As tissue-resident immune cells, KRMs are essential for maintaining normal kidney function. These macrophages are complex, highly adaptable renal resident mononuclear phagocytes with diverse functions, which originate from the yolk sac during early embryogenesis and persist in the kidney throughout development (19,20). KRMs help maintain systemic homeostasis through various mechanisms, such as clearing cellular debris, modulating local inflammation and promoting tissue repair (21). In adult tissues, KRMs possess self-renewal capabilities with minimal input from peripheral blood, helping sustain renal homeostasis, monitor the immune microenvironment, promote angiogenesis and mitigate AKI. Following kidney injury, KRMs aid in tissue repair and regeneration (22). Additionally, KRMs can reduce renal injury by selectively inhibiting interleukin (IL)-6 production from endothelial cells through IL-1 receptor antagonist expression (23). Furthermore, KRMs regulate renal sympathetic nerve activity, influencing salt and water balance and further promoting renal function recovery (24).

In SA-AKI, monocyte recruitment is a critical pathophysiological event. This process involves multiple mechanisms that synergistically contribute to uncontrolled inflammation and exacerbated renal injury. These mechanisms include the release of chemoattractants, expression of adhesion molecules, activation of inflammatory cascades and microcirculatory dysfunction (25). During sepsis, renal tubular epithelial cells upregulate the expression of C-C motif ligand chemokine 2 (CCL2) at both the mRNA and protein levels through the combined actions of chemokine receptors CCR2 and C-X3-C motif chemokine receptor 1 (CX3CR1); this upregulation drives monocyte chemotaxis (26). Moreover, the endothelial glycocalyx, produced by vascular endothelial cells, undergoes degradation during sepsis due to inflammatory responses and oxidative stress. The glycocalyx, a critical component of the vascular endothelial barrier, when damaged, increases vascular permeability, facilitating the contact and adhesion of monocytes to endothelial cells (27). Monocytes infiltrating the kidney can differentiate into M1 or M2 macrophages, exerting pro-inflammatory or anti-inflammatory effects, respectively. Notably, a specific monocyte subset, such as Ly6Chigh monocytes, strongly adheres to the renal vascular wall in a CX3CR1-dependent manner during the early stages of sepsis. This subset plays a protective role via CX3CR1-dependent adhesion mechanisms (28).

Sepsis is primarily induced by lipopolysaccharide (LPS) released from Gram-negative bacteria. LPS binds to TLRs on renal cells, triggering the release of DAMPs (29). These molecules act as endogenous 'danger signals', recognized by receptors on macrophages, leading to their activation. This activation results in the extensive release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), IL-1β, IL-6 and the chemoattractant CCL2, initiating a cytokine storm and exacerbating renal inflammatory injury (30,31). Macrophages exhibit high plasticity and can polarize into distinct phenotypes, typically classified as M1 and M2. M1 macrophages primarily contribute to inflammation by releasing pro-inflammatory cytokines (such as TNF-α, IL-1β and IL-6) and reactive oxygen species (ROS), driving inflammation and tissue damage. By contrast, M2 macrophages are involved in tissue repair and inflammation resolution (32). Thus, modulation of macrophage polarization represents a potential strategy for alleviating renal injury in SA-AKI. Macrophage polarization is a dynamic process and excessive suppression of M1 polarization may impair pathogen clearance, hindering tissue healing. Conversely, overactivation of M2 macrophages can lead to immunosuppression, increasing infection risk (33,34). Therefore, precise regulation of the M1/M2 balance is critical to avoid adverse outcomes.

Macrophage metabolic reprogramming plays a pivotal role in SA-AKI. During sepsis, macrophages undergo significant metabolic changes to support the inflammatory response and cellular survival (35). This reprogramming involves a shift from fatty acid oxidation (FAO) to a dual reliance on glycolysis and FAO. M1 macrophages predominantly utilize aerobic glycolysis to rapidly initiate immune responses, while M2 macrophages rely on oxidative phosphorylation (OXPHOS) to exert anti-inflammatory effects and prevent tissue damage (36). In the early stages of sepsis, macrophages activate the AKT/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor-1α signaling pathway, which enhances glycolytic enzyme activity and suppresses the tricarboxylic acid (TCA) cycle, initiating glycolysis to generate ATP, supporting cell survival and pro-inflammatory responses (35). However, excessive glycolysis can induce immunosuppression, impairing host defense and immune function. This immunosuppressive state is characterized by pro-inflammatory cytokines (such as TNF-α, IL-6 and CCL2) and T-cell-recruiting chemoattractants, as well as anti-inflammatory cytokines (such as IL-4, IL-10) (37). Nevertheless, this metabolic shift can impair mitochondrial function and reduce ATP production. Limiting glycolysis can mitigate the inflammatory response (38,39). While the transition from OXPHOS to aerobic glycolysis is essential for renal survival in early sepsis, failure to restore OXPHOS in the later stages may result in persistent inflammation and renal fibrosis (35). During the late inflammatory phase, cells activate peroxisome proliferator-activated receptor-γ coactivator 1α and carnitine palmitoyltransferase 1 through mediators such as sirtuin (Sirt)6, signal transducer and activator of transcription 3 (STAT3) and sirtuin 1, promoting a metabolic shift back to OXPHOS. Restoration of OXPHOS stimulates mitochondrial biogenesis, generates ATP and exerts anti-inflammatory effects, promoting renal function recovery (35). Additionally, lactate, a key metabolite in macrophage metabolism, influences the macrophage phenotype through lactylation, further impacting disease progression (40).

Amino acid metabolism, which regulates macrophage activation, is one of the earliest metabolic alterations during macrophage polarization. Arginine, glutamine and serine metabolism play pivotal roles in this process (41). Arginine catabolism regulates macrophage activation primarily through inducible nitric oxide synthase (iNOS) and arginase 1 (Arg1). iNOS, predominantly expressed in M1 macrophages, catalyzes the synthesis of nitric oxide and L-citrulline from arginine. Nitric oxide, a ROS, helps M1 macrophages combat pathogen invasion (40-42). By contrast, Arg1, highly expressed in M2 macrophages, catalyzes the hydrolysis of arginine into urea and L-ornithine. The metabolites of L-ornithine, including polyamines and proline, influence macrophage proliferation and collagen synthesis (42-44). A distinctive feature of M2 macrophages is their increased glutamine metabolism, with one-third of the carbon in TCA cycle metabolites of M2 macrophages derived from glutamine. Glutaminolysis generates α-ketoglutarate (α-KG), which enhances M2 macrophage activation and governs metabolic reprogramming through Jmjd3-dependent regulation. Additionally, α-KG, via a prolyl hydroxylase-dependent mechanism, inhibits the NF-κB pathway, thereby limiting M1 macrophage activation and modulating IKKβ activity (45). Serine metabolism also plays a pivotal role in macrophage functional polarization. It has been shown that serine metabolism suppresses insulin-like growth factor-1 (IGF1) transcription by increasing the promoter abundance of H3K27me3 through S-adenosylmethionine. Deficiency in serine metabolism alters M1 macrophage polarization and modulates Janus kinase (JAK)/STAT1 signaling via IGF1-dependent p38 activation (46).

In conclusion, during SA-AKI, macrophage metabolic reprogramming may be a critical component of the host defense response. However, specific regulatory strategies require further investigation to precisely modulate macrophage metabolism for therapeutic purposes.

NF-κB is a dimeric transcription factor composed of five protein family members and is present in nearly all human cells (47); it plays a critical role in inflammation and immunity by regulating the expression of a broad range of chemoattractants, cytokines, transcription factors and regulatory proteins (47). The binding of LPS to its receptor, TLR4, on macrophages activates the myeloid differentiation primary response 88 (MyD88)-dependent signaling pathway. This pathway activates the IKK complex, which phosphorylates IκB proteins, leading to their ubiquitination and proteasomal degradation. Degradation of IκB releases NF-κB dimers, such as p50/RelA (p65), allowing their translocation to the nucleus (48). Within the nucleus, NF-κB binds to specific κB sites on DNA via its Rel homology domain, promoting the transcription of inflammatory genes, including TNF-α and IL-1β, thereby amplifying the inflammatory response (48). The NF-κB pathway interacts extensively with other signaling pathways. For instance, the PI3K/AKT/NF-κB signaling pathway plays a pivotal role in regulating macrophage polarization (49). Moreover, complex regulatory interactions exist between NF-κB and pathways such as the MAPK and STAT pathways.

The PI3K/AKT/mTOR signaling pathway is a critical cascade that governs various cellular processes, including growth, proliferation, survival, metabolism and migration (50). A study has shown that LPS-induced activation of TLR4 in macrophages triggers the PI3K/AKT/mTOR pathway, leading to the production of muscle-type pyruvate kinase isozyme, which then facilitates the acetylation of high mobility group box 1 (HMGB1). Acetylated HMGB1 promotes LPS uptake by macrophages and inhibits macrophage apoptosis (51). This pathway is also essential for regulating macrophage polarization towards M1 or M2 phenotypes. Androulidaki et al (52) demonstrated that AKT1 modulates macrophage polarization upon LPS stimulation. AKT1 deficiency promotes M1 polarization, while AKT2 deficiency favors M2 polarization. For instance, Aquaporin 1 has been shown to mitigate SA-AKI by promoting M2 polarization via the PI3K/AKT pathway (53,54).

The JAK/STAT pathway is a key mechanism in cell communication, enabling cells to respond to external stimuli (55); it plays a critical role in various physiological and pathological processes, including cell proliferation, metabolism, immune response and inflammation (55). During sepsis, the release of large quantities of pro-inflammatory cytokines (such as TNF-α, IL-6 and IL-1β) activates the JAK/STAT signaling pathway. Activated STAT proteins translocate to the nucleus, driving the transcription of additional inflammatory mediators, thus amplifying the inflammatory response and contributing to kidney damage (56,57). STAT inhibitors can effectively reduce inflammation by restoring the CD11blowF4/80high macrophage population, which exhibits potential anti-inflammatory properties, thus protecting the kidneys from injury (58). For example, curcumin has been demonstrated to alleviate inflammation and apoptosis by modulating the JAK2/STAT3 pathway, mitigating SA-AKI (59).

The JAK/STAT pathway also regulates immune cell function. In sepsis, this pathway influences macrophage activation and differentiation, enabling macrophages to produce inflammatory cytokines through receptor-interacting serine/threonine-protein kinase and the NLRP3 inflammasome, thus impacting the intensity and duration of the immune response (51,56). For instance, mesenchymal stem cells (MSCs) with upregulated heme oxygenase-1 expression can ameliorate SA-AKI by activating the JAK/STAT3 pathway (60). Moreover, blocking TLR4/TNF1 can promote a phenotypic shift of M1 macrophages towards the M2 phenotype by inhibiting STAT1/STAT3 expression and increasing Suppressor of cytokine signaling 3 expression (61). Acyl-CoA thioesterase 11, an IL-1β-associated gene involved in fatty acid metabolism, promotes the accumulation of fatty acids, such as eicosatetraenoic acid (EA) and stearic acid, within macrophages (62). This accumulation inhibits JAK/STAT signaling activation via palmitoylation of interferon-γ (IFN-γ) receptor 2 at the C261 site (62). Eicosatetraenoic acid has also been shown to alleviate sepsis-associated organ damage via the same pathway (62). Additionally, macrophages expressing the chemokine CCL5 activate several pathways related to immune and inflammatory responses, including IL-6/JAK/STAT3 signaling, TGF-β signaling and inflammatory responses, recruiting neutrophils and exacerbating SA-AKI (63). In summary, the JAK/STAT signaling pathway plays a complex role in the pathophysiology of SA-AKI. By regulating inflammatory responses, immune modulation and apoptosis, this pathway contributes to the initiation and progression of renal injury. Thus, targeting the JAK/STAT pathway may offer novel therapeutic strategies for SA-AKI.

Accumulative evidence suggests that the M1/M2 dichotomy does not fully encompass the complex behaviors and functions of macrophages in vivo (26,64,65). Macrophages may exhibit multiple phenotypes and even co-express both M1 and M2 markers simultaneously. For example, macrophages can display mixed M1/M2 phenotypes, which are essential for regulating the assembly and structure of the extracellular matrix (66). Additionally, M2 macrophages represent not a single phenotype but several subtypes, including M2a, M2b, M2c and M2d, each characterized by distinct surface markers, cytokine secretion profiles and immune effector functions (67,68). M2a and M2b macrophages are particularly prevalent in renal tissue. M2a macrophages, typically induced by IL-4 or IL-13, express high levels of Arg1 and the mannose receptor and are primarily involved in wound healing, fibrosis and allergic responses (67). M2b macrophages, stimulated by immune complexes or IL-1β, exhibit immunomodulatory and anti-inflammatory effects. These cells produce anti-inflammatory cytokines such as IL-10, while also secreting pro-inflammatory cytokines such as IL-1β and TNF-α, thereby participating in immune complex-mediated diseases (69). In the later stages of sepsis, promoting the M2b macrophage phenotype may help maintain immune homeostasis and facilitate tissue healing. However, the activity of M2b macrophages must be precisely regulated to prevent exacerbation of inflammation or suppression of immune responses. M2c macrophages, induced by IL-10 or TGF-β, are primarily involved in immunosuppression and tissue remodeling. They express surface markers such as CD163 and signal regulatory protein α (SIRPα) (67,68). M2d macrophages, induced by adenosine A2A receptor agonists or IL-6, play a major role in tumor angiogenesis and immunosuppression (67). Future research should focus on investigating M2 macrophage subtypes and their specific functions in SA-AKI, providing a theoretical foundation for more targeted therapies.

Fibrosis, a common pathological feature of chronic disorders, is characterized by excessive activation of myofibroblasts and abnormal deposition of extracellular matrix in tissues (70). Macrophages can directly transdifferentiate into myofibroblasts via MMT, promoting renal fibrosis (71,72). Recently, MMT has been recognized as a novel source of myofibroblasts and plays a critical role in fibrotic processes across multiple organs. The regulatory mechanisms underlying MMT remain incompletely understood, but the TGF-β1/Smad3 signaling cascade is the most extensively studied pathway (73,74). Although no direct evidence currently links MMT to SA-AKI, a study has confirmed increased expression of TGF-β R2 and phosphorylated Smad3 in the kidneys of septic mice (75). Given the critical role of the TGF-β1/Smad3 pathway in MMT, it is hypothesized that MMT may contribute to the development and progression of renal fibrosis following SA-AKI. Therapeutic strategies targeting MMT hold promise for improving the long-term prognosis of SA-AKI, although further experimental validation is needed.

Catalytic nanoparticles offer a promising alternative to conventional anti-infective therapies by modulating innate immune responses and engineering macrophages for immunotherapy, thus providing innovative treatment options for infectious diseases such as sepsis. For example, ultrasound-responsive piezoelectric catalytic nanoparticles enhance macrophage-mediated antibacterial phagocytosis and bactericidal activity through intracellular piezoelectric catalysis (76). Bone marrow-derived macrophages co-cultured with these piezoelectric nanoparticles form piezoelectric macrophages, which, upon activation via ultrasound irradiation, can be utilized in adoptive cell therapy. This approach has proven effective against immunosuppressive bacterial infections, including sepsis (76). However, challenges remain in targeting these piezoelectric nanomaterials to macrophages and kidneys, as they are typically non-degradable and considered biologically inert, necessitating further investigation into their long-term effects and biosafety. Another novel nanoparticle modulates metabolic reprogramming in macrophages to mitigate the septic cytokine storm (77). Additionally, engineered apoptotic extracellular vesicles derived from macrophages can alleviate symptoms in septic patients by clearing toxins and regulating inflammatory responses (78). Nicotinamide adenine dinucleotide (NAD⁺), an immunomodulator, shows promise for sepsis treatment. Co-incubation of LPS-activated macrophages with NAD⁺-loaded lipid nanoparticles not only reduces the production of pro-inflammatory cytokines and ROS by macrophages but also enhances their viability (79). Moreover, nanoparticles formed by coordination between Ce³⁺ and astragalin (CeAst nanoparticles), encapsulated with macrophage membranes and modified with a kidney-targeting peptide, form the CeAst@MK system. This nanoplatform enables precise kidney targeting and promotes M2 macrophage polarization (80). The CeAst@MK system exhibits excellent biocompatibility and in vivo safety, indicating notable potential for clinical translation. A novel system of mannose-conjugated, PEGylated graphene oxide nanoparticles loaded with a sesquiterpene lactone (GMO@ GO@PEG@MAN) not only targets the kidneys but also binds to macrophages and promotes the transition from M1 to M2 macrophages (81). Given the promising outcomes of these macrophage-based therapies in sepsis treatment, they hold notable potential for managing SA-AKI. Ongoing optimization of therapeutic strategies, deeper exploration of underlying mechanisms and enhanced clinical translational research are expected to improve the prognosis of patients with SA-AKI. As an emerging therapeutic approach, macrophage-based therapy shows broad potential in SA-AKI management. Through continuous refinement of treatment strategies and further investigation into its mechanisms, new avenues for improving patient outcomes in SA-AKI are anticipated.

Neutrophil metabolic reprogramming refers to the adjustment of metabolic pathways in response to physiological or pathological conditions. Typically, neutrophils utilize multiple metabolic pathways, including glycolysis (101), the pentose phosphate pathway (PPP) and FAO, to support immune functions such as chemotaxis, ROS production, neutrophil extracellular trap (NET) formation and degranulation (102). Under normal conditions, glycolysis serves as the primary energy source. However, in inflammatory or tumor microenvironments, neutrophils may shift to alternative metabolic pathways, such as FAO, to sustain effector functions. A study has shown that during sepsis, levels of glycolysis, PPP and fatty acid amide hydrolase are elevated in neutrophils (103). 2-deoxy-D-glucose alleviates excessive inflammatory responses by enhancing neutrophil recruitment, highlighting the link between metabolic regulation and infection/inflammation (104). Furthermore, during the acute phase of sepsis, the long non-coding RNA GSEC (containing a G-quadruplex sequence) is upregulated in sepsis-induced neutrophils, enhancing the transcription and translation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 mRNA, which promotes neutrophil glycolysis and the production of inflammatory cytokines such as TNF-α, IL-1β and IL-6 (35). Thus, neutrophil metabolic reprogramming in SA-AKI likely contributes to the increased release of ROS, NETs and other factors, exacerbating disease progression. This process represents an interesting area for future investigation in SA-AKI.

Additionally, NETs play a notable role in the development of SA-AKI. NETs are web-like structures composed of DNA, histones and antimicrobial proteins, released by activated neutrophils (105). The formation of NETs is regulated by the pore-forming protein gasdermin D and depends on NADPH oxidase and neutrophil elastase activity (106). NETs can suppress macrophage phagocytosis, leading to persistent inflammation and tissue damage. Inhibiting NET formation may alleviate SA-AKI by restoring the infiltration and survival of GAS6⁺ macrophages, promoting the clearance of damaged cells and the resolution of inflammation (107). However, while NETs provide a fibrous scaffold to entangle bacteria or pathogens, excessive activation of NETs can worsen inflammation and tissue injury (108). Furthermore, prolonged disturbances in the pro-/anti-inflammatory balance lead to pathogenic NET formation, which is a hallmark of systemic inflammatory response syndrome (107). NETs can exacerbate kidney damage by releasing cytokines and histones. Histones within NETs directly damage renal tubular epithelial cells (109), while the DNA component can activate the complement system (110), thereby intensifying the inflammatory response. Notably, defective NET formation has been shown to be protective in SA-AKI models (111).

Neutrophils do not remain fixed at the site of inflammation; they can exit via a process known as rTEM (112,113), in which neutrophils move back across the endothelium from the interstitial space into the bloodstream. This re-migration occurs through interactions between neutrophil surface molecules, such as β2 integrins, and corresponding ligands on vascular endothelial cells, with regulation by various cytokines and chemoattractants. rTEM plays a dual role: On the one hand, it may help reduce local inflammatory damage by decreasing neutrophil numbers in the affected tissue (114), while on the other hand, activated neutrophils re-entering the circulation can carry inflammatory mediators, releasing them into the bloodstream and potentially causing remote organ damage (115). For example, one study showed that extracellular vesicles derived from endothelial cells exacerbate remote lung injury by promoting rTEM (116). It is plausible that rTEM also contributes significantly to SA-AKI, warranting further investigation.

Additionally, neutrophil gelatinase-associated lipocalin (NGAL) is crucial in the pathogenesis and progression of SA-AKI. NGAL functions as a notable renal growth factor, facilitating the differentiation of renal progenitor cells into renal tubular epithelial cells (117). During the initial stages of AKI, NGAL is upregulated in a compensatory manner to promote tubular repair and regeneration (117). NGAL, primarily secreted by neutrophils, is also produced by endothelial cells upon stimulation by TNF-α, LPS and IL-1β (118). After the kidney sustains ischemic, septic or nephrotoxic injury, it releases large amounts of NGAL into both urine and serum. Thus, NGAL is considered a promising early biomarker for SA-AKI (119-122). Beyond serving as an early diagnostic biomarker, serum and urine NGAL can predict the progression of AKI to CKD in patients with SA-AKI (123).

Numerous innovative nanotechnology-based therapies targeting neutrophils have been developed. In diseases associated with neutrophil infiltration, neutrophils serve not only as therapeutic targets but also as ideal carriers for targeted drug delivery (124). For example, a targeted nanodrug delivery platform, Ac-PGP (a peptide sequence that targets the CXCR2 receptor on neutrophils)-tetrahedral framework nucleic acid (tFNA), utilizes tFNA and a neutrophil hitchhiking mechanism (125). DNA-based nanorobots have also been employed to target, load and modulate neutrophils for precise drug delivery and anti-inflammatory effects (125,126). Ly6G nanoparticles loaded with a selective phosphodiesterase 4 inhibitor can effectively suppress the release of cytokines and chemoattractants from activated neutrophils, preventing organ damage caused by excessive neutrophil accumulation and migration (127). Additionally, nanomaterials loaded with astragaloside IV, a natural compound with anti-inflammatory and antioxidant properties, can precisely target neutrophils and inhibit NET formation, mitigating sepsis-induced inflammatory responses and organ damage (128). Similarly, nanomaterials loaded with Coenzyme Q10, an antioxidant, significantly enhance kidney delivery efficiency, offering a new approach to alleviating kidney damage (129). Nanozymes, nanomaterials with enzyme-like activities, also play a vital role in SA-AKI treatment by catalyzing specific biochemical reactions and protecting the kidneys through mechanisms such as scavenging excess ROS and modulating inflammatory signaling pathways (130). Neutrophil-targeted nanodrug delivery systems provide novel strategies for SA-AKI treatment by enabling precise intervention in neutrophil-mediated kidney injury, optimizing nanocarrier design and facilitating clinical translation.

Although studies targeting neutrophil-mediated injury pathways have shown promising results, neutropenia remains a high-risk condition in critically ill septic patients (131). Compared with non-neutropenic patients, severe sepsis triggers a distinct inflammatory response in neutropenic patients (131). Levels of IL-6, IL-8 and granulocyte colony-stimulating factor (CSF) are significantly elevated in neutropenic septic patients and are independently associated with an increased risk of AKI (131). Therefore, the development of therapeutic strategies targeting neutrophils must be carefully balanced to avoid excessive suppression of their functions, which could impair renal repair.

B cells, a key subset of lymphocytes, play an essential role in the immune response. As summarized in Fig. 6, B cells produce antibodies, presenting antigens and secreting cytokines, thereby mediating both adaptive and innate immune responses, maintaining immune balance and renal homeostasis (197). However, due to their pathogenic role in organ transplantation and autoimmune diseases, B cells are considered to have detrimental effects in AKI (198). In a cisplatin-induced AKI model, Inaba et al (199) observed that renal B cells were a significant source of CCL7, promoting the recruitment of neutrophils and monocytes to the injured kidney and exacerbating AKI severity. Similarly, in a study of unilateral ureteral obstruction-induced AKI, Han et al (200), found that early accumulation of B cells in the kidney accelerated the mobilization and infiltration of monocytes/macrophages, aggravating fibrosis induced by AKI. Clinical studies on SA-AKI have shown an association between the plasma lymphocyte ratio and renal function, with 1 study revealing that septic patients who recovered renal function had fewer B lymphocytes at hospital admission (201). Sepsis increases the expression of programmed death-ligand 1 (PD-L1) on B lymphocytes. Programmed cell death protein 1 (PD-1) impairs immunity by inducing apoptosis, inhibiting T-cell activation, increasing IL-10 production and rendering T cells unresponsive while reducing their cytokine secretion, leading to T-cell exhaustion. Glutamine administration has been shown to reduce the expression of PD-1/PD-L1 on B cells, alleviating kidney damage (202).

Under normal physiological conditions, T cells play a pivotal role in maintaining renal immune homeostasis (203) (Fig. 6); they regulate immune responses, preventing autoimmune reactions and excessive inflammation, thereby protecting the kidneys from damage. T cells continuously monitor renal tissues, identifying and eliminating potential pathogens or abnormal cells to preserve kidney health (204). Following the onset of SA-AKI, T cells, as key immune cells combating pathogen infections, play a decisive role in the pathogenesis and progression of the disease.

T cell subsets exert distinct immunomodulatory functions in the kidneys. T lymphocytes can be classified into two major subsets: CD4⁺ Th cells and CD8⁺ T cells. Th cells are further divided into Th1, Th2 and Th17 subsets. Th1 cells primarily produce IFN-γ and TNF-α, exerting pro-inflammatory effects. Th2 cells secrete IL-4, IL-5, IL-10 and IL-13 (205), predominantly mediating anti-inflammatory effects. Th17 cells mainly produce IL-17 and IL-22 (206). After kidney injury, IL-1 secreted by renal DCs and macrophages promotes the differentiation and activation of Th17 cells (207). Th17 cells infiltrate the renal parenchyma during murine AKI, defend against extracellular pathogens through the production of their signature cytokine IL-17 and play a pivotal role in promoting autoimmune diseases and tissue inflammation (208).

Regulatory T (Treg) cells are a unique subset of CD4⁺ T cells, comprising a small fraction of the total CD4⁺ T cell population; they mediate tissue repair by synthesizing pro-repair molecules that promote regeneration and play a critical role in anti-inflammatory processes (209,210). Treg cells exert protective effects through several mechanisms. For instance, they express CD73 (ecto-5'-nucleotidase), an enzyme that catalyzes the production of extracellular adenosine (211). Adenosine binding to the A2A receptor on Treg cells increases their surface expression of PD-1, which is essential for their suppression of innate immune responses (7). Additionally, Treg cells can be identified by the expression of the transcription factor Forkhead Box P3 and employ multiple mechanisms to suppress other immune cells (212). These cells secrete anti-inflammatory mediators such as IL-10, IL-35 and TGF-β, inhibit Th17 cell activity, promote their own proliferation, suppress excessive T lymphocyte responses and reduce pro-inflammatory mediators, thus directly inhibiting innate immune responses (213,214). Moreover, an imbalance in the Th17/Treg ratio is believed to be associated with the occurrence and severity of SA-AKI (215). Targeted regulation of Treg cells may potentially improve renal function. The α7 nicotinic acetylcholine receptor (α7nAChR), highly expressed on Treg cells, can modulate Treg cell activity. Shi et al (216) demonstrated that the α7nAChR agonist PNU-282987 ameliorated CLP-induced AKI by activating Treg cells. While the immunosuppressive function of Treg cells is beneficial in mitigating inflammatory injury, excessive immunosuppression in infections such as sepsis may impair the ability of the host to clear pathogens (217). A study has indicated that fish oil emulsion alleviates kidney damage under septic conditions by reversing elevated Treg cell expression and downregulating inflammatory mediators (218). Future research should focus on developing strategies to precisely modulate Treg cell activity, potentially enhancing Treg cell recruitment to renal tissues while avoiding systemic immunosuppression.

In sepsis, lymphocyte dysfunction occurs not only in peripheral blood cells but also in target organs (219). T cell priming is regulated by a balance of positive and negative co-stimulatory molecules, with imbalances in these molecules (also known as immune checkpoint molecules) being closely linked to immune dysfunction (220). A common feature of sepsis-associated immunosuppression is impaired lymphocyte function and increased expression of inhibitory checkpoint molecules such as PD-1. Activation of the PD-1/PD-L1 pathway by lactate can induce immunosuppression by promoting lymphocyte apoptosis in SA-AKI. Blocking the lactate receptor or PD-1/PD-L1 can restore lymphocyte function and alleviate kidney damage (221). Additionally, MSCs can restore the balance between Th17 and Treg cells via the galectin-9/T-cell immunoglobulin and mucin domain-containing molecule-3 pathway, reduce inflammatory cell infiltration and reestablish the equilibrium between pro-inflammatory and anti-inflammatory responses, thus improving SA-AKI (222). Dysregulation of T cells can also lead to the abnormal release of immunomodulatory molecules, such as excessive inflammatory cytokines, exacerbating tissue inflammatory injury. In this context, glutamine has been shown to alleviate SA-AKI by balancing T cell polarization and reducing T cell apoptosis (223). Given the imbalance in T cell subsets in patients with SA-AKI, future therapeutic strategies should aim to selectively expand protective T lymphocyte subsets or suppress damaging T cell subsets.

Several potential therapeutic targets related to T cells in SA-AKI have been identified. In addition to α7nAChR agonists, MSCs and anti-PD-L1 antibodies, recombinant human soluble thrombomodulin (rTM), a single-transmembrane, multi-domain glycoprotein receptor for thrombin, has emerged as a promising candidate (224). rTM not only reduces the upregulation of pro-inflammatory cytokines and chemoattractants induced by LPS, thereby decreasing leukocyte infiltration into the kidneys, but also mitigates kidney damage by reducing the accumulation of CD4⁺ T cells, CD11c⁺ cells and F4/80⁺ cells in SA-AKI. This effect is mediated through enhanced phosphorylation of c-Jun, which diminishes cytokine production and apoptosis signaling (224). Additionally, CD28 plays a role in regulating TNF-α and IL-10 homeostasis, influencing the expression of chemoattractants. Through the CD28 pathway, T cells modulate renal function during sepsis (225).

In addition to therapeutic targets, certain T cell-related biomarkers may serve as predictors for SA-AKI. Ma et al (226) demonstrated that T cell knock-out mice exhibit reduced inflammatory cytokine secretion in renal tissue after LPS injection and that T cell suppression alleviates sepsis-induced inflammation and kidney damage. Therefore, T cell hyperactivation or upregulation could serve as a biomarker for worsening SA-AKI, and therapies targeting T cells or blocking receptors for inflammatory cytokine secretion may offer benefits in treating SA-AKI (226). Elevated plasma levels of IL-10 and soluble CD25 (a marker of Treg cells) in patients with SA-AKI may also serve as novel biomarkers (227). Moreover, ATP content in CD4⁺ T cells (ATP_CD4) has been shown to correlate with survival in sepsis patients. Low ATP_CD4 levels at 48 h post-onset may indicate a higher likelihood of complete renal recovery, making it a potential prognostic indicator (228).

Future research should focus on elucidating the mechanisms of T cells in SA-AKI, including interactions among different subsets and signaling pathways. Integrating the regulation of immune checkpoint molecules, MSCs application, exploration of potential therapeutic targets and the development of biomarkers will contribute to the formulation of comprehensive treatment strategies to improve the prognosis of patients with SA-AKI.