Carotid intima-media thickness (cIMT) and carotid artery distensibility are reliable screening methods for vascular alterations and the assessment of cardiovascular risk in adult and pediatric cohorts. We sought to establish an international reference data set for the childhood and adolescence period and explore the impact of developmental changes in body dimensions and blood pressure (BP) on carotid wall thickness and elasticity. cIMT, the distensibility coefficient, the incremental modulus of elasticity, and the stiffness index β were assessed in 1155 children aged 6 to 18 years and sex-specific reference charts normalized to age or height were constructed from 1051 nonobese and nonhypertensive children. The role of body dimensions, BP, and family history, as well as the association between cIMT and distensibility, was investigated. cIMT increased and distensibility decreased with age, height, body mass index, and BP. A significant sex difference was apparent from the age of 15 years. Age- and height-normalized cIMT and distensibility values differed in children who are short or tall for their age. By stepwise multivariate analysis, standardized systolic BP and body mass index were independently positively associated with cIMT SD scores (SDS). Systolic BP SDS independently predicted all distensibility measures. Distensibility coefficient SDS was negatively and β SDS positively associated with cIMT SDS, whereas incremental modulus of elasticity was independent of cIMT. Morphological and functional aspects of the common carotid artery are particularly influenced by age, body dimensions, and BP. The reference charts established in this study allow to accurately compare vascular phenotypes of children with chronic conditions with those of healthy children.

Background and objectives Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome.

We studied the long-term outcome of 64 children with biopsy-proven Schönlein-Henoch purpura (SHP) nephritis over 1-23 years of follow-up. Overall renal survival 10 years after onset was 73%. Multivariate logistic regression analysis identified initial renal insufficiency (P=0.004), nephrotic syndrome (P=0.037), and the severity of histological alterations, as defined by the proportion of glomerular crescents (P=0.051), as significant independent predictors of progressive renal failure. Four patients followed for more than 19 years showed glomerular damage after transient recovery. Eight children with crescentic nephritis associated with a rapidly progressive course and/or persistent nephrotic syndrome were treated by at least seven sessions of plasma exchange (PE) within 16 weeks of onset of purpura. During treatment serum creatinine levels dropped in each patient from a mean of 2.3 to 1.1 mg/dl, followed by a rebound increase. Repeated courses of PE in 5 patients produced comparable responses. Four patients undergoing PE reached end-stage renal disease at 1.2.-3.7 years after onset, whilst 3 finally were in preterminal renal failure (creatinine 3.2-6.1 mg/dl after 7-13.5 years), and 1 patient reached a normal glomerular filtration rate. Our experience suggests that initial renal insufficiency is the best single predictor of the further clinical course in children with SHP nephritis. Early PE appears to delay the progression in some patients with severe, rapidly progressive forms of the disease.

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Rituximab is an effective treatment option in the short- and long-term control of treatment refractory SSNS. Further controlled studies are needed to address optimal patient selection, dose and safety of rituximab infusions.

Abstract-␣-Adducin polymorphism in humans is associated with abnormal renal sodium handling and high blood pressure. The mechanisms by which mutations in adducin affect the renal set point for sodium excretion are not known. Decreases in Na ϩ ,K ϩ -ATPase activity attributable to endocytosis of active units in renal tubule cells by dopamine regulates sodium excretion during high-salt diet. Milan rats carrying the hypertensive adducin phenotype have a higher renal tubule Na ϩ ,K ϩ -ATPase activity, and their Na ϩ ,K ϩ -ATPase molecules do not undergo endocytosis in response to dopamine as do those of the normotensive strain. Dopamine fails to promote the interaction between adaptins and the Na ϩ ,K ϩ -ATPase because of adaptin-2 subunit hyperphosphorylation. Expression of the hypertensive rat or human variant of adducin into normal renal epithelial cells recreates the hypertensive phenotype with higher Na ϩ ,K ϩ -ATPase activity, 2-subunit hyperphosphorylation, and impaired Na ϩ ,K ϩ -ATPase endocytosis. Thus, increased renal Na ϩ ,K ϩ -ATPase activity and altered sodium reabsorption in certain forms of hypertension could be attributed to a mutant form of adducin that impairs the dynamic regulation of renal Na ϩ ,K ϩ -ATPase endocytosis in response to natriuretic signals. Key Words: high blood pressure Ⅲ sodium retention Ⅲ protein trafficking Ⅲ cytoskeleton Ⅲ endocytosis S pontaneous mutations in ␣-adducin gene favor renal sodium retention and the development of high blood pressure in humans and rodents. 1 The estimated frequency of the mutated allele fluctuates among 8% in African Americans, 15% to 20% in whites, and 50% in Japanese individuals. The resulting phenotype is similar in rats and humans despite species differences in the mutation sites (human G460W/ S586C; rats F316Y). These polymorphisms affect the pressure natriuresis curve, the lithium clearance (an indicator of proximal tubule [PCT] sodium transport), 2 and the chronic blood pressure response to diuretics. 3,4 Recent studies further substantiate the role of adducin in human hypertension and the associated renal or cardiac alterations. 5,6 Many of these findings have been obtained in low-renin hypertensive patients, 7 in whom renal Na ϩ retention is a particularly important pathogenetic factor, or in patients carrying the gene variants known to affect renal Na ϩ handling. 8 At the cellular level, adducin plays an active role in cytoskeleton organization by regulating actin dynamics. 9 The mutated hypertensive variant of the adducin ␣-subunit increases the rate of actin polymerization and bundling in a cell-free system compared with the wild-type variant. 10 In cultured renal cells stably transfected with the mutated ␣-adducin, the actin cytoskeleton network appears thicker and Na ϩ ,K ϩ -ATPase activity is higher than in cells transfected with the wild-type variant. 10 In renal epithelial cells, the Na ϩ ,K ϩ -ATPase is located at the basolateral membrane domain and is critical for vectorial sodium transport. Its regulation by catecholamines cont...

Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome.

Twenty-four-hour ambulatory blood pressure monitoring (ABPM) has proven to have better reproducibility than office blood pressure (BP) and is increasingly used for the study of hypertension in children and adolescents. The aim of our study was to assess 24-h BP profiles and to compare the results of office BP measurements with ABPM in stable liver transplant recipients transplanted before the age of 18 yr. ABPM was performed in 29 patients (nine males, 20 females), aged 3.9-24.8 yr (median 10.8 yr). The investigation was conducted 1.1-11.5 yr (median 5.1 yr) following transplantation. ABPM confirmed hypertension in one out of three office hypertensive patients. Seven patients (24%), whose office BP recordings were within the normotensive range, were reclassified as hypertensive. Non-dippers (n = 17), arbitrarily defined as patients with less than 10% nocturnal fall in BP, were similarly distributed among patients with ambulatory normotension and ambulatory hypertension (chi(2), p = 0.79). In addition, non-dippers showed a negative correlation between 24-h total urinary albumin excretion and both systolic and diastolic nocturnal decline in BP (Rho = -0.48, p < 0.05 and Rho = -0.86, p < 0.01, respectively). Our study found office BP readings to be poorly representative of 24-h BP profile. Larger studies are needed to confirm our observations as well as to determine whether routine BP measurements in the follow-up of paediatric liver transplant recipients should be based solely on office BP.