Clinical trial NCT01007994
Conditions: Hypertension Secondary to Kidney Transplant
Keywords: Nocturnal hypertension Pediatric Renal Transplant Pulse Wave Velocity Echocardiogram Pediatric Renal Transplant Recipient
Sponsor: Northwell Health
Start date: 2009-11-01; Completion date: 2020-08-01
Enrollment: 33 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The proposed study investigated the effect of chronotherapeutic alteration of anti-hypertensive medication on nocturnal hypertension and end-organ injury in pediatric renal transplant recipients who are non-dippers. Additionally, the investigators examined the association between response to intervention, serum adiponectin levels and adiponectin gene polymorphisms. The investigators hypothesized that (1) evening administration of anti-hypertensive medication will convert subjects from non-dipper to dipper status, improve mean nocturnal blood pressure (BP), and improve nocturnal BP load, (2) evening administration of anti-hypertensive medication will reduce albuminuria, left ventricular mass index (LVMI), rate of decline of glomerular filtration rate (eGFR) and will decrease pulse wave velocity (PWV).

Detailed description:
Study Design and Population A prospective, randomized, open label, blinded end-point (PROBE) pilot trial in pediatric kidney transplant recipients with non-dipping was conducted to determine the effect of chronotherapeutic alteration of anti-hypertensive medication on nocturnal BP. Non-dipper status was defined as \<10% decline in systolic or diastolic BP from daytime to nighttime on ABPM. Participants were required to have a minimum of one follow-up study visit in order to be included in the analysis. Participants were recruited from Cohen Children's Medical Center in New Hyde Park, New York and from the Children's Hospital of Philadelphia (CHOP) in Philadelphia, Pennsylvania from 2010 to 2018.

Intervention Participants randomized to the treatment group were assigned to receive a new anti-hypertensive medication in the evening (1 hour prior to bed time) in addition to their regular baseline medications. The intervention medication was enalapril, an angiotensin converting enzyme inhibitor (ACEi). If the participant was already on an ACEi or there was a contraindication to starting an ACEi (e.g. hyperkalemia, history of allergic reaction to ACEi), then isradipine was added instead. If the participant was already on an ACEi and calcium channel blocker at baseline, then propranolol was the new medication added. The choice of medications was made based on the pharmacokinetic profile of the medications (quick-onset and short to intermediate acting) to lower nocturnal BP with evening administration. The dose of the new medication was titrated up to the target dose if the medication was tolerated and there were no adverse events reported at the two-week visit. Participants in the new medication group were evaluated at 2 weeks, 6 weeks, 3 months and 6 months by the study team to assess for side effects. Participants started on an ACEi had serum electrolytes, BUN and creatinine, and a pregnancy test monitored at each study visit. Participants with side effects were switched to a different class of medication. Participants randomized to the control group continued to take their medications as usual. Participants in the control group were followed at baseline, 3 months and 6 months. No changes to other BP medications were allowed during the 6-month study period. Any participant who developed hypertensive daytime casual BP on repeated measurements was withdrawn from the study.

Randomization and Blinding Participants were randomized in a 1:1 ratio to intervention or control arms in parallel utilizing a blocked randomization strategy (in blocks of 2 and 4) in order to ensure similar numbers of participants in each arm. The randomization scheme was computer generated. Group assignments were concealed in sealed envelops and randomization allocation was done sequentially by a person not directly involved with the study. Interpretation of the outcome data (ABPM, echocardiograms, PWV, labs) was adjudicated by investigators blinded to the treatment group. Laboratory technicians and echocardiographers were blinded to the participant treatment group.

Study Procedures Cardiovascular Measures 24-hour ABPM, echocardiography and PWV were performed at baseline, 3 months and 6 months. Echocardiography was performed using 2-D echo in M-mode in accordance with the recommendations of the American Society of Echocardiography. The SphygmoCor Vx PWV system (AtCor Medical Pty Ltd, Australia) was used to measure the velocity of the BP waveform between the carotid artery and the radial artery. Two PWV readings were obtained and the average was used for analysis. A 22-item pediatric sleep questionnaire was administered to the parent/guardian of the study subject to identify subjects with sleep-related breathing disorders. This questionnaire has been validated and tested for reliability in predicting obstructive sleep apnea. The Treatment Satisfaction Questionnaire for Medications (TSQM) was administered to assess patient satisfaction with the change in treatment and the impact of the therapy on quality of life. The tool gathers information about effectiveness of medication, side effects, convenience and global satisfaction, rated from 0-100 for each parameter.

Statistical Analysis Descriptive statistics were used to characterize demographic and clinical measures in participants. Fisher's exact test and Student's t-test were used to compare baseline variables between the treatment and control groups. Student's t-tests were used to compare continuous ABPM variables (nocturnal dip percent, mean BP, BP load) between treatment and control groups at 3 and 6 months post-intervention. Fisher's exact test was conducted to compare the proportion of participants who changed dipper status and nocturnal hypertension status between the two groups at 3 and 6 months. Within-person changes in each group were examined using the paired Student's t-test and McNemar's test. Student's t-test or Wilcoxon Rank Sum test for non-normally distributed variables were used to compare values of delta LVMI and eGFR between groups at each time point and paired tests for within-person changes. Intention-to-treat analysis was done. Statistical analyses was done using SPSS 25 (IBM Inc.) statistical package. A p-value \< 0.05 was the criterion for statistical significance. For the primary outcome, the comparison of 14 subjects in each group provided 80% power (α = 0.05) to detect a 50% change from non-dipper status to dipper status in the treatment group compared to a 5% change in the control group. The study was not powered for analysis of secondary outcomes (LVMI, PWV, eGFR) as this was an exploratory aim for this pilot study.

Arms: arm 1: A new anti-hypertensive medication (enalapril, propranolol or isradipine) will be added at 8pm. arm 2: Subjects in the control group will continue to take their medications as usual.
Interventions: intervention 1: New Medication: Enalapril, Isradipine, Propranolol
Intervention descriptions: intervention 1: Enalapril will be added in the evening at 8 pm. If the subject is already on an ACEI or there is a contraindication to starting an ACEI the subject will be started on isradipine instead. If the subject is already on an ACEI and calcium channel blocker at baseline, propranolol will then be the new medication added.

Dosing will be as follows:

ACEI: Enalapril \< 40 kg starting dose 2.5 mg titrate to 5 mg \> 40 kg starting dose 5 mg titrate to 10mg Calcium Channel Blocker: Isradipine \< 40 kg 2.5 mg \> 40 kg starting dose 2.5 mg titrate to 5 mg Beta Blocker: Propranolol \<40 kg starting dose 10 mg titrate to 20 mg \>40 kg starting dose 20 mg titrate to 40 mg

Protocol documents:
Prot_SAP_000.pdf: 
Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 1 of 31 
Reduction of Nocturnal Hypertension in Pediatric Renal Transplant Recipients 
 
 
PART A.  Specific Aims 
Nocturnal hypertension and an abnormal decline in nocturnal blood pressure (non-dipping pattern) are 
commonly found during ambulatory blood pressure monitoring (ABPM) in pediatric renal transplant recipients.  
These entities are independently associated with progressive renal dysfunction, proteinuria, cardiovascular 
morbidity and mortality in adults with hypertension and chronic kidney disease.  Hence, optimization of anti-
hypertensive medications to normalize nocturnal blood pressure and restore the nocturnal dip is a therapeutic 
target with potential cardiovascular and renal benefit.  Tailoring of anti-hypertensive medications to the 
circadian variation of blood pressure, or chronotherapy, has been utilized as a means of reducing nocturnal 
blood pressure and converting non-dippers back to the normal dipping pattern.  Furthermore, adiponectin, an 
adipocytokine, has been associated with hypertension.  The genetic variation of adiponectin in relationship to 
dipper status has not been explored.   
The proposed study will investigate the effect of chronotherapeutic alteration of anti-hypertensive 
medication on nocturnal hypertension and end-organ injury in pediatric renal transplant recipients who are non-
dippers.  Additionally, we aim to examine the association between response to intervention, serum adiponectin 
levels and adiponectin gene polymorphisms.  We hypothesize that (1) evening administration of anti-
hypertensive medication will convert subjects from non-dipper to dipper status, improve mean nocturnal blood 
pressure (BP), and improve nocturnal BP load, (2) evening administration of anti-hypertensive medication will 
reduce albuminuria, left ventricular mass index (LVMI), rate of decline of glomerular filtration rate (eGFR) and 
will decrease pulse wave velocity (PWV), and (3) lower adiponectin levels and presence of adiponectin gene 
polymorphisms will be associated with less of a response to the intervention. The proposed study will explore 
these hypotheses in a clinical trial.  The specific aims of this proposal are as follows:   
 
Specific Aim #1: 
To institute a prospective, randomized, open label, blinded end-point trial in pediatric renal transplant recipients 
who are non-dippers to determine whether adding an evening anti-hypertensive medication improves nocturnal 
hypertension. 
  
Secondary Aims:  
1. To examine whether adding an evening anti-hypertensive medication modifies albuminuria, LVMI, PWV and 
eGFR slope in pediatric renal transplant recipients who are non-dippers. 
2. To determine the association of serum adiponectin levels and single-nucleotide polymorphisms (SNPs) of 
the adiponectin (ADIPOQ) gene with response to chronotherapeutic alteration of anti-hypertensive medication 
and outcomes of change in microalbuminuia, LVMI, PWV and eGFR slope in pediatric renal transplant 
recipients who are non-dippers.   
 
PART B.  Significance and Background 
 
Ambulatory Blood Pressure Monitoring 
Ambulatory blood pressure monitoring (ABPM) is a non-invasive technique for measuring multiple BP readings 
over a 24-hour period during regular activities and sleep.  This modality has several advantages over 
conventional casual BP.  Namely, ABPM provides measurements outside of the healthcare environment 
thereby eliminating the white coat effect.  ABPM can assess many parameters of BP including averages of 
systolic and diastolic BP, heart rate, BP variability, and circadian changes during the sleep and awake periods.  
The modality can also be used to test the efficacy of anti-hypertensive treatment.  Perhaps more importantly, 
ABPM is superior to casual BP in correlating with target organ damage, cardiovascular risk and long-term 
prognosis in children and adults 1-3.   
The use of ABPM in children has been validated 4,5 and recommendations for the standard assessment 
of ABPM in children and adolescents have been recently developed 4.  Accordingly, the interpretation of ABPM 
studies is based on a combination of BP parameters.  Mean systolic and diastolic BP for the 24 hour, daytime 
and night-time periods are calculated and referenced against normative data (mean BP greater than the 95% 
for height and sex indicate hypertension) 6,7.  BP load is another ABPM parameter defined as the percentage of 
BP measurements above the 95th% for sex and height for the 24 hour, daytime and night-time periods.  BP 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 2 of 31 
loads greater than 25% to 30% are considered elevated 4.  Nocturnal dipping refers to the physiological decline 
in BP during sleep.  Nocturnal dipper status is determined by the percent drop in mean systolic BP or diastolic 
BP between daytime and night-time periods (N/D ratio).  Normal dipper status is defined as at least 10% drop 
(N/D ratio 0.9 or less) in mean BP between daytime and night-time.  Non-dipper status is defined as less than 
10% drop (N/D ratio >0.9) in mean BP between daytime and night-time 4.  Non-dippers are further classified to 
reverse-dippers when nocturnal BP is above the daytime mean.   
 
Nocturnal Dipping 
ABPM has allowed for the characterization of the 24 hour circadian variation in blood pressure.  In most 
individuals, the normal circadian pattern includes a sharp morning rise in BP, two daytime peaks around 9 a.m. 
and 7 p.m., a post-parandial dip around 3 p.m. and a decline during sleep 8.  The normal circadian 24 hour BP 
variation is affected by a variety of external factors and internal factors such as autonomic nervous system 
tone, catecholamines, the renin-angiotensin-aldosterone axis, hematologic factors, and oxidative stress 8.   
 
In normal dippers, the night-time mean BP is 10 -20% lower than the awake BP.  Non-dippers do not 
demonstrate this physiological decline in blood pressure during sleep, which may represent a pathological 
condition.  A variety of  conditions have been associated with non-dipping status, including renal 
transplantation 9, sleep apnea 10, chronic kidney disease 11-13, essential hypertension 14, diabetes 15 and 
cerebro-vascular disease 16, to name a few.  The mechanisms underlying the lack of blood pressure decline 
are unclear.  Some have postulated that higher nocturnal blood pressures are needed to enhance natriuresis in 
sodium sensitive individuals 17.  Alterations in the autonomic nervous system 18, renin-angiotensin system 19, 
and poor sleep quality 20 are also thought to play a role.       
 
The non-dipping phenomenon appears to have clinical significance and is now considered to be a risk 
factor for cardiovascular disease.  In the general adult population, non-dipping and nocturnal BP were found to 
be strong predictors of cardiovascular morbidity and mortality 21,22.  A prospective study of 1,187 patients with 
essential hypertension demonstrated that non-dippers had three times as many cardiovascular events than 
dippers 23.  The non-dipping pattern has also been associated with increased target organ damage such as left 
ventricular hypertrophy 24, stroke 25, proteinuria 26 and progression of renal insufficiency 27 in adults with 
hypertension.       
 
 
Hypertension in Renal Transplantation 
Hypertension is a common occurrence after renal transplantation in children.  In the North American Pediatric 
Renal Transplant Cooperative Study (NAPRTCS), which is a registry of greater than 6,500 pediatric renal 
transplants from 126 centers, 65 – 73% of pediatric transplant recipients were on anti-hypertensive 
medications 2 years post-transplant, and 59 - 69% were on medications 5 years post-transplant 28. The use of 
ABPM is now recognized as the preferred method to diagnose hypertension in the pediatric renal transplant 
population over casual blood pressure 29.  Giordano et al. assessed 37 renal transplant children and diagnosed 
hypertension in 62% by ABPM while only 43% were detected by casual blood pressure 30.  Eleven single 
center studies have evaluated ambulatory blood pressure in pediatric renal transplant recipients to date 30-40.  
The prevalence of hypertension in these studies ranged from 36% to 85%, in spite of anti-hypertensive 
treatment in the majority of children.   
The pathogenesis of hypertension in kidney transplant patients is multi-factorial, involving interactions 
among immunosuppressive therapy, host and allograft risk factors.  Corticosteroids increase sodium retention 
with resultant volume expansion and elevated blood pressure.  Calcineurin inhibitors cause vasoconstriction by 
stimulating vasoactive factors.  Host-related factors include pre-transplant hypertension, native kidney disease, 
high salt diet and obesity.  Risk factors related to the kidney allograft include donor age, ischemia time, graft 
dysfunction, renal artery stenosis and inherited abnormal sodium excretion 41.   
 
Nocturnal Hypertension in Renal Transplantation 
Of the published ABPM studies in pediatric transplant recipients, six reported isolated nocturnal hypertension 
in 22% to 76%.  The mean systolic dip ranged from 3% to 8.9% and diastolic dip ranged from 8.7% to 13.9%, 
indicating that diastolic dipping was more preserved when compared to systolic dipping.  When mentioned, an 
abnormal dipping pattern was found in 23% to 85% of transplant recipients, with systolic non-dipping greater 
than diastolic non-dipping.  Some recipients experienced reversed dipping.  McGlothan et al. reported a 
predominance of nocturnal hypertension in 29 pediatric renal transplant recipients.  Isolated nocturnal 
hypertension was present in 41% with diastolic hypertension being more common.  Blood pressure loads were 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
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higher in the night-time compared to the daytime.  Systolic nocturnal dip was blunted in 43% and reversed in 
17%, and the diastolic nocturnal dip was blunted in 30% of recipients and reversed in 7% 9.   
 
The effect of renal transplantation on circadian variation of blood pressure over time is not known, 
however some longitudinal studies in adults suggest that it may improve.  Covic et al. showed that out of 20 
renal transplant recipients who were non-dippers one month after transplant, 40% became dippers at one year 
42.  However, 55% remained non-dippers.  Lipkin et al. demonstrated an increased prevalence of dippers from 
69% after 37 months to 83% after 124 months 43.  In the only longitudinal study of pediatric transplant 
recipients, Krmar et al. observed that only 11 of 37 recipients maintained consistent dipper status (either dipper 
or non-dipper) on repeat ABPM with a mean follow-up time of 3.3± 2.2 years (range 1-8) 33.  However, in all 
these longitudinal studies, antihypertensive therapy was started and titrated over time which may have affected 
the dipping status.  The mechanisms for normalization of the circadian blood pressure profile are not known.    
 
Nocturnal Hypertension and End Organ Effects 
Young adults with a history of renal transplantation during childhood and adolescence have a greater than 10 
fold risk of cardiovascular death compared to the general population 44.  Hypertension plays a major role in the 
morbidity and mortality associated with cardiovascular disease, which is the second leading cause of death in 
pediatric renal transplant patients 37.  Whether pediatric transplant recipients who are non-dippers are at higher 
risk for cardiovascular outcomes in adult life is unknown.  One study in adults with CKD found that daytime and 
night-time BP were predictive of myocardial infarction, stroke and death 45.  Non-dipping was associated with 
increased risk, but the relationship did not hold after adjustment for other risk factors.  In hemodialysis patients, 
non-dipping was associated with a hazard ratio of 2.5 for cardiovascular events and 9.6 for cardiovascular 
death 46.  Toprak et al. reported that adult transplant recipients who were non-dippers had higher LVMI than 
dippers and nocturnal systolic load was an independent predictor of LVMI 47. In a study of 28 pediatric renal 
transplant recipients, LVMI significantly correlated with 24 hour systolic BP, but was not correlated with the 
absolute value of systolic or diastolic nocturnal dip.  There was no mention of LVMI based on dipper status or 
nocturnal blood pressure 36.  A study of 40 pediatric renal transplant recipients found no association between 
LVMI and dipping status or blood pressure load 38. 
 
Hypertension in pediatric renal transplant patients has been shown to be associated with allograft 
dysfunction 48,49.  Due to the lack of prospective studies, no definitive answer can be given to date whether 
non-dipping or nocturnal blood pressure influences renal function in childhood.  In adults with chronic kidney 
disease (CKD), the non-dipping pattern of ambulatory BP is associated with a faster progression of CKD.  In a 
longitudinal study of 48 hypertensive patients with CKD, Timio et al. demonstrated that non-dippers had a 
faster rate of decrease in creatinine clearance  than dippers 27.  Non-dippers also had greater increase in 
urinary protein excretion than dippers.  A study of 217 veterans with CKD showed that non-dipping and night-
time ambulatory BP were stronger predictors of all-cause mortality and the combination of mortality plus 
progression to ESRD than daytime BP 50.  Davidson et al. likewise showed a greater decrease in GFR in non-
dippers (mean change, -15.9%)  compared to dippers (mean change, 1.3%) after a median follow-up of 3.2 
years independent of blood pressure levels and risk factors for CKD 51.  Similarly, a study of 119 adult renal 
transplant recipients found that lack of nocturnal dip was associated with poor allograft function and high 
resistive index on ultrasound 52.  For every 10% nocturnal drop in systolic BP, GFR increased by 4.6 ml/min 
per 1.73 m2.  Two additional groups found that non-dipper status was associated with lower creatinine 
clearance 53,54.  In the only pediatric study that evaluated allograft function, Krmar et al. retrospectively showed 
no difference in the rate of decline of GFR in subjects with nocturnal hypertension compared to those without 
nocturnal hypertension 33. Non-dipper status was not evaluated.   
 
Chronotherapy of Hypertension 
Given that non-dipper status and nocturnal hypertension are modifiable risk factors for allograft dysfunction, 
cardiovascular morbidity and mortality, optimization of anti-hypertensive therapy to normalize circadian 
variation in BP is a potential therapeutic target.  Chronotherapy is the practice of administering medications in 
synchrony with circadian patterns in order to maximize health benefit while minimizing adverse effects 55.  
Chronotherapy of hypertension can be accomplished by the specific timing of conventional anti-hypertensive 
medications based on individual needs.  For those with nocturnal hypertension and non-dipping status, 
evening administration of BP medications may be ideal.   
 
An uncontrolled study in 32 non-dipper patients with CKD showed that shifting one anti-hypertensive 
medication from morning to evening resulted in restoration of normal dipping status in 87.5% of patients after 8 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 4 of 31 
weeks 56.  Lower nocturnal BP means and office casual BP were also found.  Urinary protein excretion was 
lower after the intervention while GFR and urine sodium excretion remained unchanged.  These results were 
found independent of the class of medication shifted.  Portaluppi et al. demonstrated that evening 
administration of isradipine reduced nocturnal blood pressure, but no information was given regarding the 
effect on nocturnal dip 57.  In hypertensive adult subjects, evening (vs. morning) administration of valsartan 
reversed the non-dipping pattern in 73% of patients and reduced urinary albumin excretion by 41% after three 
months 58.  Currently, there is a prospective study underway of 3,000 adults which will evaluate whether 
normalizing BP toward a more dipper profile using chronotherapeutic strategies reduces cardiovascular, 
cerebrovascular and kidney risk 59. There are no pediatric or renal transplant chronotherapeutic studies 
published to date.          
 
Adiponectin and Hypertension 
Adiponectin is a protein secreted by adipose tissue with insulin sensitizing, vasculo-protective, anti-atherogenic 
and anti-inflammatory properties.  Data suggest that the HMW multimer of adiponectin is the active isoform 
and that HMW adiponectin or the ratio of HWM adiponectin to total adiponectin (HMWr) is a better biomarker of 
clinical health and disease than total adiponectin 60.  Reduced levels of adiponectin are thought to play an 
important role in the development of obesity-related cardiovascular and metabolic diseases, including 
hypertension.  Several studies in adults and children have reported that lower adiponectin correlates with 
higher BP 61-64. Furthermore, two studies demonstrated that lower adiponectin levels are found in non-dippers 
compared to dippers 
65,66.  More recently, two prospective clinical studies in adults reported that 
normotentensive subjects in the lowest percentile group of adiponectin conferred a 2.76 to 3.42 increased risk 
of developing hypertension 3 to 5 years later when compared to those in the highest percentile group 67,68.  The 
results of these studies intimate that adiponectin may play a significant role in the pathogenesis of 
hypertension. 
Single nucleotide polymorphisms (SNPs) of the adiponectin gene (ADIPOQ, Gene ID 9370, GeneBank 
ID NM_004797) have been associated with the metabolic syndrome, cardiovascular disease and diabetes 69-71.  
The association between SNPs of adiponectin and hypertension has yet to be fully explored. Iwashima et al. 
found that the TC genotype of the I164T polymorphism was associated with lower serum adiponectin levels 
and hypertension in a cohort of Japanese men 62.  Another group reported that the genotype and allele 
frequency distributions of SNP276 were different in women with pre-eclampsia vs. controls, and that the TT 
genotype was associated with protection against pre-eclampsia 72.  There are no studies of adiponectin SNPs 
in renal transplant recipients to date.   
 
FGF-23 and Hypertension 
FGF23 is a hormone produced by osteoblasts/osteocytes in bone that acts on the kidney to regulate 
phosphate and vitamin D metabolism through activation of FGF receptor/α-Klotho co-receptor complexes. High 
FGF23 predicts graft failure in transplant patients, is independently related with chronic kidney disease (CKD) 
progression, and associates with endothelial dysfunction in adults. Furthermore, independently of serum 
phosphate, high FGF23 associates with mortality and left ventricular hypertrophy in dialysis patients and with 
atherosclerosis in elderly individuals in the general population. FGF23 also predicts a high risk for death and 
cardiovascular events in predialysis CKD patients and in subjects with coronary artery disease73. Elevated 
circulating FGF23 concentrations have been associated with left ventricular hypertrophy (LVH), and it has been 
suggested that FGF23 exerts a direct effect on the myocardium.  Data on the cardiovascular effects of FGF23 
on cardiovascular disease is limited.  One study examined found an inverse relationship between FGF23 and 
renal function in 44 pediatric transplant patients 74. It is possible that elevated FGF23 may exert its negative 
impact through distinct mechanisms of action independent from its role as a regulator of phosphorus 
homeostasis.  
 
Significance of the Research 
Nocturnal hypertension and non-dipper status are associated with end-organ damage, cardiovascular 
morbidity and mortality in adults with hypertension and kidney disease.  The long term effects of non-dipping 
on cardiovascular and allograft outcomes in pediatric renal transplant recipients are not known, however, the 
likelihood of a similar effect is probable.  Thus, it is of interest to find an intervention to normalize the circadian 
variation in BP toward more of a dipper profile.  This study aims to investigate chronotherapeutic alterations of 
anti-hypertensive medications in pediatric renal transplant recipients with the purpose of improving nocturnal 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 5 of 31 
hypertension and target-organ injury. The effectiveness of a chronotherapeutic approach has not yet been 
explored in pediatric renal transplant recipients.   If this study’s hypotheses are proven correct, then this simple 
strategy may retard progression of renal dysfunction and protect against future cardiovascular morbidity and 
mortality in pediatric renal transplant recipients.   
 
PART C.  Preliminary Studies and Experience of the Investigator 
The experience of the candidate in studies pertaining to cardiovascular risk factors and hypertension in renal 
transplant recipients and her background in epidemiology and biostatistics provide support to the strengths and 
feasibility of the proposed study.  The candidate was the primary investigator in two prospective studies 
evaluating 1) the relationship between adiponectin and ambulatory blood pressure and 2) cardiorespiratory 
fitness in pediatric renal transplant recipients.  She was also a co-investigator in a study of vascular 
dysfunction in transplant recipients.  In addition, she has written case reports and chapters in the area of 
hypertension.   
 
I.  Ambulatory Blood Pressure in Pediatric Renal Transplant Recipients 
We performed a cross-sectional study of thirty-two pediatric renal transplant recipients, aged 14.5 ± 2.8 (range 
8 to19) years, at The Children’s Hospital of Philadelphia (manuscript attached in Appendix).  Subjects were 
predominantly male (n = 23, 72%), non-black (n = 24, 75%) and non-obese (n = 27, 84%).  Median time (inter-
quartile range) since diagnosis of end stage renal disease (ESRD) was 4.9 (2.2 to 9.9) years and time since 
transplant was 1.9 (0.4 to 12.7) years.  Median eGFR was 90.0 (70 to 183) ml/min/1.73m2.  All subjects were 
on prednisone; other immunosuppression included: tacrolimus 26 (81%), mycophenolate mofetil 14 (44%), 
sirolimus 12 (38%) and azathioprine 4 (13%).  Thirteen (41%) subjects were on anti-hypertensive medications:  
Angiotensin Converting Enzyme Inhibitor (ACEI) 6 (19%), Angiotensin II Receptor Blocker (ARB) 5 (16%), 
calcium channel blocker 9 (28%) and beta-blocker 4 (13%).  Nine subjects held ACEI or ARB medications for 
one week prior to completing the study due to protocol requirements.  
 
Table 1.  24 hr ambulatory blood pressure monitor results of pediatric renal transplant recipients 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean daytime, night-time and 24 hour indexed BP [mean BP divided by the sex and height specific 95th 
percentiles for systolic and diastolic BP 3,7] of all subjects were less than one (Table 1).  Subjects with 
hypertension, indicated by BP index greater than one, are shown in Figure 1. Fifteen subjects (47%) had 
nocturnal hypertension and four subjects (13%) had daytime hypertension. Twelve of the 15 (80%) subjects 
with nocturnal hypertension on ABPM had normal office casual blood pressures.  An abnormal nocturnal 
dipping pattern was seen in 62% (systolic) and 47% (diastolic) of subjects (Figure 2).  The frequency of dippers 
and non-dippers in years post-transplant is demonstrated in Figure 3.  The majority of non-dippers were found 
in the first two years post-transplant, however, non-dippers were also seen after several years. Ten of the 18 
non-dippers were treated with anti-hypertensive medications.  Mean BP loads were as follows: daytime systolic 
18% and diastolic 12%; night-time systolic 27% and diastolic 29%.     
 
Blood Pressure 
           N= 32 
                                      
Mean ± SD 
BP Index ± SD N (%) with BP  index >1 
24 h systolic BP  
115 ± 13 mm Hg 
0.94 ±  0.08 
8 (25%) 
24 h diastolic BP  
68 ± 7  mm Hg 
0.90 ± 0.08 
4 (13%) 
Daytime systolic BP   
118 ± 12  mm Hg 
0.92 ± 0.08 
4 (13%) 
Daytime diastolic BP  
71 ± 7  mm Hg 
0.87 ± 0.07 
0 (0%) 
Night-time systolic BP  
108 ± 13  mm Hg 
0.97 ± 0.11 
13 (41%) 
Night-time diastolic BP  
62 ± 8  mm Hg 
0.94 ± 0.10 
12 (38%) 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 6 of 31 
 
 
 
 
 
Figure 1.  Percent of pediatric renal transplant recipients 
with blood pressure index greater than one, indicating 
hypertension. 
 
 
 
 
 
 
 
 
 
 
 
Figure 2.  Percent of pediatric renal transplant recipients 
who are dippers vs. non-dippers.  
 
 
 
 
 
 
                          
 
 
 
Our results demonstrated that half of pediatric renal transplant subjects had nocturnal hypertension and 
were non-dippers.  Notably, most of these patients had masked hypertension as they had normal casual 
office blood pressures.  Blood pressure loads were also appreciably elevated at night-time compared to the 
daytime.   
 
 
II.  Adiponectin in Renal Transplant Recipients 
Serum total adiponectin and HMW adiponectin to total adiponectin ratio (HMWr) were measured in the same 
group of pediatric renal transplant recipients.   The mean serum total adiponectin level was 9.6 ± 4.9 (median 
8.3, range 2.8 to 21.9) µg/ml and HMWr was 0.45 ± 0.11 (median 0.46, range 0.22 to 0.61). Although total 
adiponectin was lower in male subjects and obese subjects, no significant difference was determined based on 
sex (male 9.4 ± 5.4 µg/ml vs. female 10.0 ± 3.5 µg/ml, p = 0.368), obesity status (obese 7.2 ± 4.2 µg/ml vs. 
non-obese 10.0 ± 4.9 µg/ml, p = 0.223) or immunosuppressive medication. This also was true for HMWr.   
0
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
9
10
11
12
13
Years Since Transplant
Number of Transplant Recipients
Dippers
Non-Dippers
0 
10 
20 
30 
40 
50 
60 
70 
80 
90 
100 
Systolic 
Dip 
Diastolic 
Dip 
Nocturnal Dipper Status 
Dipper 
Non-Dipper 
0 
50 
100 
Night Diastolic 
Night Systolic 
Day Diastolic 
Day Systolic 
24 Diastolic 
24 Systolic 
Hypertension 
% BP index > 1 
Figure 3.  Frequency of dippers and non-dippers 
years post-transplant. 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 7 of 31 
 
To determine the independent anthropometric and clinical predictors of adiponectin in this cohort, 
variables were entered into stepwise multiple linear regression models.  Tanner stage of pubertal maturation 
(stage 1 through 3 as the referent group with an indicator variable for Tanner stages 4 and 5), history of 
dialysis (no dialysis as referent group) and time since diagnosis of ESRD were independent predictors of 
log-transformed total adiponectin (R2 = 0.46).  Mature pubertal stage (β = -0.470, 95% CI: -0.773 to -0.167, p = 
0.004) and prior history of dialysis (β = -0.444, 95% CI: -0.756 to -0.133, p = 0.007) independently associated 
with lower total adiponectin.  A 1 month change in time since diagnosis of ESRD was associated with a 0.3% 
increase in total adiponectin (β = 0.003, 95% CI: 0.0004 to 0.006, p = 0.026).  In linear regression models 
predicting HMWr2 (power transformed, R2 = 0.53), pubertal stage, sex, sirolimus use and HDL were 
statistically significant determinants.  Mature pubertal stage independently associated with lower HMWr2 (β = -
0.094, 95% CI: -0.141 to -0.047, p < 0.001).  Female sex (β = 0.075, 95% CI: 0.021 to 0.130, p = 0.009) and 
sirolimus use (β = 0.115, 95% CI: 0.061 to 0.170, p < 0.001) were associated with greater HMWr2.  HMWr2 
increased by 0.003 (95% CI: 0.001 to 0.004, p = 0.01) for a 1-unit increase in HDL.   
We hypothesized that measures of fat mass (total and central) would be associated with adiponectin, 
however, this was not the case.  In addition, adiponectin levels were not significantly lower in obese subjects 
compared to non-obese subjects, contrary to what was expected.  Authors have reported that adiponectin 
correlates inversely with estimates of fat mass in transplant recipients (BMI) 75,76 while others have not 77,78.  
Some postulate that qualitative changes in adipose tissue rather than quantitative changes may mediate the 
risk of hypertension 79.  The effect of renal transplantation and immunosuppressive medications on the 
functional aspects of adipose tissue has yet to be determined.   
 
III.  Adiponectin and Hypertension in Renal Transplant Recipients 
When hypertensive subjects (defined as any BP index > 1) were compared to non-hypertensive subjects, lower 
total adiponectin (7.3 ± 3.3 µg/ml vs. 11.6 ± 5.2 µg/ml, p = 0.01) and HMWr (0.38 ± 0.10 vs. 0.50 ± 0.09, p = 
0.002) were seen in the hypertensive group (Figure 4).  There was a trend for lower adiponectin levels in non-
dippers compared to dippers however statistical significance was not met (Figure 5).  This may have been a 
power issue related to the small sample size.   
 
 
Figure 4.  Adiponectin levels in hypertensive subjects vs. normotensive renal transplant subjects. 
   
 
0.00
1.00
HTN
0.00
5.00
10.00
15.00
Total Adiponectin
0.00
1.00
HTN
0.00
0.20
0.40
0.60
HMW Ratio
0
1
Diastolic Dipper
0.00
5.00
10.00
15.00
Total Adiponectin
0
1
Systolic Dipper
0.00
5.00
10.00
15.00
Total Adiponectin
NO 
NO 
YES 
 
 
YES 
 
 
P = 0.01 
P = 0.002 
NO 
NO 
YES 
YES 
P = 0.08 
P = 0.97 
YES 
 
 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 8 of 31 
 
Figure 5.  Adiponectin levels in dipper vs. non-dipper.    
 
We found that total adiponectin and HMWr negatively correlated with systolic and diastolic BP in the 
daytime, night-time and 24 hour periods (Table 2).  Lower total adiponectin was independently associated 
with greater BP in all ABPM parameters, except for night-time systolic BP in multiple regression analysis 
adjusted for fat mass for height z-score, eGFR, age and sex.  HMWr was inversely associated with all 
ambulatory BP indexes.  
 
In logistic regression, we demonstrated that lower total adiponectin and HMWr were significant 
independent determinants of hypertension in pediatric transplant subjects.    For log total adiponectin, 
the OR was 0.05 (95% CI: 0.01 to 0.51, p = 0.011), indicating that the odds of having hypertension decreased 
by 95% when log total adiponectin increased by 1 unit after adjustment for covariates.  In the model using 
HMWr2, the OR was 0.11 (CI: 0.02 to 0.61, p = 0.011), indicating that the odds of having hypertension 
decreased by 89% when HMWr2 increased by 10 units.  
 
 
Table 2.  Correlation and Regression Coefficients for Adiponectin and ABPM 
 
BP  
Total Adiponectin 
HMWr 
 
Spearman 
Regression* 
Spearman 
Regression* 
24 systolic 
BP index  
r = -0.36 
p = 0.041  
β = -0.067 
-0.133 to -0.0001  
p = 0.050  
r = -0.41 
p = 0.021  
β = -0.400 
 -0.769 to -0.031 
p = 0.035  
24 diastolic 
BP index  
r = -0.43 
p = 0.015  
β = -0.079 
 -0.134 to -0.024 
 p = 0.007  
r = -0.42 
p = 0.016  
β = -0.494 
 -0.791 to -0.198  
p = 0.002  
Daytime 
systolic BP 
index  
r = -0.45 
p = 0.011  
β = -0.071 
 -0.129 to -0.013 
p = 0.019  
r = -0.39 
p = 0.026  
β = -0.386 
-0.725 to -0.071 
p = 0.019  
Daytime 
diastolic 
BP index  
r = -0.57  
p = 0.001  
β = -0.086 
 -0.135 to -0.036  
p = 0.002  
r = -0.44 
p = 0.011  
β = -0.47 
 -0.759 to -0.198  
p = 0.002  
Night-time 
systolic BP 
index  
r = -0.35 
p = 0.048  
β = -0.073 
 -0.165 to 0.019 
p = 0.114  
r = -0.45 
p = 0.011  
β = -0.556 
 -1.049 to -0.062 
p = 0.029  
Night-time 
diastolic 
BP index  
r = -0.36 
p = 0.042  
β = -0.093  
 -.170 to -0.017  
p = 0.019  
r = -0.42 
p = 0.016 
β = -0.59 
-1.007 to -0.173 
p = 0.007 
* Total Adiponectin was log transformed.  HMWr was power transformed (HMWr2). 
 
 
IV.  Other Cardiovascular Risk Factors in Pediatric Renal Transplant Recipients   
 
Cardiorespiratory Aerobic Fitness 
We also studied the non-traditional cardiovascular risk factor of aerobic fitness in 50 pediatric transplant 
recipients and 70 healthy controls (manuscript attached in Appendix).  The impact of body size, fat-free mass 
(FFM) and fat mass (FM) on cardiorespiratory fitness in pediatric renal transplant recipients has not been 
established.  Study objectives were to assess maximal oxygen consumption (VO2max) in transplants and 
controls, adjusted for body composition, and to identify risk factors for reduced fitness in transplant recipients.  
Cycle ergometry and DXA were obtained in subjects, ages 8 to 21 yr. Control recruitment was targeted to 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 9 of 31 
include obese subjects with body mass index Z-scores comparable to transplant recipients. Allometric 
regression models were utilized.  Transplant recipients had significantly lower height Z-scores (p < 0.001) and 
comparable BMI Z-scores.  VO2max per body weight (ml/kg/min) and per FFM (ml/kgFFM/min) did not differ 
between groups.  However, VO2max was 13% lower (95% CI 18, 8; p < 0.001) in transplant recipients 
compared with controls, adjusted for FM, FFM, sex and race.   Greater FFM, lower FM, non-black race, and 
male sex were independently associated with greater VO2max.   Within transplant recipients, hemoglobin levels 
were positively associated with VO2max (p = 0.04) and sirolimus use was associated with lower VO2max (p < 
0.01).  In conclusion, transplant recipients had significant VO2max deficits that were not captured by 
conventional measures (ml/kg/min). Greater FM was an independent risk factor for low VO2max.  Lower fitness 
in TX may be related to sirolimus effects on skeletal muscle.   
 
 
Vascular Function 
Vascular dysfunction was evaluated in a pilot study of 9 pediatric renal transplant recipients and 18 healthy 
controls.  Pathologic outcome measures included the stiffness of the conduit arteries. Physiologic outcome 
measures included the vascular response to lack of oxygen (flow-dependant vasodilatation), identification of 
circulating endothelial cells, and endothelial precursor cells (EPC) that provide estimates of chronicity and 
extent of vascular injury.   Results demonstrated that pediatric renal transplant recipients had reduced 
brachial artery reactivity compared to controls, p= 0.023 (Figure 6).  Pediatric renal transplant recipients had 
increased pulse wave velocity compared to controls, p = 0.013 (Figure 7).   And, increased circulating 
hematopoeitic cells with increased circulating EPC was demonstrated in the renal transplant group compared 
to controls (Figure 8).  We concluded that pediatric renal transplant recipients have pathological, physiological 
and biochemical evidence for impaired vascular function. This vascular impairment likely results in accelerated 
atherosclerosis with premature cardiovascular events in early adulthood.  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Figure 6.  Brachial artery reactivity in pediatric renal    
transplant recipients compared to controls. 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse wave velocity
0.00
2.00
4.00
6.00
8.00
10.00
12.00
Controls n = 17
Transplants n = 7
M/sec
 
 
0.0
5.0
10.0 
15.0 
20.0 
Controls n = 18
Transplants n = 9 
Percent change
Figure 7.  Pulse wave velocity in pediatric 
renal transplant recipients compared to 
controls. 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 10 of 31 
 
 
 
 
PART D.  Experimental Design and Methods 
 
I.  Overview of Study Design 
A  prospective, randomized, open label, blinded end-point trial in pediatric renal transplant recipients who are 
non-dippers will be conducted to determine the effect of chronotherapeutic alteration of anti-hypertensive 
medication on nocturnal blood pressure.  This study design has been previously validated for use in trials with 
ABPM measurements 80.  The trial will examine the effects of adding an evening medication.  An estimated 
total of 100 pediatric renal transplant recipients will be enrolled for baseline studies at two pediatric tertiary 
hospitals over a three year time period.    Baseline studies include 24 hour ABPM, echocardiography, PWV, 
urine albumin to creatinine ratio, and laboratory tests (creatinine, electrolytes, adiponectin, FGF23) and genetic 
testing for SNPs of the adiponectin gene (ADIPOQ).  Subjects identified as non-dippers on baseline 24 hour 
ABPM will have their blood pressure medication changed and repeat testing will be done at 3 and 6 months.  
Subjects identified as dippers on ABPM will not continue participation in the study after baseline testing.  
 
The expected sample size of the non-dipper subjects continuing the study is 40.  Non-dipper subjects will be  
randomized to one of two arms:  (1) New medication group – a new anti-hypertensive medication will be added 
in the evening, (2) Control group – anti-hypertensive medications are not altered.  24 hour ABPM, 
echocardiography, PWV, urine albumin to creatinine ratio, and laboratory tests (creatinine, electrolytes, 
adiponectin, FGF23) will be tested at baseline, 3 months and 6 months after the intervention.   Genetic testing 
for SNPs of the adiponectin gene (ADIPOQ) will only be performed at baseline. Principles set out in these 
guidelines will be implemented.   
 
 
Primary Outcome Measure:  The efficacy of chronotherapuetic alteration of anti-hypertensive medication will 
be tested by comparing the proportion of subjects in each of the treatment arms who change from non-dipper 
(N/D ratio > 0.9) to dipper status (N/D ratio ≤ 0.9).   
 
Secondary Outcome Measures: 
1.  Change in night-time systolic/diastolic blood pressure 
2.  Change in night-time blood pressure load 
3.  Change in left ventricular mass index 
4.  Change in albumin:creatinine ratio 
5.  Change in slope of estimated glomerular filtration rate 
6.  Change in pulse wave velocity 
7.  Association of serum adiponectin levels and SNPs of adiponectin with outcomes 
8.  Association of serum FGF23 levels with outcomes 
 
 
II.  Study Sites 
Endothelial precursor cells
0
0.0002
0.0004
0.0006
0.0008
0.001
0.0012
cd34+
cd34+ cd133+
vegf-r2+
cd34- cd133+
vegf-r2+
control n = 7
patient n = 3
Figure 8.  Endothelial precursor cells in pediatric 
renal transplant recipients compared to controls. 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 11 of 31 
Subjects will be recruited from Cohen Children’s Medical Center of North Shore-LIJ Health Systems (CCMC) in 
New Hyde Park, New York and from The Children’s Hospital of Philadelphia (CHOP) in Philadelphia, 
Pennsylvania.  
 
III.  Study Subjects 
Patients from both institutions come from a large geographic area with a diverse racial composition. There are 
currently 200 children greater than 5 years of age who are followed at CHOP and 50 children who are followed 
at SCH.  Pediatric renal transplant recipients who meet eligibility criteria will be invited to have baseline testing 
done.  Eligible subjects who are identified as non-dippers on ABPM will then be invited to continue participation 
in the study.  Recruitment and informed consent will be done in person during nephrology clinics by a member 
of the study team.  No advertisements will be used.  Eligibility criteria include:   
Inclusion Criteria 
1) Subjects age 5-21 years 
2) Stable kidney transplant recipients (<30% change in eGFR in past 3 months) 
3) eGFR > 30 ml/min/1.73 m2 
4) >6 months since kidney transplant 
5) ABPM: Non-dipper status defined as <10% decline (N/D ratio >0.9) in systolic or diastolic blood pressure 
from daytime to night-time 
Exclusion Criteria 
1) ABPM:  Subjects with daytime mean blood pressure > 95% for height and sex 7 (to avoid confounding 
effect of necessary addition of daytime anti-hypertensive therapy)  
2) Subjects with nephrotic range proteinuria 
3) Subjects with major co-morbid conditions such as cardiac disease, pulmonary disease and diabetes 
mellitus 
4) Subjects/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study 
schedules or procedures 
5) Subjects who are pregnant will not be eligible for  the new medication group 
 
Subjects may voluntarily withdraw from the study at any time.   
 
IV.  Randomization and Blinding 
Subjects will be randomized to the treatment group or control group utilizing a blocked randomization strategy 
in order to ensure similar numbers of subjects in each arm.  An independent examiner not directly involved in 
the study will allocate the groups in variable blocks of 2 and 4 in numbered sealed envelopes. The independent 
examiner will likely be our department secretary.  She will have a random assignment of groups generated by 
a computer in blocks of 2 and 4.  She will place the group assignments in sealed numbered envelopes.  The 
research coordinator and study investigators will not know the group assignments prior to enrolling the 
subjects.  As each subject is enrolled, they will be assigned to the group in the envelope in numerical order. 
Investigators involved in the statistical analysis of the data, laboratory technicians and echocardiographers will 
be blinded to the subject treatment group. 
 
V.  Study Procedures 
The outline of study procedures is as follows: 
 
Study Procedures 
 
Baseline 
 
2 week 
6 week 
3 Month 
6 Month 
Review Inclusion/Exclusion Criteria 
X 
 
 
 
 
I 
N
T
 
 
 
 
Informed Consent/Assent 
X 
 
 
 
 
Randomization 
x 
 
 
 
 
Demographics/Medical History 
X 
 
 
 
 
Height and Weight 
x 
 
 
x 
X 
Tanner Stage 
x 
 
 
 
 
Pediatric Sleep Questionnaire 
x 
 
 
 
 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 12 of 31 
Serum creatinine/BUN* 
x 
E
R
V
E
N
T 
I
O
N 
x 
x 
x 
X 
Serum electrolytes * 
x 
x 
x 
x 
X 
Serum Phosphorus 
x 
 
 
x 
x 
Urine albumin: creatinine ratio 
x 
 
 
x 
X 
CBC with differential 
x 
 
 
x 
X 
Uric Acid 
x 
 
 
x 
X 
Insulin 
x 
 
 
x 
x 
hsCRP 
x 
 
 
x 
x 
Lipid Profile 
x 
 
 
x 
x 
Serum FGF23 
x 
 
 
x 
x 
Intact PTH 
x 
 
 
x 
x 
Vitamin D 25 and Vitamin D 1,25 
x 
 
 
x 
x 
Serum Adiponectin   
x 
 
 
x 
X 
Adiponectin Genetic Testing 
x 
 
 
 
 
Urine Pregnancy Test** 
x 
x 
x 
x 
x 
24 hr ABPM 
X 
 
 
x 
X 
Echocardiogram 
x 
 
 
 
x 
X 
Pulse Wave Velocity 
x 
 
 
x 
X 
Treatment Satisfaction 
Questionnaire 
 
 
 
 
x 
Adverse Event/Serious Adverse 
Event Assessment 
x 
x 
x 
x 
X 
*  Subjects started on an ACE inhibitor  will have serum creatinine/BUN and electrolytes checked two and six weeks after 
the intervention.  **  Urine Pregnancy tests will be done on subjects started on an ACE inhibitor.   
 
 
a.  Screening Visit 
Eligibility and demographic data will be collected on all pediatric renal transplant recipients during the study 
interval.  Subject and disease characteristics will be recorded for all ineligible subjects and those declining 
participation.  Potential subjects will be screened using the protocol inclusion and exclusion criteria.  Study 
subjects who meet the eligibility criteria will be asked to participate in the study in person by a member of the 
study team.  Parental/guardian permission (informed consent) and, if applicable, child assent, will be obtained 
prior to any study related procedures being performed.  24 hour ABPM and baseline studies will be obtained.   
 
b. Baseline Visit 
All subjects who participate in the study will have baseline studies (height, weight, Tanner Stage, Pediatric 
Sleep Questionnaire, echocardiography, PWV, urine, blood work – 2 tablespoons of blood, genetic testing – 1 
teaspoon of blood) completed within two weeks of the blood pressure study. Echocardiography and PWV will 
be performed at each of the respective institutions.  Subjects who meet the 24 hour ABPM criteria (non-dipper 
status) will then be randomized into one of the treatment groups.  Subjects who do not meet blood pressure 
criteria will not continue in the study past the baseline visit.  Female subjects greater than 9 years old (or if 
post-menarchal) randomized to the new medication group will have urine pregnancy test done. 
 
c. Intervention 
 
Subjects will be randomized into one of two arms: 
 
 
Control Group - Subjects in the control group will continue to take their medications as usual.  
 
 
 
New Medication Group - Enalapril will be added in the evening at 8 pm.  If the subject is already on an ACEI or 
there is a contraindication to starting an ACEI (e.g. worsening renal function, hyperkalemia, history of allergic 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 13 of 31 
reaction to ACEI) the subject will be started on isradipine instead.  If the subject is already on an ACEI and 
calcium channel blocker at baseline, propranolol will then be the new medication added.  The choice of 
medications was made based on the pharmacokinetic profile of the medications (quick-onset and short acting) 
to lower nocturnal blood pressure with evening administration.   Enalapril and isradipine have been shown to 
effectively change the N/D ratio toward a more dipper profile in clinical trials with adults 57,81. Subjects started 
on Enalapril will have urine pregnancy testing done at each visit.   Dosing will be as follows: 
 
Medication 
Dose 
ACEI:  Enalapril  (half-life 2 hours, peak 
effect 0.5  - 1.5 hours) 
< 40 kg starting dose 2.5 mg titrate to 5 mg 
> 40 kg  starting dose 5 mg titrate to 10mg 
Calcium Channel Blocker: Isradipine (half-
life 8 hours, peak effect 1 - 1.5 hours) 
< 40 kg     2.5 mg 
> 40 kg starting dose 2.5 mg titrate to 5 mg 
Beta Blocker: Propranolol (half-life 3.9 – 
6.4 hours, peak effect 1 – 4 hours) 
<40 kg starting dose 10 mg titrate to 20 mg 
>40 kg starting dose 20 mg titrate to 40 mg  
 
 
d.  Safety Visit 
Subjects in the new medication group will be evaluated at two and six weeks by the study team to assess for 
side effects. The dose of the new medication will be titrated up to the target dose if tolerated at the two week 
visit.  Subjects started on ACEI will have serum electrolytes, BUN and creatinine checked (1 teaspoon of 
blood).  Should the subject develop side effects to ACEI (cough, angioedema, hyperkalemia or worsening renal 
function), the subject will be switched to isradipine. 
 
e.  3 Month and 6 Month Visits 
24 hour ABPM, echocardiogram, PWV and laboratory studies will be performed at 3 months and 6 months 
post-intervention. 
 
f.  End of study 
At the conclusion of the study, those who were started on a new medication will be given the option to continue 
the medicine if there was a positive impact on the subject’s blood pressure (e.g. lower daytime or night-time 
blood pressure, restoring of the nocturnal dip).  If there was no positive effect of the blood pressure medication, 
the medication will be weaned off over the time course of one month.   
 
VI. Study Outcomes 
 
Demographic and Clinical Data 
The medical record will be abstracted for the following variables: age, age at transplant, race, type of transplant 
(deceased vs. living donor), current medications, BMI at the time of transplant, history of delayed graft function, 
history of rejection, prior nephrectomy of the native kidney, and dialysis history.  Casual blood pressure from 
clinic visits will be recorded.   
 
Anthropometric and Pubertal Data 
Height and weight will be measured using standardized electronic scales and height boards. Body Mass Index 
(BMI) will be calculated using the measured height and weight.  BMI is defined as weight (kg) / height (m)2, 
expressed as kg/m2 and converted to age and gender specific percentiles based on the CDC growth data 82. 
Age- and sex-specific Z-scores (standard deviation scores) for height, weight and BMI will be calculated 82.  
Obesity is defined as a BMI greater than the 95th percentile for age and sex 83. The stage of pubertal 
development will  be determined using a validated self-assessment questionnaire 84 and classified according to 
the method of Tanner 85.   
 
Ambulatory Blood Pressure Monitoring 
ABPM will be performed using oscillometric Spacelab 90217 monitors and software (Spacelabs Medical, 
Redmond, CA) according to recommended guidelines 4.  An appropriate sized blood pressure cuff will be 
placed on the non-dominant arm with a small monitor attached to a belt.  The subject will wear the monitor 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 14 of 31 
continuously for 24 hours, encouraged to carry on with usual activities.  BP recordings will be programmed to 
occur every 20 minutes during the day and every 60 minutes while sleeping.  ABPM will be considered 
satisfactory for analysis if there is a minimum 40 readings during the 24 hours with at least 6 readings at night.  
Traces will be rejected and ABPM repeated if BP values are missing for a continuous period greater than 2 
hours or if greater than 10% of values are artifactual.  All ABPM will be interpreted by the primary investigator.   
Measured variables include systolic and diastolic mean BP, BP load and BP index for the 24 hour 
period, daytime period and night-time period.  BP load is defined as the percentage of BP values above the 
sex and height specific 95th percentiles for BP for each subject 3,7.   BP indexes are calculated by dividing the 
average BP of the subject by the sex and height specific 95th percentiles for systolic and diastolic BP 3,7.  
Therefore, a BP index >1 indicates the presence of hypertension.  Nocturnal dipper status is determined by the 
percent drop in mean systolic BP or diastolic BP between daytime and night-time periods (N/D ratio).  N/D ratio 
= [(mean daytime BP – mean night-time BP) / mean awake BP)].  Normal dipper status is defined as at least 
10% drop (N/D ratio 0.9 or less) in mean systolic BP or diastolic BP between daytime and night-time.  Non-
dipper status is defined as less than 10% drop (N/D ratio >0.9) in mean systolic BP or diastolic BP between 
daytime and night-time.   
 
Laboratory Evaluations 
A venous blood sample (2 tablespoons) will be obtained from each subject after an overnight fast for serum 
urea, creatinine, potassium, sodium, hematocrit, albumin, total cholesterol, triglycerides, glucose, insulin, highly 
sensitive CRP, phosphorus, PTH, vitamin D 25, vitamin D 1,25 and uric acid.  In addition, serum total 
adiponectin and HMW adiponectin will be measured using a sandwich format enzyme-linked immunosorbent 
assay kit (Adiponectin Multimeric EIA, Daiichi Pure Chemical, Tokyo, Japan) according to the manufacturer’s 
protocol.  HMW adiponectin to total adiponectin ratio (HMWr) will be calculated by dividing HMW adiponectin 
by total adiponectin. FGF-23 will be measured using a second-generation human FGF23 (C-Terminal) ELISA 
(Immutopics International, San Clemente, CA).  eGFR will be estimated using the Schwartz formula 86.  
Homeostasis model assessment of insulin resistance (HOMA-IR) will be calculated according to the following 
equation: insulin (U/ml) × fasting glucose (mmol/liter) ÷ 22.5 87. Subjects will bring first morning urine 
specimens to study visits, which will be collected at home. First morning spot urine will be collected for albumin 
and creatinine and a urine albumin to creatinine ratio will be calculated. Urine pregnancy tests will be done on 
female subjects in trial #2 at baseline, 2 weeks, 6 weeks, 3 months and 6 months. Routine blood and urine will 
be analyzed by the hospital laboratory at each respective institution.  Technicians performing laboratory 
evaluations will be blinded to the intervention and outcomes.  Adiponectin and highly sensitive CRP will be 
analyzed by the GCRC at SCH.    
 
Genetic Testing 
DNA will be extracted from whole blood (1 teaspoon) and the genome will be amplified.  Five SNPs of the 
ADIPOQ known to affect adiponectin levels or are associated with insulin resistance, cardiovascular disease or 
diabetes will be selected for genotyping 69-71.  These include: rs266729 (5’ flanking region), rs1501299 (intron 
1), rs1501299 (intron 2), rs2241766 (exon 2) and rs822395 (intron 1).   
     
Echocardiography 
Echocardiography will be performed using 2-D echo in M-mode with subjects positioned in the partial left 
decubitus position. Measurements of the interventricular septal thickness (IVS), posterior wall thickness (PWT), 
and left ventricular internal dimension (LVID) will be obtained at or just below the mitral valve tips in 
accordance with the recommendations of the American Society of Echocardiography 88. Left ventricular (LV) 
mass will be calculated using the formula by Devereux et al:  LV mass (g) = 0.81[1.04(IVS + PWT + LVID)3 - 
(LVID)3] + 0.06 89.  Left ventricular mass index will be derived by dividing LV mass in grams by the subject’s 
height in meters raised to the 2.7 power 90.  The technicians and cardiologists will be blinded to the intervention 
and blood pressure outcomes.  Inter- and intra-observer measures of agreement will be monitored using 
Kappa statistic and intra-class correlation coefficients.  
 
Pulse Wave Velocity 
The SphygmoCor Vx pulse wave velocity system (AtCor Medical Pty Ltd, West Ryde (Sydney), Australia) will 
be used to measure the velocity of the blood pressure waveform between the carotid artery and the radial 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 15 of 31 
artery.  The technicians will be blinded to the intervention and blood pressure outcomes.  Inter and intra-
observer measures of agreement will be monitored using Kappa statistic and intraclass correlation coefficients. 
 
Pediatric Sleep Questionnaire 
Obstructive sleep apnea has been associated with abnormal nocturnal dip 73.   Therefore, a 22 item pediatric 
sleep questionnaire developed by Chervin et al. will be administered to the parent/guardian of the study subject 
to identify subjects with sleep-related breathing disorders (Appendix) 91.  This questionnaire has been validated 
and tested for reliability in predicting obstructive sleep apnea.  The questionnaire is graded as follows:  Yes = 
1, No = 0, Don’t Know = missing.  The total is added and divided by the total number of questions minus those 
missing answers.  A cut off of 33% suggest a diagnosis of a sleep related breathing disorder.   
 
 
Treatment Satisfaction Questionnaire for Medications  
Treatment Satisfaction Questionnaire for Medications (TSQM) developed by Atkinson et al. will be 
administered to assess patient satisfaction with the change in treatment and the impact of the therapy on 
quality of life 92.  The tool gathers information about effectiveness of medication, side effects, convenience and 
global satisfaction.  
 
 
PART E.  Statistical Considerations 
 
a.  Statistical Analysis 
Statistical analyses will be done using SPSS 15.0 (SPSS Inc., Chicago, IL) statistical package. A two-tailed p-
value < 0.05 is the criterion for statistical significance.  Intention to treat analysis will be done.   
Descriptive statistics will be used to characterize outcome measures in subjects.  Means, standard 
deviations, 95% confidence intervals, medians, and minimum and maximum values will be tabulated and 
reported for all continuous variables.  Frequency counts and percentages will be used for categorical variables.  
The distributions of each outcome will be examined for normality.  Baseline demographic and clinical data 
between dipper and non-dipper status subjects will be examined. Statistical analyses for both trials will be 
similar.  Differences in means in the treatment group will be compared to the control group using Student’s t-
test, or the Wilcoxon Rank Sum test if the data are not normally distributed.  Differences in proportions will be 
assessed using the chi-square test.   
  
Specific Aim #1: To analyze the primary outcome, chi-square will be conducted to compare the proportion of 
subjects who change from non-dipper to dipper status in the two groups at 3 and 6 months.  Within-person 
changes of change in nocturnal dip in each group will also be examined using the paired Student’s t- test.  
Secondary outcome measures of change in systolic/diastolic night-time mean blood pressure and nocturnal 
blood pressure load between the two groups will be assessed by Student’s t-test.  Within-person changes in 
each group will be assessed using paired Student’s t-test.   
 
Secondary Aim #1: Student’s t-test or Wilcoxon Rank Sum test for non-normally distributed variables will be 
used to compare values of albuminuria, LVMI and eGFR between groups at each time point.  Paired tests will 
be used to assess within-person changes.  Pearson correlation and linear regression will be used to examine 
the association between change in albuminuria, LVMI, PWV and eGFR and change in nocturnal mean blood 
pressure, N/D ratio and nocturnal BP load.  Regression analysis will be adjusted for sex, Tanner stage, race, 
Pediatric Sleep Questionnaire Score, BMI z-score and mean blood pressure to evaluate the independent effect 
of the nocturnal dip.  Variables may be log transformed to improve the fit of the models.   
 
Secondary Aim #2:  Similar to Aim #1.2, Student’s t-test or Wilcoxon Rank Sum test will be used to compare 
values of total adiponectin and HMWr between groups at each time point.  Within-person differences will be 
done using paired tests. Spearman correlation and linear regression will be used to examine the association 
between adiponectin and genetic tests with response to outcome (BP, albuminura, LVMI, pulse wave velocity, 
GFR).  Regression analysis will be adjusted for sex, Tanner stage, race, Pediatric Sleep Questionnaire Score 
and BMI z-score.  Variables may be log transformed to improve the fit of the models.   


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 16 of 31 
 
 
b.  Sample Size Estimates 
Sample size estimates were calculated for the primary outcome of percent change from non-dipper (N/D ratio 
> 0.9) to dipper status (N/D ratio ≤ 0.9).  The comparison of 14 subjects in each group provides 80% power (α 
= 0.05) to detect a 50% change from non-dipper status to dipper status in the treatment groups compared to a 
5% change in the control group.  However, sample size estimates were also calculated for the secondary 
outcome measure of change in pulse wave velocity.  The comparison of 20 subjects in each group provides 
80% power (α = 0.05) to detect a 15% change in pulse wave velocity in the treatment group compared to the 
control group (Reference: Breise et al. 2008, PWV mean 5.43 +/- 0.9)92.  The investigators believe that a 
sample size of 20 in each group is attainable and will therefore power the study according to the secondary 
outcome measure of change in pulse wave velocity.   
 
 
c.  Patient Flow 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This patient flow diagram demonstrates that the target sample size is attainable over a three year period.  Of 
note, there will be an estimated 30 new patients followed each additional year eligible for the study.   
 
d.  Limitations 
The proposed study is limited by the small sample size and lack of a double-blinded placebo controlled design.   
However, the prospective randomized open label blinded end-point design has been previously used and 
validated for ABPM trials 79.  The heterogeneity of anti-hypertensive medications is also a limitation, but the 
design of two studies run in parallel was chosen to address this issue.  Also, the children that choose to 
participate in the study may be more motivated and concerned with their health than those that choose not to 
participate (selection bias).  We will record the subject and disease characteristics for all eligible subjects that 
decline participation. The difficulty in measuring residual confounding factors such as the complexity of ESRD 
course, past medical histories and fluctuating values of covariates (e.g. recent rejection episode) is also a 
limitation.   Additionally, six months may be too short a time period to see the effect of changing from non-
dipper to dipper status on end organ damage and function. Despite the aforementioned limitations, we believe 
that this study has many strengths and the results of the proposed study will be generalizable to the pediatric 
transplant population. 
 
 
PART F.  PROTECTION OF HUMAN SUBJECTS 
Risk to Subjects 
CHOP 200 patients 
SCH 50 patients 
250 total patients 
100 Dipper patients 
150 Non-dipper patients 
 Eligible for New 
Medication group 
 
60% 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 17 of 31 
a.  Human Subjects Involvement and Characteristics 
The proposed study will involve human subjects, in particular, children and adolescents aged 5-21 years of 
age.  The purpose of the study is to examine treatment of nocturnal hypertension in a pediatric population, 
therefore, other age groups are excluded from this study.  Other inclusion/exclusion criteria are listed 
elsewhere in the protocol.  This vulnerable population will be protected.  Assent will be obtained from the 
participants and participants may withdraw from the study at any time. 
 
b.  Sources of Material 
The subjects’ medical record will be abstracted for clinical data.  All other data (blood specimens, echo, pulse 
wave velocity, ABPM) will be obtained specifically for the proposed research.   
 
c.  Potential Risks 
The study procedures stipulated in this proposal are non-invasive and pose minimal risk to the subjects.  
Peripheral blood draws may cause pain, bruising, blood clots under the skin, lightheadedness, fainting, and 
rarely, fainting. 24-hour ambulatory blood pressure monitoring (ABPM) may cause discomfort from blood 
pressure cuff inflation, difficulty sleeping, and rarely, small, purplish spots on the upper arm and bruising under 
the blood pressure cuff.  Echocardiogram may cause local skin irritation that generally resolves without taking 
any action, from the gel used with the device that sends and receives sound waves.  Pulse wave velocity 
measurement may cause local skin irritation from the adhesive on the disc from adhesive on the disc that 
generally resolves without taking any action.that generally resolves without taking any action.  Subjects may 
feel embarrassed when looking at pictures for measures of growth and development.   
 
The medications started for the intervention have potential side effects and incur moderate risk: Side 
effects of the new medications include: Enalapril:  hypotension, dizziness, cough, hyperkalemia, nausea, 
vomiting, muscle weakness, rash, angioedema, increased creatinine, hyponatremia, kidney and liver failure.  
Isradapine:  Swelling of the legs or arms, skin flushing, excessive growth of the gums, dizziness, headache, 
chest pain, disorders of the heart and blood vessels, fast heart rate(edema, tachycardia,  dizziness, tiredness, 
fatigue, nausea, vomiting.  Propranolol:  Slow heart rate, low blood pressure, sleepiness, fatigue, interference 
with thinking or concentration, loss of appetite, nausea, vomiting, diarrhea,  insomnia, feeling of “pins and 
needles” or numbness, depression, mental disorder with severe loss of contact with reality, or high blood 
sugar.  Propanolol can interfere with blood clotting. Propanolol can cause skin irritation, rash, bumps, blisters 
or hives on the palms of the hands and soles of the feet, face, arms or legs. Propranolol can also cause a very 
serious disease involving the skin called Stevens-Johnson Syndrome. It usually starts with symptoms of a cold 
(fever, sore throat, chills, headache, tiredness), and sometimes nausea and vomiting, that may last from 1-14 
days. This is followed by skin irritations that look like bulls eyes. They develop in clusters and are not itchy. 
They can occur anywhere, but are usually seen on the hands, and soles of the feet. They may occur inside the 
mouth and become very sore.  
  
 
Genetic testing for SNPs of adiponectin also poses a moderate risk. The results of genetic testing will not be 
disclosed to the subject or treating clinical team.  The alternative to participation in the study is to not 
participate in the study.  Renal transplant recipients are not routinely screened for nocturnal hypertension by 
ABPM and therefore would not have an alternative treatment.   
 
Adequacy of Protection of Risk 
a. Recruitment and Informed Consent 
Study subjects who meet the eligibility criteria will be approached in person by Nephrology physicians or the 
study coordinator in the Renal Transplant Clinic.  Written informed consent from the participant, participant’s 
parent or legal guardian and assent from the patients will be obtained before any study procedure is initiated.  
Participants who turn 18 years of age during the course of the study will be approached for informed consent.  
No study procedure will be continued in these participants unless informed consent is obtained.  No 
advertisements will be used for recruitment of renal transplant patients.   
 
b. Protection Against Risk 
We will monitor for clinical adverse events throughout the study.  We will report promptly report all 
unanticipated problems related to research to the IRB and GCRC. Refer to separate DSMP for specifics. 
Participation in all areas of the study is completely voluntary.  Should the subjects become intolerant of any 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 18 of 31 
aspect of the study, their participation (or the specific procedure) will be discontinued.  Study investigators will 
be responsible for communicating to subjects information arising from the study (on harm or benefit), or from 
other research on the same topic, that could affect subjects’ willingness to continue the study.  Study 
investigators will give results of the echocardiography and ABPM to the treating physicians to discuss with the 
subject.  All other aspects of the study will be kept confidential.  Data will be stored in a locked cabinet and 
password protected file.   
 
c.  Potential Benefits to Subjects and Others 
Ambulatory blood pressure monitoring will allow the medical team to identify patients with undiagnosed 
hypertension and uncontrolled hypertension. One group might receive more effective treatment and/or have 
fewer side effects than the other treatment groups. This study has considerable future potential benefit for all 
children with renal transplants.   
 
d. Scientific Value 
The effectiveness of a chronotherapeutic approach has not yet been explored in pediatric renal transplant 
recipients.   If this study’s hypotheses are proven correct, then this simple strategy may retard progression of 
renal dysfunction and protect against future cardiovascular morbidity and mortality in pediatric renal transplant 
recipients.  The potential benefits from the information gathered from this study outweigh the risks.   
 
PART G.  INCLUSION OF WOMEN AND MINORITIES 
All transplant patients who meet the above inclusion criteria will be invited to participate in the study regardless 
of gender or race.  The study will include females and minorities consistent with the demographics of the 
transplant program.   
 
PART H.  INCLUSION OF CHILDREN 
The proposed study will involve children and adolescents aged 5-21 years of age.  The purpose of the study is 
to examine treatment of nocturnal hypertension in a pediatric population, therefore, other age groups are 
excluded from this study.  The investigative team consists of pediatric trained physicians and nurses who have 
expertise with the pediatric population.  Subjects will be recruited from children’s hospitals with adequate 
facilities to accommodate children.  Sample size analysis was done to ensure a sufficient number of subjects to 
contribute to a meaningful analysis relative to the purpose of the study. 
 
PART I.  DATA AND SAFETY MONITORING PLAN 
Refer to separate DSMP.   
 
IX.  Payment to Subjects/Families 
Subjects will be compensated $50 per study visit for parking, meals, transportation and the child’s time and 
inconvenience for taking part in this study.  Payment will be made at the completion of each visit. 
X.  Publication Policy 
We plan to publish the results (positive or negative) of this study in academic journals and/or national 
meetings.  We will not disclose protected health information about this study.  Any proven evidence of 
falsification of data will be dealt with to take appropriate action against such unacceptable procedures.   
 
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Morris N, Udry, J. Validation of a self-administered instrument to assess stage of adolescent 
development Journal of Youth and Adolescence,. 1980;9(3):271-280. 
85. 
Tanner JM. Assessment of skeletal maturity and prediction of adult height (TW2 method). London ; New 
York: Academic Press; 1975. 
86. 
Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in full-term infants 
during the first year of life. J Pediatr. 1984;104(6):849-854. 
87. 
Haffner SM, Miettinen H, Stern MP. The homeostasis model in the San Antonio Heart Study. Diabetes 
Care. 1997;20(7):1087-1092. 
88. 
Lai WW, Geva T, Shirali GS, et al. Guidelines and standards for performance of a pediatric 
echocardiogram: a report from the Task Force of the Pediatric Council of the American Society of 
Echocardiography. J Am Soc Echocardiogr. 2006;19(12):1413-1430. 


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89. 
Devereux RB, Alonso DR, Lutas EM, et al. Echocardiographic assessment of left ventricular 
hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986;57(6):450-458. 
90. 
de Simone G, Daniels SR, Devereux RB, et al. Left ventricular mass and body size in normotensive 
children and adults: assessment of allometric relations and impact of overweight. J Am Coll Cardiol. 
1992;20(5):1251-1260. 
91. 
USRDS. Annual Report. 2006. 
92. 
Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of treatment satisfaction, the 
Treatment Satisfaction Questionnaire for Medication (TSQM), using a national panel study of chronic 
disease. Health Qual Life Outcomes. 2004;2:12. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 24 of 31 
 
 
 
 
 
APPENDICES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pediatric Sleep Questionnaire 
 
Patient’s Name: _____________________________ Date:_______________ 
 
Name of individual completing questionnaire: _______________________  
 
Relationship to patient: __________________________________________       
Please answer the following questions by checking the box under the yes, no, or don’t know column to the 
right. 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 25 of 31 
 
 
 
 
 
 
 
 
 
 
While sleeping, does your child…  
YES  
NO  
Don’t know  
…snore more than half the time?  
 
 
 
…always snore?  
 
 
 
…snore loudly?  
 
 
 
…have “heavy” or loud breathing?  
 
 
 
…have trouble breathing, or struggle to breathe?  
 
 
 
 
 
 
 
Have you ever…  
 
 
 
…seen your child stop breathing during the night?  
 
 
 
 
 
 
 
Does your child…  
 
 
 
…tend to breathe through the mouth during the day?  
 
 
 
…have a dry mouth on waking up in the morning?  
 
 
 
…occasionally wet the bed?  
 
 
 
 
 
 
 
Does your child…  
 
 
 
…wake up felling unrefreshed in the morning?  
 
 
 
…have a problem with sleepiness during the day?  
 
 
 
Has a teacher or other supervisor commented that your 
child appears sleepy during the day?  
 
 
 
Is it hard to wake your child up in the morning?  
 
 
 
Does your child wake up with headaches in the morning?  
 
 
 
Did your child stop growing at a normal rate at any time 
since birth?  
 
 
 
Is your child overweight?  
 
 
 
 
 
 
 
This child often…  
 
 
 
…does not seem to listen when spoken to directly  
 
 
 
…has difficulty organizing task and activities  
 
 
 
…is easily distracted by extraneous stimuli  
 
 
 
This child often…  
 
 
 
…fidgets with hands or feet or squirms in seat  
 
 
 
…is ‘on the go’ of often acts as if ‘driven by a motor’  
 
 
 
…interrupts or intrudes on others (e.g. butts into 
conversations or games)  
 
 
 
 
 
 
From RD Chervin, et. al., Sleep Medicine, 2000, p. 21-32 
 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 26 of 31 
 
 
 
 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 27 of 31 
 
 
 
 
 
 
 
 
 


C hri sti n e B. S et h n a, M D, E d M  
v. 1 1. 2 5. 1 3      
 
 
 
P a g e 2 8  of 3 1   
 
 
T S Q M 	  ( V er si o n 1. 4) 
Tr e at m e nt S ati sf a cti o n Q u e sti o n n air e f or M e di c ati o n  
I n str u cti o n s: Pl e a s e t a k e s o m e ti m e t o t hi n k a b o ut y o ur l e v el of s ati sf a cti o n or di s s ati sf a cti o n 
wit h t h e m e di c ati o n y o u ar e t a ki n g i n t hi s cli ni c al tri al. W e ar e i nt er e st e d i n y o ur e v al u ati o n of 
t h e eff e cti v e n e s s, si d e eff e ct s, a n d c o n v e ni e n c e of t h e m e di c ati o n o v er t h e l a st t w o t o t hr e e 
w e e k s, or si n c e y o u l a st u s e d it. F or e a c h q u e sti o n, pl e a s e pl a c e a si n gl e c h e c k m ar k n e xt t o 
t h e r e s p o n s e t h at m o st cl o s el y c orr e s p o n d s t o y o ur o w n e x p eri e n c e s. 
 
1.  H o w s ati sfi e d or di s s ati sfi e d ar e y o u wit h t h e a bilit y of t h e m e di c ati o n t o pr e v e nt or tr e at y o ur c o n diti o n ?  
1  E xtr e m el y Di s s ati sfi e d  
2  V er y Di s s ati sfi e d  
3  Di s s ati sfi e d  
4  S o m e w h at S ati sfi e d  
5   S ati sfi e d  
6  V er y S ati sfi e d  
7  E xtr e m el y S ati sfi e d  
2.  H o w s ati sfi e d or di s s ati sfi e d ar e y o u wit h t h e w a y t h e m e di c ati o n r eli e v e s y o ur s y m pt o m s ?  
1  E xtr e m el y Di s s ati sfi e d  
2  V er y Di s s ati sfi e d  
3  Di s s ati sfi e d  
4  S o m e w h at S ati sfi e d  
5   S ati sfi e d  
6  V er y S ati sfi e d  
7  E xtr e m el y S ati sfi e d  
3.  H o w s ati sfi e d or di s s ati sfi e d ar e y o u wit h t h e a m o u nt of ti m e it t a k e s t h e m e di c ati o n t o st art w or ki n g ? 
1  E xtr e m el y Di s s ati sfi e d  
2  V er y Di s s ati sfi e d  
3  Di s s ati sfi e d  
4  S o m e w h at S ati sfi e d  
5   S ati sfi e d  
6  V er y S ati sfi e d  
7  E xtr e m el y S ati sfi e d  
4.  A s a r e s ult of t a ki n g t hi s m e di c ati o n d o y o u e x p eri e n c e a n y si d e eff e ct s at all ?  
1  Y e s  
0  N o (if N o, t h e n pl e a s e s ki p t o Q u e sti o n 9)  
5.  H o w b ot h er s o m e ar e t h e si d e eff e ct s of t h e m e di c ati o n y o u t a k e t o tr e at y o ur c o n diti o n ?  
1  E xtr e m el y B ot h er s o m e  
2  V er y B ot h er s o m e  
3  S o m e w h at B ot h er s o m e  
4  A Littl e B ot h er s o m e  


C hri sti n e B. S et h n a, M D, E d M  
v. 1 1. 2 5. 1 3      
 
 
 
P a g e 2 9  of 3 1   
5   N ot at All B ot h er s o m e  
 
 
 
6.  T o w h at e xt e nt d o t h e si d e eff e ct s i nt erf er e wit h y o ur p h y si c al  h e alt h a n d a bilit y t o f u n cti o n (i. e., str e n gt h, 
e n er g y l e v el s, et c.) ?  
1  A Gr e at D e al  
2  Q uit e a Bit  
3  S o m e w h at  
4  Mi ni m all y  
5   N ot at All  
7.  T o w h at e xt e nt d o t h e si d e eff e ct s i nt erf er e wit h y o ur m e nt al  f u n cti o n (i. e., a bilit y t o t hi n k cl e arl y, st a y a w a y, 
et c.) ?  
1  A Gr e at D e al  
2  Q uit e a Bit  
3  S o m e w h at  
4  Mi ni m all y  
5   N ot at All  
8.  T o w h at d e gr e e h a v e m e di c ati o n si d e eff e ct s aff e ct e d y o ur o v er all s ati sf a cti o n wit h t h e m e di c ati o n ?  
1  A Gr e at D e al  
2  Q uit e a Bit  
3  S o m e w h at  
4  Mi ni m all y  
5   N ot at All  
9.  H o w e a s y or diffi c ult i s it t o u s e t h e m e di c ati o n i n it s c urr e nt f or m ?  
1  E xtr e m el y Diffi c ult  
2  V er y Diffi c ult  
3  Diffi c ult  
4  S o m e w h at E a s y  
5   E a s y  
6  V er y E a s y  
7  E xtr e m el y E a s y  
 
1 0.  H o w e a s y or diffi c ult i s it t o pl a n w h e n y o u will u s e t h e m e di c ati o n e a c h ti m e  
1  E xtr e m el y Diffi c ult  
2  V er y Diffi c ult  
3  Diffi c ult  
4  S o m e w h at E a s y  
5   E a s y  
6  V er y E a s y  
7  E xtr e m el y E a s y  
 
 
 


C hri sti n e B. S et h n a, M D, E d M  
v. 1 1. 2 5. 1 3      
 
 
 
P a g e 3 0  of 3 1   
 
 
 
1 1.  H o w c o n v e ni e nt or i n c o n v e ni e nt i s it t o t a k e t h e m e di c ati o n a s i n str u ct e d ?  
1  E xtr e m el y I n c o n v e ni e nt  
2  V er y I n c o n v e ni e nt  
3  I n c o n v e ni e nt 
4  S o m e w h at C o n v e ni e nt  
5   C o n v e ni e nt  
6  V er y C o n v e ni e nt  
7  E xtr e m el y C o n v e ni e nt   
1 2.  O v er all, h o w c o nfi d e nt ar e y o u t h at t a ki n g t hi s m e di c ati o n i s a g o o d t hi n g f or y o u ?  
1  N ot at All C o n v e ni e nt  
2  A Littl e C o n v e ni e nt  
3  S o m e w h at C o n v e ni e nt  
4  V er y C o n v e ni e nt  
5   E xtr e m el y C o n v e ni e nt  
1 3.  H o w c ert ai n ar e y o u t h at t h e g o o d t hi n g s a b o ut y o ur m e di c ati o n o ut w ei g h t h e b a d t hi n g s ?  
1  N ot at All C ert ai n  
2  A Littl e C ert ai n  
3  S o m e w h at C ert ai n  
4  V er y C ert ai n  
5   E xtr e m el y C ert ai n  
1 4.  T a ki n g all t hi n g s i nt o a c c o u nt, h o w s ati sfi e d or di s s ati sfi e d ar e y o u wit h t hi s m e di c ati o n. 
1  E xtr e m el y Di s s ati sfi e d  
2  V er y Di s s ati sfi e d  
3  Di s s ati sfi e d  
4  S o m e w h at S ati sfi e d  
5   S ati sfi e d  
6  V er y S ati sfi e d  
7  E xtr e m el y S ati sfi e d  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Christine B. Sethna, MD, EdM 
v. 11.25.13      
 
 
 
Page 31 of 31 
 
 
 
 
TSQM Scoring Algorithm 
 
TSQM Scale scores computed by adding the items loading on each factor. The lowest 
possible  
score is subtracted from this composite score and divided by the greatest possible score 
minus  
the lowest possible score. This provided a transformed score between 0 and 1 that should be  
multiplied by 100. (see below) [Note that only one item may be missing from each scale before  
the subscale should be considered invalid for that respondent]  
 
EFFECTIVENESS  
([(Item 1 + Item 2 + Item 3) – 3] divided by 18) * 100  
 
If one item is missing  
 
([(Sum(Item 1? + Item 2? + Item 3?)) – 2] divided by 12) * 100  
 
SIDE-EFFECTS  
If Question 4 is answered ‘No’ then score = 100  
Else…  
([Sum(Item 5 to Item 8) – 4] divided by 16) * 100  
 
If one item is missing  
 
([(Sum(Item5? to Item8?)) – 3] divided by 12) * 100  
 
CONVENIENCE  
([Sum(Item 9 to Item 11) – 3] divided by 18) * 100  
 
If one item is missing  
 
([(Sum(Item9? to Item11?)) – 2] divided by 12) * 100  
 
GLOBAL SATISFACTION  
([Sum(Item 12 to Item 14) – 3] divided by 14) * 100  
 
If either Item 12 or 13 is missing  
 
([(Sum(Item12? to Item14?)) – 2] divided by 10) * 100  
 
If Item 14 is missing  
 
([(Sum(Item12 and Item13)) – 2] divided by 8) * 100  
 
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