Urinary Dickkopf-3 as a Noninvasive Biomarker Reflecting Renal Inflammation in Patients with Microscopic Polyangiitis

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis predominantly affects the elderly individuals, and renal involvement critically determines the prognosis of microscopic polyangiitis (MPA). Although renal biopsy provides valuable prognostic information, it is often difficult to perform in patients with severe comorbidities. Myeloperoxidase (MPO)-ANCA is useful for diagnosis and disease activity assessment but has limited value in predicting renal outcomes. Dickkopf-3 (Dkk-3), a secreted glycoprotein that regulates cell differentiation, proliferation, and apoptosis, has been shown in animal studies to promote tubular repair and regeneration under stress, while also contributing to renal fibrosis. However, the clinical significance of urinary Dkk-3 in human MPA remains unclear.

We enrolled 54 patients diagnosed with MPA (mean age, 73.6 ± 1.8 years; 18 males) from among 333 individuals with acute kidney injury treated at Saitama Medical Center, Saitama Medical University between December 2020 and August 2025. Nineteen healthy volunteers served as controls. Urinary Dkk-3 concentrations at diagnosis were quantified using ELISA (DY1118, R&D Systems, San Diego, CA, USA) and analyzed for correlations with clinical parameters. Immunohistochemical staining of renal biopsy specimens from MPA patients was performed to evaluate Dkk-3 expression and localization. Statistical analyses were performed using GraphPad Prism 9. Group comparisons were made using Student’s t-test, Welch’s t-test, or the Mann-Whitney U test; multiple comparisons with the Kruskal-Wallis test; and correlations with Spearman’s rank correlation test.

Urinary Dkk-3 levels were markedly higher in MPA patients than in healthy controls (9.5 ± 1.2 vs. 1.0 ± 0.1 ng/mL; p < 0.001). Urinary Dkk-3 correlated significantly with serum creatinine, estimated glomerular filtration rate (eGFR), C-reactive protein (CRP), urinary neutrophil gelatinase-associated lipocalin (NGAL), β2-microglobulin, kidney injury molecule-1 (KIM-1), and N-acetyl-β-D-glucosaminidase (NAG). No correlation was observed with urinary protein, urinary sediment, or MPO-ANCA levels. Urinary Dkk-3 was not associated with the EUVAS classification, tubular atrophy, or interstitial fibrosis. Immunohistochemistry showed no Dkk-3 expression in normal kidneys, whereas in MPA kidneys, Dkk-3 was localized to proximal tubular epithelial cells and infiltrating interstitial cells. Double immunofluorescence revealed co-localization of Dkk-3 with CD68-positive macrophages but not with CD3-positive T cells. Moreover, urinary Dkk-3 levels decreased following corticosteroid therapy.

Urinary Dkk-3 correlated with renal function parameters but not with disease activity markers such as MPO-ANCA, proteinuria, or urinary sediment, and declined after corticosteroid treatment. Although urinary Dkk-3 has been associated with interstitial fibrosis in acute kidney injury, no such relationship was observed in MPA. The localization of Dkk-3 in CD68-positive macrophages suggests that urinary Dkk-3 reflects intrarenal inflammation rather than chronic structural damage. These findings indicate that urinary Dkk-3 may serve as a non-invasive biomarker of renal inflammation in MPA. Given that renal biopsy is often contraindicated in elderly patients with severe comorbidities, urinary Dkk-3 measurement may provide a practical tool for assessing disease activity and treatment response.