V‐Set Immunoglobulin Domain–Containing Protein 4 as a Novel Serum Biomarker of Lupus Nephritis and Renal Pathology Activity

Abstract

ObjectiveTo discover novel serum biomarkers that have diagnostic or predictive value in lupus nephritis (LN).MethodsUsing a quantitative protein microarray, we screened for high‐abundant proteome expression in the serum of patients with LN compared to healthy controls. Top candidates from this screening were validated using a larger cohort of patients with LN compared to a disease control cohort (subjects with other chronic kidney diseases) and a healthy control cohort. Promising markers were then selected using a machine‐learning model and further validated with a larger patient cohort. The corresponding autoantibodies and immune complexes containing these proteins were also examined.ResultsIn total, 13 proteins were found to be significantly elevated in LN patient serum in the screening, among which 8 proteins were validated by enzyme‐linked immunosorbent assay using 81 serum samples from LN patients and control subjects. Three serum markers with LN diagnostic potential were identified using feature importance analysis and further validated using 155 serum samples from LN patients and control subjects. V‐set immunoglobulin domain–containing protein 4 (VSIG4) appeared to be the most promising marker in distinguishing LN from healthy controls, with an area under the curve of 0.93. VSIG4 could also discriminate active LN from inactive LN. Furthermore, serum VSIG4 levels were positively correlated with all of the following clinical parameters: the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (Spearman's rank correlation rs = 0.42, P < 0.001), the renal domain score of the SLEDAI (rs = 0.46, P < 0.001), the urinary protein‐to‐creatinine ratio (rs = 0.56, P < 0.001), and the serum creatinine level (rs = 0.41, P < 0.001). Importantly, we found that serum VSIG4 levels tracked with LN disease activity longitudinally, and that serum VSIG4 levels reflected the renal pathology activity index (AI), particularly the AI components of crescent formation and hyaline deposits.ConclusionVSIG4 may be a promising novel serum biomarker and therapeutic target in patients with LN.image

Advancing Point-of-Care Diagnosis: Digitalizing Combinatorial Biomarker Signals for Lupus Nephritis

“…This high AUC value is likely due to the small cohort size utilized in this study. VSIG4’s diagnostic utility in lupus has been rigorously evaluated with a larger cohort in a previous study [ 25 ]. To further validate these findings, our portable smartphone-based diagnostic system will be subjected to a larger cohort in subsequent investigations to enhance the robustness of our results and conclusions.…”

“…BSA-Biotin was used as a positive control, while phosphate-buffered saline (PBS) was used as a negative control. Based on the prior research [ 25 ], we selected the epoxy-modified polymer slide (STRATEC Consumables GmbH, Birkenfeld, Germany) for the immobilization of the antibodies and their subsequent detection.…”

“…In this study, we introduce our smartphone-based analyzing and reporting system (SBARS) developed for the precise detection and quantification of biomarker signals in colorimetric microarray images. Based on our literature research [ 24 ] and our recent findings [ 25 ], two promising protein biomarkers, v-set and immunoglobulin domain containing-4 (VSIG4) and TNF receptor superfamily member 1 (BTNFRSF1b), were selected for the development of the smartphone-based multiplexed biomarker detection platform for lupus nephritis (LN). The rationale behind the development of this smartphone-based detection platform is rooted in its capacity to facilitate the early detection and ongoing management of LN, a critical concern in the realm of autoimmune diseases.…”

Systemic lupus in the era of machine learning medicine

“…133 Novel biomarkers for LN activity include renal IFI16 135 and V-set immunoglobulin domain-containing protein 4. 136 For extrarenal flares, 59 63 66 101 106 113 137-148 approximately half of the reports used genetic or genetic expression datasets. Novel biomarkers predicting SLE flares or increased disease activity include MX2 106 and M1 143 gene expression and a nine-protein combination (PHACTR2, GOT2, L-selectin, CMC4, MAP2K1, CMPK2, ECPAS, SRA1 and STAT2).…”

“… 133 Novel biomarkers for LN activity include renal IFI16 135 and V-set immunoglobulin domain-containing protein 4. 136 …”