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BEACON: The Biomarker Effectiveness Analysis in Contrast Nephropathy

PI: Raghavan Murugan, MD

Co-Is: John Kellum, MD; Steven Weisbord, Paul Palevsky, Joyce Chang

Funding: R01DK106256 (Project period: 9/20/16 to 6/30/21)

The Biomarker Effectiveness Analysis in Contrast Nephropathy (BEACON)

Contrast-induced acute kidney injury (CIAKI) is a serious complication occurring in patients with chronic kidney disease undergoing angiography and is associated with adverse renal and cardiovascular outcomes. We will address two key questions that remain in high-risk patients undergoing angiography. First, early detection of CIAKI after contrast exposure is problematic because rise in serum creatinine or decline in urine output occur over several days and many cases are under-diagnosed. Second, early risk stratification for long-term adverse events is also problematic because existing risk prediction models only have a modest predictive value. Availability of a biomarker that detects subclinical CIAKI before creatinine and also aids in risk stratification will change primary and secondary prevention strategies. The FDA has recently approved two novel, highly sensitive, urinary cell cycle arrest biomarkers for early detection of AKI. We have shown that these biomarkers: tissue inhibitor of metalloproteinase (TIMP)-2 and insulin growth factor binding protein (IGFBP)7, detect AKI before serum creatinine in critically ill patients and are associated with long-term adverse outcomes. Whether these markers can be used to predict renal and cardiovascular outcomes in patients undergoing angiography is yet unknown. We have been recently funded by the Department of Veterans Affairs to conduct a multicenter, randomized, clinical trial in 7,680 high-risk patients undergoing angiography to compare the effectiveness of intravenous sodium bicarbonate with isotonic sodium chloride, and oral N- acetylcysteine with placebo, for the prevention of serious adverse outcomes associated with CIAKI. The NIDDK has funded an associated biorepository to examine known and yet-to-be identified biomarkers for CIAKI. We propose to leverage these resources to conduct an ancillary observational study entitled Biomarker Effectiveness Analysis in Contrast Nephropathy (BEACON). Using urine and plasma samples obtained before and at four hours after angiography in 2000 subjects, we will address two specific aims. Aim 1 will examine the accuracy of urinary TIMP-2, IGFBP7, and select other plasma biomarkers in predicting the composite renal outcome of death, dialysis dependence, or persistent renal injury at day 90 after contrast exposure (Aim 1a); biomarker reclassification of risk for adverse renal outcomes and develop a risk score (Aim 1b); and predicting the progression of chronic kidney disease (Aim 1c). Aim 2 will examine the accuracy of urinary TIMP-2 and IGFBP7 in predicting the composite outcome of hospitalization with acute coronary syndrome; heart failure; cerebrovascular accident; or all-cause mortality within 90 days (Aim 2a); and biomarker reclassification of risk for cardiovascular events (Aim 2b). The proposed work will advance NIDDK’s mission of early detection, risk-stratification, and prognostication of CIAKI. It will provide new scientific knowledge on using biomarkers to monitor patients undergoing angiography and will have a high impact on clinical practice, physicians, and policy makers.

Patients with chronic kidney disease undergoing various radiology procedures involving a contrast dye are at a higher risk of developing kidney and cardiac problems that are difficult to predict and treat in a timely manner. This proposed study will examine various urine and blood proteins to predict which patients will develop kidney injury and dialysis dependence, heart attacks, heart failure, strokes and death after receiving a contrast dye. This study is necessary in order to improve the health of patients with chronic kidney disease by developing effective treatments to prevent kidney injury after the use of contrast dye in common testing procedures.