**4. Biomarkers**

The reduction in glomerular filtration rate (GFR) is the main abnormality which is responsible for the clinical picture of AKI. Since serum creatinine level (SCr) is negatively correlated with GFR value, SCr level has been used worldwide as a marker to estimate renal function for years. But it is understood now that creatinine may not be appropriate marker for couple of reasons to measure the GFR in AKI. Addition to tubular secretion; there are some factors which effect serum creatinine concentration for example; age, sex, muscle mass, metabolism of creatinine, and volume status. Therefore the measurement of SCr level only has very limited utility to evaluate total kidney function. It was understood that serum creatinine value is neither perfectly sensitive nor specific as a biomarker to determine GFR value. However Cystatin C was reported recently as the best alternative to SCr as an endogenous GFR marker and also it is able to predict AKI 1-2 days earlier than SCr. Cystatin C is a low molecular weight protein produced by all nucleated cells that is freely filtered by the glomerulus and then reabsorbed and metabolized by the proximal tubule (Herget-Rosenthal, 2005). Serum levels of Cystatin C are dependent not only on clearance but also on production rate and acute changes in volume of distribution. Higher dose of corticosteroid and hyperthyroidism may increase serum Cystatin C level and it may be decreased by hypothyroidism.

However, tubular cell injury may precede but not always lead to a reduction of GFR. The relationship between functional and structural changes in the kidney is inconsistent. For instance, in sepsis, changes in kidney function might be severe but in contrast histological

with sepsis it might bring more risk for ARF and also to increase the mortality rate

A similar study was designed previously for the Turkish ICU population of two tertiary hospitals, and RIFLE criteria were used for the definition of AKI (Yegenaga, 2010). In this Turkish ICU population, AKI incidence was 56,8% including Risk of RIFLE, and mortality rate was 65% in AKI and and it was found 35% in non AKI group. In this study it was observed that mortality rate was correlated well with the severity of RIFLE criteria; in the risk group 56%, in injury 68%, and in failure it was found as 72%. Multivariate logistic regression revealed that unlike the previous study age and serum bilirubin level were not significant anymore, but SOFA score (OR: 1.49, CI:1.085-2.205, p=0.045), baseline serum creatinine level (OR: 1.87,CI:1.391-2.520, p<0.001), and every 1 liter of extra positive fluid balance (OR: 1.56, CI:1.029-2.373, p=0.036) were independent risk factors for AKI. This study also brought up the importance of fluid overload in critically ill patients with sepsis; despite more vasopressor use and more fluid resuscitation, kidney damage starts very early and that is difficult to reverse. Previously in this particular population fluid loading was known as early intervention, but based on the observation in this and in some other recent reports fluid therapy should be performed cautiously. It is claimed that fluid overload may increase intra-abdominal pressure, leading to abdominal compartment syndrome, which has been recently recognized as an important cause of AKI in critically ill patients (Schrier, 2004). Furthermore fluid overload has been demonstrated to cause other organ failure in addition to kidney in ICU patients (Malbraina, 2005); for example impairment of cardiac function,

The reduction in glomerular filtration rate (GFR) is the main abnormality which is responsible for the clinical picture of AKI. Since serum creatinine level (SCr) is negatively correlated with GFR value, SCr level has been used worldwide as a marker to estimate renal function for years. But it is understood now that creatinine may not be appropriate marker for couple of reasons to measure the GFR in AKI. Addition to tubular secretion; there are some factors which effect serum creatinine concentration for example; age, sex, muscle mass, metabolism of creatinine, and volume status. Therefore the measurement of SCr level only has very limited utility to evaluate total kidney function. It was understood that serum creatinine value is neither perfectly sensitive nor specific as a biomarker to determine GFR value. However Cystatin C was reported recently as the best alternative to SCr as an endogenous GFR marker and also it is able to predict AKI 1-2 days earlier than SCr. Cystatin C is a low molecular weight protein produced by all nucleated cells that is freely filtered by the glomerulus and then reabsorbed and metabolized by the proximal tubule (Herget-Rosenthal, 2005). Serum levels of Cystatin C are dependent not only on clearance but also on production rate and acute changes in volume of distribution. Higher dose of corticosteroid and hyperthyroidism may increase serum Cystatin C level and it may be decreased by

However, tubular cell injury may precede but not always lead to a reduction of GFR. The relationship between functional and structural changes in the kidney is inconsistent. For instance, in sepsis, changes in kidney function might be severe but in contrast histological

(Payen, 2008).

worsens the lung injury (Essen, 2002).

**4. Biomarkers** 

hypothyroidism.

findings may not be clear. The earliest sign of ischemic or nephrotoxic AKI may not be decreasing in GFR level, therefore in this particular condition biomarkers should be able to identify tubular injury even before GFR falls and increasing in serum SCr level. Furthermore early identification of kidney injury will be critical for future developments in treatment or prevention of AKI (Cruz, 2010).

Several more biomarkers of AKI have been introduced recently, Neutrophil Gelatinase-Associated Lipocaline (NGAL) also known as Lipocalin-2 or siderocalin is one of the best studied biomarker of AKI to date. And it is rapidly up-regulated in the blood and in urine post-AKI. It was reported that; even though Cystatin C seems to be a better marker for AKI then SCr, Urine NGAL is superior to Cystatin C for earlier detection of AKI. In fact, cystatin C is mainly a marker of clearance, and its serum concentration may increase only after the GFR begins to decrease. Unlikely, NGAL which is rapidly induced in kidney tubule cells in response to ischemic injury, and its appearance in urine and serum is independent of the GFR but is highly predictive of a subsequent decline in GFR (Mishra, 2003).

Another promising biomarker is KIM-1, a type-1 transmembrane glycoprotein that is highly expressed in proximal tubule cells after ischemic and nephrotoxic injury. In a study with patient undergoing cardiac surgery, urine KIM-1 levels peaked 12 hours after injury in AKI and predicted the need for dialysis or mortality in hospitalised patients. KIM-1 seems to be more specific to ischemic and nephrotoxic kidney injury than NGAL and it is not significantly affected by chronic kidney disease or urinary tract infection (Liangos, 2007).

A pro-inflamatory cytokine IL-18 was also reported to be up-regulated and easily detected in the urine of animals with ischemic AKI. In a study, urine IL-18 levels were found markedly increased in patient with AKI but not in the patients with urinary tract infection, chronic kidney disease, nephritic syndrome, and prerenal failure. Urinary IL-18 showed sensitivty > 90% and specifity>95% for the diagnosis of AKI (Parikh, 2008). Both urine IL-18 and NGAL were found as sequential predictive biomarkers of AKI in children undergoing cardiac surgery. The patients in whom AKI developed 2-3 days after surgery, urine NGAL peaked at 25 fold within 2 hours and declined 6 hours after surgery, whereas urine IL-18 levels peaked 12 hours after surgery (Parikh, 2006).
