Reduction of Night-time Blood Pressure in Pediatric Renal Transplant Recipients
Condition: Hypertension Secondary to Kidney Transplant
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): New Medication: Enalapril, Isradipine, Propranolol
Intervention type(s): Drug
Intervention description(s): 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
Other intervention name(s): Vasotec, DynaCirc, Inderal
Intervention MeSH terms: Propranolol; Enalapril; Isradipine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Nocturnal hypertension; Pediatric; Renal Transplant; Pulse Wave Velocity; Echocardiogram; Pediatric Renal Transplant Recipient