Pediatric Hypertension and the Renin-Angiotensin SystEm (PHRASE)

NCT04752293 | Recruiting

• 2 other identifiers: IRB000686791K23HL148394-01A1
• Study Type: observational
• Target: 125
• Locations: 1 country
• Sites: 1

Brief Summary

Studying the causal roles of components of the renin-angiotensin-aldosterone system (including angiotensin-(1-7) (Ang-(1-7)), angiotensin-converting enzyme 2 (ACE2), Ang II, and ACE), uric acid, and klotho in pediatric hypertension and related target organ injury, including in the heart, kidneys, vasculature, and brain. Recruiting children with a new hypertension diagnosis over a 2-year period from the Hypertension and Pediatric Nephrology Clinics affiliated with Brenner Children's Hospital at Atrium Health Wake Forest Baptist and Atrium Health Levine Children's Hospital. Healthy control participants will be recruited from local general primary care practices. Collecting blood and urine samples to analyze components of the renin-angiotensin-aldosterone system (Ang-(1-7), ACE2, Ang II, ACE), uric acid, and klotho, and measuring blood pressure, heart structure and function, autonomic function, vascular function, and kidney function at baseline, year 1, and year 2. Objectives are to investigate phenotypic and treatment response variability and to causally infer if Ang-(1-7), ACE2, Ang II, ACE, uric acid, and klotho contribute to target organ injury due to hypertension.

Conditions

Left Ventricular Dysfunction; Left Atrial Dilatation; Left Ventricular Diastolic Dysfunction; Kidney Diseases; Kidney Injury; Kidney Dysfunction; Sodium Urine High; Blood Pressure Disorders; Uric Acid Retention; Angiotensin Hypertension; Autonomic Dysfunction; Autonomic Imbalance; Pediatric Kidney Disease; Pediatric Obesity; Proteinuria; Albuminuria; Hypertension; Left Ventricular Hypertrophy

Keywords

High Blood Pressure; Elevated Blood Pressure; Hypertension; Pediatric Hypertension; Target Organ Damage; Left Ventricular Hypertrophy; Albuminuria; Uric Acid; Klotho; Fibroblast Growth Factor 23; Renin-Angiotensin-Aldosterone System; Renin-Angiotensin System; Angiotensin-(1-7); Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme; Causal Inference; Causal Mediation Analysis; Sensitivity Analysis; Predictive Analysis; Left Ventricular Diastolic Dysfunction; Kidney Injury; Heart Rate Variability; Sodium; Pediatric Obesity; Lifecourse; Kidney Function; Ambulatory Blood Pressure Monitoring; Echocardiogram

Outcome Measures

Primary Outcomes (48)

• Baseline Urine Angiotensin-(1-7)/Creatinine Ratio

  Urine angiotensin-(1-7) quantified by a highly developed radioimmunoassay well validated against mass spectrometry and standardized to urine creatinine, quantified by a modified Jaffe assay traceable to isotope dilution mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Urine Angiotensin-(1-7)/Creatinine Ratio

  Urine angiotensin-(1-7) quantified by a highly developed radioimmunoassay well validated against mass spectrometry and standardized to urine creatinine, quantified by a modified Jaffe assay traceable to isotope dilution mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Urine Angiotensin II/Angiotensin-(1-7) Ratio

  Urine angiotensin II and angiotensin-(1-7) quantified by highly developed radioimmunoassays well validated against mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Urine Angiotensin II/Angiotensin-(1-7) Ratio

  Urine angiotensin II and angiotensin-(1-7) quantified by highly developed radioimmunoassays well validated against mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Plasma Angiotensin-(1-7) Level

  Plasma angiotensin-(1-7) quantified by a highly developed radioimmunoassay well validated against mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Plasma Angiotensin-(1-7) Level

  Plasma angiotensin-(1-7) quantified by a highly developed radioimmunoassay well validated against mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Plasma Angiotensin II/Angiotensin-(1-7) Ratio

  Plasma angiotensin II and angiotensin-(1-7) quantified by highly developed radioimmunoassays well validated against mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Plasma Angiotensin II/Angiotensin-(1-7) Ratio

  Plasma angiotensin II and angiotensin-(1-7) quantified by highly developed radioimmunoassays well validated against mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Serum Uric Acid Level

  Serum uric acid quantified by a validated uricase assay. Report as a continuous variable with measures of central tendency (e.g., mean) and dispersion (e.g., standard deviation, 95 percent confidence interval).

  Baseline

• Change in Serum Uric Acid Level

  Serum uric acid quantified by a validated uricase assay. Report as a continuous variable with measures of central tendency (e.g., mean) and dispersion (e.g., standard deviation, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Plasma Klotho Level

  Plasma α-klotho quantified by a well-validated ELISA. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Plasma Klotho Level

  Plasma α-klotho quantified by a well-validated ELISA. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Urine Klotho/Creatinine Ratio

  Urine α-klotho quantified by a well-validated ELISA and standardized to urine creatinine, quantified by a modified Jaffe assay traceable to isotope dilution mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Urine Klotho/Creatinine Ratio

  Urine α-klotho quantified by a well-validated ELISA and standardized to urine creatinine, quantified by a modified Jaffe assay traceable to isotope dilution mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Manual Systolic Blood Pressure

  Average of 3 manual measurements per national guidelines. Report measures of central tendency (e.g., mean) and dispersion (e.g., standard deviation, 95 percent confidence interval).

  Baseline

• Change in Manual Systolic Blood Pressure

  Average of 3 manual measurements per national guidelines. Report measures of central tendency (e.g., mean) and dispersion (e.g., standard deviation, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Manual Diastolic Blood Pressure

  Average of 3 manual measurements per national guidelines. Report measures of central tendency (e.g., mean) and dispersion (e.g., standard deviation, 95 percent confidence interval).

  Baseline

• Change in Manual Diastolic Blood Pressure

  Average of 3 manual measurements per national guidelines. Report measures of central tendency (e.g., mean) and dispersion (e.g., standard deviation, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Manual Systolic Blood Pressure Z-score

  Average of 3 manual measurements per national guidelines with calculated z-score referenced to normative values by age, sex, and height. Report measures of central tendency (e.g., mean) and dispersion (e.g., standard deviation, 95 percent confidence interval).

  Baseline

• Change in Manual Systolic Blood Pressure Z-score

  Average of 3 manual measurements per national guidelines with calculated z-score referenced to normative values by age, sex, and height. Report measures of central tendency (e.g., mean) and dispersion (e.g., standard deviation, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Manual Diastolic Blood Pressure Z-score

  Average of 3 manual measurements per national guidelines with calculated z-score referenced to normative values by age, sex, and height. Report measures of central tendency (e.g., mean) and dispersion (e.g., standard deviation, 95 percent confidence interval).

  Baseline

• Change in Manual Diastolic Blood Pressure Z-score

  Average of 3 manual measurements per national guidelines with calculated z-score referenced to normative values by age, sex, and height. Report measures of central tendency (e.g., mean) and dispersion (e.g., standard deviation, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Ambulatory Systolic Blood Pressure 24-Hour Mean

  Measured via ambulatory blood pressure (BP) monitoring. Average systolic BP over a 24-hour period. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Ambulatory Systolic Blood Pressure 24-Hour Mean

  Measured via ambulatory blood pressure (BP) monitoring. Average systolic BP over a 24-hour period. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Ambulatory Diastolic Blood Pressure 24-Hour Mean

  Measured via ambulatory blood pressure (BP) monitoring. Average diastolic BP over a 24-hour period. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Ambulatory Diastolic Blood Pressure 24-Hour Mean

  Measured via ambulatory blood pressure (BP) monitoring. Average diastolic BP over a 24-hour period. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Left Ventricular Mass Height Index

  Left ventricular mass measured via echocardiogram and indexed to height as g/m\^2.7. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Left Ventricular Mass Height Index

  Left ventricular mass measured via echocardiogram and indexed to height as g/m\^2.7. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Left Ventricular Mass Body Surface Area Index

  Left ventricular mass measured via echocardiogram and indexed to body surface area (BSA) as g/BSA. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Left Ventricular Mass Body Surface Area Index

  Left ventricular mass measured via echocardiogram and indexed to body surface area (BSA) as g/BSA. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Left Ventricular Hypertrophy

  Measured via echocardiogram. Binary variable defined as left ventricular mass index (LVMI) \>51 g/m\^2.7 (all participants), \>115 g/body surface area (BSA) (males), or \>95 g/BSA (females), per national guidelines. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval).

  Baseline

• Change in Left Ventricular Hypertrophy

  Measured via echocardiogram. Binary variable defined as left ventricular mass index (LVMI) \>51 g/m\^2.7 (all participants), \>115 g/body surface area (BSA) (males), or \>95 g/BSA (females), per national guidelines. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval).

  Baseline through 2 years

• Baseline Urine Albumin/Creatinine Ratio

  Measured in fasting first-morning urine samples. Albumin analyzed in the Clinical Laboratory and creatinine analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Urine Albumin/Creatinine Ratio

  Measured in fasting first-morning urine samples. Albumin analyzed in the Clinical Laboratory and creatinine analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Albuminuria

  Measured in fasting first-morning urine samples. Albumin analyzed in the Clinical Laboratory and creatinine analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry. Binary variable defined as an albumin/creatinine ratio \>30 mg/g. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval).

  Baseline

• Change in Albuminuria

  Measured in fasting first-morning urine samples. Albumin analyzed in the Clinical Laboratory and creatinine analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry. Binary variable defined as an albumin/creatinine ratio \>30 mg/g. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval).

  Baseline through 2 years

• Baseline Serum Creatinine Level

  Measured in the serum and analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Serum Creatinine Level

  Measured in the serum and analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Estimated Glomerular Filtration Rate

  Estimated using validated, non-race-based, age-appropriate equations (modified Schwartz equation and height- and age-based full-age-spectrum equations with serum creatinine (analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry) and serum cystatin C (analyzed via the Clinical Laboratory). Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Estimated Glomerular Filtration Rate

  Estimated using validated, non-race-based, age-appropriate equations (modified Schwartz equation and height- and age-based full-age-spectrum equations with serum creatinine (analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry) and serum cystatin C (analyzed via the Clinical Laboratory). Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Urine Sodium Concentration

  Measured sodium and creatinine in fasting, first-morning urine samples. Sodium analyzed in the Clinical Laboratory, and creatinine analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Urine Sodium Concentration

  Measured sodium and creatinine in fasting, first-morning urine samples. Sodium analyzed in the Clinical Laboratory, and creatinine analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Urine Sodium/Potassium Ratio

  Measured sodium and potassium in fasting, first-morning urine samples and analyzed in the Clinical Laboratory. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Urine Sodium/Potassium Ratio

  Measured sodium and potassium in fasting, first-morning urine samples and analyzed in the Clinical Laboratory. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Plasma Renin Activity

  Measured in the plasma with a well-validated assay. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Plasma Renin Activity

  Measured in the plasma with a well-validated assay. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

• Baseline Serum Aldosterone Level

  Measured in the serum with a well-validated assay. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline

• Change in Serum Aldosterone Level

  Measured in the serum with a well-validated assay. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).

  Baseline through 2 years

Secondary Outcomes (105)

• Baseline Urine Angiotensin II/Creatinine Ratio

  Baseline

• Change in Urine Angiotensin II/Creatinine Ratio

  Baseline through 2 years

• Baseline Urine Angiotensin-Converting Enzyme 2 Level

  Baseline

• Change in Urine Angiotensin-Converting Enzyme 2 Level

  Baseline through 2 years

• Baseline Urine Angiotensin-Converting Enzyme Level

  Baseline

Study Arms (2)

Hypertension Cohort

Participants with newly diagnosed primary hypertension

Control Cohort

Healthy participants with normal blood pressure

Eligibility Criteria

• Age: 7 Years - 18 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Hypertension Cohort: Participants will be recruited from among new patients referred to the Hypertension Clinic at Brenner Children's Hospital. Patient population at this clinic, which sees over 300 new patients/year, is 55% White, 25% Black, 16% Hispanic, and 62% male. Goal is to enroll 100 participants over a 2-year period. Control Cohort: Participants for this cohort will be recruited from among healthy patients seen at local pediatrics practices. Goal is to enroll 25 participants over a 2-year period, frequency-matched to the Hypertension Cohort on age, self-identified race, and sex.

You may qualify if:

• years of age at time of enrollment
• Confirmed new diagnosis of primary hypertension: no identifiable secondary cause, referred to hypertension or nephrology clinic
• Age \<13 years: BP ≥95th %ile or ≥130/80 mmHg (whichever is lower)
• Age ≥13 years: BP ≥130/80 mmHg
• Participants and their caregivers must be willing and able to commit to completing the study assessments

You may not qualify if:

• \<7 years or \>18 years of age at time of enrollment
• BP confirmed as normal or in the elevated BP category based on ≥3 prior office BP measurements on separate days;
• Age \<13 years: BP \<95th %ile or \<130/80 mmHg (whichever is lower)
• Age ≥13 years: BP \<130/80 mmHg
• A confirmed secondary cause of hypertension
• Confounding medical condition (heart or kidney disease \[except hypertension-associated heart changes on echocardiogram or albuminuria\], vascular/inflammatory disease, or diabetes)
• Inability to complete study assessments
• Non-English/Spanish speakers
• Current pregnancy
• Ward of the State
• years of age at time of enrollment
• Normal BP based on ≥3 prior office BP measurements on separate days;
• Age \<13 years: BP \<90th %ile or \<120/80 mmHg (whichever is lower)
• Age ≥13 years: BP \<120/80 mmHg
• Participants and their caregivers must be willing and able to commit to completing the study assessments

Sponsors & Collaborators

• Wake Forest University Health Sciences: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Wake Forest Health Sciences

Winston-Salem, North Carolina, 27157, United States

RECRUITING

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Biospecimen

Retention: SAMPLES WITH DNA

Collecting blood, urine, and saliva samples from participants in the Hypertension Cohort and the Control Cohort. Banking sub-samples of blood, urine, and saliva for future analysis, including for omics-based research (genomics, proteomics, etc.)

MeSH Terms

Conditions

Hypertension; Hypertrophy, Left Ventricular; Ventricular Dysfunction, Left; Kidney Diseases; Hyperuricemia; Primary Dysautonomias; Pediatric Obesity; Proteinuria; Albuminuria

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Cardiomegaly; Heart Diseases; Hypertrophy; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Ventricular Dysfunction; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Pathologic Processes; Autonomic Nervous System Diseases; Nervous System Diseases; Obesity; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Urination Disorders; Urological Manifestations

Study Officials

• Andrew M South, MD, MS

  Wake Forest Health Sciences

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andrew M South, MD, MS

CONTACT

336.716.9640; asouth@wakehealth.edu

Caroline B Lucas

CONTACT

336.713.8038; cblucas@wakehealth.edu

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 21, 2021
• First Posted: February 12, 2021
• Study Start: May 19, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: December 11, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: Beginning 12 months and ending six years following article publication.
• Access Criteria: Data will be shared with investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose and who provide a methodologically sound proposal. Data will be shared for meta-analysis of individual participant data and/or to achieve aims in the approved proposal.

Locations

US (1)