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

Pediatric Obesity Clinical Trial

— PHRAS  

Official title:

The Role of the Renin-Angiotensin System in Pediatric Primary Hypertension (PHRAS)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03310684
• Other study ID #: IRB00041266
• Status: Active, not recruiting
• Start date: December 3, 2018
• Est. completion date: July 30, 2024

Study information

• Verified date: July 2023
• Source: Wake Forest University Health Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Description:

This proposal is to begin to elucidate the origins of pediatric primary hypertension and determine how it causes cardiac and renal disease. The primary hypothesis is than an altered renin-angiotensin system leads to the development of pediatric primary hypertension-related organ damage in the heart and kidney, specifically left ventricular hypertrophy and albuminuria. It is postulated that relative increase in angiotensin (Ang) ll tone compared to Ang-(1-7) tone in the circulation and the kidney (measured in the plasma and urine, respectively) leads to disease. The secondary hypotheses are that abnormalities in renin-angiotensin system tone are related to higher uric acid and FGF23, lower klotho, and, with concurrent obesity, contribute to nonalcoholic fatty liver disease. The investigators will recruit 100 subjects aged 5-17 years who are referred for a new diagnosis of pediatric primary hypertension to the Pediatric Nephrology clinic at Brenner Children's Hospital, 50 normotensive subjects with obesity recruited from the Brenner Families-in-Training program, and 10 healthy normotensive from a general pediatrics clinic in the Wake Forest Baptist Health System.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 160
• Est. completion date: July 30, 2024
• Est. primary completion date: July 30, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 5 Years to 17 Years

Eligibility

Inclusion Criteria:

• 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).

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Essential Hypertension
• Hypertension
• Pediatric Disorder
• Pediatric Obesity
• Primary Hypertension

Locations

Country	Name	City	State
United States	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Wake Forest University Health Sciences

Country where clinical trial is conducted

United States, 

References & Publications (20)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Albuminuria	Albumin-to-creatinine ratio >30 mg/g	Yearly for 3 years
Secondary	Ambulatory systolic blood pressure load	Percent of 24-hour ambulatory systolic blood pressure above the 95th percentile (>25% abnormal)	Yearly for 3 years
Secondary	Ambulatory diastolic blood pressure load	Percent of 24-hour ambulatory diastolic blood pressure above the 95th percentile (>25% abnormal)	Yearly for 3 years
Secondary	Ambulatory systolic blood pressure nocturnal dipping	Percent of 24-hour ambulatory systolic blood pressure that drops below the mean blood pressure overnight	Yearly for 3 years
Secondary	Ambulatory diastolic blood pressure nocturnal dipping	Percent of 24-hour ambulatory diastolic blood pressure that drops below the mean blood pressure overnight	Yearly for 3 years
Secondary	Clinic systolic blood pressure	Auscultated systolic blood pressure (mmHg)	Yearly for 3 years
Secondary	Clinic diastolic blood pressure	Auscultated diastolic blood pressure (mmHg)	Yearly for 3 years
Secondary	Nonalcoholic fatty liver disease	Fat infiltration (yes or no) as measured on liver ultrasound with elastography in subjects with overweight/obesity (BMI >=85th percentile)	Yearly for 3 years
Secondary	Continuous systolic blood pressure	Systolic blood pressure measured continuously for 10 minutes (mmHg)	Yearly for 3 years
Secondary	Continuous diastolic blood pressure	Diastolic blood pressure measured continuously for 10 minutes (mmHg)	Yearly for 3 years