BACKGROUND:Office blood pressure (BP) trajectories may help assess hypertension progression and the effects of antihypertensive treatment in children with chronic kidney disease. METHODS:Analysis of antihypertensive treatment and BP slopes in 320 patients from the 4C study (Cardiovascular Comorbidity in Children with Chronic Kidney Disease) cohort with chronic kidney disease before renal replacement therapy, based on a minimum of 3 individual observations and 2 years of follow-up. RESULTS:At enrollment, 70 (22%) patients had uncontrolled or untreated hypertension, 130 (41%) patients had controlled hypertension, and 120 (37%) patients had normotension without antihypertensive treatment. Antihypertensive treatment medication was prescribed for 53% of patients at baseline and initiated or added for 91 patients (AHT-I [group with intensification of antihypertensive treatment] group, 28%) during follow-up. Overall BP SD score remained stable over time in the cohort (β=-0.037±0.034, P=0.34 and -0.029±0.348, P=0.093 per year for systolic and diastolic BP SD score). In the AHT-I group, systolic and diastolic BP SD scores were higher at baseline and decreased significantly during follow-up (-0.22±0.07, P<0.003 and -0.12±0.05 SD score per year, P=0.01). Only 8 of 70 (11%) patients from the previously untreated/uncontrolled group remained untreated at the last observation, while 31 (44%) were controlled during follow-up. Of the 120 normotensive patients at baseline, 60% remained normotensive while 40% progressed to uncontrolled/untreated (n=23, 19%) or controlled (n=24, 20%) hypertension. CONCLUSIONS:Although the overall BP of the population remained stable over time, individual patterns of BP management showed considerable variability. BP control improved significantly with intensified antihypertensive therapy; however, a significant number of previously normotensive individuals developed new-onset hypertension during the observation period.

AbstractRationaleTo investigate blood pressure (BP) trajectories, and the impact of pharmacological intervention in children with chronic kidney disease (CKD).MethodsAnalysis of antihypertensive treatment (AHT) and BP slopes in 320 patients of the 4C Study cohort with CKD prior to renal replacement therapy, based on a minimum of three individual observations and two years of follow-up.ResultsAt enrollment, 70 patients (22%) had uncontrolled or untreated hypertension, 130 patients (41%) had controlled hypertension, and 120 patients (37%) had normotension without antihypertensive treatment. AHT medication was prescribed in 53% of patients at baseline and initiated or added in 91 patients (AHT-I, 28%) during follow-up.Overall BP standard deviation score (SDS) remained stable over time in the cohort (ß= -0.037±0.034, p=0.34 and -0.029± 0.348, p=0.093 per year for systolic and diastolic BP SDS). In the AHT-I group, systolic and diastolic BP SDS was higher at baseline and decreased significantly during follow-up (−0.22±0.07, p<.003 and -0.12±0.05 SDS per year, p=0.01). Only 8/70 (11%) patients of the previously untreated/uncontrolled group remained untreated at the last observation, while 31 (44%) were controlled during follow-up. Of the 120 normotensive patients at baseline, 60% remained normotensive while 40% progressed to uncontrolled/untreated (n=23, 19%) or controlled (n=24, 20%) hypertension.ConclusionsThe study provides comprehensive real-world evidence on long-term management of blood pressure in children with CKD from the 4C Study. Although blood pressure control improved significantly with the intensification of antihypertensive therapy, a notable proportion of previously normotensive patients developed de novo hypertension over the observation period.

Background: Mortality rates in children with end stage renal disease (ESRD) are higher in girls. Cardiovascular complications are among the most common causes of death. Pulse wave velocity (PWV), a measure of aortic stiffness, is associated with mortality in adults with ESRD. We investigated whether sex differences in aortic PWV were present in children who underwent tx in the 4C study. Method: Of 336 children undergoing RRT, 236 (156 boys) received tx and were longitudinally analyzed. PWV was normalized for sex and height; systolic and diastolic blood pressure (BP) for age, sex, and height. Results: Whereas PWV z-scores did not differ between girls and boys as they entered chronic kidney disease (CKD) stage 4 (boys=0.18±1.6 and girls=0.18±1.9), PWV was higher in girls at the last visit before start of RRT (0.45±1.9 vs. 0.25±1.5) and three years after tx (0.83±1.3 vs. 0.30±1.1). We did not find sex differences in the mean time between reaching eGFR ≤30 ml/min/1.73m2 to tx or the months on dialysis. At inclusion eGFR was similar (boys=24.3±8.7; girls=23.4±8.2 ml/min/1.73m), but the current rate of eGFR loss at the last visit before RRT start was greater in girls than in boys (-0.42±0.48 vs -0.33±0.57 ml/min/1.73m per month). A stratified analysis of the time periods before and after tx disclosed an association of PWV increase with eGFR decline prior to RRT in girls (an average eGFR decline of -1 ml/min/1.73m2/month within the period before RRT start was associated with an increase of 0.58 PWV). Further independently associated factors contributing to higher PWV were increasing diastolic BP z-score (DBP), serum calcium, and HDL, whereas RAAS blockers had a protective effect. In the model after tx, the higher PWV in girls after transplantation was explained by the faster eGFR decline in girls prior to tx. Further factors associated with higher PWV were longer time after tx, higher DBP, larger cholesterol increase and higher PWV at last visit prior to RRT. Discussion: Girls with advanced CKD show more pronounced aortic stiffening when compared to boys, leading to a significant sex difference that persists after tx. This difference could explain the higher mortality rate seen in girls with ESRD.

Background The early impact of renal transplantation on subclinical cardiovascular measures in pediatric patients has not been widely investigated. This analysis is performed for pediatric patients participating in the prospective cardiovascular comorbidity in children with chronic kidney disease study and focuses on the early effects of renal replacement therapy (RRT) modality on cardiovascular comorbidity in patients receiving a preemptive transplant or started on dialysis. Methods We compared measures indicating subclinical cardiovascular organ damage (aortal pulse wave velocity, carotid intima media thickness, left ventricular mass index) and evaluated cardiovascular risk factors in 166 pediatric patients before and 6 to 18 months after start of RRT (n = 76 transplantation, n = 90 dialysis). Results RRT modality had a significant impact on the change in arterial structure and function: compared to dialysis treatment, transplantation was independently associated with decreases in pulse wave velocity (ss = -0.67; P < 0.001) and intima media thickness (ss = -0.40; P = 0.008). Independent of RRT modality, an increase in pulse wave velocity was associated with an increase in diastolic blood pressure (ss = 0.31; P < 0.001). Increasing intima media thickness was associated with a larger increase in body mass index (ss = 0.26; P = 0.003) and the use of antihypertensive agents after RRT (ss = 0.41; P = 0.007). Changes in left ventricular mass index were associated with changes in systolic blood pressure (ss = 1.47; P = 0.01). Conclusions In comparison with initiating dialysis, preemptive transplantation prevented further deterioration of the subclinical vascular organ damage early after transplantation. Classic cardiovascular risk factors, such as hypertension and obesity are of major importance for the development of cardiovascular organ damage after renal transplantation.

Background:We investigated the effects of nutritional vitamin D supplementation on markers of bone and mineral metabolism, i.e. serum levels of fibroblast growth factor 23 (FGF23), Klotho, bone alkaline phosphatase (BAP) and sclerostin, in two cohorts with chronic kidney disease (CKD). Methods:In all, 80 vitamin D-deficient children were selected: 40 with mild to moderate CKD from the ERGO study, a randomized trial of ergocalciferol supplementation [estimated glomerular filtration rate (eGFR) 55 mL/min/1.73 m2], and 40 with advanced CKD from the observational Cardiovascular Comorbidity in Children with Chronic Kidney Disease (4C) study (eGFR 24 mL/min/1.73 m2). In each study, vitamin D supplementation was started in 20 children and 20 matched children not receiving vitamin D served as controls. Measures were taken at baseline and after a median period of 8 months. Age- and gender-related standard deviation scores (SDSs) were calculated. Results:Before vitamin D supplementation, children in the ERGO study had normal FGF23 (median 0.31 SDS) and BAP (-0.10 SDS) but decreased Klotho and sclerostin (-0.77 and -1.04 SDS, respectively), whereas 4C patients had increased FGF23 (3.87 SDS), BAP (0.78 SDS) and sclerostin (0.76 SDS) but normal Klotho (-0.27 SDS) levels. Vitamin D supplementation further increased FGF23 in 4C but not in ERGO patients. Serum Klotho and sclerostin normalized with vitamin D supplementation in ERGO but remained unchanged in 4C patients. BAP levels were unchanged in all patients. In the total cohort, significant effects of vitamin D supplementation were noted for Klotho at eGFR 40-70 mL/min/1.73 m2. Conclusions:Vitamin D supplementation normalized Klotho and sclerostin in children with mild to moderate CKD but further increased FGF23 in advanced CKD.

Background Patients with chronic kidney disease (CKD) are exposed to both traditional 'Framingham' and uremia related cardiovascular risk factors that drive atherosclerotic and arteriosclerotic disease, but these cannot be differentiated using conventional ultrasound. We used ultra-high-frequency ultrasound (UHFUS) to differentiate medial thickness (MT) from intimal thickness (IT) in CKD patients, identify their determinants and monitor their progression. Methods Fifty-four children and adolescents with CKD and 12 healthy controls underwent UHFUS measurements using 55-70MHz transducers in common carotid and dorsal pedal arteries. Annual follow-up imaging was performed in 31 patients. Results CKD patients had higher carotid MT and dorsal pedal IT and MT compared to controls. The carotid MT in CKD correlated with serum phosphate (p<0.001, r = 0.42), PTH (p = 0.03, r = 0.36) and mean arterial pressure (p = 0.03, r = 0.34). Following multivariable analysis, being on dialysis, serum phosphate levels and mean arterial pressure remained the only independent predictors of carotid MT (R2 64%). Transplanted children had lower carotid and dorsal pedal MT compared to CKD and dialysis patients (p = 0.02 and p = 0.01 respectively). At 1-year follow-up, transplanted children had a decrease in carotid MT (p = 0.01), but an increase in dorsal pedal IT (p = 0.04) that independently correlated with annualized change in BMI. Conclusions Using UHFUS, we have shown that CKD is associated with exclusively medial arterial changes that attenuate when the uremic milieu is ameliorated after transplantation. In contrast, after transplantation intimal disease develops as hypertension and obesity become prevalent, representing rapid vascular remodeling in response to a changing cardiovascular risk factor profile.

Cardiovascular disease is the second-most common cause of death in pediatric renal transplant recipients. The aim of this study was to evaluate subclinical cardiovascular target organ damage defined as the presence of arterio- and atherosclerotic lesions and cardiac remodeling and to analyze contributing risk factors in a large cohort of children after renal transplantation (RT).

Background and objectives Cardiovascular disease is the most important comorbidity affecting long-term survival in children with CKD. Design, setting, participants, & measurements The Cardiovascular Comorbidity in Children with CKD Study is a multicenter, prospective, observational study in children ages 6-17 years old with initial GFR of 10-60 ml/min per 1.73 m(2). The cardiovascular status is monitored annually, and subclinical cardiovascular disease is assessed by noninvasive measurements of surrogate markers, including the left ventricular mass index, carotid intimamedia thickness, and central pulse wave velocity. We here report baseline data at study entry and an explorative analysis of variables associated with surrogate markers. Results A total of 737 patients were screened from October of 2009 to August of 2011 in 55 centers in 12 European countries, and baseline data were analyzed in 688 patients. Sixty-four percent had congenital anomalies of the kidney and urinary tract; 26.1% of children had uncontrolled hypertension (24-hour ambulatory BP monitoring; n=545), and the prevalence increased from 24.4% in CKD stage 3 to 47.4% in CKD stage 5. The prevalence of left ventricular hypertrophy was higher with each CKD stage, from 10.6% in CKD stage 3a to 48% in CKD stage 5. Carotid intima-media thickness was elevated in 41.6%, with only 10.8% of patients displaying measurements below the 50th percentile. Pulse wave velocity was increased in 20.1%. The office systolic BP SD score was the single independent factor significantly associated with all surrogate markers of cardiovascular disease. The intermediate end point score (derived from the number of surrogate marker measurements >95th percentile) was independently associated with a diagnosis of congenital anomalies of the kidney and urinary tract, time since diagnosis of CKD, body mass index, office systolic BP, serum phosphorus, and the hemoglobin level. Conclusions The baseline data of this large pediatric cohort show that surrogate markers for cardiovascular disease are closely associated with systolic hypertension and stage of CKD.

BACKGROUND AND OBJECTIVES:Vitamin D deficiency is endemic in children with CKD. We sought to investigate the association of genetic disposition, environmental factors, vitamin D supplementation, and renal function on vitamin D status in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Serum 25-hydroxy-vitamin D, 1,25-dihydroxy-vitamin D, and 24,25-dihydroxy-vitamin D concentrations were measured cross-sectionally in 500 children from 12 European countries with CKD stages 3-5. All patients were participants of the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study, had CKD stage 3-5, and were age 6-18 years old. Patients were genotyped for single-nucleotide polymorphisms in the genes encoding 25-hydroxylase, vitamin D binding protein, 7-dehydrocholesterol reductase, and 24-hydroxylase. Associations of genetic status, season, local solar radiation, oral vitamin D supplementation, and disease-associated factors with vitamin D status were assessed. RESULTS:Two thirds of patients were vitamin D deficient (25-hydroxy-vitamin D <16 ng/ml). 25-Hydroxy-vitamin D concentrations varied with season and were twofold higher in vitamin D-supplemented patients (21.6 [14.1] versus 10.4 [10.1] ng/ml; P<0.001). Glomerulopathy, albuminuria, and girls were associated with lower 25-hydroxy-vitamin D levels. 24,25-dihydroxy-vitamin D levels were closely correlated with 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D (r=0.87 and r=0.55; both P<0.001). 24,25-dihydroxy-vitamin D concentrations were higher with higher c-terminal fibroblast growth factor 23 and inversely correlated with intact parathyroid hormone. Whereas 25-hydroxy-vitamin D levels were independent of renal function, 24,25-dihydroxy-vitamin D levels were lower with lower eGFR. Vitamin D deficiency was more prevalent in Turkey than in other European regions independent of supplementation status and disease-related factors. Single-nucleotide polymorphisms in the vitamin D binding protein gene were independently associated with lower 25-hydroxy-vitamin D and higher 24,25-dihydroxy-vitamin D. CONCLUSIONS:Disease-related factors and vitamin D supplementation are the main correlates of vitamin D status in children with CKD. Variants in the vitamin D binding protein showed weak associations with the vitamin D status.

Introduction: Premature arterial disease has been reported in chronic kidney disease (CKD) patients. However, using conventional methods it is not possible to determine whether these are driven by metabolic (medial) abnormalities rather than traditional cardiovascular (intimal) risk factors. Hypothesis: Using an ultra high-resolution ultrasound (UHRUS) technique to measure medial and intimal arterial changes will allow assessment of their determinants and progression in predialysis, dialysis and renal transplanted children. Methods: Intimal (IT) and medial (MT) thickness of the carotid, radial and dorsal pedal arteries were measured by UHRUS (40-750MHz) in 54 children (19 pre-dialysis CKD, 20 on dialysis and 15 post-transplant) at baseline and compared to 20 matched healthy controls. One year follow up measurements were performed in 24 children (11 pre-dialysis CKD and 15 post-transplant). Conventional ultrasound (CUS) for carotid IMT was measured for comparison. Results: All CKD patients had higher radial IT compared to controls (p=0.05). CUS measurements were similar between patient groups. CKD children on dialysis for >1year had greater carotid and dorsal pedal MT compared to those on dialysis for At 1-year follow-up transplanted children had a decrease in carotid and radial MT (p = 0.01 for both), but an increase in dorsal pedal IT (p=0.04). Increased dorsal pedal IT in transplanted patients was associated with a higher systolic BP z- score (p = 0.2, r = 0.22). Children with pre-dialysis CKD (n=6) had a decrease in radial MT (p=0.04), but no other significant changes. Conclusions: UHRUS assessment in CKD patients identified modifiable risk factors for intimal and medial vascular disease, which were not detected by CUS. Our findings suggest vascular remodeling in response to a changing cardiovascular risk factor profile after renal transplantation and provide important information for effective CV stratification and treatment of these patients.

BACKGROUND Chronic kidney disease (CKD) in children is characterized by rapid progression and a high incidence of end-stage renal disease and therefore constitutes an important health problem. While unbiased genetic screens have identified common risk variants influencing renal function and CKD in adults, the presence and identity of such variants in pediatric CKD are unknown. METHODS The international Pediatric Investigation for Genetic Factors Linked with Renal Progression (PediGFR) Consortium comprises three pediatric CKD cohorts: Chronic Kidney Disease in Children (CKiD), Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) and Cardiovascular Comorbidity in Children with CKD (4C). Clean genotype data from > 10 million genotyped or imputed single-nucleotide polymorphisms (SNPs) were available for 1136 patients with measurements of serum creatinine at study enrollment. Genome-wide association studies were conducted to relate the SNPs to creatinine-based estimated glomerular filtration rate (eGFR crea) and proteinuria (urinary albumin- or protein-to-creatinine ratio ≥ 300 and ≥ 500 mg/g, respectively). In addition, European-ancestry PediGFR patients (cases) were compared with 1347 European-ancestry children without kidney disease (controls) to identify genetic variants associated with the presence of CKD. RESULTS SNPs with suggestive association P-values < 1 × 10(-5) were identified in 10 regions for eGFR crea, four regions for proteinuria and six regions for CKD including some plausible biological candidates. No SNP was associated at genome-wide significance (P < 5 × 10(-8)). Investigation of the candidate genes for proteinuria in adults from the general population provided support for a region on chromosome 15 near RSL24D1/UNC13C/RAB27A. Conversely, targeted investigation of genes harboring GFR-associated variants in adults from the general population did not reveal significantly associated SNPs in children with CKD. CONCLUSIONS Our findings suggest that larger collaborative efforts will be needed to draw reliable conclusions about the presence and identity of common variants associated with eGFR, proteinuria and CKD in pediatric populations.

BACKGROUNDAortic pulse wave velocity (PWV), an indicator of arterial stiffness, independently predicts cardiovascular mortality risk in adults. Arterial stiffening advances with age and seems accelerated in children with certain disease conditions such as chronic kidney disease or diabetes. The Vicorder, an oscillometric device to measure PWV, has been validated in children, but reference values in a large pediatric cohort, association to carotid stiffness and influence of individual and family risk factors have not been determined.METHODSPulse waves were captured in 1,003 healthy children (aged 6-18 years) in 6 centers and gender-specific reference data normalized to age/height were constructed. In 589 children carotid distensibility and intima media thickness were measured. Gestational and family history was reported.RESULTSPWV correlated with age (r = 0.57, P < 0.0001) with significant gender-related differences starting at age 9. Further significant correlations were seen for height, weight, body mass index, blood pressure, pulse pressure, and heart rate. Independent predictors for PWV in a multivariate regression analysis were gender, age, height, weight, mean arterial pressure, and heart rate. Risk factors for higher PWV included small for gestational age at birth, secondhand smoking, parental hypertension, and obesity. PWV showed weak correlations with 2 of the carotid distensibility measures, but not with intima media thickness.CONCLUSIONThis study defines reference values for PWV captured by the Vicorder device in children and adolescents and reveals associations with potential cardiovascular risk factors in a healthy population. Gender-specific percentiles for age/height will allow for the assessment of pediatric cohorts using this oscillometric method.