We conducted an untargeted proteomic profiling of circulating inflammatory proteins using SOMASCAN platform to find those that predicted 10-year ESRD risk in two cohort study. Subjects with Type 1 Diabetes (T1D) served as a discovery cohort and a T2D cohort was used in validation. We identified a kidney risk inflammatory signature (KRIS) that robustly predicted progression to ESRD. The signature comprised 17 proteins out of 194 examined. KRIS was enriched for members of TNFR Superfamily (p=0.007) including TNFR1, TNFR2, TNFRSF19, TNFRSF19L, TNFRSF21 and TNFRSF27. Other KRIS proteins included IL15RA, IL17F, DAF, CLM6, TNFSF15, CCL14, CCL15, CSF1, TIMD3, IL1R1 and IL18R1. Hazard ratio (95% CI) for the top KRIS protein, TNFR1 was 3.6 (2.8, 4.6), p < 10-25. KRIS was neither enriched in receptors for other cytokines nor in cytokine ligands. Pathway analyses pointed to candidate therapeutic targets and aligned them by ranks. Eight proteins are currently targeted with compounds used for other clinical indications. Kidney tissue expression analysis and urinary proteomics suggested a systemic source of KRIS proteins.

In summary, our study identifies and validates a powerful protein signature enriched in TNFRSF members associated with 10-year ESRD risk in diabetes. These findings should inform future drug development strategies.

M. Niewczas: None. J.K. Skupien: None. V. Nair: None. A. Smiles: None. J. Park: None. E. Satake: None. C.A. Simeone: None. J. Tsay: None. W. Ju: None. M. Kretzler: Research Support; Self; AstraZeneca, Novo Nordisk Inc., Boehringer Ingelheim GmbH, National Institute of Diabetes and Digestive and Kidney Diseases, Eli Lilly and Company, Gilead Sciences, Inc. K. Susztak: Research Support; Self; Regeneron Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline plc., Merck & Co., Inc., Eli Lilly and Company, Ono Pharmaceutical Co., Ltd.. A. Krolewski: None.

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