24 kDa heterodimer composed of the two monomers S100A8 (10,835 Da) and S100A9 (13,242 Da) promotion of repair after AKIAKI 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 biomarker under a range of conditions. For example, urinary and plasma NGAL predicting AKI after cardiopulmonary bypass has been studied in over 1,000 adults and over 300 children. In children, urinary and plasma NGAL levels peak within 6 h, whereas SCr continues to rise for up to 48 h post insult. Higher levels of urinary NGAL are associated with both a fivefold increase in the odds of developing AKI as well as improved risk prediction for those who went on to develop severe AKI. No association was found for urinary NGAL with mild AKI (stage 1). Plasma NGAL had a weak association with mild AKI, and no association with severe AKI. The adult study yielded similar results; however, post-operative plasma NGAL levels were also shown to have an association with severe AKI. In adults, the area under the receiver operator curve (AUROC) for the detection of AKI was 0.67 for urinary NGAL, and 0.7 for plasma NGAL. In children, the AUROC was 0.71 and 0.56 respectively [35, 36]. A value of 0.72 has been derived for the prediction of AKI by urinary NGAL from meta-analysis. With regard to kinetics, a study of 196 children undergoing cardiopulmonary bypass revealed that urinary NGAL levels rose markedly within 2 h of surgery with the 2-h value correlating with clinical outcomes such as length of hospital stay and need for haemofiltration [37]. Of note, in non-cardiac surgical patients, NGAL levels were elevated post operatively only in patients who had sustained rises in SCr, or in those with irreversible injury to the kidney [37]. Although the performance of predicting AKI using NGAL is somewhat variable, it may be that the application of NGAL as part of a panel of biomarkers may aid in discrimination and under such conditions, may prove to be a reasonable and a promising tool for AKI risk prediction and diagnosis.
Interleukin 18
Interleukin 18 (IL-18) is a pro-inflammatory cytokine. Similar to NGAL, it is produced in the renal tubule cells and is detectable in urine. As observed with NGAL, several studies have demonstrated that levels of urinary IL-18 are raised at 4–6 h post CPB, significantly earlier than SCr and that IL-18 may have potential in the prediction of severity of AKI [35, 36]. However, despite early promise, several meta-analyses have derived AUCs ranging from 0.66 to 0.77 [38, 39]. In keeping with NGAL, raised levels are also known to correlate with other co-morbidities including cardiac and lung injury, and urinary tract infection [40]. This is unsurprising, given that IL-18 is a non-specific marker of infection and as such may be elevated for reasons other than AKI.
Urinary KIM-1
KIM-1 is a type 1 transmembrane glycoprotein, which may be measured at the point of care. KIM-1 expression is upregulated in response to ischaemic injury to the kidneys and may have a role in the remodelling of kidneys through signalling of apoptotic renal tubular cells and their subsequent phagocytosis [41]. While KIM-1 is a marker of renal injury, it also exhibits the ability to predict AKI. Interestingly, in a study on 123 patients, KIM-1 was found to be elevated pre-operatively in patients who subsequently developed AKI and elevated urinary KIM-1 has also been shown to be associated with a higher risk of mortality [42, 43]. Meta-analysis of 11 studies (4 of which followed patients undergoing CPB) estimated an AUROC of 0.86 for AKI prediction using KIM-1 values 2–6 h post insult. In keeping with NGAL, KIM-1 appears to perform better in infants and children rather than in adults, as data derived from an adult surgical cohort demonstrates where the derived AUROC was 0.72 [38, 44].
Liver Type Fatty Acid Binding Protein
Liver type fatty acid binding protein (L-FABP) facilitates long chain fatty acid transport and the reduction of oxidative stress. Believed to have a reno-protective role renal ischaemia reduces the reabsorption of L-FABP in the proximal tubule as evidenced by urinary L-FABP levels being strongly correlated with renal cold-ischaemic time in renal transplant surgery [35]. Similar AUROC values are quoted for L-FABP of approximately 0.72 for AKI prediction [38].
