Key messages
• Nephrotic syndrome (a condition where the kidneys leak protein from the blood into the urine) is usually treated with steroid medication (powerful anti-inflammatory medicines). However, due to the potential side effects (poor growth, cataracts, weak and brittle bones, and high blood pressure), other immunosuppressive medicines (medicines that dampen down the body's immune system) have been investigated.
• Rituximab compared to a placebo (dummy medicine) probably reduces the risk of a relapse at six and 12 months, but may increase the number who have severe reactions to the infusion. Rituximab probably reduces the risk of relapse at 12 months when compared to tacrolimus, and may reduce the risk when compared to mycophenolate mofetil.
• We found that mycophenolate mofetil prolongs the length of remission induced by rituximab.
What is nephrotic syndrome, and what medicines should you give if it happens again?
Children with nephrotic syndrome lose large 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 are lost in the urine. Corticosteroid medication, such as prednisone, can stop protein loss, but this often happens again (relapse). Giving children further corticosteroids can lead to poor growth, cataracts, osteoporosis (a condition in which bones become weak and brittle) and high blood pressure. A wide range of medicines have been tried to treat relapses in children and to prevent further relapses in children who relapse frequently. Immunosuppressive medicines (medicines that dampen down the body's immune system) have different mechanisms of action and have been demonstrated to provide longer remission (a period of time when signs and symptoms of nephrotic syndrome disappear) compared with steroids alone. Using these may enable steroids to be withdrawn or the dose reduced.
What did we want to find out?
We wanted to find out the best treatment options for children who have frequent relapses of nephrotic syndrome to stop the leaking of protein from the blood into the urine and to avoid the harmful side effects of steroids. We also wanted to find out if these other treatment options were associated with any unwanted effects.
What did we do?
We searched for all studies that compared the benefits and harms of randomly allocating non-steroid immunosuppressive medicines to children who have frequent repeated episodes of nephrotic syndrome.
We compared and summarised the studies' results and rated our confidence in the information based on factors such as study methods and sizes.
What did we find?
We found 58 studies randomising 3720 children looking at a wide variety of non-steroid treatment options. Half of the studies were conducted in multiple centres around the world, and most were done in South and East Asia (28 studies) and Europe (20 studies). The number of children randomised ranged from 14 to 211.
Rituximab compared to a placebo (dummy medicine) probably reduces the risk of a relapse at six and 12 months, but may increase the number who have severe reactions to the infusion. Rituximab probably reduces the risk of relapse at 12 months when compared to tacrolimus, and may reduce the risk when compared to mycophenolate mofetil. We also found that mycophenolate mofetil prolongs the length of remission induced by rituximab.
Tacrolimus, cyclosporin, mycophenolate mofetil, and levamisole may reduce the risk of relapse in children with frequently relapsing nephrotic syndrome. Cyclophosphamide and chlorambucil compared with steroids probably reduce the number of children who experience a relapse.
What are the limitations of the evidence?
We are confident that mycophenolate mofetil prolongs the length of remission induced by rituximab. We are moderately confident that rituximab compared to placebo or tacrolimus reduces the risk of relapse in children who experience frequent relapses of nephrotic syndrome. We are also moderately confident that cyclophosphamide and chlorambucil compared with steroids probably reduce the number of children who experience a relapse. We are less confident about the effects of other non-steroid immunosuppressive medicines on reducing the risk of relapse.
We are not confident in the evidence for adverse events, as they were rarely or poorly reported for all of our comparisons.
How up to date is the evidence?
The evidence is current to October 2024.
New studies incorporated in this review update indicate that rituximab compared with prednisone, tacrolimus, or MMF is a valuable additional agent for managing children with relapsing SSNS. Comparative studies of CNIs, MMF, and levamisole suggest that CNIs may be more effective than MMF and that levamisole may be similar in efficacy to MMF. Important new studies suggest that MMF prolongs remission following rituximab, that levamisole may prevent infection-related relapse more effectively than changing from alternate-day to daily prednisone and that levamisole and prednisone compared with prednisone alone may prolong the time to first relapse. There are currently 23 ongoing studies which should improve our understanding of how to treat children with frequently relapsing SSNS.
About 80% of children with steroid-sensitive nephrotic syndrome (SSNS) have relapses. Of these children, half will 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 with frequently relapsing SSNS. In addition, these medications could be used with corticosteroids in the initial episode of SSNS to prolong the period of remission. This is the fifth update of a review first published in 2001 and updated in 2005, 2008, 2013 and 2020.
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.
We searched the Cochrane Kidney and Transplant Register of Studies up to October 2024 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 Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.
Randomised controlled trials (RCTs) or quasi-RCTs were included if they involved children with SSNS and compared non-corticosteroid immunosuppressive medications with placebo, corticosteroids or no treatment; different non-corticosteroid immunosuppressive medications, or different doses, durations or routes of administration of the same non-corticosteroid immunosuppressive medication.
Two authors independently assessed study eligibility, risk of bias and extracted data from the included studies. 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). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
We identified 58 studies (122 reports) randomising 3720 children. Half were multicentre studies, and most studies were undertaken in South and East Asia (28 studies) and Europe (20 studies). The numbers of children randomised ranged from 14 to 211. Risk of bias assessment indicated that 32 and 33 studies were at low risk of bias for sequence generation and allocation concealment, respectively. Eleven studies were at low risk of performance bias and 13 were at low risk of detection bias. Forty-eight and 36 studies were at low risk of incomplete and selective reporting, respectively.
Rituximab with or without prednisone compared with placebo with or without prednisone probably reduces the number of children experiencing relapse at six months (5 studies, 182 children: RR 0.22, 95% CI 0.11 to 0.43) and 12 months (3 studies, 108 children: RR 0.38, 95% CI 0.13 to 1.09) (moderate certainty), may increase the number with severe infusion reactions (4 studies, 162 children: RR 5.21, 95% CI 1.19 to 22.89; low certainty), but not severe infection or arthropathy (low certainty).
Rituximab compared with tacrolimus probably reduces the risk of relapse at 12 months (4 studies, 238 children: RR 0.64, 95% CI 0.42 to 0.96) and may reduce the risk of relapse when compared with low dose mycophenolate mofetil (MMF) (1 study, 30 children: RR 0.17, 95% CI 0.04 to 0.62). Rituximab followed by MMF for 500 days reduces the risk of relapse compared with rituximab followed by placebo for 500 days (1 study, 78 children: RR 0.29, 95% CI 0.13 to 0.63; high certainty). Rituximab probably does not differ from ofatumumab in the riisk of relapse and 12 months (1 study, 140 children: RR 1.03, 95% CI 0.75 to 1.41; moderate certainty) or in adverse events.
MMF and levamisole (1 study, 149 children: RR 0.90, 95% CI 0.70 to 1.16) may have similar effects on the number of children who relapse at 12 months (low certainty). Cyclosporin compared with MMF may reduce the risk of relapse at 12 months (3 studies, 114 children: RR 1.57, 95% CI 1.08 to 2.30) (low certainty).
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). Preliminary data from single studies indicate that levamisole and prednisone compared with prednisone alone may delay the onset of relapse after the initial episode of SSNS and that levamisole compared with increasing prednisone administration from alternate day to daily at the onset of infection may reduce the risk of relapse with infection (low certainty).
Cyclosporin compared with prednisone may reduce the number of children who relapse (1 study, 104 children: RR 0.33, 95% CI 0.13 to 0.83) (low certainty). 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) (low certainty).
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).