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Indoxyl sulfate associates with cardiovascular phenotype in children with chronic kidney disease

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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.

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Funding

This study was made possible by grants from the European Renal Association-European Dialysis and Transplant Association (www.era-edta.org), the Kuratorium für Dialyse und Nierentransplantation (KfH) Foundation for Preventive Medicine, the German Federal Ministry of Education and Research (reference no. 01EO0802), and Pfizer Deutschland GmbH. The entire study was solely initiated and performed by the investigators of the 4C study group. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Pediatric Pulmonology, Immunology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany

    Johannes Holle

  2. Department of Pediatric Nephrology, Charité - Universitätsmedizin Berlin, Berlin, Germany

    Uwe Querfeld

  3. Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany

    Marietta Kirchner

  4. Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children’s Hospital Heidelberg, Heidelberg, Germany

    Alexandros Anninos & Jürgen Okun

  5. Division of Pediatric Nephrology and Gastroenterology, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

    Daniela Thurn-Valsassina

  6. Department of Pediatric Nephrology, School of Medicine, Cukurova University, Adana, Turkey

    Aysun Bayazit & Ali Anarat

  7. Department of Nephrology and Hypertension, The Children’s Memorial Health Institute, Warsaw, Poland

    Ana Niemirska

  8. Division of Pediatric Nephrology, Istanbul University Cerrahpasa Faculty of Medicine, Istanbul, Turkey

    Nur Canpolat & Salim Caliskan

  9. Department of Pediatric Nephrology, Ege University Faculty of Medicine, Izmir, Turkey

    Ipek Kaplan Bulut

  10. Division of Pediatric Nephrology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Ali Duzova & Zeynep Birsin Özcakar

  11. Division of Pediatric Nephrology, Great Ormond Street Hospital, London, UK

    Rukshana Shroff

  12. Division of Rheumatology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Yelda Bilginer

  13. Department of Pediatric Nephrology, Istanbul Medeniyet University, Istanbul, Turkey

    Cengiz Candan

  14. Pediatric Nephrology Unit, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche, Bordeaux University Hospital, Bordeaux, France

    Jerome Harambat

  15. Department of Pediatric Nephrology, Gazi University School of Medicine, Ankara, Turkey

    Oguz Soylemezoglu

  16. Inselspital, University of Bern, Berne, Switzerland

    Sibylle Tschumi

  17. Division of Pediatric Nephrology, University Children’s and Adolescent’s Hospital, Cologne, Germany

    Sandra Habbig

  18. Department of Pediatric Nephrology, Sanliurfa Children’s Hospital, Sanliurfa, Turkey

    Ebru Yilmaz

  19. Department of Pediatric Nephrology, Istanbul Aydın University, Istanbul, Turkey

    Ayse Balat

  20. Department of Pediatric Nephrology, Medical University of Gdansk, Gdansk, Poland

    Aleksandra Zurowska

  21. Department of Pediatric Nephrology, Ankara University Faculty of Medicine, Ankara, Turkey

    Nilgun Cakar

  22. Department of General Pediatrics, Pediatric Nephrology, University Children’s Hospital Muenster, Muenster, Germany

    Birgitta Kranz

  23. Division of Pediatric Nephrology, Department of Pediatrics, Medical Faculty of Celal Bayar University, Manisa, Turkey

    Pelin Ertan

  24. Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany

    Anette Melk

  25. Clinic of Pediatrics, Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania

    Karolis Azukaitis

  26. Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University Children’s Hospital Heidelberg, Heidelberg, Germany

    Franz Schaefer

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  1. Johannes Holle
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  2. Uwe Querfeld
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  11. Ali Duzova
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  12. Ali Anarat
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  18. Zeynep Birsin Özcakar
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  19. Oguz Soylemezoglu
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  20. Sibylle Tschumi
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  21. Sandra Habbig
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  22. Ebru Yilmaz
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  23. Ayse Balat
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  24. Aleksandra Zurowska
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  25. Nilgun Cakar
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  26. Birgitta Kranz
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  27. Pelin Ertan
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  28. Anette Melk
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  29. Karolis Azukaitis
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  30. Franz Schaefer
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Corresponding author

Correspondence to Johannes Holle.

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Conflict of interest

This study was partly funded by Pfizer Deutschland GmbH. There are no patents, products in development, or marketed products to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable standards.

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Informed consent was obtained from all individual participants included in the study.

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Holle, J., Querfeld, U., Kirchner, M. et al. Indoxyl sulfate associates with cardiovascular phenotype in children with chronic kidney disease. Pediatr Nephrol 34, 2571–2582 (2019). https://doi.org/10.1007/s00467-019-04331-6

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  • DOI: https://doi.org/10.1007/s00467-019-04331-6

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