GDF-15 and uEGF Independently Associate With CKD Progression in Children

Julia Bartels¹, Mansoureh Tabatabaeifar¹, Marietta Kirchner², Karolis Azukaitis³, Anke Doyon¹, Aysun Bayazit⁴, Ali Düzova⁵, Nur Canpolat⁶, Ipek Kaplan Bulut⁷, Lukasz Obrycki⁸, Bruno Ranchin⁹, Rukshana Shroff¹⁰, Francesca Lugani¹¹, Cengiz Candan¹², Jerome Harambat¹³, Harika Alpay¹⁴, Mieczyslaw Litwin⁸, Augustina Jankauskiene³, Günter Klaus¹⁵, Dorota Drozdz¹⁶, Giovanni Montini^{17

18}, Aleksandra Zurowska¹⁹, Alberto Caldas Afonso²⁰, Elke Wühl¹, Anette Melk²¹, Uwe Querfeld²², Otto Mehls¹, Franz Schaefer¹; 4C Study and ESCAPE Trial Consortia

Collaborators, Affiliations

Collaborators

4C Study and ESCAPE Trial Consortia:
G Cortina, K Arbeiter, J Dusek, J Harambat, B Ranchin, M Fischbach, A Zalosczyk, U Querfeld, S Habbig, M Galiano, R Büscher, C Gimpel, M Kemper, A Melk, D Thurn, F Schaefer, A Doyon, E Wühl, M Pohl, S Wygoda, N Jeck, B Kranz, M Wigger, G Montini, F Lugani, S Testa, E Vidal, C Matteucci, S Picca, A Jankauskiene, K Azukaitis, A Zurowska, D Drodz, M Tkaczyk, T Urasinski, M Litwin, A Niemirska, M Szczepanska, A Texeira, A Peco-Antic, B Bucher, G Laube, A Anarat, A K Bayazit, F Yalcinkaya, E Basin, N Cakar, O Soylemezoglu, A Düzova, Y Bilginer, H Erdogan, O Donmez, A Balat, A Kiyak, S Caliskan, N Canpolat, C Candan, M Civilibal, S Emre, G Ozcelik, S Mir, B Sözeri, O Yavascan, Y Tabel, P Ertan, E Yilmaz, R Shroff

Affiliations

¹ Division of Pediatric Nephrology, Medical Faculty Heidelberg, Center for Pediatrics and Adolescent Medicine, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany.
² Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
³ Clinic of Pediatrics, Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania.
⁴ Department of Pediatric Nephrology, Cukurova University, Adana, Türkiye.
⁵ Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Türkiye.
⁶ Istanbul University Cerrahpasa Medical Faculty, Istanbul, Türkiye.
⁷ Ege University Faculty of Medicine, Izmir, Türkiye.
⁸ Department of Nephrology, Kidney Transplantation and Arterial Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.
⁹ Pediatric Nephrology Unit, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Université de Lyon, Lyon, France.
¹⁰ Department of Pediatric Nephrology, UCL Great Ormond Street Hospital and Institute of Child Health, London, UK.
¹¹ Department of Pediatric Nephrology, Istituto Gaslini, Genoa, Italy.
¹² Göztepe Educational and Research Hospital, Istanbul, Türkiye.
¹³ Department of Pediatrics, Bordeaux University Hospital, Bordeaux, France.
¹⁴ Department of Pediatric Nephrology, Marmara University Faculty of Medicine, Istanbul, Türkiye.
¹⁵ Department of General Pediatrics, Philipps-University, Marburg, Germany.
¹⁶ Department of Pediatric Nephrology and Hypertension, Pediatric Institute, Jagiellonian University Medical College, Cracow, Poland.
¹⁷ Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplant Unit, Milan, Italy.
¹⁸ Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
¹⁹ Department Pediatrics, Nephrology & Hypertension, Medical University Gdansk, Gdansk, Poland.
²⁰ Centro Materno Infantil do Norte, Centro Hospitalar do Porto, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
²¹ Department of Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
²² Charité Children's Hospital, Berlin, Germany.

PMID: 41141543
PMCID: PMC12545905
DOI: 10.1016/j.ekir.2025.07.004

GDF-15 and uEGF Independently Associate With CKD Progression in Children

Julia Bartels et al. Kidney Int Rep. 2025.

. 2025 Jul 16;10(10):3369-3378.

doi: 10.1016/j.ekir.2025.07.004. eCollection 2025 Oct.

Authors

Collaborators

4C Study and ESCAPE Trial Consortia:
G Cortina, K Arbeiter, J Dusek, J Harambat, B Ranchin, M Fischbach, A Zalosczyk, U Querfeld, S Habbig, M Galiano, R Büscher, C Gimpel, M Kemper, A Melk, D Thurn, F Schaefer, A Doyon, E Wühl, M Pohl, S Wygoda, N Jeck, B Kranz, M Wigger, G Montini, F Lugani, S Testa, E Vidal, C Matteucci, S Picca, A Jankauskiene, K Azukaitis, A Zurowska, D Drodz, M Tkaczyk, T Urasinski, M Litwin, A Niemirska, M Szczepanska, A Texeira, A Peco-Antic, B Bucher, G Laube, A Anarat, A K Bayazit, F Yalcinkaya, E Basin, N Cakar, O Soylemezoglu, A Düzova, Y Bilginer, H Erdogan, O Donmez, A Balat, A Kiyak, S Caliskan, N Canpolat, C Candan, M Civilibal, S Emre, G Ozcelik, S Mir, B Sözeri, O Yavascan, Y Tabel, P Ertan, E Yilmaz, R Shroff

Affiliations

¹ Division of Pediatric Nephrology, Medical Faculty Heidelberg, Center for Pediatrics and Adolescent Medicine, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany.
² Institute of Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany.
³ Clinic of Pediatrics, Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, Vilnius, Lithuania.
⁴ Department of Pediatric Nephrology, Cukurova University, Adana, Türkiye.
⁵ Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Türkiye.
⁶ Istanbul University Cerrahpasa Medical Faculty, Istanbul, Türkiye.
⁷ Ege University Faculty of Medicine, Izmir, Türkiye.
⁸ Department of Nephrology, Kidney Transplantation and Arterial Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.
⁹ Pediatric Nephrology Unit, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Université de Lyon, Lyon, France.
¹⁰ Department of Pediatric Nephrology, UCL Great Ormond Street Hospital and Institute of Child Health, London, UK.
¹¹ Department of Pediatric Nephrology, Istituto Gaslini, Genoa, Italy.
¹² Göztepe Educational and Research Hospital, Istanbul, Türkiye.
¹³ Department of Pediatrics, Bordeaux University Hospital, Bordeaux, France.
¹⁴ Department of Pediatric Nephrology, Marmara University Faculty of Medicine, Istanbul, Türkiye.
¹⁵ Department of General Pediatrics, Philipps-University, Marburg, Germany.
¹⁶ Department of Pediatric Nephrology and Hypertension, Pediatric Institute, Jagiellonian University Medical College, Cracow, Poland.
¹⁷ Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplant Unit, Milan, Italy.
¹⁸ Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
¹⁹ Department Pediatrics, Nephrology & Hypertension, Medical University Gdansk, Gdansk, Poland.
²⁰ Centro Materno Infantil do Norte, Centro Hospitalar do Porto, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
²¹ Department of Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
²² Charité Children's Hospital, Berlin, Germany.

PMID: 41141543
PMCID: PMC12545905
DOI: 10.1016/j.ekir.2025.07.004

Abstract

Introduction: Currently, there is limited ability to predict the progression of chronic kidney disease (CKD) in children. Previously we reported that low levels of urinary epidermal growth factor (uEGF) predict CKD progression in children. In the present study, we investigated a novel serum biomarker, growth differentiation factor 15 (GDF-15), in 2 European pediatric CKD cohorts. We additionally explored the combined effect of GDF-15 and/or uEGF on CKD progression in children.

Methods: The association between serum GDF-15 levels and CKD progression was analyzed in 671 patients of the Cardiovascular Comorbidity in Children with CKD (4C) study, aged 6 to 17 years with an estimated glomerular filtration rate (eGFR) of 10 to 60 ml/min per 1.73 m² at baseline, and median follow-up of 8 years. The composite end point was start of kidney replacement therapy, 50% eGFR loss, or eGFR < 10 ml/min per 1.73 m². Results were validated in 329 participants from the ESCAPE trial.

Results: Higher GDF-15 levels were associated with an increased risk of CKD progression (hazard ratio: 1.40; 95% confidence interval [CI]: 1.10-1.77), independent of age, sex, baseline eGFR, proteinuria, and systolic blood pressure. Whereas adding either GDF-15 or uEGF individually to a model containing these variables improved model fit, combining both markers improved the model further. External validation in the ESCAPE cohort confirmed these results.

Conclusion: Serum GDF-15 and urine EGF levels may provide complementary information on the risk of CKD progression in children and might be included in future prognostic biomarker panels aimed at personalized, risk-stratified management of pediatric CKD.

Keywords: CKD progression; chronic kidney disease; epidermal growth factor; growth differentiation factor 15; pediatric CKD.

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Figures

**Figure 1**
CKD progression-free kidney survival by serum GDF-15 quartiles in 4C cohort (a) and ESCAPE cohort (b). CKD, chronic kidney disease; GDF-15, growth differentiation factor 15.

**Figure 2**
Calibration plot of predicted and observed survival probability in the ESCAPE validation cohort. GDF, growth differentiation factor.

See this image and copyright information in PMC

References

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GDF-15 and uEGF Independently Associate With CKD Progression in Children

Collaborators

Affiliations

GDF-15 and uEGF Independently Associate With CKD Progression in Children

Authors

Collaborators

Affiliations

Abstract

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References

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