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.