Urinary Vitamin D-Binding Protein as a Novel Biomarker for Lupus Nephritis Predicts the Development of Proteinuric Flare in Systemic Lupus Erythematosus

Abstract

Background: Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE), which occurs in up to 50% of patients. Conventional biomarkers for assessing renal disease activity are imperfect in predicting clinical outcomes associated with LN. The aim of this study is to identify urinary protein biomarkers that reliably reflect disease activity or predict clinical outcomes. Methods: A quantitative proteomic analysis of pooled urine samples was performed to identify urinary protein biomarker candidates that can differentiate between SLE patients with and without LN. Selected biomarker candidates were further verified using urine samples from a larger cohort of SLE patients (n = 121) presenting with LN (n = 62) and without LN (n = 59) by enzyme-linked immunosorbent assay (ELISA) to investigate their predictive values for LN activity measure. Furthermore, association between urinary level of selected panel of potential biomarkers and prognosis of LN was assessed with a 4-year follow-up study of renal outcomes. Results: Urinary vitamin D-binding protein (VDBP), transthyretin (TTR), and retinol binding protein 4 (RBP4) were significantly elevated in SLE patients with LN, especially in patients with active LN (n = 21), compared to those without LN. Among them, VDBP was well correlated with severity of proteinuria (Spearmans rho = 0.661, P < 0.001) and renal SLE disease activity index (renal SLEDAI) (Spearmans rho = 0.520, P < 0.001). In the 4 year follow-up, VDBP was found to be a significant risk factor (hazard ratio 9.627, 95% CI 1.698 to 54.571, P = 0.011) for the development of proteinuric flare in SLE patients without proteinuria (n = 100) after adjustments of multiple confounders. Conclusion: Urinary VDBP was not only correlated with proteinuria and renal SLEDAI, but also predicted the development of proteinuria in SLE patients.