Urinary biomarkers for active Lupus Nephritis that have survived independent validation across cohorts

Most reported biomarkers for lupus nephritis (LN) have not been independently validated across cohorts. Moreover, many of the documented biomarker candidates have been reported to be elevated in LN compared to healthy controls. However, biomarkers that distinguish patients with active LN (ALN) from inactive systemic lupus erythematosus (iSLE) hold significant clinical utility. Hence, our review attempts to identify urine protein biomarkers for LN that have been independently validated across two or more cohorts and exhibit good diagnostic potential for distinguishing ALN from iSLE. PubMed and OVID were screened for studies assessing the diagnostic value of urinary biomarkers in patients with ALN compared to iSLE. Forty peer-reviewed articles were evaluated, encompassing urine biomarker data from 3,411 distinct patients. Of the 32 candidate biomarkers identified, fourteen were repeatedly reported/tested in four or more papers each, namely ALCAM, CCL2 (MCP1), CD163, HAVCR1 (KIM-1), HPGDS, ICAM-1 (CD54), ICAM-2 (CD102), IGFBP-2, LCN2, NCAM-1 (CD56), SELE (E-Selectin), SELL (L-Selectin), TNFSF12 (TWEAK), and VCAM-1, with most exhibiting C-statistics of 0.80 or more across multiple studies when discriminating patients with ALN from iSLE. The 32 reproducibly elevated biomarkers for active LN mapped to nine functional categories. The urinary proteins reported here promise to serve as a liquid biopsy for ALN. Besides representing potential candidates for diagnostic, monitoring, predictive, and prognostic biomarkers in LN, they also provide a window into potential molecular processes within the kidney that may be driving LN. Thus, ongoing advances in proteomics, which offer wider proteome coverage at increased sensitivity, are likely to further reshape our perspective of urinary biomarkers for LN.