Corticosteroid therapy for nephrotic syndrome in children

• Published in: Cochrane database of systematic reviews no. 8; p. CD001533
• Main Authors: Hahn, Deirdre, Samuel, Susan M, Willis, Narelle S, Craig, Jonathan C, Hobson, Elisabeth M
• Format: Journal Article
• Language: English
• Published: England 31.08.2020
• ISSN: 1469-493X
• DOI: 10.1002/14651858.CD001533.pub6

In nephrotic syndrome protein leaks from 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 effects such as obesity, poor growth, hypertension, diabetes mellitus, osteoporosis, and behavioural disturbances. This is an update of a review first published in 2000 and updated in 2002, 2005, 2007, and 2015. 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 searched the Cochrane Kidney and Transplant Register of Studies up to 30 May 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. Randomised controlled trials (RCTs) performed in children (one to 18 years) in their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent. Two authors independently assessed risk of bias and extracted data. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). In this 2020 review update 16 new included studies were identified providing a total of 48 included studies with 3941 randomised participants. Risk of bias methodology was often poorly performed with only 25 studies and 22 studies respectively assessed to be at low risk for random sequence generation and allocation concealment. Only nine studies (19%) were at low risk of bias for performance (blinding of participants and personnel) and 11 studies were at low risk of detection bias (blinding of outcome assessment); nine of these studies were placebo-controlled RCTs. Twenty-two studies (fewer than 50%) were at low risk for attrition bias and 23 studies were at low risk for reporting bias (selective outcome reporting). In seven studies, which evaluated children in their initial episode of SSNS and were at low risk of bias for selection bias, 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 0.99, 95% CI 0.82 to 1.19; 585 participants, 4 studies; I2 = 0%) or when comparing three months with five to seven months of therapy (RR 0.99, 95% CI 0.74 to 1.33; 376 participants, 3 studies; I2 = 35%; high certainty evidence). In analyses of eight 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 0.91, 95% CI 0.78 to 1.06; 637 participants; 5 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 participants, 3 studies; I2 = 53%). Little or no difference was noted in adverse effects between the different treatment durations. Among children with relapsing SSNS, two small studies showed that time to remission did not differ between prednisone doses of 1 mg/kg compared with the conventional dose of 2 mg/kg (MD 0.71 days, 95% CI -0.43 to 1.86; 79 participants) and that the total prednisone dose administered was lower (MD -20.60 mg/kg, 95% CI -25.65 to -15.55; 20 participants). Two studies found little or no difference in the number with relapse at six months when comparing dosing by weight with dosing by surface area (RR 1.03, 95% CI 0.71 to 1.49; 146 participants). One study found a reduced risk of relapse with low daily dosing compared with alternate daily dosing (MD -0.90 number of relapses/year, 95% CI -1.33 to -0.47). Four studies found that in children with frequently relapsing disease, daily prednisone during viral infections compared with alternate-day prednisone or no treatment reduced the risk of relapse. There are now four well designed studies randomising 823 children which have clearly 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 the times to remission using half the conventional induction dose of 2 mg/kg or 60 mg/m2. It is imperative that a much larger study be carried out to confirm these findings. Lower dose prednisone therapy administered daily during an upper respiratory infection or other infection reduces the risk of relapse compared with continuing alternate-day prednisone or no prednisone based on four small studies. The results of a much larger RCT enrolling more than 300 children are awaited to determine the relative efficacies and adverse effects of using alternate-day compared with daily prednisone to prevent relapse in children with intercurrent infections.