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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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    Indoxyl sulfate associates with cardiovascular phenotype in children with chronic kidney disease
    (Springer Verlag, 2019) Holle J.; Querfeld U.; Kirchner M.; Anninos A.; Okun J.; Thurn-Valsassina D.; Bayazit A.; Niemirska A.; Canpolat N.; Bulut I.K.; Duzova A.; Anarat A.; Shroff R.; Bilginer Y.; Caliskan S.; Candan C.; Harambat J.; Özcakar Z.B.; Soylemezoglu O.; Tschumi S.; Habbig S.; Yilmaz E.; Balat A.; Zurowska A.; Cakar N.; Kranz B.; Ertan P.; Melk A.; Azukaitis K.; Schaefer F.
    Background: Cardiovascular disease is the leading cause of death in children with chronic kidney disease (CKD). Serum levels of gut-derived uremic toxins increase with deterioration of kidney function and are associated with cardiac comorbidities in adult CKD patients. Methods: Indoxyl sulfate (IS) and p-cresyl sulfate (pCS) were measured by high-performance liquid chromatography in serum of children participating in the Cardiovascular Comorbidity in Children with CKD (4C) Study. Results were correlated with measurements of the carotid intima-media thickness (cIMT), central pulse wave velocity (PWV), and left ventricular mass index (LVMI) in children aged 6–17 years with initial eGFR of 10–60 ml/min per 1.73 m2. Results: The median serum levels of total IS and of pCS, measured in 609 patients, were 5.3 µmol/l (8.7) and 17.0 µmol/l (21.6), respectively. In a multivariable regression model, IS and pCS showed significant positive associations with urea and negative associations with eGFR and uric acid. Furthermore, positive associations of pCS with age, serum albumin, and non-Mediterranean residency and a negative association with glomerular disease were observed. By multivariable regression analysis, only IS was significantly associated with a higher cIMT SDS at baseline and progression of PWV SDS within 12 months, independent of other risk factors. Conclusions: Serum levels of gut-derived uremic toxins IS and pCS correlated inversely with eGFR in children. Only IS was significantly associated with surrogate markers of cardiovascular disease in this large pediatric CKD cohort. © 2019, IPNA.
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    Isolated nocturnal and isolated daytime hypertension associate with altered cardiovascular morphology and function in children with chronic kidney disease: Findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease study
    (Lippincott Williams and Wilkins, 2019) Düzova A.; Karabay Bayazit A.; Canpolat N.; Niemirska A.; Kaplan Bulut I.; Azukaitis K.; Karagoz T.; Oguz B.; Erdem S.; Anarat A.; Ranchin B.; Shroff R.; Djukic M.; Harambat J.; Yilmaz A.; Yildiz N.; Ozcakar B.; Büscher A.; Lugani F.; Wygoda S.; Tschumi S.; Zaloszyc A.; Jankauskiene A.; Laube G.; Galiano M.; Kirchner M.; Querfeld U.; Melk A.; Schaefer F.; Wühl E.
    Introduction:Prevalence of isolated nocturnal hypertension (INH) and isolated daytime hypertension (IDH) is around 10% in adults. Data in children, especially in chronic kidney disease (CKD), are lacking. The aim of this cross-sectional multicenter cohort study was to define the prevalence of INH and IDH and its association with cardiovascular morphology and function, that is, pulse wave velocity (PWV), carotid intima-media thickness (cIMT), or left ventricular mass index (LVMI) in children with CKD.Methods:Ambulatory blood pressure (BP) monitoring profiles were analyzed in 456 children with CKD stages III-V participating in the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study (64.3% males, 71.3% congenital anomaly of the kidney and urinary tract, age 12.5 ± 3.2 years, estimated glomerular filtration rate 29 ± 12 ml/min per 1.73 m2). Baseline PWV, cIMT, and LVMI were compared in normotension, INH, IDH, or sustained 24-h hypertension.Results:Prevalence of sustained hypertension was 18.4%, of INH 13.4%, and of IDH 3.7%. PWV SDS (SD score) and cIMT SDS were significantly higher in sustained hypertension and INH, and PWV SDS was significantly higher in IDH, compared with normotension. LVMI was significantly increased in sustained hypertension, but not in INH or IDH. Determinants of INH were smallness for gestational age, older age, higher height SDS and parathyroid hormone, and shorter duration of CKD. In logistic regression analysis, day/night-time hypertension or ambulatory BP monitoring pattern (normal, INH, IDH, sustained hypertension) were independently associated with cardiovascular outcome measures: elevated night-time BP was associated with increased cIMT, PWV, and left ventricular hypertrophy; INH was associated with cIMT.Conclusion:INH is present in almost one out of seven children with predialysis CKD; INH and nocturnal hypertension in general are associated with alterations of arterial morphology and function. © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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    Timing and Modality of Kidney Replacement Therapy in Children and Adolescents
    (Elsevier Inc., 2024) Thumfart J.; Wagner S.; Kirchner M.; Azukaitis K.; Bayazit A.K.; Obrycki L.; Canpolat N.
    Introduction: The choice and timing of kidney replacement therapy (KRT) is influenced by clinical factors, laboratory features, feasibility issues, family preferences, and clinicians' attitudes. We analyzed the factors associated with KRT modality and timing in a multicenter, multinational prospective pediatric cohort study. Methods: A total of 695 pediatric patients with chronic kidney disease (CKD) enrolled into the Cardiovascular Comorbidity in Children with CKD (4C) study at age 6 to 17 years with estimated glomerular filtration rate (eGFR) of 10 to 60 ml/min per 1.73 m2 were investigated. Competing risk regression was performed to identify factors associated with initiation of dialysis or preemptive transplantation (Tx), including primary renal diagnosis, demographics, anthropometrics, and laboratory parameters. Results: During the 8-year observation period, 342 patients (49%) started KRT. Of these, 200 patients started dialysis, whereas 142 patients underwent preemptive Tx. A lower eGFR at enrolment (Hazard ratio [HR]: 0.76 [95% confidence interval: 0.74–0.78]), a steeper eGFR slope (HR: 0.90 [0.85–0.95], and a higher systolic blood pressure SD score (SDS) (HR: 2.07 [1.49–2.87]) increased the likelihood of KRT initiation. Patients with glomerulopathies were more likely to start dialysis than children with congenital anomalies of the kidneys and urinary tracts (CAKUT) (HR: 3.81 [2.52–5.76]). Lower body mass index (BMI) SDS (HR: 0.73 [0.6–0.89]) and lower hemoglobin (HR: 0.8 [0.72–0.9]) were associated with higher likelihood of dialysis. A significant center effect was observed, accounting for 6.8% (dialysis) to 8.7% (preemptive Tx) of explained variation. Conclusion: The timing and choice of KRT in pediatric patients is influenced by the rate of kidney function loss, the underlying kidney disease, nutritional status, blood pressure, anemia and center-specific factors. © 2024