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KSR Number: KSRA69384

Efficacy and safety of immunosuppressive medications for steroid-resistant nephrotic syndrome in children: a systematic review and network meta-analysis

Risk of Bias Assessment

Overall summary: High risk of bias in the review

Bottom Line

Current evidence suggests that tacrolimus and cyclosporine may be preferred initial treatments for children with steroid-resistant nephrotic syndrome. Moreover, mycophenolate mofetil may also be considered as an alternative option for this patient population. There were some limitations with the review methods that could have impacted the sensitivity of the searches and consequently the inclusion of a number of relevant studies. Further studies are needed to evaluate the relative benefits and harms of tacrolimus versus cyclosporin and the safety and efficacy of mycophenolate mofetil in children with steroid-resistant nephrotic syndrome.

Risk of Bias Assessment

Overall summary High risk of bias in the review


The search strategy was not reported, and although heterogeneity assessment was pre-specified it was not clearly reported. Therefore it was not possible to assess this further.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? No
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review High

Details of Review

Number of studies 18
Number of participants 786
Last search date January 2017
Review type Intervention
Objective To evaluate the efficacy and safety of available immunosuppressive agents in paediatric patients with steroid-resistant nephrotic syndrome.
Population Children with initial steroid-resistant nephrotic syndrome (SRNS) (defined as persistence of proteinuria > 3+ on a dipstick test, urinary protein-creatinine (UP/C) ratio >0.2 grams (g)/mmol or 40 milligrams (mg)/m2/hours (h) after four weeks or more of daily corticosteroid use) and children with delayed SRNS).

Trials involving patients experiencing steroid-sensitive nephrotic syndrome, congenital nephrotic syndrome and other kidney or systemic forms were excluded.
Interventions Cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil (MMF), azathioprine, chlorambucil, rituximab, or levamisole.
Comparator Cyclophosphamide, cyclosporine, tacrolimus, MMF, azathioprine, chlorambucil, rituximab, or levamisole, placebo/non-treatment and/or another immunosuppressive medication.
Outcome The number/portion with complete remission (CR, defined as oedema-free and urine protein was < 1+ on dipstick tests, urinary UP/C < 0.02 g/mmol or 4 mg/m2/h for three or more consecutive days).

Number/portion with partial remission (PR, defined as proteinuria < 2+, urinary UP/C < 0.2 g/mmol or 40 mg/m2/h);

Total number/portion in remission (defined as the total number in remission, including patients in CR or PR).

The incidence of adverse secondary effects (defined as sequelae occurring within the initial post-treatment period).
Study design Parallel randomised controlled trials.


The pooled analysis reported that cyclosporine had significantly better efficacy for achieving both CR and PR relative to placebo/non-treatment (P/NT), while it had better efficacy than i.v. cyclophosphamide for both PR and total remission (TR) outcomes, than MMF for TR. Additionally, tacrolimus was more efficacious than intravenous (i.v.) cyclophosphamide for TR, while i.v. cyclophosphamide was more efficacious than oral cyclophosphamide for CR.

For adverse secondary effects (ASEs), oral cyclophosphamide was found to be safer than i.v. cyclophosphamide, while tacrolimus was found to be safer than both cyclosporin and i.v. cyclophosphamide. There were no significant differences in safety revealed by other direct comparisons between immunosuppressants in paediatric patients with steroid-resistant nephrotic syndrome.

The network meta-analysis (NMA) reported that tacrolimus was more efficacious for achieving CR than i.v. cyclophosphamide (odds ratio [OR] 0.21, 95% confidence interval [CI] 0.09 to 0.45), oral cyclophosphamide (OR 0.12, 95% CI 0.04 to 0.36), chlorambucil (OR 0.12, 95% CI 0.02 to 0.85) and P/NT (OR 0.12, 95% CI 0.04 to 0.43). Meanwhile, cyclosporin therapy was associated with a better CR rate than i.v. cyclophosphamide, MMF, oral cyclophosphamide, chlorambucil, azathioprine, or P/NT. However, there were no significant differences between all the comparisons in PR improvement.

The NMA reported that tacrolimus was more efficacious for achieving TR than i.v. cyclophosphamide (OR 0.16, 95% CI 0.08 to 0.34), oral cyclophosphamide (OR 0.13, 95% CI 0.05 to 0.40) and P/NT (OR 0.17, 95% CI 0.04 to 0.68). Cyclosporin was more likely to yield more TR outcomes than i.v. cyclophosphamide (OR 5.48, 95% CI 2.15 to 13.99), oral cyclophosphamide (OR 6.65, 95% CI 2.01 to 21.98) or P/NT (OR 5.29, 95% CI 1.28 to 21.91). However, MMF was more efficacious in TR than oral cyclophosphamide. Moreover, i.v. cyclophosphamide (OR 3.42, 95% CI 1.02 to 11.50) or rituximab-cyclosporin dual therapy (OR 59.56, 95% CI 2.12 to 1670.83) were more likely to result in ASEs than tacrolimus.

Medications with the highest cumulative probabilities of CR were cyclosporin (88.7%), tacrolimus (86.4%), rituximab-cyclosporin (82.8%), while medications with the lowest probabilities were P/NT (24.5%) and oral cyclophosphamide (24.2%). Similarly, cumulative probabilities of the analysed pharmacotherapies being the most efficacious medication for PR were tacrolimus (74.1%), cyclosporin (71.7%), MMF (65.9%), while medications with the lowest probabilities were azathioprine (33.5%), and P/NT (26.1%). Finally, for TR, medications with the highest cumulative probabilities were tacrolimus (91.5%), cyclosporin (87.8%), while drugs with the lowest probabilities were i.v. cyclophosphamide (28.1%), azathioprine (28.1%) and oral cyclophosphamide (19.6%). The cumulative probabilities of being the most adverse medication were rituximab-cyclosporin (96.8%), MMF (62.8%), while tacrolimus (7.3%) and oral cyclophosphamide (27.8%) were ranked as the safest drugs.

Full Risk of Bias Assessment

The research objective was clearly stated and appropriate inclusion criteria were defined. No restrictions were reported based on study characteristics. Trials for which only abstracts were published (with no additional data available from other sources) were excluded.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Probably yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Probably yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Probably no
Concerns regarding specification of study eligibility criteria High

MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE were searched for relevant studies. The reference lists of all included publications and relevant reviews were screened and was searched for trials in progress. Search keywords were provided, but a formal search strategy was not reported. No search restrictions were placed on date, publication format or language.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Probably yes
2.2 Were methods additional to database searching used to identify relevant reports? Probably yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? No information
2.4 Were restrictions based on date, publication format, or language appropriate? Probably yes
2.5 Were efforts made to minimise error in selection of studies? Yes
Concerns regarding methods used to identify and/or select studies Unclear

Data extraction was performed by two authors independently. Sufficient study characteristics appear to have been extracted to allow interpretation of the results. Relevant study results appear to have been extracted. The methodological quality of included studies was assessed using the Cochrane risk of bias tool. Two authors were independently involved in the assessment of risk of bias.

3.1 Were efforts made to minimise error in data collection? Yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Probably yes
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Probably yes
3.5 Were efforts made to minimise error in risk of bias assessment? Yes
Concerns regarding methods used to collect data and appraise studies Low

The synthesis appeared to include all relevant studies. The method of analysis was explained and appeared appropriate. Heterogeneity assessment was pre-specified, but was not clearly reported, therefore it was not possible to assess this further. No evidence of significant publication bias (asymmetry) was found using the funnel plot. The quality of individual studies was considered in the synthesis.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably no
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Probably yes
Concerns regarding synthesis and findings Unclear