Originally published in the 2014 CLN Daily, the official publication of the AACC Annual Meeting & Clinical Lab Expo
What do insulin-like growth factor-binding protein (IGFBP) 7 and tissue inhibitor of metalloproteinases (TIMP)-2 have in common? Other than the fact that neither rolls off the tongue easily and that you may not have heard of them, they may become the future of assessing acute kidney injury (AKI). New biomarkers are critical in this field, as researchers continue to look to a world beyond creatinine. While creatinine remains one of the most used markers of kidney dysfunction, it is notoriously lacking as a sensitive marker of early renal damage. Creatinine can take days to increase following AKI, which may be too long to prevent irreversible kidney damage. Therefore, markers that increase quickly after renal damage occurs are key. With CDC statistics showing that more than 10% of U.S. adults have chronic kidney disease, this diagnostic area affects millions of people.
In a Mid-Day short course today at 12:30 pm titled Biomarkers of Acute Kidney Injury, Robert Fitzgerald, PhD, John Kellum, MD, and Denise Uettwiller-Geiger, PhD will review the most recent advances in this area.
Fitzgerald will emphasize the need for investigation of early markers of kidney injury. “The diagnosis of acute kidney injury currently happens only after the injury is present,” Fitzgerald said. “Identifying early biomarkers could potentially change the timeframe for diagnosis allowing clinicians to prevent injury before it becomes apparent through elevations of creatinine.” Importantly, he pointed out that “this could provide actionable data that so that patient outcomes are improved.”
Fitzgerald, Kellum and Uettwiller-Geiger were directly involved in clinical trials of IGFBP7 and TIMP-2 in urine and will share the findings of those studies. In another multi-site international validation study, the combination of both markers provided the best risk stratification in patients with moderate to severe AKI (Crit Care 2013;17:R25). “These markers are potential game changers that have solid science supporting their use,” Fitzgerald said.
During the course, the presenters will share the basic science as well as clinical trial data supporting the use of these markers to diagnose acute kidney injury. Kellum will deal with “how these and other biomarkers might be used in clinical situations,” he said. He’ll aim to answer questions such as “why have they been developed the way they have and how are they likely to change practice?”
Uettwiller-Geiger will highlight the analytical validation of these types of biomarkers, as well as the role that the laboratory plays in the diagnosis and management of AKI. Data generated during validations are especially important because they are often used to evaluate which cutoffs provide the best clinical utility.
Recent trials examining urinary IGFBP7 and TIMP-2 used the ability to predict moderate to severe AKI within 12 hours as a primary endpoint. IGFBP7 and TIMP-2 concentrations are multiplied together to determine a risk score. The researchers found that at-risk, critically ill patients with scores >0.3 (ng/mL)2/1,000 were 7 times more likely to develop AKI (Am J Respir Crit Care Med 2014;189:932-9). When variables such as illness severity and baseline kidney function were adjusted for, this increased to a 16.5-fold higher risk for AKI in patients with scores greater than the 0.3 (ng/mL)2/1,000 cutoff. This study also included an important component in the analytical validation process: blinded adjudication by experts qualified to evaluate the clinical outcomes predicted by the study.
While new biomarkers of AKI need continued study and validation in diverse patient populations, these studies appear to be a promising step in the right direction. The earlier that laboratories can alert clinicians to kidney damage, the better the opportunity for risk stratification, medical intervention, and proper triaging.