Neutrophil gelatinase-associated lipocalin (NGAL), also known as lipocalin-2 (LCN-2), is a 25-kDa polypeptide that plays an important role in the innate immune response to bacterial infection1). NGAL was first reported as an early biomarker for ischemic renal injury after cardiac surgery in children2). Mishra et al. reported that NGAL was an excellent predictor of AKI after cardiac surgery2). NGAL seems to be an important marker in the kidney after ischemic or nephrotoxic injury, and can be detected in the blood and urine of humans soon after renal injury3,4). Several studies have confirmed these findings in patients with worsening renal function secondary to cardiopulmonary bypass (CPB) surgery, coronary angiography, or acute heart failure5-8). NGAL expression is significantly increased in the plasma and/or urine of these patients compared to patients with stable renal function. In a study of 119 patients admitted with acute heart failure, elevated plasma NGAL at time of admission predicted the development of type 1 CRS6). Above a cutoff value of 170 ng/mL, NGAL was associated with development of type 1 CRS within 48 to 72 hours with a sensitivity of 100% and a specificity of 86.7%6). Renal injury is also common in patients with chronic heart failure. In chronic heart failure patients, both urine and serum NGAL levels were found to correlate with renal function9). Furthermore, it was reported that both serum and urine NGAL levels correlated with various markers of renal function, such as serum creatinine, cystatin C, and albuminuria9,10). Therefore, it has been speculated that NGAL may be a potential indicator of kidney injury in CRS.

Kidney injury molecule-1 (KIM-1) is a transmembrane glycoprotein with an immunoglobulin and mucin domain. The proximal tubule is sensitive to ischemic injury. KIM-1 is markedly induced in response to renal injury and is expressed on the proximal tubule apical membrane. A number of studies have demonstrated KIM-1 to be a marker of AKI occurring after CPB surgery and cardiac catheterization8,11,12). Urinary KIM-1 was also associated with increased risk of death or hospitalization, independent of GFR in patients with chronic heart failure13).

Cystatin C (CysC) has a low molecular weight (13.3 kDa), and it is an endogenous cysteine proteinase inhibitor produced by nucleated cells at a constant rate. It is filtered by glomerular filtration, reabsorbed and catabolyzed by renal tubules, and not secreted in the urine except after tubular injury. If renal function and glomerular filtration rate (GFR) decrease, the blood levels of CysC rise. It has been proposed that serum levels of CysC are a more precise and better early marker of renal function than serum creatinine levels. Several studies of biomarkers in cardiac surgery patients have shown that urine CysC at various time points was able to predict AKI14). Plasma CysC levels were significantly higher at various times after CPB surgery among patients who developed AKI compared to those who did not. Furthermore, CysC showed superior diagnostic accuracy for detecting declining GFR compared with serum creatinine in patients after CPB surgery15). Changes in CysC levels also have been investigated in recent studies to assess contrast-induced nephropathy7). It has been shown that the plasma level of CysC was a strong and independent marker of CRS and mortality in acute heart failure patients16). In patients with chronic systolic heart failure, plasma CysC levels were directly correlated with ventricular dysfunction and were suggested as a prognostic factor17).

The enzyme N-acetyl-β-D-glucosaminidase (NAG) is a lysosomal brush border enzyme found predominantly in proximal tubular cells. It has a large molecular weight (>130 kDa) and is therefore not filtered by glomerular filtration. Urinary NAG has been shown to be a marker of kidney injury, particularly tubular damage, in patients with nephrotoxicity such as that due to radiocontrast media, environmental toxins, and ischemia18,19). It was reported that urinary NAG is increased in postoperative AKI patients with cardiac surgery but not in stable renal function11). Similar to KIM-1, NAG was also associated with increased risk of death or hospitalization in chronic heart failure13).

Interleukin-18 (IL-18) is an 18-kDa pro-inflammatory cytokine originating from proximal tubular cells and is detected in the urine after acute proximal tubular damage. In patients with kidney transplantation, the urine level of IL-18 has been studied as a biomarker for delayed graft function20). However, IL-18 has shown inconsistent results in prediction of postoperative AKI in cardiac surgery patients11,21).

It is possible that a combination of promising biomarkers such as NGAL, KIM-1, and CysC could be applied for the early detection of postoperative AKI in CRS. It was reported that using combined biomarkers (KIM-1, NAG, and NGAL) for early detection of postoperative AKI enhanced the sensitivity compared to using single biomarkers8). Fig. 122) shows representative curves of the predicted time course in the use of combined biomarkers for the detection of AKI in CRS patients. However, the translational process of how to combine the biomarkers and apply the knowledge gained from them in the clinical field remains an obstacle.

Three different natriuretic peptides (NPs) have been identified: atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and N-terminal fragment proBNP (NT-proBNP). The main stimulus for secretion of BNP and NT-proBNP is increased left ventricular (LV) wall stress caused by volume expansion, such as with heart failure.

NPs were found to be increased in patients with renal dysfunction and were correlated with renal function23). Despite these findings, a recent study showed that NPs had a high predictive value for volume expansion and cardiac events in dialysis patients24,25). However, the best predictive cut-off values for BNP or NT-proBNP were much higher than those measured in the general population. NT-proBNP levels are more stable than BNP levels because of their longer half-life. No studies have compared the diagnostic accuracy of BNP and NT-proBNP in patients with renal dysfunction, but both BNP and NT-proBNP have been shown to have similar predictive values for LV hypertrophy and coronary disease in predialysis patients with chronic kidney disease (CKD)26). In a study of hemodialysis patients, NT-proBNP was significantly predictive of mortality, and this relationship to mortality was higher with NT-pro-BNP than with other biomarkers27).

NPs also have prognostic potential in CKD patients without clinical signs of heart disease. Carr SJ et al. demonstrated that the plasma BNP level predicted the overall mortality and cardiovascular events in patients with predialysis CKD without clinical signs of heart failure28). A recent study also indicated that NT-proBNP was a more powerful predictor for mortality and cardiovascular death in asymptomatic dialysis patients compared with cardiac troponin T (cTnT)29).

These NPs may provide objective clinical guidance in CKD patients and thus may improve the cardiovascular outcomes of CKD patients. Several studies have suggested that NT-proBNP- or BNP-guided treatment reduced cardiovascular events and heart failure-related deaths in patients with heart failure30,31).

Cardiac troponins (cTn) such as cTnT and troponin I (cTnI) are present in the heart muscle and are released into the circulation upon myocardial injury. cTn is frequently increased in CKD patients despite the absence of myocardial ischemia. This elevation in expression is caused by impaired renal function, which delays clearance, combined with the fact that CKD patients already have the possibility of occult subclinical myocardial injury during uremia. cTnT levels are more frequently increased compared with cTnI in patients with end stage renal disease (ESRD)32). Despite this controversy, cTn still plays an important role in the prediction of cardiac event in patients with renal dysfunction. Recent clinical data reported that elevated cTnT was a powerful predictor of poor prognosis regardless of renal function33). Elevated cTnT is also linked to LV hypertrophy and systolic dysfunction in ESRD patients34). The significance of cTnI levels remains ambiguous, because of the lack of standardization of the assay for this protein. Only limited and inconclusive data has suggested a predictive value of cTnI for mortality in patients with ESRD, whereas it is recommended to use cTnT as a prognostic factor and for mortality stratification in ESRD35). Additionally, cTnT had a more powerful value for prognostication of cardiovascular outcome beyond the standard clinical and biochemical markers in ESRD. Furthermore, the predictive value of cTnT for mortality and cardiovascular outcomes was independent of inflammation and renal function.

There is also evidence supporting important roles for proinflammatory cytokines in heart failure. The overproduction and release of pro-inflammatory cytokines, particularly tumor necrosis factor-alpha, IL-1, and IL-6, showed potential as a marker of myocardial cell injury. Asymmetric dimethylarginine and myeloperoxidase are also promising markers whose expression levels have been demonstrated to correlate with cardiac outcome in CRS.