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    Cardiovascular phenotypes in children with CKD: The 4C study
    (American Society of Nephrology, 2017) Schaefer F.; Doyon A.; Azukaitis K.; Bayazit A.; Canpolat N.; Duzova A.; Niemirska A.; Sözeri B.; Thurn D.; Anarat A.; Ranchin B.; Litwin M.; Caliskan S.; Candan C.; Baskin E.; Yilmaz E.; Mir S.; Kirchner M.; Sander A.; Haffner D.; Melk A.; Wühl E.; Shroff R.; Querfeld U.; 4C Study Consortium
    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 m2. 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 intima-media 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. © 2016 by the American Society of Nephrology.
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    Genetic, environmental, and disease-associated correlates of vitamin D status in children with CKD
    (American Society of Nephrology, 2016) Doyon A.; Schmiedchen B.; Sander A.; Bayazit A.; Duzova A.; Canpolat N.; Thurn D.; Azukaitis K.; Anarat A.; Bacchetta J.; Mir S.; Shroff R.; Yilmaz E.; Candan C.; Kemper M.; Fischbach M.; Cortina G.; Klaus G.; Wuttke M.; Köttgen A.; Melk A.; Querfeld U.; Schaefer F.; 4C Study Consortium
    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 patientswere 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 genewere independently associated with lower 25-hydroxy-vitamin Dand 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 showedweak associations with the vitamin D status. © 2016 by the American Society of Nephrology.