Key messages
• For children with steroid-resistant nephrotic syndrome (a condition where treatment with steroids does not stop the leaking of protein from the blood into the urine), calcineurin inhibitors (immunosuppressive medicines that decrease the body's immune response) may increase the likelihood of complete or partial remission (a decrease in or disappearance of signs and symptoms of nephrotic syndrome) compared with placebo (an inactive or 'dummy' medicine), no treatment or cyclophosphamide (another type of immunosuppressant).
• Tacrolimus, a powerful immunosuppressive medicine, may be better than cyclosporin (another immunosuppressant) at helping children avoid relapse when signs and symptoms of the disease return. Cyclosporin probably increases excessive hair growth and overgrowth of gum tissue around the teeth compared to tacrolimus.
• The results from other comparisons were unclear due to the small number of studies and the limited reporting of outcomes.
What is idiopathic steroid-resistant nephrotic syndrome?
Nephrotic syndrome is a condition where the kidneys leak protein from the blood into the urine. Idiopathic means its cause is unknown. Children with the condition may have swelling, weight gain, tiredness, and a higher risk of infections.
How is it treated?
Corticosteroids are medicines that help reduce inflammation and calm down an overactive immune system. They are used in the first instance to achieve remission (a decrease in or the disappearance of signs and symptoms of nephrotic syndrome). Other medicines such as calcineurin inhibitors (immunosuppressants that decrease the body's immune response; e.g. cyclosporin and tacrolimus) are required for children who do not respond to corticosteroids in their first episode of nephrotic syndrome (initial resistance) or who develop steroid resistance after one or more responses to corticosteroids (delayed resistance).
What did we want to find out?
We wanted to find out what treatments would result in the remission of nephrotic syndrome in children who do not respond to initial treatment with corticosteroids or who develop delayed steroid resistance.
What did we do?
We searched for studies that assessed the benefits and harms of randomly allocated alternative treatments for children with nephrotic syndrome who develop steroid resistance. We compared and summarised the results of the trials and rated our confidence in the information, based on factors such as study methods and sizes.
What did we find?
We included 29 studies analysing 1248 children with steroid-resistant nephrotic syndrome. Studies were carried out in India (8), USA (6), Italy (4), China (2), France (1), Mexico (1) and Thailand (1); six studies were international. Seventeen studies were carried out in multiple centres, and 12 were single-centre studies. We identified 18 different comparisons, with the number of studies per comparison ranging from one to four.
Main results
• Cyclosporin, compared with placebo, no treatment or a corticosteroid, may increase the number of children in whom urine protein disappears (complete remission) or is markedly reduced (partial remission).
• Calcineurin inhibitors (cyclosporin, tacrolimus) may also increase the number of children who achieve complete or partial remission compared with intravenous cyclophosphamide (another immunosuppressant).
• There may be little or no benefit from other immunosuppressants studied.
• Tacrolimus may reduce the number of children who relapse (signs and symptoms of the disease returning) compared to cyclosporin.
• Cyclosporin probably increases excessive hair growth and overgrowth of gum tissue around the teeth compared to tacrolimus.
The results from other comparisons were unclear due to the small number of studies per comparison and the limited reporting of outcomes.
What are the limitations of the evidence?
The small number of studies (per comparison) and the small size of the studies were limitations in this review. Not all the studies provided data about the outcomes we were interested in. We are unsure about the results.
How current is the evidence?
The evidence is current to January 2025.
Calcineurin inhibitors may increase the likelihood of complete or partial remission compared with placebo/no treatment or cyclophosphamide. For other regimens, it remains unclear 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 people with SRNS.
Nephrotic syndrome is a condition in which the glomeruli of the kidney leak large amounts of protein from the blood into the urine. Most children who present with their first episode of nephrotic syndrome achieve remission with corticosteroids. 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 (cyclosporin or tacrolimus), and with non-immunosuppressive agents, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. However, response to these agents is limited, so newer agents, including anti-CD20 antibodies (rituximab, ofatumumab) and dual endothelin-angiotensin receptor antagonists (sparsentan), are being assessed for efficacy and safety. This is an update of a review first published in 2004 and updated in 2006, 2010, 2016 and 2019.
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.
The Cochrane Kidney and Transplant (CKT) Information Specialist searched the CKT Register of Studies to 28 January 2025 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.
We included randomised controlled trials (RCTs) and quasi-RCTs that compared different immunosuppressive or non-immunosuppressive agents with placebo, prednisone or another agent given orally or parenterally in children aged three months to 18 years with steroid-resistant nephrotic syndrome (SRNS). We included studies that enrolled children and adults, in which paediatric data could not be separated from adult data.
Two review authors independently screened the search results, determined study eligibility, assessed risk of bias and extracted study data. We expressed dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with 95% CIs. We used a random-effects model to pool data, and GRADE to assess the certainty of the evidence. The main outcomes of interest were treatment response (complete, partial, or complete or partial remission), kidney failure and adverse events.
We included 29 studies (1248 evaluated children). Sixteen studies were at low risk of bias for sequence generation and allocation concealment. Seven and 21 studies were at low risk of performance and detection bias, respectively. Sixteen, 15 and 15 studies were at low risk of attrition bias, reporting bias and other bias, respectively.
Compared with placebo, corticosteroid or no treatment, cyclosporin may increase the number who achieve complete remission (RR 3.50, 95% CI 1.09 to 11.20; 4 studies, 74 children) or complete or partial remission (RR 3.15, 95% CI 1.04 to 9.57; 4 studies, 74 children) by two to six months (low-certainty evidence). It is uncertain whether cyclosporin reduces the likelihood of kidney failure or increases the likelihood of worsening hypertension or infection (very low-certainty evidence).
Compared with intravenous cyclophosphamide, calcineurin inhibitors may increase the number with complete remission (RR 3.43, 95% CI 1.84 to 6.41; 2 studies, 156 children) and complete or partial remission (RR 1.98, 95% CI 1.25 to 3.13; 2 studies, 156 children) at three to six months (low-certainty evidence), and probably reduces the number with treatment failure (no response, serious infection, persistently elevated creatinine) and medications ceased due to adverse events (moderate-certainty evidence), with little or no increase in serious infections (moderate-certainty evidence). Kidney failure was not reported.
Tacrolimus may make little or no difference to the number who achieve complete, or complete or partial remission at six and 12 months compared with cyclosporin, but may reduce the number who relapse during treatment (RR 0.22, 95% CI 0.06 to 0.90; 1 study, 34 children) or the number with worsening hypertension (low-certainty evidence). Hypertrichosis and gingival hyperplasia probably increased with cyclosporin. Kidney failure was not reported.
Compared with mycophenolate mofetil (MMF) and dexamethasone, cyclosporin probably makes little or no difference to complete, partial, or complete or partial remission (moderate-certainty evidence), and may make little or no difference to kidney failure, serious infection requiring hospitalisation or hypertension (low-certainty evidence).
Among children who have achieved complete remission, tacrolimus compared with MMF may increase the number who maintain complete, partial, or complete or partial response for 12 months, but may make little or no difference to serious adverse events and serious infection (low-certainty evidence).
Oral cyclophosphamide plus prednisone compared with prednisone alone may make little or no difference to the number who achieve complete remission (low-certainty evidence) and has uncertain effects on adverse events. Kidney failure was not reported.
Compared with oral cyclophosphamide plus intravenous dexamethasone, intravenous cyclophosphamide may make little or no difference to complete, partial, or complete or partial remission at six months. There may be little or no difference in bacterial infections; however, hypertension may decrease (all low-certainty evidence). Kidney failure was not reported.
It is uncertain whether rituximab/cyclosporin/prednisolone compared with cyclosporin/prednisolone increases the likelihood of remission or reduces adverse events because the certainty of the evidence is very low. Kidney failure was not reported.