The Canadian Childhood Nephrotic Syndrome (CHILDNEPH) Project
Conditions: Nephrotic Syndrome in Children, Nephrotic Syndrome, Minimal Change, Nephrotic Syndrome，Idiopathic
Sponsor: University of Calgary

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 1 
 
 
 
 
The Canadian Childhood Nephrotic Syndrome Project 
(CHILDNEPH) 
 
NCT – Pending 
 
February 25, 2015 
 
 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 2 
 
1.0 OVERVIEW 
 
Nephrotic syndrome is the most common acquired kidney disease in children.1   Affected children have 
recurrent episodes (or relapses) of proteinuria that may lead to life-threatening complications including 
sepsis, peritonitis and thromboembolism.2  The goals of treatment are to induce remission of proteinuria, 
reduce the number of relapses, minimize toxicity of treatments and delay kidney damage.3 The first-line 
treatment for nephrotic syndrome is oral steroids, and many children will need repeated courses of 
steroids for relapsing disease.2,4 However, steroid treatment is associated with many side effects, 
including obesity, growth retardation, hypertension, cataracts, poor bone health, and cosmetic effects.2,5-
15 Various other non-steroid immunosuppressive drugs are often used in the course of illness to decrease 
frequency of relapses and to avoid side effects of prolonged and recurrent steroid use.16  Treatment 
protocols for relapsing nephrotic syndrome are therefore complex, requiring multiple drugs and multiple 
courses of therapy over long periods of time for disease control.     
 
International clinical practice guidelines are available to guide treatment of nephrotic syndrome;17 
however, many of the recommendations are based on poor quality evidence and very few randomized 
controlled trials - leading to considerable debate among physicians regarding best treatment 
approaches.18,19  As a result, drug treatment protocols and processes of care for childhood nephrotic 
syndrome are highly variable among physicians and care centres; evidence practice gaps also exist.20,21  
In a survey of Canadian pediatric nephrologists, we found striking variation in dose and duration of 
steroids and second line agents reportedly used for first presentation and relapses of nephrotic 
syndrome.22  Lack of consensus between physicians and centres regarding best treatment approach can 
lead to a frustrating experience for patients and families, poor satisfaction with clinical care, and sub-
optimal outcomes.19,23  Using a priority setting survey, we identified that addressing these issues in the 
management of childhood nephrotic syndrome is the top priority for the Canadian pediatric nephrology 
community. 
 
In Canada, little research has been done to evaluate and improve outcomes of children with nephrotic 
syndrome. It is not known whether variability in treatments affects patient outcomes – addressing this 
problem is a necessary first step towards improving care and patient experience.  A carefully constructed 
prospective longitudinal cohort with a large and generalizable sample of patients can help us answer this 
question. Therefore, we have established the first national prospective cohort of children with nephrotic 
syndrome with the overall goal to provide best care based on best evidence.  
 
Over the last 2 years, we received start-up funds from Canadian Institutes of Health Research (CIHR) 
and other sources to establish this cohort in 13 sites across Canada. We have enrolled 77 patients to date 
and have provided our preliminary data in this application. The funds received to date are inadequate to 
reach the sample size needed and to complete the observation period required to address the research 
questions as proposed within this application. We have noted in the proposal and budget, the progress of 
our ongoing work and where new funds are needed.  We have also carefully considered past review 
committee comments in this re-submission. 
 
We will use the prospective cohort to address the following 2 objectives: 
 
Objective 1 
a) To determine the association of steroid dose prescribed (total dose prescribed during observation 
period divided by total number of days on treatment) and relapse rates (primary outcome defined 
as total number of relapses divided by total observation time).   
Objective 2  
a) to determine the associations between centre-, physician-, patient-level characteristics and i) 
steroid dose prescribed, and ii) length of steroid treatment for first presentation and subsequent 
relapses of nephrotic syndrome;  

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 3 
 
b) To identify reasons for practice variation in treatments for nephrotic syndrome between and 
among pediatric nephrology care providers and centres.  
 
For Objective 1, we will evaluate association of steroid dose prescribed with relapse rates, adjusting for 
patient characteristics.  For objective 2, we will use multi-level modeling with patients nested within 
physicians and physicians nested within health centres, to evaluate the association of patient-, physician- 
and centre-related factors with variability in steroid treatment dose prescribed.  An embedded qualitative 
study utilizing focus groups of health care providers will enrich the quantitative results by providing an 
understanding of attitudes, beliefs and local factors driving 
variation in care at participating centres, while considering 
provider characteristics (training background, experience) and 
centre characteristics (use of standardized protocols). 
Quantitative and qualitative results will be integrated (using a 
convergent parallel mixed methods design) for interpretation 
at the end of study, and collectively inform strategies for 
development and implementation of best practice treatment 
protocols across centres to improve overall provision of care 
in this patient population. See adjacent figure for overview of 
study.    
 
2.0 DISEASE BURDEN AND MANAGEMENT ISSUES 
 
 
2.1 Childhood nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia and 
edema.1 The incidence rate of nephrotic syndrome is 2 to 7 cases per 100,000 children per year and 
prevalence is estimated as 16 per 100,000 children.1,24-26 In Canada, approximately 150 children will be 
diagnosed with nephrotic syndrome each year and there are an estimated 1,000 prevalent patients (data 
collected from participating sites, see attached support letters). Although the cause of this disease is 
unknown in most children, nephrotic syndrome can occur in association with genetic mutations in the 
components of the glomerular filtration barrier, comorbid conditions or environmental triggers.1 Without 
treatment, children with nephrotic syndrome develop edema-related complications, pleural effusions, 
severe infections (e.g. peritonitis, pneumonia, sepsis), thromboembolism and eventually, progress to 
kidney failure or death.27-29  Most (70-90%) children with nephrotic syndrome will have a relapsing 
course of proteinuria (range of 1 to >20 relapses during childhood) leading to significant morbidity.10,30  
Therefore, nephrotic syndrome is associated with substantial health system costs which include specialist 
and multi-disciplinary health care team visits, hospital admissions for control of edema, infection or 
thrombosis and for kidney biopsies.31  
 
2.2 Steroids are the treatment of choice for first presentation and subsequent relapses of nephrotic 
syndrome.  Clinical response to steroids is the most important predictor of disease course.2  Steroid 
sensitive patients typically respond to treatment with remission of proteinuria within 2 weeks of therapy 
and maintain normal kidney function. Steroid resistant patients, defined as those who fail to achieve 
complete remission of proteinuria after 8 weeks of steroid therapy, have a high risk (>50% in 5 years) of 
kidney failure.32,33  Approximately 90% of children with nephrotic syndrome are steroid sensitive, and 
they will be the focus of our study.34,35 Among these patients remission is achievable with steroid 
treatment; however, relapses are common requiring multiple courses of steroids and steroid sparing 
immunosuppressive drugs - leading to significant side effects drug toxicity.  Of the children who relapse, 
up to 50% will have frequent relapses (≥2 relapses within 6 months of first response or ≥4 relapses in 
any 12 month period) or become steroid dependent (2 consecutive relapses during tapering of steroid 
therapy, or relapse within 14 days of steroid cessation).10,30  Steroid toxicity reported in children with 
nephrotic syndrome includes growth retardation and obesity,7,9,13,36 hypertension,11,37  posterior sub-

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 4 
 
capsular cataracts,6,12 decreased bone mineral density,14,15 and impaired glucose tolerance.8 Minimizing 
relapse rates and steroid exposure are the most important goals in caring for these patients and remain 
the most relevant clinical outcomes.  
 
2.3 Steroid treatment protocols used for nephrotic syndrome today were developed over 40 years 
ago, and revised over time.  These protocols were drafted as part of an international cohort study of 
children with nephrotic syndrome (International Study of Kidney Disease in Children, ISKDC) between 
1967-1974, with the aim to induce remission of proteinuria and reduce risk of relapses.34  Later in the 
1980s and 1990s, clinical trial evidence generated by the German working group for pediatric nephrology 
supported that longer initial courses of steroid therapy led to fewer relapses over time.38,39  As a result, 
many Canadian pediatric nephrology physicians and centres changed their steroid protocols from the 
original ISKDC regimen of 4 weeks of daily steroid therapy followed by 4 weeks of alternate day therapy 
to 6 weeks of daily steroid therapy followed by 6 weeks of alternate day therapy for first presentation of 
nephrotic syndrome (total therapy time increased to 3 months from 2 months). More recently, the results 
of a meta-analysis published in 2007 suggested prolonging therapy up to 6 months for first presentation 
of nephrotic syndrome may decrease the number of relapses over time compared to 3 month regimens40 
- prompting some physicians to adopt 6 month steroid protocols.   
 
2.4 Although a reasonable body of evidence is available to guide practice, practice variation is 
common in nephrotic syndrome.  The available evidence base for treatment of first presentation and 
relapses of nephrotic syndrome were synthesized and published in several systematic reviews, local 
guidelines,2,40,41 and also in a recent international clinical practice guideline.42  Nevertheless, lack of 
consensus regarding best treatment approaches is a well-known international phenomenon. Variation in 
care was documented in surveys of American pediatric nephrologists in 2000 and 2009; however, little 
has been done to address this problem in the United States or elsewhere.20,21 We performed a similar 
survey which was sent to all Canadian pediatric nephrologists (n=58) and achieved a 69% response rate. 
The results showed significant variation in steroid protocols and also in the choice of steroid sparing 
drugs and biopsy practices (see manuscript attached, Samuel S, Pediatr Nephrol 2013).  The total duration 
of steroid therapy ranged from a minimum of 7.5 weeks to a maximum of 26 weeks (median 16 weeks) 
for first presentation of nephrotic syndrome – likely contributing to considerable variation in cumulative 
steroid exposure among patients who may otherwise have similar clinical presentations.  Sample 
protocols used by Canadian physicians and centres are shown in Appendix Tables 1a and 1b.  The overall 
impact of this variability in steroid exposure on relapse rates of Canadian children with nephrotic 
syndrome has not been formally assessed and remains the most important and compelling unanswered 
question. 
 
2.5  Patient-, physician- or centre-related factors may be associated with practice variation in 
nephrotic syndrome.   Physicians make decisions about dose and duration of therapy while considering 
both efficacy and toxicity of drugs in the context of individual patient clinical presentations and 
preferences.  Physicians may also be influenced by their training background, familiarity with the 
literature, and their work environments.  In our survey of practice patterns, duration of steroid therapy 
prescribed was associated with year of graduation for physicians (i.e. years in practice) and the presence 
or absence of a standardized protocol in centres43 – providing preliminary evidence that physician and 
centre-specific factors also play a role in variation of care. We also found widespread variation in the 
choice of second line agents – likely driven by beliefs regarding efficacy of each agent compared to 
toxicity. For example, we know anecdotally that many Canadian pediatric nephrologists avoid using 
cyclophosphamide, a well studied and effective drug for frequently relapsing and steroid dependent 
nephrotic syndrome due to risk of infertility and cancer, and prefer using tacrolimus a less well studied 
drug with a more favorable side effect profile.22,44  Therefore, understanding ‘why there is practice 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 5 
 
variation’ is a key step to overcome barriers to implementation of best practice approaches across many 
centres.  No study to date has assessed reasons for variation in nephrotic syndrome care. 
 
2.6 There is uncertainty in the literature regarding best treatment protocols for childhood 
nephrotic syndrome. The evidence supporting many guideline recommendations for steroid therapy and 
second line agents are based on small numbers of randomized controlled trials (RCTs), some with very 
few patients – leading to lack of trust among the physician groups in the robustness of the literature.44,45 
In addition, the literature continues to evolve with conflicting messages. Three recent RCTs (2 in the 
same January 2015 Kidney International issue) were published; they all suggest that there is no benefit 
to prolonged steroid treatment of up to 6 months compared to 3 months for first presentation of nephrotic 
syndrome.46-48 A recent editorial published with these new RCTs suggest that future trials should no 
longer just focus on duration of steroid therapy over the short term, but rather study emerging novel 
treatments for nephrotic syndrome and long term outcomes.45 In the light of new evidence, and prevalent 
practice variation, we believe that a national observational cohort study is a necessary first step to obtain 
valuable generalizable data. These data will: 1) inform whether there is a need to develop standardized 
protocols to reduce practice variation by identifying differences in patient outcomes based on steroid 
prescribed; 2) provide observational patient outcome data to complement interpretation of published 
short term clinical trial results; and 3) assist in strategic prioritization of future clinical trial questions 
regarding new and old therapeutics.  
 
2.7 We need a collaborative research network and data infrastructure to improve outcomes in 
childhood nephrotic syndrome, a rare pediatric chronic disease.  Childhood nephrotic syndrome is 
one of the most common acquired kidney diseases in children, but, it meets the Canadian Institutes for 
Health Research (CIHR) definition of a ‘rare’ disease (affects one person out of 2,000 or fewer).49 No 
single centre or region in Canada has sufficient patient numbers to produce generalizable knowledge 
regarding effective treatments, the most significant barrier to generating high quality evidence and one 
that can be overcome by multi-centre collaborative studies.  Clinical research networks, with the 
combination of high quality data and large sample size accrual, are proven powerful tools to improve 
health outcomes of children with rare diseases.  For example, the ImproveCareNow network for pediatric 
inflammatory bowel disease includes 445 pediatric gastroenterologists and 50 sites, and has seen 
remission rates for Crohn’s disease and colitis improve from 49% to 78% in just 5 years.50-52  For steroid 
sensitive nephrotic syndrome in particular, there is a severe lack of well characterized clinical and/or 
research cohorts. There is only one single-centre cohort study in Canada documenting outcomes of 
steroid sensitive patients (INSIGHT study, with a focus on genetic investigations)53 – creating a major 
gap in knowledge regarding overall quality of clinical care and patients’ clinical progression and 
outcomes. Funding this proposal will sustain a national network, composed of >20 investigators, with an 
estimated 50 physicians who will enroll from 13 sites, and establish the only national longitudinal 
observational cohort study for children with nephrotic syndrome.  
 
2.8 Expected results and significance: We expect to observe differences in relapse rates based on 
steroid prescribed (Objective 1) and we expect to find that physician and centre characteristics play an 
important role in determining variation in treatment protocols (Objective 2).   Our KT strategies will 
utilize the collective information gathered in this study regarding steroid prescribed and relationship to 
outcomes, and factors determining variation in treatments, to develop best practice approaches for 
treatment of nephrotic syndrome, and to identify physicians and centres most or least likely to implement 
these approaches.  This project will also provide the unprecedented opportunity for every child with 
nephrotic syndrome and every physician treating children with nephrotic syndrome to be enrolled into 
the observational cohort, their data being used to inform development, implementation and iterative 
refinement of treatment protocols, and provide foundational clinical data to prioritize future clinical trials.  
3.0 METHODS 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 6 
 
 
We have conceptualized our study, evaluating clinical care and 
outcomes of childhood nephrotic syndrome, based on Donabedian’s 
well known ‘structure, process, and outcome’ framework for health 
services evaluation.54  Our work plan to achieve objectives 1 and 2 
(to evaluate association of steroid dose prescribed with outcomes, 
and to understand sources of variability in treatments), using both 
quantitative and qualitative methods and a nested data architecture 
with patients’ data linked to their physicians and physicians’ data 
linked to their centres (see adjacent figure), will broadly address 
structure, process and outcome elements operating at three levels.  
First in section 3.1 below, we provide details regarding creation and 
characterization of the prospective cohort – the means by which we will achieve objectives 1 and 2.    
 
3.1 Cohort Creation and Characterization 
 
Population and setting: All children who present to pediatric nephrology clinics with a clinical 
diagnosis of nephrotic syndrome will be eligible for enrollment into the longitudinal cohort.  All pediatric 
nephrology centres in Canada (n=13) are participating in this national study (see attached support letters). 
All pediatric nephrologists who care for children with nephrotic syndrome in Canada are eligible for 
enrollment.   
 
Enrollment period: The enrollment period for the prospective cohort will last 4.0 years. The observation 
period will continue for an additional 6 months after the enrollment period (to ensure minimum 6 months 
follow-up for all patients by end of study).   
 
Inclusion criteria: A patient is eligible to enter the cohort if he/she meets one of the following 2 criteria. 
See Appendix, Figure 1 for patient enrollment plan. 
• A child with first presentation of nephrotic syndrome who meets the following criteria: age 1 to 
≤17.5 years; edema present; urinalysis shows proteinuria (> 3+ on dipstick; > 3 g/L on urinalysis or 
urine protein to creatinine ratio > 200 mg/mmol); serum albumin < 25 g/L; and no prior treatment 
with steroids. 
• A child with an established diagnosis of childhood nephrotic syndrome who presents at the beginning 
of either a first or second relapse (defined as proteinuria > 3+ on dipstick, > 3g/L on urinalysis or 
urine protein to creatinine ratio > 200 mg/mmol for 3 consecutive days) during enrollment period, 
prior to start of steroid sparing agents or kidney biopsy. 
 
Exclusion criteria:  Patients will be excluded if they meet one of the following criteria either at 
enrollment or during course of study: 1) secondary cause of nephrotic syndrome (e.g. lupus, malignancy); 
2) C3 low suggesting high likelihood of secondary cause of nephrotic syndrome.  Patients ultimately 
shown to be steroid resistant will be excluded from the final analysis, but will continue to be followed in 
the prospective cohort.  Enrolled patients who turn 18 years of age during the study will exit the study.  
Further follow-up will be sought for these adult patients using a revised ethics application. 
 
Patient enrollment:  Two team members from each participating site will be primary contacts for the 
study (one physician and one nurse/research staff). Every 2 weeks these individuals will generate a list 
of patients seen with nephrotic syndrome by reviewing inpatient and outpatient data (clinic scheduling 
records) to determine eligibility.  All patients with a clinical diagnosis of nephrotic syndrome who meet 
the inclusion and exclusion criteria will be introduced to the study by the primary treating physician.  The 
site investigator will approach patient/parents to obtain informed consent and will also obtain assent from 
older patients (age >12 years). Patients will be enrolled in the study if they meet inclusion criteria and 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 7 
 
their legal guardian has given informed consent.  Consent forms will be available in English and French. 
Logs of all patients screened and consented, and for those who declined the reason will be kept.   
 
Physician enrollment: Informed consent will be obtained from physicians within participating 
nephrology care teams to allow their demographic information (age, gender, location of nephrology 
training, years in practice) to be collected. Physician data will be linked to their patient’s data in the 
nested data architecture. Once linked, physician identifying information will be removed.  If a consenting 
patient’s physician declines to participate in the study, the patient’s data will be linked to a generic 
category of ‘unknown physician.’  
 
Patient data being collected: Study data will be collected at the following study points (see Figure 
below and more details shown in Appendix, Figure 2): 1) study entry (whether first presentation, first 
relapse or second relapse); 2) at the beginning of all subsequent relapses [defined as proteinuria > 3+ on 
dipstick, > 3g/L on urinalysis or urine protein to creatinine ratio > 200 mg/mmol for 3 consecutive days 
or start of full dose steroids (60 mg/m2 or 2mg/kg)]; 3) at the end of first presentation and end of all 
subsequent relapses [defined as both remission of proteinuria – negative or <1.0 g/L protein on dipstick 
for 3 consecutive days, and off steroids]; 4) study visits every 6 months after entry; 5) at start of all steroid 
sparing agents; 6) at time all kidney biopsies; and 7) study end. 
  
 
 
At entry, we will record demographic information (age, gender, ethnicity, family income, parental 
education, past medical history), height, weight, blood pressure, blood test results (C3, albumin, 
cholesterol, creatinine), urine protein values by dipstick (routine clinical practice is to use urine albumin 
dipsticks [Albustix™, Bayer], but urine protein to creatinine ratio will be recorded if available), medical 
history and details of steroid prescription.  For patients entering at first or second relapse, demographic 
and treatment information regarding first presentation and/or first relapse will be collected using 
retrospective chart review when available. We will allow for enrollment up to second relapse 
(lengthening time interval to obtain consent) in order to maximize patient recruitment.  Standardized 
assessments by physicians will be performed at the following study points: study entry, semi-annual 
study visits, and at study end.    
 
Data for study points will be obtained using one or all of the following methods: chart review, reviewing 
patient log books of daily home urine protein measurements and steroid dose given, and phone calls to 
family to confirm details of clinical course (including date of proteinuria remission for each relapse). 
Logs maintained by patients are part of routine clinical care in nephrotic syndrome; all study patients 
will be provided with standardized log books for medications and relapse tracking.  This schedule and 
method of assessments for study points were designed to mirror routine clinical care (as reported by most 
sites) and to maximize feasibility while maintaining ongoing engagement by study patients and 
physicians.  
 
Defining an episode of treatment: As nephrotic syndrome is a relapsing and remitting disease, a 
significant portion of the study data will involve documenting treatment for both first presentation and 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 8 
 
relapses of nephrotic syndrome (called ‘episodes’ in this study).  Detailed steroid prescription 
information will be recorded at entry, and at the beginning and end of all subsequent episodes.     
 
 
 
 
 
The standard definitions used in nephrotic syndrome are provided in Appendix, Table 2.  The data 
collection forms, shown in Appendix Figure 3, are designed to capture steroid prescriptions for each 
episode from the date of start of full dose steroid therapy (60 mg/m2 or 2mg/kg) to cessation of steroid 
therapy or restart of full dose therapy. Each patient’s steroid prescription for an episode will be linked to 
the prescribing physician. 
 
Data quality and standardization: Standardized case report forms will be used for data collection 
regarding the clinical course, outcomes and treatments for childhood nephrotic syndrome. All patient and 
physician data will be entered by study staff into a multi-centre online database (REDCap™, a web-
application which allows users to build databases securely for the purposes of research and in particular 
for longitudinal cohort studies, http://project-redcap.org/ hosted by Women and Children’s Research 
Institute, Edmonton, see letter from Dr. Sandra Davidge).  Data are being monitored weekly to address 
data quality issues in real-time. Based on the 77 subjects enrolled to date, we have confirmed that the 
majority of data to be collected for this study is recorded routinely by nursing staff in clinical care, and 
the web based system does not pose significant additional onerous data entry requirements. 
 
The study will be coordinated centrally in Calgary.  Two central study staff (study nurse and data analyst) 
will train all other site-specific study staff regarding study goals and objectives, data management and 
data entry. We put in place several measures to ensure data consistency and standardization including: 
piloting case report forms and standardizing forms; training site staff for data element definitions; using 
a data dictionary; establishing inter-rater reliability for data entry using two study staff at each site at 
start of study; and pre-study patient visit planning to standardize data collection and entry.  Every 3 
months, data analyst will review data entry completeness for individual patients and send reminders to 
appropriate site investigators for data completion. There will be a 2 step review for data completeness 
for each patient record – first by the data analyst and second by a lead investigator or designate.  Data 
are time-stamped as complete after review.  Key measures of data quality were identified a priori; a 
sample data quality report is attached in Appendix, Tables 3 and page 16.   
 
Privacy and confidentiality: We will assign unique study numbers to patients, physicians and centres – 
to protect anonymity of all participants and centres.  All identifying information will be securely stored 
at individual sites and will not be shared with central study staff.   
 
Characterizing the cohort: We will describe (using means with standard deviation, medians with 
interquartile range and proportions as appropriate) the cohort demographics, and all outcomes of interest 
by centre-, physician, and patient- level variables. We will describe the following outcomes: overall 
steroid prescribed (total dose and number of treatment days), time to first relapse, relapse rate during 
observation, time to steroid sparing agents, choices of steroid sparing agents and indication, time to 
kidney biopsy, reasons for biopsy, complications of steroid therapy.  Outcomes related to complications 
of steroid treatment will include: anthropometric changes during observation period (age- and sex-
specific standard-deviation scores (z scores) for height, weight, and body-mass index); persistent 
systolic/diastolic blood pressure ≥ 95th percentile during observation period [yes/no] and requirement for 
antihypertensive therapy [yes/no] and duration of therapy; and external manifestations of steroid toxicity 
evident during semi-annual study visits (Cushingoid faces [yes/no], hypertrichosis [yes/no], cataracts 
[yes/no], striae [yes/no], acne [yes/no]). Definitions of external manifestations of steroid toxicity are 
An episode is defined as the time from start of full dose steroid therapy (60 mg/m2 or 2mg/kg) to 
cessation of steroids or re-start of full dose steroids as in steroid dependent patients who relapse 
while tapering steroids. 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 9 
 
similar to those observed in prior nephrotic syndrome steroid dosing studies.38 See Appendix, Table 4 
for detailed description of these variables.   
 
3.2 Work plan for objective 1  
 
Design: To determine the association of steroid dose prescribed with relapse rates, we will use the 
prospective cohort as described in section 3.1.  We hypothesize that increasing steroid dose prescribed 
per unit time will be associated with decreasing relapse rates.  All patients with steroid sensitive nephrotic 
syndrome enrolled into the prospective cohort will be eligible for this study. The observation period will 
span a maximum of 4 years and minimum of 6 months. Figure 4 in the Appendix provides a visual 
representation of the outcome and exposure as defined below for this objective. 
 
Outcome: The primary outcome of interest is relapse rate (number of relapses/per person unit time). 
Relapse rate is the most clinically relevant outcome for nephrotic syndrome and the best indicator of 
morbidity experienced by patients; this outcome definition is consistent with prior literature in this area.40  
 
Exposure: The exposure is steroid prescribed per unit time - that is the total dose patients were prescribed 
as treatment for episodes of proteinuria divided by the sum of duration of 'days on steroids' during 
observation period. Days on steroids is defined by the sum of the length in days of all episodes (see 
definition of episode in section 3.1, also graphically represented in Appendix Figure 4) observed.  This 
definition is consistent with measures of steroid exposure used in prior nephrotic syndrome steroid dosing 
studies conducted in Europe and in a Canadian study of steroid associated osteoporosis in children.38,55 
Systemic steroid exposure (both oral and intravenous) will be converted into prednisone equivalents 
(mg/m2) using standard dose conversion tables and weight based dosing criteria [mg/kg] will be 
converted to mg/m2.   
 
Analysis plan: The unit of analysis is the patient. Given that the main outcome of interest is relapse rate, 
we will use Poisson regression models with steroid prescribed per unit time as the exposure and relapse 
rate per unit time as the outcome, adjusting for patient level variables (age, gender, ethnicity, household 
income, parental education) and episode at entry into study (either first presentation, first relapse or 
second relapse), and taking into account time at risk.  We are not using multi-level (hierarchical) analysis 
in this objective, as there is no clustering at the patient-level. There is only one measurement per patient, 
relapse rate adding all episodes experienced by one patient as a count.   
 
Feasible sample and power considerations: We estimated a feasible sample based on data gathered 
from 2 sources: an ongoing longitudinal study of children with nephrotic syndrome (INSIGHT study, led 
by Dr. R. Parekh) recruiting a Toronto based cohort,53 and our preliminary data (Appendix Figure 5 for 
preliminary recruitment rate).  Based on the expected consent rate of 72%, and estimated drop out of 
10% (due to loss to follow-up or steroid resistance), we estimate that we will be able to enrol and follow, 
at least, 520 patients over a period of 4.0 years (65 patients every 6 months).  In our preliminary work, 
we have already enrolled 77 patients from 6 sites, thus our total estimated sample is 597 patients.  
 
Although we hypothesize that increasing steroid dose prescribed per unit time will be associated with 
decreasing relapse rates, no studies to date have reported a specific magnitude of the effect of steroid 
prescribed per unit time on relapse rates. A systematic review of available clinical trials examining this 
issue, published in 2007, only reports on risk ratios based on the dichotomous outcome of any relapse at 
a pre-specified time interval (usually 12 or 24 months).40  Our outcome of interest is an actual rate (count 
of relapses/person years).  Hence, a power based, effect size dependent sample size calculation was not 
performed.  At a significance level alpha = 0.05, and under the following assumptions of a mean daily 
steroid dose of 30.64 mg/m2 with a standard deviation (of the dose) of 8.85, a base rate of relapse of 1.68 
per person year, average follow up (time at risk of relapse) of 2 years and a conservative correlation (R2) 
of the steroid dose with other covariates of 0.2, we would have 90% power to detect an incidence rate 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 10 
 
ratio of 0.989 or smaller (i.e. a larger effect size) in a multiple Poisson regression.  We are allowing for 
a 2 tailed test to allow the possibility of the effect being on either side of the null.  
 
3.3 Work Plan for Objective 2  
 
Design: To determine the associations between centre-, physician-, patient-level characteristics and i) 
steroid dose prescribed, and ii) length of steroid treatment for first presentation and subsequent relapses 
of nephrotic syndrome, and to identify reasons for practice variation between and among pediatric 
nephrology care providers and centres, we will use a mixed methods approach as defined by Creswell & 
Plano Clark.56  The primary study is a quantitative study using the prospective cohort as described.  A 
qualitative study, serving a supplementary role, is embedded within the larger quantitative study to 
provide a deeper understanding of the complex multi-level processes that lead to practice variation 
between centres and between physicians within centres.  True to qualitative approaches, no a priori 
hypothesis is specified for this aim.  At the completion of quantitative and qualitative studies, we will 
use a convergent parallel mixed methods analytic approach (both quantitative and qualitative data 
collected and analysed during the same phase of research, then two sets of results are merged for an 
overall interpretation), to compare qualitative and quantitative data across centre-, physician- and patient-
level attributes.  The results of both components will inform the ‘greater whole’ - a comprehensive 
understanding of why there is variability in care for nephrotic syndrome – a key step to overcoming 
barriers to implementation of best practice approaches for treatment of nephrotic syndrome across 
Canada and to make future randomized controlled trials more feasible.  
 
Description of the quantitative study: We will use the prospective cohort described in section 3.1 to 
determine the associations between centre-, physician-, patient-level characteristics and outcomes. All 
patients with steroid sensitive nephrotic syndrome and all physicians enrolled into the prospective cohort 
will be eligible for this study. We will use the hierarchical data in the prospective cohort.  The observation 
period for this objective will be a maximum of 4.0 years and minimum of 6 months.  
 
Outcomes: The primary outcome is steroid prescribed per episode.  We will examine: a) total dose 
patients receive for an episode; and b) average daily dose by dividing the total dose by duration (in days) 
of the episode.  Dose will always be in mg/m2 prednisone equivalents.  This outcome definition is 
consistent with measures of steroid exposure used in prior nephrotic syndrome steroid dosing studies.38,55  
We are evaluating steroid prescription per episode because in this objective, we will study determinants 
of variability in steroid prescription for episodes of proteinuria rather than patient outcomes related to 
cumulative exposure of steroids (e.g. relapse rate). All episodes will be categorized either as first 
presentation or relapse.  The secondary outcome will be length of episode in days.  
 
Exposures:  Exposure variables of interest are categorized into centre-, physician- and patient-level 
variables. Centre-level variable is defined as existence of a standardized protocol within centre for 
treating first presentation and relapses (information will be obtained from the site investigator as 
existence of centre based protocols [yes/no]).  Physician-level variables are gender, year of graduation 
from nephrology fellowship, and location of nephrology training (Canada vs. outside Canada). These 
centre- and physician-level variables were shown to impact variability in practice patterns according to 
our published survey.22  Patient-level variables are age, gender, ethnicity, and status at entry into study 
(first presentation, relapse). These variables are further described in Appendix, Table 5. 
 
Analysis plan: We will describe the primary and secondary outcomes according to each of centre-, 
physician- and patient-level characteristics with 95% confidence intervals. To study the associations of 
centre-, physician-, patient-level characteristics with the primary outcome (steroid prescribed per 
episode), we will use mixed effects models with fixed effects for centre (standardized protocols yes/no), 
physician (gender, years in practice, location of training), and patient (age, gender, ethnicity) 
characteristics and random effects to account for physicians clustering within centre, patients clustering 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 11 
 
within physician, and episodes clustering within patients.  We will create separate models to examine 
both total dose patients receive for the episode, and average daily dose by dividing the total dose by 
duration (in days) of the episode.   The unit of analysis will be the episode. Each episode will be 
categorized as either first episode or relapse at the patient level in the same model.  The same 
methodology will be used to study the length of episode in days (secondary outcome). 
 
Description of the embedded qualitative study:  The embedded qualitative study will enrich the 
quantitative results by providing detail regarding attitudes, beliefs and local factors driving variation in 
care - fundamental to understanding the complexity of health care professional decision-making.57,58   
Theoretically grounded in the Ottawa Model of Research Use,59 we are conducting focus groups with 
health professionals who care for children with nephrotic syndrome to probe the reasons for variation in 
steroid protocols (‘why do people do what they do’).  Ten focus groups, one per site with 6-8 participants 
per group and each lasting 60 minutes, are planned. Informed consent will be obtained and participant 
responses will be anonymized. We are not requesting funds from CIHR for this study as we have 
completed 8 of these 10 focus groups; however, we have provided the interview guide and the 
preliminary results in the Appendix (pages 22-24) - as it is a critical component of our mixed methods 
design and KT plan.   
 
Integration of quantitative and qualitative studies: We will independently analyze the qualitative and 
quantitative data using analyses for Objective 2 as detailed above.  We will use a convergent mixed 
methods analytic approach to compare the results obtained in the quantitative with qualitative 
components (Appendix Figure 6), using matrices of the hierarchies of centre-, physician- and patient-
levels and explanatory quantitative variables at each level and themes related to these same levels arising 
from the qualitative study (e.g., existence of standardized protocols in each centre, age and training 
background of the physician, patient’s age and ethnicity; Appendix Table 6), asking whether two types 
of data are congruent or not.   
 
Feasible sample and power considerations: For objective 2, there is no knowledge on expected effects 
from the explanatory variables on the outcome. Therefore, power calculations, which are based on having 
a specific alternative hypothesis, are not feasible.  The analysis to be performed is a mixed effects model 
with three random effects (physicians within centre, patients within physicians and episodes within 
patients), for which there is no simple analytic formula to calculate the needed sample size. The 
innovative method of Monte Carlo simulation based on the number of subjects potentially available still 
needs to have as input the expected effects from each of the explanatory variables.  In the case of this 
linear mixed model (for primary outcome), the effect of each variable is measured by its coefficient in 
the regression (for fixed effects) and by the estimated variance of the random effects. As justified in 
Objective 1, we expect a feasible sample of 597 subjects. Given this estimated enrollment number, and 
that we will have a total of 8 explanatory variables plus 3 random effects (estimated as parameters in the 
model), we are complying with the guideline of 10 observations (at the unit of analysis level) per 
variable.60  As the unit of analysis will be the episode and an estimated 70% of patients will have more 
than one episode during the study, it is important to note that the 597 patients will yield from 597 to 1015 
observations (episode at entry plus one additional relapse). This will ensure that estimates of random 
effects are feasible.    
 
3.4 Summary of progress and preliminary results 
  
With start-up funds obtained from CIHR and other sources, we launched the prospective cohort at 13 
centres and have recruited 77 patients from 6 centres to date. The remaining 7 centres are either approved 
or close to full approval (ethics and contracts). All sites will be recruiting by June 2015 – demonstrating 
feasibility to complete the work plan as described in this proposal.  Our preliminary data is provided in 
the Appendix. Baseline demographics of the patient and physician cohort enrolled to date are shown in 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 12 
 
Tables 7 & 8.  Preliminary data from the cohort demonstrating variation in steroid prescriptions by key 
patient demographic variables and by type of episode of treatment are shown in Tables 9a-c. Graphical 
representations of steroid prescribed per episode for different patient scenarios are shown in Figures 7a-
d. Variation in steroid prescriptions between physicians within one site and variation in steroid 
prescriptions between sites are shown in Tables 10 and 11 respectively.  We also show differences among 
patients in ‘time on and off steroids’ by site in Figure 8, and the average daily steroid dose over time by 
site in Figure 9. Finally, in Figure 10 and Table 12, we show differences in relapses (survival curve, and 
absolute relapse numbers) by site.    
 
4.0 LIMITATIONS AND CONTINGENCY PLANS  
 
There are several limitations of our work that must be acknowledged.  Recruitment into the cohort study 
may be slow at times due to either seasonal variation in incidence of disease, or due to unforeseen site 
based challenges in recruitment. In the early phases of this study, we have demonstrated increasing 
recruitment rates. We will sustain recruitment by providing monthly enrolment reports, study reminders 
and scientific updates to site investigators. We will hold annual face-to-face investigator meetings to 
monitor study progress, build cohesion amongst members and solve any issues that may arise during the 
study. We may miss enrolment of patients living in non-metropolitan regions, particularly those who are 
managed by general pediatricians; however, we estimated this loss to be <5%.  Contamination of 
treatment protocols may occur due to the study itself and resulting increased interactions between 
physicians within sites and between sites. We acknowledge that due to the national scope of this study, 
and its aims, we may influence practice over time; this is unavoidable and indicates the impact and 
novelty of the study.  Furthermore as new evidence emerges such as the recent RCTs, practice may be 
influenced. To address changing practice over time we will monitor for and report this trend within the 
data.  We may not capture all unknown confounders at centre, physician and patient levels despite our 
detailed data collection. For example, tracking patient adherence to steroid therapy would reduce some 
confounding due to non-adherence; such monitoring is beyond the scope of this study but will be part of 
our future work.  
 
We also carefully considered potential areas where the analytic plan may fail to answer our research 
questions. We considered whether we will observe variation in care at all three levels in a relatively small 
patient sample and particularly small and potentially homogeneous physician groups.  We are reassured 
by examining our preliminary data that even with fewer than a hundred patients, we are able to detect 
variation between sites, between physicians within centres, and within physician between patients. If we 
were to see homogeneity among physician groups within centres (e.g. cohesive physician groups with 
centre specific standardized protocols), we will reduce our model to two levels – centre and patient, if 
needed.  
 
5.0 RESEARCH TEAM 
 
We have assembled a strong and cohesive national team to ensure success of this project. We performed 
substantial collaborative work among Canadian pediatric nephrologists, from all 13 academic pediatric 
health centres in Canada, over the last 4 years, which has led to successful launch of this Project in August 
2013. See list of project team members and progress at each site in Table 13 in Appendix.  Key members 
of the research team and supporting infrastructure are described below.   
 
Principal applicant:   Dr. Susan Samuel is a Clinician Scientist at the University of Calgary. She is 
supported by salary awards from the CIHR Canadian Child Health Clinician Scientist Program 
(CCHCSP) and the Kidney Foundation of Canada Kidney Research Scientist Core Education and 
National Training Program (KRESCENT), with 75% protected time for research activities. She has 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 13 
 
successfully led multi-centre collaborative health services research in pediatric nephrology using national 
administrative data; and has a proven track record in leading this project. 61-64  
 
Co-applicants:   Dr. Nettel-Aguirre PhD, PStat, a biostatistician at the University of Calgary Department 
of Pediatrics, is overseeing the quantitative study design and all analytic methods.   Dr. Shannon Scott, 
RN PhD from the University of Alberta is a national expert in child health, KT, and qualitative and mixed 
methods research.  She is a Canada Research Chair (Tier 2) for KT in Child Health.  As a co-applicant, 
she will advise on mixed methods approach, and guide KT activities.  Dr. Michael Zappitelli from McGill 
University is Principal Investigator and co-investigator of multi-centre collaborative studies on pediatric 
acute kidney injury.  Drs. Zappitelli and Samuel collaborated over the past 3 years to develop this project 
and will ensure its success over the next 5 years. Dr. Catherine Morgan (University of Alberta), Dr. 
Allison Dart (University of Manitoba), Dr. Rulan Parekh, and Dr. Cherry Mammen (University of British 
Columbia) are pediatric nephrologists and investigators trained in clinical epidemiology.  They will 
provide oversight for the study, design data collection forms, recruit patients at their centres and be 
involved in data analysis and manuscript preparation.  Dr. Allison Eddy, is the Chair of Pediatrics at the 
University of British Columbia and is an international expert in nephrotic syndrome.1 She will advise the 
study team, assist in KT activities both nationally and internationally.   
 
Supporting national infrastructure: We will receive mentorship and support from the Canadian 
Kidney Knowledge Translation and Generation Network (CANN-NET; www.cann-net.ca), a CIHR 
funded national network promoting best practices in nephrology. We will also receive support from the 
Maternal, Infant, Child, Youth Network (MICYRN). See attached letters from Dr. Braden Manns and 
Dr. Anne Junker. 
 
6.0 KT PLAN 
 
Integrated KT plan: We are using an integrated KT model wherein decision-makers and end-users 
(pediatric nephrologists and parents) are engaged at all stages of the research process from priority setting 
and identification of key questions to interpretation and dissemination of results. 65,66  The involvement 
of decision-makers and end-users throughout will be critical for the success of the research aims and to 
ensure efficient and timely data collection at all participating centres.   
 
For all 13 Canadian pediatric nephrology centres, we have identified site investigators (see letters of 
support attached) who are acting as local champions for this Project.  We also have strong support from 
the leadership of Canadian Association of Pediatric Nephrologists (see letter from Dr. Maury Pinsk, 
President). The Association has provided several opportunities for us to engage pediatric nephrologists 
at semi-annual meetings and will also assist with our KT plan.  
 
We have recently engaged committed parents, from different geographical regions and backgrounds, 
who are willing to partner with the study team to ensure patients and families are engaged in KT and 
that patient and family priorities are addressed in the future directions of this national initiative (see 
support letter from Ms. Andrea Galbraith, parent of child with steroid sensitive nephrotic syndrome). 
We will host at least 2 parent group teleconferences over the next 6 months to educate parents and/or 
patients about this national research initiative, our study plan and to learn from them about the daily 
challenges that they face, and how research might inform these. We envision that this will lead to a 
long-term meaningful engagement in KT and dissemination activities during this course of this study.  
 
We are holding face-face to investigator and team meetings yearly in conjunction with the Canadian 
Society of Nephrology annual general meeting.  We will also host a Canadian Childhood Nephrotic 
Syndrome Project Symposium on September 17 and 18 of this year in Calgary – to plan for the next 
steps and sequential building blocks in our research program. The symposium will bring together the 
national study team, both local and international experts, as well as basic and translational researchers 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 14 
 
working in this area, in order to foster creativity and innovation through trans-disciplinary 
collaborations.  The parent group will be invited to participate in this symposium and we will also use 
this opportunity to conduct a semi-structured group interview to elicit patient/parent priorities and 
ensure that these priorities align with our work plan for the future. We have applied for a CIHR 
planning and dissemination grant to fund this meeting.  
 
In the final year of funding, all stakeholders (investigators, principal knowledge users, site investigators 
from all 13 sites, and invited experts including representation from parent/patient groups) will be invited 
to a face-to-face meeting to assist in the interpretation of study results.  Both the quantitative and 
qualitative results of the study (description of cohort, clinical course including steroid exposure and use 
of second line agents by centre, physician and patient variables, association of variability in steroid 
treatment on relapse rates, results of multi-level mixed methods models showing factors significantly 
associated with variation in steroid treatment, and common themes regarding variation in care elicited 
from focus groups) will be presented. All clinical practice guideline recommendations will also be 
reviewed.  Utilizing all this information, we will draft best practice approaches for treatment of first 
presentation and subsequent relapses of nephrotic syndrome acceptable to all stakeholders.  We will 
develop an implementation plan, informed by results of Objective 2 (centre-, physician- and patient-level 
characteristics driving variability in care), and ensure that the comprehensive results of this study are 
disseminated to physicians and other relevant stakeholders within each centre.   
 
End-of-grant KT plan:  We published our study plan in the new journal of Canadian Journal of Kidney 
Health and Disease (Samuel et al. 2014, see attached manuscript). Our next manuscript will describe the 
results of the qualitative study (target completion date June 2015).  The remainder of our manuscript plan 
- to disseminate the quantitative and mixed methods results are detailed in the Appendix page 38, Gantt 
chart. We will present our findings at local (nephrology divisional rounds and pediatric grand rounds 
with telehealth connections to rural sites and primary care pediatrics offices), national (Canadian Society 
of Nephrology and Canadian Pediatric Society meetings) and international (American Society of 
Nephrology meeting, special interest group meetings for pediatric nephrology).  The Principal Applicant, 
co-applicants and site liaisons are members of these organizations and will ensure effective and prompt 
dissemination of research findings to relevant knowledge user groups locally, nationally and 
internationally.   
 
7.0 SUMMARY AND SIGNIFICANCE  
 
Funding the Canadian Childhood Nephrotic Syndrome Project will address important unanswered 
questions in childhood nephrotic syndrome – what is the impact of variability in steroid treatments on 
patient outcomes (Objective 1) and who and what drives variability in care (Objective 2)?  The integrated 
results of the study will allow us to develop best practice approaches for treatment of nephrotic syndrome 
and to develop an implementation plan to ensure uptake of our study results nationally and 
internationally.  This study will provide key information to strategically prioritize future clinical trial 
questions (what to study, in which patients, when, and how to get buy-in from key stakeholders), and 
will build basic research infrastructure needed to conduct these trials to address critical knowledge gaps 
in the treatment of nephrotic syndrome.  The novel national longitudinal web based patient data collection 
system developed as part of this study will also provide a platform to evaluate clinical care and outcomes 
on an ongoing basis in the future, and ultimately create a best practice approach to treatment of nephrotic 
syndrome.   
 
 
 
 
REFERENCES 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 15 
 
1. 
Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. Aug 23 2003;362(9384):629-
639. 
2. 
Gipson DS, Massengill SF, Yao L, et al. Management of childhood onset nephrotic syndrome. 
Pediatrics. Aug 2009;124(2):747-757. 
3. 
Sinha A, Hari P, Sharma PK, et al. Disease course in steroid sensitive nephrotic syndrome. 
Indian Pediatr. Nov 2012;49(11):881-887. 
4. 
Arneil GC. Treatment of nephrosis with prednisolone. Lancet. Apr 14 1956;270(6920):409-411. 
5. 
Hodson EM, Willis NS, Craig JC. Non-corticosteroid treatment for nephrotic syndrome in 
children. Cochrane Database Syst Rev. 2008(1):CD002290. 
6. 
Brocklebank JT, Harcourt RB, Meadow SR. Corticosteroid-induced cataracts in idiopathic 
nephrotic syndrome. Archives of disease in childhood. Jan 1982;57(1):30-34. 
7. 
Donatti TL, Koch VH, Fujimura MD, Okay Y. Growth in steroid-responsive nephrotic 
syndrome: a study of 85 pediatric patients. Pediatr Nephrol. Aug 2003;18(8):789-795. 
8. 
Fakhouri F, Bocquet N, Taupin P, et al. Steroid-sensitive nephrotic syndrome: from childhood 
to adulthood. American journal of kidney diseases : the official journal of the National Kidney 
Foundation. Mar 2003;41(3):550-557. 
9. 
Foster BJ, Shults J, Zemel BS, Leonard MB. Risk factors for glucocorticoid-induced obesity in 
children with steroid-sensitive nephrotic syndrome. Pediatr Nephrol. Jul 2006;21(7):973-980. 
10. 
Koskimies O, Vilska J, Rapola J, Hallman N. Long-term outcome of primary nephrotic 
syndrome. Archives of disease in childhood. Jul 1982;57(7):544-548. 
11. 
Kuster S, Mehls O, Seidel C, Ritz E. Blood pressure in minimal change and other types of 
nephrotic syndrome. American journal of nephrology. 1990;10 Suppl 1:76-80. 
12. 
Ng JS, Wong W, Law RW, Hui J, Wong EN, Lam DS. Ocular complications of paediatric 
patients with nephrotic syndrome. Clinical & experimental ophthalmology. Aug 
2001;29(4):239-243. 
13. 
Rees L, Greene SA, Adlard P, et al. Growth and endocrine function in steroid sensitive 
nephrotic syndrome. Archives of disease in childhood. May 1988;63(5):484-490. 
14. 
Feber J, Gaboury I, Ni A, et al. Skeletal findings in children recently initiating glucocorticoids 
for the treatment of nephrotic syndrome. Osteoporosis international : a journal established as 
result of cooperation between the European Foundation for Osteoporosis and the National 
Osteoporosis Foundation of the USA. Feb 2012;23(2):751-760. 
15. 
Leonard MB, Feldman HI, Shults J, Zemel BS, Foster BJ, Stallings VA. Long-term, high-dose 
glucocorticoids and bone mineral content in childhood glucocorticoid-sensitive nephrotic 
syndrome. The New England journal of medicine. Aug 26 2004;351(9):868-875. 
16. 
Durkan A, Hodson EM, Willis NS, Craig JC. Non-corticosteroid treatment for nephrotic 
syndrome in children. Cochrane Database Syst Rev. 2005(2):CD002290. 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 16 
 
17. 
 http:\\kdigo.org. Accessed November 19, 2013. 
18. 
Hodson EM, Craig JC. Corticosteroid therapy for steroid-sensitive nephrotic syndrome in 
children: dose or duration? J Am Soc Nephrol. Jan 2013;24(1):7-9. 
19. 
Fujinaga S, Endo A, Ohtomo Y, Ohtsuka Y, Shimizu T. Uncertainty in management of 
childhood-onset idiopathic nephrotic syndrome: is the long-term prognosis really favorable? 
Pediatr Nephrol. Dec 2013;28(12):2235-2238. 
20. 
MacHardy N, Miles PV, Massengill SF, et al. Management patterns of childhood-onset 
nephrotic syndrome. Pediatr Nephrol. Nov 2009;24(11):2193-2201. 
21. 
Lande MB, Leonard MB. Variability among pediatric nephrologists in the initial therapy of 
nephrotic syndrome. Pediatr Nephrol. Aug 2000;14(8-9):766-769. 
22. 
Samuel S, Morgan CJ, Bitzan M, et al. Substantial practice variation exists in the management 
of childhood nephrotic syndrome. Pediatr Nephrol. Dec 2013;28(12):2289-2298. 
23. 
Pasini A, Aceto G, Ammenti A, et al. Best practice guidelines for idiopathic nephrotic 
syndrome: recommendations versus reality. Pediatr Nephrol. Jan 2015;30(1):91-101. 
24. 
Schlesinger ER, Sultz HA, Mosher WE, Feldman JG. The nephrotic syndrome. Its incidence 
and implications for the community. Am J Dis Child. Dec 1968;116(6):623-632. 
25. 
Sharples PM, Poulton J, White RH. Steroid responsive nephrotic syndrome is more common in 
Asians. Arch Dis Child. Nov 1985;60(11):1014-1017. 
26. 
Feehally J, Kendell NP, Swift PG, Walls J. High incidence of minimal change nephrotic 
syndrome in Asians. Archives of disease in childhood. Nov 1985;60(11):1018-1020. 
27. 
Kerlin BA, Ayoob R, Smoyer WE. Epidemiology and pathophysiology of nephrotic syndrome-
associated thromboembolic disease. Clinical journal of the American Society of Nephrology : 
CJASN. Mar 2012;7(3):513-520. 
28. 
McIntyre P, Craig JC. Prevention of serious bacterial infection in children with nephrotic 
syndrome. Journal of paediatrics and child health. Aug 1998;34(4):314-317. 
29. 
Hingorani SR, Weiss NS, Watkins SL. Predictors of peritonitis in children with nephrotic 
syndrome. Pediatr Nephrol. Aug 2002;17(8):678-682. 
30. 
Tarshish P, Tobin JN, Bernstein J, Edelmann CM, Jr. Prognostic significance of the early 
course of minimal change nephrotic syndrome: report of the International Study of Kidney 
Disease in Children. Journal of the American Society of Nephrology : JASN. May 
1997;8(5):769-776. 
31. 
Ayoob RM, Hains DS, Smoyer WE. Trends in hospitalization characteristics for pediatric 
nephrotic syndrome in the USA. Clinical nephrology. Aug 2012;78(2):106-111. 
32. 
Hodson EM, Willis NS, Craig JC. Interventions for idiopathic steroid-resistant nephrotic 
syndrome in children. Cochrane Database Syst Rev. 2010(11):CD003594. 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 17 
 
33. 
Gipson DS, Chin H, Presler TP, et al. Differential risk of remission and ESRD in childhood 
FSGS. Pediatr Nephrol. Mar 2006;21(3):344-349. 
34. 
Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory 
characteristics at time of diagnosis. A report of the International Study of Kidney Disease in 
Children. Kidney Int. Feb 1978;13(2):159-165. 
35. 
The primary nephrotic syndrome in children. Identification of patients with minimal change 
nephrotic syndrome from initial response to prednisone. A report of the International Study of 
Kidney Disease in Children. J Pediatr. Apr 1981;98(4):561-564. 
36. 
Emma F, Sesto A, Rizzoni G. Long-term linear growth of children with severe steroid-
responsive nephrotic syndrome. Pediatr Nephrol. Aug 2003;18(8):783-788. 
37. 
Kyrieleis HA, Lowik MM, Pronk I, et al. Long-term outcome of biopsy-proven, frequently 
relapsing minimal-change nephrotic syndrome in children. Clinical journal of the American 
Society of Nephrology : CJASN. Oct 2009;4(10):1593-1600. 
38. 
Ehrich JH, Brodehl J. Long versus standard prednisone therapy for initial treatment of 
idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft fur Padiatrische Nephrologie. 
Eur J Pediatr. Apr 1993;152(4):357-361. 
39. 
Short versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome 
in children. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Lancet. Feb 20 
1988;1(8582):380-383. 
40. 
Hodson EM, Willis NS, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. 
Cochrane Database Syst Rev. 2007(4):CD001533. 
41. 
Hodson EM, Knight JF, Willis NS, Craig JC. Corticosteroid therapy in nephrotic syndrome: a 
meta-analysis of randomised controlled trials. Arch Dis Child. Jul 2000;83(1):45-51. 
42. 
Group KDIGOKGW. KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney inter. 
Suppl. 2012;2:139-274. 
43. 
Samuel S, Morgan CJ, Bitzan M, et al. Substantial practice variation exists in the management 
of childhood nephrotic syndrome. Pediatr Nephrol. Aug 6 2013. 
44. 
Samuel S, Bitzan M, Zappitelli M, et al. Canadian Society of Nephrology Commentary on the 
2012 KDIGO clinical practice guideline for glomerulonephritis: management of nephrotic 
syndrome in children. Am J Kidney Dis. Mar 2014;63(3):354-362. 
45. 
Hoyer PF. New lessons from randomized trials in steroid-sensitive nephrotic syndrome: clear 
evidence against long steroid therapy. Kidney Int. Jan 2015;87(1):17-19. 
46. 
Sinha A, Saha A, Kumar M, et al. Extending initial prednisolone treatment in a randomized 
control trial from 3 to 6 months did not significantly influence the course of illness in children 
with steroid-sensitive nephrotic syndrome. Kidney Int. Jan 2015;87(1):217-224. 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 18 
 
47. 
Yoshikawa N, Nakanishi K, Sako M, et al. A multicenter randomized trial indicates initial 
prednisolone treatment for childhood nephrotic syndrome for two months is not inferior to six-
month treatment. Kidney Int. Jan 2015;87(1):225-232. 
48. 
Teeninga N, Kist-van Holthe JE, van Rijswijk N, et al. Extending prednisolone treatment does 
not reduce relapses in childhood nephrotic syndrome. J Am Soc Nephrol. Jan 2013;24(1):149-
159. 
49. 
 http://www.cihr-irsc.gc.ca/e/44945.html. Accessed February 25, 2014. 
50. 
Colletti RB, Baldassano RN, Milov DE, et al. Variation in care in pediatric Crohn disease. J 
Pediatr Gastroenterol Nutr. Sep 2009;49(3):297-303. 
51. 
Crandall W, Kappelman MD, Colletti RB, et al. ImproveCareNow: The development of a 
pediatric inflammatory bowel disease improvement network. Inflamm Bowel Dis. Jan 
2011;17(1):450-457. 
52. 
Crandall WV, Margolis PA, Kappelman MD, et al. Improved outcomes in a quality 
improvement collaborative for pediatric inflammatory bowel disease. Pediatrics. Apr 
2012;129(4):e1030-1041. 
53. 
Hussain N, Zello JA, Vasilevska-Ristovska J, et al. The rationale and design of Insight into 
Nephrotic Syndrome: Investigating Genes, Health and Therapeutics (INSIGHT): a prospective 
cohort study of childhood nephrotic syndrome. BMC Nephrol. 2013;14:25. 
54. 
Donabedian A. The quality of care. How can it be assessed? JAMA. Sep 23-30 
1988;260(12):1743-1748. 
55. 
Rodd C, Lang B, Ramsay T, et al. Incident vertebral fractures among children with rheumatic 
disorders 12 months after glucocorticoid initiation: a national observational study. Arthritis 
Care Res (Hoboken). Jan 2012;64(1):122-131. 
56. 
Creswell J, Plano Clark VL., . Designing and Conducting Mixed Methods Research. 2nd edition 
ed: Sage Publications, Inc.; 2011. 
57. 
Morse J FP. Qualitative Research Methods for Health Professionals. (2nd Ed.): Thousand Oaks: 
Sage; 1995. 
58. 
Logan J, Graham, I. . Toward a Comprehensive Interdisciplinary Model of Health Care. Science 
Communication. 1998;20:227. 
59. 
Graham ID, Logan J. Innovations in knowledge transfer and continuity of care. The Canadian 
journal of nursing research = Revue canadienne de recherche en sciences infirmieres. Jun 
2004;36(2):89-103. 
60. 
Kleinbaum DG KL, Nizam A, Muller KE. Applied regression analysis and other multivariable 
methods: Duxbury; 2008. 
61. 
Samuel SM, Foster BJ, Tonelli MA, et al. Dialysis and transplantation among Aboriginal 
children with kidney failure. CMAJ : Canadian Medical Association journal = journal de 
l'Association medicale canadienne. Jul 12 2011;183(10):E665-672. 

Samuel, Susan M.  
Research Proposal 
The Canadian Childhood Nephrotic Syndrome Project (CHILDNEPH Project)   
   
Page 19 
 
62. 
Samuel SM, Nettel-Aguirre A, Hemmelgarn BR, et al. Graft failure and adaptation period to 
adult healthcare centers in pediatric renal transplant patients. Transplantation. Jun 27 
2011;91(12):1380-1385. 
63. 
Samuel SM, Tonelli MA, Foster BJ, et al. Survival in pediatric dialysis and transplant patients. 
Clinical journal of the American Society of Nephrology : CJASN. May 2011;6(5):1094-1099. 
64. 
Samuel SM, Tonelli MA, Foster BJ, et al. Overview of the Canadian pediatric end-stage renal 
disease database. BMC nephrology. 2010;11:21. 
65. 
Graham ID, Logan J, Harrison MB, et al. Lost in knowledge translation: time for a map? J 
Contin Educ Health Prof. Winter 2006;26(1):13-24. 
66. 
Straus SE, Tetroe J, Graham I. Defining knowledge translation. CMAJ. Aug 4 2009;181(3-
4):165-168.