Franz Schaefer1, Howard Trachtman2, Elke Wühl1, Marietta Kirchner3, Salim S Hayek4, Ali Anarat5, Ali Duzova6, Sevgi Mir7, Dusan Paripovic8, Alev Yilmaz9, Francesca Lugani10, Klaus Arbeiter11, Mieczyslaw Litwin12, Jun Oh13, Maria Chiara Matteucci14, Jutta Gellermann15, Simone Wygoda16, Augustina Jankauskiene17, Günter Klaus18, Jiri Dusek19, Sara Testa20, Aleksandra Zurowska21, Alberto Caldas Afonso22, Melissa Tracy23, Changli Wei23, Sanja Sever24, William Smoyer25, Jochen Reiser23. 1. Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany. 2. Department of Pediatrics, Division of Nephrology, New York University Langone Medical Center, New York. 3. Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany. 4. Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia. 5. Department of Pediatric Nephrology, Faculty of Medicine, Cukurova University, Adana, Turkey. 6. Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey. 7. Pediatric Nephrology, Ege University Faculty of Medicine, Izmir, Turkey. 8. University Children's Hospital Belgrade, Belgrade, Serbia. 9. Department of Pediatric Nephrology, Istanbul Medical Faculty, Istanbul, Turkey. 10. Pediatric Nephrology, Giannina Gasline Institute, Genova, Italy. 11. Pediatric Nephrology, Vienna University Children's Hospital, Vienna, Austria. 12. Nephrology, Kidney Transplantation and Hypertension, Children's Memorial Health Institute, Warzaw, Poland. 13. Pediatric Nephrology, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 14. Division of Pediatric Nephrology, Bambino Gesù Children's Hospital and Research Institute, Rome, Italy. 15. Pediatric Nephrology, Charité Children's Hospital, Berlin, Germany. 16. Children's Dialysis Center, Hospital St Georg, Leipzig, Germany. 17. Vilnius University, Pediatric Center, Vilnius, Lithuania. 18. KfH Kidney Center for Children, Marburg, Germany. 19. Pediatrics, University Hospital Motol, Prague, Czech Republic. 20. Pediatric Nephrology and Dialysis, Fondazione OSP Maggiore Policlinico, Milano, Italy. 21. Department of Pediatric and Adolescent Nephrology, Medical University Gdańsk, Gdańsk, Poland. 22. Pediatrics, Hospital São João, Porto, Portugal. 23. Department of Medicine, Rush University Medical Center, Chicago, Illinois. 24. Harvard Medical School and Division of Nephrology, Massachusetts General Hospital, Charlestown. 25. The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus.
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.
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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