Joslin Kidney Panel of Circulating Proteins: A Tool for ESKD Risk Discrimination and Individualized Diabetic Kidney Disease Treatment

Background: To facilitate personalized treatment of diabetic kidney disease (DKD), we developed the Joslin Kidney Panel (JKP) of 21 circulating proteins associated with progression to end-stage kidney disease (ESKD). Prognostic models using baseline concentrations of JKP proteins in circulation and clinical markers were then developed to stratify individuals according to ESKD risk and according to response to fenofibrate, a potential reno-protective drug. Methods: The custom-made Joslin OLINK multipurpose proteomics platform was used to quantify JKP proteins. Association between baseline serum/plasma concentrations of these proteins and kidney outcomes was examined in five independent study groups. Results: In Type 1 diabetes individuals from Joslin (N=59), FinnDiane (N=389), and Steno (N=283), all JKP proteins were good discriminators of ESKD risk during 10-year follow-up. Baseline concentrations of KIM-1 and WFDC2 performed the best, matching or outperforming the clinical markers. An optimal model to discriminate ESKD risk that included three clinical markers and eight JKP proteins (KIM1, TNF-R2, TNF-R3, TNF-R19L, PVRL4, WFDC2, DLL1, SYND1), was developed using the FinnDiane cohort (C-index 0.868, SE±0.019) and validated in the Steno cohort (C-index 0.913, SE±0.104) and in Type 2 diabetes Joslin study (C-index 0.807, SE±0.036). In each of these studies the optimal model performed better than models based solely on three clinical markers. In a subgroup of 450 individuals with Type 2 diabetes from the ACCORD-Lipid trial, high levels of three JKP proteins (EFNA4, DLL1, IL-1RT1) predicted amelioration of fast kidney function decline during four years of follow-up in those treated with fenofibrate compared to placebo. Conclusion: Quantification of circulating JKP proteins using the Joslin OLINK platform discriminates ESKD risk in individuals with diabetes and their response to reno-protective drugs. Use of this multi-purpose precision medicine tool should facilitate studies on the etiology of DKD and enable the development of effective personalized treatment protocols for individuals with DKD.