 0.99
(0.76 to 1.29)

83 (2)

⊕⊕⊝⊝
low¹,²

619 per 1000

613 per 1000
(470 to 799)

Moderate

619 per 1000

613 per 1000
(470 to 799)

Continuing frequently relapsing or steroid‐dependent SSNS at 6 months

See comment

See comment

Not estimable

47 (1)

⊕⊕⊝⊝
low²

Adverse events: leucopenia

Study population

RR 0.37
(0.09 to 1.51)

83 (2)

⊕⊕⊝⊝
low¹,²

143 per 1000

53 per 1000
(13 to 216)

Moderate

143 per 1000

53 per 1000
(13 to 216)

Adverse events: hair loss

Study population

RR 0.19
(0.04 to 1.03)

83 (2)

⊕⊕⊝⊝
low¹,²

381 per 1000

72 per 1000
(15 to 392)

Moderate

381 per 1000

72 per 1000
(15 to 392)

Adverse events: all infections

Study population

RR 0.14
(0.03 to 0.72)

83 (2)

⊕⊕⊝⊝
low¹,²

238 per 1000

33 per 1000
(7 to 171)

Moderate

238 per 1000

33 per 1000
(7 to 171)

Adverse events: nausea and vomiting

Study population

RR 4.07
(0.21 to 80.51)

47 (1)

⊕⊕⊝⊝
low²

0 per 1000

0 per 1000
(0 to 0)

Moderate

0 per 1000

0 per 1000
(0 to 0)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

¹ One of two studies showed unclear allocation concealment
² Small numbers of participants and events

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Summary of findings 3. Cyclosporin versus alkylating agent for steroid‐sensitive nephrotic syndrome in children

Cyclosporin versus alkylating agent for steroid‐sensitive nephrotic syndrome in children

Patient or population: children with steroid‐sensitive nephrotic syndrome
Settings: tertiary centres
Intervention: cyclosporin versus alkylating agent

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Cyclosporin versus alkylating agent

Number with relapse at end of therapy
Follow‐up: 6 to 9 months

Study population

RR 0.91
(0.55 to 1.48)

95 (2)

⊕⊕⊝⊝
low¹,²

400 per 1000

364 per 1000
(220 to 592)

Moderate

425 per 1000

387 per 1000
(234 to 629)

Number with relapse at 24 months
Follow‐up: mean 24 months

Study population

RR 0.51
(0.35 to 0.74)

95 (2)

⊕⊕⊝⊝
low¹,²

860 per 1000

439 per 1000
(301 to 636)

Moderate

875 per 1000

446 per 1000
(306 to 648)

Adverse effects: increase SCr

Study population

See comment

112 (2)

⊕⊕⊝⊝
low¹,²

Risks were calculated from pooled risk differences

89 per 1000

4 per 1000
(‐80 to 89)

Moderate

81 per 1000

4 per 1000
(‐73 to 81)

Adverse effects: hypertrichosis

Study population

See comment

112 (2)

⊕⊕⊝⊝
low¹,²

Risks were calculated from pooled risk differences

339 per 1000

3 per 1000
(‐122 to 129)

Moderate

353 per 1000

4 per 1000
(‐127 to 134)

Adverse effects: gum hypertrophy

Study population

See comment

112 (2)

⊕⊕⊝⊝
low¹,²

Risks were calculated from pooled risk differences

232 per 1000

0 per 1000
(‐118 to 111)

Moderate

236 per 1000

0 per 1000
(‐120 to 113)

Adverse effects: leucopenia

Study population

See comment

66 (1)

⊕⊝⊝⊝
very low¹,²

Risks were calculated from pooled risk differences

0 per 1000

‐2147483648 per 1000
(‐2147483648 to ‐2147483648)

Moderate

0 per 1000

‐2147483648 per 1000
(‐2147483648 to ‐2147483648)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) 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; SCr: serum creatinine

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

¹ One of two studies showed unclear allocation concealment
² Small numbers of patients and events with wide confidence intervals

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Summary of findings 4. Levamisole versus steroids or placebo or both, or no treatment for steroid‐sensitive nephrotic syndrome in children

Levamisole versus steroids or placebo or both, or no treatment for steroid‐sensitive nephrotic syndrome in children

Patient or population: children with steroid‐sensitive nephrotic syndrome
Intervention: levamisole versus steroids or placebo or both, or treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Levamisole versus placebo, low dose prednisone or no specific treatment

Relapse during treatment (4 to 12 months): includingWeiss 1993

Study population

RR 0.47
(0.24 to 0.89)

375 (7)

⊕⊕⊝⊝
low1,2

739 per 1000

347 per 1000
(177 to 657)

Moderate

765 per 1000

360 per 1000
(184 to 681)

Relapse during treatment (4 to 12 months): excludingWeiss 1993

Study population

RR 0.41
(0.27 to 0.61)

327 (6)

⊕⊕⊝⊝
low1,2

727 per 1000

298 per 1000
(196 to 443)

Moderate

740 per 1000

303 per 1000
(200 to 451)

Relapse at 6 to 12 months

Study population

RR 0.62
(0.42 to 0.91)

363 (7)

⊕⊕⊝⊝
low1,2

863 per 1000

535 per 1000
(362 to 785)

Moderate

889 per 1000

551 per 1000
(373 to 809)

Mean relapse rate/patient/month

The mean relapse rate/patient/month in the intervention groups was
0.03 lower
(0.27 lower to 0.2 higher)

90 (2)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Unclear allocation concealment and no blinding in most studies
2 Significant heterogeneity between studies

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. Nephrotic syndrome results in hypoproteinaemia and generalised oedema. In children, the incidence of nephrotic syndrome in Europe, North America and New Zealand is about 2/100,000 children younger than 15 to 18 years (Arneil 1961; el Bakkali 2011; McKinney 2001; Schlesinger 1968; Wong 2007). Most children have minimal change disease, in which changes on light microscopy are minor or absent. The cause of minimal change nephrotic syndrome is unknown.

The first‐line treatment for children presenting with idiopathic nephrotic syndrome is oral corticosteroids. Of children who present with their first episode of nephrotic syndrome, 80% to 90% will achieve remission with corticosteroid therapy, and have steroid‐sensitive nephrotic syndrome (SSNS) (Koskimies 1982). However, 80% of children experience a relapsing course with recurrent episodes of oedema and proteinuria (Koskimies 1982; Tarshish 1997), and of these children, half relapse frequently either a few weeks after ceasing corticosteroids (frequently relapsing SSNS) or while on reducing doses of corticosteroids (steroid‐dependent SSNS) (ISKDC 1982).

Description of the intervention

Non‐corticosteroid immunosuppressive medications have been sought that provide longer periods of remission and enable corticosteroids to be withdrawn or the dose reduced. The alkylating agents (cyclophosphamide and chlorambucil) were shown in controlled studies to produce prolonged remissions in children with SSNS who relapsed frequently (Barratt 1970; Grupe 1976). The potential of these alkylating agents for carcinogenesis and infertility (Fairley 1972; Queshi 1972; Rapola 1973) has limited their use to one or two courses and led to investigation of other immunosuppressive agents. Calcineurin inhibitors (cyclosporin and tacrolimus), levamisole, mycophenolate mofetil (MMF), azathioprine, mizoribine, vincristine and rituximab have also been used to treat relapsing SSNS (Abeyagunawardena 2007; Abramowicz 1970; BAPN 1991; Hogg 2003; Niaudet 1992; Sinha 2006; Wang 2012; Yoshioka 2000). However these newer medications, while potentially less toxic, have been less effective in maintaining prolonged remissions once the medication has been ceased (BAPN 1991; Niaudet 1992). Recent guidelines recommend alkylating agents, levamisole, calcineurin inhibitors and MMF in these children but there is no consensus as to the most appropriate first line non‐corticosteroid immunosuppressive medication for frequently relapsing and steroid‐dependent SSNS (French NS Guideline 2008; Gipson 2009; IPNS‐IAP 2008; KDIGO 2012; Lombel 2013).

How the intervention might work

Although the immunological mechanisms involved in SSNS are not well understood, evidence is accumulating for the involvement of T and B cells in these immune mechanisms. In keeping with this is the response of childhood nephrotic syndrome to corticosteroids. While corticosteroids lead to remission in most children with idiopathic nephrotic syndrome, most children relapse one or more times and many experience significant adverse effects, which include growth retardation, obesity, diabetes mellitus, osteoporosis, hypertension and ocular changes. Several non‐corticosteroid immunosuppressive medications with different mechanisms of action have been used to treat children with frequently relapsing SSNS; several have been demonstrated to provide more prolonged periods of remission compared with corticosteroids alone. However, these medications have different adverse effects, so their use has to be carefully balanced against the frequency and severity of adverse effects with corticosteroids. It is therefore important to review in detail the studies of non‐corticosteroid immunosuppressive drugs in SSNS to determine the benefits and harms of these medications.

Why it is important to do this review

This is an update of a Cochrane review first published in 2001, and last updated 2008. The review has demonstrated that the non‐corticosteroid immunosuppressive medications (cyclophosphamide, chlorambucil and levamisole) reduce the risk of relapse in children with relapsing SSNS compared with corticosteroids alone. In addition, it has also been demonstrated that cyclosporin does not differ significantly in efficacy during administration compared with alkylating agents. Since the last update in 2008, several new medications (MMF, tacrolimus and rituximab) have become widely used in children with relapsing SSNS. In case series, MMF has been demonstrated to reduce the risk of relapse during therapy (Bagga 2003; Fujinaga 2007; Hogg 2003; Hogg 2004; Mendizabal 2004; Novak 2005). Tacrolimus is widely used in North America in preference to cyclosporin because of the side effect profile; case series suggest that tacrolimus is as effective as cyclosporin (Dotsch 2006; Sinha 2006; Wang 2012) but with some different adverse effects. A single small study (Ravani 2011) and several observational studies (Guigonis 2008; Kemper 2007; Prytula 2010) suggest that rituximab is a valuable additional medication in children with steroid‐ and calcineurin‐dependent nephrotic syndrome. Therefore, it was important to update this review to include any randomised controlled trials (RCTs) comparing these newer medications to prednisone or another non‐corticosteroid immunosuppressive drug for relapsing SSNS.

Objectives

To evaluate the benefits and harms of different immunosuppressive medications, other than corticosteroids, that are used in children who pursue a relapsing course of SSNS.

Methods

Criteria for considering studies for this review

Types of studies

RCTs or quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) were included if they were carried out in children (aged from three months to 18 years) with relapsing SSNS, if they compared non‐corticosteroid immunosuppressive drugs with placebo, steroids or no treatment, different doses or durations of the same or different non‐corticosteroid immunosuppressive medications.

Types of participants

Inclusion criteria

Children aged from three months to 18 years with relapsing SSNS (i.e. the child became oedema‐free and their urine protein was 1+ on dipstick, or < 4 mg/m²/h, or urine protein/creatinine ratio was < 0.02 g/mmol) for three consecutive days while receiving corticosteroid therapy). Relapse of nephrotic syndrome was defined as the recurrence of proteinuria measured semi‐quantitatively on urine analysis or quantitatively using albumin or protein/creatinine ratios or timed urine specimens. A kidney biopsy diagnosis of minimal change disease was not required for study inclusion.

Exclusion criteria

Children with their first episode of SSNS, children with steroid‐resistant nephrotic syndrome, children with congenital nephrotic syndrome, and children with other renal 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).

Types of interventions

We included:

  • Non‐corticosteroid immunosuppressive medications versus inactive placebo or no immunosuppressive treatment.

  • Non‐corticosteroid immunosuppressive medications (with or without concomitant use of steroids (prednisone or prednisolone)) versus steroids used alone.

  • Two different non‐corticosteroid immunosuppressive medications (with or without concomitant use of steroids).

  • Different doses and durations of the same non‐corticosteroid immunosuppressive medication (with or without concomitant use of steroids).

Types of outcome measures

Primary outcomes

  • Numbers of children with and without relapse at six or more months

Secondary outcomes

  • Mean relapse rates/patient/year

  • Mean length of time to next relapse

  • Serious adverse effects of therapy

Search methods for identification of studies

Electronic searches

Initial search

The following electronic databases were searched:

  • Cochrane Renal Group's Specialised Register.

  • Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library).

  • MEDLINE (Ovid) (from 1966) using the optimally sensitive strategy developed for the Cochrane Collaboration for the identification of RCTs (Dickersin 1994) with a specific search strategy for nephrotic syndrome in children.

  • EMBASE (Ovid) (from 1980) using a search strategy adapted from that developed for the Cochrane Collaboration for the identification of RCTs (Lefebvre 1996) together with a specific search strategy for nephrotic syndrome in children.

  • To reduce publication bias, searches were made of reference lists of nephrology textbooks, review articles and relevant studies and of nephrology scientific meetings. In addition letters seeking information about unpublished or incomplete studies were sent to investigators known to be involved in previous studies. It was planned to attempt to exclude publication bias using a funnel plot and to include the publication with the most complete data set, where duplicate publications were identified.

  • The authors contacted authors of recent review articles and RCTs for information about any possible unpublished data. No additional studies were identified in this manner.

Current update search (2013)

We searched the Cochrane Renal Group's Specialised Register to 12 June 2013 through contact with the Trials' Search Co‐ordinator using search terms relevant to this review.

The Cochrane Renal Group’s Specialised Register contains studies identified from:

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

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of renal‐related journals and the proceedings of major renal conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected renal journals

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

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

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

Searching other resources

We also searched:

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

  2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

The review was initially undertaken by five authors. For the initial review and the updates the search methods described were used to obtain titles and abstracts of studies that could be relevant to the review. The titles and abstracts were screened independently by four authors, who discarded studies that were irrelevant (e.g. studies of lipid lowering agents) although studies and reviews that might include relevant data or information on studies were retained initially. Authors independently assessed abstracts, and if necessary the full text, of these studies to determine which studies satisfied the inclusion criteria. Studies reported in non‐English language journals were translated before assessment. 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. If necessary, disagreements could be resolved in consultation.

Data extraction and management

Data extraction and risk of bias assessment was carried out independently using standard data extraction forms by the same authors, who screened the studies for eligibility. Disagreements were resolved in consultation among authors.

Assessment of risk of bias in included studies

The quality of studies to be included in the initial review and in the updates to 2008 was assessed independently by AD and EH or EH and NW without blinding to authorship or journal of publication for allocation concealment, blinding, intention‐to‐treat analysis and completeness of follow‐up (Crowther 2010). Discrepancies were resolved in discussion with JC (Durkan 2001a; Durkan 2005; Hodson 2008).

For the 2013 update, the following items were independently assessed by two authors (NP, EH) using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?

    • Participants and personnel

    • Outcome assessors

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

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

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

Measures of treatment effect

For dichotomous outcomes (relapse or no relapse) results were expressed as risk ratio (RR) with 95% confidence intervals (95% CI). Where continuous scales of measurement were used to assess the effects of treatment (time to relapse), the mean difference (MD) was used, or the standardised mean difference (SMD) if different scales had been used.

Unit of analysis issues

Results of cross‐over studies were reported in the text of the results. It was planned to include data in meta‐analyses if outcomes were reported separately for the first part of the study and included information from all or most of the participants, who completed the first part of the study.

Dealing with missing data

Where necessary we contacted study authors for additional information about their studies. Eight study authors provided additional information. We analysed available data and have referred to areas of missing data in the text.

Assessment of heterogeneity

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

Assessment of reporting biases

The search strategy included major databases, conference proceedings and prospective trial registries in an attempt to reduce reporting bias. There were insufficient studies to assess publication bias for each group of interventions. Where more than one publication of the same study was identified, all reports were reviewed to make sure that all available outcomes were included.

Although we planned to construct funnel plots to assess for the potential existence of small study bias, there were insufficient data reported to enable analysis (Higgins 2011).

Data synthesis

Data were pooled using the random‐effects model for dichotomous and continuous outcomes.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis according to three possible sources of heterogeneity, participants, treatments and risk of bias was planned but not performed because there were insufficient studies for any comparison. The summary measure data were translated into absolute risk reductions (ARR) for a range of baseline risks for alkylating agents and cyclosporin. Adverse effects were tabulated and assessed with descriptive techniques for alkylating agents and cyclosporin. Adverse effects for other medications were listed in the text and where possible included in the meta‐analyses.

Sensitivity analysis

Sensitivity analysis was undertaken to assess the contribution of individual studies to heterogeneity and to assess any changes in results following exclusion of that study.

Results

Description of studies

Results of the search

In the search for the initial review (Durkan 2001a), of the 832 titles and abstracts screened, 24 studies were identified by full text review to be RCTs or quasi‐RCTs. One study assessing levamisole (Kirubakaran 1984) was excluded because the primary outcome could not be determined. One study in Japanese language could not be translated for assessment (Tohjoh 1994). Two studies involved ineligible interventions (Rowe 1990; Trompeter 1978) and two studies involved ineligible populations (Tejani 1989; Urdaneta 1983). Therefore 17 studies (21 reports) were included in the initial review (Durkan 2001a) (Figure 1).

Figure 1
Study flow diagram

Study flow diagram

A search of databases in August 2003 found no new studies. In 2004 seven RCTs involving children with relapsing SSNS treated with non‐corticosteroid immunosuppressive medications were identified; five were identified from handsearching of conference proceedings and were in abstract form only. Four studies were excluded; two assessed herbs used in traditional Chinese medicine (Fong 1997; Zou 1997), one assessing lefluonomide (Ni 2003) and one comparing cyclophosphamide and cyclosporin (Naigui 1997) were excluded because the intervention was ineligible for this review or both children and adults were included and the paediatric data could not be separated. Therefore 20 studies (25 reports) were included in the 2005 updated review (Durkan 2005). The three newly included studies were Prasad 2004, Weiss 1993 and Yoshioka 2000.

A further search in January 2007 identified 18 studies; of these five were RCTs not previously included, one study was an abstract of a previously included study (Abramowicz 1970), one was an abstract describing an ongoing study (Gruppen 2006) and 11 were excluded (not randomised (8); reviews (2); mixed population of primary and secondary nephrotic syndrome (1)). In September 2007 an additional study was identified in abstract form. The 2008 update of this review (Hodson 2008) therefore contained 26 studies (34 reports), including six new studies (Abeyagunawardena 2006a; Abeyagunawardena 2006b; Al‐Saran 2006; Cerkauskiene 2005; Donia 2005; Dorresteijn 2007) and an ongoing study (Gruppen 2006) for a total of 27 studies (35 reports) (Hodson 2008).

In June 2013 we identified 36 new reports. There were five additional studies identified (seven reports) (Abeyagunawardena 2007; Gellermann 2011; Ishikura 2007; Ravani 2011; Sural 2001), seven new reports of six already included studies (APN 1982; Barratt 1970; Donia 2005; Dorresteijn 2007; Ponticelli 1993; Yoshioka 2000) and two additional reports of an ongoing study (Gruppen 2006). We excluded 19 studies (20 reports); 11 studies (12 reports) involved ineligible interventions, five studies (five reports) involved adult patients, one study (one report) included children with steroid‐resistant nephrotic syndrome and two studies (two reports) were not RCTs. Therefore, the 2013 update of this review included 32 studies (44 reports) with a total of 1443 participants.

Included studies

The characteristics of the 32 completed studies are shown in Characteristics of included studies. An additional study comparing levamisole with placebo is ongoing (Gruppen 2006). A total of 1443 children were included in 14 groups of comparisons (Figure 1). One study (Sural 2001) included three groups (group 1: levamisole; group 2: cyclophosphamide; group 3: prednisone). Two were cross‐over studies (Cerkauskiene 2005; Gellermann 2011).

1. Alkylating agents (cyclophosphamide, chlorambucil)

2. Calcineurin inhibitors (cyclosporin, tacrolimus)

3. Levamisole

4. Rituximab

  • Rituximab plus with cyclosporin and prednisone compared with cyclosporin and prednisolone: one study (54 children) (Ravani 2011)

5. Other interventions

Either prednisolone or prednisone was used in all studies either in combination with the study medication or to treat relapses. No RCTs comparing mizoribine or azathioprine with other non‐corticosteroid medications, MMF with steroids with or without placebo or comparing tacrolimus with steroids with or without placebo or any other corticosteroid‐sparing medication were found.

Excluded studies

We excluded 47 studies (50 reports) (Characteristics of excluded studies): 17 studies were not randomised; 16 investigated ineligible interventions; 13 involved ineligible populations. Ineligible populations were adult patients alone, a mixture of children and adult patients, patients with secondary nephrotic syndrome, patients with steroid‐resistant nephrotic syndrome, a mixture of participants with SSNS and steroid‐resistant nephrotic syndrome or patients with their first episode of nephrotic syndrome. Among the excluded studies that included children and adults with SSNS and steroid‐resistant nephrotic syndrome, results could not be separated to analyse data pertaining only to children. The final study (Kirubakaran 1984) was available only in abstract form; the primary patient and outcome data could not be extracted, and the author was unable to provide additional data.

Risk of bias in included studies

Study quality was variable (Figure 2; Figure 3). With the exception of Yoshioka 2000 that investigated mizoribine (197 children) and reported a power analysis, all included studies were small. Relapse was not defined in 10 studies (Abeyagunawardena 2006a; Abeyagunawardena 2006b; Alatas 1978; Al‐Saran 2006; Baluarte 1978; Cerkauskiene 2005; Dorresteijn 2007; Niaudet 1992; Rashid 1996; Sural 2001); a variety of definitions were applied in the other included studies.

Figure 2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

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

Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study

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

Allocation

We assessed that risk of bias for sequence generation was low in 11 studies (Abeyagunawardena 2006a; Abeyagunawardena 2006b; Abeyagunawardena 2007; Abramowicz 1970; Chiu 1973; Dayal 1994; Donia 2005; Dorresteijn 2007; Prasad 2004; Ravani 2011; Yoshioka 2000); McCrory 1973 was at high risk of bias; and the risk of bias was unclear in the remaining 19 studies.

There was low risk of bias for allocation concealment in 16 studies (Abeyagunawardena 2006a; Abeyagunawardena 2006b; Abeyagunawardena 2007; Abramowicz 1970; APN 1982; BAPN 1991; Barratt 1970; Barratt 1973; Barratt 1977; Chiu 1973; Dorresteijn 2007; ISKDC 1974; Ponticelli 1993; Ravani 2011; Weiss 1993; Yoshioka 2000); McCrory 1973 was at high risk of bias; and the risk of bias was unclear in the remaining 14 studies.

Blinding

Blinding and detection bias was low in six studies (Abramowicz 1970; Alatas 1978; BAPN 1991; Ravani 2011; Weiss 1993; Yoshioka 2000). All other studies were open‐label and assessed at high risk of bias. Lack of blinding may have influenced management and outcome assessment.

Incomplete outcome data

More than 20% of participants did not complete follow‐up in three studies which were assessed as being at high risk of attrition bias (Alatas 1978; Dorresteijn 2007; Ponticelli 1993). Completeness of follow‐up was unclear in two studies (Gellermann 2011; Rashid 1996). All other studies were considered to be at low risk of attrition bias.

Selective reporting

Selective reporting was considered to be present if studies did not report a measure of relapse that could be meta‐analysed, or did not report adverse effects of study drugs. Overall, nine studies were assessed at high risk of reporting bias. Specific issues identified were failure to document adverse effects (Alatas 1978; Barratt 1970; Barratt 1973; Barratt 1977; Weiss 1993); only combined data for both groups were available in the two cross‐over studies (Cerkauskiene 2005; Gellermann 2011); or data were available as hazard ratios (Ishikura 2007; Yoshioka 2000). Risk of reporting bias was unclear in three studies that were available only as abstracts (Abeyagunawardena 2006a; Abeyagunawardena 2006b; Abeyagunawardena 2007). The 19 remaining studies were considered to be at low risk of reporting bias.

Other potential sources of bias

Three studies (BAPN 1991; Dorresteijn 2007; Weiss 1993) received funding from pharmaceutical companies and were considered to be at high risk of bias. There were 11 studies that reported funding from governments, universities or not‐for‐profit groups and were classified at low risk of bias. The remaining 17 studies did not report if they received external funding.

Effects of interventions

See: Summary of findings for the main comparison Alkylating agents versus steroids or placebo or both for steroid‐sensitive nephrotic syndrome in children; Summary of findings 2 Intravenous versus oral cyclophosphamide for steroid‐sensitive nephrotic syndrome in children; Summary of findings 3 Cyclosporin versus alkylating agent for steroid‐sensitive nephrotic syndrome in children; Summary of findings 4 Levamisole versus steroids or placebo or both, or no treatment for steroid‐sensitive nephrotic syndrome in children

Alkylating agents

Alkylating agents versus steroids or placebo or both

Cyclophosphamide resulted in a decreased incidence of relapse at six to 12 months compared with prednisolone alone (Analysis 1.1.1 (4 studies, 157 children): RR 0.47, 95% CI 0.33 to 0.66; I² = 0%). In 27 children followed beyond 12 months the RR of relapse at 13 to 24 months was 0.21 (Analysis 1.2.1 (2 studies, 27 children): 95% CI 0.07 to 0.65; I² = 0%).

Chlorambucil reduced the risk of relapse at six months (Analysis 1.1.2 (2 studies, 41 children): RR 0.19, 95% CI 0.03 to 1.09; I² = 44%) and 12 months (Analysis 1.2.2 (2 studies, 32 children): RR 0.15, 95% CI 0.02 to 0.95; I² = 39%) compared with placebo or prednisone alone.

When the studies evaluating cyclophosphamide or chlorambucil were combined, alkylating agents significantly reduced the risk of relapse at six to 12 months (Analysis 1.1 (6 studies, 189 children): RR 0.43, 95% CI 0.31 to 0.60; I² = 3%) and 12 to 24 months (Analysis 1.2 (4 studies, 59 children): RR 0.20, 95% CI 0.09 to 0.46; I² = 0%) compared with placebo or prednisone or both.

Alkylating agents: different durations, doses, route, agent

Cyclophosphamide given for eight weeks resulted in fewer children relapsing within 12 months (Analysis 2.2.1 (1 study, 22 children): RR 0.25, 95% CI 0.07 to 0.92) compared with a two‐week course.

There was no evidence that prolonging the course of cyclophosphamide from eight weeks to 12 weeks further reduced numbers of children experiencing a relapse at 12 months (Analysis 2.2.2 (1 study, 72 children): RR 1.01, 95% CI 0.73 to 1.39) or 24 months (Analysis 2.3 (1 study, 72 children): RR 0.98, 95% CI 0.74 to 1.28).

The same total dose of cyclophosphamide given over six weeks rather than 12 weeks did not reduce numbers of children who relapsed by 12 months (Analysis 3.1 (1 study, 14 children): RR 2.33, 95% CI 0.11 to 48.99). However, there was an increase in adverse effects but this did not reach significance (Analysis 3.2).

There was no significant decrease in relapse rates when using an increasing dose regimen of chlorambucil compared with a stable dose regimen (Analysis 4.1 (1 study, 21 children): RR 0.18, 95% CI 0.01 to 3.41), however Baluarte 1978 reported a 34% increase in the incidence of leucopenia and an 18% increase in thrombocytopenia with the increasing dose regimen.

Intravenous cyclophosphamide given monthly for six months reduced the risk of relapse (Analysis 5.1 (2 studies, 83 children): RR 0.54, 95% CI 0.34 to 0.8; I² = 0%) and the number of children with frequently relapsing or steroid‐dependent at six months (Analysis 5.2 (1 study, 47 children): RR 0.40, 95% CI 0.18 to 0.89) after the end of therapy when compared with oral cyclophosphamide given for 12 weeks (Abeyagunawardena 2006b; Prasad 2004). However, there was no difference between therapies at the end of the study (21 to 24 months) (Analysis 5.3 (2 studies, 83 children): RR 0.99, 95% CI 0.76 to 1.29; I² = 0%). The cumulative dose of cyclophosphamide was lower with intravenous cyclophosphamide (100 mg/kg ‐ Prasad 2004; 132 mg/kg ‐ Abeyagunawardena 2006b) compared with oral cyclophosphamide (180 mg/kg ‐ Prasad 2004); 168 mg/kg ‐ Abeyagunawardena 2006b).

Infections were significantly more common in children treated with oral cyclophosphamide compared with intravenous therapy (Analysis 5.4.3 (2 studies, 83 children): RR 0.14, 95% CI 0.03 to 0.72; I² = 0%). Other adverse effects (hair loss, nausea and vomiting, bone marrow suppression) did not differ between groups (Analysis 5.4).

Alkylating agents: different agents

On direct comparison, there was no significant difference between chlorambucil and cyclophosphamide treatment in the risk of relapse at 12 months (Analysis 6.1 (1 study, 50 children): RR 1.15, 95% CI 0.69 to 1.94) and 24 months (Analysis 6.2 (1 study, 50 children): RR 1.31, 95% CI 0.80 to 2.13). Post hoc analysis showed chlorambucil and cyclophosphamide were more effective in preventing relapse by 24 months in children with frequently relapsing SSNS (Analysis 7.1 (1 study, 50 children): RR 0.35, 95% CI 0.15 to 0.85) compared with children with steroid‐dependent SSNS.

Adverse effects in studies evaluating alkylating agents

The number of studies reporting each adverse event, the number of events, the total number of children at risk and the percentage for each adverse event are shown for cyclophosphamide and chlorambucil (Table 1). Both alkylating agents were associated with leucopenia, thrombocytopenia and infections. Hair loss was reported uncommonly and cystitis was not seen with chlorambucil. There were nine severe infections reported with cyclophosphamide (Abeyagunawardena 2006b; APN 1982; Prasad 2004) and three serious viral infections with chlorambucil, the latter reported with the increasing dose regimen (Baluarte 1978).

Open in table viewer
Table 1. Adverse effects due to alkylating agents or cyclosporin

Adverse event

CPA studies

CPA events/patients

CPA

CHL studies

CHL events/patients

CHL

CSA studies

CSA events/patients

CSA

Infection

7

25/234

11%

4

3/75

4%

‐‐

‐‐

‐‐

Serious infection

7

12/234

5%

4

3/75

4%

‐‐

‐‐

‐‐

Leucopenia

14

65/356

18%

4

14/76

18%

‐‐

‐‐

‐‐

Medication ceased due to leucopenia

3

4/54

7%

2

3/52

6%

‐‐

‐‐

‐‐

Thrombocytopenia

4

8/131

6%

3

7/75

9%

‐‐

‐‐

‐‐

Hair loss

7

38/229

17%

3

3/75

4%

‐‐

‐‐

‐‐

Cystitis

7

7/178

4%

3

0/75

0%

‐‐

‐‐

‐‐

Gum hypertrophy

‐‐

‐‐

‐‐

‐‐

‐‐

‐‐

4

25/110

23%

Hirsutism

‐‐

‐‐

‐‐

‐‐

‐‐

‐‐

4

29/108

27%

Hypertension

‐‐

‐‐

‐‐

‐‐

‐‐

‐‐

4

14/106

13%

Kidney dysfunction

‐‐

‐‐

‐‐

‐‐

‐‐

‐‐

4

11/113

10%

CPA ‐ cyclophosphamide; CHL ‐ chlorambucil; CSA ‐ cyclosporin

Alkylating agents versus vincristine

There was no significant difference in the risk of relapse between intravenous cyclophosphamide and intravenous vincristine at 12 months (Analysis 8.1 (1 study, 39 children): RR 0.54, 95% CI 0.26 to 1.12) and 24 months (Analysis 8.2 (1 study, 39 children): RR 0.73, 95% CI 0.45 to 1.18). Although no major side effects were reported, two children treated with vincristine had abdominal cramps and constipation, and five children receiving cyclophosphamide experienced vomiting that required anti‐emetics.

Calcineurin inhibitors

Cyclosporin versus alkylating agents

There was no significant differences in the risk of relapse between cyclosporin, given for 12 months, and cyclophosphamide given for eight weeks at the end of cyclosporin therapy (Analysis 9.1.1 (1 study, 55 children): RR 1.07, 95% CI 0.48 to 2.35). Similarly there was no significant difference in the risk of relapse between cyclosporin given for 24 weeks and chlorambucil given for six weeks at the end of cyclosporin therapy (Analysis 9.1.2 (1 study, 40 children): RR 0.82, 95% CI 0.44 to 1.53).

Cyclosporin was significantly less effective compared with chlorambucil in maintaining remission at 12 months (Analysis 9.2 (1 study, 40 children): RR 0.47, 95% CI 0.29 to 0.78) and 24 months (Analysis 9.3.2 (1 study, 40 children): RR 0.58, 95% CI 0.38 to 0.87). Similarly cyclosporin was significantly less effective compared with cyclophosphamide in maintaining remission at 24 months (Analysis 9.3.1 (1 study, 55 children): RR 0.40, 95% CI 0.22 to 0.73). When the studies were combined, there was no significant difference in the number with relapse at the end of cyclosporin treatment between treatment groups (Analysis 9.1 (2 studies, 95 children): RR 0.91, 95% CI 0.55 to 1.48; I² = 0%). However alkylating agents were significantly more effective in maintaining remission once cyclosporin was ceased (Analysis 9.3 (2 studies, 95 children): RR 0.51, 95% CI 0.35 to 0.74; I² = 12%).

Creatinine levels were significantly higher and hirsutism and gum hypertrophy more common with cyclosporin compared with alkylating agents (Analysis 9.4.1; Analysis 9.4.2; Analysis 9.4.3) but leucopenia was significantly more common with alkylating agents (Analysis 9.4.5). There was no significant difference in the risk of hypertension between cyclosporin and alkylating agents (Analysis 9.4.4).

Cyclosporin versus mycophenolate mofetil

Two studies compared MMF with cyclosporin. Dorresteijn 2007 was a parallel group study. Although this small study found no significant difference in the number with one or more relapses between cyclosporin and mycophenolate mofetil at 12 months (Analysis 10.1 (1 study, 24 children): RR 5.00, 95% CI 0.68 to 36.66), the relapse rate/year (Analysis 10.2 (1 study, 24 children): MD 0.75, 95% CI 0.01 to 1.49) was significantly lower with cyclosporin compared with MMF. The small patient numbers resulted in considerable imprecision in the results with wide confidence intervals. Gellermann 2011 was a cross‐over study that enrolled 60 children. During cyclosporin therapy, no relapses were seen in 84% of children, and nine children experienced 13 relapses. During MMF therapy no relapses were seen in 64% children, but 21 children experienced 44 relapses. These data suggest that cyclosporin was more effective than MMF in preventing relapse.

Hypertrichosis and gum hypertrophy were significantly more common in children treated with cyclosporin, but other adverse effects (number with reduced GFR, hypertension, fatigue, pneumonia) did not differ between the groups (Analysis 10.3). GFR was 22 mL/min/1.73m² lower at 12 months in children treated with cyclosporin compared with those treated with MMF but this difference was not significant (Analysis 10.4).

Different doses of cyclosporin

Ishikura 2007 compared a fixed dose of cyclosporin (2.5 mg/kg/d) with doses altered to maintain cyclosporin levels at 60 to 80 ng/mL (mean dose 5.4 mg/kg/d), after both treatment groups had received cyclosporin doses to maintain levels at 80 to 100 ng/mL for six months. Data on numbers of children experiencing relapse was extrapolated from percentages in the text, and assumed that all children completed follow‐up. The number of children experiencing relapse was significantly lower with the variable dose compared with the fixed dose regimen at 12 months (Analysis 11.1.2 (1 study, 44 children): RR 0.33, 95% CI 0.16 to 0.70) and 24 months (Analysis 11.1.3 (1 study, 44 children): RR 0.65, 95% CI 0.45 to 0.94) but not at six months.

There were no significant differences in adverse effects among the different regimens (Analysis 11.2).

Adverse effects in cyclosporin studies

The number of studies, the numbers of patients with adverse effects and the total number of children treated with cyclosporin are shown are shown in Table 1. Gum hypertrophy and hirsutism were seen commonly with cyclosporin; elevated creatinine levels and hypertension occurred in 13% and 10% of children respectively.

Levamisole

Levamisole versus steroids or placebo or both, or no treatment

Levamisole was administered for four months (BAPN 1991), six months (Rashid 1996; Sural 2001; Weiss 1993) and 12 months (Abeyagunawardena 2006a; Al‐Saran 2006; Dayal 1994).

Significantly fewer children relapsed during levamisole treatment compared with placebo, prednisone or no treatment (Analysis 12.1.1 (7 studies, 375 children): RR 0.47, 95% CI 0.24 to 0.89) but there was significant heterogeneity (I² = 92%). When Weiss 1993 (which showed no effect) was excluded, levamisole was still significantly more effective than prednisone alone (Analysis 12.1.2 (6 studies, 327 children): RR 0.41, 95% CI 0.27 to 0.61). Some heterogeneity persisted (I² = 59%) but summary estimates in all six studies favoured levamisole.

There remained a statistically significant benefit of levamisole (Analysis 12.2 (7 studies, 363 children): RR 0.62, 95% CI 0.42 to 0.91) over steroid alone at six to 12 months when levamisole treatment had been ceased for three to six months in four studies (BAPN 1991; Rashid 1996; Sural 2001; Weiss 1993). However, there was significant heterogeneity (I² = 90%) which could be explained by the duration of treatment, suggesting that levamisole is effective during treatment but the effect is not sustained when treatment was ceased.

There was no significant difference between levamisole treatment compared with placebo, prednisone or no treatment for mean relapse rate/patient/month (Analysis 12.3 (2 studies, 90 patients); MD ‐0.03, 95% CI ‐0.27 to 0.20). However, there was significant heterogeneity between the studies (I² = 83%). Weiss 1993 showed no benefit and Al‐Saran 2006 showed significant benefit of levamisole compared with prednisone.

With levamisole, single cases of gastrointestinal upset were reported in two studies (Al‐Saran 2006; BAPN 1991). One child with leucopenia was reported by Sural 2001, while Al‐Saran 2006 reported no children with leucopenia. Three studies reported that no side effects occurred (Abeyagunawardena 2006b; Dayal 1994; Rashid 1996). Adverse effects were not reported in Weiss 1993.

Levamisole versus cyclophosphamide

Donia 2005 compared levamisole with monthly pulses of intravenous cyclophosphamide with both given for six months, and Sural 2001 compared 24 weeks of levamisole with 12 weeks of oral cyclophosphamide. At the end of treatment, there was no significant difference between therapy in numbers of children who relapse between levamisole and either intravenous or oral cyclophosphamide at the end of therapy and at six to nine months, 12 months, and 24 months (Analysis 13.1.1; Analysis 13.1.2; Analysis 13.1.3; Analysis 13.1.4). There was however significant heterogeneity at the end of therapy (I² = 79%) with moderate heterogeneity at six to nine months after the end of therapy (I² = 43%). Sural 2001 reported fewer relapses during treatment with cyclophosphamide compared with levamisole, while in Donia 2005, similar numbers of patients relapsed in each group. There were no significant differences in adverse effects (infections, leucopenia, abnormal liver function tests) (Analysis 13.2). No patient receiving cyclophosphamide developed haemorrhagic cystitis.

Rituximab

Rituximab plus cyclosporin and prednisolone versus cyclosporin and prednisolone

Ravani 2011 compared the short‐term efficacy of rituximab plus cyclosporin and prednisolone with cyclosporin and prednisolone alone. At three months the risk of relapse was significantly lower with rituximab plus cyclosporin and prednisolone compared with cyclosporin and prednisolone alone (Analysis 14.1 (1 study, 54 children): RR 0.38, 95% CI 0.16 to 0.93) and significantly more children could cease prednisone (Analysis 14.2.1 (1 study, 54 children): RR 10.50, 95% CI 2.73 to 40.45) and cyclosporin (Analysis 14.2.2 (1 study, 54 children): RR 17.00, 95% CI 2.43 to 118.89). The primary outcome in this study was proteinuria at three months; this was reduced by 70% in children who received rituximab.

The reported adverse effects of rituximab were bronchospasm, hypotension, fever, skin rash and joint pain (Analysis 14.3). Treatment had to be discontinued in one child.

Azathioprine

Azathioprine versus steroids

There was no statistically significant reduction in the number of children who relapsed at six months with azathioprine compared with placebo or steroids alone (Analysis 15.1 (2 studies, 60 children): RR 0.90, 95% CI 0.59 to 1.38; I² = 3%).

There was a single case of pulmonary embolus associated with azathioprine treatment (Abramowicz 1970).

Mizoribine

Mizoribine versus with placebo

Yoshioka 2000 compared mizoribine with placebo. The reported relapse rate/patient‐months was 0.0055 with mizoribine and 0.0067 with placebo (relapse RR 0.81, 95% CI 0.61 to 1.05). The cumulative remission rate did not differ between the groups (hazard ratio of cumulative remission rate 0.79, 95% CI 0.57 to 1.08).

Data on the number of children with relapse at six and 12 months who had received mizoribine or placebo could not be extracted.

The total number of adverse effects and the individual adverse effects of leucopenia and hepatic dysfunction did not differ significantly between groups (Analysis 16.1). However, hyperuricaemia was significantly more common with mizoribine (Analysis 16.1.2 (1 study, 197 children): RR 3.96, 95% CI 1.37 to 11.42).

Fusidic acid

Fusidic acid versus with steroids

Fusidic acid and prednisone was compared with prednisone alone in a cross‐over study involving 18 children (Cerkauskiene 2005). The results for all courses of fusidic acid and prednisone (14 courses) and prednisone alone (17 courses) were combined. There was no significant difference in the mean time to remission (12.6 ± 6.6 days for fusidic acid/prednisone versus 13.9 ± 7.4 days for prednisone alone) or in time to relapse (18.3 ± 23.9 weeks versus 17.8 ± 20.4 weeks). One child developed an allergic rash with fusidic acid.

Subgroup analyses

There were insufficient studies of any treatment combination to enable conducting detailed subgroup analyses.

Discussion

Summary of main results

Alkylating agents

Six studies in children with relapsing SSNS showed that oral cyclophosphamide and chlorambucil substantially reduced the risk of relapse compared with prednisone alone (summary of findings Table for the main comparison). These interventions typically reduced the risk of relapse in comparison with prednisone by about 50% for one year during and after a treatment course. In a direct comparison, there was no significant difference in efficacy between cyclophosphamide and chlorambucil. Since corticosteroids were used in combination with the study agents in most studies, there were insufficient data available to determine the efficacy of alkylating agents in comparison with placebo or no immunosuppressive treatment.

What would the benefits and harms be of using an alkylating agent in a child with relapsing nephrotic syndrome? Cohort studies (Koskimies 1982; Tarshish 1997) showed that between 35% and 53% of children relapse frequently at some time during their disease. Intervention with immunosuppressive medications would only be undertaken in this group of children whose risk for further recurrences approaches 100% with corticosteroid treatment alone. The meta‐analysis shows that the RR of relapse is 0.42 so the risk of relapse following a course of an alkylating agent is reduced from 100% to about 42%. Hence, on the benefit side of the equation, assuming that all children will relapse, 58 fewer children would relapse for every 100 children treated with an alkylating agent (Glasziou 1995). On the harm side of the equation, for every 100 children treated with an alkylating agent, between five and 11 children will suffer a significant infection and seven children would have to cease drug therapy because of leucopenia (Table 1). Children, who relapse only once during the first six months after the initial course of prednisone treatment, have only a 10% risk of developing frequently relapsing nephrotic syndrome (Tarshish 1997). Thus only 10/100 such children are considered at risk of relapsing frequently. Since alkylating agents, if administered to such children would reduce the risk of relapse by about 58%, only about 6/100 children would benefit while the number suffering adverse effects would be unchanged. Thus, the benefits of treatment would outweigh the harms only in children who relapse frequently.

Cyclophosphamide was significantly more effective in maintaining remission when administered for eight weeks compared with two weeks but there was no significant difference in efficacy between eight and 12 weeks of cyclophosphamide. The efficacy of intravenous cyclophosphamide did not differ significantly from that of oral cyclophosphamide (summary of findings Table 2).

Calcineurin inhibitors and mycophenolate mofetil

In comparative studies the efficacy of cyclosporin did not differ significantly from alkylating agents during administration, but unlike cyclosporin, the benefit of the alkylating agents was generally sustained beyond the on‐treatment period (summary of findings Table 3). The relative efficacy of MMF compared with cyclosporin remains unclear because of limited data. Comparison between dosing based on cyclosporin levels and fixed low dose cyclosporin indicated that the former was more effective in maintaining remission. Although tacrolimus is widely used as an alternative to cyclosporin to avoid the cosmetic effects of cyclosporin, no comparative RCTs of these medications were identified. Adverse effects of hypertension and kidney dysfunction occurred in 13% and 10% of children respectively (Table 1).

Levamisole

Levamisole reduced the risk of relapse compared with placebo or no treatment, but there was considerable heterogeneity in the meta‐analysis, which was partially resolved by exclusion of Weiss 1993, which showed no benefit (summary of findings Table 4). Six studies limited enrolment to children with frequently relapsing (Rashid 1996; Sural 2001; Weiss 1993) and steroid‐dependent SSNS (Abeyagunawardena 2006a; Al‐Saran 2006; BAPN 1991; Rashid 1996; Weiss 1993). Dayal 1994 enrolled children following a relapse regardless of the frequency of relapse. Thus, it was unlikely that the difference in efficacy between Weiss 1993 and the other studies related to different patient populations.

Levamisole was administered twice weekly but on consecutive days in one study (Weiss 1993) to provide a monthly dose of 20 mg/kg. It was administered on alternate days in five studies (Abeyagunawardena 2006a; Al‐Saran 2006; BAPN 1991; Rashid 1996; Sural 2001) to provide a monthly dose of 35 mg/kg. The interval between doses was thus shorter and the total dose higher in the five studies demonstrating efficacy in frequently relapsing and steroid‐dependent patients. This difference in dose frequency and total dose may be responsible for the difference in efficacy. Few side effects were reported in the levamisole studies. However, important side effects reported in other studies include neutropenia and disseminated vasculitis (Barbano 1999; Palcoux 1994).

A multicentre double blind, placebo‐controlled RCT of levamisole is being undertaken with the principal investigators based in The Netherlands (Gruppen 2006); recruitment to this study has been completed and completion is expected in 2013.

In a two comparative studies the efficacy of cyclophosphamide did not differ significantly from levamisole (Donia 2005; Sural 2001) but there was significant heterogeneity between studies.

Other medications

A single small study (Ravani 2011) suggested that rituximab significantly reduced the short‐term risk of relapse in children with steroid‐ and cyclosporin‐dependent nephrotic syndrome, but further studies are required to establish the role of rituximab in SSNS.

The efficacy of azathioprine, mizoribine and fusidic acid did not differ significantly from prednisone or placebo in RCTs indicating that these medications provide no additional benefit for children with relapsing SSNS.

Overall completeness and applicability of evidence

Although study data showed that non‐corticosteroid immunosuppressive medications were more effective than corticosteroids alone, head‐to‐head studies have not demonstrated a clear benefit of one over any other in preventing relapse of nephrotic syndrome. Comparative studies of cyclophosphamide, chlorambucil, cyclosporin, levamisole and MMF have been done but, because of insufficient power, clinically important differences in treatment effects have not been completely excluded. For example, using the upper and lower bounds of the 95% CI of the RR estimate obtained from the single comparative study of chlorambucil versus cyclophosphamide, chlorambucil could reduce the risk of recurrence by 20% or could double the risk of recurrence compared with cyclophosphamide. Similarly, compared with alkylating agents, cyclosporin could reduce the risk of relapse by 45% or could more than double the risk of relapse at the end of therapy. Adequately powered RCTs are required to determine which of the five medications is most effective.

Ideally, additional comparative studies of alkylating agents with calcineurin inhibitors, levamisole or MMF and of calcineurin inhibitors with levamisole, MMF and rituximab should be undertaken. In particular, studies evaluating MMF, tacrolimus and rituximab are required. A single very small RCT favoured cyclosporin over mycophenolate for the relapse rate but there was considerable imprecision in the results (Dorresteijn 2007). Preliminary results of a larger cross‐over study suggested that cyclosporin was more effective than MMF, but the complete results are awaited (Gellermann 2011). A single small study (Ravani 2011) suggested that rituximab was a valuable addition in children with steroid‐ and calcineurin‐dependent nephrotic syndrome.

No studies comparing tacrolimus with cyclosporin were identified.

Until further adequately‐powered comparative studies are available, the choice between non‐corticosteroid immunosuppressive medications must be based upon other non‐effectiveness considerations, such as local availability or licensing, costs, and physician and patient preferences concerning duration of treatment and frequency and nature of complications.

By stratifying recruited patients into those with frequently relapsing disease and steroid‐dependent disease, studies could also test the hypothesis that alkylating agents are more effective in the frequent relapsing group and cyclosporin is more effective in the steroid‐dependent group as suggested by post‐hoc analysis of published studies of alkylating agents (APN 1982), uncontrolled studies of cyclosporin (Hulton 1994; Niaudet 1987) and a review of 26 studies (controlled studies and cohort studies) which found that on average the two‐ and five‐year sustained remission rates following treatment with either cyclophosphamide or chlorambucil were 72% and 36% in frequently relapsing SSNS compared with 40% and 24% in steroid‐dependent SSNS (Latta 2001). Guidelines published in the USA already suggest different hierarchies for the use of non‐corticosteroid immunosuppressive medications in frequently relapsing compared with steroid‐dependent nephrotic syndrome (Gipson 2009).

Follow‐up of participants in the studies of alkylating agents was two years or less. This was insufficient to determine the risk of low sperm count and infertility, which are known to be long‐term complications of prolonged courses of alkylating agents (Latta 2001). None of the studies included in the review specifically addressed the issue of fertility as an adverse effect of alkylating agent therapy. The total doses of cyclophosphamide and chlorambucil were equal to or less than the generally accepted maximum cumulative dose of 168 mg/kg and 11.2 mg/kg respectively (KDIGO 2012) except for early studies (Alatas 1978; Baluarte 1978; Chiu 1973; Grupe 1976). However, long‐term follow‐up of SSNS patients into adult life has identified a reduction in parenthood in patients who had received any alkylating agent therapy with patients with two or more courses of alkylating agents having a significantly higher risk of not having children compared with patients with a single course (Rüth 2005). Consequently the KDIGO guidelines (KDIGO 2012) recommend that second courses of alkylating agents not be given.

Quality of the evidence

This review has several potential problems because of the limitations of the primary data. Overall, study quality was poor, with only a third and a half of studies reporting sequence generation and allocation concealment at low risk of bias respectively (Figure 2). Studies with inadequate allocation concealment can exaggerate the efficacy of the experimental treatment by 30% to 40% (Schulz 1995) and meta‐analyses of low quality studies may overestimate the benefit of therapy (Moher 1998). In addition, only 20% of studies were considered at low risk of performance and detection bias. These observations make the need for adequately powered, well designed and reported studies even more necessary.

Many therapies were only investigated in single small studies and could not be assessed in summary of findings tables. Six studies (157 participants) evaluated alkylating agents in comparison with prednisone or placebo or both (summary of findings Table for the main comparison). Two studies (83 participants) compared intravenous with oral administration of cyclophosphamide (summary of findings Table 2) and two studies (95 participants) compared alkylating agents with cyclosporin (summary of findings Table 3). The quality of the evidence was considered to be low in these comparisons because of small numbers of participants and unclear allocation concealment in some studies. Seven studies (375 participants) compared levamisole with prednisone or placebo or both (summary of findings Table 4). The quality of the evidence was considered to be low because of inconsistency in the results and significant heterogeneity between studies resulting in imprecision in results.

Because studies are not generally designed to evaluate harms of interventions unless the primary outcome is a harm‐benefit composite such as death, the number of serious adverse effects (Table 1) reported here with alkylating agents and cyclosporin may be an underestimate and may not be directly applicable to larger groups of children treated under non‐trial conditions. Nevertheless a review (Latta 2001) of 38 articles on the treatment of relapsing SSNS involving 866 children who received 902 courses of cyclophosphamide and 638 children who received 671 courses of chlorambucil found similar frequencies of adverse effects to our review.

The effects of publication bias could not be formally assessed because of the small number of studies for each medication. Subgroup analysis was not possible because of the small number of studies for each intervention.

Potential biases in the review process

The search strategy was repeated several times to June 2013 and included conference proceedings. Nevertheless it is possible that studies published in conference proceedings not routinely searched for the Cochrane Renal Group, were not identified. Data extraction and risk of bias were carried out by two authors working independently with lengthy discussions undertaken to reach agreement. Additional information was obtained for one study (Abeyagunawardena 2007) but requested information was not provided for another (Gellermann 2011). Further information from the Gellermann 2011 study may have informed more rigorous conclusions about the relative efficacies of MMF and cyclosporin. Data analysis for this update was completed by one author (NT) but checked by a second author (EH).

Agreements and disagreements with other studies or reviews

Our findings are generally in keeping with recently published guidelines. Both the recent USA (Gipson 2009) and Indian guidelines (IPNS‐IAP 2008) recommend that cyclophosphamide should be given for 12 weeks, while the KDIGO (KDIGO 2012) and French guidelines (French NS Guideline 2008) recommend eight to 12 weeks of therapy. Similarly older guidelines (Bargman 1999; Brodehl 1991; IPNG‐IAP 2001) recommend 12 weeks of cyclophosphamide for frequently relapsing and steroid‐dependent SSNS. In part, this may reflect the differences in information sources used. For example, a study which has been influential in shaping guidelines about cyclophosphamide use, found that 12 weeks of cyclophosphamide was more effective than eight weeks in preventing relapse in children with steroid‐dependent SSNS (APN 1987). However, this study used historical controls, which may be associated with an overestimate of the treatment effect (Sacks 1982). In contrast, in a study increasing the duration of cyclophosphamide from eight to 12 weeks did not improve efficacy (Ueda 1990).

This review was not able to determine which medication should be preferred initially for relapsing SSNS since data from studies were inadequate to determine which medication should be used first. Our findings are in keeping with three of the four recently published guidelines (French NS Guideline 2008; IPNS‐IAP 2008; KDIGO 2012) which do not suggest in what order corticosteroid sparing immunosuppressive drugs should be used. In contrast, Gipson 2009 suggest different orders of administration for frequently relapsing and steroid‐dependent SSNS with cyclophosphamide preferred as the initial medication for frequently relapsing disease and a calcineurin inhibitor preferred for steroid‐dependent disease.

Study flow diagram
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Figure 1

Study flow diagram

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
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Figure 2

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

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study
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Figure 3

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

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Comparison 1 Alkylating agents versus steroids or placebo or both, Outcome 1 Relapse at 6 to 12 months.
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Analysis 1.1

Comparison 1 Alkylating agents versus steroids or placebo or both, Outcome 1 Relapse at 6 to 12 months.

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Comparison 1 Alkylating agents versus steroids or placebo or both, Outcome 2 Relapse at 12 to 24 months.
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Analysis 1.2

Comparison 1 Alkylating agents versus steroids or placebo or both, Outcome 2 Relapse at 12 to 24 months.

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Comparison 2 Cyclophosphamide duration, Outcome 1 Relapse at 6 months.
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Analysis 2.1

Comparison 2 Cyclophosphamide duration, Outcome 1 Relapse at 6 months.

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Comparison 2 Cyclophosphamide duration, Outcome 2 Relapse at 12 months.
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Analysis 2.2

Comparison 2 Cyclophosphamide duration, Outcome 2 Relapse at 12 months.

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Comparison 2 Cyclophosphamide duration, Outcome 3 Relapse rate at 24 months.
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Analysis 2.3

Comparison 2 Cyclophosphamide duration, Outcome 3 Relapse rate at 24 months.

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Comparison 3 Cyclophosphamide dose, Outcome 1 Relapse at 12 months.
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Analysis 3.1

Comparison 3 Cyclophosphamide dose, Outcome 1 Relapse at 12 months.

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Comparison 3 Cyclophosphamide dose, Outcome 2 Adverse effects.
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Analysis 3.2

Comparison 3 Cyclophosphamide dose, Outcome 2 Adverse effects.

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Comparison 4 Chlorambucil dose, Outcome 1 Relapse at 12 months.
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Analysis 4.1

Comparison 4 Chlorambucil dose, Outcome 1 Relapse at 12 months.

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Comparison 5 Intravenous versus oral cyclophosphamide, Outcome 1 Relapse at 6 months.
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Analysis 5.1

Comparison 5 Intravenous versus oral cyclophosphamide, Outcome 1 Relapse at 6 months.

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Comparison 5 Intravenous versus oral cyclophosphamide, Outcome 2 Continuing frequently relapsing or steroid dependent SSNS at 6 months.
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Analysis 5.2

Comparison 5 Intravenous versus oral cyclophosphamide, Outcome 2 Continuing frequently relapsing or steroid dependent SSNS at 6 months.

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Comparison 5 Intravenous versus oral cyclophosphamide, Outcome 3 Relapse at end of study.
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Analysis 5.3

Comparison 5 Intravenous versus oral cyclophosphamide, Outcome 3 Relapse at end of study.

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Comparison 5 Intravenous versus oral cyclophosphamide, Outcome 4 Adverse events.
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Analysis 5.4

Comparison 5 Intravenous versus oral cyclophosphamide, Outcome 4 Adverse events.

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Comparison 6 Cyclophosphamide versus chlorambucil, Outcome 1 Relapse at 12 months.
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Analysis 6.1

Comparison 6 Cyclophosphamide versus chlorambucil, Outcome 1 Relapse at 12 months.

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Comparison 6 Cyclophosphamide versus chlorambucil, Outcome 2 Relapse at 24 months.
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Analysis 6.2

Comparison 6 Cyclophosphamide versus chlorambucil, Outcome 2 Relapse at 24 months.

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Comparison 7 Post hoc analysis: alkylating agents in frequently relapsing and steroid‐dependent patients, Outcome 1 Relapse at 24 months.
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Analysis 7.1

Comparison 7 Post hoc analysis: alkylating agents in frequently relapsing and steroid‐dependent patients, Outcome 1 Relapse at 24 months.

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Comparison 8 Cyclophosphamide versus vincristine, Outcome 1 Relapse at 12 months.
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Analysis 8.1

Comparison 8 Cyclophosphamide versus vincristine, Outcome 1 Relapse at 12 months.

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Comparison 8 Cyclophosphamide versus vincristine, Outcome 2 Relapse at 24 months.
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Analysis 8.2

Comparison 8 Cyclophosphamide versus vincristine, Outcome 2 Relapse at 24 months.

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Comparison 9 Alkylating agents versus cyclosporin, Outcome 1 Relapse at end of therapy (6 to 9 months).
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Analysis 9.1

Comparison 9 Alkylating agents versus cyclosporin, Outcome 1 Relapse at end of therapy (6 to 9 months).

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Comparison 9 Alkylating agents versus cyclosporin, Outcome 2 Relapse at 12 months.
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Analysis 9.2

Comparison 9 Alkylating agents versus cyclosporin, Outcome 2 Relapse at 12 months.

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Comparison 9 Alkylating agents versus cyclosporin, Outcome 3 Relapse at 12 to 24 months.
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Analysis 9.3

Comparison 9 Alkylating agents versus cyclosporin, Outcome 3 Relapse at 12 to 24 months.

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Comparison 9 Alkylating agents versus cyclosporin, Outcome 4 Adverse effects.
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Analysis 9.4

Comparison 9 Alkylating agents versus cyclosporin, Outcome 4 Adverse effects.

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Comparison 10 Mycophenolate mofetil versus cyclosporin, Outcome 1 Relapse within 12 months.
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Analysis 10.1

Comparison 10 Mycophenolate mofetil versus cyclosporin, Outcome 1 Relapse within 12 months.

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Comparison 10 Mycophenolate mofetil versus cyclosporin, Outcome 2 Relapse rate/year.
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Analysis 10.2

Comparison 10 Mycophenolate mofetil versus cyclosporin, Outcome 2 Relapse rate/year.

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Comparison 10 Mycophenolate mofetil versus cyclosporin, Outcome 3 Adverse effects.
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Analysis 10.3

Comparison 10 Mycophenolate mofetil versus cyclosporin, Outcome 3 Adverse effects.

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Comparison 10 Mycophenolate mofetil versus cyclosporin, Outcome 4 GFR at 12 months.
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Analysis 10.4

Comparison 10 Mycophenolate mofetil versus cyclosporin, Outcome 4 GFR at 12 months.

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Comparison 11 Cyclosporin dose, Outcome 1 Relapse.
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Analysis 11.1

Comparison 11 Cyclosporin dose, Outcome 1 Relapse.

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Comparison 11 Cyclosporin dose, Outcome 2 Adverse effects.
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Analysis 11.2

Comparison 11 Cyclosporin dose, Outcome 2 Adverse effects.

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Comparison 12 Levamisole versus steroids or placebo or both, or no treatment, Outcome 1 Relapse during treatment (4 to 12 months).
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Analysis 12.1

Comparison 12 Levamisole versus steroids or placebo or both, or no treatment, Outcome 1 Relapse during treatment (4 to 12 months).

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Comparison 12 Levamisole versus steroids or placebo or both, or no treatment, Outcome 2 Relapse at 6 to 12 months.
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Analysis 12.2

Comparison 12 Levamisole versus steroids or placebo or both, or no treatment, Outcome 2 Relapse at 6 to 12 months.

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Comparison 12 Levamisole versus steroids or placebo or both, or no treatment, Outcome 3 Mean relapse rate/patient/month.
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Analysis 12.3

Comparison 12 Levamisole versus steroids or placebo or both, or no treatment, Outcome 3 Mean relapse rate/patient/month.

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Comparison 13 Levamisole versus cyclophosphamide, Outcome 1 Relapse.
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Analysis 13.1

Comparison 13 Levamisole versus cyclophosphamide, Outcome 1 Relapse.

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Comparison 13 Levamisole versus cyclophosphamide, Outcome 2 Adverse effects.
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Analysis 13.2

Comparison 13 Levamisole versus cyclophosphamide, Outcome 2 Adverse effects.

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Comparison 14 Rituximab + cyclosporin and prednisolone versus cyclosporin and prednisolone alone, Outcome 1 Relapse at 3 months.
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Analysis 14.1

Comparison 14 Rituximab + cyclosporin and prednisolone versus cyclosporin and prednisolone alone, Outcome 1 Relapse at 3 months.

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Comparison 14 Rituximab + cyclosporin and prednisolone versus cyclosporin and prednisolone alone, Outcome 2 One year relapse‐free survival.
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Analysis 14.2

Comparison 14 Rituximab + cyclosporin and prednisolone versus cyclosporin and prednisolone alone, Outcome 2 One year relapse‐free survival.

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Comparison 14 Rituximab + cyclosporin and prednisolone versus cyclosporin and prednisolone alone, Outcome 3 Adverse effects.
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Analysis 14.3

Comparison 14 Rituximab + cyclosporin and prednisolone versus cyclosporin and prednisolone alone, Outcome 3 Adverse effects.

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Comparison 15 Azathioprine versus steroids, Outcome 1 Relapse at 6 months.
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Analysis 15.1

Comparison 15 Azathioprine versus steroids, Outcome 1 Relapse at 6 months.

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Comparison 16 Mizoribine versus placebo, Outcome 1 Adverse effects.
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Analysis 16.1

Comparison 16 Mizoribine versus placebo, Outcome 1 Adverse effects.

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Summary of findings for the main comparison. Alkylating agents versus steroids or placebo or both for steroid‐sensitive nephrotic syndrome in children

Alkylating agents versus steroids or placebo or both for steroid‐sensitive nephrotic syndrome in children

Patient or population: children with steroid‐sensitive nephrotic syndrome
Intervention: alkylating agents versus steroids or placebo or both

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Alkylating agents versus prednisone/placebo

Relapse at 6‐12 months

Study population

RR 0.42
(0.28 to 0.62)

189 (6)

⊕⊕⊕⊝
moderate1

763 per 1000

320 per 1000
(214 to 473)

Moderate

844 per 1000

354 per 1000
(236 to 523)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Only two studies had adequate allocation concealment. None were blinded.

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Summary of findings for the main comparison. Alkylating agents versus steroids or placebo or both for steroid‐sensitive nephrotic syndrome in children
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Summary of findings 2. Intravenous versus oral cyclophosphamide for steroid‐sensitive nephrotic syndrome in children

Intravenous versus oral cyclophosphamide for steroid‐sensitive nephrotic syndrome in children

Patient or population: children with steroid‐sensitive nephrotic syndrome
Intervention: intravenous versus oral cyclophosphamide

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Intravenous versus oral cyclophosphamide

Relapse at 6 months

Study population

RR 0.54
(0.34 to 0.88)

83 (2)

⊕⊕⊝⊝
low¹,²

524 per 1000

283 per 1000
(178 to 461)

Moderate

524 per 1000

283 per 1000
(178 to 461)

Relapse at end of study

Study population

RR 0.99
(0.76 to 1.29)

83 (2)

⊕⊕⊝⊝
low¹,²

619 per 1000

613 per 1000
(470 to 799)

Moderate

619 per 1000

613 per 1000
(470 to 799)

Continuing frequently relapsing or steroid‐dependent SSNS at 6 months

See comment

See comment

Not estimable

47 (1)

⊕⊕⊝⊝
low²

Adverse events: leucopenia

Study population

RR 0.37
(0.09 to 1.51)

83 (2)

⊕⊕⊝⊝
low¹,²

143 per 1000

53 per 1000
(13 to 216)

Moderate

143 per 1000

53 per 1000
(13 to 216)

Adverse events: hair loss

Study population

RR 0.19
(0.04 to 1.03)

83 (2)

⊕⊕⊝⊝
low¹,²

381 per 1000

72 per 1000
(15 to 392)

Moderate

381 per 1000

72 per 1000
(15 to 392)

Adverse events: all infections

Study population

RR 0.14
(0.03 to 0.72)

83 (2)

⊕⊕⊝⊝
low¹,²

238 per 1000

33 per 1000
(7 to 171)

Moderate

238 per 1000

33 per 1000
(7 to 171)

Adverse events: nausea and vomiting

Study population

RR 4.07
(0.21 to 80.51)

47 (1)

⊕⊕⊝⊝
low²

0 per 1000

0 per 1000
(0 to 0)

Moderate

0 per 1000

0 per 1000
(0 to 0)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: confidence interval; RR: risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

¹ One of two studies showed unclear allocation concealment
² Small numbers of participants and events

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Summary of findings 2. Intravenous versus oral cyclophosphamide for steroid‐sensitive nephrotic syndrome in children
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Summary of findings 3. Cyclosporin versus alkylating agent for steroid‐sensitive nephrotic syndrome in children

Cyclosporin versus alkylating agent for steroid‐sensitive nephrotic syndrome in children

Patient or population: children with steroid‐sensitive nephrotic syndrome
Settings: tertiary centres
Intervention: cyclosporin versus alkylating agent

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Cyclosporin versus alkylating agent

Number with relapse at end of therapy
Follow‐up: 6 to 9 months

Study population

RR 0.91
(0.55 to 1.48)

95 (2)

⊕⊕⊝⊝
low¹,²

400 per 1000

364 per 1000
(220 to 592)

Moderate

425 per 1000

387 per 1000
(234 to 629)

Number with relapse at 24 months
Follow‐up: mean 24 months

Study population

RR 0.51
(0.35 to 0.74)

95 (2)

⊕⊕⊝⊝
low¹,²

860 per 1000

439 per 1000
(301 to 636)

Moderate

875 per 1000

446 per 1000
(306 to 648)

Adverse effects: increase SCr

Study population

See comment

112 (2)

⊕⊕⊝⊝
low¹,²

Risks were calculated from pooled risk differences

89 per 1000

4 per 1000
(‐80 to 89)

Moderate

81 per 1000

4 per 1000
(‐73 to 81)

Adverse effects: hypertrichosis

Study population

See comment

112 (2)

⊕⊕⊝⊝
low¹,²

Risks were calculated from pooled risk differences

339 per 1000

3 per 1000
(‐122 to 129)

Moderate

353 per 1000

4 per 1000
(‐127 to 134)

Adverse effects: gum hypertrophy

Study population

See comment

112 (2)

⊕⊕⊝⊝
low¹,²

Risks were calculated from pooled risk differences

232 per 1000

0 per 1000
(‐118 to 111)

Moderate

236 per 1000

0 per 1000
(‐120 to 113)

Adverse effects: leucopenia

Study population

See comment

66 (1)

⊕⊝⊝⊝
very low¹,²

Risks were calculated from pooled risk differences

0 per 1000

‐2147483648 per 1000
(‐2147483648 to ‐2147483648)

Moderate

0 per 1000

‐2147483648 per 1000
(‐2147483648 to ‐2147483648)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) 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; SCr: serum creatinine

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

¹ One of two studies showed unclear allocation concealment
² Small numbers of patients and events with wide confidence intervals

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Summary of findings 3. Cyclosporin versus alkylating agent for steroid‐sensitive nephrotic syndrome in children
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Summary of findings 4. Levamisole versus steroids or placebo or both, or no treatment for steroid‐sensitive nephrotic syndrome in children

Levamisole versus steroids or placebo or both, or no treatment for steroid‐sensitive nephrotic syndrome in children

Patient or population: children with steroid‐sensitive nephrotic syndrome
Intervention: levamisole versus steroids or placebo or both, or treatment

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Levamisole versus placebo, low dose prednisone or no specific treatment

Relapse during treatment (4 to 12 months): includingWeiss 1993

Study population

RR 0.47
(0.24 to 0.89)

375 (7)

⊕⊕⊝⊝
low1,2

739 per 1000

347 per 1000
(177 to 657)

Moderate

765 per 1000

360 per 1000
(184 to 681)

Relapse during treatment (4 to 12 months): excludingWeiss 1993

Study population

RR 0.41
(0.27 to 0.61)

327 (6)

⊕⊕⊝⊝
low1,2

727 per 1000

298 per 1000
(196 to 443)

Moderate

740 per 1000

303 per 1000
(200 to 451)

Relapse at 6 to 12 months

Study population

RR 0.62
(0.42 to 0.91)

363 (7)

⊕⊕⊝⊝
low1,2

863 per 1000

535 per 1000
(362 to 785)

Moderate

889 per 1000

551 per 1000
(373 to 809)

Mean relapse rate/patient/month

The mean relapse rate/patient/month in the intervention groups was
0.03 lower
(0.27 lower to 0.2 higher)

90 (2)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

1 Unclear allocation concealment and no blinding in most studies
2 Significant heterogeneity between studies

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Summary of findings 4. Levamisole versus steroids or placebo or both, or no treatment for steroid‐sensitive nephrotic syndrome in children
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Table 1. Adverse effects due to alkylating agents or cyclosporin

Adverse event

CPA studies

CPA events/patients

CPA

CHL studies

CHL events/patients

CHL

CSA studies

CSA events/patients

CSA

Infection

7

25/234

11%

4

3/75

4%

‐‐

‐‐

‐‐

Serious infection

7

12/234

5%

4

3/75

4%

‐‐

‐‐

‐‐

Leucopenia

14

65/356

18%

4

14/76

18%

‐‐

‐‐

‐‐

Medication ceased due to leucopenia

3

4/54

7%

2

3/52

6%

‐‐

‐‐

‐‐

Thrombocytopenia

4

8/131

6%

3

7/75

9%

‐‐

‐‐

‐‐

Hair loss

7

38/229

17%

3

3/75

4%

‐‐

‐‐

‐‐

Cystitis

7

7/178

4%

3

0/75

0%

‐‐

‐‐

‐‐

Gum hypertrophy

‐‐

‐‐

‐‐

‐‐

‐‐

‐‐

4

25/110

23%

Hirsutism

‐‐

‐‐

‐‐

‐‐

‐‐

‐‐

4

29/108

27%

Hypertension

‐‐

‐‐

‐‐

‐‐

‐‐

‐‐

4

14/106

13%

Kidney dysfunction

‐‐

‐‐

‐‐

‐‐

‐‐

‐‐

4

11/113

10%

CPA ‐ cyclophosphamide; CHL ‐ chlorambucil; CSA ‐ cyclosporin
Figures and Tables -
Table 1. Adverse effects due to alkylating agents or cyclosporin
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Comparison 1. Alkylating agents versus steroids or placebo or both

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse at 6 to 12 months Show forest plot

6

198

Risk Ratio (M‐H, Random, 95% CI)

0.43 [0.31, 0.60]

1.1 Cyclophosphamide versus prednisone (6 or 12 months)

4

157

Risk Ratio (M‐H, Random, 95% CI)

0.47 [0.33, 0.66]

1.2 Chlorambucil versus prednisone or placebo (at 6 months)

2

41

Risk Ratio (M‐H, Random, 95% CI)

0.19 [0.03, 1.09]

2 Relapse at 12 to 24 months Show forest plot

4

59

Risk Ratio (M‐H, Random, 95% CI)

0.20 [0.09, 0.46]

2.1 Cyclophosphamide versus prednisone (12 to 24 months)

2

27

Risk Ratio (M‐H, Random, 95% CI)

0.21 [0.07, 0.65]

2.2 Chlorambucil versus prednisone or placebo (at 12 months)

2

32

Risk Ratio (M‐H, Random, 95% CI)

0.15 [0.02, 0.95]
Figures and Tables -
Comparison 1. Alkylating agents versus steroids or placebo or both
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Comparison 2. Cyclophosphamide duration

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse at 6 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.1 8 weeks versus 2 weeks

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Relapse at 12 months Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 8 weeks versus 2 weeks

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 12 weeks versus 8 weeks

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Relapse rate at 24 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3.1 12 weeks versus 2 weeks

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 2. Cyclophosphamide duration
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Comparison 3. Cyclophosphamide dose

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse at 12 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2 Adverse effects Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 Leukopenia

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Lymphopenia

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Alopecia

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.4 Gastrointestinal

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.5 Genitourinary

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 3. Cyclophosphamide dose
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Comparison 4. Chlorambucil dose

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse at 12 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only
Figures and Tables -
Comparison 4. Chlorambucil dose
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Comparison 5. Intravenous versus oral cyclophosphamide

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse at 6 months Show forest plot

2

83

Risk Ratio (M‐H, Random, 95% CI)

0.54 [0.34, 0.88]

2 Continuing frequently relapsing or steroid dependent SSNS at 6 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3 Relapse at end of study Show forest plot

2

83

Risk Ratio (M‐H, Random, 95% CI)

0.99 [0.76, 1.29]

4 Adverse events Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

4.1 Leucopenia

2

83

Risk Ratio (M‐H, Random, 95% CI)

0.37 [0.09, 1.51]

4.2 Hair loss

2

83

Risk Ratio (M‐H, Random, 95% CI)

0.19 [0.04, 1.03]

4.3 All infections

2

83

Risk Ratio (M‐H, Random, 95% CI)

0.14 [0.03, 0.72]

4.4 Nausea and vomiting

1

47

Risk Ratio (M‐H, Random, 95% CI)

4.07 [0.21, 80.51]
Figures and Tables -
Comparison 5. Intravenous versus oral cyclophosphamide
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Comparison 6. Cyclophosphamide versus chlorambucil

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse at 12 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Relapse at 24 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 6. Cyclophosphamide versus chlorambucil
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Comparison 7. Post hoc analysis: alkylating agents in frequently relapsing and steroid‐dependent patients

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse at 24 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 7. Post hoc analysis: alkylating agents in frequently relapsing and steroid‐dependent patients
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Comparison 8. Cyclophosphamide versus vincristine

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse at 12 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Relapse at 24 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 8. Cyclophosphamide versus vincristine
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Comparison 9. Alkylating agents versus cyclosporin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse at end of therapy (6 to 9 months) Show forest plot

2

95

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.55, 1.48]

1.1 Cyclophosphamide versus cyclosporin

1

55

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.48, 2.35]

1.2 Chlorambucil versus cyclosporin

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.44, 1.53]

2 Relapse at 12 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 Chlorambucil versus cyclosporin

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Relapse at 12 to 24 months Show forest plot

2

95

Risk Ratio (M‐H, Random, 95% CI)

0.51 [0.35, 0.74]

3.1 Cyclophosphamide versus cyclosporin

1

55

Risk Ratio (M‐H, Random, 95% CI)

0.4 [0.22, 0.73]

3.2 Chlorambucil versus cyclosporin

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.58 [0.38, 0.87]

4 Adverse effects Show forest plot

2

Risk Difference (M‐H, Random, 95% CI)

Subtotals only

4.1 Serum creatinine

2

112

Risk Difference (M‐H, Random, 95% CI)

‐0.08 [‐0.17, ‐0.00]

4.2 Hypertrichosis

2

112

Risk Difference (M‐H, Random, 95% CI)

‐0.34 [‐0.46, ‐0.21]

4.3 Gum hypertrophy

2

112

Risk Difference (M‐H, Random, 95% CI)

‐0.23 [‐0.35, ‐0.12]

4.4 Hypertension

1

40

Risk Difference (M‐H, Random, 95% CI)

‐0.05 [‐0.18, 0.08]

4.5 Leucopenia

1

66

Risk Difference (M‐H, Random, 95% CI)

0.4 [0.22, 0.58]
Figures and Tables -
Comparison 9. Alkylating agents versus cyclosporin
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Comparison 10. Mycophenolate mofetil versus cyclosporin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse within 12 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 Relapse rate/year Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

3 Adverse effects Show forest plot

1

Risk Difference (M‐H, Random, 95% CI)

Totals not selected

3.1 Hypertension

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.2 Hypertrichosis

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.3 Lymphopenia

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.4 Gum hypertrophy

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.5 Reduced GFR

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.6 Pneumonia

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

4 GFR at 12 months Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected
Figures and Tables -
Comparison 10. Mycophenolate mofetil versus cyclosporin
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Comparison 11. Cyclosporin dose

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.1 6 months

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 12 months

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.3 24 months

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2 Adverse effects Show forest plot

2

Risk Difference (M‐H, Random, 95% CI)

Totals not selected

2.1 Hypertension

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Psychological disorder

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.3 Obesity

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.4 Hirsutism

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.5 Transient elevated creatinine

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.6 Gum hypertrophy

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.7 GIT effects

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.8 Convulsions

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.9 Fatigue

1

Risk Difference (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 11. Cyclosporin dose
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Comparison 12. Levamisole versus steroids or placebo or both, or no treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse during treatment (4 to 12 months) Show forest plot

7

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Including Weiss 1993

7

375

Risk Ratio (M‐H, Random, 95% CI)

0.47 [0.24, 0.89]

1.2 Excluding Weiss 1993

6

327

Risk Ratio (M‐H, Random, 95% CI)

0.41 [0.27, 0.61]

2 Relapse at 6 to 12 months Show forest plot

7

363

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.42, 0.91]

3 Mean relapse rate/patient/month Show forest plot

2

90

Mean Difference (IV, Random, 95% CI)

‐0.03 [‐0.27, 0.20]
Figures and Tables -
Comparison 12. Levamisole versus steroids or placebo or both, or no treatment
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Comparison 13. Levamisole versus cyclophosphamide

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Relapse at end of therapy

2

97

Risk Ratio (M‐H, Random, 95% CI)

2.14 [0.22, 20.95]

1.2 Relapse at 6 to 9 months after therapy

2

97

Risk Ratio (M‐H, Random, 95% CI)

1.17 [0.76, 1.81]

1.3 Relapse at 12 months after therapy

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.68, 1.16]

1.4 Relapse at 24 months after therapy

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.73, 1.10]

2 Adverse effects Show forest plot

2

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Infection

1

40

Risk Ratio (M‐H, Random, 95% CI)

1.08 [0.67, 1.75]

2.2 Leucopenia

2

97

Risk Ratio (M‐H, Random, 95% CI)

0.25 [0.04, 1.48]

2.3 Abnormal liver function tests

1

40

Risk Ratio (M‐H, Random, 95% CI)

0.33 [0.01, 7.72]
Figures and Tables -
Comparison 13. Levamisole versus cyclophosphamide
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Comparison 14. Rituximab + cyclosporin and prednisolone versus cyclosporin and prednisolone alone

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse at 3 months Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2 One year relapse‐free survival Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

2.1 Prednisone

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

2.2 Cyclosporin

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3 Adverse effects Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

3.1 Bronchospasm

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.2 Hypotension

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.3 Fever

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.4 Skin rash

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

3.5 Joint pain

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 14. Rituximab + cyclosporin and prednisolone versus cyclosporin and prednisolone alone
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Comparison 15. Azathioprine versus steroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Relapse at 6 months Show forest plot

2

60

Risk Ratio (M‐H, Random, 95% CI)

0.90 [0.59, 1.38]
Figures and Tables -
Comparison 15. Azathioprine versus steroids
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Comparison 16. Mizoribine versus placebo

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse effects Show forest plot

1

Risk Ratio (M‐H, Random, 95% CI)

Totals not selected

1.1 During treatment

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.2 Hyperuricaemia

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.3 Hepatic dysfunction

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]

1.4 Leucopenia

1

Risk Ratio (M‐H, Random, 95% CI)

0.0 [0.0, 0.0]
Figures and Tables -
Comparison 16. Mizoribine versus placebo
Navigate to table in Review