Presence of Tertiary Lymphoid Structures in Kidney Biopsies Is Associated with Poorer Treatment Response in Lupus Nephritis

Background: Renal treatment response is a key prognostic factor in lupus nephritis (LN), but predictive tools are limited. Tertiary lymphoid structures (TLSs) are inducible structures in chronic inflammation that support local immune activation and have been linked to immunotherapy response in tumors. Their association with treatment response in LN, however, remains unclear. Methods: This cohort study included 198 Chinese patients with first-time biopsy-proven LN of class III, IV, V, III+V, or IV+V, diagnosed at the First Affiliated Hospital of Sun Yat-sen University between January 1, 2017, and December 31, 2023. All patients had sufficient renal tissue for multiplex immunofluorescence staining and available follow-up data. Multiplex immunofluorescence staining was performed on renal tissue specimens from eligible patients. TLSs were identified as nodular inflammatory infiltrates containing organized CD3+ and CD20+ cells. Based on the presence of CD21+ cells and organized Ki67+ proliferating cells, TLSs were further classified into immature and mature types. Treatment efficacy was evaluated according to the 2024 KDIGO clinical practice guidelines, with complete response (CR), partial response (PR), and no response (NR) assessed within 12 months. The association between TLSs and treatment response in LN was subsequently analyzed. Results: Among 198 LN patients, 89 (45.0%) had no TLSs, 80 (40.4%) had immature TLSs, and 29 (14.6%) had mature TLSs. Among these 198 patients, 113 (57.1%) achieved CR, 48 (24.2%) had PR, and 37 (18.7%) showed NR. Compared to patients without TLSs, those with TLSs showed higher proteinuria levels, greater hypoalbuminemia prevalence, and elevated Chronicity Index scores in renal biopsy. Additionally, TLS-positive patients were less likely to achieve CR than TLS-negative patients (50.5% vs. 65.2%, P=0.038). Notably, the NR rate was significantly higher in patients with mature TLSs compared to those without (34.5% vs. 16.0%, P=0.018). Conclusion: The detection of TLSs in renal biopsies correlates with reduced treatment responsiveness in LN, suggesting their potential role in defining distinct LN subphenotypes.