**3. Pathophysiology of Sepsis-Induced Acute Kidney Injury**

Sepsis is generally characterized as a life-threatening condition induced by any type of infection (e.g., bacterial, viral, mycotic) and the dysregulated response of the host organism, with subsequent organ and tissue dysfunction or failure. The diagnosis has recently been redefined according to the SEPSIS-3 consensus (The Third International Consensus Definitions for Sepsis and Septic Shock) as an increase in the SOFA (Sequential Organ Failure Assessment) score of 2 points or more. For earlier clinical decision-making, the Quick SOFA (qSOFA) criteria can be used as evaluation of: altered mental status, a respiratory rate of 22/min or greater and a systolic blood pressure of 100 mmHg or less [5]. The pathophysiology of sepsis-induced AKI appears to be multifactorial, including, among others, deleterious inflammatory cascade [6]. Underlying explanations of septic AKI development include: (1) alteration of the renal macro- and microcirculation, with subsequent endothelial dysfunction, (2) damage of renal tubular epithelial cells, (3) a change in cellular metabolic pathways and energy consumption, (4) mitochondrial injury, (5) reactive oxygen species (ROS) production and (6) cycle cell arrest [7]. However, the exact mechanism of septic AKI is still unclear. Increase in inflammatory cytokine production and activation of leukocyte activity in the context of a dysregulated immunological and inflammatory response can lead to production of intravascular microthrombi and also reduce intrarenal blood flow and oxygen delivery [8]. Regulation of the immune and adaptive immunity response in renal tubular cells occurs due to activation of the Toll-like receptor (TLRs) family in the cell membrane. There are more than 13 members of this family and they are usually activated by endotoxins. They recognize pathogen-activated molecular patterns (PAMPs) and damage-associated pathogens (DAMPs) with the promotion of leukocyte and intrinsic renal cell activation. Renal tubular cells express TLR-1, -2, -3, -4 and -6, which can be substantially involved in the pathophysiology of tubular cell damage [9,10]. The most important receptor in septic AKI pathophysiology appears to be TLR-4, that can bind the endotoxin lipopolysaccharide (LPS), leading to activation of a number of intracellular

signaling pathways via the nuclear-κB (NF-κB) transcription factor. NF-κB response to endotoxin stress leads to activation and release of the inflammatory cytokines TNFα, IL-1, IL-6 and IL-8 [11]. The activation of NF-κB depends on the phosphorylation and degradation of inhibitory κB proteins, triggered by specific kinases [9]. The basic explanation of the pathophysiological pathway in septic AKI development via activation of TLR-4 receptors in proximal tubular cells very likely lies in dysregulation of tubular integrity, with induction of tight junction disruption. This process may contribute to subsequent oliguria and decrease in renal function [12]. A recent animal study (Nakano et al., 2020), where conditional knockout of TLR-4 in proximal tubular cells reduced LPS-induced paracellular leakage of filtrate into the interstitium via TLR-4 showed that the interstitial leakage and accumulation of extracellular fluids lead to anuria and diminished the efficacy of volume resuscitation, which is frequently used in septic AKI to restore renal function [13].
