Traditional theory posits that the core mechanism of SA-AKI is reduced renal blood flow due to systemic vasodilatation, known as the “renal ischemia hypothesis” (Figure 1). During septic shock, the systemic inflammatory response syndrome (SIRS) induces increased nitric oxide (NO) synthesis in vascular endothelial cells, leading to vasodilation, decreased blood pressure, and reduced renal perfusion pressure (RPP = mean arterial pressure - central venous pressure), subsequently triggering a decline in glomerular filtration rate (GFR) (Figure 2). Animal model evidence shows a 50%–70% reduction in renal blood flow in septic rats, negatively correlating with serum creatinine elevation (Langenberg et al., 2006a; Langenberg et al., 2006b). Clinical interventions also indicate that early fluid resuscitation combined with norepinephrine to elevate mean arterial pressure (MAP) can partially restore urine output (Hernández et al., 2019). However, recent studies have found that renal blood flow does not significantly decrease in some SA-AKI patients, and even a “hyperemic AKI” phenomenon exists, focusing attention on microcirculation dysfunction as a novel mechanism. Microcirculatory shunting manifests as uneven distribution of capillary blood flow within the kidney, with stasis in some regions while large vessel blood flow remains normal (Ospina-Tascón et al., 2020). The paradox of oxygen metabolism suggests increased renal venous oxygen saturation (RvO₂), reflecting impaired oxygen utilization rather than simple oxygen delivery deficiency (Prowle, 2014). The specific manifestation of vascular paralysis is the reduced responsiveness of renal vessels to catecholamines, potentially linked to mitochondrial reactive oxygen species (ROS) inhibiting calcium-sensitive proteins in vascular smooth muscle cells (e.g., Rho kinase) (Milich et al., 2021). The current controversy centers on whether the traditional theory can explain all SA-AKI subtypes, with hemodynamic mechanisms dominating in early stages (<6 h) and microcirculation dysfunction playing a crucial role in sustained injury, necessitating stratified analysis based on patient endotypes (Stevens et al., 2024).

Renal microvascular endothelial injury is one of the initiating factors in SA-AKI, with glycocalyx degradation as its core manifestation (Xing et al., 2023; Molema et al., 2022). The glycocalyx, a proteoglycan layer (e.g., syndecan-1, hyaluronic acid) covering the endothelial cell surface, maintains vascular permeability and anticoagulant activity (Foote et al., 2022; Tarbell and Cancel, 2016). During sepsis, matrix metalloproteinase-9 (MMP-9) and hyaluronidase (HYAL1) activity upregulates, directly cleaving the glycocalyx (Xing et al., 2023; Lin et al., 2024); TNF-α and IL-1β inhibit glycocalyx synthase (e.g., EXTL3) via the TLR4/NF-κB pathway (Lei et al., 2021; Marques et al., 2022). Glycocalyx shedding leads to a series of pathological consequences: capillary leakage results in albumin extravasation and interstitial edema compressing renal tubules (Rehm et al., 2004; Gamez et al., 2024); loss of the endothelial anticoagulant barrier activates the coagulation cascade (e.g., vWF release), exacerbating intrarenal thrombotic microangiopathy (TMA) (Kei et al., 2023; Peter et al., 2023; Medica et al., 2024); and exposed adhesion molecules (e.g., ICAM-1) promote neutrophil infiltration, amplifying inflammatory damage (Zhang W. et al., 2020). Experimental glycocalyx protectants (e.g., sucrose octasulfate, anti-HYAL1 antibodies) mitigate AKI in sepsis models but have yet to enter clinical translation (Xing et al., 2023; Zhang D. et al., 2020; Yu et al., 2019).

Pyroptosis, mediated by Gasdermin D (GSDMD), is an inflammatory programmed cell death modality playing a crucial role in SA-AKI (Wu et al., 2022). In a septic environment, pathogen-associated molecular patterns (PAMPs, e.g., LPS) bind to Toll-like receptor 4 (TLR4) on the cell surface, activating the intracellular NLRP3 inflammasome. Activated NLRP3 inflammasome promotes caspase-1 cleavage, which in turn cleaves GSDMD. The N-terminal fragment of GSDMD forms pores in the cell membrane, increasing cell permeability, leading to the release of cellular contents and promoting the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18), triggering a robust inflammatory response (Li T. et al., 2022).

Deng Y et al. further investigated the role of pyroptosis in SA-AKI. They found that GSDMD expression was significantly upregulated in tubular epithelial cells (TECs), positively correlating with AKI severity. In gene knockout mouse models, knocking out the GSDMD gene significantly improved renal function, decreased renal injury marker levels, and mitigated renal histopathological damage in sepsis-induced AKI models (Jiang et al., 2021; Deng et al., 2021). This suggests that GSDMD-mediated pyroptosis plays a key role in the onset and progression of SA-AKI, and inhibiting pyroptosis may become a potential therapeutic strategy. NETs are chromatin web structures released by neutrophils, primarily capturing and killing pathogens. However, excessive NETosis leads to tissue damage in pathological states such as sepsis. Keshari A et al. studied the toxicity of NETs components. They found that components such as histones (e.g., H3Cit) and myeloperoxidase (MPO) in NETs directly induce TEC apoptosis. These components bind to receptors on the TEC surface, activating intracellular apoptotic signaling pathways, leading to cell death (Ni et al., 2021). Some studies have focused on the role of NETs in microcirculation. They found that NETs can aggregate with platelets to form thrombi, blocking renal capillaries. This microcirculatory obstruction causes local renal ischemia, further exacerbating renal injury (Ni et al., 2021). Additionally, NETs formation activates the coagulation system, promoting microthrombosis and aggravating renal pathological damage (Wu et al., 2023).

To intervene in NETs-mediated renal injury, researchers have explored multiple potential therapeutic targets. DNase I, an enzyme that degrades DNA, can effectively degrade NETs chromatin, thereby mitigating NETs-induced renal damage (Raup-Konsavage et al., 2018; Wang H. et al., 2023). Furthermore, PAD4 inhibitors (e.g., GSK484) can also exert renal protective effects by inhibiting NETs formation (Wang B. et al., 2023; Perdomo et al., 2019). These interventions have shown promising renal protective effects in animal models, providing new avenues for future clinical treatment of SA-AKI.

Mitochondria, the energy factories of cells, play a crucial role in SA-AKI. Studies have found that renal cell mitochondrial dynamics are imbalanced during sepsis, manifesting as abnormalities in mitochondrial fusion and fission processes (Pais et al., 2024; Chen Y. et al., 2024) (Figure 3). Additionally, mitochondrial oxidative phosphorylation (OXPHOS) is inhibited, leading to energy metabolic disorders (Yu et al., 2018). Specifically, mitochondrial complex I dysfunction results in excessive superoxide production, which can activate the NLRP3 inflammasome, further exacerbating inflammation (Billingham et al., 2022). Damaged mitochondria release mitochondrial DNA (mtDNA) into the cytoplasm. As a damage-associated molecular pattern (DAMP), mtDNA can activate the type I interferon response via the cGAS-STING pathway, leading to overactivation of the immune system and exacerbating renal injury (Amador-Martínez et al., 2023).

During sepsis, renal cell metabolic processes undergo significant reprogramming. Sepsis downregulates the expression of peroxisome proliferator-activated receptor α (PPARα) (Vandewalle and Libert, 2022). PPARα is a key metabolic regulator, and its downregulation inhibits fatty acid oxidation (FAO) (Chen et al., 2022). Specifically, PPARα downregulation reduces the expression of carnitine palmitoyltransferase 1A (CPT1A), a key enzyme for fatty acids to enter mitochondria for oxidation (Dong J. et al., 2024). Therefore, downregulation of PPARα and CPT1A leads to fatty acid accumulation within cells, forming lipotoxicity and further damaging cells. Simultaneously, renal cell metabolic processes compensatorily enhance glycolysis. Studies have found that hypoxia-inducible factor-1α (HIF-1α) is activated during sepsis, promoting glucose uptake (Liu et al., 2023). However, TECs lack hexokinase 2 (HK2), rendering glucose ineffective in converting to energy, leading to insufficient ATP synthesis within cells. This imbalance in energy metabolism further exacerbates cell damage and dysfunction (Shu et al., 2024).

Based on these mechanistic studies, potential therapeutic strategies are being explored. For example, PPARα agonists (e.g., fenofibrate) can restore fatty acid oxidation, mitigate lipotoxicity, and improve cellular energy metabolic status (Hong et al., 2014; Castro et al., 2024; Tang et al., 2023)]. Additionally, mitochondrial antioxidants (e.g., SS-31) can protect mitochondrial function by scavenging reactive oxygen species (ROS) within mitochondria, mitigating oxidative stress damage (Zheng et al., 2022; Peng et al., 2021). However, despite these important research advancements, many critical questions remain to be addressed. For instance, SA-AKI mechanisms significantly differ across disease stages (early vs. sustained) and renal zones (cortex vs. medulla), posing a challenge for precision interventions targeting these spatiotemporal heterogeneities. Moreover, current animal models cannot fully mimic the complex pathological processes of human SA-AKI, limiting clinical translation of research findings. In the future, emerging technologies such as single-cell spatial transcriptomics, organoid models, and dynamic biosensing technologies are expected to reveal real-time mechanistic maps of SA-AKI, revolutionizing targeted therapies.

In summary, pyroptosis, NETs-mediated damage, mitochondrial dysfunction, and metabolic reprogramming play crucial roles in the onset and progression of SA-AKI. A deeper understanding of these mechanisms will provide a theoretical basis for developing novel therapeutic strategies, potentially improving the prognosis of SA-AKI patients.

Sublethal injury refers to TECs not fully dying but losing differentiation and repair capabilities under septic stimuli.

Recent studies on SA-AKI mechanisms have shifted from a single hemodynamic model to a multidimensional interactive network. However, several critical issues remain to be addressed.

(1) Application of Biomarkers: How to distinguish different SA-AKI endotypes (e.g., inflammation-dominant vs. metabolic disorder) using biomarkers is an urgent issue. The discovery and application of biomarkers will facilitate individualized treatment and improve treatment outcomes (Manrique-Caballero et al., 2021; Kuwabara et al., 2022).

In the future, with the development of emerging technologies such as single-cell spatial transcriptomics, organoid models, and dynamic biosensing technologies, it is expected to reveal real-time mechanistic maps of SA-AKI, providing more precise evidence for targeted therapy. These technologies will help us better understand the complex pathological processes of SA-AKI, driving innovation and development in treatment strategies.

With the in-depth exploration of the pathophysiological mechanisms underlying AKI, several novel biomarkers have been identified and introduced into clinical practice. Among them, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) exhibit the greatest potential (Szumilas et al., 2024; Goldstein, 2015).

NGAL: NGAL, a 25 kD protein primarily stored in neutrophil granules and expressed in various tissues, undergoes marked upregulation upon renal injury, detectable through urine and blood tests Sun et al. (2021). Studies have demonstrated that NGAL can indicate the onset of AKI in septic patients with higher sensitivity and specificity than serum creatinine (Sun et al., 2024).

KIM-1: KIM-1, a transmembrane glycoprotein, undergoes substantial upregulation in response to renal ischemic or toxic injury. By clearing apoptotic cellular debris and oxidized lipids within the lumen, KIM-1 mitigates renal damage (Alhilal et al., 2024). Clinical studies have closely associated changes in urine KIM-1 concentrations with the occurrence and severity of AKI (Brozat et al., 2024).

IL-18: IL-18, a pro-inflammatory cytokine, is increasingly recognized for its role in renal injury. Research has shown that urine IL-18 concentrations can significantly elevate prior to AKI onset, enabling early prediction of AKI (Zhou J. et al., 2024). Furthermore, IL-18 has proven useful in identifying severe tubular necrosis in renal transplant patients (Liu et al., 2018; Piancatelli et al., 2016).

Cystatin C, a low-molecular-weight protein produced by nuclear cells and almost exclusively filtered by the glomerulus for subsequent reabsorption and degradation (Shlipak et al., 2022; Ding et al., 2022), offers several advantages over serum creatinine:

Minimal Influence from Non-Renal Factors: Cystatin C concentrations are less affected by factors such as age, gender, and muscle mass, thus more accurately reflecting GFR (Xu X. et al., 2023; Farrington et al., 2023).

Higher Early Sensitivity: Cystatin C exhibits greater sensitivity in detecting early renal functional impairment, enabling earlier identification of renal abnormalities (Campbell et al., 2023).

With advancements in omics technology, urinary exosomal miRNAs and metabolomic profiles have emerged as research hotspots (Erdbrügger et al., 2021; McGlinchey et al., 2022). Urinary exosomal miRNAs reflect renal cellular injury status, offering potential for early diagnosis and prognostic assessment (Dong Y. J. et al., 2024; Lu et al., 2020). Metabolomic technology, by analyzing urine metabolite profiles, reveals metabolic characteristics of renal injury, providing novel insights for early AKI diagnosis and treatment (Kammer et al., 2019).

Early intervention is crucial in sepsis and septic shock management, particularly within the “golden hour” for bundle therapy (Bissell et al., 2019; Rhodes et al., 2017). Bundle therapy combines a series of proven effective treatment measures to enhance therapeutic efficacy and patient prognosis. For renal function protection, early fluid resuscitation and hemodynamic management are pivotal (Saad and Maybauer, 2017).

Rapid administration of 30 ml/kg of crystalloid for fluid resuscitation is a vital component of early intervention in septic shock patients. This measure aims to swiftly restore blood volume, maintain effective tissue perfusion and oxygenation, thereby reducing AKI risk. However, recent guidelines have downgraded this recommendation from “recommended” to “suggested,” indicating the need for individualized adjustment based on patient-specific conditions (Aston et al., 2023).

Fluid resuscitation is essential in sepsis treatment, but excessive fluid infusion may lead to interstitial edema, dilutional coagulopathy, and immune dysfunction. Consequently, the restrictive fluid resuscitation strategy has garnered attention. Studies have shown that restrictive fluid resuscitation reduces mechanical ventilation duration and improves prognosis without increasing AKI or renal replacement therapy (RRT) risk.

Differences exist between restrictive and traditional fluid resuscitation in sepsis treatment outcomes. In terms of 60-day mortality, the early goal-directed therapy (EGDT) group exhibited significantly lower mortality than the standard care group (Investigators et al., 2014), though some studies found no significant improvement in 60-day mortality in the EGDT group (Mouncey Paul et al., 2015). For 90-day mortality, the CLASSIC trial found no mortality reduction benefit with restrictive fluid resuscitation compared to standard fluid resuscitation (Plummer and Bellomo, 2022). In terms of organ support needs, the EGDT group was significantly lower than the standard care group (Investigators et al., 2014), but no significant difference was observed between the restrictive and standard fluid resuscitation groups in the CLASSIC trial (Plummer and Bellomo, 2022). For hospital stay, the EGDT group was significantly longer than the standard care group (Investigators et al., 2014), while no significant difference was found between the two groups in the CLASSIC trial (Plummer and Bellomo, 2022). In terms of vasoactive drugs and red blood cell transfusions, the EGDT group showed a significant increase in usage (Mouncey Paul et al., 2015), but no significant difference was observed between the two groups in the CLASSIC trial (Plummer and Bellomo, 2022). In terms of microcirculation and hemodynamic indicators, the restrictive fluid resuscitation strategy places greater emphasis on hemodynamic stability and microcirculation improvement (Bakker et al., 2022; Wheeler, 2015). In terms of renal replacement therapy (RRT) usage, no significant difference was observed between the two groups in the CLASSIC trial (Plummer and Bellomo, 2022). In terms of long-term survival, a multicenter trial showed significantly higher long-term survival in the restrictive fluid resuscitation group compared to the standard care group, but no significant difference was observed between the two groups in the CLASSIC trial. In terms of adverse events, the incidence of serious adverse events in the restrictive fluid resuscitation group was not significantly different from that in the standard care group.

Regarding fluid choice, balanced crystalloids (e.g., lactate Ringer’s solution or Ringer’s acetate solution) offer certain advantages over normal saline. Normal saline may induce hyperchloremic metabolic acidosis, whereas balanced crystalloids better maintain electrolyte balance and reduce renal burden. Additionally, for patients receiving substantial crystalloid resuscitation, combining albumin is recommended to enhance plasma colloid osmotic pressure and mitigate tissue edema.

In septic shock treatment, vasopressor use is crucial for maintaining blood pressure and tissue perfusion. Norepinephrine is the preferred vasopressor due to its effectiveness in increasing mean arterial pressure (MAP) with minimal impact on cardiac output. However, norepinephrine alone may insufficiently maintain adequate renal perfusion, prompting the common strategy of combining vasopressin.

The use of norepinephrine combined with low-dose vasopressin in septic shock treatment presents potential side effects. On the one hand, low-dose vasopressin may reduce the risk of renal failure, as demonstrated by the VANISH trial (Gordon et al., 2016), but other studies have indicated that it may cause renal impairment (Huang et al., 2021). On the other hand, vasopressin maintains MAP by increasing vascular resistance, which may lead to hypertension, negative effect especially in patients with hypertension or cardiovascular disease risks (Nagendran et al., 2019). Furthermore, its use may also cause adverse reactions such as myocardial ischemia and intestinal ischemia, resulting in hyponatremia, affecting the nervous system and overall health, and increasing the risk of certain adverse reactions when used in combination with corticosteroids, such as hypertension and renal impairment (Nagendran et al., 2019). Additionally, vasopressin may cause other adverse reactions such as skin necrosis and decreased platelet count (Morelli et al., 2009).

Traditional hemodynamic management primarily focuses on systemic hemodynamic parameters such as MAP and central venous pressure (CVP). However, these parameters do not fully reflect tissue and organ perfusion status. Recently, advancements in microcirculation monitoring technology have provided new means for individualized hemodynamic management.

By monitoring microcirculation, a more accurate assessment of tissue perfusion status can be achieved, enabling individualized MAP target management. For example, some patients may require a higher MAP to ensure renal perfusion, while for others, a lower MAP may be sufficient. This precision management strategy helps reduce the incidence of renal injury and improve patient prognosis.

CRRT is a vital means of treating severe AKI, but the timing of its initiation has been a controversial issue in clinical practice. Traditionally, the timing of CRRT initiation has been based on changes in serum creatinine levels and urine output. However, recent studies suggest that early initiation of CRRT may be more beneficial to patient prognosis.

The ELAIN and IDEAL-ICU trials provide new insights into the timing of CRRT initiation (Tomar et al., 2021; Gaudry et al., 2022; Zarbock et al., 2016). Both the ELAIN trial and the IDEAL-ICU trial explored the timing of initiating continuous renal replacement therapy (CRRT) in patients with AKI. The ELAIN trial enrolled 231 patients meeting KDIGO Stage 2 AKI criteria and found that early initiation of CRRT (within 8 h after diagnosis) significantly reduced 90-day all-cause mortality (39.3% vs. 54.7%, P = 0.016), improved renal function recovery rates (60.6% vs. 53.7%), and shortened hospital stay and mechanical ventilation duration (Gordon et al., 2016). However, the IDEAL-ICU trial enrolled 600 critically ill patients, including 488 with sepsis or AKI, and showed that early initiation of CRRT (within 12 h after reaching KDIGO Stage 3 AKI) was associated with higher mortality than delayed initiation (59% vs. 54%), suggesting that early initiation may pose other risks (Hellman et al., 2021; Tandukar and Palevsky, 2019). Both trials emphasize the importance of early intervention, but the results differ: the ELAIN trial supports early initiation of CRRT, while the IDEAL-ICU trial suggests that delayed initiation may be more beneficial, which may be related to patient severity and treatment strategies.

These study results have important implications for clinical practice. In patients with severe AKI, especially those meeting KDIGO Stage 2 criteria, early initiation of CRRT may be more effective (Gaudry et al., 2022; Zarbock et al., 2016); however, in patients with sepsis-associated AKI, early initiation may not always be the best choice, and individualized decisions should be made based on the patient’s specific condition (Hellman et al., 2021; Ostermann et al., 2016).

Advancements in filter membrane materials have provided new possibilities for optimizing CRRT. For example, the AN69Oxiris filter membrane exhibits excellent biocompatibility and immune adsorption capabilities, effectively removing inflammatory mediators from the blood (Zang et al., 2022; Kim et al., 2024). The application of this filter membrane material not only improves renal function but may also have a positive effect on the control of systemic inflammatory response syndrome (SIRS) (Kim et al., 2024).