For children with a first presentation of nephrotic syndrome, an extended sixteen-week treatment regimen with prednisolone does not reduce the risk of relapse compared with the standard eight-week course. Most children will experience a relapse with either regimen, but the longer course may delay it by a month or so which may, in turn, reduce the resource use, such as emergency department visits, shorter admissions and less need to see the GP. This can also make the longer course cheaper overall.
Nephrotic syndrome is a condition where the kidneys leak large amounts of protein into the urine. This can result in a range of problems, including swelling, blood clots and a higher chance of getting infections. Corticosteroids are known to be effective in treating the condition, but concerns about their side effects have led to differences of opinion about how long to continue initial treatment.
This NIHR-funded study suggests that while the clinical benefits are similar, patients and commissioners might prefer the longer courses for the slight benefit in quality of life and cost-saving from fewer, shorter hospital admissions.
Why was this study needed?
Nephrotic syndrome is usually first diagnosed in children aged around two to three years. About 1 in every 50,000 children are diagnosed each year in the UK.
The first-line treatment is a course of high-dose corticosteroids, usually prednisolone, for eight weeks. Children respond well to this, and the condition goes into remission. But many will experience relapses and need further courses of prednisolone.
A Cochrane review in 2005 based on small trials, suggested that a longer course of prednisolone (minimum three months) could reduce the number of children who relapse. However, long-term use of corticosteroids is associated with major adverse events, and concern over this has led to continued variation in practice.
This study aimed to determine the best treatment regimen for children in the UK presenting with nephrotic syndrome for the first time.
What did this study do?
The PREDNOS study was a randomised controlled trial of 237 children, aged 1 to 14 years. They were recruited from 86 hospitals in the UK.
The control group (118 children) received a standard course of prednisolone treatment: 60mg/m2 per day in the first four weeks, then 40mg/m2 on alternate days in weeks five to eight.
The intervention group (119 children) had an extended course of prednisolone treatment: 60mg/m2 per day in the first four weeks, followed by 12 weeks of alternate day tablets, starting at 60mg/m2 and tapering by 10mg/m2 every two weeks.
For all participants, the first four weeks were open-label. For weeks 5 to 16, participants were blinded. Matching dummy pills (placebo) were given to the control group.
Participants were followed up for at least two years.
What did it find?
- A similarly high proportion relapsed during the trial: 81% (88/109) in the control group and 80% (91/114) in the intervention group.
- The median time to the first relapse was 87 days for the control group (interquartile range [IQR] 65 to 134 days), compared with 139 days for the intervention group (IQR 90 to 179 days) but this was not significantly different (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.64 to 1.16).
- There was no difference between the groups in the number of participants who developed frequently-relapsing nephrotic syndrome, defined as two or more relapses within the first six months or four relapses within any 12-month period: 50% of the control group compared with 53% of the intervention group (relative risk [RR] 1.04, 95% CI 0.81 to 1.35).
- Serious adverse events occurred in 25% (39 events in 27 children) in the control group, compared to 17% (28 events in 19 children) in the intervention group.
- A cost analysis alongside the trial showed that the intervention was associated with savings of £1,673 per patient over 24 months. This was due to a lower rate of hospital admission, shorter duration of hospital stay (by about three days), fewer emergency visits to hospital, and fewer outpatient and primary care visits.
What does current guidance say on this issue?
The British National Formulary for Children has the following prescribing information for prednisolone for children with nephrotic syndrome: initially 60 mg/m2 once daily for four to six weeks, then reduced to 40 mg/m2 once daily on alternate days for four to six weeks, then withdrawn by reducing the dose gradually.
Examples of local NHS guidance distinguish between a standard and an intensified regimen, which may be used in children at high risk of relapse. The standard regimen is the same as that given to the control group in this study. The intensified regimen is similar to this study’s intervention group medication, continued until remission and then a lower dose over a longer period to prevent relapse.
What are the implications?
This study has not shown any benefit in reducing relapse rate by giving an extended course of prednisolone to children in the UK presenting for the first time with nephrotic syndrome.
However, parents and children may prefer extended treatment, as it results in fewer hospital admissions and appointments.
For the family of children with nephrotic syndrome and commissioners, a cheaper intervention with fewer, shorter hospital admissions might be an unexpected, yet important, benefit.
Citation and Funding
Webb NJ, Woolley RL, Lambe T et al. Sixteen-week versus standard eight-week prednisolone therapy for childhood nephrotic syndrome: the PREDNOS RCT. Health Technol Assess. 2019;23(26).
This project was funded by the NIHR Health Technology Assessment Programme (project number 08/53/31).
Christian MT. Nephrotic syndrome. Nottingham: Nottingham University Hospitals NHS Trust; 2017.
NHS website. Nephrotic syndrome in children. London: Department of Health; 2019.
Paediatric Formulary Committee. Prednisolone. BNF for Children (online). London: BMJ Group, Pharmaceutical Press, and RCPCH Publications; accessed 02 September 2019.
Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre