Leveraging Clinical Trials of Diabetic Kidney Disease to Advance Biomarkers

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 DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) and end stage renal diseases (ESRD) represent an enormous burden in the United States and worldwide. Diabetic kidney disease (DKD) is the single largest cause of CKD and ESRD. DKD is progressive and few therapies are able to alter its course. Currently, clinical risk assessment of DKD depends upon measures of estimated GFR (eGFR) and glomerular injury (albuminuria), however, these two markers fall short of providing sufficient risk stratification for progression to advanced DKD, ESRD and cardiovascular (CV) events. Development of prognostic biomarkers of those at high risk of progression will aide both future clinical trials, by serving to enrich the enrollment with patients with a higher event rate, thereby allowing for a reduced sample size to detect an intervention with a given relative risk reduction. Moreover, there is an urgent need to identify th subgroups of patients that are most likely to drive benefit from various forms of intensive therapy (predictive biomarkers) and to identify better surrogate endpoints. By leveraging the data and stored blood and urine samples from three large clinical trials in patients with type 2 diabetes (VA- NEPHRON-D, ACCORD, and Sun-MACRO), we will measure 15 blood and urine biomarkers from diverse pathways including inflammatory, glomerular, tubule injury, and tubulointerstitial fibrosis markers. From these data, we will derive and validate biomarker panels for prognosis of renal endpoints (GFR progression and dialysis) in Aim 1 and cardiovascular events and death in Aim 2. Moreover, since the samples are derived from randomized controlled trials, we will test for effect modification by biomarkers (Aim 3) to determine if there were sub-groups that demonstrated benefit with various interventions employed in the trials (specifically, dual renin angiotensin aldosterone blockade, intensive glycemic control, or lower systolic blood pressure targets). The data and samples from these trials will be available to the CKD-BIOCon for collaborative studies with other groups. We will also collaborate with experts from the Critical Path Institute and the FDA to advance promising biomarkers through the newly developed FDA and EMA qualification processes so that they can be integrated in the regulatory review process for newer drug development trials.