Marc B. Lande

Effects of Childhood Primary Hypertension on Carotid Intima Media Thickness: A Matched Controlled Study

To determine whether carotid intima media thickness is increased in children with primary hypertension, the current study compared carotid intima media thickness in hypertensive children with that of normotensive control subjects matched closely for body mass index and determined the relationship between carotid intima media thickness and hypertension severity determined by ambulatory blood pressure monitoring. Children with newly diagnosed office hypertension (n=28) had carotid intima media thickness, left ventricular mass index, and ambulatory blood pressure monitoring performed. Carotid intima media thickness was performed in normotensive control subjects (n=28) matched pairwise to hypertensive subjects for age (±1 year), gender, and body mass index (±10%). Eighty-two percent of subjects were overweight or obese (body mass index ≥85th percentile). The median carotid intima media thickness of hypertensive subjects was greater than that of matched controls (0.67 versus 0.63 mm; P=0.045). In the hypertensive subjects, carotid intima media thickness correlated strongly with several ambulatory blood pressure monitoring parameters, with the strongest correlation for daytime systolic blood pressure index (r=0.57; P=0.003). In the hypertensive group, the prevalence of left ventricular hypertrophy was 32%, but unlike carotid intima media thickness, left ventricular mass index did not correlate with ambulatory blood pressure monitoring. Together, the findings that hypertensive subjects had increased carotid intima media thickness compared with matched controls and that higher carotid intima media thickness correlated with more severe hypertension by ambulatory blood pressure monitoring provide strong evidence that carotid intima media thickness is increased in childhood primary hypertension, independent of the effects of obesity.

Elevated blood pressure and decreased cognitive function among school-age children and adolescents in the United States

OBJECTIVE To evaluate the relationship between elevated blood pressure (BP) and cognitive test performance in a nationally representative sample of children. Study design The National Health and Nutrition Examination Survey III provides cross-sectional data for children 6 to 16 years, including BP and cognitive test scores. Elevated BP was defined as systolic or diastolic BP >or=90th percentile. Cognitive tests were compared for children with elevated and normal BP. Linear regression was used to evaluate the relation between elevated BP and decreased test scores. RESULTS Among the 5077 children, 3.4% had systolic BP >or=90th percentile and 1.6% diastolic BP >or=90th percentile. Children with elevated systolic BP had lower average scores compared with normotensive children for digit span (7.9 vs 8.7, P=.01), block design (8.6 vs 9.5, P=.03), and mathematics (89.6 vs 93.8, P=.01). Elevated diastolic BP was associated with lower average scores on block design (9.5 vs 11, P=.01). Linear regression showed that elevated systolic BP was independently associated with lower digit span scores (P=.032). CONCLUSION Children with elevation of systolic BP are at risk for central nervous system end-organ damage, as manifested by decreased digit span test scores.

Health-Related Quality of Life of Children With Mild to Moderate Chronic Kidney Disease

OBJECTIVE: To compare the health-related quality of life (HRQoL) of children with chronic kidney disease (CKD) with healthy children; to evaluate the association between CKD severity and HRQoL; and to identity demographic, socioeconomic, and health-status variables that are associated with impairment in HRQoL in children with mild to moderate CKD. METHODS: This was a cross-sectional assessment of HRQoL in children who were aged 2 to 16 and had mild to moderate CKD using the Pediatric Inventory of Quality of Life Core Scales (PedsQL). Overall HRQoL and PedsQL domain means for parents and youth were compared with previously published norms by using independent sample t tests. Study participants were categorized by kidney disease stage (measured by iohexol-based glomerular filtration rate [iGFR]), and group differences in HRQoL were evaluated by using analysis of variance and Cuzick trend tests. The association between hypothesized predictors of HRQoL and PedsQL scores was evaluated with linear and logistic regression analyses. RESULTS: The study sample comprised 402 participants (mean age: 11 years, 60% male, 70% white, median iGFR: 42.5 mL/min per 1.73 m2, median CKD duration: 7 years). Youth with CKD had significantly lower physical, school, emotional, and social domain scores than healthy youth. iGFR was not associated with HRQoL. Longer disease duration and older age were associated with higher PedsQL scores in the domains of physical, emotional, and social functioning. Older age was associated with lower school domain scores. Maternal education ≥16 years was associated with higher PedsQL scores in the domains of physical, school, and social functioning. Short stature was associated with lower scores in the physical functioning domain. CONCLUSIONS: Children with mild to moderate CKD, in comparison with healthy children, reported poorer overall HRQoL and poorer physical, school, emotional, and social functioning. Early intervention to improve linear growth and to address school functioning difficulties is recommended.

Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism

Many Mendelian traits are likely unrecognized owing to absence of traditional segregation patterns in families due to causation by de novo mutations, incomplete penetrance, and/or variable expressivity. Genome-level sequencing can overcome these complications. Extreme childhood phenotypes are promising candidates for new Mendelian traits. One example is early onset hypertension, a rare form of a global cause of morbidity and mortality. We performed exome sequencing of 40 unrelated subjects with hypertension due to primary aldosteronism by age 10. Five subjects (12.5%) shared the identical, previously unidentified, heterozygous CACNA1HM1549V mutation. Two mutations were demonstrated to be de novo events, and all mutations occurred independently. CACNA1H encodes a voltage-gated calcium channel (CaV3.2) expressed in adrenal glomerulosa. CACNA1HM1549V showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production. This mutation explains disease pathogenesis and provides new insight into mechanisms mediating aldosterone production and hypertension. DOI: http://dx.doi.org/10.7554/eLife.06315.001

Phosphorylation of Aquaporin-2 Does Not Alter the Membrane Water Permeability of Rat Papillary Water Channel-containing Vesicles

Antidiuretic hormone modulates the water permeability (P) of epithelial cells in the rat kidney by vesicle-mediated insertion and removal of the aquaporin-2 (AQP-2) water channel. AQP-2 possesses a single consensus cAMP-dependent protein kinase A (PKA) phosphorylation site (Ser-256) hypothesized to regulate channel P(Kuwahara, M., Fushimi, K., Terada, Y., Bai, L., Sasaki, S., and Marumo, F.(1995) J. Biol. Chem. 270, 10384-10387). To test whether PKA phosphorylation of AQP-2 alters channel P, we compared the P values of purified AQP-2 endosomes after incubation with either PKA or alkaline phosphatase. Studies using [-P]ATP reveal that AQP-2 endosomes contain endogenous PKA and phosphatase activities that add and remove P label from AQP-2. However, the P (0.16 ± 0.06 cm/s) of endosomes containing phosphorylated AQP-2 (0.7 ± 0.3 mol of PO/mol of protein) is not significantly different from the same AQP-2 endosomes where 95 ± 8% of the phosphate has been removed (P 0.14 ± 0.06 cm/s). These data do not support a role for PKA phosphorylation in alteration of AQP-2s P. Instead, AQP-2 phosphorylation by PKA may modulate AQP-2s distribution between plasma membrane and intracellular vesicle compartments.

Left ventricular mass index in children with white coat hypertension

OBJECTIVES To determine whether children with white coat hypertension (WCH) have evidence of target-organ damage by comparing the left ventricular mass index (LVMI) of subjects with WCH with that of matched normotensive and hypertensive controls. STUDY DESIGN Each subject in the WCH group was matched by body mass index (BMI; +/- 10%), age (+/- 1 year), and sex to a normotensive control and a hypertensive control. Echocardiograms were reviewed to determine the LVMI for each subject. These triple matches were analyzed using repeated-measures analysis of variance to detect differences in LVMI among the 3 groups. RESULTS A total of 27 matched triplets were established. The groups were comparable for sex, age, and BMI. Mean LVMI was 29.2 g/m(2.7) for the normotensive group, 32.3 g/m(2.7) for the WCH group, and 35.1 g/m(2.7) for the sustained hypertensive group (normotensive vs WCH, P = .028; WCH vs sustained hypertension, P = .07). Left ventricular hypertrophy was not present in any subject in the normotensive or WCH groups, but was found in 26% of the sustained hypertensive subjects (P < .001). CONCLUSIONS After controlling closely for BMI, the LVMI in the subjects with WCH was between that of the normotensives and sustained hypertensives, suggesting that WCH may be associated with hypertensive end-organ effects.

Neurocognitive Functioning of Children and Adolescents with Mild-to-Moderate Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Few data exist on the neurocognitive functioning of children with mild-to-moderate chronic kidney disease (CKD). The primary objectives of this paper are (1) to determine the neurocognitive status in this population and (2) to identify sociodemographic and health-status variables associated with neurocognitive functioning. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a cross-sectional study of 368 children, aged 6 to 16 years, from the Chronic Kidney Disease in Children (CKiD) cohort. Median iGFR was 43 ml/min per 1.73 m(2), and the median duration of CKD was 8.0 years. Approximately 26% had underlying glomerular disease. Measures of intelligence, academic achievement, attention regulation, and executive functioning were obtained at study entry. The prevalence of neurocognitive deficits was determined by comparing participant scores on each measure of neurocognitive functioning with normative data. The association between hypothesized predictors of neurocognitive dysfunction was evaluated using multivariate regression analyses. RESULTS Neurocognitive functioning was within the average range for the entire group; however, 21% to 40% of participants scored at least one SD below the mean on measures of intelligence quotient (IQ), academic achievement, attention regulation, or executive functioning. Higher iohexol-based GFR (iGFR) predicted a lesser risk for poor performance on measures of executive function. Participants having elevated proteinuria (i.e., urine protein/creatinine >2) scored lower on verbal IQ, full-scale IQ, and attention variability than those without elevated proteinuria. CONCLUSIONS Whereas most children with mild-to-moderate CKD have no major neurocognitive deficits, a substantial percentage did show neurocognitive dysfunction that places them at risk for poor long-term educational and occupational outcomes.

Human red cell Aquaporin CHIP. II. Expression during normal fetal development and in a novel form of congenital dyserythropoietic anemia.

Channel-forming integral protein (CHIP) is the archetypal member of the Aquaporin family of water channels. Delayed CHIP expression was shown recently in perinatal rat (Smith, B. L., R. Baumgarten, S. Nielsen, D. Raben, M. L. Zeidel, and P. Agre. 1993. J. Clin. Invest. 92:2035-2041); here we delineate the human patterns. Compared with adult, second and third trimester human fetal red cells had lower CHIP/spectrin ratios (0.72 +/- 0.12, 0.94 +/- 0.22 vs 1.18 +/- 0.11) and reduced osmotic water permeability (0.029, 0.026 vs 0.037 cm/s); CHIP was already present in human renal tubules by the second trimester. A patient with a novel form of congenital dyserythropoietic anemia (CDA) with persistent embryonic and fetal globins and absent red cell CD44 protein was studied because of reduced CHIP-associated Colton antigens. Novel CDA red cells contained < 10% of the normal level of CHIP and had remarkably low osmotic water permeability (< 0.01 cm/s), but no mutation was identified in Aquaporin-1, the gene encoding CHIP. These studies demonstrate: (a) unlike rat, human CHIP expression occurs early in fetal development; (b) red cell water channels are greatly reduced in a rare phenotype; and (c) disrupted expression of red cell CHIP and CD44 suggests an approach to the molecular defect in a novel form of CDA.

Parental Assessments of Internalizing and Externalizing Behavior and Executive Function in Children with Primary Hypertension

OBJECTIVE To determine the relations between hypertension and parental ratings of behavior and executive functions in children with primary hypertension and to examine the potential moderating influence of obesity. STUDY DESIGN Hypertensive and normotensive control groups were matched for age, sex, race, intelligence quotient, maternal education, household income, and obesity. Parents completed the Child Behavior Checklist to assess Internalizing and Externalizing problems and the Behavior Rating Inventory of Executive Function to assess behavioral correlates of executive function. RESULTS Thirty-two hypertensive subjects and 32 normotensive control subjects (aged 10 to 18 years) were enrolled. On the Child Behavior Checklist, hypertensives had higher Internalizing T-scores (53 vs 44.5, P = .02) with 37% falling within the clinically significant range vs 6% of control subjects (P = .005). Internalizing score increased with increasing body mass index percentile in hypertensive but not normotensive subjects. Hypertensives had worse Behavior Rating Inventory of Executive Function Global Executive Composite T-scores compared with control subjects (50 vs 43, P = .009). CONCLUSIONS Children with both hypertension and obesity demonstrate higher rates of clinically significant internalizing problems, and hypertensives (irrespective of obesity) demonstrate lower parental ratings of executive function compared with normotensive control subjects.

Reversible Fanconi syndrome associated with valproate therapy

Two children with developmental delay and seizure disorders had Fanconi syndrome associated with valproate therapy. Both recovered normal proximal tubular function within 4 months of discontinuing valproate therapy.