Urinary DKK3 as a biomarker for short-term kidney function decline in children with chronic kidney disease: an observational cohort study

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dc.authoridQuerfeld, Uwe/0000-0001-6783-3822
dc.authorscopusid36097022700
dc.authorscopusid57204505793
dc.authorscopusid57223941535
dc.authorscopusid57192834712
dc.authorscopusid57204500729
dc.authorscopusid58249667700
dc.authorscopusid24476602300
dc.contributor.authorSpeer, Thimoteus
dc.contributor.authorSchunk, Stefan J.
dc.contributor.authorSarakpi, Tamim
dc.contributor.authorSchmit, David
dc.contributor.authorWagner, Martina
dc.contributor.authorArnold, Ludger
dc.contributor.authorZewinger, Stephen
dc.date.accessioned2024-08-25T18:51:19Z
dc.date.available2024-08-25T18:51:19Z
dc.date.issued2023
dc.departmentEge Üniversitesien_US
dc.description.abstractBackground Childhood-onset chronic kidney disease is a progressive condition that can have a major effect on life expectancy and quality. We evaluated the usefulness of the kidney tubular cell stress marker urinary Dickkopf-related protein 3 (DKK3) in determining the short-term risk of chronic kidney disease progression in children and identifying those who will benefit from specific nephroprotective interventions.Methods In this observational cohort study, we assessed the association between urinary DKK3 and the combined kidney endpoint (ie, the composite of 50% reduction of the estimated glomerular filtration rate [eGFR] or progression to end-stage kidney disease) or the risk of kidney replacement therapy (ie, dialysis or transplantation), and the interaction of the combined kidney endpoint with intensified blood pressure reduction in the randomised controlled ESCAPE trial. Moreover, urinary DKK3 and eGFR were quantified in children aged 3-18 years with chronic kidney disease and urine samples available enrolled in the prospective multicentre ESCAPE (NCT00221845; derivation cohort) and 4C (NCT01046448; validation cohort) studies at baseline and at 6-monthly follow-up visits. Analyses were adjusted for age, sex, hypertension, systolic blood pressure SD score (SDS), BMI SDS, albuminuria, and eGFR. Findings 659 children were included in the analysis (231 from ESCAPE and 428 from 4C), with 1173 half-year blocks in ESCAPE and 2762 in 4C. In both cohorts, urinary DKK3 above the median (ie, >1689 pg/mg creatinine) was associated with significantly greater 6-month eGFR decline than with urinary DKK3 at or below the median (-5 center dot 6% [95% CI -8 center dot 6 to -2 center dot 7] vs 1 center dot 0% [-1 center dot 9 to 3 center dot 9], p<0 center dot 0001, in ESCAPE; -6 center dot 2% [-7 center dot 3 to -5 center dot 0] vs -1 center dot 5% [-2 center dot 9 to -0 center dot 1], p<0 center dot 0001, in 4C), independently of diagnosis, eGFR, and albuminuria. In ESCAPE, the beneficial effect of intensified blood pressure control was limited to children with urinary DKK3 higher than 1689 pg/mg creatinine, in terms of the combined kidney endpoint (HR 0 center dot 27 [95% CI 0 center dot 14 to 0 center dot 55], p=0 center dot 0003, number needed to treat 4 center dot 0 [95% CI 3 center dot 7 to 4 center dot 4] vs 250 center dot 0 [66 center dot 9 to infinity]) and the need for kidney replacement therapy (HR 0 center dot 33 [0 center dot 13 to 0 center dot 85], p=0 center dot 021, number needed to treat 6 center dot 7 [6 center dot 1 to 7 center dot 2] vs 31 center dot 0 [27 center dot 4 to 35 center dot 9]). In 4C, inhibition of the renin-angiotensin-aldosterone system resulted in significantly lower urinary DKK3 concentrations (least-squares mean 12 235 pg/mg creatinine [95% CI 10 036 to 14 433] in patients not on angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers vs 6861 pg/mg creatinine [5616 to 8106] in those taking angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers, p<0 center dot 0001).Interpretation Urinary DKK3 indicates short-term risk of declining kidney function in children with chronic kidney disease and might allow a personalised medicine approach by identifying those who benefit from pharmacological nephroprotection, such as intensified blood pressure lowering.en_US
dc.description.sponsorshipGerman Research Foundation [SFB TRR 219, 322900939]; European Renal Association Research Programme; Kuratorium fur Dialyse und Nierentransplantation (KfH) Foundation for Preventive Medicine; German Federal Ministry of Education and Research [01EO0802]en_US
dc.description.sponsorshipSJS, TSp, and DF are supported by the German Research Foundation (SFB TRR 219, project identifier 322900939) . Support for the 4C study was received from the European Renal Association Research Programme, the Kuratorium fuer Dialyse und Nierentransplantation (KfH) Foundation for Preventive Medicine, and the German Federal Ministry of Education and Research (01EO0802) .en_US
dc.identifier.doi10.1016/S2352-4642(23)00049-4
dc.identifier.endpage414en_US
dc.identifier.issn2352-4642
dc.identifier.issue6en_US
dc.identifier.pmid37119829en_US
dc.identifier.scopus2-s2.0-85159229859en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage405en_US
dc.identifier.urihttps://doi.org/10.1016/S2352-4642(23)00049-4
dc.identifier.urihttps://hdl.handle.net/11454/102531
dc.identifier.volume7en_US
dc.identifier.wosWOS:001004275600001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherElsevier Sci Ltden_US
dc.relation.ispartofLancet Child & Adolescent Healthen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.snmz20240825_Gen_US
dc.subjectBlood-Pressureen_US
dc.subjectRenal-Functionen_US
dc.subjectDickkopf-3en_US
dc.titleUrinary DKK3 as a biomarker for short-term kidney function decline in children with chronic kidney disease: an observational cohort studyen_US
dc.typeArticleen_US

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