A serum biomarker panel and miniarray detection system for tracking disease activity and flare risk in lupus nephritis

Abstract

Introduction: Lupus nephritis (LN) leads to end stage renal disease (ESRD), and early diagnosis and disease monitoring of LN could significantly reduce the risk. however, there is not such a system clinically. In this study we aim to develop a biomarker-panel based point-of-care system for LN. Methods: Immunoassay screening combined with genomic expression databases and machine learning techniques was used to identify a biomarker panel of LN. A quantitative biomarker-panel mini-array (BPMA) system was developed and the sensitivity, specificity, reproducibility, and stability of the were examined. The performance of BPMA in disease monitoring was validated with machine models using a larger cohort of LN. The BPMA was also used to determine LN flare using a machine-learning generated flare score (F-Score). Results: Among 32 promising LN serum biomarkers, VSIG4, TNFRSF1b, VCAM1, ALCAM, OPN, and IgG anti-dsDNA antibody were selected to constitute an LN biomarker Panel, which exhibited excellent discriminative value in distinguishing LN from healthy controls (AUC = 1.0) and active LN from inactive LN (AUC = 0.92), respectively. Also, the 6-biomarker panel exhibited a strong correlation with key clinical parameters of LN. A multiplexed immunoarray was constructed with the 6-biomarker panel (named BPMA-S6 thereafter). An LN-specific 8-point standard curve was generated for each protein biomarker. Cross-reaction between these biomarkers was minimal (< 1%). BPMA-S6 test results were highly correlated with those from ELISA (Spearman’s correlation: fluorescent detection, rs = 0.95; colorimetric detection, rs = 0.91). The discriminative value of BPMA-S6 for LN was further validated using an independent cohort (AUC = 0.94). Using a longitudinal cohort of LN, the derived F-Score exhibited superior discriminative value in the training dataset (AUC = 0.92) and testing dataset (AUC=0.82) to distinguish flare vs remission. Conclusion: BPMA-S6 may represent a promising point-of-care test (POCT) for the diagnosis, disease monitoring, and assessment of LN flare.