Urinary DKK3 signals declining kidney function and treatment response in children

medwireNews: Increased urinary Dickkopf-related protein 3 (DKK3) levels could indicate declining kidney function in children with chronic kidney disease (CKD) and be a marker of treatment response, report researchers in The Lancet Child and Adolescent Health.

In their post-hoc analysis of the ESCAPE trial and 4C study, the team found that children with CKD and a DKK3 concentration above 1689 pg/mg of creatinine were a significant 2.22 and 1.5 times more likely, respectively, to have a 5% or greater decline in estimated glomerular filtration rate (eGFR) at 6 months than those with lower concentrations.

Moreover, Franz Schaefer (Heidelberg University Hospital, Germany) and colleagues found that children with higher DKK3 levels in the randomized controlled ESCAPE trial were more likely to benefit from intensive blood pressure control with renin–angiotensin–aldosterone system (RAAS) blockade than those with lower levels.

“Measurement of urinary DKK3 might therefore represent a tool to detect patients in whom specific therapeutic strategies should be used to slow chronic kidney disease progression as an individualised medicine approach,” they say.

A total of 659 children with CKD were included in the analysis: 231 aged 3–18 years with an eGFR of 15–80 mL/min per 1.73 m² from the ESCAPE trial and 428 aged 6–17 years with an eGFR of 10–60 mL/min per 1.73 m² from the prospective observational 4C study.

Among children with DKK3 concentrations above the median of 1689 pg/mg of creatinine, eGFR declined by an average 5.6% in the ESCAPE trial and 6.2% in the 4C study. This compared with a steady rate of 1.0% and 1.5%, respectively, among children with lower DKK3 concentrations.

This relationship was irrespective of the cause of CKD or baseline eGFR, the researchers note, which they say “is in marked contrast to most other biomarkers that have hitherto been associated with chronic kidney disease progression in children.” The association was also independent of age and the presence of proteinuria among other clinical parameters.

In the ESCAPE trial, the children were randomly assigned to either conventional (50–95th percentile of 24-hour mean arterial blood pressure) or intensified (<50th percentile) blood pressure control and the latest results showed that the beneficial effect of intensified blood pressure control was only seen in those children with urinary DKK3 higher than 1689 pg/mg creatinine.

With intensified blood pressure control, these children were a significant 73% less likely than those receiving conventional blood pressure control to have a 50% reduction in eGFR and progression to end-stage kidney disease and 67% less likely to need kidney replacement therapy, with respective numbers needed to treat of 4.0 versus 250.0 and 6.7 versus 31.0.

The team also looked at the relationship between RAAS inhibition and urinary DKK3 concentrations in the 4C participants. RAAS inhibition resulted in significantly lower urinary DKK3 concentrations, of least-squares mean 12,235 pg/mg creatinine, among patients who were not taking angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers, compared with 6861 pg/mg creatinine in those who were taking these medications.

“In the future, identification of patients at high risk of progressive chronic kidney injury by urinary DKK3 measurement might pave the way to select patients for specific therapies such as sodium–glucose co-transporter 2 (SGLT2) inhibition or novel therapeutic approaches such as anti-inflammatory or complement-inhibiting treatments,” the researchers suggest.

Adding to this in a related commentary, Brendon Neuen and Sean Kennedy, both from the University of New South Wales in Sydney, Australia, say: “By focusing our attention on biomarkers that predict treatment response, we will hopefully be able to accelerate progress in our understanding of the pathophysiological mechanisms of chronic kidney disease in children and help us realise the potential of precision medicine in paediatric and adult nephrology.”

 News stories are provided by medwireNews, which is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group

This independent news story was supported by an educational grant from L’Institut Servier, Suresnes, France.

Lancet Child Adolesc Health 2023 doi:10.1016/S2352-4642(23)00049-4
Lancet Child Adolesc Health 2023 doi:10.1016/S2352-4642(23)00102-5