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Abstract: TH-OR33

Urinary DKK3 Predicts Short-Term eGFR Decline and Nephroprotective Efficacy of Antihypertensive Therapy in Children With CKD: Findings From the 4C Study and ESCAPE Trial

Session Information

Category: Pediatric Nephrology

  • 1800 Pediatric Nephrology

Authors

  • Schaefer, Franz S., Ruprecht Karls Universitat Heidelberg, Heidelberg, Baden-Württemberg, Germany
  • Speer, Thimoteus, Universitatsklinikum des Saarlandes und Medizinische Fakultat der Universitat des Saarlandes, Homburg, Saarland, Germany
  • Schunk, Stefan J., Universitatsklinikum des Saarlandes und Medizinische Fakultat der Universitat des Saarlandes, Homburg, Saarland, Germany
  • Fliser, Danilo, Universitatsklinikum des Saarlandes und Medizinische Fakultat der Universitat des Saarlandes, Homburg, Saarland, Germany

Group or Team Name

  • 4C trial and ESCAPE study investigators
Background

Childhood-onset chronic kidney disease (CKD) is a progressive condition with major impact on life expectancy and quality. We evaluated the usefulness of the kidney tubular cell stress marker urinary Dickkopf-3 (uDKK3) in determining the short-term risk of CKD progression in children and identifying those who will benefit from specific nephroprotective interventions.

Methods

We assessed the association between uDKK3 and kidney endpoints, and its interaction with intensified blood pressure reduction in the randomized-controlled ESCAPE trial. Estimated glomerular filtration rate (eGFR) and uDKK3 were quantified in 659 children with CKD enrolled in the prospective multicenter ESCAPE and 4C studies at baseline and at 6-monthly follow-up visits, yielding 3,935 semi-annual evaluation blocks.

Results

In ESCAPE, the effect of intensified blood pressure control on the kidney survival endpoint and the need for kidney replacement therapy was limited to children with uDKK3 above the median, i.e. >1,689 pg/mg (HR 0.33, 95%CI:0.17-0.64; NNT 4.1 vs. 25.0 and HR 0.27, 95%CI:0.11-0.66; NNT 6.7 vs. 55.6). In 4C, inhibition of the renin-angiotensin-system resulted in lower uDKK3 levels (12,235 vs. 6,861 pg/mg, P=4.7*10-6). In both cohorts, uDKK3 >1,689 pg/mg creatinine was associated with significantly greater 6-month eGFR decline (ESCAPE: -6.3%, 95%CI:-7.8–-4.9% vs. 0.2%, 95%CI:-1.1–1.6%, P=4.2x10-10; 4C: -6.5%, 95%CI:-13.4–0.4 vs. -1.7%, 95%CI:-8.6–5.2, P=2.4x10-10 ), independently of kidney diagnosis, eGFR, and albuminuria.

Conclusion

uDKK3 is associated with a greater short-term risk of declining kidney function and may allow a personalized medicine approach to pharmacological nephroprotection by identifying children who benefit from intensified blood pressure lowering.