Serum soluble mediator signatures of lupus nephritis: histological features and response to treatment.

Lupus nephritis (LN) management remains challenging, and novel noninvasive biomarkers are needed. This study quantified serum soluble mediators in the Accelerating Medicines Partnership (AMP) LN cohort to identify biomarkers of histological features and treatment response. SLE patients (n=268) undergoing clinically indicated kidney biopsies (urine protein/creatinine ratio [UPCR] > 0.5) were recruited through the AMP RA/SLE network. Serum was collected at biopsy and 3-, 6-, and 12-months post-biopsy, alongside samples from 22 healthy controls. Concentrations of 66 immune mediators were quantified using xMAP multiplex assays, and TNF-α converting enzyme (TACE) measured by ELISA. Seven mediators with >95% values below detection limits were excluded from analyses. Bootstrapped LASSO regression identified proliferative LN (class III/IV+V) predictors from baseline mediators. Associations with 12-month treatment response (complete/partial vs. no response) were tested using 3-month changes in LASSO-selected mediators and UPCR via logistic regression. Molecular clustering of mediator profiles was performed to identify LN subgroups. Proliferative LN patients (class [III or IV] + V; n=160) displayed a distinct mediator profile compared to non-proliferative LN (class I/II/V; n=96). LASSO regression identified 20 mediators predictive of proliferative LN (AUC, 0.82; 95% CI, 0.81-0.91), including elevated syndecan-1, TNFRI, TNFRII, and VCAM-1, as well as decreased CCL3/MIP-1α, CD40L, and IL-5 levels. Among proliferative LN patients, 3-month reductions in syndecan-1 and VCAM-1, mediators associated with intrarenal LN activity and/or chronicity, predicted 12-month treatment response. A model incorporating these reductions and a decline in UPCR predicted treatment response in proliferative LN (0.90; 95% CI, 0.82-0.98). Molecular clustering revealed 4 distinct LN subgroups with unique soluble mediator signatures and clinical features, not captured by histology alone. Serum soluble mediators, particularly syndecan-1 and VCAM-1, reflect LN histological activity and early decreases predict treatment response, supporting their potential utility as noninvasive longitudinal biomarkers. The substantial heterogeneity within LN highlights the potential for biomarker-guided reclassification to advance precision medicine approaches.