Corticosteroid therapy for nephrotic syndrome in children

Abstract

Background

In nephrotic syndrome protein leaks from the blood to 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 mortality 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 2003, 2005 and 2007.

Objectives

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.

Search methods

We searched the Cochrane Renal Group's Specialised Register to 26 February 2015 through contact with the Trials Search Co‐ordinator using search terms relevant to this review.

Selection criteria

Randomised controlled trials (RCTs) performed in children (three months to 18 years) in their initial or subsequent episode of SSNS, comparing different durations, total doses or other dose strategies using any corticosteroid agent.

Data collection and analysis

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).

Main results

Ten new studies were identified so a total of 34 studies (3033 total participants) were included in the 2015 review update. The risk of bias attributes were frequently poorly performed. Low risk of bias was reported in 18 studies for sequence generation, 16 studies for allocation concealment, seven for performance and detection bias, 15 for incomplete reporting and 16 for selective reporting. Three months or more of prednisone significantly reduced the risk of frequently relapsing nephrotic syndrome (FRNS) (6 studies, 582 children: RR 0.68, 95% CI 0.47 to 1.00) and of relapse by 12 to 24 months (8 studies, 741 children: RR 0.80, 95% CI 0.64 to 1.00) compared with two months. Five or six months of prednisone significantly reduced the risk of relapse (7 studies, 763 children: RR 0.62, 95% CI 0.45 to 0.85) but not FRNS (5 studies, 591 children: RR 0.78, 95% CI 0.50 to 1.22) compared with three months. However there was significant heterogeneity in the analyses. Subgroup analysis stratified by risk of bias for allocation concealment showed that the risk for FRNS did not differ significantly between two or three months of prednisone and three to six months among studies at low risk of bias but was significantly reduced in extended duration studies compared with two or three months in studies at high risk or unclear risk of bias. There were no significant differences in the risk of adverse effects between extended duration and two or three months of prednisone. Four studies found that in children with FRNS, daily prednisone during viral infections compared with alternate‐day prednisone or no treatment significantly reduced the rate of relapse.

Authors' conclusions

In this 2015 update the addition of three well‐designed studies has changed the conclusion of this review. Studies of long versus shorter duration of corticosteroids have heterogeneous treatment effects, with the older high risk of bias studies tending to over‐estimate the effect of longer course therapy, compared with more recently published low risk of bias studies. Among studies at low risk of bias, there was no significant difference in the risk for FRNS between prednisone given for two or three months and longer durations or total dose of therapy indicating that there is no benefit of increasing the duration of prednisone beyond two or three months in the initial episode of SSNS.

The risk of relapse in children with FRNS is reduced by the administration of daily prednisone at onset of an upper respiratory tract or viral infection. Three additional studies have increased the evidence supporting this conclusion. This management strategy may be considered for children with FRNS. A paucity of data on prednisone use in relapsing nephrotic syndrome remains. In particular there are no data from RCTs evaluating the efficacy and safety of prolonged courses of low dose alternate‐day prednisone although this management strategy is recommended in current guidelines.

Plain language summary

Corticosteroid therapy for children with nephrotic syndrome

Nephrotic syndrome is a condition where the kidneys leak protein from the blood into the urine. When it is untreated, children can often die from infections. Most children, with nephrotic syndrome, respond to corticosteroid drugs (prednisone, prednisolone) reducing the risk of serious infection. However they usually have repeat episodes, which are often triggered by viral infections. Corticosteroid drugs can have serious side effects.

We looked at evidence from 34 studies enrolling 3033 children. Fourteen of 21 studies, in children with their first episode of nephrotic syndrome, evaluated prednisone for two or three months compared with longer durations. Thirteen studies evaluated different corticosteroid regimens in children with frequently relapsing disease (FRNS). Studies were of variable methodological quality with only about half of the studies at low risk of bias.

Among studies of long versus shorter duration of prednisone, older studies at high or unclear risk of bias tended to over‐estimate the effect of longer course therapy compared with new studies at low risk of bias. Studies at low risk of bias found no significant differences in the risk of relapse or the development of FRNS between prednisone given for three to six months compared with two or three months. Therefore there is no benefit of increasing the duration of prednisone beyond two or three months in the initial episode of SSNS.

Based on four studies in children with frequently relapsing nephrotic syndrome, prednisone given for five to seven days at the onset of a viral infection reduces the risk of relapse.

This review updates information previously published in 2000, 2003, 2005 and 2007. The addition of three new studies evaluating different durations of prednisone in the first episode of nephrotic syndrome has changed the conclusions expressed in previous versions of this review