Johannes Holle1, Uwe Querfeld2, Marietta Kirchner3, Alexandros Anninos4, Jürgen Okun4, Daniela Thurn-Valsassina5, Aysun Bayazit6, Ana Niemirska7, Nur Canpolat8, Ipek Kaplan Bulut9, Ali Duzova10, Ali Anarat6, Rukshana Shroff11, Yelda Bilginer12, Salim Caliskan8, Cengiz Candan13, Jerome Harambat14, Zeynep Birsin Özcakar10, Oguz Soylemezoglu15, Sibylle Tschumi16, Sandra Habbig17, Ebru Yilmaz18, Ayse Balat19, Aleksandra Zurowska20, Nilgun Cakar21, Birgitta Kranz22, Pelin Ertan23, Anette Melk24, Karolis Azukaitis25, Franz Schaefer26. 1. Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. johannes-benjamin.holle@charite.de. 2. Department of Pediatric Nephrology, Charité - Universitätsmedizin Berlin, Berlin, Germany. 3. Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany. 4. Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children's Hospital Heidelberg, Heidelberg, Germany. 5. Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. 6. Department of Pediatric Nephrology, School of Medicine, Cukurova University, Adana, Turkey. 7. Department of Nephrology and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland. 8. Division of Pediatric Nephrology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey. 9. Department of Pediatric Nephrology, Ege University Faculty of Medicine, Izmir, Turkey. 10. Division of Pediatric Nephrology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey. 11. Division of Pediatric Nephrology, Great Ormond Street Hospital, London, UK. 12. Division of Rheumatology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey. 13. Department of Pediatric Nephrology, Istanbul Medeniyet University, Istanbul, Turkey. 14. Pediatric Nephrology Unit, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche, Bordeaux University Hospital, Bordeaux, France. 15. Department of Pediatric Nephrology, Gazi University School of Medicine, Ankara, Turkey. 16. Inselspital, University of Bern, Berne, Switzerland. 17. Division of Pediatric Nephrology, University Children's and Adolescent's Hospital, Cologne, Germany. 18. Department of Pediatric Nephrology, Sanliurfa Children's Hospital, Sanliurfa, Turkey. 19. Department of Pediatric Nephrology, Istanbul Aydın University, Istanbul, Turkey. 20. Department of Pediatric Nephrology, Medical University of Gdansk, Gdansk, Poland. 21. Department of Pediatric Nephrology, Ankara University Faculty of Medicine, Ankara, Turkey. 22. Department of General Pediatrics, Pediatric Nephrology, University Children's Hospital Muenster, Muenster, Germany. 23. Division of Pediatric Nephrology, Department of Pediatrics, Medical Faculty of Celal Bayar University, Manisa, Turkey. 24. Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany. 25. Clinic of Pediatrics, Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania. 26. Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University Children's Hospital Heidelberg, Heidelberg, Germany.
Abstract
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.
BACKGROUND:Cardiovascular diseaseis 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 CKDpatients. 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.
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