Screening and Management of Pediatric High Blood Pressure-Challenges to Implementing the Clinical Practice Guideline.

PURPOSE OF REVIEW: Elevated blood pressure (BP) and hypertension in childhood convey risk for hypertension and cardiovascular events in adulthood. Early recognition of abnormal BPs is key to preventing or lessening this risk. However, the process for making the diagnosis of hypertension is complex, and overall adherence to the 2017 American Academy of Pediatrics Clinical Practice Guidelines (CPG) is poor. We will review obstacles to adherence to the CPG and approaches designed to improve the diagnosis and management of hypertension in children. RECENT FINDINGS: Baseline data from the multi-center quality improvement intervention, "Boosting Primary Care Awareness and Treatment of Hypertension" (BP-CATCH), demonstrate that childhood hypertension remains underdiagnosed. Other studies confirm a lack of compliance with the process outlined in the CPG. The provision of electronic prompts, coaching, and education results in modest improvements. The combination of embedded medical record tools and education seems to offer the most hope for improvement.

White Coat Hypertension Persistence in Children and Adolescents: The Pediatric Nephrology Research Consortium Study.

OBJECTIVES: To determine whether youth with white coat hypertension on initial ambulatory blood pressure monitoring (ABPM) continue to demonstrate the same pattern on repeat ABPM. STUDY DESIGN: Retrospective longitudinal cohort study of patients referred for high blood pressure (BP) and diagnosed with white coat hypertension by ABPM who had follow-up ABPM 0.5-4.6 years later at 11 centers in the Pediatric Nephrology Research Consortium. We classified ABPM phenotype using the American Heart Association guidelines. At baseline, we classified those with hypertensive BP in the clinic as "stable white coat hypertension," and those with normal BP as "intermittent white coat hypertension." We used multivariable generalized linear mixed effect models to estimate the association of baseline characteristics with abnormal ABPM phenotype progression. RESULTS: Eighty-nine patients met the inclusion criteria (median age, 13.9 years; 78% male). Median interval time between ABPM measurements was 14 months. On follow-up ABPM, 61% progressed to an abnormal ABPM phenotype (23% ambulatory hypertension, 38% ambulatory prehypertension). Individuals age 12-17 years and those with stable white coat hypertension had greater proportions progressing to either prehypertension or ambulatory hypertension. In the multivariable models, baseline wake systolic BP index ≥0.9 was significantly associated with higher odds of progressing to ambulatory hypertension (OR 3.07, 95% CI 1.02-9.23). CONCLUSIONS: The majority of the patients with white coat hypertension progressed to an abnormal ABPM phenotype. This study supports the 2017 American Academy of Pediatrics Clinical Practice Guideline's recommendation for follow-up of ABPM in patients with white coat hypertension.

Salt sensitivity of blood pressure in childhood and adolescence.

Although moderation of sodium intake is recommended population-wide, it remains uncertain who benefits from salt restriction. Salt sensitivity refers to changes in blood pressure in response to sodium intake and may occur with or without hypertension. Unfortunately, there is no practical way to assess salt sensitivity in daily practice. Assessment of salt sensitivity even in research studies is challenging with varying protocols utilized which may contribute to differing results. Building on studies in animals and adults, risk factors and conditions associated with salt sensitivity have been identified in the pediatric and young adult populations. This review presents the limited evidence linking obesity, low birth weight, diabetes, chronic kidney disease, and race/ethnicity with salt sensitivity in children, adolescents, and young adults. The impact of stress on sodium handling is also reviewed. The influence of age on the timing of introduction of dietary salt restriction and the long-term influence of salt sensitivity on risk for hypertension are considered. Lastly, interventions other than salt restriction that may improve salt sensitivity and may inform recommendations to families are reviewed.

Ambulatory blood pressure monitoring in children undergoing polysomnography.

Ambulatory blood pressure monitoring (ABPM) is recommended for the diagnosis of hypertension in children at high risk, such as children with obesity or obstructive sleep apnea (OSA). Nocturnal hypertension is highly predictive of cardiovascular outcomes. ABPM allows for early detection of nocturnal hypertension in children. Although OSA is the most common sleep disorder associated with hypertension, studies have also shown an increase in cardiovascular risk in adult patients with other sleep disorders; therefore, there is an imperative need to provide early diagnosis in children at high risk. In the present study, we evaluated the feasibility of using ABPM during polysomnography (PSG) in children referred for sleep disordered breathing to the Seattle Children's Hospital Sleep Disorders Center. A total of 41 children aged 7-18 years were included in this study. The ABPM monitor was worn for a mean (SD) of 10.2 (1.5) hr. No significant changes were seen in PSG parameters when ABPM was co-performed with PSG, including sleep efficiency and arousals. In total, 12 of the 41 patients were identified as having nocturnal hypertension. Our study is important in that it shows that concomitant use of ABPM during PSG can aid in the early identification of nocturnal hypertension in this population.

Changes in Ambulatory Blood Pressure Phenotype over Time in Children and Adolescents with Elevated Blood Pressures.

OBJECTIVE: To determine the stability of ambulatory blood pressure monitoring (ABPM) over time in children referred for evaluation of elevated BPs and assess for factors predicting change. STUDY DESIGN: This retrospective chart review conducted at Seattle Children's Hospital and University of Pittsburgh Medical Center Children's Hospital of Pittsburgh identified 124 children referred for elevated BPs with 2 ABPM studies at least 6 months apart. All subjects received lifestyle counseling. Subjects with secondary hypertension (HTN) or on antihypertensive medication were excluded. ABPM phenotype was classified using American Heart Association guidelines as showing normal BP, prehypertension, and HTN. Generalized linear mixed effect regression models were used to regress stable, improving, or worsening HTN outcomes at study follow-up on baseline BP index and load variables. RESULTS: The median age of patients was 14.1 years (73% males) and the median interval between studies was 18 months. ABPM phenotype changed in 58 of 124 children, with 16% worsening and 31% improving. Older age was associated with persistence of HTN. Although not significant, decrease in body mass index z-score tracked with sustained normal ambulatory BPs. CONCLUSIONS: Although the sample size is small, our study suggests ABPM phenotype shows variability over time. Further study is required to identify factors supporting risk for progression of ABPM phenotype over time.

Use of Automated Office Blood Pressure Measurement in the Evaluation of Elevated Blood Pressures in Children and Adolescents.

OBJECTIVES: To determine the level of agreement between automated office blood pressures (AOBP), auscultated or manual office BP (manual office blood pressure), and 24-hour ABPM, and to explore the ability of AOBP and manual office blood pressure to correctly identify daytime ambulatory hypertension in children. STUDY DESIGN: We retrospectively compared BPs obtained by AOBP and manual office blood pressure to predict daytime hypertension on ABPM. Six BPs were taken by AOBP followed by manual office blood pressure. Office hypertension was defined by BPs ≥95th percentile for sex and height percentiles for those <13 years of age and a BP of ≥130/80 mm Hg for ages ≥13 years. Daytime ambulatory hypertension was diagnosed if mean wake BPs were ≥95th percentile and BP loads were ≥25%. Application of adult ABPM thresholds for daytime hypertension (130/80 mm Hg) was assessed in ages ≥13 years. Sensitivity and specificity were calculated considering ABPM as the reference. RESULTS: Complete data were available for 187 patient encounters. Overall, the best agreement was found if both AOBP and manual office blood pressure showed hypertension, but owing to low sensitivity up to 49% of children with hypertension would be misclassified. The use of adult thresholds for ABPM did not improve agreement. CONCLUSIONS: Neither AOBP nor manual office blood pressure confirm or exclude daytime ambulatory hypertension with confidence. These results suggest an ongoing role for ABPM in evaluation of hypertension in children.

Evaluation and Management of Elevated Blood Pressure in Children and Adolescents with Attention Deficit Hyperactivity Disorder.

PURPOSE OF REVIEW: To understand the impact of attention deficit hyperactivity disorder (ADHD) and its medications on blood pressure (BP) in children and adolescents and provide recommendations for management of elevated BP in children and adolescents with ADHD. RECENT FINDINGS: ADHD medications have cardiovascular effects including elevated BP. However, the bulk of the evidence indicates that stimulants and other ADHD medications are safe and do not cause severe cardiovascular diseases. BP should be assessed carefully at the time of ADHD diagnosis, because some behavioral changes similar to ADHD may be associated with hypertension. ADHD medications appear to be safe. However, their long-term impact on the cardiovascular system is not clearly understood and needs further investigation. BP should be monitored regularly during ADHD pharmacotherapy in order to optimize the management of both conditions.

Evaluation and Management of Stage 2 Hypertension in Pediatric Patients.

PURPOSE OF REVIEW: To update the definition and clinical practice of stage 2 hypertension (HTN) in pediatrics. RECENT FINDINGS: The 2017 American Academy of Pediatrics Clinical Practice Guideline (AAP CPG) for Screening and Management of High Blood Pressure in Children and Adolescent includes new normative blood pressure tables for children and adolescents ages 1 to 17 years and new definitions for stage 2 HTN. This review will highlight these aspects as well as new recommendations in the guideline specific to stage 2 HTN. It will outline how the new guideline differs from the previous 2004 guideline, the implications of these differences, and suggested changes in evaluation and management of stage 2 HTN. Lastly, the review will address topics relevant to daily clinical practice including competitive athletic participation, investigation for secondary HTN and HTN comorbidities, and blood pressure-lowering therapy. With the publication of the new AAP CPG introducing revised normative tables, the prevalence of stage 2 HTN in pediatrics is expected to rise. Based on the new guidelines, there is less emphasis on investigation for secondary HTN and more attention to lifestyle modifications for primary HTN. Future research should address whether there is BP level within the stage 2 HTN range above which the approach to evaluation and management should be altered in this heterogeneous patient population.

Epidemiology of peritonitis following maintenance peritoneal dialysis catheter placement during infancy: a report of the SCOPE collaborative.

BACKGROUND: Maintenance peritoneal dialysis (PD) is the dialysis modality of choice for infants and young children. However, there are limited outcome data for those who undergo PD catheter insertion and initiate maintenance PD within the first year of life. METHODS: Using data from the Children's Hospital Association's Standardizing Care to Improve Outcomes in Pediatric End Stage Renal Disease (ESRD) Collaborative (SCOPE), we examined peritonitis rates and patient survival in 156 infants from 29 North American pediatric dialysis centers who had a chronic PD catheter placed prior to their first birthday. RESULTS: In-hospital and overall annualized rates of peritonitis were 1.73 and 0.76 episodes per patient-year, respectively. Polycystic kidney disease was the most frequent renal diagnosis and pulmonary hypoplasia the most common co-morbidity in infants with peritonitis. Multivariable regression models demonstrated that nephrectomy at or prior to PD catheter placement and G-tube insertion after catheter placement were associated with a nearly sixfold and nearly threefold increased risk of peritonitis, respectively. Infants with peritonitis had longer initial hospital stays and lower overall survival (86.3 vs. 95.6%, respectively; P < 0.02) than those without an episode of peritonitis. CONCLUSIONS: In this large cohort of infants with ESRD, the frequency of peritonitis was high and several risk factors associated with the development of peritonitis were identified. Given that peritonitis was associated with a longer duration of initial hospitalization and increased mortality, increased attention to the potentially modifiable risk factors for infection is needed.

COQ2 nephropathy: a treatable cause of nephrotic syndrome in children.

BACKGROUND: Nephrotic syndrome can be caused by a subgroup of mitochondrial diseases classified as primary coenzyme Q10 (CoQ10) deficiency. Pathogenic COQ2 variants are a cause of primary CoQ10 deficiency and present with phenotypes ranging from isolated nephrotic syndrome to fatal multisystem disease. CASE-DIAGNOSIS/TREATMENT: We report three pediatric patients with COQ2 variants presenting with nephrotic syndrome. Two of these patients had normal leukocyte CoQ10 levels prior to treatment. Pathologic findings varied from mesangial sclerosis to focal segmental glomerulosclerosis, with all patients having abnormal appearing mitochondria on kidney biopsy. In two of the three patients treated with CoQ10 supplementation, the nephrotic syndrome resolved; and at follow-up, both have normal renal function and stable proteinuria. CONCLUSIONS: COQ2 nephropathy should be suspected in patients presenting with nephrotic syndrome, although less common than disease due to mutations in NPHS1, NPHS2, and WT1. The index of suspicion should remain high, and we suggest that providers consider genetic evaluation even in patients with normal leukocyte CoQ10 levels, as levels may be within normal range even with significant clinical disease. Early molecular diagnosis and specific treatment are essential in the management of this severe yet treatable condition.

Changing outpatient referral patterns in a small pediatric nephrology practice.

BACKGROUND: We have noted a large number of referrals for abnormal kidney imaging and laboratory tests and postulated that such referrals have increased significantly over time. Understanding changes in referral patterns is helpful in tailoring education and communication between specialists and primary providers. METHODS: We performed a retrospective chart review of new patient referrals to Mary Bridge Children's Nephrology clinic for early (2002 to 2004) and late (2011 to 2013) cohorts. The overall and individual frequencies of referrals for various indications were compared. RESULTS: The overall number of new visits was similar for early (511) and late (509) cohorts. The frequency of referrals for solitary kidneys and multi-cystic dysplastic kidneys, microalbuminuria and abnormal laboratory results increased significantly (Odds Ratio (OR) and 95% Confidence Interval of OR: 1.920 [1.079, 3.390], 2.862 [1.023, 8.006], 2.006 [1.083, 3.716], respectively) over the time interval while the proportion of referrals for urinary tract infections (UTIs) and vesicoureteral reflux (VUR) decreased by half (OR: 0.472, 95% CI: 0.288, 0.633). Similarly, referrals for urinary tract dilation and hydronephrosis occurred significantly less often (8% versus 6%, OR: 0.737, 95% CI: 0.452, 1.204) with similar changes in referrals for voiding issues (OR: 0.281, 95% CI: 0.137, 0.575). However, these changes were not statistically significant. Frequencies for other indications showed little variation. CONCLUSIONS: Changes in indications for referral likely reflect evolution of practice in management of UTIs and VUR and increased use of imaging and laboratory testing by pediatric providers. These findings have relevance for ongoing education of pediatricians and support the need for collaboration between primary providers and nephrologists to assure the judicious use of resources.

Angiotensin II and the Natriuretic and Blood Pressure Response to Mental Stress in African Americans.

Objective: To test the hypothesis that Angiotensin II (Ang II) is a contributing factor to the response pattern in African Americans (AAs) who retain rather than excrete sodium during mental stress. Design/Study Participants: Double-blind, randomized, cross-over trial of 87 healthy AAs aged 18 to 50 years. Interventions: The study participants received either a placebo or irbesartan, (150 mg PO), an Ang II receptor antagonist, for seven days prior to stress testing. Urinary sodium excretion (UNaV) and systolic blood pressure (SBP) were collected prior to and throughout a mental stress protocol (rest and stress period). Setting: A southeastern university. Main Outcome Measures: Ang II, SBP, and sodium retention. Results: During the placebo condition, 62 participants showed the expected increase in UNaV (excreters) while 25 participants reduced UNaV during stress (retainers). Irbesartan retainers demonstrated a reversal in the direction of their natriuretic response, now increasing UNaV in response to stress (∆ UNaV of -.094 mmol/min with placebo vs .052 mmol/min on irbesartan; P<.001). In excreters, irbesartan reduced SBP levels during both rest (-2.36 mm Hg; P=.03) and stress (-4.59;P<.0001), and an even more pronounced reduction in SBP was demonstrated by retainers on treatment during both rest (-4.29 mm Hg; P=.03) and stress (-6.12; P<.001). Conclusions: Ang II contributes to sodium retention in retainers. Furthermore, our findings indicate that suppression of Ang II has a beneficial effect on SBP during rest and stress in this population.

Stress and salt sensitivity in primary hypertension.

As the development of hypertension and target organ damage becomes more prevalent, it becomes exceedingly important to determine the underlying mechanisms through which this detrimental development occurs. Specifically, our studies and others have explored mechanisms through which stress elicits a salt-sensitive response in approximately 20-30 % of the population, resulting in the early development of hypertension and target organ damage. Data associated with this stress-induced cardiovascular response pattern have recently demonstrated additional effects across the body systems including factors contributing to the development of osteoporosis, obesity, autoimmune disease, and chronic inflammation. As each of these diseases become more prevalent in conjunction with hypertension, further research may discover stress and salt sensitivity to be at the "heart" of the matter for the development of many of today's most deadly conditions.

Ambulatory Blood Pressure and Number of Subclinical Target Organ Injury Markers in Youth: The SHIP AHOY Study.

Background: Hypertension in adolescence is associated with subclinical target organ injury (TOI). We aimed to determine whether different blood pressure (BP) thresholds were associated with increasing number of TOI markers in healthy adolescents. Methods: 244 participants (mean age 15.5±1.8 years, 60.1% male) were studied. Participants were divided based on both systolic clinic and ambulatory BP (ABP), into low- (<75 th percentile), mid- (75 th -90 th percentile) and high-risk (>90 th percentile) groups. TOI assessments included left ventricular mass, systolic and diastolic function, and vascular stiffness. The number of TOI markers for each participant was calculated. A multivariable general linear model was constructed to evaluate the association of different participant characteristics with higher numbers of TOI markers. Results: 47.5% of participants had at least one TOI marker: 31.2% had one, 11.9% two, 3.7% three, and 0.8% four. The number of TOI markers increased according to the BP risk groups: the percentage of participants with more than one TOI in the low-, mid-, and high groups based on clinic BP was 6.7%, 19.1%, and 21.8% (p=0.02), and based on ABP was 9.6%, 15.8%, and 32.2% (p<0.001). In a multivariable regression analysis, both clinic BP percentile and ambulatory SBP index were independently associated with the number of TOI markers. When both clinic and ABP were included in the model, only the ambulatory SBP index was significantly associated with the number of markers. Conclusion: High SBP, especially when assessed by ABPM, was associated with an increasing number of subclinical cardiovascular injury markers in adolescents.

A Multi-Omics Approach to Defining Target Organ Injury in Youth with Primary Hypertension.

BACKGROUND: Primary hypertension in childhood tracks into adulthood and may be associated with increased cardiovascular risk. Studies conducted in children and adolescents provide an opportunity to explore the early cardiovascular target organ injury (CV-TOI) in a population free from many of the comorbid cardiovascular disease risk factors that confound studies in adults. METHODS: Youths (n=132, mean age 15.8 years) were stratified by blood pressure (BP) as low, elevated, and high-BP and by left ventricular mass index (LVMI) as low- and high-LVMI. Systemic circulating RNA, miRNA, and methylation profiles in peripheral blood mononuclear cells and deep proteome profiles in serum were determined using high-throughput sequencing techniques. RESULTS: VASH1 gene expression was elevated in youths with high-BP with and without high-LVMI. VASH1 expression levels positively correlated with systolic BP (r=0.3143, p=0.0034). The expression of hsa-miR-335-5p, one of the VASH1-predicted miRNAs, was downregulated in high-BP with high-LVMI youths and was inversely correlated with systolic BP (r=-0.1891, p=0.0489). GSE1 hypermethylation, circulating PROZ upregulation (log2FC=0.61, p=0.0049 and log2FC=0.62, p=0.0064), and SOD3 downregulation (log2FC=-0.70, p=0.0042 and log2FC=-0.64, p=0.010) were observed in youths with elevated BP and high-BP with high-LVMI. Comparing the transcriptomic and proteomic profiles revealed elevated HYAL1 levels in youths displaying high-BP and high-LVMI. CONCLUSIONS: The findings are compatible with a novel blood pressure-associated mechanism that may occur through impaired angiogenesis and extracellular matrix degradation through dysregulation of Vasohibin-1 and Hyaluronidase1 was identified as a possible mediator of CV-TOI in youth with high-BP and suggests strategies for ameliorating TOI in adult-onset primary hypertension.

Sodium intake and blood pressure in children.

Elevation of blood pressure (BP) and the risk for progression to hypertension (HTN) is of increasing concern in children and adolescents. Indeed, it is increasingly recognized that target organ injury may begin with even low levels of BP elevation. Sodium intake has long been recognized as a modifiable risk factor for HTN. While it seems clear that sodium impacts BP in children, its effects may be enhanced by other factors including obesity and increasing age. Evidence from animal and human studies indicates that sodium may have adverse consequences on the cardiovascular system independent of HTN. Thus, moderation of sodium intake over a lifetime may reduce risk for cardiovascular morbidity in adulthood. An appetite for salt is acquired, and intake beyond our need is almost universal. Considering that eating habits in childhood have been shown to track into adulthood, modest sodium intake should be advocated as part of a healthy lifestyle.

Cardiovascular Risk Factors and Target Organ Damage in Adolescents: The SHIP AHOY Study.

BACKGROUND: Development of cardiovascular disease in adults has been directly linked to an adverse metabolic phenotype. While there is evidence that development of these risk factors in childhood persists into adulthood and the development of cardiovascular disease, less is known about whether these risk factors are associated with target organ damage during adolescence. METHODS: We collected data from 379 adolescents (mean age 15.5, 60% male) with blood pressure between the 75th and 95th percentile to determine if there is a metabolic phenotype that predicts cardiovascular changes (left ventricular mass, systolic and diastolic function, pulse wave velocity, and renal function). We determined the number of risk factors for cardiovascular disease (hypertension, dyslipidemia, obesity, and insulin resistance) present in each participant. Generalized linear models were constructed to determine if the number of cardiovascular risk factors (CVRFs) were associated with measures of target organ damage. RESULTS: The number of CVRFs present were associated with statistically significant differences in increased left ventricular mass index, increased pulse wave velocity, decreased peak longitudinal strain, urine albumin to creatine ratio and echocardiographic parameters of diastolic dysfunction. Generalized linear models showed that dyslipidemia and insulin resistance were independently associated with markers of diastolic dysfunction (P ≤ .05) while increased blood pressure was associated with all makers of target organ damage (P ≤ .03). CONCLUSIONS: These data suggest the of the number of CVRFs present is independently associated with early changes in markers of target organ damage during adolescence.

Association of Blood Pressure-Related Increase in Vascular Stiffness on Other Measures of Target Organ Damage in Youth.

BACKGROUND: Hypertension-related increased arterial stiffness predicts development of target organ damage (TOD) and cardiovascular disease. We hypothesized that blood pressure (BP)-related increased arterial stiffness is present in youth with elevated BP and is associated with TOD. METHODS: Participants were stratified by systolic BP into low- (systolic BP <75th percentile, n=155), mid- (systolic BP ≥80th and <90th percentile, n=88), and high-risk BP categories (≥90th percentile, n=139), based on age-, sex- and height-specific pediatric BP cut points. Clinic BP, 24-hour ambulatory BP monitoring, anthropometrics, and laboratory data were obtained. Arterial stiffness measures included carotid-femoral pulse wave velocity and aortic stiffness. Left ventricular mass index, left ventricular systolic and diastolic function, and urine albumin/creatinine were collected. ANOVA with Bonferroni correction was used to evaluate differences in cardiovascular risk factors, pulse wave velocity, and cardiac function across groups. General linear models were used to examine factors associated with arterial stiffness and to determine whether arterial stiffness is associated with TOD after accounting for BP. RESULTS: Pulse wave velocity increased across groups. Aortic distensibility, distensibility coefficient, and compliance were greater in low than in the mid or high group. Significant determinants of arterial stiffness were sex, age, adiposity, BP, and LDL (low-density lipoprotein) cholesterol. Pulse wave velocity and aortic compliance were significantly associated with TOD (systolic and diastolic cardiac function and urine albumin/creatinine ratio) after controlling for BP. CONCLUSIONS: Higher arterial stiffness is associated with elevated BP and TOD in youth emphasizing the need for primary prevention of cardiovascular disease.