Pediatric Hypertension and the Renin-Angiotensin SystEm (PHRASE)

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.

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.

Eligibility Criteria:
INCLUSION CRITERIA: HYPERTENSION COHORT

* 7-18 years of age at time of enrollment
* Confirmed new diagnosis of primary hypertension: no identifiable secondary cause, referred to hypertension or nephrology clinic

  * Age \<13 years: BP ≥95th %ile or ≥130/80 mmHg (whichever is lower)
  * Age ≥13 years: BP ≥130/80 mmHg
* Participants and their caregivers must be willing and able to commit to completing the study assessments

EXCLUSION CRITERIA: HYPERTENSION COHORT

* \<7 years or \>18 years of age at time of enrollment
* BP confirmed as normal or in the elevated BP category based on ≥3 prior office BP measurements on separate days;

  * Age \<13 years: BP \<95th %ile or \<130/80 mmHg (whichever is lower)
  * Age ≥13 years: BP \<130/80 mmHg
* A confirmed secondary cause of hypertension
* Confounding medical condition (heart or kidney disease \[except hypertension-associated heart changes on echocardiogram or albuminuria\], vascular/inflammatory disease, or diabetes)
* Inability to complete study assessments
* Non-English/Spanish speakers
* Current pregnancy
* Ward of the State

INCLUSION CRITERIA: CONTROL COHORT

* 7-18 years of age at time of enrollment
* Normal BP based on ≥3 prior office BP measurements on separate days;

  * Age \<13 years: BP \<90th %ile or \<120/80 mmHg (whichever is lower)
  * Age ≥13 years: BP \<120/80 mmHg
* Participants and their caregivers must be willing and able to commit to completing the study assessments

EXCLUSION CRITERIA: CONTROL COHORT

* \<7 or \>18 years of age at time of enrollment
* Elevated BP or hypertension, based on ≥3 prior office BP measurements on separate days:

  * Age \<13 years: BP ≥90th %ile or ≥120/80 mmHg (whichever is lower)
  * Age ≥13 years: BP ≥120/80 mmHg
* History of elevated BP or hypertension
* Current use of BP-lowering medications
* Confounding medical condition (heart or kidney disease, vascular/inflammatory disease, or diabetes)
* Inability to complete study assessments
* Non-English/Spanish speakers
* Current pregnancy
* Ward of the State