Urinary Dickkopf-3 as a biomarker for kidney-function decline: a systematic review and meta-analysis.

BACKGROUND: Urinary Dickkopf-3 (uDKK3) is a tubular-stress glycoprotein linked experimentally to tubular injury, context-dependent Wnt signaling and tubulointerstitial remodeling. Human studies now span CKD, kidney histology, cardiorenal disease and transplantation, but the clinical estimands and assay platforms differ. METHODS: We searched PubMed, Embase, CENTRAL/Cochrane, ClinicalTrials.gov and conference sources to 28 May 2026 for human urinary DKK3 studies reporting kidney-function decline/progression, kidney failure, fibrosis/histology or transplant/donor outcomes. Risk of bias was assessed with QUIPS. The primary progression synthesis pooled one threshold/categorical HR or OR per cohort using Paule-Mandel random effects with HKSJ intervals; fibrosis correlations were Fisher-z pooled. We also performed an exploratory assay-aware sensitivity analysis using platform classifications extracted from the source articles. RESULTS: We included 24 full-text studies, 6 unique abstracts and relevant registry/parent-trial records. Across 8 native-kidney estimates, higher uDKK3 was associated with kidney-function decline or progression (pooled relative effect [HR/OR composite] 1.82, 95% CI 1.44-2.30; I2=32%; 95% prediction interval 1.15-2.89). The HR-only sensitivity estimate was 1.70 (95% CI 1.20-2.41). Assay-stratified analyses were directionally positive in ReFiNE/DiaRen or urine-validated assays and in other/RUO/unclear platforms, with overlapping and imprecise intervals. In 3 biopsy cohorts, the pooled fibrosis correlation was directionally positive but imprecise after HKSJ correction (r=0.62, 95% CI -0.04 to 0.91; conventional CI 0.36-0.80; I2=86%). Pathology-discrimination studies supported a fibrosis-enriched, rather than fibrosis-specific, signal. Prediction and transplant data were promising but less mature. CONCLUSIONS: Higher uDKK3 was consistently associated with kidney-function decline and showed a fibrosis-enriched signal in biopsy cohorts, supporting its use as a complementary tubular-stress biomarker for risk enrichment alongside, not instead of, eGFR and albuminuria. Demonstrating incremental clinical value will require assay-aware interpretation, cross-platform harmonization, population-specific cut-off validation and prospective tests of utility.