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Belatacept is an intravenously infused selective T cell costimulation blocker approved for preventing organ rejection in renal transplant recipients aged ≥18 years. This phase I trial examined the pharmacokinetics and pharmacodynamics (percentage CD86 receptor occupancy [%CD86RO]) of a single dose of belatacept (7.5 mg/kg) administered to kidney transplant recipients aged 12-17 years receiving a stable calcineurin inhibitor-based immunosuppressive regimen. Nine adolescents (mean age 15.1 years) who were seropositive for Epstein-Barr virus were enrolled; all completed the 6-month study. Pharmacokinetics suggested relatively low variability of exposure (coefficients of variation for maximum observed serum concentration [Cmax ] and area under the serum concentration-time curve from time zero extrapolated to infinity [AUC0-INF ] were 20% and 25%, respectively). Mean half-life (T1/2 ) occurred 7.2 days postinfusion. Belatacept total body clearance was 0.48 mL/h/kg, and volume of distribution at steady-state (Vss ) was low at 0.09 L/kg. Compared with historical data from healthy adult volunteers administered a single dose of belatacept 10 mg/kg and adult kidney transplant recipients administered multiple doses of belatacept 5 mg/kg, pharmacokinetic values for adolescents were similar, indicating consistency across adolescent and adult populations. Mean %CD86RO increased with increasing belatacept concentration, indicating a direct relationship between pharmacokinetics and pharmacodynamics. Four patients reported 7 serious adverse events; none was considered related to belatacept. These data will inform belatacept dose selection in future studies of adolescent kidney transplant recipients.

Despite its discovery more than 150 years ago, the cause of primary hypertension remains unknown. Most studies suggest that hypertension involves genetic, congenital or acquired risk factors that result in a relative inability of the kidney to excrete salt (sodium chloride) in the kidneys. Here we review recent studies that suggest there may be two phases, with an initial phase driven by renal vasoconstriction that causes low-grade ischemia to the kidney, followed by the infiltration of immune cells that leads to a local autoimmune reaction that maintains the renal vasoconstriction. Evidence suggests that multiple mechanisms could trigger the initial renal vasoconstriction, but one way may involve fructose that is provided in the diet (such as from table sugar or high fructose corn syrup) or produced endogenously. The fructose metabolism increases intracellular uric acid, which recruits NADPH oxidase to the mitochondria while inhibiting AMP-activated protein kinase. A drop in intracellular ATP level occurs, triggering a survival response. Leptin levels rise, triggering activation of the sympathetic central nervous system, while vasopressin levels rise, causing vasoconstriction in its own right and stimulating aldosterone production via the vasopressin 1b receptor. Low-grade renal injury and autoimmune-mediated inflammation occur. High-salt diets can amplify this process by raising osmolality and triggering more fructose production. Thus, primary hypertension may result from the overactivation of a survival response triggered by fructose metabolism. Restricting salt and sugar and hydrating with ample water may be helpful in the prevention of primary hypertension. [ABSTRACT FROM AUTHOR]

The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs. 160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid. [ABSTRACT FROM AUTHOR]

Background: Childhood hypertension is increasingly common and likely contributes to the premature development of cardiovascular and renal disease. Early detection of hypertensive cardiac damage may allow for prompt therapy and reduce the risk of late morbidity and mortality. While left ventricular mass index (LVMI) has been used as a surrogate of hypertensive cardiac damage in children, its prognostic and diagnostic value is not completely understood in this population.Objective: To test the hypothesis that strain assessment using automated function imaging (AFI) detects cardiac changes in hypertensive children earlier than standard 2D echocardiographic techniques.METHODS: A cross-sectional study of hypertensive children < 19 years old between October 2010 and May 2012 was performed. Any patient who was newly diagnosed with hypertension and underwent echocardiographic examination including standard 2D, Doppler, and automated function imaging (AFI) modalities was included. Global peak longitudinal systolic strain (GLPSS) was measured using a 17 segment model of the left ventricle. All echocardiographic measures were compared to normative reference values for age.Results: Twenty four patients (mean age 14.6 ± 2.7 years, 67% male) were identified. Mean systolic and diastolic blood pressure index was 1.1 ± 0.1 and 0.9 ± 0.1, respectively. Mean LVMI did not significantly differ from 95th-percentile normative values (41.6 ± 11.2 g/m2.7 vs. 39.3 ± 1.5 g/m2.7, p = 0.328). Mean GLPSS was significantly lower than 5th-percentile normative values (-17.6 ± 2.5 vs. -19.5 ± 0.42, p = 0.001) and were decreased across all myocardial segments. Left atrial volume was significantly higher than reported normal values in children (27.6 ± 7.3 ml/m2 vs. 22.0 ± 6.0 ml/m2, p = 0.002). No patient exhibited abnormal shortening or ejection fraction, mitral E-wave to A-wave ratio, or lateral mitral E-wave to e’-wave ratio.Conclusions: A population of unselected, newly diagnosed hypertensive adolescents had atypically low GLPSS and increased left atrial volume. The use of GLPSS measured by AFI may be a more sensitive marker of early myocardial remodeling in hypertensive children and routine measurement of GLPSS should be considered. [ABSTRACT FROM AUTHOR]