**1. Introduction**

Acute kidney injury (AKI) is an intricate clinical syndrome defined by a sudden decrease of kidney function, the accumulation of nitrogen waste products such as urea, electrolyte, and acid-base disturbances and volume overload [1]. The incidence of such complication has been increasing in recent years, affecting 20% of adult and 33% of pediatric patients during hospital admission, especially among subjects with predisposing factors, such as advanced age, diabetes, cardiovascular disease, chronic kidney disease (CKD), or those exposed to nephrotoxins or to cardio-pulmonary bypass. Patients developing AKI have increased morbidity and worse surviving rates than those with normal renal function. In addition, it increases ICU and in-hospital stay, risk of infection, and hospitalization costs. AKI associates a pooled mortality rate of 23.9% in adults and 13.8% in children, rates that increase with higher degrees of severity [1–3].

Diagnosis of AKI should comprise several steps, including a thoughtful clinical evaluation, physical examination, consideration of alternative diagnoses, and laboratory data. An abrupt increase of serum creatinine (≥0.3 mg/dL) is still the laboratory finding most closely associated to AKI [4–6]. Creatinine is an uncharged 113 Da molecule formed in muscles from creatine, freely filtered at the glomerulus and completely eliminated through the kidney in healthy subjects [7]. Although serum creatinine fulfills most requisites of an ideal filtration marker, it is far from being perfect. In healthy

individuals approximately 15% of urinary creatinine is secreted in the proximal tubule, a percentage that can be increased in CKD patients [8]. Additionally, as a product of muscular catabolism, serum creatinine is not an adequate marker of kidney function in subjects with extremely high or low muscle mass such as the elderly or children [9]. Certain drugs (i.e., trimethoprim, cimetidine) can also interfere with tubular secretion of creatinine, producing an increase of serum creatinine levels without real kidney function loss [10,11]. Finally, there is a 48–72 h delay between actual kidney injury and the rise of serum creatinine, which limits early diagnosis and initiation of the appropriate therapeutic measures [12].

Several possible solutions have been developed to overcome this issue. Equations that estimate glomerular filtration rate (eGFR) take into account individual characteristics such as age, gender, weight, or ethnicity to better estimate renal function [13,14]. However, serum creatinine-derived eGFR equations should not be used in the AKI setting due high biases and unacceptably poor performance [15]. Moreover, GFR is not a constant parameter; it changes throughout the day and it is modified by protein consumption and other processes [16].

The development of proteomic technology has triggered extensive research in novel protein indicators that may help characterize AKI mechanisms, improve risk stratification, and facilitate clinical decision making and treatment response monitoring [17]. As a result, multiple potential markers have been discovered in recent years, such as kidney injury molecule-1 (KIM-1) [18,19], neutrophil gelatinase-associated lipocalin (NGAL) [20,21], cystatin C [22], N-acetyl-β-D-glucosaminidase (NAG) [23,24], or liver fatty-acid binding protein (L-FABP) [25,26]. However, despite intensive research effort, none of the discovered biomarkers have managed to replace serum creatinine in clinical practice. Timing of sample procurement, differences in urine concentration and flow, inconsistency among laboratory assays, or higher price are some of the barriers that routine application of novel renal biomarkers must overcome [27]. Additional validation studies that may associate biomarker levels to patient-centered clinical outcomes such as dialysis or death are needed [28].
