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.

Public Health Relevance

There is an urgent need to continue drug discovery and conduct efficient randomized controlled trials of novel agents in patients with diabetic kidney disease in those most likely to progress and respond to intervention. By leveraging the banked urine and blood samples and data from large clinical trials in patients with type 2 diabetes, we can develop and validate biomarkers that will serve as drug development tools to improve efficiency and reduce cost of the future clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK106962-02
Application #
9143761
Study Section
Special Emphasis Panel (ZDK1-GRB-J (M1)S)
Program Officer
Kimmel, Paul
Project Start
2015-09-14
Project End
2020-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
2
Fiscal Year
2016
Total Cost
$446,508
Indirect Cost
$104,354
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Coca, Steven G (2018) ""Scanning"" into the Future: The Promise of SOMAScan Technology for Kidney Disease. Kidney Int Rep 3:1020-1022
Chauhan, Kinsuk; Verghese, Divya Anna; Rao, Veena et al. (2018) Plasma endostatin predicts kidney outcomes in patients with type 2 diabetes. Kidney Int :
Nadkarni, Girish N; Chauhan, Kinsuk; Verghese, Divya A et al. (2018) Plasma biomarkers are associated with renal outcomes in individuals with APOL1 risk variants. Kidney Int 93:1409-1416
Nadkarni, Girish N; Ferrandino, Rocco; Chang, Alexander et al. (2017) Acute Kidney Injury in Patients on SGLT2 Inhibitors: A Propensity-Matched Analysis. Diabetes Care 40:1479-1485
Coca, Steven G; Nadkarni, Girish N; Huang, Yuan et al. (2017) Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease. J Am Soc Nephrol 28:2786-2793
Tummalapalli, Lekha; Nadkarni, Girish N; Coca, Steven G (2016) Biomarkers for predicting outcomes in chronic kidney disease. Curr Opin Nephrol Hypertens 25:480-486
Nadkarni, Girish N; Coca, Steven G (2016) Temporal Trends in AKI: Insights from Big Data. Clin J Am Soc Nephrol 11:1-3
Nadkarni, Girish N; Rao, Veena; Ismail-Beigi, Faramarz et al. (2016) Association of Urinary Biomarkers of Inflammation, Injury, and Fibrosis with Renal Function Decline: The ACCORD Trial. Clin J Am Soc Nephrol 11:1343-52