Sepsis-Associated Acute Kidney Injury: What's New Regarding Its Diagnostics and Therapeutics?

Abstract

Sepsis-associated acute kidney injury (SA-AKI) is defined as the development of AKI in the context of a potentially life-threatening organ dysfunction attributed to an abnormal immune response to infection. SA-AKI has been associated with increased mortality when compared to sepsis or AKI alone. Therefore, its early recognition is of the utmost importance in terms of its morbidity and mortality rates. The aim of this review is to shed light on the pathophysiological pathways implicated in SA-AKI as well as its diagnostics and therapeutics. In this review, we will elucidate upon serum and urinary biomarkers, such as creatinine, cystatin, neutrophil gelatinase-associated lipocalin (NGAL), proenkephalin A 119-159, interleukin-6, interleukin-8 and interleukin-18, soluble toll-like receptor 2 (sTLR2), chemokine ligand 2 (CCL2) and chemokine C-C-motif 14 (CCL14). In addition, the role of RNA omics as well as machine learning programs for the timely diagnosis of SA-AKI will be further discussed. Moreover, regarding SA-AKI treatment, we will elaborate upon potential therapeutic agents that are being studied, based on the pathophysiology of SA-AKI, in humans and in animal models.

Keywords: RNA omics; diagnostics; human recombinant alkaline phosphatase; pathophysiology; sepsis-associated acute kidney injury; therapeutics.

Figure 1

(a). The vital role of inflammation in the development of SA-AKI. The activation of TLRs on kidney TECs by MAMPs or DAMPs triggers the production of cytokines, chemokines, and ROS, initiating a systemic inflammatory response. This culminates in a cytokine storm, which promotes renal injury through the action of pro-inflammatory mediators such as IL-6, IL-8, and TNF-α, ultimately contributing to SA-AKI. Inflammation also influences metabolic reprogramming, driving a shift towards glycolysis, enhances cell death pathways such as apoptosis, necroptosis, and pyroptosis, and disrupts hemodynamic stability, including alterations in renal blood flow and microvascular function, which together exacerbate kidney injury [6,7,8,9,10,11]. Abbreviations: CCL-2: Chemokine C-C motif ligand 2; DAMPs: Damage-Associated Molecular Patterns; IL: Interleukin; MAMPs: Microbial-Associated Molecular Patterns; ROS: Reactive Oxygen Species; SA-AKI: Sepsis-Associated Acute Kidney Injury; TECs: Tubular Epithelial Cells; TLR: Toll-Like Receptor; TNF-α: Tumor Necrosis Factor-alpha. Created in BioRender. Kounatidis, D. (2024) https://BioRender.com/o88k763 (accessed on 8 December 2024). (b). Metabolic reprogramming, cell death, and hemodynamic alterations during SA-AKI. During sepsis, inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β) are produced in response to infection and alter cellular metabolic pathways in immune cells and renal TECs. This inflammatory milieu induces a metabolic shift from OXPHOS to aerobic glycolysis, a process known as the Warburg effect, which supports rapid energy production in response to cellular stress. Activated immune cells, such as M1 macrophages and Th17 cells, heavily rely on aerobic glycolysis to meet the high energy demands of cytokine production and other immune functions. Glycolysis also promotes the production of ROS, which amplifies inflammation. TECs, which normally depend on mitochondrial OXPHOS for ATP production, experience mitochondrial dysfunction during inflammation. This dysfunction induces a metabolic switch to glycolysis to conserve energy under hypoxic and inflamed conditions. However, this shift leads to reduced ATP production, impairing cellular processes and repair mechanisms, ultimately resulting in TEC injury and death. While initially protective, prolonged metabolic reprogramming contributes to energy deficits and impaired repair, culminating in cell death, such as apoptosis and ferroptosis. Additionally, persistent inflammation and platelet activation cause macrovascular and microvascular alterations, including impaired renal blood flow and microthrombi formation, which exacerbate ischemia and worsen SA-AKI [10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34]. Abbreviations: ATP: Adenosine Triphosphate; IL: Interleukin; OXPHOS: Oxidative Phosphorylation; PLTs: Platelets; ROS: Reactive Oxygen Species; SA-AKI: Sepsis-Associated Acute Kidney Injury; TECs: Tubular Epithelial Cells; Th17: T helper 17; TNF-α: Tumor Necrosis Factor-alpha. Created in BioRender. Kounatidis, D. (2024) https://BioRender.com/i25a010 (accessed on 8 December 2024).

Figure 2

Emerging therapeutic interventions in SA-AKI: This figure depicts the mechanisms of action for four therapeutic agents in the context of SA-AKI. Recombinant ALP reduces the toxicity of LPS by dephosphorylation, thereby mitigating pro-inflammatory pathways. DLT, a herbal mixture, demonstrates anti-inflammatory and antioxidant effects, primarily through the inhibition of the PARP1/HMGB1 pathway. Similarly, epalrestat exerts anti-inflammatory effects by targeting the PKC/NF-κB pathway through AKR1B1 inhibition, leading to decreased IL-6 and TNF-α levels. Lastly, melittin enhances GPX4 expression via NRF2 nuclear translocation, diminishing ferroptosis, and oxidative stress [87,93,97,98]. Abbreviations: AKR1B1: Aldose Reductase; ALP: Alkaline Phosphatase; DLT: Danlou Tablet; GPX4: Glutathione Peroxidase 4; HMGB1: High-Mobility Group Box 1; IL-6: Interleukin-6; LPS: Lipopolysaccharide; NF-κB: Nuclear Factor kappa-light-chain-enhancer of Activated B cells; NRF2: Nuclear Factor Erythroid 2-Related Factor 2; PARP1: Poly (ADP-ribose) Polymerase 1; PKC: Protein Kinase C; ROS: Reactive Oxygen Species; SI-AKI: Sepsis-Associated Acute Kidney Injury; TNF-α: Tumor Necrosis Factor-alpha. Created in BioRender. Kounatidis, D. (2024) https://BioRender.com/e41h240 (accessed on 8 December 2024).