Mieczysław Litwin

Strict blood-pressure control and progression of renal failure in children.

BACKGROUND Although inhibition of the renin-angiotensin system delays the progression of renal failure in adults with chronic kidney disease, the blood-pressure target for optimal renal protection is controversial. We assessed the long-term renoprotective effect of intensified blood-pressure control among children who were receiving a fixed high dose of an angiotensin-converting-enzyme (ACE) inhibitor. METHODS After a 6-month run-in period, 385 children, 3 to 18 years of age, with chronic kidney disease (glomerular filtration rate of 15 to 80 ml per minute per 1.73 m(2) of body-surface area) received ramipril at a dose of 6 mg per square meter of body-surface area per day. Patients were randomly assigned to intensified blood-pressure control (with a target 24-hour mean arterial pressure below the 50th percentile) or conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that does not target the renin-angiotensin system; patients were followed for 5 years. The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion. RESULTS A total of 29.9% of the patients in the group that received intensified blood-pressure control reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the group that received conventional blood-pressure control (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P=0.02). The two groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs. 26.5%). Proteinuria gradually rebounded during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of renal disease. CONCLUSIONS Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)

Normative values for intima-media thickness and distensibility of large arteries in healthy adolescents.

Objective Sonographic evaluation of arterial wall morphology and elasticity is increasingly accepted as a non-invasive tool in cardiovascular assessment. Several studies suggest that intima–media thickness (IMT) and arterial elasticity indices may sensitively reflect different vasculopathic processes in children. However, normative values and the impact of adolescent growth are largely unknown. Methods We assessed the IMT of the common carotid (cIMT) and femoral arteries (fIMT), carotid elasticity indices and interacting anthropometric factors in 247 healthy subjects aged 10–20 years. Results cIMT, fIMT, incremental elastic modulus (Einc) and circumferential wall stress (CWS) were positively, and distensibility coefficient (DC) inversely, correlated with age, height, body mass index (BMI), systolic blood pressure (BP) and brachial pulse pressure (r = 0.56 to −0.45, P < 0.05 to 0.0001). DC (r = −0.29, P < 0.0001) and stiffness index β (r = 0.25, P < 0.0001), but not Einc, were significantly associated with cIMT independently of age. All vascular parameters showed non-Gaussian distributions. Excessively high IMT was associated with BMI and pulse pressure above the 90th percentile, and elevated Einc with high-normal BMI. Multivariate analysis identified independent positive effects of standardized BMI and brachial pulse pressure on normalized cIMT, negative effects of systolic BP and cIMT on DC, a positive effect of cIMT on stiffness, and positive effects of systolic BP and BMI on Einc and CWS. Conclusions Morphological and functional measures of large arteries should be normalized to take account of changes during adolescence and skewed distributions. Relative body mass, systolic blood pressure and/or pulse pressure are determinants of IMT and elasticity.

Altered morphologic properties of large arteries in children with chronic renal failure and after renal transplantation

Increased intima-media thickness of the carotid arteries (cIMT) has been found in young adults with childhood-onset chronic kidney disease (CKD). The disease stage at which these patients first develop abnormalities of arterial texture is unknown. The objective of this study was to determine the onset and character of arterial changes in children aged 10 to 20 yr with different stages of CKD and to identify risk factors for early arteriopathy. High-resolution ultrasonography was conducted of common cIMT and femoral superficial artery IMT. Fifty-five children with stages 2 to 4 CKD (GFR 51 +/- 31 ml/min per 1.73 m2), 37 on dialysis, and 34 after renal transplantation (Rtx; GFR 73 +/- 31 ml/min per 1.73 m2) were studied. Control subjects were 270 healthy children, matched for age and gender. Compared with control subjects, cIMT, femoral superficial artery IMT (both as absolute values and as SD score of median of normal value), wall cross-sectional area, and lumen cross-sectional area of carotid artery were significantly increased in all patient groups and most markedly abnormal in dialysis patients. cIMT in CKD and Rtx patients was significantly lower in comparison with dialysis patients. cIMT correlated with mean past serum Ca x P product, the cumulative dose of calcium-based phosphate binders, and the time-averaged mean calcitriol dose. The cumulative phosphate binder intake, time-averaged Ca x P product, and young age were independent predictors of an increased cIMT. In children with CKD, thickening of IMT occurs early in the course of disease and is most marked in dialyzed patients. The changes may be partly reversible after Rtx.

SIX2 and BMP4 Mutations Associate With Anomalous Kidney Development

Renal hypodysplasia (RHD) is characterized by reduced kidney size and/or maldevelopment of the renal tissue following abnormal organogenesis. Mutations in renal developmental genes have been identified in a subset of affected individuals. Here, we report the first mutations in BMP4 and SIX2 identified in patients with RHD. We detected 3 BMP4 mutations in 5 RHD patients, and 3 SIX2 mutations in 5 different RHD patients. Overexpression assays in zebrafish demonstrated that these mutations affect the function of Bmp4 and Six2 in vivo. Overexpression of zebrafish six2.1 and bmp4 resulted in dorsalization and ventralization, respectively, suggesting opposing roles in mesendoderm formation. When mutant constructs containing the identified human mutations were overexpressed instead, these effects were attenuated. Morpholino knockdown of bmp4 and six2.1 affected glomerulogenesis, suggesting specific roles for these genes in the formation of the pronephros. In summary, these studies implicate conserved roles for Six2 and Bmp4 in the development of the renal system. Defects in these proteins could affect kidney development at multiple stages, leading to the congenital anomalies observed in patients with RHD.

2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents

Increasing prevalence of hypertension (HTN) in children and adolescents has become a significant public health issue driving a considerable amount of research. Aspects discussed in this document include advances in the definition of HTN in 16 year or older, clinical significance of isolated systolic HTN in youth, the importance of out of office and central blood pressure measurement, new risk factors for HTN, methods to assess vascular phenotypes, clustering of cardiovascular risk factors and treatment strategies among others. The recommendations of the present document synthesize a considerable amount of scientific data and clinical experience and represent the best clinical wisdom upon which physicians, nurses and families should base their decisions. In addition, as they call attention to the burden of HTN in children and adolescents, and its contribution to the current epidemic of cardiovascular disease, these guidelines should encourage public policy makers to develop a global effort to improve identification and treatment of high blood pressure among children and adolescents.

Intima–media thickness measurements in children with cardiovascular risk factors

Measuring intima–media thickness (IMT) is now a standard diagnostic procedure in assessing cardiovascular risk and hypertensive target-organ damage (TOD) in adults. There is also an increasing number of pediatric publications evaluating IMT in children from high-risk groups, such as those with arterial hypertension, diabetes, chronic kidney disease, obesity, dyslipidemia, and homocystinurias. It has been shown that carotid IMT is strongly related with other markers of TOD in children with arterial hypertension and with metabolic cardiovascular risk factors. In children with coarctation of the aorta, carotid IMT correlated both with blood pressure and even with mild residual aortic gradient. On the other hand, studies in children with high cardiovascular risk have shown that normalization of blood pressure and metabolic abnormalities led to regression of arterial changes and decrease of IMT. Although not yet accepted as standard pediatric procedure, IMT measurement is emerging as a promising method of assessing TOD and cardiovascular risk and monitoring treatment efficacy. From a practical point of view, clinical utility of IMT measurements seems to be similar to use of echocardiography in assessing left ventricular mass. However, IMT measurements in children and adolescents should be standardized to avoid bias caused by the use of different measurement methods.

The Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) Study: Objectives, Design, and Methodology

BACKGROUND AND OBJECTIVES Children and adolescents with chronic kidney disease (CKD) are at high risk for cardiovascular morbidity and mortality. A systemic arteriopathy and cardiomyopathy has been characterized in pediatric dialysis patients by the presence of morphologic and functional abnormalities. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Cardiovascular Comorbidity in Children with CKD (4C) Study is a multicenter, prospective, observational study aiming to recruit more than 600 children, aged 6 to 17 years, with initial GFR of 10 to 45 ml/min per 1.73 m(2). The prevalence, degree, and progression of cardiovascular comorbidity as well as its association with CKD progression will be explored through longitudinal follow-up. The morphology and function of the heart and large arteries will be monitored by sensitive noninvasive methods and compared with aged-matched healthy controls. Multiple clinical, anthropometric, biochemical, and pharmacologic risk factors will be monitored prospectively and related to the cardiovascular status. A whole-genome association study will be performed to identify common genetic variants associated with progression of cardiovascular alterations and/or renal failure. Monitoring will be continued as patients reach end-stage renal disease and undergo different renal replacement therapies. RESULTS While cardiovascular morbidity in adults is related to older age and additional risk factor load (e.g., diabetes), the role of CKD-specific factors in the initiation and progression of cardiac and vascular disease are likely to be characterized with greater sensitivity in the pediatric age group. CONCLUSIONS The 4C study is expected to provide innovative insight into cardiovascular and renal disease progression in CKD.

Carotid Artery Intima-Media Thickness and Distensibility in Children and Adolescents Reference Values and Role of Body Dimensions

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 &bgr; 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 &bgr; 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.

Evolution of large-vessel arteriopathy in paediatric patients with chronic kidney disease

UNLABELLED This observational study was designed to verify the hypothesis that the treatment modality significantly affects the evolution of CKD-associated arteriopathy. PATIENTS Paediatric patients (mean age 13.8 +/- 4.2 years) with chronic kidney disease (CKD) stages 3-5, including 24 patients with mean GFR 54 +/- 21 ml/min/1.73 m(2) (CKD group) and 32 patients in end-stage renal disease, of whom 19 received a renal allograft (D-Rtx) and 13 remained on dialysis (D-D). METHODS Sonography of the common carotid artery was performed at baseline and after 12 months. Intima-media thickness (IMT) and the cross-sectional areas of the vessel wall (WCSA) and lumen (LCSA) were measured and normalized to age (SDS). RESULTS At baseline IMT-SDS and WCSA-SDS were increased above normal, and were significantly higher in D than in CKD patients (P < 0.001). IMT-SDS increased over time in CKD and D-D patients (1.4 +/- 1.7 to 2.1 +/- 1.2, P = 0.05). In contrast, IMT-SDS (2.8 +/- 0.6 to 2.0 +/- 0.6, P < 0.005) decreased in those D-Rtx patients who had elevated values prior to transplantation. The total number of patients with elevated cIMT-SDS changed from 7 to 13 in the 24 CKD, from 8 to 11 in the 13 D-D and from 11 to 12 in the 19 D-Rtx patients. While IMT-SDS was independently correlated with blood pressure and serum phosphate in the CKD and D patients, only total dialysis vintage (r = 0.50; P < 0.05) and the IMT-SDS attained at the time of grafting (r = 0.46, P < 0.05) correlated with IMT-SDS 1 year post-Rtx. CONCLUSION While vascular lesions rapidly progress in CKD and D patients, abolition of the uraemic state by Rtx leads to stabilization or partial regression of CKD-associated arteriopathy. Cumulative dialysis duration and the degree of arterial damage prevalent at the time of grafting are the main determinants of persistent arteriopathy 1 year after Rtx.

Oscillometric blood pressure percentiles for Polish normal-weight school-aged children and adolescents.

Objective: The objective of this study was to construct blood pressure (BP) references with the use of a validated oscillometric device for normal-weight, school-aged children and adolescents and to study BP predictors. Methods: BP was measured in 14 266 randomly selected, normal-weight Polish children and adolescents aged 7–18 years, who were free of chronic disease, using a validated oscillometric device (Datascope Accutor Plus). Height, weight and waist circumference were measured. BP percentiles were constructed for age and height simultaneously with the use of a polynomial regression model. The normative values of BP were compared with the US normal-weight reference, German oscillometric reference, and Polish auscultatory reference. Results: Reference BP percentiles by sex, age and height are presented. At median height, the age-specific differences in the 90th BP percentiles compared with German oscillometric reference ranged in the case of boys from −3 to 2 mmHg and from −5 to −1 mmHg, SBP and DBP, respectively, and in the case of girls from 0 to 3 mmHg and from −5 to −1 mmHg, SBP and DBP, respectively. As compared to weight, waist circumference was stronger SBP predictor in low birth weight boys. Conclusion: The study provides BP references for oscillmetric device, based on a current, nationally representative sample of normal-weight Polish children and adolescents. The normative values of BP were compared taking into consideration the height and BMI differences, the pubertal spurt, the methods of BP measurement and percentile construction.