Furthermore, in the critically ill, low SCr may be observed related to reduced muscle bulk, liver disease, poor nutritional status and also augmented renal clearance. Comparing creatinine measurements obtained from different laboratories may confound the diagnosis further. Perhaps the most important limitation regarding the SCr as a marker of AKI is the creatinine kinetics associated with acute dysfunction with 24–36 h needed to elapse after a definite renal insult before a rise in SCr is detectable in many cases [27, 28]. It follows that any attempts to either prevent AKI in patient populations or indeed identify patients at risk are thwarted by the fact that the variables used to define AKI, creatinine and urine output, are such imprecise tools. Hence, there has been much interest in the pursuit of a quantifiable indicator that will allow for the early detection of AKI. Understandably this has been earmarked as an area of considerable research interest driven, in part, by the clinical models of care based on other biomarkers with cardiac troponins being the best known examples.
AKI Biomarkers
Twenty years ago, an NIH study group defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [29]. Therefore, biomarkers may inform as to the underlying aetiology of a condition as well as the probable response to therapy. Hence, they may be diagnostic and/or prognostic. Moreover, they may provide information as to the long-term outcome associated with the condition. Despite its limitations, SCr may be used as an example of a biomarker, as this will indicate a reduction in glomerular filtration rate, given it is a marker of filtration, which may be associated with an AKI and will also provide information with regard to the development and monitoring of CKD. However, extensive interest in biomarkers, particularly the so-called novel or molecular biomarkers with special focus on AKI, has been around early recognition of AKI, given the inherent flaws in employing standard measures as markers of acute injury. Therefore a strategy, whereby patients are identified early, may allow specific actions to be taken to attenuate the AKI process, although till date a considerable evidence gap exists with regard to such potential interventions.
As of now, there have been numerous studies on many different potential biomarkers of renal dysfunction under many different conditions. Some of the more intensely studied are outlined in Table 1. The predominant feature is that the best performing biomarkers tend to be markers of urinary infection and range from markers of “renal stress” (e.g., tissue Inhibitor of metalloproteinase-2 [TIMP-2]; insulin-like growth factor binding protein-7 [IGFBP-7]) to those of tubular damage (e.g., Kidney Injury Molecule [KIM-1]). Most studies on biomarkers of AKI have concentrated on the ability of the biomarker to predict the development of AKI. By definition this must be prediction of changes either in SCr and/or in urine output. Therefore, the imperfect tests for AKI are used as the gold-standard for the assessment of AKI biomarkers and this reliance on SCr and urine output detracts from any other information that these candidate molecules may be delivering. Furthermore, the kinetic profile of the biomarker may be entirely different when compared to the kinetics of SCr post insult and therefore, a biomarker may be elevated in the hours after an insult but probably will be undetectable by the time the SCr has risen. This is outlined graphically in Figure 1. For this reason, several studies have addressed the use of AKI biomarkers in the postoperative period. Here there is a timed insult and also the possibility to measure pre-insult markers in order to detect a rise.
Table 1. Summary of biomarkers for renal dysfunction
| Biomarker | Characteristics | Considerations |
| NGAL | A 25-kDa protein of the family of lipocalins with its capacity to bind iron-siderophore complexes (bacteriostatic function) | May be elevated in sepsis, chronic kidney disease and urinary tract infections Lack of specific cut-off values |
| IL-18 | A 24 kDa cytokine from the IL-1 family of cytokines (regulates innate and adaptive immunity) | No certain prediction of AKI in adults |
| L-FABP | A 14 kDa protein from the large superfamily of lipid binding proteins (aids the regulation of fatty acids uptake and the intracellular transport) | Strongly associated with anaemia in non-diabetic patients |
| KIM-1 | A 38.7 kDa type I transmembrane glycoprotein with an extracellular immunoglobulin-like domain topping a long mucin-like domain (tubular regeneration; mediates the phagocytosis of apoptotic cells) | May be elevated in the setting of chronic proteinuria and inflammatory diseases High cost and poor availability |
| IGFBP-7TIMP-2 | A 29-kDa secreted protein known to bind to and inhibit signalling through IGF-1 receptors (involved in G1 cell cycle arrest)A 21 kDa protein, endogenous inhibitors of metalloproteinase activities | May be elevated in diabetes |
| Calprotectin | A 24 kDa heterodimer composed of the two monomers S100A8 (10,835 Da) and S100A9 (13,242 Da) promotion of repair after AKI | May be elevated in urinary tract infections, rheumatoid arthritis, inflammatory bowel disease, myocardial infarction and urothelial cancer |
| Urine AGT | A 453-amino acid long protein with 10 N-terminal amino acids (renal RAS activation may contribute to pathogenesis of AKI) | Need validation in other clinical settings May be considered as prognostic biomarker The data as a diagnostic biomarker is limited |
| Urine micro RNA | Endogenous, non-coding and small (18–22 nucleotides) RNA molecules; miR-210 levels, a micro RNA upregulated by hypoxia inducible factor; miR-21 controlled necrosis and apoptosis of renal TECs and promoted cellular proliferation in response to renal ischaemia-reperfusion injury | Need validation in appropriate clinical settings |
AKI Biomarkers in the Surgical Patient
Major surgery is a recognised risk factor for AKI due to a combination of potential renal insults including relative hypotension and hypovolaemia, sepsis, the use of nephrotoxic agents, blood or blood product transfusion and reperfusion injury [30–33]. As alluded to, much of the surgical literature has focused on the verification of AKI biomarkers as a method of identifying AKI in a timely manner in these high-risk patients. However, several common themes regarding limitations in the discovery and validation of novel biomarkers for renal injury exist within this body of evidence. First, much of the initial data was described in children. The reasoning for this is that levels of some biomarkers can be significantly affected by comorbidities, hence, the use of this population may limit the effects of such confounders [34]. Second, the majority of studies address patients undergoing cardiopulmonary bypass. Third, the timings and methods of measurements vary considerably between trials including a wide range in cut-off values used to determine a “positive result.” To date many different candidate molecules have been explored, some of which are highlighted below.
Fig. 1. Hypothetical profile of acute kidney injury (AKI) Biomarkers following injury. Biomarker A rises acutely following injury but also decays rapidly so much so that it may fall below the threshold for diagnosis of AKI before conventional markers have started to rise. This may reflect renal stress. Biomarker B may be indicative of renal damage and as such has a slower onset but remains elevated above the diagnostic threshold. The theoretical profile of serum creatinine (SCr) is also shown, which may not attain diagnostic significance.
Neutrophil Gelatinase-Associated Lipocalin
Neutrophil gelatinase-associated lipocalin (NGAL) has been extensively examined as a renal injury