Browse the corpus

Interventions for idiopathic steroid-resistant nephrotic syndrome in children. BACKGROUND: The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy. Children who fail to respond to corticosteroids in the first episode of nephrotic syndrome (initial resistance) or develop resistance after one or more responses to corticosteroids (delayed resistance) may be treated with immunosuppressive agents including calcineurin inhibitors (CNI) (cyclosporin or tacrolimus) and with non-immunosuppressive agents such as angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). However, response to these agents is limited so newer agents are being assessed for efficacy. This is an update of a review first published in 2004 and updated in 2006, 2010 and 2016. OBJECTIVES: To evaluate the benefits and harms of different interventions used in children with idiopathic nephrotic syndrome, who do not achieve remission following four weeks or more of daily corticosteroid therapy. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies to 17 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs were included if they compared different immunosuppressive agents or non-immunosuppressive agents with placebo, prednisone or other agent given orally or parenterally in children aged three months to 18 years with steroid-resistant nephrotic syndrome (SRNS). Studies, which enrolled children and adults but in which paediatric data could not be separated from adult data, were also included. DATA COLLECTION AND ANALYSIS: Two authors independently searched the literature, determined study eligibility, assessed risk of bias and extracted data. For dichotomous outcomes, results were expressed as risk ratios (RR) and 95% confidence intervals (CI). For continuous outcomes, results were expressed as mean difference (MD) and 95% CI. Data were pooled using the random effects model. The certainty of the evidence was assessed using the GRADE approach. MAIN RESULTS: Twenty-five studies (1063 participants) were included. Fourteen studies were at low risk of bias for sequence generation and allocation concealment. Five and 19 studies were at low risk of performance and detection bias. Fourteen, 14 and 13 studies were at low risk of attrition bias, reporting bias and other bias respectively. Cyclosporin compared with placebo or no treatment may increase the number of participants who achieve complete remission (4 studies, 74 participants: RR 3.50, 95% CI 1.09 to 11.20) or complete or partial remission (4 studies, 74 children: RR 3.15, 95% CI 1.04 to 9.57) by 6 months (low certainty evidence). It is uncertain whether cyclosporin increases the likelihood of worsening hypertension or reduces the likelihood of end-stage kidney disease (very low certainty evidence). CNI compared with IV cyclophosphamide (CPA) may increase the number of participants with complete or partial remission at 3 to 6 months (2 studies, 156 children: RR 1.98, 95% CI 1.25 to 3.13) (low certainty evidence) and probably reduces the number with treatment failure (non response, serious infection, persistently elevated creatinine (1 study, 124 participants: RR 0.32, 95% CI 0.18 to 0.58) (moderate certainty evidence) with little or no increase in serious infections (1 study, 131 participants: RR 0.49, 95% CI 0.16 to 1.56) (moderate certainty evidence). Tacrolimus compared with cyclosporin may make little or no difference to the number who achieve complete or partial remission (2 studies, 58 participants: RR 1.05, 95% CI 0.87 to 1.25) (low certainty evidence) or in the number with worsening hypertension (2 studies, 58 participants: RR 0.41, 95% CI 0.08 to 2.15) (low certainty evidence). Cyclosporin compared with mycophenolate mofetil (MMF) and dexamethasone probably makes little or no difference to the number who achieve complete or partial remission (1 study, 138 participants: RR 2.14, 95% CI 0.87 to 5.24) (moderate certainty evidence) and makes little or no difference to the number dying (1 study, 138 participants: RR 2.14, 95% CI 0.87 to 5.24) or with 50% reduction in glomerular filtration rate (GFR) (1 study, 138 participants: RR 2.29, 95% CI 0.46 to 11.41) (low certainty evidence). Among children, who have achieved complete remission, tacrolimus compared with MMF may increase the number of children who maintain complete or partial response for 12 months (1 study, 60 children: RR 2.01, 95% CI 1.32 to 3.07) (low certainty evidence). Oral CPA with prednisone compared with prednisone alone may make little or no difference to the number who achieve complete remission (2 studies, 84 children: RR 1.06, 95% CI 0.61 to 1.87) (low certainty evidence). IV CPA compared with oral CPA (2 studies, 61 children: RR 1.58, 95% CI 0.65 to 3.85) and IV compared with oral CPA plus IV dexamethasone (1 study, 49 children: RR 1.13, 95% CI 0.65 to 1.96) may make little or no difference to the number who achieve complete remission (low certainty evidence). It is uncertain whether rituximab and cyclosporin compared with cyclosporin increases the likelihood of remission because the certainty of the evidence is very low. It is uncertain whether adalimumab or galactose compared with conservative therapy increases the likelihood of remission because the certainty of the evidence is very low. Two studies reported that ACEi may reduce proteinuria in children with SRNS. One study reported that the dual angiotensin II and endothelin Type A receptor antagonist, sparsentan, may reduce proteinuria more effectively than the angiotensin receptor blocker, irbesartan. AUTHORS' CONCLUSIONS: To date RCTs have demonstrated that CNIs may increase the likelihood of complete or partial remission compared with placebo/no treatment or CPA. For other regimens assessed, it remains uncertain whether the interventions alter outcomes because the certainty of the evidence is low. Further adequately powered, well designed RCTs are needed to evaluate other regimens for children with idiopathic SRNS. Since SRNS represents a spectrum of diseases, future studies should enrol children from better defined groups of patients with SRNS.

Interventions for idiopathic steroid-resistant nephrotic syndrome in children. 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.