**8. Gentamicin-Induced Nephrotoxicity Pathophysiology and Biomarkers**

Gentamicin is an aminoglycoside concentration-dependent antibiotic agent with bactericidal effects against Gram-negative bacterial pathogens e.g., *Escherichia coli*, *Pseudomonas aeruginosa*, *Proteus* and *Klebsiella*. Renal elimination by glomerular filtration is the predominant type of removal of unchanged gentamicin from the human organism. Gentamicin enters to some extent the proximal tubular cells, where it is accumulated in the lysosomes with alteration of their enzymes [48]. The gentamicin volume of distribution is, approximately, an equivalent to the extracellular body weight, and it generally decreases with age. The gentamicin elimination half-life in adults with physiological renal function is very short and ranges between 2 and 3 h [49]. The incidence of acute renal failure during gentamicin treatment can account for approximately 10–20% of all cases [50]. The nephrotoxicity of gentamicin is a very complex pathophysiological process with both tubular and glomerular involvement (Figure 1). Besides the cellular uptake in proximal convoluted cells and acute tubular necrosis, it can induce mesangial cell contraction and proliferation mediated by platelet-activating factor and also an increase in free intracellular calcium concentration. Moreover, it can induce activation of the phospholipase A2 enzyme and increased production of eicosanoids in mesangial cells, production of ROS and mesangial cell apoptosis [51]. For early detection of progression from minimal to moderate kidney injury in animals treated by gentamicin, the urinary biomarkers clusterin, KIM-1, Cystatin C and NGAL were compared to serum BUN and creatinine. As predictable, all of these biomarkers showed earlier onset changes than the generally used serum BUN and creatinine in AKI diagnosis [52]. Another explanation of gentamicin nephrotoxicity is experimental evaluation of toxicity biomarkers through specific gene expression associated with apoptosis or cell necrosis. Of 10 analyzed genes associated with apoptosis, in four, *TP53*, *CASP3*, *CASP8* and *CASP9*, an increase in expression was found. In addition, the regulation of these genes produced proteins capable of cleaving specific substrates leading to cell death. Moreover, a decrease in antiapoptotic genes e.g., *BCL2L1* has been found [53]. In an experimental study carried out on drug-induced, predominantly tubular (gentamicin and cisplatine) and glomerular (puromycin and doxorubicin) kidney injury, among several commonly downregulated miRNAs, *miR-143-3p* and *miR-122-5p* were proposed as potential tubular and *miR-3473* as glomerular biomarker candidates [54].

**Figure 1.** Simplified pathophysiology of acute kidney injury development in sepsis and selected antibiotic treatment [6,10,42,47,48,51,55,56]. DNA—deoxyribonucleic acid, ICAM-1—intercellular adhesion molecule-1, IKK—I-kinase, IL-6—interleukin 6, IL-8—interleukin 8, *MBD2*—Methyl-CpG Binding Domain Protein 2, MCP-1—monocyte chemoattractant protein 1, NF-κB—nuclear factor—kappa B, PTC—proximal tubular cells, ROS—reactive oxygen species, TLR4—Toll-like receptor 4, TNFα—tumor necrosis factor alpha
