1135-P: Pigment Epithelium–Derived Factor, Diabetic Kidney Disease, and Hypertension—Deciphering the Proteomic Response to Metabolic Bariatric Surgery in Adolescents

Introduction & Objective: This study aims to explore the effects of metabolic bariatric surgery (MBS) on plasma proteins linked to diabetic kidney disease and hypertension in youth with type 2 diabetes (T2D). Methods: We measured 7604 proteins in 326 plasma samples from severely obese youth, both with and without T2D, in the Teen-LABS study, examining pre- and post-MBS changes (6 month, 1, 2-, 3-, 4-, and 5-year follow-up). This analysis focused on proteins identified in the TODAY cohort as predictors of severe albuminuria (ACR ≥300 mg/g) and hypertension (SBP≥130/80 mm Hg), in youth with T2D (n=374), using Cox proportional hazard models adjusted for age, sex, HbA1c, log-transformed triglycerides and estimated insulin sensitivity. A mixed model evaluated proteomic changes post-MBS, maintaining a 5% false discovery rate with reported q-values. Results: In Teen-LABS, several proteins associated with a higher risk of severe albuminuria and hypertension in TODAY showed notable post-surgical downregulation. Higher pigment epithelium-derived factor (PEDF) at baseline predicted onset to severe albuminuria (HR: 1.63, 95% CI 1.12, 2.37, per 1 SD increment) and hypertension (HR: 1.41, 95% CI 1.22, 1.63, per 1 SD increment) over 15 years in TODAY after multivariable adjustments. In Teen-LABS, PEDF decreased post-MBS compared to baseline at 6 months follow-up (logFC: -0.30, q-value=1.24x10-31), year 1 (logFC: -0.28, q-value=2.35x10-29), year 2 (logFC: -0.32, q-value=1.85x10-34), year 3 (logFC: -0.28, q-value=6.95x10-29), year 4 (logFC: -0.30, q-value=4.13x10-28) and year 5 (logFC: -0.30, q-value=2.78x10-26). Conclusion: These analyses show durable attenuation of plasma PEDF after MBS, a protein strongly associated with risk of severe albuminuria and hypertension in youth with T2D. PEDF is implicated in endothelial dysfunction and vascular damage through impaired angiogenesis and endothelial repair mechanisms. Disclosure P. Narongkiatikhun: None. Y. Choi: None. N. Nguyen: None. K. Nash: None. K.L. Tommerdahl: None. M. Kretzler: Research Support; Boehringer-Ingelheim, Certa, Traveere Pharmaceuticals, Maze Therapeutics, Roche Pharmaceuticals, AstraZeneca, Novo Nordisk, Moderna, Inc., Chinook Therapeutics Inc., angion, Lilly Diabetes, Renalytix, Gilead Sciences, Inc., Regeneron Pharmaceuticals Inc., Janssen Pharmaceuticals, Inc. T. Inge: Consultant; Medtronic, Eli Lilly and Company, Brainstorm Therapeutics. Stock/Shareholder; Standard Bariatrics. Consultant; Teleflex. J.R. Ryder: None. L. Pyle: None. P. Bjornstad: Consultant; AstraZeneca, Boehringer-Ingelheim. Advisory Panel; Lilly Diabetes, Novo Nordisk, Bayer Inc., Horizon Therapeutics plc. Funding National Institutes of Health