PROJECT SUMMARY/ABSTRACT With the rising prevalence of diabetes in the US and other countries, there is an ongoing research effort to find biomarkers allowing the identification of patients with diabetes at high risk of end stage kidney disease (ESKD). With support from NIH and JDRF, we have identified 21 serum proteins that were significantly associated with increased risk of kidney function loss and ESKD in the Joslin Kidney Study, and have developed an ad hoc OLINK multiplex assay (so called Joslin Kidney Panel [JKP]) to measure these biomarkers. Preliminary data strongly suggest that a subset of the JKP can significantly improve the ability to predict ESKD risk in subjects with type 2 diabetes (T2D) when added to GFR and allbuminuria. In this proposal, we aim to validate these preliminary findings in other settings, in order to develop improved algorithms for ESKD risk prediction. We intend to accomplish these goals using existing data and specimens from individuals with and without T2D from 1. the Chronic Renal Insufficiency Cohort (CRIC) Study; and 2. the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and its follow-up study ACCORDION. Our Specific Aims are: 1: To identify the most informative of the 21 biomarkers in the Joslin Kidney Panel and evaluate their performance, when added to GFR and albuminuria, in predicting ESKD risk among subjects with T2D and chronic kidney disease. We will measure the 21 proteins of the JKP in baseline serum specimens from ~1,500 CRIC participants with T2D, and will use these data together with GFR and albuminuria to develop and internally validate multi-marker prognostic algorithms predicting the risk of ESKD (primary outcome) or the composite of ESKD and/or 50% loss of kidney function (secondary outcome) during 10 years of follow-up. 2: To evaluate the generalizability of findings from CRIC to T2D individuals with a broader spectrum of kidney function. We will assay the JKP in baseline serum specimens from a case- cohort sample of ~2,000 ACCORD/ACCORDION participants and will use these data to investigate the generalizability of the predictive algorithms built in CRIC to diabetic patients with different characteristics. The prognostic models developed in Aim 1 and externally validated in Aim 2 will be used to build a web-based Kidney Risk Calculator for the estimation of the 10-year risk of ESKD in a clinical setting. 3: To evaluate the transferability of the Kidney Risk Calculator from diabetic to non-diabetic kidney disease. We will measure the 21 JKP biomarkers in baseline serum samples from ~1,700 non-diabetic subjects from the CRIC study and will assess the performance of the Kidney Risk Calculator developed in Aim 2 in predicting the risk of ESKD and ESKD/50% kidney function loss in patients with non-diabetic kidney disease. The proposed research has a high likelihood of resulting in the development of improved prognostic tools for the stratification of patients with diabetes according to their risk of progression to ESKD. This would be a great advancement for optimizing patient care and for improving the efficiency of clinical trials of new ESKD-preventing interventions.

NARRATIVE In this proposal we aim to develop improved algorithms for the estimation of ESKD risk in Type 2 diabetes (T2D) by adding newly identified biomarkers to established clinical predictors such as GFR and albuminuria. A more precise estimation of ESKD risk would be beneficial in several respects: it would improve the cost-benefit ratio of currently available ESKD-preventive therapies, it would help optimize clinical care by allowing referral of patients to nephrologists early in the trajectory to ESKD, and it would increase the efficiency of clinical trials aimed at testing new therapies by facilitating the enrollment of patients with a high likelihood of experiencing significant kidney function loss within the limited timeframe of the trial.