Sepsis-Related Acute Kidney Injury Based on the Gut-Kidney Axis
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection[1,2]. The most common manifestation is multiple organ dysfunction, particularly renal dysfunction, known as sepsis-associated acute kidney injury (SA-AKI)[3]. SA-AKI is common in patients with severe sepsis, with an incidence of 40% to 50% in intensive care unit (ICU) patients[4], and a mortality rate as high as 70%[5]. Most patients have already progressed to acute kidney injury (AKI) before the initiation of pharmacological treatment[6], but the specific pathophysiological mechanisms remain unclear[3]. Prior to the onset of sepsis, the gut microbiota undergoes changes through various mechanisms, making the host more susceptible to sepsis, including the proliferation of pathogenic gut bacteria, activation of the immune system, strong inflammatory responses, and reduced production of beneficial microbial products (such as short-chain fatty acids, SCFAs)[7,8]. After the onset of sepsis, changes in the normal gut microbiota structure are also significantly associated with poor prognosis[9]. The gut and kidneys form a bidirectional synergistic relationship known as the “gut-kidney axis,” which facilitates bidirectional communication between the gut microbiota and kidney function, playing a key role in the development of sepsis and SA-AKI, and participating in various pathological injury mechanisms with both positive and negative effects[10,11,12]. Therefore, this article summarizes the changes in gut microbiota, gut barrier, and kidney function in septic patients, exploring the interactions between changes in gut microbiota composition, gut barrier dysfunction, and kidney injury, which is of great significance for guiding the treatment of SA-AKI patients and reversing gastrointestinal dysfunction.
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1. The “Gut-Kidney Axis” Theory
In 2011, Meijers and Evenepoel[13] first proposed the “gut-kidney axis” theory, which posits that chronic kidney failure leads to dysbiosis of the colonic microbiota, resulting in the production of metabolic toxins (mainly indole sulfate and p-cresol) that enter the circulation, causing inflammatory responses and oxidative stress damage, thereby exacerbating kidney injury. The “gut-kidney axis” refers to the interaction between the gastrointestinal tract and the kidneys, where the gut regulates kidney function through various neuroendocrine hormones, including glucagon-like peptide-1 (GLP-1), guanylin, uroguanylin, secretin, vasoactive intestinal peptide, polypeptides, gastrin, and cholecystokinin, which are gut-derived factors that can modulate kidney function[14,15]. The core viewpoint of the “gut-kidney axis” theory suggests that patients with chronic kidney disease (CKD) experience dysbiosis of the gut microbiota (internal environment) during disease progression, leading to an imbalance in gut microbiota, including a reduction in beneficial bacteria and an increase in pathogenic bacteria that produce uremic toxins, resulting in the accumulation of gut-derived uremic toxins in the blood that cannot be timely cleared by the damaged kidneys, further deteriorating kidney function and ultimately forming a vicious cycle between the gut and kidneys. On the other hand, the dysbiotic gut microbiota can also disrupt the intestinal epithelial barrier function, allowing gut-derived uremic toxins and pathogenic bacteria to translocate into the bloodstream, activating the intestinal mucosal immune system, thereby inducing a systemic micro-inflammatory response that exacerbates kidney damage[13,14,16]. Any disruption in this bidirectional communication can lead to various severe complications, such as CKD, end-stage renal disease (ESRD), and SA-AKI.
2. SA-AKI
2.1 Definition of SA-AKI:
SA-AKI is the most common complication of sepsis, with many patients meeting the recognized criteria for both sepsis and AKI, thus being considered to have SA-AKI or sepsis-associated AKI[17]. Unlike other types of AKI, clinical and basic scientific evidence indicates that the occurrence of SA-AKI is a complex pathological process. SA-AKI differs from non-sepsis-related AKI in that renal blood flow perfusion does not decrease but rather increases. The main culprit of SA-AKI is excessive inflammatory response, driven by many specific pathophysiological mechanisms, characterized by unique temporal features (onset, duration)[18,19]. The primary pathological manifestation of SA-AKI is apoptosis of renal tubular cells[20], with necrosis, pyroptosis, and autophagy-dependent cell death also playing significant roles[21], among which necrosis and ferroptosis are recently identified modes of programmed cell death[6].
2.2 Pathophysiological Mechanisms of SA-AKI:
SA-AKI is characterized by oliguria and reduced renal solute clearance, leading to disturbances in electrolyte and acid-base balance, fluid overload, and toxic accumulation of metabolic products and drugs that rely on renal elimination[22]. The pathogenesis of SA-AKI is not fully understood, but it has been established that three abnormalities—inflammatory cascades, macrovascular and microvascular dysfunction, and cellular responses—are potential pathophysiological mechanisms of SA-AKI[20,23,24].
2.2.1 Inflammatory Cascade:
Widespread and dysregulated inflammation is one of the defining features of the pathophysiology of sepsis and a major cause of many downstream complications, including kidney injury through various mechanisms[22]. In the state of sepsis, slow peritubular blood flow may also amplify inflammatory signals, as activated leukocytes may transport for extended periods, leading to prolonged exposure of adjacent endothelial and epithelial cells to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs)[25]. Inflammatory mediators such as DAMPs and PAMPs are released into the vascular space and bind to receptors on immune cells, such as Toll-like receptors (TLRs)[23]. This response subsequently initiates a series of signaling cascades, with receptor activation triggering the local release of additional inflammatory mediators and the recruitment of peritubular inflammatory infiltrating cells[23,26]. In SA-AKI patients, there is an increase in inflammatory cytokines and oxidative stress, with elevated myeloperoxidase (MPO) activity and increased levels of hydrogen peroxide (H2O2) and malondialdehyde (MDA)[20]. Furthermore, various mechanisms have been proposed for the tubular injury caused by SA-AKI, including the ultrafiltration of circulating microbial toxins, which triggers the release of inflammatory mediators that induce stress and damage to renal tubular cells[18], and renal tubular epithelial cells (TECs) express TLRs, particularly TLR2 and TLR4. Therefore, once PAMPs or DAMPs are filtered by the glomeruli, similar pathways will be activated, leading to increased oxidative stress, reactive oxygen species (ROS) production, and mitochondrial damage[25,27]. In animal experiments, lipopolysaccharides (LPS) induce the release of inflammatory cytokines (especially tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β)) through the TLR4 signaling pathway, participating in oxidative stress, which can activate TECs, leading to cellular functional damage, subsequently causing renal microcirculation disorders and hypoperfusion, ultimately resulting in SA-AKI.
2.2.2 Circulatory Dysfunction:
Sepsis is characterized by systemic vasodilation, uneven regional blood flow distribution, and a significant decrease in functional capillary density[18]. It was previously thought that renal hypoperfusion and ischemia were the main causes of SA-AKI, but animal experiments do not fully support this traditional view[27,28]. Only a portion of SA-AKI is caused by renal hypoperfusion[27]. Other in vitro studies have confirmed that plasma obtained from patients with SA-AKI-induced TEC dysfunction does not contribute to ischemia/reperfusion injury[27,29]. Changes in vascular function and tone caused by sepsis can lead to reduced renal blood flow (RBF), insufficient delivery of oxygen and metabolic substrates, and inadequate clearance of cellular byproducts (such as lactate). However, the relationship between systemic blood pressure, RBF, and renal oxygenation is complex. While microcirculatory and macrocirculatory defects may trigger SA-AKI, attributing all pathophysiological features to this mechanism is inaccurate[22]. Renal vascular constriction is a response to inflammatory damage rather than the initiating event of renal injury[18].
In clinical sepsis, these early hemodynamic changes are accompanied by increased cardiac output and vasodilation, likely associated with inflammatory damage to endothelial cells and renal tubular cells[18,23], as well as characteristic microcirculatory disturbances, including endothelial dysfunction, impaired erythrocyte deformability, damage and shedding of the glycocalyx, increased activation, adhesion, and recruitment of leukocytes, and platelet adhesion and fibrin deposition activating the coagulation cascade[25]. Microcirculatory blood flow disturbances have been clearly identified as independent markers predicting prognosis in sepsis patients[25]. Preclinical studies suggest that microcirculatory blood flow disturbances may play a significant role in the pathophysiology of SA-AKI[18,30], showing differences in peripheral hypoperfusion between patients with and without sepsis-related AKI, which may be due to the use of vasoactive drugs. Using the perfusion index (PI) to assess peripheral perfusion abnormalities is an important prognostic marker for SA-AKI patients[30]. Sepsis can promote the detachment of pericytes in peritubular capillaries and the transdifferentiation of pericytes into myofibroblasts, which may further induce immune cell infiltration into the interstitial space and the occurrence of white matter congestion and hypoxia. This condition appears early in the infection and may be a primary cause of microcirculatory abnormalities and renal injury[24,31].
Circulating inflammatory mediators alter vascular endothelium, leading to endothelial dysfunction. In animal models of SA-AKI, the reduction in glomerular blood flow is attributed to the inhibition of endothelial nitric oxide synthase activation in arterioles and glomeruli, while the reduction in cortical peritubular capillary perfusion is related to epithelial oxidative stress[31]. Inflammatory cytokines stimulate endothelial cells to produce nitric oxide, leading to vasodilation and loss of autoregulatory function. Elevated levels of circulating vascular endothelial growth factor and decreased levels of circulating sphingosine-1-phosphate, loss of glycocalyx components in glomerular endothelial cells, and loosening of tight cell junctions lead to increased microvascular permeability, allowing intravascular fluid to enter tissues, resulting in relative hypovolemia within the vasculature. Additionally, activated endothelium contributes to a pro-thrombotic state, which can lead to microvascular thrombosis[22].
Studies have shown that microvascular endothelial cells in renal cortical arterioles, glomeruli, peritubular capillaries, and post-capillary venules exhibit intrinsic molecular and phenotypic heterogeneity and respond to SA-AKI in a segment-specific manner. Although coagulopathy occurs in all microvascular segments, the molecules involved differ between segments. The expression of adhesion molecules and the induction of leukocyte recruitment also occur heterogeneously. Evidence of similar endothelial cell responses has been found in renal and blood samples from sepsis patients. The relationship between segment-specific changes in microvasculature in SA-AKI patients and loss of kidney function requires comprehensive study[31].
2.2.3 Immune Mechanisms/Cellular Responses:
Overactive dysregulated innate immune responses lead to the activation of inflammatory molecular cascades and the complement system, with cellular innate immunity contributing to SA-AKI[24]. The leakage of cytochrome C (Cyt C) and mitochondrial damage are among the earliest events in SA-AKI. Studies have shown that the release of Cyt C into the extracellular space increases in AKI and is negatively correlated with mitochondrial morphology and cell survival[30]; during sepsis, renal tissue undergoes changes in mitochondrial function and structure[22]. As a key player in energy production, mitochondria play an important role in the pathophysiology of SA-AKI[24]. Research indicates that the decrease in mitochondrial energy production and the accompanying oxygen consumption in sepsis patients correspond to a decrease in renal oxygenation, which may be an adaptive phenomenon in sepsis patients. Dysfunction of the electron transport chain can lead to excessive ROS production, imposing oxidative stress on cells, and subsequent changes in mitochondrial membrane permeability can dissipate the electrochemical gradient required for ATP production and potentially lead to mitochondrial swelling that triggers apoptosis[22]. Mitochondria are common targets of inflammatory damage, which can lead to dysfunction, increased ROS production, and subsequent harm to host cells[25]. Mitochondrial autophagy provides the advantage of clearing dysfunctional mitochondria, thereby reducing ROS or reactive nitrogen species production, maintaining and renewing the mitochondrial pool for energy conservation, limiting oxidative stress damage, and importantly, intercepting pro-apoptotic signals at the mitochondrial level[32,33,34,35]. Detection of the expression of genes related to mitochondrial biogenesis, fission, and fusion reflects the total mitochondrial content, with the expression of translocase of outer mitochondrial membrane 20 (TOM20) decreasing 12 to 24 hours after cecal ligation and puncture (CLP), suggesting that mitochondrial biogenesis in the kidneys is inhibited after CLP, and an increase in cellular autophagy is observed early in SA-AKI[36].
TEC responses to injury may be accomplished by limiting pro-apoptotic triggers, i.e., by downregulating energy consumption through metabolic reprogramming to maintain energy homeostasis, protecting cells from the effects of energy imbalance; moreover, metabolic reprogramming determines the response characteristics and repair phenotype after inflammation resolution[25]. Yang et al.[37] found that G1-S cell cycle arrest is associated with kidney injury in a CLP-induced sepsis rodent model, and recovery of kidney function 48 hours after CLP parallels cell cycle progression. Cell cycle arrest can provide protective effects in the early stages by limiting replication costs and the consequences of replicating damaged DNA under conditions of metabolic downregulation, but cell cycle progression and replication may require sufficient repair later, thus prolonged arrest may be harmful. Therefore, elucidating the timing of cell cycle arrest or progression’s impact on cell injury and repair is crucial for understanding key mechanisms of cell protection and serves as a basis for translating this mechanism into targeted therapeutic interventions[25].
3. Sepsis, SA-AKI, and the Gut System
3.1 Sepsis, SA-AKI, and Gut Microbiota:
The human body harbors trillions of microbial cells, and the synergistic action of these microbial cells is vital for human life. These microbial cell populations reach their highest density in the gut, collectively forming a complex community known as the gut microbiota[38]. This microbiota develops during the host’s infancy and ultimately matures in adulthood, forming a complex and unique ecosystem that influences human health[39]. Gut bacteria exist at approximately 1,000 to 1,200 species at the species level, but 75% to 82% of them are unculturable. Gut microbiota can hydrolyze complex plant polysaccharides, thereby enhancing the host’s metabolic capacity and producing SCFAs[39,40]. SCFAs can improve energy metabolism in colonic cells, promote the growth and differentiation of intestinal epithelial cells, and enhance the liver’s metabolism of fats and carbohydrates; some SCFAs even have anti-inflammatory effects[41,42]. Gut microbiota can also synthesize essential amino acids and vitamins, promoting the development of epithelial cells, and their colonization on intestinal epithelial cells can prevent the invasion of pathogens, playing a crucial role in maintaining the health of the organism[43].
The metabolism of undigested substances in the gastrointestinal tract is a key mechanism of interaction between the gut microbiota and the host. Substances ingested or secreted into the intestinal lumen by the host provide essential nutrients for the microbiota, becoming part of the gut microbiota, and then the products of microbial enzymes can interact with host tissues after local absorption in the intestinal epithelium. To fully utilize the large amounts of substances entering the gastrointestinal tract, a healthy gut microbiota exhibits a rich enzyme repertoire, producing a wide range of metabolites and compounds that can influence host physiology, maintaining stable communities and intestinal ecosystems[44,45,46].
Before the onset of sepsis, changes in the gut microbiota can make the host more susceptible to sepsis through various mechanisms, including the proliferation of pathogenic gut bacteria; activation of the immune system, leading to strong inflammatory responses; and reduced production of beneficial microbial products (such as SCFAs)[7]. The gut microbiota’s regulation of sepsis responses presents potential therapeutic targets for sepsis. The loss of normal gut microbiota structure and function is associated with various diseases, including Clostridioides difficile infection (CDI), inflammatory bowel disease, and obesity. Although the pathogenesis of sepsis involves multiple factors and is not fully understood, increasing evidence suggests that gut microbiota disruption can easily lead to sepsis and negatively impact its outcomes[9]. There is a strong correlation between gut microbiota disruption and the occurrence of sepsis. Nevertheless, these studies have not assessed the impact of microbiota changes on the risk of sepsis occurrence and the potential confounding factors of that risk, thus requiring further validation. Additionally, once sepsis occurs, the destruction of the gut microbiota will worsen, increasing the likelihood of organ dysfunction. In the presence of protective symbiotic bacteria, pathogenic bacteria with disease potential in the healthy host’s intestinal lumen may not proliferate and cause disease. The loss of protective bacteria can lead to pathogen proliferation, while changes in the normal gut microbiota structure can lead to worse prognosis[47,48].
Innate immunity (macrophages and neutrophils) and adaptive immunity (helper T cells 17) are key factors in the gut ecological imbalance that occurs in AKI[49]. An increase in Enterobacteriaceae, a decrease in Lactobacillus, and a decrease in Ruminococcus are markers of ecological imbalance induced by ischemia/reperfusion injury, which reduces SCFAs, leading to intestinal inflammation and complications such as intestinal permeability, increasing the production of gut-derived uremic toxins (such as indole sulfate and p-cresol), thereby altering immune homeostasis and further worsening AKI[49,50,51].
3.2 Sepsis, SA-AKI, and Gut Barrier Function:
The gastrointestinal tract is a unique organ that, in addition to digesting food, undergoes dynamic interactions between host cells and a complex environment. One of the important roles of intestinal epithelial cells (IECs) is to digest ingested food and absorb nutrients and dietary factors[52]. At the same time, IECs serve as a physical barrier, promoting tight junctions (TJs) between cells, with many tight junction proteins forming partially sealed paracellular pathways. TJs play a crucial role in gut barrier function, effectively sealing adjacent intestinal mucosal cells at the apex. The structure of TJs includes transmembrane proteins (such as claudins, occludin, and junctional adhesion molecule-A (JAM-A)) and intracellular plaque proteins (such as zonula occludens (ZO) and cingulin), which regulate the paracellular permeability of water, ions, and macromolecules between adjacent cells. One of the important roles of TJ structure is to provide a physical barrier against inflammatory molecules in the lumen, and damage to the integrity and structure of the TJ barrier leads to excessive activation of immune cells and chronic inflammation in different tissues[52,53]. The mucosal layer serves as a chemical barrier, crucial for limiting contact between the microbiota and epithelial cells[54,55]. IECs and the mucosal layer, together with the cellular immune system, separate the intestinal lumen from the host’s internal environment, serving as the first physical barrier against external factors and maintaining a symbiotic relationship with commensal bacteria[54,56].
In septic patients, impaired intestinal integrity leads to increased apoptosis, resulting in altered barrier permeability[56]. Gut barrier dysfunction promotes the occurrence and progression of sepsis, triggering uncontrollable systemic inflammatory responses and leading to life-threatening clinical conditions[53]. When sepsis occurs, excessive inflammatory responses lead to IEC apoptosis[57]. The TJs between IECs are disrupted, widening the paracellular spaces, resulting in compromised intestinal mucosal integrity[58]. Furthermore, intestinal mucosal damage exacerbates bacterial translocation, and virulence factors further activate the host’s immune inflammatory defense mechanisms, ultimately leading to multiple organ failure and life-threatening clinical symptoms[59].
AKI can lead to the accumulation of urea, increasing the flow of urea into the gut, where urea is converted to ammonia, disrupting the TJs of the intestinal epithelium[49,60]. Simultaneously, neutrophils, pro-inflammatory macrophages, and helper T cells 17 accumulate in the gut, compromising barrier integrity and enhancing bacterial translocation[60,61].
4. Interactions Between the Gut and Kidneys in SA-AKI
Increasing evidence suggests a bidirectional relationship between the host and gut microbiota in various kidney diseases[15]. Gut microbiota-derived metabolites are key molecular mediators of the microbiota-host axis, and the kidney’s excretory capacity is an important component of the host’s gut microbiota symbiosis. Studies have shown that CKD is a metabolic disease characterized by the accumulation of gut microbiota metabolites in the blood, adversely affecting host physiological functions[10,14,62]. The gut and kidneys form a bidirectional synergistic relationship known as the “gut-kidney axis,” where the loss of endothelial barrier integrity and gut microbiota dysbiosis are major pathophysiological changes in sepsis, playing a key role in SA-AKI, responding to various pathological injuries with both positive and negative effects[10].
The gut’s barrier function relies on the presence of “the apical membrane of IECs and TJs between adjacent cells” and “JAM,” preventing the escape of luminal contents into the environment outside the local intestinal lumen[52,54,63]. Inflammation is one of the important factors in the occurrence of SA-AKI; during SA-AKI, increased inflammatory factors can damage the gut’s barrier function and act on the TJ complex to regulate intestinal permeability[62]. When sepsis alters the expression of tight junction proteins such as ZO-1, claudin proteins of certain subtypes, and occludin, it may lead to excessive increases in intestinal permeability. This high permeability may also result from changes in the components of JAM. Cytokines activate myosin light chain kinase (MLCK), which can increase intestinal permeability by phosphorylating myosin light chains, leading to the opening of TJs. MLCK activation is associated with the overexpression of IL-6, TNF-α, and IL-1β, ultimately resulting in increased intestinal permeability, amplifying systemic inflammatory responses, and further exacerbating kidney injury[63].
The gut microbiota also plays an important role in sepsis; the quantity and distribution of gut bacteria and the structure of the microbiota may change with the progression of sepsis, leading to gut mucosal damage, subsequently triggering gut barrier dysfunction, activating the immune system, producing strong inflammatory responses, and reducing the production of beneficial metabolites (such as SCFAs)[7], thereby affecting the interactions between gut microbiota and kidney function during the onset and progression of sepsis. The mechanisms of gut-kidney crosstalk may provide potential bases for the development of new therapeutic strategies for sepsis.
References: Zhang Li, Wang Yi, Yu Xiangyou. Research Progress on Sepsis-Related Acute Kidney Injury Based on the Gut-Kidney Axis [J]. Chinese Journal of Critical Care Medicine, 2023, 35(3): 329-333.
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