Acute Kidney Injury Emerging Biomarkers for the Early Detection of Acute Kidney Injury Prasad Devarajan, MD Cincinnati Children’s Hospital Medical Center, University of Cincinnati School of Medicine


Abstract


Acute kidney injury (AKI) is a common and serious condition, the diagnosis of which depends on serum creatinine measurements. Unfortunately, creatinine is a delayed and unreliable indicator of AKI. The lack of early biomarkers has crippled our ability to translate promising experimental therapies to human AKI. Fortunately, understanding the early stress response of the kidney to acute injuries has revealed a number of potential biomarkers. The current status of the most promising of these novel AKI biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), and interleukin-18 (IL-18), is reviewed. In particular, NGAL is emerging as an excellent biomarker in the plasma and urine, for the prediction of AKI, for monitoring clinical trials in AKI, and for the prognosis of AKI in several common clinical scenarios. However, biomarker combinations may be required to improve our ability to predict AKI and its outcomes in a context-specific manner. It is vital that additional large future studies demonstrate (i) the association between biomarkers and hard clinical outcomes independent of serum creatinine concentrations, and (ii) that randomization to a treatment for AKI based on high biomarker levels results in an improvement in clinical outcomes. These should be the next challenges to overcome in order to dramatically improve the outcome of AKI.


Keywords


Acute kidney injury, acute renal failure, biomarker, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin-18, liver-type fatty acid binding protein


Disclosure: Prasad Devarajan, MD, is a co-inventor on neutrophil gelatinase-associated lipocalin (NGAL) patents. Abbott Diagnostics has signed an exclusive licensing agreement with Cincinnati Children’s Hospital for developing urine NGAL as a biomarker of acute renal failure. Biosite® Incorporated has signed an exclusive licensing agreement with Cincinnati Children’s Hospital for developing plasma NGAL as a biomarker of acute renal failure. Dr Devarajan has received honoraria for speaking assignments from Biosite® Incorporated and Abbott Diagnostics. Acknowledgement: Studies cited in this article that were performed by the author’s laboratory were supported by grants from the National Institutes of Health (NIH) (R01 DK53289, RO1 DK069749, and R21 DK070163). Received: October 17, 2010 Accepted: November 15, 2010 Citation: US Nephrology, 2010;5(2):38–44 Correspondence: Prasad Devarajan, MD, MLC 7022, 3333 Burnet Avenue, Cincinnati, OH 45229-3039. E: prasad.devarajan@cchmc.org


Support: The publication of this article was funded by Abbott Diagnostics. The views and opinions expressed are those of the author and not necessarily those of Abbott Diagnostics.


Acute kidney injury (AKI, previously referred to as acute renal failure) is largely asymptomatic, and establishing the diagnosis in this increasingly common disorder currently hinges on functional biomarkers such as serial serum creatinine measurements. Unfortunately, serum creatinine is a delayed and unreliable indicator of AKI for a variety of reasons.1–4 First, serum creatinine is influenced by several non-renal factors such as age, gender, muscle mass, muscle metabolism, medications, nutrition status, tubular secretion, and especially hydration status. A deceptive reduction in serum creatinine is a common observation in critically ill subjects and in the post-operative state due to early fluid resuscitation. Second, a number of acute and chronic kidney conditions can exist with no increase in serum creatinine due to the concept of renal reserve; it is estimated that >50% of kidney function must be lost before serum creatinine rises. Third, serum creatinine concentrations do not reflect the true decrease in glomerular filtration rate in the acute


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setting, since several hours to days must elapse before a new equilibrium between the presumably steady state production and the decreased excretion of creatinine is established. This is further confounded by the observation that sepsis (which is the most common cause of AKI in hospitalized patients) is associated with a reduction in creatinine generation and therefore a falsely low serum creatinine concentration. Fourth, an increase in serum creatinine represents a late indication of a functional change in glomerular filtration rate, which lags behind important structural changes that occur in the kidney during the early damage stage of AKI. Indeed, animal studies have identified several interventions that can prevent and/or treat AKI if instituted early in the disease course, well before the serum creatinine begins to rise.2 The lack of early biomarkers has hampered our ability to translate these promising therapies to human AKI. Also lacking are reliable methods to assess the efficacy of protective or therapeutic interventions, and early


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