Donald L. Batisky

Efficacy, Safety, and Pharmacokinetics of Candesartan Cilexetil in Hypertensive Children Aged 6 to 17 Years

This 4‐week randomized, double blind, placebo‐controlled study (N=240), 1‐year open label trial (N=233), and single‐dose pharmacokinetic study (N=22) evaluated candesartan cilexetil (3 doses) in hypertensive children aged 6 to 17 years. Seventy‐one percent were 12 years of age or older, 71% were male, and 47% were black. Systolic (SBP)/diastolic (DBP) blood pressure declined 8.6/4.8–11.2/8.0 mm Hg with candesartan and 3.7/1.8 mm Hg with placebo (P<.01 compared to placebo for SBP and for the mid and high doses for DBP; placebo‐corrected 4.9/3.0–7.5/6.2 mm Hg). The slopes for dose were not, however, different from zero (P>.05). The response rate (SBP and DBP <95th percentile) after 1 year was 53%. The pharmacokinetic profiles in 6‐ to 12‐ and 12‐ to 17‐year‐olds were similar and were comparable to adults. Eight candesartan patients discontinued treatment because of an adverse event. Candesartan is an effective, well‐tolerated antihypertensive agent for children aged 6 to 17 years and has a pharmacokinetic profile that is similar to that in adults.

A multicenter study of neurocognition in children with hypertension: methods, challenges, and solutions.

Hypertensive adults demonstrate decreased performance on neurocognitive testing compared with that of normotensive controls. There is now emerging, preliminary evidence that children with hypertension also manifest neurocognitive differences when compared with normotensive controls, findings postulated to potentially represent early signs of hypertensive target organ damage to the brain. However, reports in children to date have been limited to database and single-center studies. We have established an ongoing, prospective, multicenter study of neurocognition in children with primary hypertension. This article outlines the study methods, with particular attention to the unique challenges in this area of clinical research. We highlight aspects of the study design that are specifically designed as solutions to these challenges.

Neurocognitive Function in Children with Primary Hypertension

Objective To compare neurocognitive test performance of children with primary hypertension with that of normotensive controls. Study design Seventy‐five children (10‐18 years of age) with newly diagnosed, untreated hypertension and 75 frequency‐matched normotensive controls had baseline neurocognitive testing as part of a prospective multicenter study of cognition in primary hypertension. Subjects completed tests of general intelligence, attention, memory, executive function, and processing speed. Parents completed rating scales of executive function and the Sleep‐Related Breathing Disorder scale of the Pediatric Sleep Questionnaire (PSQ‐SRBD). Results Hypertension and control groups did not differ significantly in age, sex, maternal education, income, race, ethnicity, obesity, anxiety, depression, cholesterol, glucose, insulin, and C‐reactive protein. Subjects with hypertension had greater PSQ‐SRBD scores (P = .04) and triglycerides (P = .037). Multivariate analyses showed that hypertension was independently associated with worse performance on the Rey Auditory Verbal Learning Test (List A Trial 1, P = .034; List A Total, P = .009; Short delay recall, P = .013), CogState Groton Maze Learning Test delayed recall (P = .002), Grooved Pegboard dominant hand (P = .045), and Wechsler Abbreviated Scales of Intelligence Vocabulary (P = .016). Results indicated a significant interaction between disordered sleep (PSQ‐SRBD score) and hypertension on ratings of executive function (P = .04), such that hypertension heightened the association between increased disordered sleep and worse executive function. Conclusions Youth with primary hypertension demonstrated significantly lower performance on neurocognitive testing compared with normotensive controls, in particular, on measures of memory, attention, and executive functions.

Sleep disordered breathing as measured by SRBD-PSQ and neurocognition in children with hypertension.

BACKGROUND Cognitive test performance is decreased in hypertensive adults and children, a finding postulated to represent early target-organ damage to the brain. Hypertensive children are often obese, a comorbidity associated with sleep disordered breathing (SDB), itself associated with cognitive problems; potentially confounding the relation between hypertension (HTN) and neurocognition. Our objective was to determine the association between SDB as measured by a scale and questionnaire score and neurocognition among participants enrolled in an ongoing multicenter study of cognition in children with HTN. METHODS Subjects completed laboratory-based neurocognitive tests. Parents and subjects completed rating scales of executive function, mood, and behavior problems. Parents completed the Sleep-Related Breathing Disorder scale of the Pediatric Sleep Questionnaire (SRBD-PSQ). RESULTS To date, 38 HTN subjects and 34 control subjects have completed neurocognitive testing and the SRBD-PSQ. Median SRBD-PSQ scores were similar between groups but the HTN group had a higher percentage of subjects with SRBD-PSQ scores in the range suggestive of obstructive sleep apnea (26% vs. 6%, P = 0.03). Overall, higher SRBD-PSQ scores were not significantly associated with worse performance on laboratory-based measures of executive function and other cognitive domains but were significantly associated with worse scores on rating scales of executive function as well as mood and behavior problems. CONCLUSIONS A larger proportion of children with HTN had scores suggestive of SDB. The results underscore the importance of using a multi-method approach in the assessment of cognition and adjusting for potential confounding effects of SDB in studies of cognition in hypertensive children.

What Is the Optimal First-Line Agent in Children Requiring Antihypertensive Medication?

There has been an evolution in the understanding of the treatment of hypertension in children and adolescents over the past decade. This has been fueled in part by the increased attention paid to the clinical problem, given the increasing numbers of children and adolescents being diagnosed with this condition. There has also been a growing number of clinical trials performed and completed that demonstrate the blood pressure (BP)-lowering effects of antihypertensives and the side effect profiles of these medications, and that has led to FDA-labeling of many antihypertensive medications for use in children and adolescents. However, none of these trials has provided definitive data on the optimal first line agent for this patient population. Clinical experience and other approaches discussed in this review are still necessary to guide treatment of hypertension in the young. The quest for the optimal antihypertensive agent is just beginning, and it is going to take some extraordinary effort to reach that goal.

Immunogenicity of Human Papillomavirus Recombinant Vaccine in Children with CKD

BACKGROUND AND OBJECTIVES There is a disproportionate burden of human papillomavirus (HPV) -related genital tract disease in patients with CKD and kidney transplantation; therefore, the potential effect of the quadrivalent HPV vaccine (Gardasil; Merck GmbH, Darmstadt, Germany) is profound. Immune abnormalities associated with CKD and immunosuppression may prevent optimal vaccine response. Our objective was to determine antibody response to the HPV vaccine in adolescent girls with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This cohort study conducted from 2008 to 2012 included 57 girls aged 9-21 years old with CKD (n=25), on dialysis (n=9), or with status postkidney transplantation (n=23) who received the standard three-dose vaccine series of the HPV vaccine recruited from two pediatric nephrology clinics. Antibody levels to HPV genotypes 6, 11, 16, and 18 were measured before vaccine dose 1 (baseline), <12 months after vaccine dose 3 (blood draw 2), and ≥12 months after vaccine dose 3 (blood draw 3). Seropositivity was defined as antibody level above an established threshold for each HPV genotype. Not all participants completed three blood draws. RESULTS Antibody response to all four HPV genotypes was 100% in the CKD and dialysis groups with samples drawn at <12 and ≥12 months after dose 3 of the HPV vaccine. Among patients with transplants, the percentages of patients achieving seropositivity were significantly lower at blood draw 2 for HPV genotypes 6 (63.6%; P=0.003), 11 (63.6%; P=0.003), and 18 (72.7%; P=0.02) and blood draw 3 for HPV genotypes 6 (62.5%; P=0.02), 11 (50%; P=0.001), 16 (75%; P=0.04), and 18 (50%; P=0.001). CONCLUSIONS Antibody response to the quadrivalent recombinant HPV vaccine was robust and sustained in girls and young women with CKD and on dialysis. A less robust response to the vaccine was observed among those with a kidney transplant. Additional study is needed to determine if vaccination before kidney transplantation or an alternative vaccination regimen would benefit transplant recipients.

Blood pressure variability, prehypertension, and hypertension in adolescents

Medical conditions diagnosed during adolescence may have long term impacts on the health of an individual. As a result, identifying cardiovascular risk factors earlier in life such as prehypertension (pre-HTN) and hypertension (HTN) can have significant benefits across an individual’s lifespan. Diagnosing elevated blood pressure (BP) during adolescence can be difficult, partially due to the natural variability that occurs during this period of life. Levels of BP that define adolescent prehypertension/hypertension are provided as well as an abridged review of BP variability across research groups. Strategies for BP management of adolescents are considered, with the primary focus on nonpharmacologic interventions.

Neurocognitive Function in Children with Primary Hypertension after Initiation of Antihypertensive Therapy

Objective To determine the change in neurocognitive test performance in children with primary hypertension after initiation of antihypertensive therapy. Study design Subjects with hypertension and normotensive control subjects had neurocognitive testing at baseline and again after 1 year, during which time the subjects with hypertension received antihypertensive therapy. Subjects completed tests of general intelligence, attention, memory, executive function, and processing speed, and parents completed rating scales of executive function. Results Fifty‐five subjects with hypertension and 66 normotensive control subjects underwent both baseline and 1‐year assessments. Overall, the blood pressure (BP) of subjects with hypertension improved (24‐hour systolic BP load: mean baseline vs 1 year, 58% vs 38%, P < .001). Primary multivariable analyses showed that the hypertension group improved in scores of subtests of the Rey Auditory Verbal Learning Test, Grooved Pegboard, and Delis‐Kaplan Executive Function System Tower Test (P < .05). However, the control group also improved in the same measures with similar effects sizes. Secondary analyses by effectiveness of antihypertensive therapy showed that subjects with persistent ambulatory hypertension at 1 year (n = 17) did not improve in subtests of Rey Auditory Verbal Learning Test and had limited improvement in Grooved Pegboard. Conclusions Overall, children with hypertension did not improve in neurocognitive test performance after 1 year of antihypertensive therapy, beyond that also seen in normotensive controls, suggesting improvements with age or practice effects because of repeated neurocognitive testing. However, the degree to which antihypertensive therapy improves BP may affect its impact upon neurocognitive function.

Aliskiren, the first direct renin inhibitor: assessing a role in pediatric hypertension and kidney diseases

This article provides a review of the role of aliskiren, a direct renin inhibitor, in pediatric hypertension and kidney diseases. Among the many mechanisms involved in regulating blood pressure, the renin–angiotensin–aldosterone system (RAAS) plays a major role. Additionally, the RAAS has been identified as a contributing factor to cardiovascular and renal diseases for more than three decades. The potential benefits of inhibiting the RAAS by aliskiren alone or in combination with other RAAS blockers (ACEIs, ARBs) seem to be theoretically promising. However, caution should be exercised in treating children, especially in those with significant chronic kidney disease until there is more evidence regarding the safety and efficacy of this new drug in the pediatric population from ongoing clinical trials.

Childhood Obesity and Blood Pressure Regulation

Obesity in children and adolescents continues to occur with increasing frequency and has been associated with the development of clinical consequences of obesity such as hypertension. This chapter will begin with a review of the definitions of hypertension and prehypertension in children and adolescents, followed by discussion of the epidemiology of obesity hypertension. After examining the complex relationship between obesity and hypertension and potential mechanisms contributing to the development of obesity hypertension, clinical approaches to the management of hypertension in the setting of obesity are discussed. The clinical management is multifaceted as one must consider that treating obesity may in fact lead to improved blood pressure. Yet, treating obesity takes time and motivation, and while awaiting the effects of changes in lifestyle on blood pressure, use of antihypertensive medications may be indicated in some children.