**4. Biomarkers of Sepsis-Induced Acute Kidney Injury**

Many potential biomarkers have been studied in recent years in the context of sepsis and septic AKI. These can be divided into: (1) standard biomarkers, (2) additional urinary and/or serum biomarkers, (3) metabolomics, (4) other experimental proteomics and (5) microRNAs (miRNAs). Generally, AKI is diagnosed by the standard use of serum creatinine concentration and urinary output, as mentioned, with additional evaluation of serum concentration of urea. In addition, we can include Neutrophile gelatinase-associated lipocalin (NGAL), Cystatin C, Kidney Injury Molecule -1 (KIM-1), Interleukin 18 (IL-18), urinary Insulin-like growth factor-binding protein-7 (IGFBP-7), urinary tissue inhibitor of metalloproteinase 2 (TIMP-2), calprotectin, urine angiotensinogen and liver fatty acid binding protein [14]. In clinical practice, especially in patients with AKI in ICUs, it is very useful to have a biomarker capable of predicting the need for RRT initiation, renal recovery or transition to chronic nephropathy. According to a meta-analysis of 63 studies comprising 15,928 critically ill patients, the best evidence was for blood NGAL and Cystatin C followed by urinary TIMP-2 and IGFBP-7 [15]. However, decision-making in the case of RRT initiation is based on a number of clinical and laboratory findings, not only biomarkers, and none of these is specific to any particular type of AKI [16]. The major limitation of biomarkers in the AKI condition lies in comparing biomarkers to serum creatinine and diuresis, the basic diagnostic tools for AKI [17].

In recent experimental animal models of septic AKI, some potential novel metabolomic biomarkers have been identified using nuclear magnetic resonance spectroscopy on urine, renal tissue and in serum. Alterations in the concentration of several metabolites have been found e.g., lactate, *N*-acetylglutamine, alanine, pyruvate, myoinositol, glutamine, valine, glucose, ascorbic acid, aminoadipic acid, *N*-acetylaspartate and betaine and these correlate with serum creatinine and NGAL [18]. Further, many heat shock proteins (HSP) families and their bioactivity are described in various kidney diseases. In ischemic, toxic or other forms of AKI, the following have been found expressed in several renal cell types (podocytes, mesangial cells, tubular cells, fibroblasts, endothelial cells, macrophages): HSP27, HSP70, HSP60, HSP47, HSP90 and HSP32 [19]. Their main role in renal cytoprotection is still under investigation. However, many of them can block the apoptotic death pathway, oxidative stress, cell proliferation and differentiation, mediation of the inflammatory response and inhibit fibrogenesis [19]. A study of 56 critically ill patients, where 17 of them suffered from AKI, revealed that urinary HSP72 levels significantly increased in the period of three days before AKI and remained elevated during AKI diagnosis [20].
