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).
• Children experiencing nephrotic syndrome for the first time only need two to three months of prednisone (a type of steroid medication), as longer durations do not reduce the risk of a repeat episode or reduce the risk that the child will have frequent repeat episodes.
• Although the risk of side effects may be low, many of the studies did not report information that we could analyse.
What is nephrotic syndrome, and why should you treat it with steroids?
Nephrotic syndrome is a condition where the kidneys leak protein from the blood into the urine. When left untreated, children can suffer from serious infections. In most children with nephrotic syndrome, this protein leak is stopped with steroid therapy. Steroids are powerful anti-inflammatory medicines and can be used for a wide range of conditions, but they can also have serious side effects. These side effects can include depression and anxiety, high blood pressure, eye disorders such as cataracts, increased risk of infection, weight gain and reduced growth. Children can also have repeat episodes of nephrotic syndrome, which is often triggered by viral infection.
What did we want to find out?
We wanted to find out the best treatment options for children with nephrotic syndrome to stop the leaking of protein from the blood into the urine and to avoid the harmful side effects of steroids.
What did we do?
We searched for all studies that compared the benefits and harms of randomly allocating steroid medicines to:
• children who experience nephrotic syndrome for the first time; or
• children who have frequent repeat 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 54 studies randomising 4670 children looking at a wide variety of steroid treatment options. Studies were conducted in countries around the world, and most were done in South Asia (23 studies). Twenty-three studies compared giving the steroid prednisone for two or three months with longer durations (three to seven months) to children who experience nephrotic syndrome for the first time. The remaining studies looked at children who had frequent repeat episodes of nephrotic syndrome.
We found longer durations of prednisone (three to seven months) made little to no difference in the risk of children experiencing repeat episodes of nephrotic syndrome or in the number of children who have frequent repeat episodes compared to shorter durations of prednisone (two to three months). There may be no differences in the type and number of side effects with either longer or shorter durations of steroids; however, these were often not reported by the studies.
What are the limitations of the evidence?
We are confident that children experiencing nephrotic syndrome for the first time only need two to three months of prednisone, as longer durations do not reduce the risk of a repeat episode or reduce the risk that the child will have frequent repeat episodes.
We are less confident in the risk of side effects because many of the studies did not report information that we could use.
How up-to-date is the evidence?
The evidence is current to July 2024.
There are four well-designed studies randomising 823 children, which have demonstrated that there is no benefit of prolonging prednisone therapy beyond two to three months in the first episode of SSNS. Small studies in children with relapsing disease have identified no differences in efficacy using lower induction doses or shorter durations of prednisone therapy. Large, well-designed studies are required to confirm these findings. While previous small studies had suggested that changing from alternate-day to daily prednisone therapy at the onset of infection reduced the likelihood of relapse, a much larger and well-designed study found no reduction in the number relapsing when administering daily prednisone at the onset of infection.
In nephrotic syndrome, protein leaks from the blood into the urine through the glomeruli, resulting in hypoproteinaemia and generalised oedema. While most children with nephrotic syndrome respond to corticosteroids, 80% experience a relapsing course. Corticosteroids have reduced the death rate to around 3%; however, corticosteroids have well-recognised potentially serious adverse events such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis, cataracts, glaucoma and behavioural disturbances. This is an update of a review first published in 2000 and updated in 2002, 2005, 2007, 2015 and 2020.
The aim of this review was to assess the benefits and harms of different corticosteroid regimens in children with steroid-sensitive nephrotic syndrome (SSNS). The benefits and harms of therapy were studied in two groups of children: 1) children in their initial episode of SSNS and 2) children who experience a relapsing course of SSNS.
We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 9 July 2024 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) performed in children (one to 18 years) during their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent.
Summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
In this 2024 update, we included five new studies, resulting in 54 studies randomising 4670 children.
Risk of bias methodology was often poorly performed, with only 31 studies and 28 studies respectively assessed to be at low risk for random sequence generation and allocation concealment. Ten studies were at low risk of performance bias (blinding of participants and personnel), and 12 studies were at low risk of detection bias (blinding of outcome assessment); nine of these studies were placebo-controlled RCTs. Twenty-seven studies (fewer than 50%) were at low risk for attrition bias, and 26 studies were at low risk for reporting bias (selective outcome reporting).
In studies at low risk of selection bias evaluating children in their initial episode of SSNS, there is little or no difference in the number of children with frequent relapses when comparing two months of prednisone with three months or more (RR 0.96, 95% CI 0.83 to 1.10; 755 children, 5 studies; I2 = 0%; high certainty evidence) or when comparing three months with five to seven months of therapy (RR 0.99, 95% CI 0.74 to 1.33; 376 children, 3 studies; I2 = 35%; high certainty evidence). In analyses of studies at low risk of selection bias, there is little or no difference in the number of children with any relapse by 12 to 24 months when comparing two months of prednisone with three months or more (RR 0.93, 95% CI 0.81 to 1.06; 808 children; 6 studies; I2 = 47%) or when comparing three months with five to seven months of therapy (RR 0.88, 95% CI 0.70 to 1.11; 377 children, 3 studies; I2 = 53%). Little or no difference was noted in adverse events between the different treatment durations.
Amongst children with relapsing SSNS, four small studies (177 children) utilising lower doses of prednisone compared with standard regimens found little or no differences between groups in the numbers with relapse (RR 1.01, 95% CI 0.85 to 1.20; I2 = 0%). A fifth study (117 children) reported little or no difference between two weeks and four weeks of alternate-day prednisone after remission with daily prednisone.
A recent large, well-designed study with 271 children found that administering daily prednisone compared with alternate-day prednisone or no prednisone during viral infection did not reduce the risk of relapse. In contrast, four previous small studies in children with frequently relapsing disease had reported that daily prednisone during viral infections compared with alternate-day prednisone or no treatment reduced the risk of relapse.