Association of Serum Soluble Urokinase Receptor Levels With Progression of Kidney Disease in Children

Franz Schaefer, Howard Trachtman, Elke Wühl, Marietta Kirchner, Salim S Hayek, Ali Anarat, Ali Duzova, Sevgi Mir, Dusan Paripovic, Alev Yilmaz, Francesca Lugani, Klaus Arbeiter, Mieczyslaw Litwin, Jun Oh, Maria Chiara Matteucci, Jutta Gellermann, Simone Wygoda, Augustina Jankauskiene, Günter Klaus, Jiri DusekSara Testa, Aleksandra Zurowska, Alberto Caldas Afonso, Melissa Tracy, Changli Wei, Sanja Sever, William Smoyer, Jochen Reiser, ESCAPE Trial Consortium and the 4C Study Group

Research output: Contribution to journalArticle

Abstract

Importance: Conventional methods to diagnose and monitor chronic kidney disease (CKD) in children, such as creatinine level and cystatin C-derived estimated glomerular filtration rate (eGFR) and assessment of proteinuria in spot or timed urine samples, are of limited value in identifying patients at risk of progressive kidney function loss. Serum soluble urokinase receptor (suPAR) levels strongly predict incident CKD stage 3 in adults.

Objective: To determine whether elevated suPAR levels are associated with renal disease progression in children with CKD.

Design, Setting, and Participants: Post hoc analysis of 2 prospectively followed up pediatric CKD cohorts, ie, the ESCAPE Trial (1999-2007) and the 4C Study (2010-2016), with serum suPAR level measured at enrollment and longitudinal eGFR measured prospectively. In the 2 trials, a total of 898 children were observed at 30 (ESCAPE Trial; n = 256) and 55 (4C Study; n = 642) tertiary care hospitals in 13 European countries. Renal diagnoses included congenital anomalies of the kidneys and urinary tract (n = 637 [70.9%]), tubulointerstitial nephropathies (n = 92 [10.2%]), glomerulopathies (n = 69 [7.7%]), postischemic CKD (n = 42 [4.7%]), and other CKD (n = 58 [6.5%]). Total follow-up duration was up to 7.9 years, and median follow-up was 3.1 years. Analyses were conducted from October 2016 to December 2016.

Exposures: Serum suPAR level was measured at enrollment, and eGFR was measured every 2 months in the ESCAPE Trial and every 6 months in the 4C Study. The primary end point of CKD progression was a composite of 50% eGFR loss, eGFR less than 10 mL/min/1.73 m2, or initiation of renal replacement therapy.

Main Outcomes and Measures: The primary end point in this study was renal survival, defined as a composite of 50% loss of GFR that persisted for at least 1 month, the start of renal replacement therapy, or an eGFR less than 10 mL/min/1.73 m2.

Results: Of the 898 included children, 560 (62.4%) were male, and the mean (SD) patient age at enrollment was 11.9 (3.5) years. The mean (SD) eGFR was 34 (16) mL/min/1.73 m2. The 5-year end point-free renal survival was 64.5% (95% CI, 57.4-71.7) in children with suPAR levels in the lowest quartile compared with 35.9% (95% CI, 28.7-43.0) in those in the highest quartile (P < .001). By multivariable analysis, the risk of attaining the end point was higher in children with glomerulopathies and increased with age, blood pressure, proteinuria, and lower eGFR at baseline. In patients with baseline eGFR greater than 40 mL/min/1.73 m2, higher log-transformed suPAR levels were associated with a higher risk of CKD progression after adjustment for traditional risk factors (hazard ratio, 5.12; 95% CI, 1.56-16.7; P = .007).

Conclusions and Relevance: Patients with high suPAR levels were more likely to have progression of their kidney disease. Further studies should determine whether suPAR levels can identify children at risk for future CKD.

Original languageEnglish
Pages (from-to)e172914
JournalJAMA Pediatrics
Volume171
Issue number11
DOIs
Publication statusPublished - Nov 6 2017

Keywords

  • Adolescent
  • Biomarkers
  • Child
  • Disease Progression
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Prospective Studies
  • Receptors, Urokinase Plasminogen Activator
  • Renal Insufficiency, Chronic
  • Renal Replacement Therapy
  • Journal Article
  • Observational Study

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    Schaefer, F., Trachtman, H., Wühl, E., Kirchner, M., Hayek, S. S., Anarat, A., Duzova, A., Mir, S., Paripovic, D., Yilmaz, A., Lugani, F., Arbeiter, K., Litwin, M., Oh, J., Matteucci, M. C., Gellermann, J., Wygoda, S., Jankauskiene, A., Klaus, G., ... ESCAPE Trial Consortium and the 4C Study Group (2017). Association of Serum Soluble Urokinase Receptor Levels With Progression of Kidney Disease in Children. JAMA Pediatrics, 171(11), e172914. https://doi.org/10.1001/jamapediatrics.2017.2914