Acute kidney injury (AKI), a sudden decrease in kidney function or kidney damage within a few hours or days, occurs in up to 1 in 5 hospitalized patients, with highest frequency in the intensive care unit. AKI can lead to chronic kidney disease (CKD), kidney failure, heart disease or even death, and early detection is essential for preserving kidney tissue and improving outcomes. Unfortunately, the standard test for detecting AKI (a rise in serum creatinine) occurs after at least 33% of kidney function has already been lost. As a result, the American Society of Nephrology has identified the need for an AKI biomarker as a top priority in 2005. Their goal was to discover a biomarker for AKI with similar clinical performance characteristics to troponin for acute myocardial infarction. This unknown, ideal AKI biomarker must possess the following characteristics: predict and diagnose AKI, identify the location of injury, identify type and etiology of injury, predict outcomes, and enable initiation and monitoring of therapeutic interventions. So, the hunt for a kidney troponin began…
Over a decade later, a number of molecules have emerged as candidate biomarkers of AKI. These include neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin 18 (IL-18), tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7), among others. Numerous studies have examined the clinical utility of these biomarkers, especially in the setting of cardiac surgery patients where AKI frequency is high. However, results varied greatly and comparison among studies is complicated by several factors, including heterogeneous AKI definitions and timing of biomarker measurements. In a recent meta-analysis study “Urinary, Plasma, and Serum Biomarkers' Utility for Predicting Acute Kidney Injury Associated With Cardiac Surgery in Adults: A Meta-analysis” published by Ho et al. (2015) in the American Journal of Kidney Disease , the authors concluded that known adult urinary, plasma and serum biomarkers of AKI possess modest discrimination at best when measured within 24 hours of cardiac surgery. As a result, the hunt for the ideal AKI biomarker continues.
Of recent interest is the FDA-approved NephroCheck® test which measures IGFBP-7 and TIMP-2 and uses both to generate a risk score for developing AKI within 12 hours of testing. While initial studies have shown great potential with very promising area under the receiver operator curve (AUROC >0.75), it is important to recognize that this test incorrectly gave a positive result in about half of patients without AKI [1, 2].
Moving forward, it is essential that new studies standardize their sample collection protocols and use the same AKI definition (Kidney Disease Improving Global Outcomes being the latest ) to allow meaningful comparisons and meta-analysis. Still, the largest drawback is that all studies are being compared to creatinine as the “gold standard”. Thus, it is almost impossible to prove that a novel biomarker is better than creatinine. This is best summarized by Chirag Parikh, MD, PhD, FACP, Professor of Medicine (Nephrology) and Director of the Program of Applied Translational Research at Yale University: “There may be an excellent biomarker among the few names you have mentioned but we will never know!” (personal communication, July 2016). Dr. Parikh is also the Principal Investigator of the NIH sponsored TRIBE-AKI consortium that is conducting three large studies for validating novel kidney injury biomarkers in the setting of cardiac surgery, kidney transplantation and hepatorenal syndrome. His recommendation is that future studies incorporate kidney biopsies as the gold standard for kidney injury so that head-to-head comparisons can be performed between creatinine and these novel biomarkers. However, obtaining IRB approval to perform research-based biopsy in critically ill patients is challenging, which is one reason why these studies are lacking. Alternatively, he recommends long-term follow-up studies where the performance of these biomarkers is assessed against clinical AKI outcomes (mortality, cardiovascular disease, or CKD), which go above and beyond creatinine. So, what if we already have the ideal AKI biomarker but we just need the right study to prove it?
- Ho J, Tangri N, Komenda P, Kaushal A, Sood M, Brar R et al. Urinary, Plasma, and Serum Biomarkers' Utility for Predicting Acute Kidney Injury Associated With Cardiac Surgery in Adults: A Meta-analysis. Am J Kidney Dis 2015;66(6):993-1005.
- FDA News Release. FDA allows marketing of the first test to assess risk of developing acute kidney injury. September 5, 2014. URL: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm412910.htm. Accessed: July 22, 2016.
- KDIGO Clinical Practice Guidelines for Acute Kidney Injury. Kidney International Supplements 2012, 2:1-128.