1861-LB: Targeting Lp-PLA2—A Novel Therapeutic Approach for Diabetic Kidney Disease

Introduction and Objective: Lp-PLA2 is primarily secreted by macrophages, with its expression upregulated in most chronic inflammatory diseases. In DKD patients, elevated plasma Lp-PLA2 levels significantly associate with UACR, yet the underlying mechanisms remain undefined. This study establishes a translational research framework integrating preclinical and clinical investigations to: 1) Elucidate the mechanistic basis of the Lp-PLA2 -UACR association; 2) Identify optimal DKD patient subgroups for Lp-PLA2 -targeted therapy. Methods: 1. Test the ameliorative effect of the Lp-PLA2 inhibitor SR1375 on UACR in a DKD translational mice model.2. Establish the correlation between Lp-PLA2 levels and UACR in renal biopsy tissues obtained from DKD patients.3. Analyze the rate of improvement in UACR in DKD patients treated with SR1375 and identify the most appropriate patient subtype by stratification. Results: 1. SR1375 significantly reduced UACR and UAE in DKD mice, achieving a maximum reduction of 65.5%, which coincided with improvements in renal cell death, tubulointerstitial inflammation, and glomerular/tubulointerstitial fibrosis.2. In DKD patients, elevated renal Lp-PLA2 mRNA levels first showed a positive correlation with UACR, and they were detected in both immune cells and renal parenchymal cells. Notably, the association and distribution described here represent the first international findings.3. Among participants with baseline UACR >100 mg/g*Cr in the clinical trial, those treated with SR1375 for 12 weeks experienced an average 49.7% reduction in UACR, compared to a 17.5% reduction in the placebo group. Conclusion: Elevated Lp-PLA2 levels correlate with inflammation, tissue injury and UACR, identifying moderate-to-severe DKD patients with overt proteinuria as optimal candidates for SR1375. Disclosure R. Zheng: None. H. Shi: None. H. Meihua: None. L. Jin: None. F. Wang: None. L. You: None. J. Xue: None. L. Wang: None. Y. Chen: None. S. Li: None. X. Huang: None.