Pediatric Hypertension and the Renin-Angiotensin SystEm (PHRASE)

Study Overview
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Brief Summary
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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.

Detailed Description
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This longitudinal prospective cohort study is recruiting children and adolescents aged 7-18 years with newly diagnosed primary hypertension over a 2-year period from the Hypertension and Pediatric Nephrology Clinics affiliated with Brenner Children's Hospital at Atrium Health Wake Forest Baptist, which sees over 300 new patients a year, and the Pediatric Nephrology Clinic at Atrium Health Levine Children's Hospital (Hypertension Cohort). Also recruiting healthy control participants aged 7-18 years with normal blood pressure from local primary care practices (Control Cohort). Collecting blood and urine to analyze Ang-(1-7), ACE2, Ang II, ACE, uric acid, and klotho and measuring pediatric-specific outcomes (blood pressure (casual and ambulatory monitoring), indices of heart structure and function on echocardiogram (left ventricular systolic and diastolic function, left ventricular hypertrophy, etc.), kidney function (creatinine, estimated glomerular filtration rate, albuminuria, proteinuria, urine sodium/potassium), autonomic function (heart rate variability, blood pressure variability, baroreflex sensitivity), and vascular function (arterial stiffness, augmentation index)) at baseline and year 1 (Hypertension Cohort and Control Cohort) and year 2 (Hypertension Cohort). The objectives are to investigate if Ang-(1-7), ACE2, Ang II, and ACE identify 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, with these Specific Aims: Aim 1: (1) Determine if plasma Ang-(1-7) or urine Ang-(1-7)/creatinine differ between the Hypertension vs. Control Cohorts and (2) assess if plasma Ang-(1-7) or urine Ang-(1-7)/creatinine mediate the effect of lisinopril-induced blood pressure reduction on the outcomes (change in heart function and structure, autonomic function, vascular function, and kidney function). Hypothesis 1a: Baseline Ang-(1-7) is lower in the Hypertension vs. Control Cohort. Hypothesis 1b: Increased Ang-(1-7) levels over time mediate the effect of lisinopril-induced decreased blood pressure on improved outcomes over 2 years in the Hypertension Cohort. Aim 2: (1) Evaluate if plasma Ang-(1-7) or urine Ang-(1-7)/creatinine predict treatment response in participants in the Hypertension Cohort (change in casual blood pressure, ambulatory blood pressure, heart function/structure, autonomic function, vascular function, and kidney function); (2) compare to plasma renin activity and aldosterone; and (3) employ sensitivity analyses to quantify the impact of unmeasured confounding. Hypothesis 2: Lower baseline Ang-(1-7) predicts greater outcome improvements in the Hypertension Cohort with lower unmeasured confounding and with greater predictive ability compared to plasma renin activity and aldosterone. Aim 3: Determine if plasma Ang-(1-7) or urine Ang-(1-7)/creatinine mediate the effects of uric acid and klotho on the outcomes in participants in the Hypertension Cohort. (1) Apply causal mediation to estimate if plasma Ang-(1-7) mediates the effects of uric acid on the outcomes (change in casual blood pressure, ambulatory blood pressure, heart function/structure, autonomic function, and vascular function). (2) Apply causal mediation to estimate if urine Ang-(1-7)/creatinine mediates the effects of klotho on the outcomes (change in casual blood pressure, ambulatory blood pressure, and kidney function). Hypothesis 3a: Lower plasma Ang-(1-7) mediates the effect of high uric acid on the outcomes in the Hypertension Cohort. Hypothesis 3b: Lower urine Ang-(1-7)/creatinine mediates the effect of low klotho on the outcomes in the Hypertension Cohort. Anticipated results have great potential to impact patient care by establishing Ang-(1-7), ACE2, Ang II, and ACE as biomarkers of treatment response, by establishing how Ang-(1-7) and other components of the renin-angiotensin-aldosterone system change in response to an ACE inhibitor, by indicating which patients would benefit most from ACE inhibitors, by identifying novel etiologies of hypertension centered on alterations to the renin-angiotensin-aldosterone system, uric acid, and klotho, and by leading to novel treatments. Indeed, these have been questions of great interest during the COVID-19 pandemic, as ACE2 is the binding site for Severe acute respiratory syndrome (SARS)-CoV-2. Ultimately, the results from this study will improve patient outcomes by promoting cardiovascular health and preventing cardiovascular disease across the lifecourse.

Official Title
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Pediatric Hypertension and the Renin-Angiotensin SystEm (PHRASE): The Role of Angiotensin-(1-7) in Hypertension and Hypertension-Induced Heart and Kidney Damage

Conditions
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Hypertension, Left Ventricular Hypertrophy, 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

Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: HYPERTENSION COHORT 7-18 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 EXCLUSION CRITERIA: HYPERTENSION COHORT <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 INCLUSION CRITERIA: CONTROL COHORT 7-18 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 EXCLUSION CRITERIA: CONTROL COHORT <7 or >18 years of age at time of enrollment Elevated BP or hypertension, 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 History of elevated BP or hypertension Current use of BP-lowering medications Confounding medical condition (heart or kidney disease, vascular/inflammatory disease, or diabetes) Inability to complete study assessments Non-English/Spanish speakers Current pregnancy Ward of the State

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Hypertension Cohort<br>Participants with newly diagnosed primary hypertension | |
| Control Cohort<br>Healthy participants with normal blood pressure | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline Urine Angiotensin II/Creatinine Ratio | Urine angiotensin II 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 II/Creatinine Ratio | Urine angiotensin II 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-Converting Enzyme 2 Level | Measure angiotensin-converting enzyme 2 content and enzymatic activity in first-morning urine samples using established fluorescence-based methods. 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-Converting Enzyme 2 Level | Measure angiotensin-converting enzyme 2 content and enzymatic activity in first-morning urine samples using established fluorescence-based methods. 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-Converting Enzyme Level | Measure angiotensin-converting enzyme content and enzymatic activity in first-morning urine samples using established fluorescence-based methods. 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-Converting Enzyme Level | Measure angiotensin-converting enzyme content and enzymatic activity in first-morning urine samples using established fluorescence-based methods. 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-Converting Enzyme/Angiotensin-Converting Enzyme 2 Ratio | Measure angiotensin-converting enzyme and angiotensin-converting enzyme 2 content and enzymatic activity in first-morning urine samples using established fluorescence-based methods. 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-Converting Enzyme/Angiotensin-Converting Enzyme 2 Ratio | Measure angiotensin-converting enzyme and angiotensin-converting enzyme 2 content and enzymatic activity in first-morning urine samples using established fluorescence-based methods. 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 Level | Plasma angiotensin II 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 II Level | Plasma angiotensin II 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 Serum Angiotensin-Converting Enzyme 2 Level | Measure angiotensin-converting enzyme 2 content and enzymatic activity in serum samples using established fluorescence-based methods. 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 Angiotensin-Converting Enzyme 2 Level | Measure angiotensin-converting enzyme 2 content and enzymatic activity in serum samples using established fluorescence-based methods. 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 Angiotensin-Converting Enzyme Level | Measure angiotensin-converting enzyme content and enzymatic activity in serum samples using established fluorescence-based methods. 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 Angiotensin-Converting Enzyme Level | Measure angiotensin-converting enzyme content and enzymatic activity in serum samples using established fluorescence-based methods. 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 Angiotensin-Converting Enzyme/Angiotensin-Converting Enzyme 2 Ratio | Measure angiotensin-converting enzyme and angiotensin-converting enzyme 2 content and enzymatic activity in serum samples using established fluorescence-based methods. 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 Angiotensin-Converting Enzyme/Angiotensin-Converting Enzyme 2 Ratio | Measure angiotensin-converting enzyme and angiotensin-converting enzyme 2 content and enzymatic activity in serum samples using established fluorescence-based methods. 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 Hyperuricemia | Serum uric acid quantified by a validated uricase assay. Hyperuricemia defined as ≥8.0 mg/dl, reported with relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline | 
| Change in Hyperuricemia | Serum uric acid quantified by a validated uricase assay. Hyperuricemia defined as ≥8.0 mg/dl, reported with relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline through 2 years | 
| Baseline Manual Blood Pressure Classification | Based on average of 3 manual blood pressure (BP) measurements per age-specific national guidelines and age, sex, and height-based BP percentile. Categorized as a 4-level ordinal variable: (1) normal, <90th percentile or <120/80 mmHg; (2) elevated BP, ≥90th to <95th percentile or 120-129/<80 mmHg; (3) stage 1 hypertension, ≥95th to <95th percentile + 12 mmHg or 130-139/80-89 mmHg; (4) stage 2 hypertension, ≥95th percentile + 12 mmHg or ≥140/90 mmHg). Report relative measures (e.g., odds ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline | 
| Change in Manual Blood Pressure Classification | Based on average of 3 manual blood pressure (BP) measurements per age-specific national guidelines and age, sex, and height-based BP percentile. Categorized as a 4-level ordinal variable: (1) normal, <90th percentile or <120/80 mmHg; (2) elevated BP, ≥90th to <95th percentile or 120-129/<80 mmHg; (3) stage 1 hypertension, ≥95th to <95th percentile + 12 mmHg or 130-139/80-89 mmHg; (4) stage 2 hypertension, ≥95th percentile + 12 mmHg or ≥140/90 mmHg). Report relative measures (e.g., odds ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline through 2 years | 
| Baseline Ambulatory Systolic Blood Pressure 24-Hour Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of systolic BP readings over a 24-hour period that are ≥95th percentile for height per national guidelines. 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 Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of systolic BP readings over a 24-hour period that are ≥95th percentile for height per national guidelines. 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 Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of diastolic BP readings over a 24-hour period that are ≥95th percentile for height per national guidelines. 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 Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of diastolic BP readings over a 24-hour period that are ≥95th percentile for height per national guidelines. 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 Systolic Blood Pressure 24-Hour Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP over 24-hour period divided by the 95th percentile for sex and height, per national guidelines. 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 Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP over 24-hour period divided by the 95th percentile for sex and height, per national guidelines. 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 Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP over 24-hour period divided by the 95th percentile for sex and height, per national guidelines. 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 Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP over 24-hour period divided by the 95th percentile for sex and height, per national guidelines. 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 Systolic Blood Pressure Awake Mean | Measured via ambulatory blood pressure (BP) monitoring. Average systolic BP while awake. 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 Awake Mean | Measured via ambulatory blood pressure (BP) monitoring. Average systolic BP while awake. 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 Awake Mean | Measured via ambulatory blood pressure (BP) monitoring. Average diastolic BP while awake. 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 Awake Mean | Measured via ambulatory blood pressure (BP) monitoring. Average diastolic BP while awake. 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 Systolic Blood Pressure Awake Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of systolic BP readings while awake that are ≥95th percentile for height per national guidelines. 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 Awake Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of systolic BP readings while awake that are ≥95th percentile for height per national guidelines. 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 Awake Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of diastolic BP readings while awake that are ≥95th percentile for height per national guidelines. 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 Awake Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of diastolic BP readings while awake that are ≥95th percentile for height per national guidelines. 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 Systolic Blood Pressure Awake Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP while awake divided by the 95th percentile for sex and height, per national guidelines. 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 Awake Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP while awake divided by the 95th percentile for sex and height, per national guidelines. 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 Awake Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP while awake divided by the 95th percentile for sex and height, per national guidelines. 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 Awake Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP while awake divided by the 95th percentile for sex and height, per national guidelines. 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 Systolic Blood Pressure Asleep Mean | Measured via ambulatory blood pressure (BP) monitoring. Average systolic BP while asleep. 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 Asleep Mean | Measured via ambulatory blood pressure (BP) monitoring. Average systolic BP while asleep. 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 Asleep Mean | Measured via ambulatory blood pressure (BP) monitoring. Average diastolic BP while asleep. 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 Asleep Mean | Measured via ambulatory blood pressure (BP) monitoring. Average diastolic BP while asleep. 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 Systolic Blood Pressure Asleep Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of systolic BP readings while asleep that are ≥95th percentile for height per national guidelines. 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 Asleep Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of systolic BP readings while asleep that are ≥95th percentile for height per national guidelines. 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 Asleep Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of diastolic BP readings while asleep that are ≥95th percentile for height per national guidelines. 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 Asleep Load | Measured via ambulatory blood pressure (BP) monitoring. Proportion of diastolic BP readings while asleep that are ≥95th percentile for height per national guidelines. 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 Systolic Blood Pressure Asleep Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP while asleep divided by the 95th percentile for sex and height, per national guidelines. 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 Asleep Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP while asleep divided by the 95th percentile for sex and height, per national guidelines. 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 Asleep Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP while asleep divided by the 95th percentile for sex and height, per national guidelines. 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 Asleep Index | Measured via ambulatory blood pressure (BP) monitoring. Defined as mean BP while asleep divided by the 95th percentile for sex and height, per national guidelines. 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 Systolic Blood Pressure Nocturnal Dipping | Measured via ambulatory blood pressure (BP) monitoring. Proportion calculated as ([ mean awake - mean asleep systolic BP ] / [mean awake systolic BP ]) x 100, per national guidelines. 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 Nocturnal Dipping | Measured via ambulatory blood pressure (BP) monitoring. Proportion calculated as ([ mean awake - mean asleep systolic BP ] / [mean awake systolic BP ]) x 100, per national guidelines. 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 Nocturnal Dipping | Measured via ambulatory blood pressure (BP) monitoring. Proportion calculated as ([ mean awake - mean asleep diastolic BP ] / [mean awake diastolic BP ]) x 100, per national guidelines. 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 Nocturnal Dipping | Measured via ambulatory blood pressure (BP) monitoring. Proportion calculated as ([ mean awake - mean asleep diastolic BP ] / [mean awake diastolic BP ]) x 100, per national guidelines. 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 Inadequate Nocturnal Dipping | Measured via ambulatory blood pressure (BP) monitoring. Binary variable defined as the proportion of BP nocturnal dipping <10 percent, per national guidelines. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline | 
| Change in Ambulatory Inadequate Nocturnal Dipping | Measured via ambulatory blo od pressure (BP) monitoring. Binary variable defined as the proportion of BP nocturnal dipping <10 percent, 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 Ambulatory Hypertension | Measured via ambulatory blood pressure (BP) monitoring. Binary variable defined as mean BP ≥95 percentile for height AND load ≥25 percent for any time period, per national guidelines. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline | 
| Change in Ambulatory Hypertension | Measured via ambulatory blood pressure (BP) monitoring. Binary variable defined as mean BP ≥95 percentile for height AND load ≥25 percent for any time period, 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 Relative Left Ventricular Wall Thickness | Measured via echocardiogram. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval). | Baseline | 
| Change in Relative Left Ventricular Wall Thickness | Measured via echocardiogram. 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 Elevated Relative Left Ventricular Wall Thickness | Measured via echocardiogram. Binary variable defined as >0.42, per national guidelines. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline | 
| Change in Elevated Relative Left Ventricular Wall Thickness | Measured via echocardiogram. Binary variable defined as >0.42, 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 Left Ventricular Geometry Classification | Measured via echocardiogram. 4-level ordinal variable defined as (1) normal (normal left ventricular mass index (LVMI) and normal relative left ventricular wall thickness (RLVWT)); 2) concentric remodeling (normal LVMI and high RLVWT); 3) eccentric hypertrophy (high LVMI and normal RLVWT); 4) concentric hypertrophy (high LVMI and high RLVWT), per national guidelines. Report relative measures (e.g., risk ratio, odds ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline | 
| Change in Left Ventricular Geometry Classification | Measured via echocardiogram. 4-level ordinal variable defined as (1) normal (normal left ventricular mass index (LVMI) and normal relative left ventricular wall thickness (RLVWT)); 2) concentric remodeling (normal LVMI and high RLVWT); 3) eccentric hypertrophy (high LVMI and normal RLVWT); 4) concentric hypertrophy (high LVMI and high RLVWT), per national guidelines. Report relative measures (e.g., risk ratio, odds ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline through 2 years | 
| Baseline Left Ventricular Systolic Function | Measured via echocardiogram. Report measures of central tendency (e.g., mean, median) with dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval). | Baseline | 
| Change in Left Ventricular Systolic Function | Measured via echocardiogram. Report measures of central tendency (e.g., mean, median) with dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval). | Baseline through 2 years | 
| Baseline Left Ventricular Diastolic Function | Measured via echocardiogram. Report measures of central tendency (e.g., mean, median) with dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval). | Baseline | 
| Change in Left Ventricular Diastolic Function | Measured via echocardiogram. Report measures of central tendency (e.g., mean, median) with dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval). | Baseline through 2 years | 
| Baseline Left Atrial Size | Measured via echocardiogram. Report measures of central tendency (e.g., mean, median) with dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval). | Baseline | 
| Change in Left Atrial Size | Measured via echocardiogram. Report measures of central tendency (e.g., mean, median) with dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval). | Baseline through 2 years | 
| Baseline Left Atrial Enlargement | Measured via echocardiogram. Binary variable defined ≥29 ml/m^2, per national guidelines. Report relative measures (e.g., risk ratio) with measures of dispersion (e.g., 95 percent confidence interval). | Baseline | 
| Change in Left Atrial Enlargement | Measured via echocardiogram. Binary variable defined ≥29 ml/m^2, per national guidelines. Report relative measures (e.g., risk ratio) with measures of dispersion (e.g., 95 percent confidence interval). | Baseline through 2 years | 
| Baseline Urine Protein/Creatinine Ratio | Measured in fasting first-morning urine samples. Protein 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 Protein/Creatinine Ratio | Measured in fasting first-morning urine samples. Protein 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 Proteinuria | Measured in fasting first-morning urine samples. Protein analyzed in the Clinical Laboratory and creatinine analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry. Binary variable defined as a protein/creatinine ratio >0.2 mg/mg. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline | 
| Change in Proteinuria | Measured in fasting first-morning urine samples. Protein analyzed in the Clinical Laboratory and creatinine analyzed via a modified Jaffe assay traceable to isotope dilution mass spectrometry. Binary variable defined as a protein/creatinine ratio >0.2 mg/mg. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline through 2 years | 
| Baseline Serum Cystatin C Level | Measured in the serum and 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 Serum Cystatin C Level | Measured in the serum and 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 Elevated 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. Binary variable defined as urine sodium/creatinine ratio >1 mmol/mg. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline | 
| Change in Elevated 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. Binary variable defined as urine sodium/creatinine ratio >1 mmol/mg. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline through 2 years | 
| Baseline Elevated Urine Sodium/Potassium Ratio | Measured sodium and potassium in fasting, first-morning urine samples and analyzed in the Clinical Laboratory. Binary variable defined as urine sodium/potassium ratio >1 mmol/mmol. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline | 
| Change in Elevated Urine Sodium/Potassium Ratio | Measured sodium and potassium in fasting, first-morning urine samples and analyzed in the Clinical Laboratory. Binary variable defined as urine sodium/potassium ratio >1 mmol/mmol. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Baseline through 2 years | 
| Low 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). Defined as <90 ml/min/1.73 m^2. Report relative measures (e.g., risk ratio) and measures of dispersion (e.g., 95 percent confidence interval). | Through study completion up to 2 years | 
| Baseline Urine Uric Acid/Creatinine Ratio | Measured in fasting first-morning urine samples. Uric acid quantified by well-validated uricase assay and creatinine via 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 percentile confidence interval). | Baseline | 
| Change in Urine Uric Acid/Creatinine Ratio | Measured in fasting first-morning urine samples. Uric acid quantified by well-validated uricase assay and creatinine via 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 percentile confidence interval). | Baseline through 2 years | 
| Baseline Urine Uric Acid Per Glomerular Filtration Rate | Measured in fasting first-morning urine and serum samples. Uric acid quantified by well-validated uricase assay and creatinine via modified Jaffe assay traceable to isotope dilution mass spectrometry. Calculated as [urine uric acid x serum creatinine] / [urine creatinine]. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percentile confidence interval). | Baseline | 
| Change in Urine Uric Acid Per Glomerular Filtration Rate | Measured in fasting first-morning urine and serum samples. Uric acid quantified by well-validated uricase assay and creatinine via modified Jaffe assay traceable to isotope dilution mass spectrometry. Calculated as [urine uric acid x serum creatinine] / [urine creatinine]. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percentile confidence interval). | Baseline through 2 years | 
| Baseline Fractional Excretion of Urine Uric Acid | Measured in fasting first-morning urine and serum samples. Uric acid quantified by well-validated uricase assay and creatinine via modified Jaffe assay traceable to isotope dilution mass spectrometry. Calculated as [urine uric acid x serum creatinine] / [urine creatinine x serum uric acid]. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percentile confidence interval). | Baseline | 
| Change in Fractional Excretion of Urine Uric Acid | Measured in fasting first-morning urine and serum samples. Uric acid quantified by well-validated uricase assay and creatinine via modified Jaffe assay traceable to isotope dilution mass spectrometry. Calculated as [urine uric acid x serum creatinine] / [urine creatinine x serum uric acid]. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percentile confidence interval). | Baseline through 2 years | 
| Baseline Serum Fibroblast Growth Factor 23 Level | Quantified in serum using a validated ELISA. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percentile confidence interval). | Baseline | 
| Change in Serum Fibroblast Growth Factor 23 Level | Quantified in serum using a validated ELISA. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percentile confidence interval). | Baseline through 2 years | 
| Baseline Urine Fibroblast Growth Factor 23 Level | Quantified in first-morning urine using a validated ELISA, 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 percentile confidence interval). | Baseline | 
| Change in Urine Fibroblast Growth Factor 23 Level | Quantified in first-morning urine using a validated ELISA, 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 percentile confidence interval). | Baseline through 2 years | 
| Baseline Obesity | Height and weight measured in triplicate and average value recorded. Body mass index calculated and obesity defined per national guidelines as body mass index ≥95th percentile for age and sex or ≥30.0 kg/m^2. Report relative measures (e.g., risk ratio, odds ratio) with measures of dispersion (e.g., 95 percentile confidence interval). | Baseline | 
| Baseline Dietary Sodium Intake | Estimated dietary sodium intake from self-administered food frequency questionnaire. Report measures of central tendency (e.g., mean, median) with dispersion (e.g., standard deviation, interquartile range, 95 percentile confidence interval) | Baseline | 
| Baseline Disordered Eating | 5-item SCOFF questionnaire. Positive if participant answers yes to 2 or more of the 5 questions. Report relative measures (e.g., risk ratio) with measures of dispersion (e.g., 95 percentile confidence interval). | Baseline | 
| Change in Disordered Eating | 5-item SCOFF questionnaire. Positive if participant answers yes to 2 or more of the 5 questions. Report relative measures (e.g., risk ratio) with measures of dispersion (e.g., 95 percentile confidence interval). | Baseline through 2 years | 
| Baseline Financial Stress | Assessed with a validated questionnaire consisting of one question measured on a 5-point ordinal scale: 1) not hard at all; 2) not very hard; 3) somewhat hard; 4) hard; 5) very hard. Positive if participant reports somewhat hard, hard, or very hard. Report relative measures (e.g., risk ratio, odds ratio) with measures of dispersion (e.g., 95 percentile confidence interval). | Baseline | 
| Change in Financial Stress | Assessed with a validated questionnaire consisting of one question measured on a 5-point ordinal scale: 1) not hard at all; 2) not very hard; 3) somewhat hard; 4) hard; 5) very hard. Positive if participant reports somewhat hard, hard, or very hard. Report relative measures (e.g., risk ratio, odds ratio) with measures of dispersion (e.g., 95 percentile confidence interval). | Baseline through 2 years | 
| Baseline Food Insecurity | Assessed with a validated questionnaire consisting of two questions both scored on a 3-point ordinal scale: 1) never true; 2) sometimes true; 3) often true. Positive if participant reports somewhat true or often true to either question. Report relative measures (e.g., risk ratio) with measures of dispersion (e.g., 95 percentile confidence interval). | Baseline | 
| Change in Food Insecurity | Assessed with a validated questionnaire consisting of two questions both scored on a 3-point ordinal scale: 1) never true; 2) sometimes true; 3) often true. Positive if participant reports somewhat true or often true to either question. Report relative measures (e.g., risk ratio) with measures of dispersion (e.g., 95 percentile confidence interval). | Baseline through 2 years | 
| Baseline Transportation Stress | Assessed with a validated questionnaire consisting of two binary questions. Positive if participant reports yes to either question. Report relative measures (e.g., risk ratio) with measures of dispersion (e.g., 95 percentile confidence interval). | Baseline | 
| Change in Transportation Stress | Assessed with a validated questionnaire consisting of two binary questions. Positive if participant reports yes to either question. Report relative measures (e.g., risk ratio) with measures of dispersion (e.g., 95 percentile confidence interval). | Baseline through 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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