Pediatric Primary Hypertension and the Renin-Angiotensin System (PHRAS)

NCT03310684 | Completed

• 1 other identifier: IRB00041266
• Study Type: observational
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

Pediatric primary hypertension is increasingly common, occurring in 5-10% of normal-weight children and up to 25% of children with obesity. It is a risk factor for adult cardiovascular and renal disease. But even during childhood, hypertension is associated with significant morbidity, including cognitive impairment and organ damage. In the heart and kidneys, this organ damage is characterized by thickened heart muscle (left ventricular hypertrophy) and spillage of protein in the urine (albuminuria). Obese children are also at risk for fatty liver disease. However, the cause of pediatric primary hypertension, the role of obesity, and the mechanisms behind heart and kidney injury are poorly understood. Due to these limitations, there are no first-line medications, and treatment is often inadequate. An altered renin-angiotensin system may cause primary hypertension and related organ damage. Evidence suggests uric acid, FGF23, klotho, and obesity play a role in renin-angiotensin system-mediated injury. An improved comprehension of the pathophysiology of pediatric primary hypertension could enhance clinical care by targeting treatment to the cause of disease and informing novel measurement of organ damage.

Conditions

Pediatric Disorder; Pediatric Obesity; Primary Hypertension

Keywords

Renin-Angiotensin system; Hypertension; Obesity; Angiotensin-(1-7); Angiotensin II; FGF23; Klotho; Uric acid; Left ventricular hypertrophy

Outcome Measures

Primary Outcomes (1)

• Left ventricular hypertrophy

  Left ventricular hypertrophy according to elevated left ventricular mass index (\>51 g/m\^2.7 (\>8 years of age, both sexes) or \>115 g/body surface area (males) and \>95 g/body surface area (females)) on serial echocardiogram.

  Yearly for 3 years

Secondary Outcomes (10)

• Albuminuria

  Yearly for 3 years

• Ambulatory systolic blood pressure load

  Yearly for 3 years

• Ambulatory diastolic blood pressure load

  Yearly for 3 years

• Ambulatory systolic blood pressure nocturnal dipping

  Yearly for 3 years

• Ambulatory diastolic blood pressure nocturnal dipping

  Yearly for 3 years

Study Arms (3)

Hypertensive

Clinical data will be collected from the electronic medical record, including height, weight, age, sex, parent-reported race, and past medical and family histories. Antihypertensive medication type and dosage will be recorded. Blood and urine samples will be collected at baseline and yearly for three years. All subjects will receive baseline and yearly echocardiograms. Subjects with overweight/obesity (BMI \>=85th percentile for age and sex) will receive baseline and yearly ultrasounds of the liver to evaluate for hepatic fat infiltration. Auscultated, continuous and ambulatory blood pressure will be measured at baseline and yearly.

Normotensive with Obesity

Clinical data will be collected from the electronic medical record, including height, weight, age, sex, parent-reported race, and past medical and family histories. Subjects will receive a baseline ultrasound of the liver to evaluate hepatic fat infiltration as per standard of care. Blood and urine will be collected at baseline to measure liver function (AST, ALT) and uric acid, angiotensin ll, and angiotensin-(1-7).

Healthy Normotensive

Clinical data will be collected from the electronic medical record, including height, weight, age, sex, parent-reported race, and past medical and family histories. Subjects will have baseline echocardiograms. Blood pressure will be measured at baseline and at one year. Continuous blood pressure and ambulatory blood pressure monitoring will be assessed at baseline. Blood and urine samples will be used to measure uric acid, FGF23, klotho, and albumin, as well as the predictors angiotensin ll and angiotensin-(1-7).

Eligibility Criteria

• Age: 5 Years - 17 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

Patients of the Pediatric Nephrology Clinic and Pediatric Gastroenterology Clinic at Brenner Children's Hospital. Patients from a general pediatric clinic at Wake Forest Baptist Health.

You may qualify if:

• Hypertension cohort: 5 to 17 years old with a new diagnosis of pediatric primary hypertension (systolic or diastolic blood pressure \>=95th percentile for age/sex/height or \>=130/80 mmHg.
• Normotensive controls with obesity: 5 to 17 years old with normal systolic and diastolic blood pressure (\<90th percentile for age/sex/height or \<120/80 mmHg) and BMI \>=85th percentile for age/sex.
• Normotensive controls: 5 to 17 years old with normal systolic and diastolic blood pressure (\<90th percentile for age/sex/height or \<120/80 mmHg).

You may not qualify if:

• Secondary hypertension
• Confounding medical condition (e.g. diabetes mellitus, chronic kidney disease, heart disease, vascular disease, inflammatory or rheumatologic disease)
• Non-English and non-Spanish speaking
• Inability to complete assessments

Sponsors & Collaborators

• Wake Forest University Health Sciences: lead

Study Sites (1)

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

Related Publications (20)

• 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. doi: 10.1161/CIRCULATIONAHA.106.683243. Epub 2007 Sep 10.

  PMID: 17846287 BACKGROUND

• Richey PA, Disessa TG, Somes GW, Alpert BS, Jones DP. Left ventricular geometry in children and adolescents with primary hypertension. Am J Hypertens. 2010 Jan;23(1):24-9. doi: 10.1038/ajh.2009.164. Epub 2009 Oct 22.

  PMID: 19851297 BACKGROUND

• Iyer SN, Ferrario CM, Chappell MC. Angiotensin-(1-7) contributes to the antihypertensive effects of blockade of the renin-angiotensin system. Hypertension. 1998 Jan;31(1 Pt 2):356-61. doi: 10.1161/01.hyp.31.1.356.

  PMID: 9453328 BACKGROUND

• 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.

  PMID: 22215705 BACKGROUND

• Simoes 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. doi: 10.1016/j.jpeds.2004.03.055.

  PMID: 15238914 BACKGROUND

• 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.

  PMID: 27636897 BACKGROUND

• 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. doi: 10.1016/s0895-7061(97)00400-7.

  PMID: 9524041 BACKGROUND

• 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.

  PMID: 25868431 BACKGROUND

• 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.

  PMID: 18728266 BACKGROUND

• Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, Lan HY, Kivlighn S, Johnson RJ. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001 Nov;38(5):1101-6. doi: 10.1161/hy1101.092839.

  PMID: 11711505 BACKGROUND

• Seeherunvong W, Abitbol CL, Chandar J, Rusconi P, Zilleruelo GE, Freundlich M. Fibroblast growth factor 23 and left ventricular hypertrophy in children on dialysis. Pediatr Nephrol. 2012 Nov;27(11):2129-2136. doi: 10.1007/s00467-012-2224-7. Epub 2012 Jun 19.

  PMID: 22710695 BACKGROUND

• Engeli S, Bohnke J, Gorzelniak K, Janke J, Schling P, Bader M, Luft FC, Sharma AM. Weight loss and the renin-angiotensin-aldosterone system. Hypertension. 2005 Mar;45(3):356-62. doi: 10.1161/01.HYP.0000154361.47683.d3. Epub 2005 Jan 3.

  PMID: 15630041 BACKGROUND

• Zhang H, Yang H, Lai C, Xu X, Huang K, Fu J. Quantitative relationship between liver fat content and metabolic syndrome in obese children and adolescents. Clin Endocrinol (Oxf). 2015 Jul;83(1):43-9. doi: 10.1111/cen.12758. Epub 2015 Mar 16.

  PMID: 25711346 BACKGROUND

• 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.

  PMID: 12043359 BACKGROUND

• Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am. 1987 Jun;34(3):571-90. doi: 10.1016/s0031-3955(16)36251-4.

  PMID: 3588043 BACKGROUND

• 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.

  PMID: 26645307 BACKGROUND

• 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. No abstract available.

  PMID: 24591341 BACKGROUND

• 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.

  PMID: 19423289 BACKGROUND

• Rademacher ER, Sinaiko AR. Albuminuria in children. Curr Opin Nephrol Hypertens. 2009 May;18(3):246-51. doi: 10.1097/MNH.0b013e3283294b98.

  PMID: 19276802 BACKGROUND

• 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. doi: 10.1007/s00246-006-1390-4. Epub 2007 Feb 16.

  PMID: 17308944 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood and urine samples.

MeSH Terms

Conditions

Pediatric Obesity; Essential Hypertension; Hypertension; Obesity; Hypertrophy, Left Ventricular

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Vascular Diseases; Cardiovascular Diseases; Cardiomegaly; Heart Diseases; Hypertrophy; Pathological Conditions, Anatomical

Study Officials

• Andrew M South, MD MS

  Wake Forest University Health Sciences

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: October 2, 2017
• First Posted: October 16, 2017
• Study Start: December 3, 2018
• Primary Completion: April 26, 2023
• Study Completion: April 26, 2023
• Last Updated: February 28, 2025

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)