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NIHR Signal Length of steroid course for childhood nephrotic syndrome makes little difference to later recurrences

Published on 3 September 2019

doi: 10.3310/signal-000812

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.

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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).

Bibliography

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.

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).

Bibliography

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.

Sixteen-week versus standard eight-week prednisolone therapy for childhood nephrotic syndrome: the PREDNOS RCT

Published on 3 June 2019

Webb N J, Woolley R L, Lambe T, Frew E, Brettell E A, Barsoum E N, Trompeter R S, Cummins C, Wheatley K & Ives N J.

Health Technology Assessment Volume 23 Issue 26 , 2019

Background The optimal corticosteroid regimen for treating the presenting episode of steroid-sensitive nephrotic syndrome (SSNS) remains uncertain. Most UK centres use an 8-week regimen, despite previous systematic reviews indicating that longer regimens reduce the risk of relapse and frequently relapsing nephrotic syndrome (FRNS). Objectives The primary objective was to determine whether or not an extended 16-week course of prednisolone increases the time to first relapse. The secondary objectives were to compare the relapse rate, FRNS and steroid-dependent nephrotic syndrome (SDNS) rates, requirement for alternative immunosuppressive agents and corticosteroid-related adverse events (AEs), including adverse behaviour and costs. Design Randomised double-blind parallel-group placebo-controlled trial, including a cost-effectiveness analysis. Setting One hundred and twenty-five UK paediatric departments. Participants Two hundred and thirty-seven children presenting with a first episode of SSNS. Participants aged between 1 and 15 years were randomised (1 : 1) according to a minimisation algorithm to ensure balance of ethnicity (South Asian, white or other) and age (≤ 5 or ≥ 6 years). Interventions The control group (n = 118) received standard course (SC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1–4, 40 mg/m2 of prednisolone on alternate days in weeks 5–8 and matching placebo on alternate days in weeks 9–18 (total 2240 mg/m2). The intervention group (n = 119) received extended course (EC) prednisolone therapy: 60 mg/m2/day of prednisolone in weeks 1–4; started at 60 mg/m2 of prednisolone on alternate days in weeks 5–16, tapering by 10 mg/m2 every 2 weeks (total 3150 mg/m2). Main outcome measures The primary outcome measure was time to first relapse [Albustix® (Siemens Healthcare Limited, Frimley, UK)-positive proteinuria +++ or greater for 3 consecutive days or the presence of generalised oedema plus +++ proteinuria]. The secondary outcome measures were relapse rate, incidence of FRNS and SDNS, other immunosuppressive therapy use, rates of serious adverse events (SAEs) and AEs and the incidence of behavioural change [using Achenbach Child Behaviour Checklist (ACBC)]. A comprehensive cost-effectiveness analysis was performed. The analysis was by intention to treat. Participants were followed for a minimum of 24 months. Results There was no significant difference in time to first relapse between the SC and EC groups (hazard ratio 0.87, 95% confidence interval 0.65 to 1.17; log-rank p = 0.3). There were also no differences in the incidence of FRNS (SC 50% vs. EC 53%; p = 0.7), SDNS (44% vs. 42%; p = 0.8) or requirement for other immunosuppressive therapy (56% vs. 54%; p = 0.8). The total prednisolone dose received following completion of study medication was 5475 mg vs. 6674 mg (p = 0.07). SAE rates were not significantly different (25% vs. 17%; p = 0.1) and neither were AEs, except poor behaviour (yes/no), which was less frequent with EC treatment. There were no differences in ACBC scores. EC therapy was associated with a mean increase in generic health benefit [0.0162 additional quality-adjusted life-years (QALYs)] and cost savings (£4369 vs. £2696). Limitations Study drug formulation may have prevented some younger children who were unable to swallow whole or crushed tablets from participating. Conclusions This trial has not shown any clinical benefit for EC prednisolone therapy in UK children. The cost-effectiveness analysis suggested that EC therapy may be cheaper, with the possibility of a small QALY benefit. Future work Studies investigating EC versus SC therapy in younger children and further cost-effectiveness analyses are warranted. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 26. See the NIHR Journals Library website for further project information.

Expert commentary

PREDNOS is a practice-challenging paper in an opinion-based field. Two hundred and thirty-seven children were recruited from 125 UK centres to a double-blind, placebo-controlled, randomised trial.

This study showed that an extended 16-week course of prednisolone for children with steroid-sensitive nephrotic syndrome did not reduce the rate of relapse compared with a standard 8-week course.

Interestingly, the cost-effectiveness analysis found that the extended course of treatment was cheaper, by £3,260, than the standard course and produced a small gain in quality of life compared to the standard course.

This study defines what we can expect for children who present with steroid-sensitive disease – 80% of patients in the study had a relapse, and this is what we should be telling our patients. They are not unlucky if they have a relapse, they are lucky if they don’t have one. Expect relapses; they are not the result of too rapid a weaning regime.

Associate Professor Catherine Quinlan, Paediatric Nephrologist and Clinician Scientist at the Royal Children’s Hospital and the Murdoch Children’s Research Institute in Melbourne, Australia.

The commentator declares no conflicting interests