Open Access Protocol

REducing STEroids in Relapsing

Nephrotic syndrome: the RESTERN
study— protocol of a national, double-
blind, randomised, placebo-controlled,
non-inferiority intervention study
A M Schijvens,1 E M Dorresteijn,2 N Roeleveld,3 R ter Heine,4 J A E van Wijk,5
A H M Bouts,6 M G Keijzer-Veen,7 N C A J van de Kar,1 L P W J van den Heuvel,1,8
M F Schreuder1

To cite: Schijvens AM, Abstract

Dorresteijn EM, Roeleveld N, Strengths and limitations of this study
Introduction  Oral corticosteroids are the first-line
et al. REducing STEroids in treatment for idiopathic childhood nephrotic syndrome.
Relapsing Nephrotic syndrome: ►► Double-blind, randomised, placebo-controlled study.
Most children experience several relapses, needing
the RESTERN study— protocol ►► Nationwide inclusion.
of a national, double-blind, repeated courses of corticosteroid therapy. This exposes ►► Large study cohort.
randomised, placebo- them to side effects and long-term complications. For most ►► Two common practices in the Netherlands regarding
controlled, non-inferiority patients, long-term prognosis is for complete resolution of the current treatment of relapsing nephrotic
intervention study. BMJ Open the disease over time and maintenance of normal kidney syndrome.
2017;7:e018148. doi:10.1136/ function. Therefore, it is vital to focus on minimising adverse ►► Side effects and toxicity of steroids might jeopardise
bmjopen-2017-018148 events of the disease and its therapy. Unfortunately, no the double-blind design of the study.
►► Prepublication history and randomised controlled trials are available to determine the
additional material for this paper optimal corticosteroid treatment of an infrequent relapse of
are available online. To view nephrotic syndrome. Recent studies show that treatment
Trial registration number  NTR5670, EudraCT no 2016-
please visit the journal (http://​ schedules for the first episode can safely be shortened
002430-76.
dx.​doi.​org/​10.​1136/​bmjopen-​ to 2 months. The hypothesis of the REducing STEroids in
2017-​018148). Relapsing Nephrotic syndrome (RESTERN) study is that a
4-week reduction of alternate-day steroids after inducing
Received 8 June 2017 Introduction
Revised 25 August 2017 remission is effective and safe, reduces steroid exposure by
Nephrotic syndrome is characterised by
Accepted 11 September 2017 35% on average and is therefore preferable.
Methods and analysis  The RESTERN study is a
the triad of severe proteinuria, hypoalbu-
nationwide, double-blind, randomised, placebo-controlled, minaemia and oedema. It is one of the most
non-inferiority intervention study. Children aged 1–18 years common glomerular diseases in children with
with a relapse of steroid-sensitive nephrotic syndrome an incidence of 1–7 per 100 000 children per
are eligible for this study. Study subjects (n=144) will be year (Dutch data: 1.52/100 000) and a prev-
randomly assigned to either current standard therapy in alence of 16 per 100 000 children.1–3 Most
the Netherlands or a reduced prednisolone schedule. The children have minimal change nephrotic
primary outcome of the RESTERN study is the time to first syndrome and will have favourable prognosis
relapse after the final prednisolone dose. The secondary with complete resolution of the disease over
outcomes are the number or relapses, progression time and maintenance of normal kidney
to frequent relapsing or steroid dependent nephrotic function.4
syndrome and the cumulative dosage of prednisolone For over 60  years, corticosteroids have
during the study period.
been the first-line treatment for idiopathic
Ethics and dissemination  This non-inferiority trial will be
nephrotic syndrome in children as over
performed in accordance with the Declaration of Helsinki
and has been approved by the medical ethical committee
80%–90% of patients achieve complete
of Arnhem-Nijmegen and the Dutch Competent Authority remission after prednisolone treatment.5 6
(Central Committee on Research Involving Human Yet, over 80% of the patients experience one
For numbered affiliations see Subjects, CCMO). After completion of this study, results will or more relapses and around 50% suffer from
end of article. frequent relapses, thereby needing addi-
be published in national and international peer-reviewed
Correspondence to scientific journals. Papers will be published according to tional courses of corticosteroid therapy.7 This
A M Schijvens; CCMO guidelines. The final report will be made available to exposes them to the side effects and long-
​anne.​schijvens@​radboudumc.​nl trial participants. term complications of corticosteroid therapy,

Schijvens AM, et al. BMJ Open 2017;7:e018148. doi:10.1136/bmjopen-2017-018148 1

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such as growth retardation (8%–16%), osteopaenia

Box  Inclusion and exclusion criteria
(13%–63%), mood disorders and cataract (6%–20%).8–11
The currently used treatment regimens for a nephrotic Inclusion criteria
syndrome relapse are mostly based on practice guidelines ►► Age over 1 and less than 18 years
of the International Study of Kidney Disease in Children ►► Steroid-sensitive nephrotic syndrome
(ISKDC)12 and the Arbeitsgemeinschaft für Pädiatrische ►► At least one episode of nephrotic syndrome in the preceding
Nephrologie (APN).13 In the Netherlands, the standard 24 months that was treated with prednisolone
treatment schedule consists of 60 mg/m2 prednisolone 2
►► The last prednisolone use (at a dose over 10 mg/m on alternate
daily until complete remission is achieved for 3 days, days) for the treatment of a previous episode was at least 4 weeks
followed by 40 mg/m2 prednisolone on alternate days for ago
4–6 weeks.14 15 ►► Subjects without maintenance immunosuppressive therapy
►► Subjects with maintenance immunosuppressive therapy
Several trials have been conducted to study the dura-
–– Long-term immunosuppressive therapies: levamisole,
tion of the initial corticosteroid treatment regimen, as
ciclosporin, tacrolimus, mycophenolate mofetil (Cellcept),
Hodson et al suggested that a prolonged period of pred- mycophenolate sodium (Myfortic), prednisolone maximum
nisolone might reduce chances of subsequent relapses.16 of 4 mg/m2 on alternate days
A previous nationwide study in the Netherlands –– Cyclophosphamide (oral or intravenous), at least 3  months
addressed the issue of duration of corticosteroids for the postcompletion of therapy
initial presentation and showed that the duration had no –– A single dose or course of intravenous rituximab, at least
impact on subsequent relapses.7 A few recent, well-con- 3 months postcompletion of therapy
ducted trials suggest that it may be safe to reduce the ►► Signed informed consent from the parent or legal representative
duration and thereby cumulative dose of corticosteroid and/or the patient, depending on the age of the patient
therapy for the initial episode of nephrotic syndrome Exclusion criteria
from 6 to 2 or 3 months.17–21 With recent studies showing ►► Steroid resistant nephrotic syndrome
no benefit for longer duration of initial prednisolone ►► Receiving or within 3 months after receiving, cyclophosphamide or
treatment, one may conclude that we still don’t know the rituximab
optimal treatment duration of relapses. In addition, as ►► Daily prednisolone maintenance therapy at any dose
stated in the KDIGO (Kidney Disease: Improving Global ►► Alternate-day prednisolone maintenance therapy at a dose over
Outcomes) clinical practice guideline glomerulone- 4 mg/m2
►► Documented or suspected significant non-compliance
phritis, “there are no RCTs examining relapse regimens
►► Pregnancy
with corticosteroids in infrequent relapsing nephrotic
►► Stimulant drug use
syndrome”.22 With the current evidence against longer ►► Comorbidity
steroid therapy for the initial treatment, the time is now –– Kidney transplant recipient
to determine whether this holds true for treatment of –– Any disease that requires the variation in oral prednisolone to be
relapses as well, in both children with and without main- at the discretion of the treating physician(s)
tenance immunosuppressive therapy. ►► Concomitant use of moderate and strong CYP3A inducers
The aim of the RESTERN study (REducing STEroids in ►► Concomitant use of moderate and strong CYP3A inhibitors, other
Relapsing Nephrotic syndrome) is to assess the safety and than ciclosporin
effectiveness of a reduced alternate day steroid schedule
for treatment of a nephrotic syndrome relapse in compar-
ison with the current standard therapy. Study objectives
The primary objective of this study is to investigate
the effectiveness of a reduced steroid schedule for the
Methods and analysis treatment of a relapse in children with steroid-sensi-
Trial design and setting tive nephrotic syndrome. Secondary objectives are the
The RESTERN study is designed as a nationwide, double- following:
blind, randomised, placebo-controlled, non-inferi- ►► To study the influence of maintenance immunosup-
ority intervention study with two treatment arms. The pressive therapy on the effectiveness of a reduced
study is performed and coordinated by a single centre steroid schedule for the treatment of a relapse in
(Radboudumc Amalia Children’s Hospital) where the children with steroid-sensitive nephrotic syndrome.
research team is instituted, with inclusion of patients Maintenance immunosuppressive therapies include
throughout the Netherlands from all secondary and levamisole, ciclosporin, tacrolimus, mycophenolate
tertiary hospitals. mofetil and mycophenolate sodium, and alternate-day
prednisolone with a maximum of 4 mg/m2;
Eligibility criteria ►► To investigate the occurrence of relapses, frequency
Children aged over 1 and less than 18  years with of relapses and progression to steroid dependent and
steroid-sensitive nephrotic syndrome will be assessed for frequent relapsing nephrotic syndrome in children
possible inclusion in the study. A detailed description of with nephrotic syndrome under the standard treat-
the inclusion and exclusion criteria is shown in box. ment regimen;

2 Schijvens AM, et al. BMJ Open 2017;7:e018148. doi:10.1136/bmjopen-2017-018148

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►► To study the influence of maintenance immuno- oral prednisolone (40 mg/m2, with a maximum of 40 mg)
suppressive therapy on the occurrence of subse- and the placebo group will receive 4 weeks of alter-
quent relapses, frequency of subsequent relapses nate-day oral placebo (figure 1). Prednisolone (5 mg/
and progression to steroid dependent and frequent mL) or placebo will be provided as an oral solution (see
relapsing nephrotic syndrome under the standard Investigational medicinal product section).
regimen; Children will be withdrawn if they are unable to take
►► To study the effectiveness of a reduced steroid the study medication and will be treated according to
schedule for the treatment of a relapse and occur- the standard treatment regimen (oral prednisolone
rence and frequency of subsequent relapses in chil- 40 mg/m2 on alternate days). Maintenance immuno-
dren with steroid dependent nephrotic syndrome. suppressive therapy, including levamisole, ciclosporin,
tacrolimus, mycophenolate mofetil and mycophenolate
Interventions
Eligible patients will be randomised between stan- sodium, is continued throughout the treatment period.
dard prednisolone treatment and a reduced treatment Alternate-day prednisolone maintenance therapy with
schedule. At the start of a relapse, participants are treated a maximum of 4 mg/m2, is discontinued during the
according to the current standard therapy, consisting of non-randomised treatment and restarted after rando-
daily oral prednisolone (60 mg/m2). After 3 days of remis- misation, administered at the same day as the study
sion, defined as 3 consecutive days of absent proteinuria medication. Antihypertensive agents, antiproteinuric
based on urine dipstick analysis, standard care dictates agents and/or diuretics may be continued at the discre-
that prednisolone is changed to an alternate-day dosing tion of the treating physician.
of 40 mg/m2 with a maximum of 40 mg. After 2 weeks of All children will be followed for 2 years and subsequent
alternate-day prednisolone, participants are randomised nephrotic syndrome relapses will be treated according
between the two treatment arms. The standard treatment to the current standard treatment protocol in the
group will receive an additional 4 weeks of alternate-day Netherlands.

Figure 1  Intervention schedule and study procedures. AD, alternate days.

Schijvens AM, et al. BMJ Open 2017;7:e018148. doi:10.1136/bmjopen-2017-018148 3

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Investigational medicinal product Table 1  Study questionnaires

A prednisolone or placebo solution (5 mg/mL) will
Questionnaire Information Time points
be produced compliant with current Good Manufac-
turing Practice at the department of pharmacy of our Questionnaire 1 General information, At the start of
institute. The standardised formulation of the oral medical history, alternate day
relapse information prednisolone
solution is based on the Dutch Pharmacists Formulary.
The investigational medicinal product is an aqueous Questionnaire 2 Information study One week after
medication period initiation of study
solution preserved with methylparaben, buffered at a
medication
pH of 7.1 with a phosphate buffer and contains sorbitol
Questionnaire 3 Information after After the final dose
and banana essence to mask the bitter taste of pred-
study medication of study medication
nisolone sodium phosphate. For the placebo, prednis- period
olone sodium phosphate is left out of the product. A
Questionnaire 4 Information At the time of a new
pilot palatability study of the investigational medicinal subsequent relapses relapse
product showed no relevant visual or taste differences
Questionnaire 5 Follow-up 1 year One year after
of the drug or placebo. Drug dispensing and account-
randomisation
ability is performed on individual basis from the central
Questionnaire 6 Follow-up 2 years Two years after
pharmacy. randomisation

Outcomes
The primary outcome of the RESTERN study is the time
to first relapse. This is defined as the time (in days) Sample size
from the final prednisolone dose until the first day of The sample size calculation is based on the non-inferi-
ority design and calculated for the primary outcome:
treatment of the next relapse.
time to first relapse after the final prednisolone dose.
Secondary outcomes include the following:
Based on previous data, average time to relapse in
1. The number of relapses per patient after the final
the first year is approximately 185 days with an SD of
prednisolone dose, censored at 12 and 24 months of
120 days.7 Using the power calculation for a non-in-
follow-up; feriority trial with a continuous primary outcome, a
2. Progression to frequent relapsing nephrotic syn- power of 80% and a non-inferiority limit of 50 days, 72
drome, defined as four or more relapses in any patients per group are required. Using a Cox propor-
12-month period (KDIGO criteria), censored at tional hazard time-to-relapse analysis (survival analysis),
24 months of follow-up; similar numbers can be calculated. With an estimated
3. Progression to steroid dependent nephrotic syn- prevalence of nephrotic syndrome of 15 in every
drome, defined as two consecutive relapses during 100 000 children, a population most at risk between the
corticosteroid therapy or within 14 days of ceasing ages of 2 and 12 years, about 270 children may be at risk
therapy (KDIGO criteria), censored at 24 months of of developing a nephrotic syndrome relapse each year.
follow-up; The necessary inclusion rate is therefore approximately
4. Cumulative dosage of prednisolone (mg/m2) during 50%. Subjects will be replaced after withdrawal. Based
study period, censored at 12 and 24 months of follow- on withdrawal rates of a previous nephrotic syndrome
up. clinical trial in the Netherlands7 a maximum of 23
subjects (16%) will be replaced. The reason for with-
Participant timeline drawal will be recorded in the medical status report and
During the period of daily prednisolone, participants the trial master file.
determine the timing of remission by daily urine
dipstick analysis. In order to objectively establish Recruitment
remission of nephrotic syndrome, participants are Study subjects will be notified about the existence of
requested to deliver a urine sample to the local hospital the RESTERN study via their treating physician, the
within 5 days of attaining remission to confirm the patient associations and/or the study website (www.​
absence of proteinuria. During the 2 weeks of alter- restern.​nl). Written informed consent for participation
nate-day prednisolone and the subsequent 4 weeks of will be obtained from the parents or legal representa-
study medication, participants are requested to check tive(s) and/or the patient, depending on the age of the
their urine for proteinuria at least weekly. In addi- patient.
tion, patients are requested to fill out digital question- Randomisation and blinding
naires at different time points (figure 1). As shown in Participants will be randomly allocated in a 1:1 ratio to
table 1, follow-up information will be collected at 1 receive either prednisolone or placebo. The randomisa-
and 2 years after randomisation and when a relapse tion will be performed by the pharmacy of our institute
occurs. using the data management system Castor Electronic

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Data Capture23 with stratification for treatment with data. Further details regarding statistical analysis of the
immunosuppressive maintenance therapy. Castor uses primary and secondary outcomes can be found in the
a variable block algorithm with random blocks of 4, 6 statistical analysis plan (online supplementary file 1).
or 8. The randomisation list remains preserved by the
pharmacy and will not be accessible to the investigators
until the end of the follow-up of the last patient. An Monitoring
unblinding procedure at the hospital pharmacy depart- As the standard treatment group will receive the current
ment will be available at all times. The true group allo- standard therapy for a nephrotic syndrome relapse in the
cation will be unmasked only if necessary and after the Netherlands, no specific safety surveillance is needed for
database is locked. this group. The placebo arm provides the participants
with a reduced prednisolone exposure, which is there-
Data collection fore unlikely to result in any adverse events. However,
Participants are requested to maintain a digital study log the main concern in this study is that the reduced treat-
in which results from dipstick analysis, medication and ment schedule may result in an earlier relapse, which
special remarks are gathered. In addition, participants is the primary endpoint of the study. An external Data
receive digital questionnaires about their medical history, Safety and Monitoring Board (DSMB) will be convened
previous relapses and the current nephrotic syndrome to monitor safety outcomes and to provide the principal
relapse. Moreover, the digital questionnaires include ques- investigator with recommendations regarding reconsider-
tions about side effects and steroid toxicity at different ation of the trial. The DSMB will consist of two members:
time points, for example, during the period of daily pred- a methodologist and a paediatric nephrologist with expe-
nisolone, alternate-day prednisolone and study medica- rience in clinical trials, both independent of the trial.
tion. First, patients are asked if the different side effects Interim analysis performed by the DSMB will take place
were present during the specific time period. Second, the 3 months after the first 40 participants have received study
level of inconvenience is assessed (ranging from not at all medication. Aim is to check for a significant difference
inconvenient to very inconvenient). Local paediatricians in relapse rate between the two groups. Further details
and paediatric nephrologists will be requested to provide about the interim analysis can be found in the statistical
patient information at different time points. Patients analysis plan. An independent research coordinator will
randomised who did not take their allocated treatment monitor the study to verify that the rights and well-being
will be considered as having deviated from the protocol. of human subjects are protected, the reported trial data
If a patient or their representative withdraws consent for are accurate, complete and verifiable from source docu-
data collection, only data up to the point of withdrawal ments and the conduct of the trial is in compliance with
will be used in the analysis. the currently approved protocol and GCP. The coordi-
nating investigators will report the serious adverse events
Data management and will submit an annual safety report to the medical
The study will use the Good Clinical Practice (GCP) ethical committee and competent authority.
compliant, web-based application Castor Electronic Data
Capture to record data.23 Data will be entered in the case
report form in Castor by the coordinating investigators Ethics and dissemination
at the Radboudumc. The digital questionnaires will auto- Ethics approval
matically be uploaded in the data management system. The RESTERN study has been approved by the medical
ethical committee of Arnhem-Nijmegen and the Dutch
Statistical analysis Competent Authority (Central Committee on Research
Statistical analysis will be conducted using IBM SPSS Statis- Involving Human Subjects, CCMO). The registration
tics. A p value <0.05 will be considered statistically signifi- number of the RESTERN study is NL8185.091.16. The
cant. The main analysis will consist of an intention-to-treat project will be conducted in line with the Declaration
analysis. Participants who are lost to follow-up or in whom of Helsinki. In addition, all researchers will follow the
trial medication is stopped prematurely will be analysed guidelines for GCP and trial outcomes will be reported
according to their allocated groups. In addition, as inten- in line with the Consolidated Standards of Reporting
tion-to-treat analysis may increase the risk of type 1 errors Trials guidelines.25 Any substantial amendments or modi-
in a non-inferiority trial, a per-protocol analysis will also fications of the protocol will be presented to the medical
be conducted.24 Missing baseline and outcome data will ethical committee and, when approved, be notified to
not be imputed. When a patient is lost to follow-up or has the Competent Authority compliant with European
withdrawn consent, all available data up until withdrawal regulations.
of consent or loss to follow-up will be used. Discrete vari-
ables will be summarised by frequencies and percentages. Consent
Continuously distributed variables will be summarised Written informed consent for participation will be
using either mean and SD for data with normal distri- obtained from the parents or legal representatives and/or
bution or median and IQR for non-normally distributed the patient, depending on the age of the patient. Patients

Schijvens AM, et al. BMJ Open 2017;7:e018148. doi:10.1136/bmjopen-2017-018148 5

Open Access

will be informed that withdrawal from the study is possible In this study, a treatment duration of 6 weeks alter-
at any time at their own discretion without necessarily nate-day prednisolone after inducing remission for the
giving reasons. The ‘code of conduct involving minors’ standard therapy group was chosen as this is the current
will be used as guideline to respond appropriately to resis- standard therapy in the Netherlands for the treatment of
tance of subjects to study procedures as established by the a nephrotic syndrome relapse. As the KDIGO recommen-
Paediatric Association of the Netherlands. dation of at least 4 weeks alternate-day steroid treatment is
based on a rather small study,28 the Dutch guidelines tradi-
Confidentiality tionally follow the 6-week alternate-day steroid schedule
All patients have their own unique patient identifica- described by the APN. However, a potential limitation of
tion number as allocated by the hospital administration. this study could be that some clinicians already reduced
Source data will be stored confidentially in the hospital the alternate-day treatment schedule from 6 to 4 weeks
information system under the subject’s identification after inducing remission based on the notion of this in the
number. Participants will also receive an identification KDIGO guideline.22 Our choice of 6 weeks alternate-day
code, all final study data will be kept under this identi- prednisolone may therefore discourage eligible patients
fication number. The investigators safeguard the key to to participate in our study as this may increase the pred-
the code. Handling of personal data will comply with the nisolone duration for some patients. The use of different
Dutch Personal Data Protection Act. Data will be stored treatment protocols in the Netherlands underlines the
until 15 years after publication. need for our randomised controlled trial to determine
the optimal dosing regimen for a nephrotic syndrome
Dissemination policy relapse. In case non-inferiority is shown, our results are
The trial is registered on the Dutch Trial Registry, trial also transferable to the KDIGO recommendation of at
number NTR5670, prior to the start of inclusion.26 least 4 weeks of alternate-day steroid treatment. However,
After completion of this study, results will be published in case inferiority is shown, additional research is needed.
in national and international peer-reviewed scientific The results of the RESTERN study may provide
journals. Papers will be published according to CCMO evidence to adapt current recommendations for national
guidelines. The final report will be made available to trial and possibly international guidelines to treat children
participants. with relapsing nephrotic syndrome. If corticosteroid
exposure could be reduced to treat relapses of nephrotic
syndrome, this would reduce the toxicity of predniso-
Discussion lone and thereby decrease the side effects and long-term
The RESTERN study aims to demonstrate that relapses of complications associated with corticosteroid therapy in
nephrotic syndrome in children can be treated effectively children with relapsing nephrotic syndrome.
and safely by a reduced duration of alternate day pred-
nisolone. Using a nationwide, double-blind, randomised,
Trial status
placebo-controlled, non-inferiority study, the hypothesis
The study started recruitment in December 2016 and is
will be tested.
currently recruiting.
Currently, corticosteroid treatment duration in children
with infrequent relapses of steroid-sensitive nephrotic Author affiliations
1
syndrome is based on empirical recommendations from Department of Pediatric Nephrology, Radboudumc Amalia Children's Hospital,
the ISKDC and APN. The RESTERN study is the first Nijmegen, The Netherlands
2
Department of Pediatric Nephrology, Erasmus MC-Sophia Children's Hospital,
randomised placebo-controlled clinical trial to investigate Rotterdam, The Netherlands
a reduced corticosteroid schedule for the treatment of 3
Department for Health Evidence, Radboudumc, Nijmegen, The Netherlands
relapsing nephrotic syndrome in childhood. So far, most 4
Department of Pharmacy, Radboudumc, Nijmegen, The Netherlands
5
studies have been conducted to investigate the initial Department of Pediatric Nephrology, VU University Medical Center, Amsterdam, The
treatment schedule. Recently, it has been shown that a Netherlands
6
Department of Pediatric Nephrology, Emma Children’s Hospital, Academic Medical
reduction in prednisolone duration for the treatment of
Center, Amsterdam, The Netherlands
a first presentation of nephrotic syndrome in children, 7
Department of Pediatric Nephrology, Wilhelmina Children's Hospital, University
with or without increased cumulative dosage, is clinically Medical Center Utrecht, Utrecht, The Netherlands
safe and results in similar treatment outcomes, while 8
Department of Growth and Regeneration, University Hospital Leuven, Leuven,
potentially reducing side effects.17 18 20 21 For frequent Belgium
relapsing nephrotic syndrome, an abstract from a single
Contributors  MFS is the principal investigator of the RESTERN study, initiated
randomised controlled trial suggests that children with
the project and drafted the protocol. AMS drafted this manuscript based on
relapsing steroid-sensitive nephrotic syndrome relapse the METC approved protocol using the SPIRIT checklist. All authors critically
less frequently if treated with tapering doses of predniso- reviewed and revised the manuscript and approved the final manuscript as
lone for 7 months compared with the standard treatment submitted.
of 2 months. Unfortunately, these results have never been Funding  This work was supported by a Senior Postdoc Grant to MFS from the
published, which makes it impossible to examine them Dutch Kidney Foundation, project number 15OKG16.
closely and evaluate for any bias.18 27 Competing interests  None declared.

6 Schijvens AM, et al. BMJ Open 2017;7:e018148. doi:10.1136/bmjopen-2017-018148

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Ethics approval  The RESTERN study has been approved by the medical ethical 11. Skrzypczyk P, Panczyk-Tomaszewska M, Roszkowska-Blaim M,
committee of Arnhem-Nijmegen and the Dutch Competent Authority (Central et al. Long-term outcomes in idiopathic nephrotic syndrome: from
Committee on Research Involving Human Subjects, CCMO). The registration number childhood to adulthood. Clin Nephrol 2014;81:166–73.
of the RESTERN study is NL8185.091.16, file no 2016-2288. 12. Arneil GC. The nephrotic syndrome. Pediatr Clin North Am
1971;18:547–59.
Provenance and peer review  Not commissioned; externally peer reviewed. 13. Anon. Alternate-day versus intermittent prednisone in frequently
relapsing nephrotic syndrome. A report of "Arbetsgemeinschaft für
Open Access This is an Open Access article distributed in accordance with the Pädiatrische Nephrologie". Lancet 1979;1:401–3.
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which 14. Lilien MR, Van de Walle JGJ. Nefrotisch syndroom. In: Van der
permits others to distribute, remix, adapt, build upon this work non-commercially, Heijden AJ, Van Wijk JA, eds. Werkboek Kindernefrologie. 2 ed.
and license their derivative works on different terms, provided the original work is Amsterdam: VU University Press, 2010:124–31.
properly cited and the use is non-commercial. See: http://​creativecommons.​org/​ 15. Ehrich JH, Brodehl J. Long versus standard prednisone therapy
licenses/​by-​nc/​4.​0/ for initial treatment of idiopathic nephrotic syndrome in children.
Arbeitsgemeinschaft für Pädiatrische Nephrologie. Eur J Pediatr
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expressly granted. nephrotic syndrome in children. Cochrane Database Sys Rev 2005.
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