# PEDIATRIC HYPERTENSION: UPDATE

EDITED BY : Ibrahim F. Shatat and Tammy M. Brady PUBLISHED IN : Frontiers in Pediatrics

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# PEDIATRIC HYPERTENSION: UPDATE

Topic Editors:

Ibrahim F. Shatat, Sidra Medicine, Weill Cornell College of Medicine-Qatar, Qatar; Medical University of South Carolina, United States Tammy M. Brady, Johns Hopkins University School of Medicine, United States

Image: EstherQueen999/Shutterstock.com

Citation: Shatat, I. F., Brady, T. M., eds (2018). Pediatric Hypertension: Update. Lausanne: Frontiers Media. doi: 10.3389/978-2-88945-654-3

# Table of Contents

	- Robert P. Woroniecki, Andrew Kahnauth, Laurie E. Panesar and Katarina Supe-Markovina
	- *78 Commentary: Left Ventricular Hypertrophy in Pediatric Hypertension: A Mini Review*

Guillermo A. Perez Fernandez

*80 The Microbiome and Blood Pressure: Can Microbes Regulate Our Blood Pressure?*

Souhaila Al Khodor, Bernd Reichert and Ibrahim F. Shatat

# Editorial: Pediatric Hypertension: Update

Ibrahim F. Shatat 1,2,3 \* and Tammy M. Brady 4

*1 Sidra Medicine, Pediatric Nephrology and Hypertension, Doha, Qatar, 2 Department of Pediatrics, Weill Cornell College of Medicine-Qatar, Ar-Rayyan, Qatar, 3 College of Nursing, Medical University of South Carolina, Charleston, SC, United States, 4 Division of Pediatric Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, United States*

Keywords: LVH, obesity, microbiome, genetic programming, pheochromocytoma, paraganglioma, developmental origins, kidney transplant

**Editorial on the Research Topic**

#### **Pediatric Hypertension: Update**

Hypertension in children and adolescents remains a significant health care concern. Epidemiological studies now report that the prevalence of pediatric hypertension ranges from 3% in the general population to up to 25% in obese children. Historically, pediatric hypertension was considered a secondary phenomenon until proven otherwise. However, more recent evidence describes primary hypertension as being more likely than secondary hypertension among children referred to subspecialty care for evaluation of elevated BP in communities where obesity is prevalent. This shift highlights the early relationship between obesity and learned behaviors such as sedentary lifestyle and increased salt/caloric intake with blood pressure.

In this special pediatric hypertension series, we have assembled contributions from global experts in childhood hypertension to provide the reader with a comprehensive and current update on the varied aspects of hypertension diagnosis, secondary etiologies, and cardiovascular comorbidities. We were fortunate to enlist a prominent group of 22 authors to contribute a wide range of articles. In total, 10 papers have been included (Lewis et al.; Peterson and Miyashita; Al Khodor et al.; Bholah and Bunchman; Woroniecki et al.; Fernandez; Ahn and Gupta; Gurusinghe et al.; Charnaya and Moudgil; Brady).

We introduced the topic of Pediatric Hypertension with a review article highlighting current methodologies and recommendations for hypertension screening in children and adolescents (Lewis et al.). The article by Michaela Lewis, Ibrahim Shatat, and Shannon Phillips walks readers through key issues contributing to both the inaccurate measurement of blood pressure and the misclassification of HTN among children and presents strategies to address these issues. As the authors point out, although national guidelines for the diagnosis and management of pediatric HTN have been available for nearly 40 years, knowledge and recognition of the problem by clinicians remains poor due to a host of influencing factors. They bring to the reader's attention a host of potential exposures known to affect BP, such as recent use of tobacco products, ecigarettes, consumption of a sodium-rich or high caffeine diet, as well as multiple over-the-counter, herbal, and prescription medications. The authors provided the readers with a comparison between

#### Edited and reviewed by:

*Michael L. Moritz, Children's Hospital of Pittsburgh, University of Pittsburgh, United States*

> \*Correspondence: *Ibrahim F. Shatat<EMAIL_ADDRESS>
#### Specialty section:

*This article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics*

Received: *31 May 2018* Accepted: *09 July 2018* Published: *31 July 2018*

#### Citation:

*Shatat IF and Brady TM (2018) Editorial: Pediatric Hypertension: Update. Front. Pediatr. 6:209. doi: 10.3389/fped.2018.00209*

**4**

different available measurement devices [Table 1 in (Lewis et al.)]. Last year and after this review (Lewis et al.), the AAP clinical practice guideline for screening and management of high blood pressure in children and adolescents (1) were published. In the new guidelines, the AAP recommends limiting screening BP measurements to preventive care visits for children without risk factors (while continuing to recommend BP screening at all visits for those at increased CVD risk), introduced updated BP tables based solely on normal-weight children, and a simplified BP classification in adolescents ≥13 years of age.

The new guidelines expanded the role for ambulatory BP monitoring (ABPM) in the diagnosis and management of pediatric hypertension. Caitlin Peterson and Yosuke Miyashita contributed an article (Peterson and Miyashita) to this collection emphasizing that 24-h ABPM should be considered standard of care in pediatric patients. In their manuscript, the authors highlight how ABP is superior to clinic BP in evaluating elevated BP and in diagnosis and classification of HTN. In Table 1 of their manuscript, they summarize pediatric studies that examined the association between TOD and ABPM, while in Table 2 they explore potential future clinical applications of 24-h ABPM.

In two of the best written reviews in the field, Sun-Young Ahn and Charu Gupta reviewed for the readers the topic of genetic programming of hypertension (Ahn and Gupta). Table 1 in this review elegantly summarizes monogenic forms of hypertension, while the text discusses methodologies employed in genetic studies of essential HTN, mechanisms for epigenetic modulation of essential HTN, pharmacogenomics and HTN, and recent advances in genetic studies of essential HTN in the pediatric population. Complementing this review, Shari Gurusinghe, Anita Tambay, and Christine Sethna reviewed the developmental origins of hypertension and the role of nephron endowment (Gurusinghe et al.). The authors guide the readers through one of the most intriguing concepts in pediatric nephrology, that is, how the in utero environment may increase the risk of both hypertension and chronic kidney disease. In Figure 2 of their manuscript, the authors propose a flow chart linking low nephron number to hypertension. Furthermore, the authors discuss the impact of ethnicity and postnatal modifiers on nephron numbers.

Tammy Brady contributed a review that focused on the unique aspects of hypertension evaluation and management in the child with comorbid obesity (Brady). Charnaya and Moudgil reviewed the etiology of post-transplant hypertension (Charnaya and Moudgil); they pointed out that HTN is both a risk factor for graft loss and a consequence of multiple transplant related factors including: donor characteristics, recipient factors, medications, and lifestyle attributes similar to those associated with hypertension in the general population. The authors further discuss other useful techniques to assess CVD in this at risk population.

In a comprehensive review of a potentially curable cause of secondary hypertension in pediatric patients, pheochromocytoma (PCC) and paraganglioma (PGL), Bholah and Bunchman point out that these conditions are inherited in as much as 80% of pediatric cases, and that all patients with mutations should be followed closely given the risk of recurrence and malignancy. In figure 1 of their review, the authors reproduced with permission from Lenders et al. (2) a proposed algorithm for genetic testing of patients with PCC or PGL based on clinical characteristics, biochemical phenotype, and tumor pathology. They also outline the pre-, intra- and postoperative management of these challenging tumors as well as follow up.

Woroniecki and colleagues discussed in their review one of the intermediate outcomes resulting from pediatric hypertension: left ventricular hypertrophy (LVH). The review covers the topic from epidemiology to current definitions, clinically relevant methods of left ventricular mass (LVM) measurements (including new methodologies such as cardiac magnetic resonance) and normalization. It also covers clinical management of LVH and how to best achieve regression of LVH in children with HTN (Woroniecki et al.). This review was followed by a commentary by Fernandez in which the author points out that the PESESCAD-HTA study found diastolic abnormalities even in prehypertensive adolescents without LVH, which underlines additional adverse effects of elevated BP and hypertension on the heart.

In the last review of this article collection on pediatric hypertension, Souhaila Al Khodor, Bernd Reichert and Ibrahim Shatat introduce the readers to the relatively new area of investigation in the field of hypertension, posing an interesting question: Can Microbes Regulate Our Blood Pressure? In Figure 2 of their review (Al Khodor et al.), the authors summarize the current hypotheses linking dysbiosis and blood pressure regulation. They point out that while the field is still in its infancy, researchers have started to examine changes in blood pressure when the microbiome is manipulated by dietary and lifestyle changes aiming to achieve a more balanced microbiome.

Our overarching goal of this compilation was to provide the reader with an up-to-date review of pediatric hypertension and to stimulate interest among academic and practicing physicians and scientists on this important topic. With longitudinal studies clearly demonstrating that blood pressure and hypertension in childhood tracks into adulthood, we hope these comprehensive reviews spur more research focused on decreasing the growing burden of hypertension and cardiovascular disease worldwide.

# AUTHOR CONTRIBUTIONS

IS wrote and reviewed the editorial. TB contributed to review process and editing.

# REFERENCES

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2018 Shatat and Brady. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Screening for Hypertension in Children and Adolescents: Methodology and Current Practice Recommendations

#### *Michaela N. Lewis\*, Ibrahim F. Shatat and Shannon M. Phillips*

*Medical University of South Carolina, Charleston, SC, USA*

Hypertension (HTN) requires urgent, uniform, and consistent attention across all frontiers of pediatric health care not only because of established links between the onset of HTN during one's youth and its sustenance throughout adulthood but also because of the sequelae associated with the disease's trajectory, such as cardiovascular disease, end organ damage, and decreased quality of life. Although national guidelines for the diagnosis and management of pediatric HTN have been available for nearly 40 years, knowledge and recognition of the problem by clinicians remain poor due to a host of influencing factors. The purpose of this article is to explicate key issues contributing to the inaccurate measurement of blood pressure and misclassification of HTN among children and to present strategies to address these issues.

#### *Edited by:*

*Agnieszka Swiatecka-Urban, University of Pittsburgh, USA*

#### *Reviewed by:*

*Francois Cachat, University Hospital of Bern, Switzerland Donald Lee Batisky, Emory University, USA*

> *\*Correspondence: Michaela N. Lewis<EMAIL_ADDRESS>
#### *Specialty section:*

*This article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics*

*Received: 24 January 2017 Accepted: 28 February 2017 Published: 15 March 2017*

#### *Citation:*

*Lewis MN, Shatat IF and Phillips SM (2017) Screening for Hypertension in Children and Adolescents: Methodology and Current Practice Recommendations. Front. Pediatr. 5:51. doi: 10.3389/fped.2017.00051*

Keywords: blood pressure measurement, hypertension, ambulatory monitoring, children, oscillometric

# INTRODUCTION

Hypertension (HTN) requires urgent, uniform, and consistent attention across all frontiers of pediatric health care not only because of established links between the onset of HTN during one's youth and its sustenance throughout adulthood but also because of the sequelae associated with the disease's trajectory, such as cardiovascular disease (CVD), end organ damage, and decreased quality of life.

Between 2011 and 2014, the prevalence of HTN among children and adolescents aged 8–17 years was approximately 2.2% (1), a number similar to other chronic childhood illnesses that garner more attention, such as asthma (9%), autism (1%), or epilepsy (1%) (2). Up to 30% of newly diagnosed hypertensive children demonstrate significant target organ damage, particularly left ventricular hypertrophy (2). Pediatric HTN is an issue attracting attention on a national level, as the reduction of the proportion of children with HTN is an active objective of the Healthy People 2020 movement (1).

Although national guidelines for the diagnosis and management of pediatric HTN have been available for nearly 40 years, knowledge and recognition of the problem by clinicians remain poor due to a host of influencing factors (3). Faulty blood pressure (BP) testing can lead to misdiagnosis and unnecessary treatment, so proper BP measurement methods are essential. To obtain accurate BP measurements, clinicians must consider the type of equipment to be used, training personnel on proper technique, the environment in which measurement is conducted, classification of BP according to recommendations, and assessment for factors that could affect BP. The purpose of this paper is to provide an overview of practice recommendations, including a discussion of factors that may impact a provider's ability to appropriately assess pediatric patients for HTN.

**7**

# PRACTICE RECOMMENDATIONS

The United States Preventive Services Task Force states that the current evidence is insufficient to assess the balance of benefits and harms of screening for primary HTN in asymptomatic children and adolescents to prevent subsequent CVD in childhood or adulthood (4). The lack of compelling evidence to universally screen healthy children was also highlighted in a review by Chiolero and colleagues (5). However, given the implications of HTN and CVD in adulthood, a lifespan approach of early screening has been advocated by the National Heart, Lung, and Blood Institute (NHLBI) (6) and the American Heart Association (AHA) (7).

The AHA (7), NHLBI (6, 8), and American Association of Pediatrics (9) recommend that children over 3 years and under 18 years receive a BP measurement at least annually, and once during every health-care episode. Children under 3 years should have their BP measured in special circumstances such as a history of being very low birth weight, history of recurrent urinary tract infections, and congenital heart disease.

#### Device Selection

When selecting a device, clinicians must consider the necessary equipment, advantages, and disadvantages associated with each option. The most commonly used devices are the mercury sphygmomanometer, the aneroid sphygmomanometer, the office oscillometric device (single and serial measure), and the ambulatory blood pressure monitor (ABPM). **Table 1** outlines key considerations for each device.

The gold standard is auscultation using a mercury sphygmomanometer; NHLBI BP classification tables are based on auscultatory measurements (6, 7). Since use of an appropriately sized cuff is critical for accurate measurement, the AHA advises clinicians have the following cuff sizes on hand: newborn/premature infant (4 cm × 8 cm), infant (6 cm × 12 cm), older child (9 cm × 18 cm), standard adult, large adult, and thigh for leg measurement or for children with large arms (7). The bladder width should be at least 40% of the patient's arm circumference midway between the olecranon and acromion processes and should cover 80–100% of the circumference of the arm (6, 7).

While the mercury sphygmomanometer is considered the gold standard, concerns have arisen about mercury contamination leading to this device being banned in some locations (7). The aneroid sphygmomanometer is a more environmentally friendly alternative that uses metal bellows and levers to register pressure. However, the aneroid sphygmomanometer tends to be less accurate than the mercury sphygmomanometer and requires regular calibration. Wall-mounted aneroid units are less likely to be dropped or subject to trauma and are more accurate than mobile devices (10).

To measure BP using either the mercury or aneroid sphygmomanometer, the clinician inflates a cuff to a pressure greater than the SBP, thus occluding the brachial artery, then gradually deflates the cuff to auscultate sounds using a stethoscope placed at the artery below the cuff. A disadvantage of both options is the potential for observer error, such as differences in training, terminal digit preference, and expectation bias due to knowledge of previous readings (5).

Oscillometric (automated) BP measurement devices have rapidly replaced sphygmomanometers in clinical practice. These devices are more ecologically friendly, easier to use, and eliminate potential sources of bias. Oscillometric devices are also beneficial in situations in which auscultation is challenging, such as with newborns and young infants, where device utilization requires tolerance of excessive motion, and in intensive care settings when repeated measurements are required (7, 11). However, there is wide variation in devices, arterial stiffness and wide pulse pressure can lead to inaccurate readings, and measurement is susceptible to movement artifact.

When selecting an oscillometric device, clinicians should seek instruments that have been validated in the pediatric population (6, 12). The Association for the Advancement of Medical Instrumentation and the British Hypertension Society each developed established protocols for validation, and more recently, the European Society of Hypertension Working Group on Blood Pressure Monitoring developed an International Protocol to validate BP measurement devices (7, 13). To assist clinicians in identifying devices that have been validated and recommended, the dabl Educational established a not-for-profit, foundation-funded website to provide up-to-date validation information on BP measurement devices1 (14). Clinicians may consult these tables to determine which devices are recommended for use in children.

Serial-measure oscillometric devices are designed to obtain a series of BP measurements at intervals of 1 min or more with the patient seated alone in a quiet room in the office setting. The number of serial measurements varies by device, typically three to six, and an average is calculated. In adults, no significant difference has been found between BP classification using serial measurement technique versus 24-h ABPM. The serial measure oscillometric device, such as the BpTru, can substantially reduce the effect of white coat HTN and masked HTN and can be a cost-efficient alternative to ABPM (15–17). The BpTru has been validated in children aged 3–18 years (18).

In some cases, ABPM is warranted to obtain a more accurate representation of the BP. With this method, BP is measured repeatedly, usually over a 24-h period, and the measurements are stored and downloaded (6, 7). ABPM is indicated when white coat HTN is suspected, to identify a non-dipping pressure pattern, to monitor drug effects (6, 7), and in situations when it is necessary to monitor BP patterns, such as chronic kidney disease, autonomic dysfunction (6), target-organ damage, and low birth weight (12).

Various ABPMs are available, but few have been formally validated in children (11). Beyond ensuring validation of a device, clinicians should identify a monitor that is lightweight, able to tolerate movement, and has pediatric cuffs. Software should be programmable to measure every 15–20 min over 24-h period, and preferably, can provide a report with pediatric reference data (19). ABPM can be conducted with a wide age range of children (20), but may not be well tolerated in all children, requires family training and cooperation, is susceptible to misreporting (12), and equipment and monitoring procedures are costly. Further, normative values differ by sex, height, and race (21, 22).

#### Care of Equipment

Equipment must be properly maintained to ensure accurate measurement. Hardware should be cleaned with disinfecting wipes, and ABPM cuff covers should be washed between patients (11). The column of mercury sphygmomanometers should be clean, should rise and fall freely, and the upper curve of the meniscus should rest at 0 mmHg. Aneroid and other non-mercury sphygmomanometers should be calibrated semiannually by connecting the manometer to mercury column or electronic testing device. The needle should rest at 0 mmHg and should read within 4 mmHg of the mercury sphygmomanometer when inflated to 100 and 200 mmHg (6, 7). Since various automated devices are available on the market, calibration should occur according to the manufacturer's recommendations (11).

#### Performance Considerations

The use of proper technique when obtaining BP readings is vital in terms of obtaining an accurate measurement and essential in reducing procedure variability. When possible, the patient should be seated with the antecubital fossa supported at heart level. The patient's feet should be on the floor, not dangling from an exam table. Clinicians should remove clothing that covers the location of the cuff. The patient's legs should be uncrossed, with the back and arm supported (7). A cuff placed over clothing can cause a 5–50 mmHg discrepancy in SBP, an unsupported back can cause a 6–10 mmHg discrepancy in SBP, and sitting with the arm unsupported can cause a 1–7 mmHg in SBP and a 5–11 mmHg discrepancy in DBP (23).

In addition to proper positioning, the patient should be in a quiet environment. The clinician should avoid overinflating the cuff, since an overly tight cuff can cause upset in young children. Avoid talking during measurement (7), since talking and active listening can cause a 10-mmHg discrepancy in SBP and DBP (23).

Using the appropriate cuff size is another critical factor, since a too-small cuff can lead to false high readings and a too-large cuff can lead to false low readings (6). A too-small cuff can cause a discrepancy of 10 mmHg in SBP and 2–8 mmHg in DBP (23). Standard cuff placement is the upper arm; the right arm is the preferred site for repeated measures to maintain consistency and for accurate comparison to standards (6). In some circumstances, such as arm fracture or in the case of acute illness, it may be necessary to measure in an alternate site or position. It is important to note that pressures vary by location and position.

1http://www.dableducational.org/welcome.html.

#### BP Classification

Accurate BP classification requires assessment of the patient's age, sex, and height (7). The clinician first determines the patient's height percentile using Centers for Disease Control and Prevention growth charts, then the clinician refers to the NHLBI (6) standardized BP classification tables to categorize the BP as normotensive, prehypertensive, or hypertensive. The AHA and the NHLBI recommend the patient's BP be measured and recorded at least twice at each occasion, and the average of SBP and DBP be recorded (6, 7). However, Becton and colleagues (24) conducted an evaluation of NHANES data and found that in greater than 90% of adolescents aged 13–18 years, the BP classification remained the same in repeat sequential measurements.

Once the BP is plotted on the appropriate table for age, sex, and height, the percentile ranking is assessed. A BP that falls below the 90th percentile is considered normotensive, while a BP that falls between the 90th and 95th percentile is classified as prehypertension. Further, adolescents with a BP greater than 120/80 should also be considered prehypertensive. Patients with a BP that falls into the prehypertensive range should be reassessed and evaluated for other risk factors (6). A BP that, on repeated assessments, consistently falls equal to or greater than the 95th percentile for age, sex, and height is classified as hypertensive (6, 7). If a BP falls between the 95th percentile and the 99th percentile plus 5 mmHg, the measurement should be repeated on two additional occasions to confirm the classification. However, if the BP is greater than the 99th percentile plus 5 mmHg, the patient should be promptly referred to a specialist for evaluation (6).

Before diagnosing a patient as hypertensive, the elevated BP should be confirmed on repeat visits, as BP measurement is more accurate if averaged over weeks or months rather than at a single visit (6, 7). An exception for this recommendation is when a patient appears symptomatic or has a profoundly elevated BP, in which case the patient should be promptly referred for further evaluation.

Pediatric HTN experts have developed and validated quick reference tables that are easier to use in the busy clinic setting than the complex NHLBI standardized BP classification tables. One example is "A Pocket Guide to Blood Pressure Measurement in Children" developed by the National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (25). This reference guide is published online by the NHLBI2 and offers tips on measurement, classification, and interpretation, and a simplified table by age and height.

2https://www.nhlbi.nih.gov/files/docs/bp\_child\_pocket.pdf.

#### REFERENCES

#### Other Special Considerations

Clinicians must also assess for factors that could affect BP, such as routine or intermittent medication use, recent use of tobacco products, and consumption of a sodium-rich or high caffeine diet. Multiple over-the-counter, herbal, and prescription medications have the potential to elevate BP, including decongestants, ephedra, ginkgo, ginseng, senna, St. John's wort, and oral contraceptives. Clinicians should also consider whether the patient is being treated for ADHD, since some medications prescribed for this condition may elevate BP. It is also important to assess for use of illegal substances such as anabolic steroids, amphetamines, and cocaine, all of which can affect BP (26).

Use of tobacco products can cause masked HTN (7), and smoking within 30 min of BP measurement can cause a 6–20 mmHg discrepancy in SBP (23). Clinicians should ask questions directed at determining recent tobacco use, but should also inquire about sustained tobacco use since this can cause arterial changes that may affect BP. Smoking in the home, by parents or other residents, should also be assessed, because secondhand smoke can increase BP (27). Clinicians should also consider e-cigarette use, which can increase the DBP; e-cigarette use tripled among middle and high school students from 2013 to 2014 (28).

Finally, clinicians should consider the effect of dietary habits and sleep habits when assessing BP. Increased consumption of processed foods and those high in sodium, and poor sleep are associated with an elevated SBP (12), and caffeine use has been associated with masked HTN (7).

#### CONCLUSION

Given the implications of CVD in adulthood, a lifespan approach of early screening for HTN in children is essential in reducing the mortality and morbidity associated with vascular compromise. While this article provides an overview of practice recommendations, current guidelines are actively being revised and updated. Adherence to recommended pediatric HTN guidelines through the use of accurate screening measures and practices and remaining abreast of practice guideline updates is the first step down the path of healing.

#### AUTHOR CONTRIBUTIONS

All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing, or revision of the manuscript.

diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. *Pediatrics* (2004) 114:555–76. doi:10.1542/peds.114.2.S2.555

**Conflict of Interest Statement:** The authors declare that the manuscript was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2017 Lewis, Shatat and Phillips. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# The Use of Ambulatory Blood Pressure Monitoring As Standard of Care in Pediatrics

*Caitlin G. Peterson and Yosuke Miyashita\**

*Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States*

Hypertension (HTN) is a significant global health problem, responsible for 7.5 million deaths each year worldwide. The prevalence of HTN is increasing in the pediatric population likely attributed to the increase in childhood obesity. Recent work has also shown that blood pressure (BP) tends to track from childhood to adulthood including BP-related target organ damage. In the last 25–30 years, pediatric use of ambulatory blood pressure monitoring (ABPM) has been expanding mainly in the setting of initial elevated BP measurement evaluation, HTN therapy efficacy follow-up, and renal disease. However, there are many clinical areas where ABPM could potentially be used but is currently underutilized. This review summarizes the current knowledge and the uses of pediatric ABPM and explores clinical areas where it can be very useful both to detect HTN and its longitudinal follow-up. And thus, ABPM could serve as a critical tool to potentially prevent early cardiovascular mortality and morbidity in wide variety of populations. With solid data to support ABPM's superiority over clinic BP measurements and these clinical areas for its expansion, ABPM should now be part of standard of care in BP evaluation and management in pediatrics.

Keywords: pediatric hypertension, ambulatory blood pressure monitoring, white coat hypertension, masked hypertension, hypertensive target organ damage

## INTRODUCTION

The prevalence of hypertension (HTN) in children and adolescents ranges from 1 to 5% while prehypertension has been reported as high as 10% with rates of both HTN and prehypertension increasing over the past two decades (1, 2) Proper assessment of blood pressure (BP) in children and adolescents is important because pediatric BP is the strongest identified predictor for adult HTN (3, 4). Most recently, BP trajectory from childhood to young adulthood has been shown to be associated with target organ changes, specifically left ventricular mass index (LVMI) and carotid intima-media thickness (cIMT) (5). In the United States, approximately 32% of adults have HTN and worldwide, the prevalence of adult HTN is around 40% (6, 7). HTN contributes to 7.5 million deaths or 12.8% of all deaths globally per year (7). In addition to its morbidity and mortality, HTN costs \$48 billion each year to the United States health-care system (8). Other common chronic diseases including coronary artery disease, renal disease, diabetes, and obesity are also adversely affected by and contribute to HTN, making it the primary risk factor-related cause of death worldwide (9). And thus, appropriate diagnosis and treatment of HTN in the pediatric population is important to prevent future cardiovascular disease and premature deaths as well as to decrease its economic burden.

#### *Edited by:*

*Ibrahim F. Shatat, MUSC, United States*

#### *Reviewed by:*

*Gaurav Kapur, Children's Hospital of Michigan, United States Susan Halbach, Seattle Children's Hospital, United States*

> *\*Correspondence: Yosuke Miyashita*

<EMAIL_ADDRESS>
#### *Specialty section:*

*This article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics*

*Received: 03 March 2017 Accepted: 19 June 2017 Published: 30 June 2017*

#### *Citation:*

*Peterson CG and Miyashita Y (2017) The Use of Ambulatory Blood Pressure Monitoring As Standard of Care in Pediatrics. Front. Pediatr. 5:153. doi: 10.3389/fped.2017.00153*

Elevated BP in children and adolescents is often found during routine well child examinations or sports participation physicals. The National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents defines HTN in the Fourth Report as average systolic BP (SBP) and/or diastolic BP (DBP) ≥the 95th percentile for age, gender, and height on three or more occasions (10). Prehypertension is defined as average SBP and/or DBP between the 90th and 95th percentile. If the 90th percentile is higher than 120/80, which is the prehypertension threshold for adults, then 120/80 is also the threshold value used in adolescents (10). Clinic BP measurements have potential problems including improper technique, terminal digit preference, observer bias, and accommodation effect. In addition, BP measurements obtained in clinics may not necessarily reflect the true BP of an individual throughout the day while repeated ambulatory BP measurements using automatic devices may reflect more representative BP values and better risk stratification (11, 12). We now have pediatric ambulatory blood pressure monitoring (ABPM) practice guidelines and increasing clinical outcome data associated with ABPM parameters (13, 14). This review will briefly discuss the current use of pediatric ABPM and will have in-depth discussion on the state-of-the-art pediatric ABPM outcome data and promising clinical areas of expansion for ABPM to make a provocative argument for its use as standard of care in pediatric BP evaluation and management.

# ABPM USE IN PEDIATRICS

In order to overcome the limitations of clinic BP measurements mentioned above, ABPM has been in use in children and adolescents in the last 25–30 years (15, 16). A detailed description of ABPM and equipment has been published by the American Heart Association (AHA) in 2008 (13), and interested readers are encouraged to review this publication. In brief, a monitor is worn in the child's home environment, which should provide more accurate measurement of their true BP including during sleep. The device consists of a light-weight monitor and appropriately sized BP cuff worn on the non-dominant arm. Awake measurements occur every 15–20 min and sleep measurements occur every 20–30 min. Most authorities define a valid study as one with at least one valid reading per hour, and >40 BP readings in the 24 h period or >65% of all possible BP readings for a partial day study(13). Both oscillometric and auscultatory devices are available and validated for children (17). The largest cross-sectional pediatric ABPM study to formulate normative data used oscillometric devices (18, 19). Oscillometric devices usually have fewer erroneous readings and are easier to use than auscultatory devices (13). Mainly for these reasons, oscillometric ABPM devices are more commonly used in current pediatric clinical practice. During the study period, a diary is kept to record when the child is awake, asleep, and active in addition to any medication taken during the study period that may influence BP. ABPM may cause mild sleep disturbance in some children but is generally well tolerated (14).

When analyzing ABPM data, the mean SBP and DBP are calculated for the 24 h period as well as awake and sleep hours. BP load is calculated as the proportion of readings above threshold values expressed in percentages. In children and adolescents, threshold values are the 95th percentile of gender and height. ABPM is not performed in young children (<5 years old) because there are no normative data for this age group, and this age group is unlikely to tolerate the frequent BP measurements. Currently, indications for ABPM include confirming the diagnosis of HTN, evaluating for white coat hypertension (WCH) and masked hypertension (MH), assessing effectiveness of antihypertensive medication, and determining if symptoms can be attributed to drug-related hypotension (14). There are six categories of BP staging based on combination of clinic BP measurements and ABPM:

## PEDIATRIC ABPM OUTCOME DATA

Adult ABPM studies have consistently reported superiority of ABPM parameters over clinic BP in predicting mortality, cardiovascular events, and target organ damage such as left ventricular hypertrophy (LVH) (20–22). In contrast to adults, there are no pediatric data available that correlate patient outcome with ABPM parameters largely due to very low incidence of mortality and cardiovascular events. However, there have been an increasing number of pediatric studies that have investigated ABPM parameters with target organ changes, including the heart, the arterial wall thickness, the kidneys, and central nervous system development. The following subsections will summarize published pediatric ABPM studies showing correlation between ABPM parameters with various target organ changes. This will be followed by subsections summarizing pediatric ABPM studies on WCH, MH, renal disease, and antihypertensive medication efficacy.

#### Target Organ Damage

**Table 1** summarizes the pediatric ABPM studies that have investigated its parameters with target organ changes and their references. Among the target organs, the most studied is the heart, specifically the correlation between ABPM parameters and LVMI, which is a representation of left ventricular mass

normalized by body surface area. It is now well established that left ventricular mass starts to increase with increasing BP even in the pediatric age range (23, 24), and LVH is an established risk factor of cardiovascular events in adults (25). There are several studies that have demonstrated that ABPM parameters are superior to clinic BP measurements in predicting higher left ventricular mass. Sorof et al. demonstrated LVMI strongly correlating with ABPM parameters such as mean SBP and SBP load where there was no correlation with clinic BP measurements (26). Maggio et al. found systolic ambulatory HTN by ABPM in 48% of obese children where clinic BP was normal in 55% of these hypertensive children, and after adjustment, LVMI was only associated with 24 h SBP (27). Richey et al. demonstrated that ABPM parameters such as higher 24 h SBP load predicted greater likelihood of increasing LVMI (28). Increased cIMT has been established as an independent risk factor for strokes in adults (29). There are now multiple pediatric studies showing an association between abnormal ABPM parameters with increased cIMT (30, 31). Further, obesity has also been associated with increased cIMT, but Lande et al. demonstrated several ABPM parameters to correlate strongly with cIMT in an age, gender, and body mass index matched study (32). In adults, microalbuminuria has been shown to be a marker of HTN-induced renal injury (33). However, pediatric ABPM studies have not demonstrated ABPM parameters to independently predict presence of microalbuminuria in non-diabetic children and adolescents to date (34, 35).

There is fairly extensive adult literature, which demonstrates that HTN is associated with poorer cognitive performance including learning and memory, executive functions; and visuospatial, visuoconstructional, psychomotor, and perceptual abilities, and chronic uncontrolled HTN predicts cognitive decline over time (36). More recently, there is emerging preliminary data, which suggest that children and adolescents with primary HTN are associated with neurocognitive deficits when compared to normotensive controls. Early studies in children on the link between HTN and cognitive function include a cross-sectional study that demonstrates children with elevated clinic SBP have an independent association with lower digit span test scores, which is a measure of short-term memory, attention, and concentration (37). This was followed by a matched longitudinal study of parental ratings of executive function of children with ABPM confirmed primary HTN. At the time of initial diagnosis, hypertensive children had lower parental rating of executive function compared to matched normotensive children (38). After 1 year of antihypertensive therapy, ABPM demonstrated improved BP in the hypertensive group, which also correlated with improvement in parental ratings of their executive function (39). Most recently, a multicentered study of neurocognition in children demonstrated that children with ABPM confirmed untreated primary HTN had lower performance on neurocognitive testing, in particular, on measures of memory, attention, and executive functions, compared to normotensive matched controls (40).

In summary, the above published studies suggest that proper diagnosis of HTN by ABPM in children and adolescents has the potential to prevent and/or to treat target organ damages, in particular, the heart, the arterial vessels, and the central nervous system, which may not be possible with clinic BP measurements alone.

#### White Coat Hypertension

White coat hypertension in children and adolescents may be fairly common as studies have reported a wide range of prevalence of 13–52% of children with elevated clinic BP measurements (41–43). ABPM serves an important role in the initial evaluation of elevated BP measurement as misdiagnosis of HTN in patients with WCH may lead to unnecessary testing and treatment, which may cause adverse side effects and events and will add unnecessary health care cost. The clinical significance of WCH is not clear at this point in children and adolescents, but there are studies to suggest that it may represent a prehypertensive state. Pediatric ABPM studies suggest that WCH may result in intermediate target organ changes (41, 44). In a study where age, gender, and BMI were matched for ABPM confirmed WCH subjects with confirmed hypertensive subjects and normotensive subjects, the mean LVMI of WCH subjects was between that of normotensive and hypertensive subjects. The difference between the WCH subjects and normotensive subjects was statistically significant (45). Another study found that ABPM confirmed WCH subjects tended to have higher LVMI than normotensive subjects but lower than hypertensive subjects, although no statistically significant differences were found between the groups (41). There is currently no practice guideline on laboratory and imaging evaluation or subsequent follow-up of children and adolescents with WCH, but efforts are underway for longitudinal studies for children and adolescents with WCH.

#### Masked HTN

The prevalence of MH in general pediatric population has been reported to be just under 10% (42, 46) and around 35–50% in children and adolescents who have risk factors for HTN such as chronic kidney disease (CKD) and post-coarctation of aorta repair (47–49). Currently, the mechanism of MH is still unclear. There are convincing data to suggest that left ventricular mass changes detected in children and adolescents with MH is very similar to those with sustained HTN (42, 46). Thus, identifying patients with MH is critical so target organ damages can be reversed and to potentially delay cardiovascular events. Diagnosis of MH is difficult since performing ABPM in all pediatric patients with normal clinic BP measurements is impractical. Identifying children with risk factors for MH with conditions discussed in sections below and/or family history of early HTN and cardiovascular events is critical since ABPM could potentially "unmask" their HTN and reduce cardiovascular risk factors. Similar to WCH, further studies are needed so that evidence-based practice guidelines could be formulated in order to identify which pediatric populations should undergo ABPM to identify MH.

#### CKD and Renal Transplantation

One of the most important populations to properly diagnose HTN is children with CKD as HTN is a well-known modifiable risk factor for progression of CKD (47, 50–52). These patients can often be missed as having HTN because of an increased risk for MH compared to the general population (49). A crosssectional analysis of CKD in Children cohort with CKD stage 2 through 4, ages 9 through 15 years, found 38% of participants had MH and 18% had HTN confirmed by ABPM (49). Seventeen percent of this cohort had LVH with 34% from the MH group and 20% with confirmed HTN with increase in LVH prevalence from 19 to 39% over a 2-year period (49). Most importantly, the reduction in the rate of progression of CKD by tight BP control was demonstrated by the Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) trial where intensified ABPMguided HTN therapy over a 5-year period led to a 35% reduction in subjects with 50% decline in renal function or progression to end stage renal disease (52).

Hypertension implication in the renal transplant children and adolescents is similar to CKD population including its high prevalence, cardiovascular significance, and prognosis of allograft. When ABPM was used in renal transplant patients, prevalence of MH was found to be around 25–45%, and prevalence of uncontrolled HTN among treated patients ranged between 18 and 82% with median prevalence of 53% suggestive of the importance of routine use of ABPM in post-renal transplant population (53). Yearly ABPM-guided HTN treatment in 22 renal transplant patients after median follow-up of 9 years showed 14 of 17 children with treated HTN had excellent BP control, and the prevalence of LVH was only 4.5% with no progression of cIMT (54). Last, tighter BP control by annual ABPM-guided therapy resulted in normotensive group to have stabilization of the allograft function at 2 years after transplantation, and in contrast, the hypertensive group had a statistically significant decline in allograft function suggestive of preservation of allograft function with better BP control (53).

Thus, based on these published reports in CKD and post-renal transplant children and adolescents, the use of ABPM appears to be critical in their longitudinal follow-up not only to properly detect HTN but also to treat their HTN to slow down the progression of CKD or to preserve their allograft function.

#### Antihypertensive Medication Efficacy

Ambulatory blood pressure monitoring is not only an effective way to properly diagnose HTN at the onset but it is also an effective way to determine the efficacy of HTN therapy. Seeman et al. demonstrated that nearly half of the pediatric patients on antihypertensive medications were found to have uncontrolled HTN by ABPM parameters. In addition, 35% of this study population had reclassification of controlled or uncontrolled HTN after having ABPM from their original classification based on clinic BP measurements, and the prevalence of LVH was significantly higher in uncontrolled HTN group compared to controlled HTN group (55). Similarly, Halbach et al. found that performing ABPM resulted in 63% of treated hypertensive children to have their medication changed (56). Last, Flynn also reported 4 out of 7 patients requiring adjustment of antihypertensive medications after undergoing ABPM (57). Thus, these studies are convincing of the clinical usefulness of ABPM for longitudinal BP assessment in efficacy of treated hypertensive children and adolescents.

Ambulatory blood pressure monitoring's superiority at detecting treatment-induced BP changes compared to clinic BP measurements makes it ideal for its use in pediatric antihypertensive medication clinical trials. Using the ESCAPE trial cohort, Gimpel et al. showed that SD of ABPM responses were up to 39% smaller than those of clinic BP measured responses. Using power analysis, they showed that depending on the magnitude of the aimed BP reduction, sample size could be reduced by 57–75% with the use of ABPM, which would be critical in reducing the number of hypertensive subjects receiving placebo drugs (58).

# CLINICAL AREAS OF EXPANSION FOR ABPM

The use of ABPM in children and adolescents has become more prevalent especially when evaluating to distinguish sustained HTN from WCH for elevated clinic BP measurements and in patients with kidney diseases including CKD and post-renal transplantation as discussed in the previous section. However, there is a wide spectrum of clinical areas where ABPM is not routinely used currently and where it could be very useful in detecting hypertensive patients. **Table 2** demonstrates these conditions in which ABPM can potentially be utilized even if they have normal clinic BP measurements.

# Coarctation of Aorta

Coarctation of aorta is one of the more common causes of secondary HTN in pediatrics and makes up about 2% of all children and adolescents with HTN (59). More recent reports have also demonstrated long-term mortality and morbidity even after

Potential clinical areas where ABPM should be used to detect masked HTN

Coarctation of aorta Non-renal solid organ transplantation Hematopoietic transplantation Diabetes mellitus Obstructive sleep apnea Turner syndrome William syndrome Neurofibromatosis, type I Sickle cell disease

Table 2 | Clinical areas of expansion for ambulatory blood pressure monitoring (ABPM).

successful coarctation repair. The survival rates of coarctation repair patients have been reported to be up to 20% less compared to age- and gender-matched populations mainly due to cardiovascular disease (60), and rates of persistent aortic hypoplasia and HTN have been reported to be as high as 20–48 and 21–42%, respectively (61, 62). Further, even in post-coarctation repair patients where the aortic arch were reported to be normal, 27% had hypertensive clinic BP measurements, 61% had HTN diagnosed by ABPM, and 55% had LVH with higher rates of LVH in ABPM confirmed hypertensive group compared to normotensive group (63). Therefore, ABPM appears to be a critical tool in following BP in post-coarctation of aorta repair patients (60, 63).

#### Non-Renal Solid Organ Transplantation

The literature on the use of ABPM is scarce in non-renal solid organ transplantation. Because of the frequent uses of glucocorticoids and nephrotoxic agents such as calcineurin inhibitors and higher prevalence of CKD, HTN has been reported to be significantly higher than the general pediatric population in liver, intestinal, and heart transplantation (64–67). In the adult cardiac transplantation data registry, HTN incidence is 90% at 5 years after transplantation, and it is one of the main risk factors for cardiac allograft vasculopathy, the fourth leading cause of death at 10 years after transplantation (68). In adult liver transplant patients, cardiovascular disease is the second most common cause of non-liver death behind cancer (69). There have been a small number of pediatric ABPM studies in liver and heart transplant recipients, and they have concluded that clinic BP readings poorly correlate with ABPM parameters (70, 71). Therefore, ABPM should be strongly considered as part of routine posttransplant surveillance evaluation for precise diagnosis of HTN so that onset of cardiovascular mortality and morbidity may be delayed. This is also a fertile area for future and larger studies to investigate the exact prevalence of HTN in these high risk groups.

#### Hematopoietic Cell Transplantation

Similarly, survivors of hematopoietic cell transplantation patients have been reported to have higher risk of HTN from multifactorial etiologies including the use of glucocorticoids, nephrotoxic medications including calcineurin inhibitors and various chemotherapy agents, total body irradiation, graft versus host disease, and kidney injury (72, 73). In a late mortality analysis of hematopoietic cell transplantation patients with median age of 25.9 years old, these survivors have a 2.3-fold increase in risk for premature cardiovascular related death (74). Seventy percent of children and adults have HTN during the first 2 years after hematopoietic cell transplant (72). Again, ABPM could be very useful aspect of routine posttransplant surveillance evaluation for the same reasons as the solid organ transplant recipients.

#### Type I Diabetes Mellitus

Ambulatory blood pressure monitoring also appears to be promising tool in following pediatric patients with type I diabetes mellitus (T1DM). Children with T1DM were frequently found to have ABPM confirmed HTN with most of them being nocturnal HTN suggestive of the important role of ABPM in this population (75). Perhaps more clinically relevant, there was an independent association between nocturnal HTN detected on ABPM with development of microalbuminuria, which is a marker of diabetic nephropathy, in a cohort of adolescents and young adults with T1DM followed for more than 5 years (76). Combining the findings of these studies, ABPM could be used routinely in children and adolescents with T1DM not only to diagnose HTN earlier but also to use it longitudinally for more strict nocturnal BP control to prevent or to slow the progression of diabetic nephropathy.

#### Obstructive Sleep Apnea

One of the more common comorbidity of obesity and obesityrelated HTN is obstructive sleep apnea, and the use of ABPM appears to be helpful in this population. In a tertiary care hospitalbased population, there was an independent association between apnea–hypopnea index and nighttime SBP and mean arterial pressure adjusting for adiposity variables suggestive of children with moderate-to-severe obstructive sleep apnea having higher ABPM parameters compared with children who were primary snorers (77). Similarly, in children with apnea–hypopnea index >5/h, ABPM parameters such as 24 h mean BP and BP loads were significantly increased, and perhaps more clinically relevant, early morning BP surge was more likely to occur in these children (78). Thus, ABPM could be very useful in detecting these abnormal BP patterns even if they have normal clinic BP in otherwise highrisk group of children and adolescents for future cardiovascular disease. Although not completely curative, adenotonsillectomy improved some of the ABPM parameters (79), suggestive of improvement in obstructive sleep apnea having contribution to lowering of BP. Best to our knowledge, although no pediatric study to date has shown lowering of BP with continuous positive airway pressure, adult literature has shown significant decreases in daytime and nighttime SBP and DBP with improvement in number of patients with prehypertension from 94 to 55% and MH from 30 to 5% (80).

# Other Pediatric Conditions with HTN Association

There are relatively common conditions in children and adolescents known to increase the risk of HTN including polycystic ovary syndrome, William syndrome, Neurofibromatosis type I, and Turner Syndrome. Single centered studies in each of these conditions have identified higher detection rates of HTN by ABPM compared to clinic BP measurements (81–85). Women with polycystic ovary syndrome have been found to have increased cardiovascular disease risk factors earlier in life (86), while women with Turner syndrome have a markedly increased incidence of ischemic heart disease, HTN, and stroke (87). Both children and adults with Williams syndrome have been found to have increased cardiovascular disease risk factors (82, 88). Traditionally, patients with sickle cell disease were observed to have lower clinic BP measurements largely attributed to poor urinary concentrating ability. However and surprisingly, a cross-sectional analysis of children with sickle cell disease found 10% to have elevated clinic BP measurements and 44% to have ABPM diagnosed HTN suggestive of high rates of MH in this population. Further, 59% of subjects were found to have impaired SBP nocturnal dipping and 13% had reversed nocturnal dipping (89).

In summary, there are a relatively large number of clinical areas discussed in this section where ABPM is currently underutilized but should be used routinely to detect MH and to follow BP longitudinally in order to prevent and to delay the onset of cardiovascular disease in growing number of high risk children and adolescents with chronic conditions. The 2016 European Society of HTN guidelines for the management of high BP in children and adolescents recommends ABPM for pediatric patients with diabetes mellitus type 1 and 2, CKD, solid organ transplants including renal, liver and heart, and severe obesity with or without sleep disordered breathing (90).

## COST EFFECTIVENESS OF ABPM

Traditional practice in pediatrics for a new diagnosis of HTN often included extensive evaluation of secondary causes of HTN including laboratory investigation, imaging studies, and target organ damage assessment, most often echocardiogram. A cost analysis at a pediatric HTN clinic where the protocol was to perform ABPM on all patients with stage I HTN clinic BP measurements found projected saving of \$2.4 million for every 1,000 patients given their WCH rate of 46% (91). The cost savings were mainly attributed to not doing renal ultrasonography and echocardiogram on children with WCH, and authors speculated that the ABPM cost savings could be even higher as laboratory testing and number of clinic visits would be reduced for children with WCH. Davis et al. found that universal ABPM use at a pediatric HTN referral center accrued the lowest average charge per

ABPM, ambulatory blood pressure monitoring; WCH, white coat hypertension).

hypertensive youth identified and concluded that its universal use may be the most economically and clinically efficient diagnostic strategy (92).

# LIMITATIONS OF ABPM

There are some limitations in our current knowledge and clinical use of pediatric ABPM. The most glaring is the need for more comprehensive normative ABPM data (14, 90). The ABPM normalized data being used today are based on values from the German Working Group on Pediatric HTN, which evaluated 1,141 children aged 5–20 years (18, 19). These children were a homogeneous Caucasian central European population, which is likely not generalizable in children of different races worldwide, and thus, normative data based on larger and multiethnic cohort are greatly needed. Another area in need of improvement is the development of BP measurement device that can measure DBP more accurately as this German normative data have almost flat DBP curve across all height in both genders (93).

Ambulatory blood pressure monitoring monitor availability in pediatric clinics is currently suboptimal. Based on a recent on-line survey among pediatric nephrologists at centers belonging to the Midwest Pediatric Nephrology Consortium in North America, 94% of the survey responders were at centers where ABPM was available, but 57% of responders stated that patients sometimes had to wait to have ABPM as monitors were not available at the time of the visits. This inconvenience is likely attributable to approximately 75% of survey responders practicing at centers owning <10 monitors (publication in press). Last, another potential barrier is the cost to start an ABPM program and its income potential. One ABPM monitor along with the software costs around \$3,500–\$4,000. In the United States, many government-based and other private health insurances either do not cover or have fairly low reimbursement rate for ABPM for children despite the cost effectiveness mentioned above and ABPM published guidelines starting in 2008. It is estimated that 190–200 ABPM studies would need to be performed to recover the initial starting cost (94). With wide spectrum of potential clinical areas of expansion as discussed

# REFERENCES

above, better monitor availability at pediatric HTN clinics will be vital in ABPM becoming routine part of BP evaluation and management.

# CONCLUSION

The health and economic burden of HTN is unquestioned worldwide. Based on recent data to suggest BP tracking from childhood to adulthood with target organ damages, earlier and proper diagnosis of HTN by ABPM is vital in the first step to prevent and to delay cardiovascular consequences of HTN. By properly identifying children and adolescents with WCH, ABPM can also reduce the number of children and adolescents undergoing unnecessary medical tests and experiencing adverse effects from unnecessary therapy. Routine use of ABPM appears to also save costs to the health-care system. Pediatric ABPM studies in the last 25–30 years are starting to demonstrate its superiority in target organ outcomes over clinic BP measurements. In addition, there are multiple clinical areas where ABPM use is currently infrequent, but its use may be very valuable in longitudinal care of many children and adolescents with chronic conditions. **Figure 1** is a schematic diagram of various points where ABPM can be utilized in pediatric HTN. Certainly, we currently have both scientific and practical shortcomings in the pediatric use of ABPM, but this also provides wealth of future research target areas. Thus, in moving forward, we advocate ABPM to be standard of care in the field of pediatric HTN in both clinical and research settings.

# AUTHOR CONTRIBUTIONS

CP and YM performed comprehensive literature search, drafting and editing of manuscript, final approval of the version, and agreed to be accountable for all aspects of the work.

# FUNDING

CP is supported by the University of Pittsburgh Pediatric Nephrology Research Training Grant T32 DK091202.

cannot predict 24-hour average blood pressure. *J Hypertens* (1985) 3(4): 343–9. doi:10.1097/00004872-198508000-00006

children at risk for hypertension. *J Pediatr* (2008) 152(3):343–8. doi:10.1016/j. jpeds.2007.07.014

kidney disease. *Hypertension* (2012) 60(1):43–50. doi:10.1161/ HYPERTENSIONAHA.111.189266

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2017 Peterson and Miyashita. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Genetic Programming of Hypertension

#### *Sun-Young Ahn1,2\* and Charu Gupta1,2*

*1Department of Nephrology, Children's National Health System, Washington, DC, United States, 2 The George Washington University School of Medicine, Washington, DC, United States*

The heritability of hypertension (HTN) is widely recognized and as a result, extensive studies ranging from genetic linkage analyses to genome-wide association studies are actively ongoing to elucidate the etiology of both monogenic and polygenic forms of HTN. Due to the complex nature of essential HTN, however, single genes affecting blood pressure (BP) variability remain difficult to isolate and identify and have rendered the development of single-gene targeted therapies challenging. The roles of other causative factors in modulating BP, such as gene–environment interactions and epigenetic factors, are increasingly being brought to the forefront. In this review, we discuss the various monogenic HTN syndromes and corresponding pathophysiologic mechanisms, the different methodologies employed in genetic studies of essential HTN, the mechanisms for epigenetic modulation of essential HTN, pharmacogenomics and HTN, and finally, recent advances in genetic studies of essential HTN in the pediatric population.

#### *Edited by:*

*Ibrahim F. Shatat, Medical University of South Carolina and Weill Cornell Medical College, United States; Sidra Medical and Research Center, Qatar*

#### *Reviewed by:*

*Ian Robert Macumber, Connecticut Children's Medical Center, United States Rasheed Gbadegesin, Duke University Medical Center, United States*

#### *\*Correspondence:*

*Sun-Young Ahn<EMAIL_ADDRESS>
#### *Specialty section:*

*This article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics*

*Received: 30 October 2017 Accepted: 13 December 2017 Published: 22 January 2018*

#### *Citation:*

*Ahn S-Y and Gupta C (2018) Genetic Programming of Hypertension. Front. Pediatr. 5:285. doi: 10.3389/fped.2017.00285*

Keywords: genetics, hypertension, children, epigenetics, pharmacogenomics, pediatrics

# INTRODUCTION

Hypertension (HTN) is a serious public health issue affecting both children and adults. Between 2009 and 2012, approximately 32.6% of adults in the US were reported to have HTN (1). In children and adolescents between 3 and 18 years of age, the prevalence of HTN has been reported to be 3.6% (2). Morbidity and mortality from HTN continue to be high in adults, with HTN accounting for an estimated 45% of deaths due to cardiac disease and 51% of deaths from strokes (3). Despite its widespread prevalence, however, the etiology of essential HTN remains largely unknown. A growing body of evidence supports the observation that HTN results from a complex interplay of genetic, epigenetic, and environmental factors. Genetic factors are thought to contribute to approximately 30–60% of blood pressure (BP) variation (3, 4). However, known genetic factors explain only 3% of BP variance (5), underscoring the fact that many genetic variants have yet to be discovered. Moreover, these findings suggest that other factors, such as gene–gene interactions and epigenetics, may play a vital role in the etiology of HTN.

The clinical implications for deciphering the genetic factors that contribute to variations in BP and response to antihypertensive medications are significant. Knowledge of an individual's predisposition to HTN can help with early implementation of preventive measures and formulation of effective therapeutic plans. In addition, pharmacogenomic information can help with the selection of personalized medication regimens, which may optimize therapeutic responses and help to reduce health-care costs. In this review, we discuss the various forms of monogenic HTN, the different study designs used to investigate the genetic epidemiology of essential HTN, the epigenetics of essential HTN, HTN pharmacogenomics, and recent advances in the genetics of essential HTN in children.

# MONOGENIC HTN

Monogenic HTN syndromes refer to hypertensive disorders that follow Mendelian inheritance patterns due to single-gene mutations. Most monogenic forms of HTN are associated with volume expansion and low serum renin levels. A summary of the various types of monogenic HTN is provided in **Table 1**. **Figure 1** presents the different pathophysiologic mechanisms that are involved in monogenic forms of HTN.

# Glucocorticoid-Remediable Aldosteronism (GRA)/Familial Hyperaldosteronism (FH) Type I

Glucocorticoid-remediable aldosteronism, an autosomal dominant disorder, was the first monogenic HTN syndrome to be identified (6). GRA is caused by a chimeric gene formed from the fusion of the promoter region of the 11 β-hydroxylase gene (*CYP11B1*) with the coding regions of the aldosterone synthase gene (*CYP11B2*) on chromosome 8q (7, 8). As a result of this chimeric gene, aldosterone production is activated by ACTH and becomes independent of renin regulation (7). The development of hyperaldosteronism, with resultant salt and water retention, leads to HTN. Patients with GRA typically present with mild hypokalemia, metabolic alkalosis, and low plasma renin levels. The early onset of GRA before 21 years of age and the development of significant hypokalemia with a thiazide diuretic are important clinical features of this condition (9).

Some patients with GRA may exhibit unique features such as cerebral aneurysms and intracranial bleeding. Therefore, screening by brain MRI at the onset of puberty in patients with GRA has been recommended (10). As the name suggests, GRA is remediable by glucocorticoids since they inhibit ACTH production, the stimulus for aldosterone production in GRA (11).

#### Other Rare Forms of FH

*GRA, glucocorticoid-remediable aldosteronism; AME, apparent mineralocorticoid excess; CAH, congenital adrenal hyperplasia; AD, autosomal dominant; AR, autosomal recessive; MC, mineralocorticoid; HTN, hypertension.*

ion selectivity, triggering membrane depolarization and increased calcium entry into the adrenal glomerulosa cells. This in turn leads to hyperaldosteronism, HTN, adrenal hyperplasia, and severe hypokalemia (13, 15). Treatment usually requires bilateral adrenalectomy, especially in drug resistant cases.

(iii) FH type IV: discovered in five unrelated families by wholeexome sequencing, FH type IV is due to a gain-of-function mutation in the *CACNA1H* gene that encodes a T-type calcium channel (13). This mutated channel allows excess calcium entry into the adrenal glomerulosa cells and subsequent hyperaldosteronism (16). Mineralocorticoid receptor antagonists may be used for the treatment of FH type IV (14).

## Syndrome of Apparent Mineralocorticoid Excess (AME)

The syndrome of AME is an autosomal recessive disorder caused by an inactivating mutation in the *HSD11B2* gene, which encodes the 11β-hydroxysteroid dehydrogenase type II enzyme. This enzyme normally converts cortisol to the less active metabolite cortisone. With the inactivating mutation, excess cortisol accumulates and binds to the mineralocorticoid receptor, leading to symptoms of mineralocorticoid excess (17). Both mild and severe phenotypes of AME have been described. The mild AME phenotype manifests as mild HTN later in life with rare or no electrolyte abnormalities, while the severe phenotype presents early in life with severe HTN, failure to thrive, and early end organ damage (18). These phenotypic differences are likely related to differences in the level of enzyme expression. Whereas 11 β-hydroxysteroid dehydrogenase type II enzyme expression is almost absent in the severe phenotype of AME, it is present in varying degrees in the mild form of AME as a result of different mutations in the *HSD11B2* gene (19, 20).

Other clinical features of AME include hypokalemia with an increased trans-tubular potassium gradient, metabolic alkalosis, hypercalciuria, and nephrocalcinosis (18, 19). These clinical features are similar to those seen in licorice abuse, because licorice inhibits the same enzyme involved in AME. Genetic testing may be done to confirm the diagnosis. Treatment usually consists of mineralocorticoid receptor antagonists (spironolactone and eplerenone), epithelial Na channel blockers (amiloride), and thiazides (for hypercalciuria) with potassium supplementation as needed (18).

Geller syndrome, otherwise known as HTN exacerbated by pregnancy, is another mineralocorticoid excess syndrome caused by an activating mineralocorticoid receptor gene mutation. As a result of this mutation, the mineralocorticoid receptor loses its specificity for aldosterone and is activated by both aldosterone and progesterone. Inherited in an autosomal dominant manner, Geller syndrome leads to early HTN, which is exacerbated during pregnancy due to activation of the mineralocorticoid receptors by progesterone. Clinical features include normal serum potassium levels in the setting of low serum renin and aldosterone levels (21).

# Congenital Adrenal Hyperplasia (CAH)

Congenital adrenal hyperplasia results from defects in enzymes involved in cortisol synthesis (14). In type IV CAH (due to 11 β-hydroxylase deficiency) and type V CAH (due to 17 α-hydroxylase deficiency), the loss of cortisol feedback inhibition on the pituitary results in increased ACTH production and adrenal hyperplasia. This in turn leads to the accumulation of cortisol precursors, which cause increased salt and water uptake and subsequent HTN *via* activation of mineralocorticoid receptors. As a result, aldosterone production is suppressed (18).

Characteristic features of type IV CAH are precocious puberty, virilization due to excess sex hormone production with androgenic action, and early onset HTN (22). Type IV CAH is treated with steroids and mineralocorticoid receptor antagonists such as spironolactone for HTN.

Type V CAH has features opposite to type IV CAH due to sex hormone synthesis blockade, which manifests as delayed sexual development in girls and ambiguous genitalia in boys. Type V CAH is treated with steroids and sex hormones, in addition to mineralocorticoid receptor antagonists for HTN (18).

## Liddle Syndrome

Liddle syndrome is an autosomal dominant condition caused by a gain-of-function mutation in the *SCNN1B/SCNN1G* gene (located on chromosome 16p), which encodes the β and γ subunits of the epithelial sodium channel ENaC. This mutation causes an inability of ENaC to be removed from cell surfaces of the cortical collecting tubules, leading to increased sodium reabsorption and subsequent HTN (23). Patients with Liddle syndrome typically present with hypokalemia, metabolic alkalosis, low renin and aldosterone levels, and early onset HTN. Treatment includes a low salt diet and ENaC inhibitors, such as amiloride and triamterene (18).

#### Pseudohypoaldosteronism Type II (Gordon Syndrome, Familial Hyperkalemic HTN)

Gordon syndrome is characterized by autosomal dominant inheritance of serine–threonine kinase gene (*WNK1* and *4*) mutations. Normally, WNK1 inhibits the function of WNK4, while WNK4 inhibits the expression of the Na–Cl cotransporter (NCC) (24). Therefore, a gain-of-function mutation in *WNK1* and lossof-function mutation in *WNK4* collectively result in increased NCC expression and activity in the distal convoluted tubule (14). This leads to salt and water retention, followed by HTN (25). The increased salt reabsorption reduces sodium delivery to the cortical collecting duct, facilitating increased potassium absorption and hyperkalemia, which is typical of Gordon syndrome. ROMK channels, which aid in potassium excretion, can also be inhibited by the *WNK4* mutation, further causing hyperkalemia (8). Other metabolic abnormalities in Gordon syndrome include mild hyperchloremic metabolic acidosis, hypercalciuria, low urinary sodium excretion (26), low serum renin, and varying aldosterone levels. Metabolic abnormalities tend to occur earlier than HTN, which tends to present in adolescence or adulthood (27). Treatment of Gordon syndrome consists of low dose thiazide diuretics.

# HTN with Brachydactyly

Hypertension with brachydactyly is caused by a mutation in the *PDE3A* gene which encodes phosphodiesterase 3A (14). Patients affected by this syndrome have severe salt-independent HTN with short phalanges and metacarpals (28). The mechanism for HTN in this syndrome remains unknown, although it has been suggested that vascular smooth muscle cell hyperplasia and increased vascular resistance may play a role (28).

# GENETIC EPIDEMIOLOGY STUDY DESIGNS FOR ESSENTIAL HTN

Traditional pedigree-based analyses are not very effective in genetic studies of essential HTN due to its complex nature. Therefore, other methodologies have been used to study the genetic epidemiology of essential HTN. The following section contains a brief description of the different study designs that have been employed in investigating the genetics of HTN, with a special focus on genome-wide association studies (GWAS) (7).

## Non-Parametric Linkage Analysis

Linkage refers to the tendency of two genes to be inherited together when they are in close physical proximity to each other on a chromosome (29). Based on this phenomenon, linkage analysis aims to locate the approximate position of a disease gene by using the location of a known marker gene (29, 30). The marker gene refers to a DNA sequence that has a known physical location and has a detectable phenotype. By investigating whether markers and disease traits co-segregate, linkage analysis can approximate the location of the disease gene (29). Non-parametric linkage analysis (or model-free analysis) is used when details regarding the disease, such as the genetic mode of inheritance, are not known (30). This method is particularly useful in studying complex diseases, such as essential HTN, where the mode of inheritance is unknown. Non-parametric linkage analysis of affected sibling pairs can provide significant insights into a particular HTN phenotype (7). However, a limitation of this method is that many affected sibling pairs are often required to achieve adequate power to detect statistically significant differences.

#### Discordant Sibling Pair Analysis

Discordant sibling pair analysis is a type of genetic linkage analysis that traces quantitative genetic trait loci. In this method, the square of the BP difference is measured as a function of the number of alleles that a sibling pair shares at known marker loci (31). If siblings with very discordant BPs are identified, then their genetic variation can be studied. The disadvantage of this method is that the process of identifying siblings with significant BP discordance can be quite challenging (7).

#### Association Studies

Association studies are based on comparisons of a particular allele frequency between cases and unaffected controls/cohorts. These studies aim to determine whether an association is present between the particular allele and a disease trait (32). Association studies can be family-based or population-based (comprising unrelated individuals) and may use a case–control or cohort approach. Population-based studies are more widely used than family-based studies, since fewer resources are required to enroll cohorts than family-based studies. Population-based studies may also require less genotyping (33). One advantage of familybased association studies, however, includes protection against population substructure-related bias. This is a selection bias that occurs when study subjects come from population subgroups with different ancestries (34). This results in spurious differences in allele frequency between cases and controls/cohorts (35). In family-based association studies, study subjects within each family come from the same source population, minimizing selection bias. Another advantage of family-based association studies is the higher likelihood of true linkage and association when significant findings are identified (33).

#### Genome-Wide Association Studies

Based on the concept of linkage disequilibrium at the population level, GWAS attempt to identify the association between genetic variants or single-nucleotide polymorphisms (SNPs), and common disease traits in populations (36). SNPs are located in particular genetic loci and refer to variations in single nucleotides (14, 37).

The Wellcome Trust Case Control Consortium (WTCCC) study, conducted in 2007, was the first study that attempted to identify variants associated with HTN using GWAS; however, no significant association was identified (38). Small sample size and the use of HTN as a discrete variable are some of the reasons for the failure of the WTCCC to identify an association between SNPs and BP (14, 39). The use of HTN as a discrete variable (presence or absence of HTN), as opposed to a continuous variable (systolic BP or diastolic BP), decreases study power and has therefore become an important consideration in subsequent GWAS designs (40).

In 2011, the International Consortium for BP GWAS identified 29 SNPs that were associated with HTN (41, 42). Since then, more than 60 SNPs have been identified that affect BP *via* mechanisms of sodium handling, kidney function, vasoconstriction, and molecular signaling (43–45). Examples of some novel SNPs linked to systolic BP and diastolic BP in both children and adults that have been identified through GWAS are listed in **Table 2**.

Despite the identification of multiple SNPs associated with HTN, each of the common variants that have been discovered to

*SNP, single-nucleotide polymorphism; GWAS, genome-wide association studies.*

this point appear to have only a small overall effect on BP (about 1 mmHg for systolic BP or 0.5 mmHg for diastolic BP) (41), with some rare variants noted to have a larger effect on BP (>1.5 mmHg) (55). These findings suggest that several genes may act in concert to modulate BP, and that other factors, such as gene–gene and gene–environment interactions, may contribute to BP variability.

A challenge of GWAS includes the difficulty in identifying the gene affected by the SNP, since the area of influence of the SNP may lie in distant genes (56). Some SNPs with genome-wide significance also exhibit pleiotropy and demonstrate strong independent links to more than one disease. For example, rs13333226 is independently associated with HTN and chronic kidney disease (57, 58).

Selection of cases and controls may also introduce a confounding bias in GWAS. False associations can be identified if the cases and controls are selected from different populations that have different baseline allele frequencies. This phenomenon is referred to as population stratification and may result when study subjects have different ancestries (35). Methods to address this issue include using genomic information to control for population structure, or using family-based study designs (29, 59). The selection of unaffected family members as controls in family-based study designs has the additional advantage of reducing environmental exposure confounders (60).

The recruitment of a large number of controls can be costly in GWAS due to the extent of genotyping involved. Thus, more studies are using genotypic information from subjects already enrolled as controls in other studies (60).

## EPIGENETICS OF HTN

Epigenetic phenomena refer to changes in gene expression in the absence of alterations of the DNA sequence itself, and include posttranslational histone modification, DNA methylation, and non-coding microRNAs (miRNAs) (61). Although epigenetic modifications are heritable and can be passed on through several generations, they can also be influenced by nutritional, pharmaceutical, fetal, and environmental factors, and may be reversible. Epigenetic events play critical roles in physiological processes such as cellular differentiation, by ensuring that only certain genes are expressed in specific cell types (3). Abnormalities in epigenetic events can lead to the development of HTN, and in fact, HTN has been linked to several epigenetic phenomena as discussed below (62).

#### DNA Methylation

DNA methylation involves the covalent binding of a methyl group to cytosine, forming 5-methylcytosine (5mC) within CpG dinucleotide sequences (61). The methyl groups come from S-adenosylmethionine, the availability of which is dependent on folate metabolism. This association with folate metabolism provides the basis for the strong link between DNA methylation and nutrition (61). DNA methylation of CpG dinucleotides (often located in the promoter regions) results in inhibition of transcription and therefore gene silencing (63). The onset and severity of HTN have been reported to be associated with the extent of DNA methylation (64). Smolarek et al. quantified the amount of 5mC in DNA from patients with essential HTN and found that lower levels of 5mC corresponded to higher stages of HTN (65). Lin et al. reported that hypomethylation of the angiotensin II type I receptor gene correlated with higher systolic and diastolic BPs. Smokers with HTN were also observed to have a lower level of methylation (66).

Interestingly, Meems et al. discovered that vitamin D-deficient parental rats had offspring with increased systolic and diastolic BPs (67). The offspring were found to have hypermethylation of the promoter region of the Panx1 gene. Furthermore, the offspring rats showed impaired endothelial relaxation, consistent with the fact that Panx1 encodes a hemichannel that plays a role in endothelial relaxation (67). These findings suggest that *in utero* nutritional status may affect childhood BPs; however, further research will be needed to determine whether prenatal and postnatal nutritional status have effects on the development of HTN in children (68).

#### Histone Modification

Posttranslational modification of the N-terminal tail of histone proteins through processes such as methylation and acetylation can lead to changes in chromatin dynamics. This in turn leads to either decreased or increased gene expression (63). Both animal and human studies have shown associations between histone modifications and HTN. One such study reported that histone modifications resulted in angiotensin-converting enzyme 1 (ACE1) upregulation in organs from hypertensive rats (69). In human endothelial cells, cell-specific histone modifications were found to regulate mRNA levels of endothelial nitric-oxide synthase (70). Endothelial nitric-oxide synthase plays a role in BP regulation by modulating vascular tone through the production of nitric oxide in the vascular endothelium.

Interestingly, Wang et al. reported that ascorbic acid prevented the development of HTN in rat offspring prenatally exposed to lipopolysaccharide (LPS) (71). LPS exposure induced histone H3 acetylation in the ACE1 promoter region, resulting in increased ACE1 gene expression and HTN in rat offspring. Prenatal treatment with ascorbic acid, however, reversed the histone modification and led to less ACE1 gene expression (71). These findings suggest potential targets for novel antihypertensive therapies that can prevent or treat HTN early in life.

#### Non-Coding RNAs

Non-coding RNAs are increasingly recognized as crucial regulators of gene expression and may influence cell-specificity of gene expression (61). Among non-coding RNAs, miRNAs have been the most widely studied in association with HTN. miRNAs are small non-coding RNAs, approximately 22 nucleotides in length, that silence mRNA expression through mRNA degradation or interference of mRNA translation (72). miRNAs have been reported to modulate BP through various mechanisms. One such mechanism is through the renin–angiotensin system pathway. In human kidneys, hsa-miR-663 was observed to regulate the mRNA levels of renin (*REN*) and apolipoprotein E (*APOE*) by binding to their 3′ untranslated regions (73). In addition, hsamiR-181a was also found to regulate the mRNA expression of *REN* and apoptosis-inducing factor mitochondrion-associated 1 (*AIFM1*). Both miRNAs were downregulated in HTN, leading to increased expression of renin mRNA (73).

Studies are also ongoing for potential treatments for HTN based on epigenetic modifications. Mutations in mitochondrial DNA (mtDNA) have been linked to the development of HTN, proposedly through the action of reactive oxygen species (74). Consistent with these findings, Li et al. observed a decrease in mtDNA-encoded cytochrome *b* (mt-Cytb) and corresponding increase in reactive oxygen species in hypertensive rats (75). Interestingly, they found that when miR21, an miRNA that was found in higher levels in the hypertensive rats compared with controls, was injected into the hypertensive rats *via* a recombinant adeno-associated virus, there was an increase in mt-Cytb levels and lower BPs (75). The authors hypothesized that miR21 plays a compensatory role in HTN. Studies such as these are promising for the development of novel therapies that utilize epigenetic mechanisms, such as miRNAs, to treat HTN.

## PHARMACOGENOMICS AND HTN

Pharmacogenomics refers to the study of genes that can affect a patient's response to drugs. The goal of pharmacogenomics is to develop tailored medications and doses that take into account the differences in each individual's response to drugs. Extensive research has been performed on the genetic aspect of responses to antihypertensive medication, which include drug interaction with the target sites, drug transport, and metabolism. The Clinical Pharmacogenetics Implementation Consortium (CPIC), formed in 2009, establishes guidelines that aid with application of results from pharmacogenetic studies to actionable prescription of drugs (76). However, due to inconsistent results across studies and therefore insufficient evidence, there are no CPIC guidelines to date for antihypertensive medications (77, 78).

The International Consortium for Antihypertensive Pharmacogenomics Studies was established in 2012 to facilitate research of genetic variants that are responsible for interpatient variability in responses to antihypertensive medications (http:// icaps-htn.org). To date, the most consistently reproducible pharmacogenomic data have been based on β-blockers and thiazide diuretics (78). Three genes, *ADRB1*, *NEDD4L*, and *YEATS4*, have been consistently linked with responses to antihypertensive drugs in various studies. The *ADRB1* gene encodes the β-1 adrenergic receptor, which is targeted by the β-blockers. Common SNPs in the *ADRB1* gene include the variants Ser49Gly (rs1801252) and Arg389Gly (rs1801253) (78). Patients who were homozygous for Arg389 and patients possessing the Ser49Arg389/Ser49Arg389 diplotype were reported to have a greater reduction in BP with metoprolol compared with those who were Gly allele carriers and those who had the Gly49Arg389/Ser49Gly389 diplotype, respectively (79, 80).

*NEDD4L* encodes a protein that downregulates the expression of ENaC in the distal nephron, thereby regulating sodium reabsorption in the kidneys (81). Several studies have shown that the more common G allele of rs4149601, located within the *NEDD4L* gene, is linked to greater systolic and diastolic BP reduction in response to thiazide diuretics (82, 83). These findings are consistent with the role of *NEDD4L* in reducing tubular sodium reabsorption.

Single-nucleotide polymorphisms (rs317689/rs315135/ rs7297610) close to the *YEATS4* gene have also been associated with varying responses to thiazide diuretics (84). The *YEATS4* gene encodes a protein, GAS41, which is involved in regulation of cellular proliferation (78). Through GWAS, the rs317689/ rs315135/rs7297610 haplotype was found to be significantly associated with diastolic BP response to hydrochlorothiazide (HCTZ) in African-Americans. The ATC haplotype was linked to a good response to HCTZ, while the ACT and the ATT haplotypes were associated with a poor response to HCTZ (84). The data on gene polymorphisms affecting responses to calcium channel blockers, ACE inhibitors, and angiotensin II receptor blockers are conflicting, and no candidate gene has shown consistent results (85, 86). A summary of recent pharmacogenomic findings on responses to antihypertensive medications is provided in **Table 3**.

# GENETICS OF ESSENTIAL HTN IN CHILDREN

Pediatric genetic studies on HTN are scarce in comparison to adult studies and are often limited by small sample size. A recent study investigated the parental effects of 33 SNPs previously identified by GWAS on the BP of young offspring (53). Based on 1,525 subjects from the Family Atherosclerosis Monitoring In early life study, significant parental effects, albeit small, were reported for the SNPs rs11191548 (*CYP17A1*) and rs17367504 (*MTHFR*) (53). The paternal genotype of rs11191548 was found to be associated with elevated systolic and diastolic BP among offspring, whereas there was no association with the maternal genotype. Both the maternal and paternal genotypes of rs17367504 were associated with elevated systolic and diastolic BP among offspring. This study also observed that the SNP rs1378942 (*CSK*) demonstrated an association with systolic BP from birth to 5 years of age (53).

Table 3 | Genes associated with responses to antihypertensive medications [modified from Burrello et al. (14)].

*CSK* is a tyrosine kinase that plays a role in actin remodeling, which in turn has been shown to affect constriction of the arterial endothelium in murine newborns (54). Although limited by sample size, this was the first study to investigate the effect of parental SNPs on young offspring, and SNPs that affect BP in the early years of life.

In another study, the polymorphism T585C of the Y2 receptor (Y2R) gene was reported to be associated with systolic and diastolic BPs in obese children (90). Y2R is a receptor for neuropeptide Y, which is a potent constrictor of vascular smooth muscle cells. Y2R has also been observed to regulate neurogenic vasoconstriction in spontaneously hypertensive rats (91). Obese children homozygous for the T585 allele in *Y2R* showed significantly lower systolic and diastolic BPs compared with heterozygotes and C allele homozygotes (90).

Genetic predisposition for BP elevation spanning from childhood to adulthood was assessed in a longitudinal study that employed a combined genetic risk score formulated from 13 SNPs previously associated with HTN in adults (92). Subjects with a higher risk score at the age of 9 years had significantly higher diastolic BPs than subjects with a lower risk score. These subjects also had a higher risk for HTN in adulthood (92). Although the effect size was small (β = 0.68 mmHg) (92), this study provides a method for detecting individuals with a genetic predisposition for HTN early in childhood and may be used to identify those patients in which early preventive measures can be implemented.

The association between SNPs and BP in certain ethnic pediatric populations has also been reported in several recent studies. In a study of Chinese children, rs17249754 (*ATP2B1*) was found to be significantly associated with an increased risk for HTN (93). This polymorphism has also been previously linked to HTN in adults. *ATP2B1* encodes a calcium-transporting ATPase that modulates cellular calcium levels in the vascular endothelium, thereby regulating the contraction of vascular smooth muscle cells (94). In a study of Lithuanian children, the insertion/deletion (I/D) polymorphism (rs4340) for *ACE* was found to have a gender-specific association with BP (95). Boys with the *ACE I/D* and *ACE I/D* + *D/D* genotype had significantly increased odds for developing HTN (95), consistent with previous findings that adults homozygous for the D allele have higher plasma ACE concentrations than heterozygotes (96). Similar to these findings, the D-allele of the *ACE I/D* polymorphism was also associated with HTN in obese Brazilian boys (97).

Childhood HTN is a significant risk factor for HTN and cardiovascular disease in adulthood (98–100). Therefore, pediatric studies that identify genetic risk factors and modifiable epigenetic factors for HTN are further needed to formulate preventive strategies that can reduce childhood HTN, and therefore morbidity and mortality later in life. Moreover, drug pharmacokinetics differ between children and adults (101). Pediatric-based pharmacogenomic research would be beneficial in identifying the genes responsible for each child's response to antihypertensive drugs. Antihypertensive drugs have multiple side effects that can have a negative impact on a child's quality of life. Identifying the genes that predispose a child to poor or adverse drug responses would be beneficial in avoiding complications and optimizing therapeutic responses.

# CONCLUSION

Hypertension results from a complex interplay of genetic, epigenetic, and environmental factors. Due to this multifactorial interaction, elucidating single, specific genetic factors that contribute to the development of HTN has been challenging. Nevertheless, novel gene mutations and epigenetic factors causing BP variability continue to be discovered and have enhanced our understanding of BP modulation and the genetic programming of HTN. Interpatient variability in response to antihypertensive medication is well established, and the field of pharmacogenomics promises to provide guidelines for precision medicine and individually tailored antihypertensive regimens that would improve medication efficacy. The majority of genetic studies on HTN to

## REFERENCES

date have been focused on adults, and there are currently few studies that have been conducted in the pediatric population. In view of the prevalence of HTN in the pediatric population, more studies on the genetic risk factors in this population are needed to enhance our understanding of the etiology of childhood HTN and to provide better preventive and therapeutic strategies for the future.

# AUTHOR CONTRIBUTIONS

S-YA and CG contributed to the conception and writing of the manuscript. Both authors provided their final approval and agreed to be accountable for all aspects of the manuscript.

hypertensive rats. *Br J Pharmacol* (2006) 148:703–13. doi:10.1038/ sj.bjp.0706774

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2018 Ahn and Gupta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

# Developmental Origins and Nephron Endowment in Hypertension

#### *Shari Gurusinghe, Anita Tambay and Christine B. Sethna\**

*Department of Pediatrics, Division of Pediatric Nephrology, Cohen Children's Medical Center of New York, New York, NY, United States*

Primary hypertension continues to be one of the main risk factors for cardiovascular disease worldwide. A stable intrauterine environment is critical for the future development and health of the fetus. The developing kidney has been found to be especially vulnerable during this time period, and epidemiological studies have demonstrated that an adverse *in utero* environment is associated with an increased risk of hypertension and chronic kidney disease. Macro- and micronutrient deficiencies as well as exposure to tobacco, alcohol, and certain medications during gestation have been shown to negatively impact nephrogenesis and reduce one's nephron number. In 1988, Brenner et al. put forth the controversial hypothesis that a reduced nephron complement is a risk factor for hypertension and chronic kidney disease in adulthood. Since then numerous animal and human studies have confirmed this relationship demonstrating that there is an inverse association between blood pressure and nephron number. As our understanding of the developmental programming of hypertension and other non-communicable diseases improves, more effective preventive health measures can be developed in the future.

#### *Edited by:*

*Ibrahim F. Shatat, MUSC – WCMC – Sidra Medical and Research Center, Qatar*

#### *Reviewed by:*

*Kimberly Jean Reidy, Albert Einstein College of Medicine, United States Kirtida Mistry, Children's National Medical Center, United States*

> *\*Correspondence: Christine B. Sethna<EMAIL_ADDRESS>
#### *Specialty section:*

*This article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics*

*Received: 29 March 2017 Accepted: 15 June 2017 Published: 29 June 2017*

#### *Citation:*

*Gurusinghe S, Tambay A and Sethna CB (2017) Developmental Origins and Nephron Endowment in Hypertension. Front. Pediatr. 5:151. doi: 10.3389/fped.2017.00151*

Keywords: hypertension, nephron, fetal origins hypothesis, low birth weight, blood pressure

# INTRODUCTION

Primary hypertension is one of the leading risk factors for morbidity and mortality in the world, and it has been designated as the primary risk factor for the global disease burden (1, 2). Approximately 75 million adults have been diagnosed with hypertension in the United States, and among industrialized countries, it affects 25–35% of individuals globally (3). It is predicted that the number of individuals affected by hypertension will continue to rise and, by 2025, approximately 1.5 billion individuals will be affected (4). Hypertension continues to be the main risk factor for cardiovascular disease (CVD), and current literature states that there is a strong, positive correlation between blood pressure and risk of CVD (5). Although the pathogenesis of hypertension remains unclear, it is evident that the kidneys play a significant role in its development.

Recently, attention has been paid to the contribution of the intrauterine environment to the development of chronic and non-communicable diseases. Epidemiological studies have demonstrated that a poor intrauterine environment is associated with an increased risk of hypertension, chronic kidney disease, and diabetes (6–9). The developing kidney, in particular, has been found to be susceptible to an unstable fetal environment (10). Although multiple factors contribute to the genesis of hypertension, reduced nephron number has been attributed to be a significant contributor (11). In this review, we discuss the various factors that influence nephron endowment. We also highlight key findings on the relationship between nephron number and blood pressure in the pediatric and adult populations.

# NEPHRON ENDOWMENT

Nephrogenesis begins at the gestation age of 9 weeks and is approximately complete by the 36th week (12–14). It is characterized by reciprocal, inductive interactions between the ureteric bud and the metanephric mesenchyme. The metanephric mesenchyme initiates ureteric branching morphogenesis *via* the secretion of growth factors, resulting in the development of the collecting duct system (15–19). Similarly, the branching ureteric bud induces the conversion of mesenchyme to epithelium in the adjacent metanephric mesenchymal cells. These cells are induced to form renal vesicles, which will further differentiate into the comma-shaped bodies and s-shaped bodies ultimately forming a mature nephron. Upon completion of this process, no new nephrons are formed. Therefore, by the end of nephrogenesis, an individual's entire nephron complement is established (10).

Among humans, the average number of nephrons per kidney is approximately 1,000,000, but there is a significant amount of variation within the human population. Nephron number can range from as low as 200,000 to as high as 2.7 million (20, 21). This variation in nephron number demonstrates the plasticity of the developing kidney, and the significant role one's environment plays in determining one's final nephron count.

## DETERMINANTS OF NEPHRON NUMBER

Nephron endowment arises from the complex interplay among one's genetic blueprint, perinatal events, and environmental exposures (**Figure 1**) (20, 22). A stable intrauterine environment is essential for proper renal organogenesis, and it is becoming more and more evident that the *in utero* environment plays a crucial role in the future development and health of the offspring (10). The following section further describes the relationship among these factors and nephron endowment.

# Birth Weight

Birth weight has been identified as the primary determinant of nephron number (23). Low birth weight due to intrauterine growth restriction or prematurity has been shown to be associated with a reduced nephron complement. When evaluating the coronal sections of kidneys from deceased neonates, Manalich et al. discovered that neonates with lower birth weights (<2,500 g) had significantly fewer glomeruli than those with normal birth weights. In addition, they observed a direct relationship between birth weight and glomerular number and an inverse relationship between glomerular volume and the number of glomeruli. This suggests that individuals with low birth weights are more likely to have fewer, larger glomeruli (24). Similarly, Hughson et al. detected a direct association between birth weight and glomerular number among Caucasian and African-American infants, children, and adults. A 1 kg increase in birth weight was found to be associated with an increase in 257,426 glomeruli. In addition, low birth weight was found to a predictor for fewer glomeruli in their study (23).

In addition, racial and ethnic populations with a high prevalence of low birth weight have been found to have fewer nephrons or smaller kidneys (25–27). Babies born to Australian Aborigines are twice as likely to be of low birth weight compared to non-Aborigines. Hoy et al. discovered that Australian Aboriginal subjects had approximately 404,000 fewer glomeruli than non-Aboriginals and a significantly larger mean glomerular volume (25). They also observed a strong association between adult height and glomerular number. These findings further corroborate the

relationship between birth weight and nephron number within this population, as birth weight is a strong predictor of adult height.

#### Genetic Factors

Numerous mouse models have demonstrated that inadequate ureteric bud branching results in decreased nephron number. Null mutations in genes implicated include those regulating the formation and function of: epidermal growth factors, fibroblast growth factors (e.g., *fgf7* and *fgf10*), glial cell-derived neurotrophic factor (*gdnf*, *c-ret*, and *gfrα*), hepatocyte growth factor (e.g., *hgf* and *c-met*), transforming growth factor β (e.g., *tgfβ2* and *tgfβ3*), and signal transduction proteins from the Wnt family (28–32). For purposes of this review, we have chosen to highlight two genes whose physiological implications have been demonstrated through studies on human subjects.

The Six2 gene has emerged as a key player in kidney development. It is expressed throughout renal organogenesis in undifferentiated mesenchymal cells and encodes a homeodomain transcriptional regulator (33). Its continual expression is needed to maintain the nephron progenitor population (34, 35). Kobayashi et al. demonstrated that Six2+ expressing cap mesenchymal cells are multipotent nephron progenitors that give rise to the multiple domains of the nephron (34). Its inactivation results in the reduction of the number of progenitor cells, and these cells autonomously maintain its own cell population (34, 35). The knock out of the Six2 gene in mice models was found to result in the formation of ectopic renal vesicles (35). Furthermore, Weber et al. discovered mutations within the Six2 gene among a subset of patients with renal hypodysplasia (36). Therefore, mutations, which affect the Six2 gene product, can adversely affect nephrogenesis.

Interestingly, genetic variants that increase nephron number have also been identified. El Kares et al. identified a variant of the ALDH1A gene, rs7169289(G), that is associated with an increased total kidney volume in newborns when adjusting for body surface area. The ALDH1A gene is involved in the metabolism of retinoic acid, and infants who were homozygous for this variant were found to have higher umbilical cord blood levels of retinoic acid (37).

#### Nutrition

Maternal nutrition plays an essential role in the development of the fetus. The developing kidney is especially vulnerable to the effects of a poor maternal diet, and maternal malnutrition during pregnancy has often been proven to be associated with suboptimal renal phenotypes among her offspring (10). Macroand micronutrient deficiencies as well as restricted caloric intake have been demonstrated to impair kidney development during gestation (10, 22).

Protein restriction during gestation significantly reduces nephron number (38–41). Woods et al. discovered that male protein-restricted rats had 25% less nephrons than protein replete controls as well as a higher mean arterial blood pressure in adulthood. Renal hyperfiltration was also observed among subjects, as protein-restricted offspring had a higher individual nephron glomerular filtration rate. Interestingly, the subjects' intrarenal renin mRNA, renin concentration, and immunostaining for renin were reduced during nephrogenesis. Subsequently, their intrarenal angiotensinogen II levels were also reduced throughout nephron development. These results imply that RAS has an additional role in the regulation of blood pressure. In addition to maintaining blood pressure in adulthood, it influences the final nephron number during nephrogenesis. Therefore, the RAS system may act as a mediator in the relationship between protein restriction and nephron number (40). A high protein diet, however, was not found to influence nephron endowment (42).

Micronutrients also significantly impact renal organogenesis (10, 22). Gilbert proposed that vitamin A is largely responsible for significant variations in nephron number among humans. Vitamin A serves as a ligand to c-RET, c-ret tyrosine kinase receptor (43). This receptor plays a critical role in early kidney development as it is involved in the initiation of ureteric branching. Maternal iron and zinc deficiencies have also been found to reduce nephron number and increase systolic blood pressure in adult offspring. However, the mechanism behind these associations is less understood (10). Overall, there are a variety of nutrient deficiencies that result in the same structural renal phenotype. Therefore, a reduced nephron number may serve as an adaptive response from the developing kidney during times of environmental stress (10).

#### Teratogens

The detrimental effects of chronic alcohol exposure to the fetus during pregnancy have been well documented. However, the effects of acute prenatal alcohol exposure are less understood, especially its influence on the developing kidney. Gray et al. investigated the effects of acute prenatal ethanol exposure on nephron endowment in rats. Either ethanol or saline was administered to Sprague-Dawley rats on embryonic days 13.5 (E13.5) and 14.5 (E14.5). Ethanol exposed rodents were found to have a 10–20% reduction in nephron number as well as a higher mean arterial blood pressure. In addition, E15.5 rats were found to have a reduced gene expression of significant regulators of ureteric branching morphogenesis (GDNF, FGF7, Wnt11, TGFβ2, and TGFβ3). Fewer ureteric branch points and tips were also found in embryonic kidneys that were cultured in media containing ethanol (44).

Tobacco exposure is another established teratogen, which has been demonstrated to be negatively associated with birth weight and positively associated with blood pressure (45, 46). Taal et al. conducted a population-based prospective cohort study of 1,072 mothers and children to investigate the association between prenatal cigarette exposure and kidney volume. Mothers who only smoked during the first trimester and those who smoked throughout their pregnancy were followed. A consistent relationship between smoke exposure and kidney volume was not observed among the offspring of mothers who smoked solely during the first trimester. However, a dose-dependent relationship between kidney volume and tobacco exposure was observed among the offspring whose mothers smoked throughout their pregnancy. Those who smoked more than 10 cigarettes a day had a smaller total fetal kidney volume than those who smoked less than five cigarettes a day (47). These results once again imply the importance of a stable intrauterine environment as disturbances may predispose an individual to cardiovascular and renal diseases.

#### Medication

Elevated levels of maternal corticosteroids during pregnancy have been shown to be associated with a low nephron complement and higher blood pressure among her offspring (22). Interestingly, both the duration and timing of the exposure determine the severity of the phenotype and only 2 days of exposure is needed to produce a nephron deficit. Administration of dexamethasone (DEX), a synthetic glucocorticoid, during embryonic day E15/16 or E17/E18 was found to decrease glomerular number and increase blood pressure in rat models. Similarly, DEX exposure during day E19/E20 or E26-28 was also found to result in hypertensive sheep offspring with a nephron deficit. However, administration of DEX before or after these time periods was not found to affect glomerular number or blood pressure. The time periods when animals were most susceptible to DEX were during times of kidney development, specifically during ureteric branching morphogenesis. Singh et al. proposed that DEX reduces nephron number by inhibiting/slowing ureteric branching. They reported that DEX exposure decreased the expression of GDNF (a promoter of ureteric branching) and increased the expression of inhibitors, BMP-4 and TGF-β1 both *in vitro* and *in vivo* (48). Ureteric branching morphogenesis is believed to be a significant process in establishing the final nephron complement as each ureteric tip induces the formation of new nephrons. Therefore, by inhibiting ureteric branching, DEX indirectly reduces nephron number (48).

Exposure to non-steroidal anti-inflammatory drugs has been shown to have variable effects on one's nephron number (22). Rodents that were exposed to cyclooxygenase-2 inhibitors from gestation to 3 weeks postbirth were found to have a significantly reduced glomerular size. Interestingly, if exposure occurred solely during gestation, no effect on glomerular size was observed (49).

#### DEVELOPMENTAL ORIGINS OF HEALTH AND DISEASE

One of the initial proponents of the fetal origins of disease was Dr. David Barker. In the 1980s, Barker and colleagues discovered an inverse relationship between birth weight and coronary artery disease mortality rates in a cohort of men and women born in Hertfordshire, United Kingdom. They observed a twofold increase in mortality rates when comparing individuals with the lowest birth weight with those with the highest birth weight (50, 51). Barker eventually proposed that fetal undernutrition during middle to late gestation "programs" coronary artery disease in adulthood (52). Future epidemiological studies supported the Barker hypothesis, demonstrating the importance of one's intrauterine environment in determining one's future health (6–9). These findings further shed light on the non-hereditary component of chronic diseases.

The theory of "developmental programming" or the "developmental origins of health and disease," states that environmental influences during sensitive periods of development can result in permanent alterations of function and structure of an organism (53). In order to increase its chances of surviving, the fetus may undergo structural and functional changes during gestation at the expense of its future health. Therefore, an adverse intrauterine environment can predispose an individual to an increased risk of hypertension and cardiovascular or renal disease (6–9). The developing kidney has been shown to be especially vulnerable to a suboptimal *in utero* environment (10). As described previously, in addition to one genetic disposition, macro- and micronutrient deficiencies and exposure to teratogens and certain medications during gestation have been found to reduce one's nephron endowment (10, 22, 44, 48). Interestingly, each of these different environmental signals elicits a similar renal phenotype in the offspring.

In 1988, Brenner et al. put forth the hypothesis that a low nephron number is a risk factor for adult hypertension (**Figure 2**). They proposed that a reduction in the total filtration surface area of the kidneys is associated with a compensatory increase in the single nephron glomerular filtration rate. In response to a reduced nephron complement, adaptive structural changes occur within the nephron including glomerular and tubular enlargement and an increase in the number of glomerular capillaries. Consequently, the afferent arteriole dilates while the efferent arteriole constricts resulting in an increase in the glomerular capillary pressure. This reduction in the afferent arteriolar resistance allows for an increased transmittance of systemic blood pressure into the glomerulus. Simultaneously, other physiological changes occur that also contribute to the development of hypertension including increased salt reabsorption, higher volume strokes and cardiac output and resetting of the pressure-natriuresis curve. Pathological changes such as podocyte detachment and tuft adhesion to Bowman's capsule have been noted in sclerosed kidneys compensating for hyperfiltration (e.g., secondary

Figure 2 | How does nephron number lead to hypertension?

to vesicoureteral reflux) (54). Over time, this sclerosis of the glomeruli fuels a vicious cycle resulting in a decreased nephron number, the compensatory glomerular hypertrophy, and the progressive hypertension and chronic kidney disease (55–57).

# NEPHRON NUMBER AND HYPERTENSION

Since initially hypothesized over 30 years ago, there have been a number of animal and human studies that have sought to determine the relationship between nephron endowment and hypertension.

#### Animal Studies

Through animal studies, it is becoming increasingly clear that a relationship exists between nephron number and hypertension. A mouse model of prematurity found that those delivered 1 and 2 days early had 17.4 and 23.6% fewer nephrons, respectively, compared to full-term mice, and the premature mice subsequently developed hypertension (58). In addition, a number of genetic knock out mice models associated with lower nephron number have demonstrated an inverse association with blood pressure (59–61).

## Low Birth Weight and Nephron Number in Humans

Human epidemiological studies have used birth weight as an indicator of fetal nutrition status and therefore a surrogate for lower nephron endowment. Systematic reviews and metaanalyses of the literature have consistently shown an inverse relationship between birth weight and blood pressure. Law et al. reviewed 34 cohort studies published before 1996. After adjustment for body mass index, regression coefficients of birth weight indicated a negative association with systolic blood pressure in 26 studies, indicating a 2–3 mmHg/kg reduction in systolic blood pressure in children and 2–4 mmHg/kg reduction in adults with increasing birth weight (62). In a review by Huxley et al. of 45 pediatric and adult studies published between 1996 and 2000, the majority (33 studies) reported a negative association between birth weight and systolic blood pressure. In aggregate, an 1 kg increase in birth weight was associated with an 1–2 mmHg/kg decrease in systolic blood pressure (63). A review by Adair et al. of 2000–2005 publications of adult studies remains consistent with the earlier ones. Of the 28 cohort studies, 25 studies found an inverse association; however, not all were adjusted for BMI (64). More recently, a meta-analysis of 27 studies conducted between 1995 and 2012 found that low birth weight (<2,500 g) compared with birth weight greater than 2,500 g was associated with an increased risk of hypertension (odds ratio 1.21; 95% confidence interval 1.13, 1.30) (65).

The relationship between birth weight and blood pressure in childhood is more complicated, and studies published since 2000 have shown inconsistent results muddied by poorly powered studies focusing on specific populations. There is also some evidence that the inverse relationship between blood pressure and birth weight becomes more pronounced as the age of the study population increases, although this finding is weak and may not be statistically significant (66). Studies of adolescents show conflicting results, and in neonates, some studies reported a positive relationship between blood pressure and birth weight (62). Rahiala et al. showed that birth weight was not an independent determinant of blood pressure in 100 children in Finland using ambulatory blood pressure monitoring (67). However, four other studies with larger sample sizes supported the inverse relationship of birth weight and ambulatory blood pressure in children (68–71). Though low birth weight does appear to be associated with hypertension, the physiological and molecular mechanisms establishing causality remain to be elucidated.

# Impact of Ethnic and Racial Factors

There is a significantly higher prevalence of hypertension in African-Americans, which is likely multifactorial in etiology. African-Americans are also at higher risk for being low birth weight. This suggests that being low birth weight could be one of the factors implicated in predisposing African-Americans to higher rates in hypertension later in life (23).

Since most of the studies in this area focused on Caucasians, there is little published on the African-American population. Hulman et al. evaluated 137 urban African-American adults and found no relationship between birth weight and adult blood pressure (72). Donker et al. looked at a biracial sample of 1,446 children aged 7–11 years and found evidence that low birth weight is a determinate of high blood pressure only in African-American males. However, the association was lost when multivariate analyses were done (73). A study by Rostand et al. analyzed 262 Caucasian and African-American 5-year-old children. An inverse relation was found for Caucasian children, but, surprisingly, a positive relationship was found for African-American children (74). However, an inverse relationship between birth weight and blood pressure was found in the longitudinal Bogolusa Heart Study and there were no racial differences found (75).