Non‐corticosteroid immunosuppressive medications for steroid‐sensitive nephrotic syndrome in children
Background About 80% of children with steroid‐sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non‐corticosteroid immunosuppressive medications prolong periods of remission, they have signifi...
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| Veröffentlicht in: | Cochrane database of systematic reviews 2020-04, Vol.2020 (4), p.CD002290 |
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| creator | Larkins, Nicholas G Liu, Isaac D Willis, Narelle S Craig, Jonathan C Hodson, Elisabeth M Hodson, Elisabeth M |
| description | Background
About 80% of children with steroid‐sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non‐corticosteroid immunosuppressive medications prolong periods of remission, they 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. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013.
Objectives
To evaluate the benefits and harms of non‐corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome.
Search methods
We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 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) or quasi‐RCTs were included if they involved children with SSNS and compared non‐corticosteroid immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non‐corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non‐corticosteroid immunosuppressive medication.
Data collection and analysis
Two authors independently assessed study eligibility, 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) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE.
Main results
We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and 10 were at low risk of detection bia |
| doi_str_mv | 10.1002/14651858.CD002290.pub5 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7160055</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2390647296</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4735-c59b18e3759aa553ab85bd048a7838f1acb0307191d3a7b3423a888f96bb51433</originalsourceid><addsrcrecordid>eNqFkctOxCAYhYnRODr6CpMu3cwIpRS6MdHxmkx0o2tCKXUwLVRox8zOR_AZfRJp5pLRjSsg5_vP-cMBYITgBEEYn6MkJYgRNpleh2ecwUnT5WQPHPXCuFf2d-4DcOz9G4Q4zWJ6CAY4TFAM2RHQj9Z8f35J61otrW-Vs7qIdF13xvquaZzyXi9UVKtCS9Fqa3xUWhetyTDqlfG67RmjmrmzwSfyS1M4W6tIm0jOdVU4ZU7AQSkqr07X5xC83N48T-_Hs6e7h-nlbCwTislYkixHTGFKMiEIwSJnJC9gwgRlmJVIyBxiSFGGCixojpMYC8ZYmaV5TlCC8RBcrHzDh4StpTKtExVvnK6FW3IrNP-tGD3nr3bBKUohDIlDcLY2cPa9U77ltfZSVZUwynaexziDaULjLA1oukKls947VW5jEOR9T3zTE9_01If3GaPdJbdjm2ICcLUCPnSlllxaOXch_x_fPyk_udyo8g</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2390647296</pqid></control><display><type>article</type><title>Non‐corticosteroid immunosuppressive medications for steroid‐sensitive nephrotic syndrome in children</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Cochrane Library</source><source>Alma/SFX Local Collection</source><creator>Larkins, Nicholas G ; Liu, Isaac D ; Willis, Narelle S ; Craig, Jonathan C ; Hodson, Elisabeth M ; Hodson, Elisabeth M</creator><creatorcontrib>Larkins, Nicholas G ; Liu, Isaac D ; Willis, Narelle S ; Craig, Jonathan C ; Hodson, Elisabeth M ; Hodson, Elisabeth M</creatorcontrib><description>Background
About 80% of children with steroid‐sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non‐corticosteroid immunosuppressive medications prolong periods of remission, they 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. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013.
Objectives
To evaluate the benefits and harms of non‐corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome.
Search methods
We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 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) or quasi‐RCTs were included if they involved children with SSNS and compared non‐corticosteroid immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non‐corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non‐corticosteroid immunosuppressive medication.
Data collection and analysis
Two authors independently assessed study eligibility, 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) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE.
Main results
We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and 10 were at low risk of detection bias. Thirty‐seven and 27 studies were at low risk of incomplete and selective reporting respectively.
Rituximab (in combination with calcineurin inhibitors (CNI) and prednisolone) versus CNI and prednisolone probably reduces the number of children who relapse at six months (5 studies, 269 children: RR 0.23, 95% CI 0.12 to 0.43) and 12 months (3 studies, 198 children: RR 0.63, 95% CI 0.42 to 0.93) (moderate certainty evidence). At six months, rituximab resulted in 126 children/1000 relapsing compared with 548 children/1000 treated with conservative treatments. Rituximab may result in infusion reactions (4 studies, 252 children: RR 5.83, 95% CI 1.34 to 25.29).
Mycophenolate mofetil (MMF) and levamisole may have similar effects on the number of children who relapse at 12 months (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16). MMF may have a similar effect on the number of children relapsing compared to cyclosporin (2 studies, 82 children: RR 1.90, 95% CI 0.66 to 5.46) (low certainty evidence). MMF compared to cyclosporin is probably less likely to result in hypertrichosis (3 studies, 140 children: RR 0.23, 95% CI 0.10 to 0.50) and gum hypertrophy (3 studies, 144 children: RR 0.09, 95% CI 0.07 to 0.42) (low certainty evidence).
Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children: RR 0.52, 95% CI 0.33 to 0.82) (low certainty evidence). Levamisole compared to cyclophosphamide may make little or no difference to the risk for relapse after 6 to 9 months (2 studies, 97 children: RR 1.17, 95% CI 0.76 to 1.81) (low certainty evidence).
Cyclosporin compared with prednisolone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty evidence). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at 12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74), suggesting that the benefit of the alkylating agents may be sustained beyond the on‐treatment period (low certainty evidence).
Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children, who experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR 0.20, 95% CI 0.09 to 0.46) (moderate certainty evidence). IV cyclophosphamide may reduce the number of children with relapse compared with oral cyclophosphamide at 6 months (2 studies, 83 children: RR 0.54, 95% CI 0.34 to 0.88), but not at 12 to 24 months (2 studies, 83 children: RR 0.99, 95% CI 0.76 to 1.29) and may result in fewer infections (2 studies, 83 children: RR 0.14, 95% CI 0.03 to 0.72) (low certainty evidence). Cyclophosphamide compared to chlorambucil may make little or no difference in the risk of relapse after 12 months (1 study, 50 children: RR 1.31, 95% CI 0.80 to 2.13) (low certainty evidence).
Authors' conclusions
New studies incorporated in this review indicate that rituximab is a valuable additional agent for managing children with steroid‐dependent nephrotic syndrome. However, the treatment effect is temporary, and many children will require additional courses of rituximab. The long‐term adverse effects of this treatment are not known. Comparative studies of CNIs, MMF, levamisole and alkylating agents have demonstrated little or no differences in efficacy but, because of insufficient power; clinically important differences in treatment effects have not been completely excluded.</description><identifier>ISSN: 1465-1858</identifier><identifier>ISSN: 1469-493X</identifier><identifier>EISSN: 1465-1858</identifier><identifier>EISSN: 1469-493X</identifier><identifier>DOI: 10.1002/14651858.CD002290.pub5</identifier><identifier>PMID: 32297308</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Adolescent ; Alkylating Agents ; Alkylating Agents - adverse effects ; Alkylating Agents - therapeutic use ; Azathioprine ; Azathioprine - adverse effects ; Azathioprine - therapeutic use ; Child ; Child health ; Child, Preschool ; Chlorambucil ; Chlorambucil - adverse effects ; Chlorambucil - therapeutic use ; CHRONIC KIDNEY DISEASE ; Cyclophosphamide ; Cyclophosphamide - adverse effects ; Cyclophosphamide - therapeutic use ; Cyclosporine ; Cyclosporine - adverse effects ; Cyclosporine - therapeutic use ; Glomerular disease ; Glomerular diseases ; Humans ; Immunosuppressive Agents ; Immunosuppressive Agents - adverse effects ; Immunosuppressive Agents - therapeutic use ; Infant ; Kidney disease ; Levamisole ; Levamisole - adverse effects ; Levamisole - therapeutic use ; Medicine General & Introductory Medical Sciences ; Mycophenolic Acid ; Mycophenolic Acid - adverse effects ; Mycophenolic Acid - therapeutic use ; Nephrotic Syndrome ; Nephrotic Syndrome - drug therapy ; Nephrotic Syndrome - prevention & control ; Prednisolone ; Prednisolone - adverse effects ; Prednisolone - therapeutic use ; Prednisone ; Prednisone - therapeutic use ; Randomized Controlled Trials as Topic ; Recurrence ; Ribonucleosides ; Ribonucleosides - therapeutic use ; Rituximab ; Rituximab - adverse effects ; Rituximab - therapeutic use ; Secondary Prevention</subject><ispartof>Cochrane database of systematic reviews, 2020-04, Vol.2020 (4), p.CD002290</ispartof><rights>Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4735-c59b18e3759aa553ab85bd048a7838f1acb0307191d3a7b3423a888f96bb51433</citedby><cites>FETCH-LOGICAL-c4735-c59b18e3759aa553ab85bd048a7838f1acb0307191d3a7b3423a888f96bb51433</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32297308$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Larkins, Nicholas G</creatorcontrib><creatorcontrib>Liu, Isaac D</creatorcontrib><creatorcontrib>Willis, Narelle S</creatorcontrib><creatorcontrib>Craig, Jonathan C</creatorcontrib><creatorcontrib>Hodson, Elisabeth M</creatorcontrib><creatorcontrib>Hodson, Elisabeth M</creatorcontrib><title>Non‐corticosteroid immunosuppressive medications for steroid‐sensitive nephrotic syndrome in children</title><title>Cochrane database of systematic reviews</title><addtitle>Cochrane Database Syst Rev</addtitle><description>Background
About 80% of children with steroid‐sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non‐corticosteroid immunosuppressive medications prolong periods of remission, they 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. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013.
Objectives
To evaluate the benefits and harms of non‐corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome.
Search methods
We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 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) or quasi‐RCTs were included if they involved children with SSNS and compared non‐corticosteroid immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non‐corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non‐corticosteroid immunosuppressive medication.
Data collection and analysis
Two authors independently assessed study eligibility, 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) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE.
Main results
We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and 10 were at low risk of detection bias. Thirty‐seven and 27 studies were at low risk of incomplete and selective reporting respectively.
Rituximab (in combination with calcineurin inhibitors (CNI) and prednisolone) versus CNI and prednisolone probably reduces the number of children who relapse at six months (5 studies, 269 children: RR 0.23, 95% CI 0.12 to 0.43) and 12 months (3 studies, 198 children: RR 0.63, 95% CI 0.42 to 0.93) (moderate certainty evidence). At six months, rituximab resulted in 126 children/1000 relapsing compared with 548 children/1000 treated with conservative treatments. Rituximab may result in infusion reactions (4 studies, 252 children: RR 5.83, 95% CI 1.34 to 25.29).
Mycophenolate mofetil (MMF) and levamisole may have similar effects on the number of children who relapse at 12 months (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16). MMF may have a similar effect on the number of children relapsing compared to cyclosporin (2 studies, 82 children: RR 1.90, 95% CI 0.66 to 5.46) (low certainty evidence). MMF compared to cyclosporin is probably less likely to result in hypertrichosis (3 studies, 140 children: RR 0.23, 95% CI 0.10 to 0.50) and gum hypertrophy (3 studies, 144 children: RR 0.09, 95% CI 0.07 to 0.42) (low certainty evidence).
Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children: RR 0.52, 95% CI 0.33 to 0.82) (low certainty evidence). Levamisole compared to cyclophosphamide may make little or no difference to the risk for relapse after 6 to 9 months (2 studies, 97 children: RR 1.17, 95% CI 0.76 to 1.81) (low certainty evidence).
Cyclosporin compared with prednisolone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty evidence). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at 12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74), suggesting that the benefit of the alkylating agents may be sustained beyond the on‐treatment period (low certainty evidence).
Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children, who experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR 0.20, 95% CI 0.09 to 0.46) (moderate certainty evidence). IV cyclophosphamide may reduce the number of children with relapse compared with oral cyclophosphamide at 6 months (2 studies, 83 children: RR 0.54, 95% CI 0.34 to 0.88), but not at 12 to 24 months (2 studies, 83 children: RR 0.99, 95% CI 0.76 to 1.29) and may result in fewer infections (2 studies, 83 children: RR 0.14, 95% CI 0.03 to 0.72) (low certainty evidence). Cyclophosphamide compared to chlorambucil may make little or no difference in the risk of relapse after 12 months (1 study, 50 children: RR 1.31, 95% CI 0.80 to 2.13) (low certainty evidence).
Authors' conclusions
New studies incorporated in this review indicate that rituximab is a valuable additional agent for managing children with steroid‐dependent nephrotic syndrome. However, the treatment effect is temporary, and many children will require additional courses of rituximab. The long‐term adverse effects of this treatment are not known. Comparative studies of CNIs, MMF, levamisole and alkylating agents have demonstrated little or no differences in efficacy but, because of insufficient power; clinically important differences in treatment effects have not been completely excluded.</description><subject>Adolescent</subject><subject>Alkylating Agents</subject><subject>Alkylating Agents - adverse effects</subject><subject>Alkylating Agents - therapeutic use</subject><subject>Azathioprine</subject><subject>Azathioprine - adverse effects</subject><subject>Azathioprine - therapeutic use</subject><subject>Child</subject><subject>Child health</subject><subject>Child, Preschool</subject><subject>Chlorambucil</subject><subject>Chlorambucil - adverse effects</subject><subject>Chlorambucil - therapeutic use</subject><subject>CHRONIC KIDNEY DISEASE</subject><subject>Cyclophosphamide</subject><subject>Cyclophosphamide - adverse effects</subject><subject>Cyclophosphamide - therapeutic use</subject><subject>Cyclosporine</subject><subject>Cyclosporine - adverse effects</subject><subject>Cyclosporine - therapeutic use</subject><subject>Glomerular disease</subject><subject>Glomerular diseases</subject><subject>Humans</subject><subject>Immunosuppressive Agents</subject><subject>Immunosuppressive Agents - adverse effects</subject><subject>Immunosuppressive Agents - therapeutic use</subject><subject>Infant</subject><subject>Kidney disease</subject><subject>Levamisole</subject><subject>Levamisole - adverse effects</subject><subject>Levamisole - therapeutic use</subject><subject>Medicine General & Introductory Medical Sciences</subject><subject>Mycophenolic Acid</subject><subject>Mycophenolic Acid - adverse effects</subject><subject>Mycophenolic Acid - therapeutic use</subject><subject>Nephrotic Syndrome</subject><subject>Nephrotic Syndrome - drug therapy</subject><subject>Nephrotic Syndrome - prevention & control</subject><subject>Prednisolone</subject><subject>Prednisolone - adverse effects</subject><subject>Prednisolone - therapeutic use</subject><subject>Prednisone</subject><subject>Prednisone - therapeutic use</subject><subject>Randomized Controlled Trials as Topic</subject><subject>Recurrence</subject><subject>Ribonucleosides</subject><subject>Ribonucleosides - therapeutic use</subject><subject>Rituximab</subject><subject>Rituximab - adverse effects</subject><subject>Rituximab - therapeutic use</subject><subject>Secondary Prevention</subject><issn>1465-1858</issn><issn>1469-493X</issn><issn>1465-1858</issn><issn>1469-493X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>RWY</sourceid><sourceid>EIF</sourceid><recordid>eNqFkctOxCAYhYnRODr6CpMu3cwIpRS6MdHxmkx0o2tCKXUwLVRox8zOR_AZfRJp5pLRjSsg5_vP-cMBYITgBEEYn6MkJYgRNpleh2ecwUnT5WQPHPXCuFf2d-4DcOz9G4Q4zWJ6CAY4TFAM2RHQj9Z8f35J61otrW-Vs7qIdF13xvquaZzyXi9UVKtCS9Fqa3xUWhetyTDqlfG67RmjmrmzwSfyS1M4W6tIm0jOdVU4ZU7AQSkqr07X5xC83N48T-_Hs6e7h-nlbCwTislYkixHTGFKMiEIwSJnJC9gwgRlmJVIyBxiSFGGCixojpMYC8ZYmaV5TlCC8RBcrHzDh4StpTKtExVvnK6FW3IrNP-tGD3nr3bBKUohDIlDcLY2cPa9U77ltfZSVZUwynaexziDaULjLA1oukKls947VW5jEOR9T3zTE9_01If3GaPdJbdjm2ICcLUCPnSlllxaOXch_x_fPyk_udyo8g</recordid><startdate>20200416</startdate><enddate>20200416</enddate><creator>Larkins, Nicholas G</creator><creator>Liu, Isaac D</creator><creator>Willis, Narelle S</creator><creator>Craig, Jonathan C</creator><creator>Hodson, Elisabeth M</creator><creator>Hodson, Elisabeth M</creator><general>John Wiley & Sons, Ltd</general><scope>7PX</scope><scope>RWY</scope><scope>ZYTZH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200416</creationdate><title>Non‐corticosteroid immunosuppressive medications for steroid‐sensitive nephrotic syndrome in children</title><author>Larkins, Nicholas G ; Liu, Isaac D ; Willis, Narelle S ; Craig, Jonathan C ; Hodson, Elisabeth M ; Hodson, Elisabeth M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4735-c59b18e3759aa553ab85bd048a7838f1acb0307191d3a7b3423a888f96bb51433</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adolescent</topic><topic>Alkylating Agents</topic><topic>Alkylating Agents - adverse effects</topic><topic>Alkylating Agents - therapeutic use</topic><topic>Azathioprine</topic><topic>Azathioprine - adverse effects</topic><topic>Azathioprine - therapeutic use</topic><topic>Child</topic><topic>Child health</topic><topic>Child, Preschool</topic><topic>Chlorambucil</topic><topic>Chlorambucil - adverse effects</topic><topic>Chlorambucil - therapeutic use</topic><topic>CHRONIC KIDNEY DISEASE</topic><topic>Cyclophosphamide</topic><topic>Cyclophosphamide - adverse effects</topic><topic>Cyclophosphamide - therapeutic use</topic><topic>Cyclosporine</topic><topic>Cyclosporine - adverse effects</topic><topic>Cyclosporine - therapeutic use</topic><topic>Glomerular disease</topic><topic>Glomerular diseases</topic><topic>Humans</topic><topic>Immunosuppressive Agents</topic><topic>Immunosuppressive Agents - adverse effects</topic><topic>Immunosuppressive Agents - therapeutic use</topic><topic>Infant</topic><topic>Kidney disease</topic><topic>Levamisole</topic><topic>Levamisole - adverse effects</topic><topic>Levamisole - therapeutic use</topic><topic>Medicine General & Introductory Medical Sciences</topic><topic>Mycophenolic Acid</topic><topic>Mycophenolic Acid - adverse effects</topic><topic>Mycophenolic Acid - therapeutic use</topic><topic>Nephrotic Syndrome</topic><topic>Nephrotic Syndrome - drug therapy</topic><topic>Nephrotic Syndrome - prevention & control</topic><topic>Prednisolone</topic><topic>Prednisolone - adverse effects</topic><topic>Prednisolone - therapeutic use</topic><topic>Prednisone</topic><topic>Prednisone - therapeutic use</topic><topic>Randomized Controlled Trials as Topic</topic><topic>Recurrence</topic><topic>Ribonucleosides</topic><topic>Ribonucleosides - therapeutic use</topic><topic>Rituximab</topic><topic>Rituximab - adverse effects</topic><topic>Rituximab - therapeutic use</topic><topic>Secondary Prevention</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Larkins, Nicholas G</creatorcontrib><creatorcontrib>Liu, Isaac D</creatorcontrib><creatorcontrib>Willis, Narelle S</creatorcontrib><creatorcontrib>Craig, Jonathan C</creatorcontrib><creatorcontrib>Hodson, Elisabeth M</creatorcontrib><creatorcontrib>Hodson, Elisabeth M</creatorcontrib><collection>Wiley-Blackwell Cochrane Library</collection><collection>Cochrane Library</collection><collection>Cochrane Library (Open Aceess)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cochrane database of systematic reviews</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Larkins, Nicholas G</au><au>Liu, Isaac D</au><au>Willis, Narelle S</au><au>Craig, Jonathan C</au><au>Hodson, Elisabeth M</au><au>Hodson, Elisabeth M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Non‐corticosteroid immunosuppressive medications for steroid‐sensitive nephrotic syndrome in children</atitle><jtitle>Cochrane database of systematic reviews</jtitle><addtitle>Cochrane Database Syst Rev</addtitle><date>2020-04-16</date><risdate>2020</risdate><volume>2020</volume><issue>4</issue><spage>CD002290</spage><pages>CD002290-</pages><issn>1465-1858</issn><issn>1469-493X</issn><eissn>1465-1858</eissn><eissn>1469-493X</eissn><abstract>Background
About 80% of children with steroid‐sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half relapse frequently, and are at risk of adverse effects from corticosteroids. While non‐corticosteroid immunosuppressive medications prolong periods of remission, they 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. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fourth update of a review first published in 2001 and updated in 2005, 2008 and 2013.
Objectives
To evaluate the benefits and harms of non‐corticosteroid immunosuppressive medications in SSNS in children with a relapsing course of SSNS and in children with their first episode of nephrotic syndrome.
Search methods
We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 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) or quasi‐RCTs were included if they involved children with SSNS and compared non‐corticosteroid immunosuppressive medications with placebo, corticosteroids (prednisone or prednisolone) or no treatment; compared different non‐corticosteroid immunosuppressive medications or different doses, durations or routes of administration of the same non‐corticosteroid immunosuppressive medication.
Data collection and analysis
Two authors independently assessed study eligibility, 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) for dichotomous outcomes or mean difference (MD) for continuous outcomes with 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE.
Main results
We identified 43 studies (91 reports) and included data from 2428 children. Risk of bias assessment indicated that 21 and 24 studies were at low risk of bias for sequence generation and allocation concealment respectively. Nine studies were at low risk of performance bias and 10 were at low risk of detection bias. Thirty‐seven and 27 studies were at low risk of incomplete and selective reporting respectively.
Rituximab (in combination with calcineurin inhibitors (CNI) and prednisolone) versus CNI and prednisolone probably reduces the number of children who relapse at six months (5 studies, 269 children: RR 0.23, 95% CI 0.12 to 0.43) and 12 months (3 studies, 198 children: RR 0.63, 95% CI 0.42 to 0.93) (moderate certainty evidence). At six months, rituximab resulted in 126 children/1000 relapsing compared with 548 children/1000 treated with conservative treatments. Rituximab may result in infusion reactions (4 studies, 252 children: RR 5.83, 95% CI 1.34 to 25.29).
Mycophenolate mofetil (MMF) and levamisole may have similar effects on the number of children who relapse at 12 months (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16). MMF may have a similar effect on the number of children relapsing compared to cyclosporin (2 studies, 82 children: RR 1.90, 95% CI 0.66 to 5.46) (low certainty evidence). MMF compared to cyclosporin is probably less likely to result in hypertrichosis (3 studies, 140 children: RR 0.23, 95% CI 0.10 to 0.50) and gum hypertrophy (3 studies, 144 children: RR 0.09, 95% CI 0.07 to 0.42) (low certainty evidence).
Levamisole compared with steroids or placebo may reduce the number of children with relapse during treatment (8 studies, 474 children: RR 0.52, 95% CI 0.33 to 0.82) (low certainty evidence). Levamisole compared to cyclophosphamide may make little or no difference to the risk for relapse after 6 to 9 months (2 studies, 97 children: RR 1.17, 95% CI 0.76 to 1.81) (low certainty evidence).
Cyclosporin compared with prednisolone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty evidence). Alkylating agents compared with cyclosporin may make little or no difference to the risk of relapse during cyclosporin treatment (2 studies, 95 children: RR 0.91, 95% CI 0.55 to 1.48) (low certainty evidence) but may reduce the risk of relapse at 12 to 24 months (2 studies, 95 children: RR 0.51, 95% CI 0.35 to 0.74), suggesting that the benefit of the alkylating agents may be sustained beyond the on‐treatment period (low certainty evidence).
Alkylating agents (cyclophosphamide and chlorambucil) compared with prednisone probably reduce the number of children, who experience relapse at six to 12 months (6 studies, 202 children: RR 0.44, 95% CI 0.32 to 0.60) and at 12 to 24 months (4 studies, 59 children: RR 0.20, 95% CI 0.09 to 0.46) (moderate certainty evidence). IV cyclophosphamide may reduce the number of children with relapse compared with oral cyclophosphamide at 6 months (2 studies, 83 children: RR 0.54, 95% CI 0.34 to 0.88), but not at 12 to 24 months (2 studies, 83 children: RR 0.99, 95% CI 0.76 to 1.29) and may result in fewer infections (2 studies, 83 children: RR 0.14, 95% CI 0.03 to 0.72) (low certainty evidence). Cyclophosphamide compared to chlorambucil may make little or no difference in the risk of relapse after 12 months (1 study, 50 children: RR 1.31, 95% CI 0.80 to 2.13) (low certainty evidence).
Authors' conclusions
New studies incorporated in this review indicate that rituximab is a valuable additional agent for managing children with steroid‐dependent nephrotic syndrome. However, the treatment effect is temporary, and many children will require additional courses of rituximab. The long‐term adverse effects of this treatment are not known. Comparative studies of CNIs, MMF, levamisole and alkylating agents have demonstrated little or no differences in efficacy but, because of insufficient power; clinically important differences in treatment effects have not been completely excluded.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>32297308</pmid><doi>10.1002/14651858.CD002290.pub5</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1465-1858 |
| ispartof | Cochrane database of systematic reviews, 2020-04, Vol.2020 (4), p.CD002290 |
| issn | 1465-1858 1469-493X 1465-1858 1469-493X |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7160055 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Cochrane Library; Alma/SFX Local Collection |
| subjects | Adolescent Alkylating Agents Alkylating Agents - adverse effects Alkylating Agents - therapeutic use Azathioprine Azathioprine - adverse effects Azathioprine - therapeutic use Child Child health Child, Preschool Chlorambucil Chlorambucil - adverse effects Chlorambucil - therapeutic use CHRONIC KIDNEY DISEASE Cyclophosphamide Cyclophosphamide - adverse effects Cyclophosphamide - therapeutic use Cyclosporine Cyclosporine - adverse effects Cyclosporine - therapeutic use Glomerular disease Glomerular diseases Humans Immunosuppressive Agents Immunosuppressive Agents - adverse effects Immunosuppressive Agents - therapeutic use Infant Kidney disease Levamisole Levamisole - adverse effects Levamisole - therapeutic use Medicine General & Introductory Medical Sciences Mycophenolic Acid Mycophenolic Acid - adverse effects Mycophenolic Acid - therapeutic use Nephrotic Syndrome Nephrotic Syndrome - drug therapy Nephrotic Syndrome - prevention & control Prednisolone Prednisolone - adverse effects Prednisolone - therapeutic use Prednisone Prednisone - therapeutic use Randomized Controlled Trials as Topic Recurrence Ribonucleosides Ribonucleosides - therapeutic use Rituximab Rituximab - adverse effects Rituximab - therapeutic use Secondary Prevention |
| title | Non‐corticosteroid immunosuppressive medications for steroid‐sensitive nephrotic syndrome in children |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T00%3A33%3A29IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Non%E2%80%90corticosteroid%20immunosuppressive%20medications%20for%20steroid%E2%80%90sensitive%20nephrotic%20syndrome%20in%20children&rft.jtitle=Cochrane%20database%20of%20systematic%20reviews&rft.au=Larkins,%20Nicholas%20G&rft.date=2020-04-16&rft.volume=2020&rft.issue=4&rft.spage=CD002290&rft.pages=CD002290-&rft.issn=1465-1858&rft.eissn=1465-1858&rft_id=info:doi/10.1002/14651858.CD002290.pub5&rft_dat=%3Cproquest_pubme%3E2390647296%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2390647296&rft_id=info:pmid/32297308&rfr_iscdi=true |