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Original Investigation
November 6, 2017

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

Author Affiliations
  • 1Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
  • 2Department of Pediatrics, Division of Nephrology, New York University Langone Medical Center, New York
  • 3Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
  • 4Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
  • 5Department of Pediatric Nephrology, Faculty of Medicine, Cukurova University, Adana, Turkey
  • 6Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey
  • 7Pediatric Nephrology, Ege University Faculty of Medicine, Izmir, Turkey
  • 8University Children’s Hospital Belgrade, Belgrade, Serbia
  • 9Department of Pediatric Nephrology, Istanbul Medical Faculty, Istanbul, Turkey
  • 10Pediatric Nephrology, Giannina Gasline Institute, Genova, Italy
  • 11Pediatric Nephrology, Vienna University Children’s Hospital, Vienna, Austria
  • 12Nephrology, Kidney Transplantation and Hypertension, Children’s Memorial Health Institute, Warzaw, Poland
  • 13Pediatric Nephrology, Children’s Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 14Division of Pediatric Nephrology, Bambino Gesù Children’s Hospital and Research Institute, Rome, Italy
  • 15Pediatric Nephrology, Charité Children’s Hospital, Berlin, Germany
  • 16Children’s Dialysis Center, Hospital St Georg, Leipzig, Germany
  • 17Vilnius University, Pediatric Center, Vilnius, Lithuania
  • 18KfH Kidney Center for Children, Marburg, Germany
  • 19Pediatrics, University Hospital Motol, Prague, Czech Republic
  • 20Pediatric Nephrology and Dialysis, Fondazione OSP Maggiore Policlinico, Milano, Italy
  • 21Department of Pediatric and Adolescent Nephrology, Medical University Gdańsk, Gdańsk, Poland
  • 22Pediatrics, Hospital São João, Porto, Portugal
  • 23Department of Medicine, Rush University Medical Center, Chicago, Illinois
  • 24Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown
  • 25The Research Institute at Nationwide Children’s Hospital, The Ohio State University, Columbus
JAMA Pediatr. 2017;171(11):e172914. doi:10.1001/jamapediatrics.2017.2914
Key Points

Question  Are elevated serum soluble urokinase receptor (suPAR) levels associated with renal disease progression in children with chronic kidney disease?

Findings  In this cohort study of 898 children, 5-year end point–free renal survival was 64.5% in children with suPAR levels in the lowest quartile compared with 35.9% in those with suPAR levels in the highest quartile. In patients with baseline estimated glomerular filtration rates greater than 40 mL/min/1.73 m2, higher log-transformed suPAR levels were associated with a higher risk of chronic kidney disease progression after adjusting for conventional risk factors.

Meaning  High suPAR levels may identify children at risk for future chronic kidney disease.

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.

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