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Meta-Analysis
. 2016 Oct 11;10(10):CD003594.
doi: 10.1002/14651858.CD003594.pub5.

Interventions for idiopathic steroid-resistant nephrotic syndrome in children

Elisabeth M Hodson  1 , Sophia C Wong, Narelle S Willis, Jonathan C Craig
Affiliations
Meta-Analysis

Interventions for idiopathic steroid-resistant nephrotic syndrome in children

Elisabeth M Hodson et al. Cochrane Database Syst Rev. .

Update in

Abstract

Background: The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy. Children who fail to respond may be treated with immunosuppressive agents including calcineurin inhibitors (cyclosporin or tacrolimus) and with non-immunosuppressive agents such as angiotensin-converting enzyme inhibitors (ACEi). Optimal combinations of these agents with the least toxicity remain to be determined. This is an update of a review first published in 2004 and updated in 2006 and 2010.

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

Search methods: We searched Cochrane Kidney and Transplant's Specialised Register (up to 2 March 2016) through contact with the Information Specialist using search terms relevant to this review.

Selection criteria: RCTs and quasi-RCTs were included if they compared different immunosuppressive agents or non-immunosuppressive agents with placebo, prednisone or other agent given orally or parenterally in children aged three months to 18 years with SRNS.

Data collection and analysis: Two authors independently searched the literature, determined study eligibility, assessed risk of bias and extracted data. For dichotomous outcomes, results were expressed as risk ratios (RR) and 95% confidence intervals (CI). Data were pooled using the random effects model.

Main results: Nineteen RCTs (820 children enrolled; 773 evaluated) were included. Most studies were small. Eleven studies were at low risk of bias for allocation concealment and only four studies were at low risk of performance bias. Fifteen, eight and 10 studies were at low risk of detection bias, attrition bias and reporting bias respectively. Cyclosporin when compared with placebo or no treatment significantly increased the number of children who achieved complete remission. However this was based on only eight children who achieved remission with cyclosporin compared with no children who achieved remission with placebo/no treatment in three small studies (49 children: RR 7.66, 95% CI 1.06 to 55.34). Calcineurin inhibitors significantly increased the number with complete or partial remission compared with IV cyclophosphamide (2 studies, 156 children: RR 1.98, 95% CI 1.25 to 3.13; I2 = 20%). There was no significant differences in the number who achieved complete remission between tacrolimus versus cyclosporin (1 study, 41 children: RR 0.86, 95% CI 0.44 to 1.66), cyclosporin versus mycophenolate mofetil plus dexamethasone (1 study, 138 children: RR 2.14, 95% CI 0.87 to 5.24), oral cyclophosphamide with prednisone versus prednisone alone (2 studies, 91 children: RR 1.06, 95% CI 0.61 to 1.87), IV versus oral cyclophosphamide (1 study, 11 children: RR 3.13, 95% CI 0.81 to 12.06), IV cyclophosphamide versus oral cyclophosphamide plus IV dexamethasone (1 study, 49 children: RR 1.13, 95% CI 0.65 to 1.96), and azathioprine with prednisone versus prednisone alone (1 study, 31 children: RR 0.94, 95% CI 0.15 to 5.84). One study found no significant differences between three agents (cyclophosphamide, mycophenolate mofetil, leflunomide) used in combination with tacrolimus and prednisone. One study found no significant difference in the percentage reduction in proteinuria (31 children: -12; 95% CI -73 to 110) between rituximab with cyclosporin/prednisolone and cyclosporin/prednisolone alone. Two studies reported ACEi significantly reduced proteinuria.

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

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Conflict of interest statement

  1. Elisabeth Hodson: none known

  2. Sophia Wong: none known

  3. Narelle Willis: none known

  4. Jonathan Craig: none known

Figures

Figure 1
Figure 1
Flowchart of included and excluded studies
Figure 2
Figure 2
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Figure 3
Figure 3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Analysis 1.1
Analysis 1.1
Comparison 1 Cyclosporin versus placebo/no treatment, Outcome 1 Complete remission.
Analysis 1.2
Analysis 1.2
Comparison 1 Cyclosporin versus placebo/no treatment, Outcome 2 Complete or partial remission.
Analysis 1.3
Analysis 1.3
Comparison 1 Cyclosporin versus placebo/no treatment, Outcome 3 Adverse events.
Analysis 2.1
Analysis 2.1
Comparison 2 Calcineurin inhibitor versus IV cyclophosphamide, Outcome 1 Treatment response at 3 to 6 months.
Analysis 2.2
Analysis 2.2
Comparison 2 Calcineurin inhibitor versus IV cyclophosphamide, Outcome 2 Mean time to remission.
Analysis 2.3
Analysis 2.3
Comparison 2 Calcineurin inhibitor versus IV cyclophosphamide, Outcome 3 Complete remission/SSNS at 12 months in 80 patients with complete or partial remission at 6 months.
Analysis 2.4
Analysis 2.4
Comparison 2 Calcineurin inhibitor versus IV cyclophosphamide, Outcome 4 Other outcomes at 12 months in 38 patients with partial remission at 6 months.
Analysis 2.5
Analysis 2.5
Comparison 2 Calcineurin inhibitor versus IV cyclophosphamide, Outcome 5 Adverse events.
Analysis 3.1
Analysis 3.1
Comparison 3 Tacrolimus versus cyclosporin, Outcome 1 Treatment response at 6 months.
Analysis 3.2
Analysis 3.2
Comparison 3 Tacrolimus versus cyclosporin, Outcome 2 Treatment response at 12 months.
Analysis 3.3
Analysis 3.3
Comparison 3 Tacrolimus versus cyclosporin, Outcome 3 Relapse following complete or partial remission.
Analysis 3.4
Analysis 3.4
Comparison 3 Tacrolimus versus cyclosporin, Outcome 4 Post hoc analysis: complete remission in initial and late onset SRNS.
Analysis 3.5
Analysis 3.5
Comparison 3 Tacrolimus versus cyclosporin, Outcome 5 Post hoc analysis: complete or partial remission in initial and late onset SRNS.
Analysis 3.6
Analysis 3.6
Comparison 3 Tacrolimus versus cyclosporin, Outcome 6 Change in eGFR over 12 months.
Analysis 3.7
Analysis 3.7
Comparison 3 Tacrolimus versus cyclosporin, Outcome 7 Adverse events.
Analysis 4.1
Analysis 4.1
Comparison 4 Cyclosporin versus mycophenolate mofetil with pulse dexamethasone, Outcome 1 Treatment response at 52 weeks.
Analysis 4.2
Analysis 4.2
Comparison 4 Cyclosporin versus mycophenolate mofetil with pulse dexamethasone, Outcome 2 Sustainable remission between 52 and 78 weeks.
Analysis 4.3
Analysis 4.3
Comparison 4 Cyclosporin versus mycophenolate mofetil with pulse dexamethasone, Outcome 3 CKD or death.
Analysis 4.4
Analysis 4.4
Comparison 4 Cyclosporin versus mycophenolate mofetil with pulse dexamethasone, Outcome 4 Adverse events (weeks 0 to 26).
Analysis 5.1
Analysis 5.1
Comparison 5 Triple therapy with cyclophosphamide, mycophenolate mofetil or leflunomide, Outcome 1 Short‐term response.
Analysis 5.2
Analysis 5.2
Comparison 5 Triple therapy with cyclophosphamide, mycophenolate mofetil or leflunomide, Outcome 2 Long‐term response.
Analysis 6.1
Analysis 6.1
Comparison 6 Tacrolimus versus mycophenolate mofetil to maintain remission, Outcome 1 Treatment response.
Analysis 6.2
Analysis 6.2
Comparison 6 Tacrolimus versus mycophenolate mofetil to maintain remission, Outcome 2 Relapses per year.
Analysis 6.3
Analysis 6.3
Comparison 6 Tacrolimus versus mycophenolate mofetil to maintain remission, Outcome 3 Prednisone dose.
Analysis 6.4
Analysis 6.4
Comparison 6 Tacrolimus versus mycophenolate mofetil to maintain remission, Outcome 4 Change in GFR.
Analysis 7.1
Analysis 7.1
Comparison 7 Oral cyclophosphamide versus prednisone/placebo, Outcome 1 Complete remission.
Analysis 7.2
Analysis 7.2
Comparison 7 Oral cyclophosphamide versus prednisone/placebo, Outcome 2 Complete or partial remission.
Analysis 7.3
Analysis 7.3
Comparison 7 Oral cyclophosphamide versus prednisone/placebo, Outcome 3 Treatment failure.
Analysis 7.4
Analysis 7.4
Comparison 7 Oral cyclophosphamide versus prednisone/placebo, Outcome 4 Adverse events.
Analysis 8.1
Analysis 8.1
Comparison 8 IV versus oral cyclophosphamide, Outcome 1 Complete remission.
Analysis 8.2
Analysis 8.2
Comparison 8 IV versus oral cyclophosphamide, Outcome 2 Adverse events.
Analysis 9.1
Analysis 9.1
Comparison 9 IV cyclophosphamide versus oral cyclophosphamide plus IV dexamethasone, Outcome 1 Treatment response at 6 months.
Analysis 9.2
Analysis 9.2
Comparison 9 IV cyclophosphamide versus oral cyclophosphamide plus IV dexamethasone, Outcome 2 Treatment response at 18 months.
Analysis 9.3
Analysis 9.3
Comparison 9 IV cyclophosphamide versus oral cyclophosphamide plus IV dexamethasone, Outcome 3 Complete or partial resistance in subgroups.
Analysis 9.4
Analysis 9.4
Comparison 9 IV cyclophosphamide versus oral cyclophosphamide plus IV dexamethasone, Outcome 4 Adverse events.
Analysis 10.1
Analysis 10.1
Comparison 10 Rituximab/cyclosporin/prednisolone versus cyclosporin/prednisolone, Outcome 1 Complete remission.
Analysis 10.2
Analysis 10.2
Comparison 10 Rituximab/cyclosporin/prednisolone versus cyclosporin/prednisolone, Outcome 2 End of study creatinine.
Analysis 10.3
Analysis 10.3
Comparison 10 Rituximab/cyclosporin/prednisolone versus cyclosporin/prednisolone, Outcome 3 End of study serum albumin.
Analysis 10.4
Analysis 10.4
Comparison 10 Rituximab/cyclosporin/prednisolone versus cyclosporin/prednisolone, Outcome 4 Adverse events.
Analysis 11.1
Analysis 11.1
Comparison 11 Chlorambucil versus indomethacin, Outcome 1 Complete remission.
Analysis 11.2
Analysis 11.2
Comparison 11 Chlorambucil versus indomethacin, Outcome 2 End‐stage kidney disease.
Analysis 12.1
Analysis 12.1
Comparison 12 Azathioprine versus placebo, Outcome 1 Complete remission.
Analysis 12.2
Analysis 12.2
Comparison 12 Azathioprine versus placebo, Outcome 2 Complete or partial remission.
Analysis 13.1
Analysis 13.1
Comparison 13 Fosinopril plus prednisone versus prednisone alone, Outcome 1 Proteinuria.
Analysis 13.2
Analysis 13.2
Comparison 13 Fosinopril plus prednisone versus prednisone alone, Outcome 2 Tubular proteinuria.
Analysis 13.3
Analysis 13.3
Comparison 13 Fosinopril plus prednisone versus prednisone alone, Outcome 3 Serum albumin.
Analysis 13.4
Analysis 13.4
Comparison 13 Fosinopril plus prednisone versus prednisone alone, Outcome 4 Systolic blood pressure.
Analysis 13.5
Analysis 13.5
Comparison 13 Fosinopril plus prednisone versus prednisone alone, Outcome 5 Creatinine clearance.
Analysis 13.6
Analysis 13.6
Comparison 13 Fosinopril plus prednisone versus prednisone alone, Outcome 6 Serum potassium.
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Update of

References

References to studies included in this review

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References to studies excluded from this review

    1. Adeniyi A, Hendrickse RG, Soothill JF. A controlled trial of cyclophosphamide and azathioprine in Nigerian children with the nephrotic syndrome and poorly selective proteinuria. Archives of Disease in Childhood 1979;54(3):204‐7. [MEDLINE: ] - PMC - PubMed
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    1. Bhaumik SK, Barman SC. Comparison of pulse methyl prednisolone vs cyclosporin based therapy in steroid resistant focal segmental glomerulosclerosis [abstract]. Indian Journal of Nephrology 2002;12(4):190. [CENTRAL: CN‐00460392]
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    1. Hiraoka M, Sudo M, West Japanese Cooperative Study of Kidney Disease in Children. Low versus standard dosage of prednisolone for initial treatment of idiopathic nephrotic syndrome in children [abstract no: A0445]. Journal of the American Society of Nephrology 1996;7(9):1335.
    2. Hiraoka M, Tsukahara H, Haruki S, Hayashi S, Takeda N, Miyagawa K, et al. Older boys benefit from higher initial prednisolone therapy for nephrotic syndrome. The West Japan Cooperative Study of Kidney Disease in Children. Kidney International 2000;58(3):1247‐52. [MEDLINE: ] - PubMed
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References to ongoing studies

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    1. Basu B. Efficacy and safety of rituximab to that of calcineurin inhibitors in children with steroid resistant nephrotic syndrome. www.clinicaltrials.gov/ct2/show/NCT023825752015; Vol. (accessed 2 March 2016).
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Additional references

    1. Chua A, Yorgin P. Steroid‐Resistant Nephrotic Syndrome. In: Molony DA, Craig JC editor(s). Evidence‐Based Nephrology. Wiley‐Blackwell, 2009.
    1. Colquitt JL, Kirby J, Green C, Cooper K, Trompeter RS. The clinical effectiveness and cost‐effectiveness of treatments for children with idiopathic steroid‐resistant nephrotic syndrome: a systematic review. Health Technology Assessment (Winchester, England) 2007;11(21):1‐93. [MEDLINE: ] - PubMed
    1. Deegens JK, Wetzels JF. Immunosuppressive treatment of focal and segmental glomerulosclerosis: lessons from a randomized controlled trial. Kidney International 2011;80(8):798‐801. [MEDLINE: ] - PubMed
    1. Ding WY, Koziell A, McCarthy HJ, Bierzynska A, Bhagavatula MK, Dudley JA, et al. Initial steroid sensitivity in children with steroid‐resistant nephrotic syndrome predicts post‐transplant recurrence. Journal of the American Society of Nephrology 2014;25(6):1342–8. [MEDLINE: ] - PMC - PubMed
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References to other published versions of this review

    1. Habashy D, Hodson E, Craig J. Interventions for idiopathic steroid‐resistant nephrotic syndrome in children. Cochrane Database of Systematic Reviews 2001, Issue 2. [DOI: 10.1002/14651858.CD003594] - DOI - PubMed
    1. Habashy D, Hodson EM, Craig JC. Interventions for steroid‐resistant nephrotic syndrome: a systematic review. Pediatric Nephrology 2003;18(9):906‐12. [MEDLINE: ] - PubMed
    1. Habashy D, Hodson E, Craig J. Interventions for idiopathic steroid‐resistant nephrotic syndrome in children. Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: 10.1002/14651858.CD003594.pub2] - DOI - PubMed
    1. Habashy D, Hodson E, Craig J. Interventions for idiopathic steroid‐resistant nephrotic syndrome in children. Cochrane Database of Systematic Reviews 2006, Issue 2. [DOI: 10.1002/14651858.CD003594.pub3] - DOI - PubMed
    1. Hodson EM, Willis NS, Craig JC. Interventions for idiopathic steroid‐resistant nephrotic syndrome in children. Cochrane Database of Systematic Reviews 2010, Issue 11. [DOI: 10.1002/14651858.CD003594.pub4] - DOI - PubMed

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