Pediatric Hypertension and the Renin-Angiotensin SystEm (PHRASE)
Study Details
Study Description
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.
Detailed Description
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Hypertension Cohort Participants with newly diagnosed primary hypertension |
|
Control Cohort Healthy participants with normal blood pressure |
Outcome Measures
Primary Outcome Measures
- Baseline Urine Angiotensin-(1-7)/Creatinine Ratio [Baseline]
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).
- Change in Urine Angiotensin-(1-7)/Creatinine Ratio [Baseline through 2 years]
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 Urine Angiotensin II/Angiotensin-(1-7) Ratio [Baseline]
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).
- Change in Urine Angiotensin II/Angiotensin-(1-7) Ratio [Baseline through 2 years]
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 Plasma Angiotensin-(1-7) Level [Baseline]
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).
- Change in Plasma Angiotensin-(1-7) Level [Baseline through 2 years]
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 Plasma Angiotensin II/Angiotensin-(1-7) Ratio [Baseline]
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).
- Change in Plasma Angiotensin II/Angiotensin-(1-7) Ratio [Baseline through 2 years]
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 Serum Uric Acid Level [Baseline]
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).
- Change in Serum Uric Acid Level [Baseline through 2 years]
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 Plasma Klotho Level [Baseline]
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).
- Change in Plasma Klotho Level [Baseline through 2 years]
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 Urine Klotho/Creatinine Ratio [Baseline]
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).
- Change in Urine Klotho/Creatinine Ratio [Baseline through 2 years]
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 Manual Systolic Blood Pressure [Baseline]
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).
- Change in Manual Systolic Blood Pressure [Baseline through 2 years]
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 Manual Diastolic Blood Pressure [Baseline]
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).
- Change in Manual Diastolic Blood Pressure [Baseline through 2 years]
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 Manual Systolic Blood Pressure Z-score [Baseline]
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).
- Change in Manual Systolic Blood Pressure Z-score [Baseline through 2 years]
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 Manual Diastolic Blood Pressure Z-score [Baseline]
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).
- Change in Manual Diastolic Blood Pressure Z-score [Baseline through 2 years]
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 Ambulatory Systolic Blood Pressure 24-Hour Mean [Baseline]
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).
- Change in Ambulatory Systolic Blood Pressure 24-Hour Mean [Baseline through 2 years]
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 Ambulatory Diastolic Blood Pressure 24-Hour Mean [Baseline]
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).
- Change in Ambulatory Diastolic Blood Pressure 24-Hour Mean [Baseline through 2 years]
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 Left Ventricular Mass Height Index [Baseline]
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).
- Change in Left Ventricular Mass Height Index [Baseline through 2 years]
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 Left Ventricular Mass Body Surface Area Index [Baseline]
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).
- Change in Left Ventricular Mass Body Surface Area Index [Baseline through 2 years]
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 Left Ventricular Hypertrophy [Baseline]
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).
- Change in Left Ventricular Hypertrophy [Baseline through 2 years]
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 Baroreflex Sensitivity [Baseline]
Measured via the CNAP™ Monitor 500i. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Change in Baroreflex Sensitivity [Baseline through 2 years]
Measured via the CNAP™ Monitor 500i. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Baseline Heart Rate Variability [Baseline]
Measured via the CNAP™ Monitor 500i. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Change in Heart Rate Variability [Baseline through 2 years]
Measured via the CNAP™ Monitor 500i. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Baseline Pulse Wave Velocity [Baseline]
Carotid-femoral pulse wave velocity measured with the SphygmoCor XCEL device. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Change in Pulse Wave Velocity [Baseline through 2 years]
Carotid-femoral pulse wave velocity measured with the SphygmoCor XCEL device. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Baseline Augmentation Index [Baseline]
Measured with the SphygmoCor XCEL device. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Change in Augmentation Index [Baseline through 2 years]
Measured with the SphygmoCor XCEL device. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Baseline Urine Albumin/Creatinine Ratio [Baseline]
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).
- Change in Urine Albumin/Creatinine Ratio [Baseline through 2 years]
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 Albuminuria [Baseline]
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).
- Change in Albuminuria [Baseline through 2 years]
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 Serum Creatinine Level [Baseline]
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).
- Change in Serum Creatinine Level [Baseline through 2 years]
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 Estimated Glomerular Filtration Rate [Baseline]
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).
- Change in Estimated Glomerular Filtration Rate [Baseline through 2 years]
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 Urine Sodium Concentration [Baseline]
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).
- Change in Urine Sodium Concentration [Baseline through 2 years]
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 Urine Sodium/Potassium Ratio [Baseline]
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).
- Change in Urine Sodium/Potassium Ratio [Baseline through 2 years]
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 Plasma Renin Activity [Baseline]
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).
- Change in Plasma Renin Activity [Baseline through 2 years]
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 Serum Aldosterone Level [Baseline]
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).
- Change in Serum Aldosterone Level [Baseline through 2 years]
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).
Secondary Outcome Measures
- Baseline Urine Angiotensin II/Creatinine Ratio [Baseline]
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).
- Change in Urine Angiotensin II/Creatinine Ratio [Baseline through 2 years]
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 Urine Angiotensin-Converting Enzyme 2 Level [Baseline]
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).
- Change in Urine Angiotensin-Converting Enzyme 2 Level [Baseline through 2 years]
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 Urine Angiotensin-Converting Enzyme Level [Baseline]
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).
- Change in Urine Angiotensin-Converting Enzyme Level [Baseline through 2 years]
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 Urine Angiotensin-Converting Enzyme/Angiotensin-Converting Enzyme 2 Ratio [Baseline]
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).
- Change in Urine Angiotensin-Converting Enzyme/Angiotensin-Converting Enzyme 2 Ratio [Baseline through 2 years]
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 Plasma Angiotensin II Level [Baseline]
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).
- Change in Plasma Angiotensin II Level [Baseline through 2 years]
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 Serum Angiotensin-Converting Enzyme 2 Level [Baseline]
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).
- Change in Serum Angiotensin-Converting Enzyme 2 Level [Baseline through 2 years]
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 Serum Angiotensin-Converting Enzyme Level [Baseline]
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).
- Change in Serum Angiotensin-Converting Enzyme Level [Baseline through 2 years]
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 Serum Angiotensin-Converting Enzyme/Angiotensin-Converting Enzyme 2 Ratio [Baseline]
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).
- Change in Serum Angiotensin-Converting Enzyme/Angiotensin-Converting Enzyme 2 Ratio [Baseline through 2 years]
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 Hyperuricemia [Baseline]
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).
- Change in Hyperuricemia [Baseline through 2 years]
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 Manual Blood Pressure Classification [Baseline]
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).
- Change in Manual Blood Pressure Classification [Baseline through 2 years]
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 Ambulatory Systolic Blood Pressure 24-Hour Load [Baseline]
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).
- Change in Ambulatory Systolic Blood Pressure 24-Hour Load [Baseline through 2 years]
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 Ambulatory Diastolic Blood Pressure 24-Hour Load [Baseline]
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).
- Change in Ambulatory Diastolic Blood Pressure 24-Hour Load [Baseline through 2 years]
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 Ambulatory Systolic Blood Pressure 24-Hour Index [Baseline]
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).
- Change in Ambulatory Systolic Blood Pressure 24-Hour Index [Baseline through 2 years]
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 Ambulatory Diastolic Blood Pressure 24-Hour Index [Baseline]
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).
- Change in Ambulatory Diastolic Blood Pressure 24-Hour Index [Baseline through 2 years]
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 Ambulatory Systolic Blood Pressure Awake Mean [Baseline]
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).
- Change in Ambulatory Systolic Blood Pressure Awake Mean [Baseline through 2 years]
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 Ambulatory Diastolic Blood Pressure Awake Mean [Baseline]
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).
- Change in Ambulatory Diastolic Blood Pressure Awake Mean [Baseline through 2 years]
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 Ambulatory Systolic Blood Pressure Awake Load [Baseline]
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).
- Change in Ambulatory Systolic Blood Pressure Awake Load [Baseline through 2 years]
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 Ambulatory Diastolic Blood Pressure Awake Load [Baseline]
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).
- Change in Ambulatory Diastolic Blood Pressure Awake Load [Baseline through 2 years]
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 Ambulatory Systolic Blood Pressure Awake Index [Baseline]
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).
- Change in Ambulatory Systolic Blood Pressure Awake Index [Baseline through 2 years]
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 Ambulatory Diastolic Blood Pressure Awake Index [Baseline]
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).
- Change in Ambulatory Diastolic Blood Pressure Awake Index [Baseline through 2 years]
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 Ambulatory Systolic Blood Pressure Asleep Mean [Baseline]
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).
- Change in Ambulatory Systolic Blood Pressure Asleep Mean [Baseline through 2 years]
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 Ambulatory Diastolic Blood Pressure Asleep Mean [Baseline]
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).
- Change in Ambulatory Diastolic Blood Pressure Asleep Mean [Baseline through 2 years]
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 Ambulatory Systolic Blood Pressure Asleep Load [Baseline]
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).
- Change in Ambulatory Systolic Blood Pressure Asleep Load [Baseline through 2 years]
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 Ambulatory Diastolic Blood Pressure Asleep Load [Baseline]
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).
- Change in Ambulatory Diastolic Blood Pressure Asleep Load [Baseline through 2 years]
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 Ambulatory Systolic Blood Pressure Asleep Index [Baseline]
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).
- Change in Ambulatory Systolic Blood Pressure Asleep Index [Baseline through 2 years]
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 Ambulatory Diastolic Blood Pressure Asleep Index [Baseline]
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).
- Change in Ambulatory Diastolic Blood Pressure Asleep Index [Baseline through 2 years]
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 Ambulatory Systolic Blood Pressure Nocturnal Dipping [Baseline]
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).
- Change in Ambulatory Systolic Blood Pressure Nocturnal Dipping [Baseline through 2 years]
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 Ambulatory Diastolic Blood Pressure Nocturnal Dipping [Baseline]
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).
- Change in Ambulatory Diastolic Blood Pressure Nocturnal Dipping [Baseline through 2 years]
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 Ambulatory Inadequate Nocturnal Dipping [Baseline]
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).
- Change in Ambulatory Inadequate Nocturnal Dipping [Baseline through 2 years]
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 Ambulatory Hypertension [Baseline]
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).
- Change in Ambulatory Hypertension [Baseline through 2 years]
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 Relative Left Ventricular Wall Thickness [Baseline]
Measured via echocardiogram. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Change in Relative Left Ventricular Wall Thickness [Baseline through 2 years]
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 Elevated Relative Left Ventricular Wall Thickness [Baseline]
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).
- Change in Elevated Relative Left Ventricular Wall Thickness [Baseline through 2 years]
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 Left Ventricular Geometry Classification [Baseline]
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).
- Change in Left Ventricular Geometry Classification [Baseline through 2 years]
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 Left Ventricular Systolic Function [Baseline]
Measured via echocardiogram. Report measures of central tendency (e.g., mean, median) with dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Change in Left Ventricular Systolic Function [Baseline through 2 years]
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 Left Ventricular Diastolic Function [Baseline]
Measured via echocardiogram. Report measures of central tendency (e.g., mean, median) with dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Change in Left Ventricular Diastolic Function [Baseline through 2 years]
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 Left Atrial Size [Baseline]
Measured via echocardiogram. Report measures of central tendency (e.g., mean, median) with dispersion (e.g., standard deviation, interquartile range, 95 percent confidence interval).
- Change in Left Atrial Size [Baseline through 2 years]
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 Left Atrial Enlargement [Baseline]
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).
- Change in Left Atrial Enlargement [Baseline through 2 years]
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 Urine Protein/Creatinine Ratio [Baseline]
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).
- Change in Urine Protein/Creatinine Ratio [Baseline through 2 years]
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 Proteinuria [Baseline]
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).
- Change in Proteinuria [Baseline through 2 years]
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 Serum Cystatin C Level [Baseline]
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).
- Change in Serum Cystatin C Level [Baseline through 2 years]
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 Elevated Urine Sodium Concentration [Baseline]
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).
- Change in Elevated Urine Sodium Concentration [Baseline through 2 years]
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 Elevated Urine Sodium/Potassium Ratio [Baseline]
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).
- Change in Elevated Urine Sodium/Potassium Ratio [Baseline through 2 years]
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).
- Low Estimated Glomerular Filtration Rate [Through study completion up to 2 years]
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).
- Baseline Urine Uric Acid/Creatinine Ratio [Baseline]
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).
- Change in Urine Uric Acid/Creatinine Ratio [Baseline through 2 years]
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 Urine Uric Acid Per Glomerular Filtration Rate [Baseline]
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).
- Change in Urine Uric Acid Per Glomerular Filtration Rate [Baseline through 2 years]
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 Fractional Excretion of Urine Uric Acid [Baseline]
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).
- Change in Fractional Excretion of Urine Uric Acid [Baseline through 2 years]
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 Serum Fibroblast Growth Factor 23 Level [Baseline]
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).
- Change in Serum Fibroblast Growth Factor 23 Level [Baseline through 2 years]
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 Urine Fibroblast Growth Factor 23 Level [Baseline]
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).
- Change in Urine Fibroblast Growth Factor 23 Level [Baseline through 2 years]
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 Obesity [Baseline]
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 Waist Circumference [Baseline]
Waist circumference measured in triplicate and average value recorded. Report measures of central tendency (e.g., mean, median) and dispersion (e.g., standard deviation, interquartile range, 95 percentile confidence interval).
- Baseline Dietary Sodium Intake [Baseline]
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 Disordered Eating [Baseline]
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).
- Change in Disordered Eating [Baseline through 2 years]
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 Financial Stress [Baseline]
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).
- Change in Financial Stress [Baseline through 2 years]
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 Food Insecurity [Baseline]
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).
- Change in Food Insecurity [Baseline through 2 years]
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 Transportation Stress [Baseline]
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).
- Change in Transportation Stress [Baseline through 2 years]
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).
Eligibility Criteria
Criteria
INCLUSION CRITERIA: HYPERTENSION COHORT
-
7-18 years of age at time of enrollment
-
Confirmed new diagnosis of primary hypertension: no identifiable secondary cause and ≥3 prior office blood pressure (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
-
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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Wake Forest Health Sciences | Winston-Salem | North Carolina | United States | 27157 |
Sponsors and Collaborators
- Wake Forest University Health Sciences
- National Heart, Lung, and Blood Institute (NHLBI)
Investigators
- Principal Investigator: Andrew M South, MD, MS, Wake Forest Health Sciences
Study Documents (Full-Text)
None provided.More Information
Publications
- Assadi F. Effect of microalbuminuria lowering on regression of left ventricular hypertrophy in children and adolescents with essential hypertension. Pediatr Cardiol. 2007 Jan-Feb;28(1):27-33. Epub 2007 Feb 16.
- Baker-Smith CM, Flinn SK, Flynn JT, Kaelber DC, Blowey D, Carroll AE, Daniels SR, de Ferranti SD, Dionne JM, Falkner B, Gidding SS, Goodwin C, Leu MG, Powers ME, Rea C, Samuels J, Simasek M, Thaker VV, Urbina EM; SUBCOMMITTEE ON SCREENING AND MANAGEMENT OF HIGH BP IN CHILDREN. Diagnosis, Evaluation, and Management of High Blood Pressure in Children and Adolescents. Pediatrics. 2018 Sep;142(3). pii: e20182096. doi: 10.1542/peds.2018-2096. Epub 2018 Aug 20.
- Benjamin DK Jr, Smith PB, Jadhav P, Gobburu JV, Murphy MD, Hasselblad V, Baker-Smith C, Califf RM, Li JS. Pediatric antihypertensive trial failures: analysis of end points and dose range. Hypertension. 2008 Apr;51(4):834-40. doi: 10.1161/HYPERTENSIONAHA.107.108886. Epub 2008 Mar 10.
- Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O'Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2018 Update: A Report From the American Heart Association. Circulation. 2018 Mar 20;137(12):e67-e492. doi: 10.1161/CIR.0000000000000558. Epub 2018 Jan 31. Review. Erratum in: Circulation. 2018 Mar 20;137(12 ):e493.
- Benter IF, Yousif MH, Anim JT, Cojocel C, Diz DI. Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME. Am J Physiol Heart Circ Physiol. 2006 Feb;290(2):H684-91.
- Butlin M, Qasem A. Large Artery Stiffness Assessment Using SphygmoCor Technology. Pulse (Basel). 2017 Jan;4(4):180-192. doi: 10.1159/000452448. Epub 2016 Dec 1. Review.
- Chappell MC, Marshall AC, Alzayadneh EM, Shaltout HA, Diz DI. Update on the Angiotensin converting enzyme 2-Angiotensin (1-7)-MAS receptor axis: fetal programing, sex differences, and intracellular pathways. Front Endocrinol (Lausanne). 2014 Jan 9;4:201. doi: 10.3389/fendo.2013.00201. Review.
- Chappell MC. Biochemical evaluation of the renin-angiotensin system: the good, bad, and absolute? Am J Physiol Heart Circ Physiol. 2016 Jan 15;310(2):H137-52. doi: 10.1152/ajpheart.00618.2015. Epub 2015 Oct 16. Review.
- Chen X, Wang Y. Tracking of blood pressure from childhood to adulthood: a systematic review and meta-regression analysis. Circulation. 2008 Jun 24;117(25):3171-80. doi: 10.1161/CIRCULATIONAHA.107.730366. Epub 2008 Jun 16. Review.
- ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2017/10/10. Identifier NCT03305562: Pediatric Hypertension Registry (PHREG); 2017/10/16. Available from: https://ClinicalTrials.gov/show/NCT03305562
- ClinicalTrials.gov [Internet]. Bethesday (MD): National Library of Medicine (US). 2017 Oct 16. Identifier NCT03310684: Pediatric Primary Hypertension and the Renin-Angiotensin System (PHRAS); 2017 Oct 16. Available from: https://ClinicalTrials.gov/show/NCT03310684
- Croghan C, Egeghy PP. Methods of dealing with values below the limit of detection using SAS. Southeastern SAS User Group. 2003;N/A
- Danaei G, Ding EL, Mozaffarian D, Taylor B, Rehm J, Murray CJ, Ezzati M. The preventable causes of death in the United States: comparative risk assessment of dietary, lifestyle, and metabolic risk factors. PLoS Med. 2009 Apr 28;6(4):e1000058. doi: 10.1371/journal.pmed.1000058. Epub 2009 Apr 28. Erratum in: PLoS Med. 2011 Jan;8(1). doi: 10.1371/annotation/0ef47acd-9dcc-4296-a897-872d182cde57.
- Dilauro M, Zimpelmann J, Robertson SJ, Genest D, Burns KD. Effect of ACE2 and angiotensin-(1-7) in a mouse model of early chronic kidney disease. Am J Physiol Renal Physiol. 2010 Jun;298(6):F1523-32. doi: 10.1152/ajprenal.00426.2009. Epub 2010 Mar 31.
- Din-Dzietham R, Liu Y, Bielo MV, Shamsa F. High blood pressure trends in children and adolescents in national surveys, 1963 to 2002. Circulation. 2007 Sep 25;116(13):1488-96. Epub 2007 Sep 10.
- Drew DA, Katz R, Kritchevsky S, Ix J, Shlipak M, Gutiérrez OM, Newman A, Hoofnagle A, Fried L, Semba RD, Sarnak M. Association between Soluble Klotho and Change in Kidney Function: The Health Aging and Body Composition Study. J Am Soc Nephrol. 2017 Jun;28(6):1859-1866. doi: 10.1681/ASN.2016080828. Epub 2017 Jan 19.
- Eakin MN, Brady T, Kandasamy V, Fivush B, Riekert KA. Disparities in antihypertensive medication adherence in adolescents. Pediatr Nephrol. 2013 Aug;28(8):1267-73. doi: 10.1007/s00467-013-2455-2. Epub 2013 Mar 20.
- ESCAPE Trial Group, Wühl E, Trivelli A, Picca S, Litwin M, Peco-Antic A, Zurowska A, Testa S, Jankauskiene A, Emre S, Caldas-Afonso A, Anarat A, Niaudet P, Mir S, Bakkaloglu A, Enke B, Montini G, Wingen AM, Sallay P, Jeck N, Berg U, Caliskan S, Wygoda S, Hohbach-Hohenfellner K, Dusek J, Urasinski T, Arbeiter K, Neuhaus T, Gellermann J, Drozdz D, Fischbach M, Möller K, Wigger M, Peruzzi L, Mehls O, Schaefer F. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009 Oct 22;361(17):1639-50. doi: 10.1056/NEJMoa0902066.
- Feber J, Ahmed M. Hypertension in children: new trends and challenges. Clin Sci (Lond). 2010 May 14;119(4):151-61. doi: 10.1042/CS20090544. Review.
- Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA. 2008 Aug 27;300(8):924-32. doi: 10.1001/jama.300.8.924.
- Ferrario CM, Martell N, Yunis C, Flack JM, Chappell MC, Brosnihan KB, Dean RH, Fernandez A, Novikov SV, Pinillas C, Luque M. Characterization of angiotensin-(1-7) in the urine of normal and essential hypertensive subjects. Am J Hypertens. 1998 Feb;11(2):137-46.
- Flynn JT, Daniels SR, Hayman LL, Maahs DM, McCrindle BW, Mitsnefes M, Zachariah JP, Urbina EM; American Heart Association Atherosclerosis, Hypertension and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young. Update: ambulatory blood pressure monitoring in children and adolescents: a scientific statement from the American Heart Association. Hypertension. 2014 May;63(5):1116-35. doi: 10.1161/HYP.0000000000000007. Epub 2014 Mar 3.
- Flynn JT, Kaelber DC, Baker-Smith CM, et al; SUBCOMMITTEE ON SCREENING AND MANAGEMENT OF HIGH BLOOD PRESSURE IN CHILDREN. Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Pediatrics. 2017; 140(3):e20171904. Pediatrics. 2017 Dec;140(6). pii: e20173035. doi: 10.1542/peds.2017-3035.
- Fortunato JE, Tegeler CL, Gerdes L, Lee SW, Pajewski NM, Franco ME, Cook JF, Shaltout HA, Tegeler CH. Use of an allostatic neurotechnology by adolescents with postural orthostatic tachycardia syndrome (POTS) is associated with improvements in heart rate variability and changes in temporal lobe electrical activity. Exp Brain Res. 2016 Mar;234(3):791-8. doi: 10.1007/s00221-015-4499-y. Epub 2015 Dec 8.
- Garin EH, Araya CE. Treatment of systemic hypertension in children and adolescents. Curr Opin Pediatr. 2009 Oct;21(5):600-4. doi: 10.1097/MOP.0b013e32832ff3a7. Review.
- Hall JE, Granger JP, do Carmo JM, da Silva AA, Dubinion J, George E, Hamza S, Speed J, Hall ME. Hypertension: physiology and pathophysiology. Compr Physiol. 2012 Oct;2(4):2393-442. doi: 10.1002/cphy.c110058. Review.
- Hansen BB, Fredrickson M, Buckner J, et al. Using Optmatch on data in SAS, Stata, etc. 2019;2019
- Hansen BB, Klopfer SO. Optimal full matching and related designs via network flows. J Comput Graph Stat 2006; 15:609-27.
- Hao G, Wang X, Treiber FA, Harshfield G, Kapuku G, Su S. Blood Pressure Trajectories From Childhood to Young Adulthood Associated With Cardiovascular Risk: Results From the 23-Year Longitudinal Georgia Stress and Heart Study. Hypertension. 2017 Mar;69(3):435-442. doi: 10.1161/HYPERTENSIONAHA.116.08312. Epub 2017 Jan 16.
- Jimenez A, Chen A, Lin JJ, South AM. Does MEST-C score predict outcomes in pediatric Henoch-Schönlein purpura nephritis? Pediatr Nephrol. 2019 Dec;34(12):2583-2589. doi: 10.1007/s00467-019-04327-2. Epub 2019 Aug 11.
- Karalliedde J, Maltese G, Hill B, Viberti G, Gnudi L. Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria. Clin J Am Soc Nephrol. 2013 Nov;8(11):1899-905. doi: 10.2215/CJN.02700313. Epub 2013 Aug 8.
- Khosla UM, Zharikov S, Finch JL, Nakagawa T, Roncal C, Mu W, Krotova K, Block ER, Prabhakar S, Johnson RJ. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005 May;67(5):1739-42.
- Khoury M, Khoury PR, Dolan LM, Kimball TR, Urbina EM. Clinical Implications of the Revised AAP Pediatric Hypertension Guidelines. Pediatrics. 2018 Aug;142(2). pii: e20180245. doi: 10.1542/peds.2018-0245. Epub 2018 Jul 5.
- Khoury PR, Mitsnefes M, Daniels SR, Kimball TR. Age-specific reference intervals for indexed left ventricular mass in children. J Am Soc Echocardiogr. 2009 Jun;22(6):709-14. doi: 10.1016/j.echo.2009.03.003. Epub 2009 May 7.
- Kim YM, Cologne JB, Cullings HM. Simple power analysis in causal mediation models for a dichotomous outcome based on the mediation proportion. J Korean Data Inf Sci Soc 2017; 28:669-84
- Knol MJ, VanderWeele TJ. Recommendations for presenting analyses of effect modification and interaction. Int J Epidemiol. 2012 Apr;41(2):514-20. doi: 10.1093/ije/dyr218. Epub 2012 Jan 9.
- Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, Wei R, Curtin LR, Roche AF, Johnson CL. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11. 2002 May;(246):1-190.
- Laslett LJ, Alagona P Jr, Clark BA 3rd, Drozda JP Jr, Saldivar F, Wilson SR, Poe C, Hart M. The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol. 2012 Dec 25;60(25 Suppl):S1-49. doi: 10.1016/j.jacc.2012.11.002. Review.
- Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, Amann M, Anderson HR, Andrews KG, Aryee M, Atkinson C, Bacchus LJ, Bahalim AN, Balakrishnan K, Balmes J, Barker-Collo S, Baxter A, Bell ML, Blore JD, Blyth F, Bonner C, Borges G, Bourne R, Boussinesq M, Brauer M, Brooks P, Bruce NG, Brunekreef B, Bryan-Hancock C, Bucello C, Buchbinder R, Bull F, Burnett RT, Byers TE, Calabria B, Carapetis J, Carnahan E, Chafe Z, Charlson F, Chen H, Chen JS, Cheng AT, Child JC, Cohen A, Colson KE, Cowie BC, Darby S, Darling S, Davis A, Degenhardt L, Dentener F, Des Jarlais DC, Devries K, Dherani M, Ding EL, Dorsey ER, Driscoll T, Edmond K, Ali SE, Engell RE, Erwin PJ, Fahimi S, Falder G, Farzadfar F, Ferrari A, Finucane MM, Flaxman S, Fowkes FG, Freedman G, Freeman MK, Gakidou E, Ghosh S, Giovannucci E, Gmel G, Graham K, Grainger R, Grant B, Gunnell D, Gutierrez HR, Hall W, Hoek HW, Hogan A, Hosgood HD 3rd, Hoy D, Hu H, Hubbell BJ, Hutchings SJ, Ibeanusi SE, Jacklyn GL, Jasrasaria R, Jonas JB, Kan H, Kanis JA, Kassebaum N, Kawakami N, Khang YH, Khatibzadeh S, Khoo JP, Kok C, Laden F, Lalloo R, Lan Q, Lathlean T, Leasher JL, Leigh J, Li Y, Lin JK, Lipshultz SE, London S, Lozano R, Lu Y, Mak J, Malekzadeh R, Mallinger L, Marcenes W, March L, Marks R, Martin R, McGale P, McGrath J, Mehta S, Mensah GA, Merriman TR, Micha R, Michaud C, Mishra V, Mohd Hanafiah K, Mokdad AA, Morawska L, Mozaffarian D, Murphy T, Naghavi M, Neal B, Nelson PK, Nolla JM, Norman R, Olives C, Omer SB, Orchard J, Osborne R, Ostro B, Page A, Pandey KD, Parry CD, Passmore E, Patra J, Pearce N, Pelizzari PM, Petzold M, Phillips MR, Pope D, Pope CA 3rd, Powles J, Rao M, Razavi H, Rehfuess EA, Rehm JT, Ritz B, Rivara FP, Roberts T, Robinson C, Rodriguez-Portales JA, Romieu I, Room R, Rosenfeld LC, Roy A, Rushton L, Salomon JA, Sampson U, Sanchez-Riera L, Sanman E, Sapkota A, Seedat S, Shi P, Shield K, Shivakoti R, Singh GM, Sleet DA, Smith E, Smith KR, Stapelberg NJ, Steenland K, Stöckl H, Stovner LJ, Straif K, Straney L, Thurston GD, Tran JH, Van Dingenen R, van Donkelaar A, Veerman JL, Vijayakumar L, Weintraub R, Weissman MM, White RA, Whiteford H, Wiersma ST, Wilkinson JD, Williams HC, Williams W, Wilson N, Woolf AD, Yip P, Zielinski JM, Lopez AD, Murray CJ, Ezzati M, AlMazroa MA, Memish ZA. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012 Dec 15;380(9859):2224-60. doi: 10.1016/S0140-6736(12)61766-8. Erratum in: Lancet. 2013 Apr 13;381(9874):1276. Lancet. 2013 Feb 23;381(9867):628. AlMazroa, Mohammad A [added]; Memish, Ziad A [added].
- Lin DY, Psaty BM, Kronmal RA. Assessing the sensitivity of regression results to unmeasured confounders in observational studies. Biometrics. 1998 Sep;54(3):948-63.
- Lin S-H. 2016. Causal mediation analysis with time-varying and multiple mediators. Doctoral Dissertation, Harvard T.H. Chan School of Public Health.
- Litwin M, Niemirska A, Sladowska-Kozlowska J, Wierzbicka A, Janas R, Wawer ZT, Wisniewski A, Feber J. Regression of target organ damage in children and adolescents with primary hypertension. Pediatr Nephrol. 2010 Dec;25(12):2489-99. doi: 10.1007/s00467-010-1626-7. Epub 2010 Aug 21.
- Loichinger MH, Towner D, Thompson KS, Ahn HJ, Bryant-Greenwood GD. Systemic and placental α-klotho: Effects of preeclampsia in the last trimester of gestation. Placenta. 2016 May;41:53-61. doi: 10.1016/j.placenta.2016.03.004. Epub 2016 Mar 8.
- Lytle LA, Nichaman MZ, Obarzanek E, Glovsky E, Montgomery D, Nicklas T, Zive M, Feldman H. Validation of 24-hour recalls assisted by food records in third-grade children. The CATCH Collaborative Group. J Am Diet Assoc. 1993 Dec;93(12):1431-6.
- McMullan CJ, Borgi L, Fisher N, Curhan G, Forman J. Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial. Clin J Am Soc Nephrol. 2017 May 8;12(5):807-816. doi: 10.2215/CJN.10771016. Epub 2017 Mar 20.
- Mitani H, Ishizaka N, Aizawa T, Ohno M, Usui S, Suzuki T, Amaki T, Mori I, Nakamura Y, Sato M, Nangaku M, Hirata Y, Nagai R. In vivo klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension. 2002 Apr;39(4):838-43.
- Morisky DE, Ang A, Krousel-Wood M, Ward HJ. Predictive validity of a medication adherence measure in an outpatient setting. J Clin Hypertens (Greenwich). 2008 May;10(5):348-54.
- Mulè G, Castiglia A, Morreale M, Geraci G, Cusumano C, Guarino L, Altieri D, Panzica M, Vaccaro F, Cottone S. Serum uric acid is not independently associated with plasma renin activity and plasma aldosterone in hypertensive adults. Nutr Metab Cardiovasc Dis. 2017 Apr;27(4):350-359. doi: 10.1016/j.numecd.2016.12.008. Epub 2016 Dec 27.
- Nagai R, Saito Y, Ohyama Y, Aizawa H, Suga T, Nakamura T, Kurabayashi M, Kuroo M. Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases. Cell Mol Life Sci. 2000 May;57(5):738-46.
- Parati G, Saul JP, Di Rienzo M, Mancia G. Spectral analysis of blood pressure and heart rate variability in evaluating cardiovascular regulation. A critical appraisal. Hypertension. 1995 Jun;25(6):1276-86. Review.
- Pendergrass KD, Gwathmey TM, Michalek RD, Grayson JM, Chappell MC. The angiotensin II-AT1 receptor stimulates reactive oxygen species within the cell nucleus. Biochem Biophys Res Commun. 2009 Jun 26;384(2):149-54. doi: 10.1016/j.bbrc.2009.04.126. Epub 2009 May 3.
- Pottel H, Björk J, Bökenkamp A, Berg U, Åsling-Monemi K, Selistre L, Dubourg L, Hansson M, Littmann K, Jones I, Sjöström P, Nyman U, Delanaye P. Estimating glomerular filtration rate at the transition from pediatric to adult care. Kidney Int. 2019 May;95(5):1234-1243. doi: 10.1016/j.kint.2018.12.020. Epub 2019 Feb 28.
- Pruette CS, Coburn SS, Eaton CK, Brady TM, Tuchman S, Mendley S, Fivush BA, Eakin MN, Riekert KA. Does a multimethod approach improve identification of medication nonadherence in adolescents with chronic kidney disease? Pediatr Nephrol. 2019 Jan;34(1):97-105. doi: 10.1007/s00467-018-4044-x. Epub 2018 Aug 16.
- Pun BT, Balas MC, Barnes-Daly MA, Thompson JL, Aldrich JM, Barr J, Byrum D, Carson SS, Devlin JW, Engel HJ, Esbrook CL, Hargett KD, Harmon L, Hielsberg C, Jackson JC, Kelly TL, Kumar V, Millner L, Morse A, Perme CS, Posa PJ, Puntillo KA, Schweickert WD, Stollings JL, Tan A, D'Agostino McGowan L, Ely EW. Caring for Critically Ill Patients with the ABCDEF Bundle: Results of the ICU Liberation Collaborative in Over 15,000 Adults. Crit Care Med. 2019 Jan;47(1):3-14. doi: 10.1097/CCM.0000000000003482.
- Rademacher ER, Sinaiko AR. Albuminuria in children. Curr Opin Nephrol Hypertens. 2009 May;18(3):246-51. doi: 10.1097/MNH.0b013e3283294b98. Review.
- Rosner B, Cook N, Portman R, Daniels S, Falkner B. Determination of blood pressure percentiles in normal-weight children: some methodological issues. Am J Epidemiol. 2008 Mar 15;167(6):653-66. doi: 10.1093/aje/kwm348. Epub 2008 Jan 29.
- Samuel JP, Samuels JA, Brooks LE, Bell CS, Pedroza C, Molony DA, Tyson JE. Comparative effectiveness of antihypertensive treatment for older children with primary hypertension: study protocol for a series of n-of-1 randomized trials. Trials. 2016 Jan 8;17:16. doi: 10.1186/s13063-015-1142-y.
- Saran R, Li Y, Robinson B, Ayanian J, Balkrishnan R, Bragg-Gresham J, Chen JT, Cope E, Gipson D, He K, Herman W, Heung M, Hirth RA, Jacobsen SS, Kalantar-Zadeh K, Kovesdy CP, Leichtman AB, Lu Y, Molnar MZ, Morgenstern H, Nallamothu B, O'Hare AM, Pisoni R, Plattner B, Port FK, Rao P, Rhee CM, Schaubel DE, Selewski DT, Shahinian V, Sim JJ, Song P, Streja E, Kurella Tamura M, Tentori F, Eggers PW, Agodoa LY, Abbott KC. US Renal Data System 2014 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis. 2015 Jul;66(1 Suppl 1):Svii, S1-305. doi: 10.1053/j.ajkd.2015.05.001. Erratum in: Am J Kidney Dis. 2015 Sep;66(3):545. Am J Kidney Dis. 2015 Sep;66(3):545.
- Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37. doi: 10.1681/ASN.2008030287. Epub 2009 Jan 21.
- Schwartz GJ, Schneider MF, Maier PS, Moxey-Mims M, Dharnidharka VR, Warady BA, Furth SL, Muñoz A. Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C. Kidney Int. 2012 Aug;82(4):445-53.
- Seeman T, Dostálek L, Gilík J. Control of hypertension in treated children and its association with target organ damage. Am J Hypertens. 2012 Mar;25(3):389-95. doi: 10.1038/ajh.2011.218. Epub 2011 Nov 17.
- Shaltout HA, Nixon PA, Chappell MC, et al. Impaired autonomic function in young adults born preterm with very low birth weight is associated with elevated serum uric acid levels [abstract]. Hypertension 2018; ePub; doi:
- Shaltout HA, Rose JC, Chappell MC, Diz DI. Angiotensin-(1-7) deficiency and baroreflex impairment precede the antenatal Betamethasone exposure-induced elevation in blood pressure. Hypertension. 2012 Feb;59(2):453-8. doi: 10.1161/HYPERTENSIONAHA.111.185876. Epub 2012 Jan 3.
- Shatat IF, Abdallah RT, Sas DJ, Hailpern SM. Serum uric acid in U.S. adolescents: distribution and relationship to demographic characteristics and cardiovascular risk factors. Pediatr Res. 2012 Jul;72(1):95-100. doi: 10.1038/pr.2012.47.
- Shatat IF, Flynn JT. Relationships between renin, aldosterone, and 24-hour ambulatory blood pressure in obese adolescents. Pediatr Res. 2011 Apr;69(4):336-40. doi: 10.1203/PDR.0b013e31820bd148.
- Shrier I, Platt RW. Reducing bias through directed acyclic graphs. BMC Med Res Methodol. 2008 Oct 30;8:70. doi: 10.1186/1471-2288-8-70.
- Simões E Silva AC, Diniz JS, Regueira Filho A, Santos RA. The renin angiotensin system in childhood hypertension: selective increase of angiotensin-(1-7) in essential hypertension. J Pediatr. 2004 Jul;145(1):93-8.
- Sorof JM, Cardwell G, Franco K, Portman RJ. Ambulatory blood pressure and left ventricular mass index in hypertensive children. Hypertension. 2002 Apr;39(4):903-8.
- South AM, Arguelles L, Finer G, Langman CB. Race, obesity, and the renin-angiotensin-aldosterone system: treatment response in children with primary hypertension. Pediatr Nephrol. 2017 Sep;32(9):1585-1594. doi: 10.1007/s00467-017-3665-9. Epub 2017 Apr 14.
- South AM, Nixon PA, Chappell MC, Diz DI, Russell GB, Jensen ET, Shaltout HA, O'Shea TM, Washburn LK. Association between preterm birth and the renin-angiotensin system in adolescence: influence of sex and obesity. J Hypertens. 2018 Oct;36(10):2092-2101. doi: 10.1097/HJH.0000000000001801.
- South AM, Nixon PA, Chappell MC, Diz DI, Russell GB, Snively BM, Shaltout HA, Rose JC, O'Shea TM, Washburn LK. Antenatal corticosteroids and the renin-angiotensin-aldosterone system in adolescents born preterm. Pediatr Res. 2017 Jan;81(1-1):88-93. doi: 10.1038/pr.2016.179. Epub 2016 Sep 16.
- South AM, Nixon PA, Chappell MC, et al. Preterm adolescents exhibit higher blood pressure and sodium retention with higher uric acid and differential circulating renin-angiotensin system expression [abstract]. FASEB J 2018; 32:883.6
- South AM, Nixon PN, Chappell MC, et al. Elevated blood pressure and sodium retention in young adults born preterm may reflect uric acid-related suppression of renal angiotensin-(1-7) [abstract]. Pediatric Academic Societies 2018; E-PAS2018:3150.3
- South AM, Nixon PN, Chappell MC, et al. Urinary α-klotho is associated with higher blood pressure and reduced urinary angiotensin-(1-7) in young adults born preterm [abstract]. Pediatric Academic Societies 2018; E-PAS2018:1502.841
- South AM, Pao AC, Grimm PC. Subclinical injury in pediatric renal transplant patients: ACE2 and Ang-(1-7) as novel biomarkers [abstract]. Clin Transl Sci 2014; 7:232-3.
- South AM, Shaltout HA, Gwathmey TM, Jensen ET, Nixon PA, Diz DI, Chappell MC, Washburn LK. Lower urinary α-Klotho is associated with lower angiotensin-(1-7) and higher blood pressure in young adults born preterm with very low birthweight. J Clin Hypertens (Greenwich). 2020 Jun;22(6):1033-1040. doi: 10.1111/jch.13897. Epub 2020 May 31.
- South AM, Shaltout HA, Nixon PA, Diz DI, Jensen ET, O'Shea TM, Chappell MC, Washburn LK. Association of circulating uric acid and angiotensin-(1-7) in relation to higher blood pressure in adolescents and the influence of preterm birth. J Hum Hypertens. 2020 Dec;34(12):818-825. doi: 10.1038/s41371-020-0335-3. Epub 2020 Apr 28.
- South AM, Shaltout HA, Washburn LK, Hendricks AS, Diz DI, Chappell MC. Fetal programming and the angiotensin-(1-7) axis: a review of the experimental and clinical data. Clin Sci (Lond). 2019 Jan 8;133(1):55-74. doi: 10.1042/CS20171550. Print 2019 Jan 15. Review.
- Su XM, Yang W. Klotho protein lowered in elderly hypertension. Int J Clin Exp Med. 2014 Aug 15;7(8):2347-50. eCollection 2014.
- Tang KL, Quan H, Rabi DM. Measuring medication adherence in patients with incident hypertension: a retrospective cohort study. BMC Health Serv Res. 2017 Feb 13;17(1):135. doi: 10.1186/s12913-017-2073-y.
- VanderWeele TJ, Ding P. Sensitivity Analysis in Observational Research: Introducing the E-Value. Ann Intern Med. 2017 Aug 15;167(4):268-274. doi: 10.7326/M16-2607. Epub 2017 Jul 11.
- VanderWeele TJ. A unification of mediation and interaction: a 4-way decomposition. Epidemiology. 2014 Sep;25(5):749-61. doi: 10.1097/EDE.0000000000000121. Erratum in: Epidemiology. 2016 Sep;27(5):e36.
- Viazzi F, Antolini L, Giussani M, Brambilla P, Galbiati S, Mastriani S, Stella A, Pontremoli R, Valsecchi MG, Genovesi S. Serum uric acid and blood pressure in children at cardiovascular risk. Pediatrics. 2013 Jul;132(1):e93-9. doi: 10.1542/peds.2013-0047. Epub 2013 Jun 17.
- Washburn LK, Nixon PA, Russell GB, Snively BM, O'Shea TM. Preterm Birth Is Associated with Higher Uric Acid Levels in Adolescents. J Pediatr. 2015 Jul;167(1):76-80. doi: 10.1016/j.jpeds.2015.03.043. Epub 2015 Apr 11.
- Washburn LK, Nixon PA, Snively BM, et al. Increased blood pressure and the circulating renin-angiotensin system in adolescents born preterm [abstract]. Pediatric Academic Societies. 2013; ePub; doi:
- Wołkow PP, Bujak-Giżycka B, Jawień J, Olszanecki R, Madej J, Rutowski J, Korbut R. Exogenous Angiotensin I Metabolism in Aorta Isolated from Streptozotocin Treated Diabetic Rats. J Diabetes Res. 2016;2016:4846819. Epub 2016 Oct 10.
- Writing Group for the Division of Cardiovascular Sciences' Strategic Vision Implementation Plan, Goff DC Jr, Buxton DB, Pearson GD, Wei GS, Gosselin TE, Addou EA, Stoney CM, Desvigne-Nickens P, Srinivas PR, Galis ZS, Pratt C, Kit KBK, Maric-Bilkan C, Nicastro HL, Wong RP, Sachdev V, Chen J, Fine L. Implementing the National Heart, Lung, and Blood Institute's Strategic Vision in the Division of Cardiovascular Sciences. Circ Res. 2019 Feb 15;124(4):491-497. doi: 10.1161/CIRCRESAHA.118.314338.
- Wühl E, Witte K, Soergel M, Mehls O, Schaefer F; German Working Group on Pediatric Hypertension. Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimensions. J Hypertens. 2002 Oct;20(10):1995-2007. Erratum in: J Hypertens. 2003 Nov;21(11):2205-6.
- Yoon HE, Ghee JY, Piao S, Song JH, Han DH, Kim S, Ohashi N, Kobori H, Kuro-o M, Yang CW. Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrol Dial Transplant. 2011 Mar;26(3):800-13. doi: 10.1093/ndt/gfq537. Epub 2010 Sep 2.
- Zhang JX, Zhang YP, Wu QN, Chen B. Uric acid induces oxidative stress via an activation of the renin-angiotensin system in 3T3-L1 adipocytes. Endocrine. 2015 Feb;48(1):135-42. doi: 10.1007/s12020-014-0239-5. Epub 2014 Mar 28.
- Zhang Z, Zheng C, Kim C, Van Poucke S, Lin S, Lan P. Causal mediation analysis in the context of clinical research. Ann Transl Med. 2016 Nov;4(21):425.
- Zhou L, Mo H, Miao J, Zhou D, Tan RJ, Hou FF, Liu Y. Klotho Ameliorates Kidney Injury and Fibrosis and Normalizes Blood Pressure by Targeting the Renin-Angiotensin System. Am J Pathol. 2015 Dec;185(12):3211-23. doi: 10.1016/j.ajpath.2015.08.004. Epub 2015 Oct 24.
- IRB00068679
- 1K23HL148394-01A1