Future Directions in Optimizing Anesthesia to Reduce Perioperative Acute Kidney Injury

Perioperative acute kidney injury (AKI) is one of the most frequent complications in surgery, which increases the incidence of postoperative complications, mortality, and the risk of post-discharge hemodialysis and has become a major burden on medical cost resources. Despite advances in anesthesia technology, perioperative AKI remains unpredictable and the current diagnostic criteria for perioperative AKI still have limitations [1]. Besides, there is no effective targeted drug therapy for AKI, and its treatment is limited to supportive care and continuous renal replacement therapy when necessary [2]. Hence, the prevention of high-risk patients and the improvement of AKI are major goals. Perioperative AKI is usually caused by a combination of factors, mainly including renal hypoperfusion, oxidative damage, and inflammation. Among them, renal hypoperfusion is the most important mechanism.

Nowadays, more and more research has found that intraoperative anesthesia can affect renal function in different ways, and several anesthetic drugs can improve perioperative AKI through antioxidant, anti-inflammatory, and other mechanisms, like propofol, sevoflurane, isoflurane, and articaine [3]. For example, an animal experiment has shown that sevoflurane can alleviate kidney injury in liver transplantation rats by greatly decreasing the 24-h serum creatinine (Scr) after reperfusion and neutrophil gelatinase-associated lipocalin (NGAL) concentrations after 2 h of reperfusion [4]. Another study has shown that propofol can protect renal function in mice after cecum ligation and puncture surgery to improve survival outcomes and alleviation of AKI [5]. The mechanisms underlying the association between these perioperative anesthetics and AKI have also been extensively studied in recent years. For instance, a study by Wang et al. found that dexmedetomidine (DEX) can improve renal function and ameliorate AKI by regulating p75 neurotrophin receptor/p38 mitogen-activated protein kinase/Jun N-terminal kinase signaling pathways [6]. However, the specific mechanisms of these anesthetic drugs for AKI still have many ambiguities. Considering the current lack of summary about the protection and mechanisms of tranquilizers and anesthetic drugs to perioperative AKI, we reviewed the pathogenesis and mechanism of perioperative AKI and analyzed the risk factors involved in it. Meanwhile, we summarized the latest research and mechanisms of perioperative anesthesia on AKI and concluded the clinical data of related drugs in Table 1. With this knowledge, this article may indicate the directions of the safe use of tranquilizers and DEX drugs, and make people better understand perioperative management for preventing perioperative AKI.

Perioperative AKI is defined as an acute decrease in renal function that occurs from preoperative days 5–7 to postoperative days 7–12 [17]. However, AKI has not had a unified definition for many years. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines published in 2012 have now become widely accepted diagnostic criteria for AKI: (1) a 0.3 mg/dL increase in Scr within 48 h, (2) a 50% rise in Scr within 7 days, or (3) a urine output of <0.5 mL/kg/h for >6 h. The guidelines also classify AKI into three stages by different Scr and/or urine output [18]. The reported incidence of perioperative AKI is 2–18% in patients and 22–57% in intensive care patients [19]. In the USA, it is estimated that 30–40% of AKI cases occur postoperatively [20]. Cardiac surgery, especially using cardiopulmonary bypass (CPB), has a perioperative incidence of more than 20% and is the surgery with the highest incidence of AKI. Vascular surgery also carries a higher risk of AKI, with postoperative AKI rates ranging from 20% to 70% [21]. Furthermore, the incidence of AKI after orthotopic liver transplantation ranges from 17% to 95% depending on the definition, which is typically due to a combination of factors [22]. Notably, AKI occurs in the first week after liver transplantation surgery due possibly to prerenal azotemia and acute tubular necrosis, while in 2–4 weeks the majority of causes are sepsis and calcineurin inhibitor toxicity [23].

There are many types of risk factors related to perioperative AKI. The more risk factors, the greater the likelihood of developing AKI. These risk factors can be classified into six groups: adverse clinical status, underlying disease, use of nephrotoxic drugs, contrast injection, some surgical interventions, and anesthetic factors, and are summarized in Table 2 according to preoperative, intraoperative, and postoperative factors. First, patients with poor clinical status are more prone to AKI, including age ≥56 years, preoperative creatinine >106 mol/L, hypoalbuminemia, smoking, coagulopathy, obesity, etc. [24, 25]. Patients with underlying diseases are also more likely to develop perioperative AKI, such as chronic kidney diseases (CKD), hypertension, peripheral vascular disease, diabetes, and chronic obstructive pulmonary disease [18, 26]. Among them, preoperative CKD history is a major risk factor for AKI, conferring as much as a 10-fold risk. At the same time, patients with AKI are also more likely to develop CKD [27]. Besides, up to 25% of severe AKI cases are thought to be caused by nephrotoxic drugs, including nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and some antibiotics [28]. Intravenous or arterial injection of contrast media also increases the risk of perioperative AKI, and arterial injection of contrast media is more nephrotoxic [29]. Some special operations may also increase the risk of AKI, such as CPB, intraoperative blood transfusion, increased intra-abdominal pressure in abdominal surgery, and so on. CPB lasting for more than 2 h has been verified to induce a significant increase in the incidence of AKI after cardiac surgery [30]. Finally, anesthesia factors have also been found to have a significant impact on perioperative AKI. A study showed that epidural analgesia during subtotal hepatectomy may also induce AKI with sympatholysis, peripheral vasodilation, and hypotension [31]. Rodgers et al. [32] have demonstrated that patients treated with spinal anesthesia are less likely to develop AKI than those treated with general anesthesia. Nevertheless, the relationship between perioperative anesthetics and AKI is still unclear at present, and more experimental evidence is needed to explore its underlying mechanism.

Perioperative AKI is usually caused by multiple injuries from complex causes, mainly due to the combined effect of renal hypoperfusion, oxidative damage, and inflammation (Fig. 1). Among them, renal hypoperfusion is the main factor. During surgery and critical illness, systemic changes in cardiac output, systemic vascular resistance, and renal venous pressure can alter renal cortical and medullary perfusion. Symons et al. [54] classified the causes of renal hypoperfusion into four categories: volume depletion, decreased cardiac output, decreased systemic vascular resistance, and increased renal artery resistance. First, the kidneys can release vasopressin (ADH) and angiotensin II by activating the sympathetic nervous system, and activate the renin-angiotensin-aldosterone system to make water-sodium retent to maintain glomerular filtration rate (GFR) [24]. However, when renal hypoperfusion lasts too long, angiopoietin II can promote afferent arteriole contraction, which instead leads to renal tubule ischemia and decreased GFR. However, compared to norepinephrine alone, Meersch proved that angiotensin II could reduce renin plasma concentrations significantly in patients at risk for AKI (high postoperative Δ-renin) with hypotonia after cardiac surgery, which acts as a hormone substitution therapy [55]. Moreover, ischemia-reperfusion (IR) induces renal mitochondria to produce reactive oxygen species, which impairs endothelial function and perfusion homeostasis by decreasing nitric oxide production. Furthermore, it will activate pro-inflammatory transcription factors such as nuclear factor-kappa B (NF-кB), and destroy surrounding tissue by oxidizing lipids, DNA, and other proteins [37]. Systemic inflammation induced by surgical stress and cytokine release can induce irreversible microcirculatory disturbances in renal tubules, further increasing systemic inflammation [56]. Neutrophils and macrophages are also recruited to the renal interstitium to regulate inflammation. Damaged endothelial cells will increase the production of intercellular adhesion molecule-1, which can stimulate white blood cells and cause blockage of small blood vessels, thereby increasing local inflammation within kidney tissue [18]. In addition, Paneth cells located in the small intestine can be activated by AKI-induced inflammation, which can induce great release of inflammatory mediators such as interleukin-17A (IL-17A) and may lead to sepsis and multiple organ failure [57]. Although there are a lot of studies have been performed on perioperative AKI, most of them are retrospective studies. In the future, we still need more prospective work to explore the pathogenesis of perioperative AKI.

Anesthesia is an important factor affecting renal function in the perioperative period. Proper anesthetic management can reduce the risk of postoperative renal complications, and the choice of anesthetic may also affect renal outcome [58]. Anesthetics we list below appear to exhibit the potential to attenuate AKI through different mechanisms (Table 3, Fig. 2).

Propofol, an ultra-fast-acting intravenous anesthetic with anti-inflammatory and antioxidant properties [59, 60] and few adverse effects [75], has been widely used in clinical applications. Among the widely used anesthetics, accumulated data suggest that it has a protective effect against renal ischemia/reperfusion injury (IRI) [76]. With the continuous in-depth study of its renal protective mechanism, propofol is regarded as a promising renal protectant and various clinical studies have shown that it can reduce the risk of perioperative AKI. A study comparing the first 48 h of outcomes in intensive care unit patients receiving propofol or midazolam showed that receiving propofol was associated with a lower risk of AKI, fluid-related complications, and the need for RRT [15]. In another clinical study, Yoo et al. demonstrated a significant reduction in the incidence and severity of AKI in CPB patients undergoing valvular heart surgery using propofol anesthesia compared to sevoflurane. It was also reported that postoperative cystatin C, serum IL-6, C-reactive protein, and fractional neutrophil count were significantly decreased [10], which may be related to the anti-inflammatory property of propofol [60]. However, due to the limitations of the experiment such as the small sample size, the effect of propofol on AKI has always been controversial. In a retrospective observational study involving 5,663 individuals (blood creatinine not tested 1 month before surgery was not included in the study), Oh et al. failed to observe an association between propofol use in the perioperative period and the occurrence of AKI after total hip or knee arthroplasty. Therefore, more clinical trials need to be conducted.

However, the research progress of propofol in mice with AKI has made remarkable achievements. Propofol exhibited the ability to lessen oxidative stress and decrease AKI after autologous orthotopic liver transplantation by reducing connexin32 (Cx32) activity, according to a study on male rats which were given the selective Cx32 inhibitor, 2-aminoethoxydiphenyl borate or propofol or not [62]. Another study showed that propofol treatment could increase bone morphogenetic protein-7 expression, decrease inflammatory cytokines (tumor necrosis factor [TNF-α] and monocyte chemotactic protein [MCP-1]), and inhibit oxidative stress (free radical production, H₂O₂-induced oxidative stress damage) to reduce the risk of kidney exposure to AKI caused by sepsis [63]. Small noncoding RNAs known as microRNAs (miRNAs) have the potential to serve as biomarkers for the early detection of AKI [77]. Chemokine C-C motif ligand 2 (CCL-2) may be central to the pathological process of renal injury and has potential as a predictor of renal function in patients with kidney disease [78, 79]. Zheng et al. found that miR-290-5p could inversely regulate the expression of CCL-2. In cecal ligation and puncture-treated mice, propofol treatment was shown to inhibit inflammation and reduce renal injury in vivo by increasing miR-290-5p levels and decreasing CCL-2 expression [5]. Furthermore, propofol is a potent membranous antioxidant and cytoprotective agent, which can alleviate hypothermia and ischemic AKI in renal transplantation [61].

Historically, several volatile anesthetics used clinically in the past are nephrotoxic (e.g., methoxyflurane) and were no longer routinely administered, but recent studies have shown that modern halogenated volatile anesthetics induce potent anti-inflammatory and anti-necrotic effects and protect the organism from ischemic AKI (e.g., isoflurane, desflurane, and sevoflurane) [80]. Sevoflurane is a widely used volatile anesthetic with antioxidant stress and anti-inflammatory activities, which has a powerful multi-organ protective effect in the perioperative period. Sevoflurane could improve renal function and effectively regulate IR injury and prevent ischemic AKI in vivo and in vitro [80, 81]. In a pediatric liver transplantation trial, patients in the sevoflurane group had more stable hemodynamics and significantly lower levels of TNF-α, IL-18, and serum NGAL during hepatic reperfusion than those in the propofol group. NGAL is a marker of renal injury which is significantly elevated in urine after AKI [65, 66]. Compared to propofol, sevoflurane anesthesia may be associated with a small decrease in the incidence of AKI after pediatric liver transplantation [7]. Anyway, due to the different evaluation criteria and the existence of experimental limitations, the effect of propofol and sevoflurane has always been controversial. Sevoflurane performed worse than propofol during anesthesia in a single-center parallel randomized controlled study in terms of decreased urine production, salt excretion, and elevated plasma renin. Sevoflurane-induced renal hypoperfusion could raise the risk of renal impairment in patients with additional risk factors, such as chronic kidney disease, even if there is not a clear link between intraoperative oliguria and postoperative AKI [82]. In another Volatile Anesthetic Protection of Renal Transplants-1 (VAPOR-1) randomized controlled trial, sevoflurane anesthesia increased the risk of kidney damage compared to propofol anesthesia [83]. However, multiple studies demonstrate the protective effect of volatile anesthetics against renal IR injury [76], and more experiments are needed before selecting anesthetics.

Decades ago, sevoflurane was found to degrade into compound A, which is nephrotoxic in rats. However, it has not been discovered that compound A affects human renal function [84]. IRI is one of the major contributors of AKI [85]. If tissue damage caused by IRI can be moderately alleviated, AKI could be controlled. Early in 2004, volatile anesthetics were reported to protect the kidney from IRI by reducing necrosis and inflammatory renal cell death. In addition, this study suggests that the reduction of cytokine and chemokine expression by volatile anesthetics may contribute to the decrease of renal injury after IR [64]. A subsequent study conducted on liver transplantation mice anesthetized by sevoflurane showed significant reductions in plasma TNF-α and IL-6 concentrations and a significantly lower NGAL (which means improved renal function) after 2 h of reperfusion, which is consistent with previous findings [4]. Similar experimental results were revealed in another research [67]. In the following years, Lee also proposed that sevoflurane prevents renal IRI via transforming growth factor-β1 (TGF-β1). Through TGF-β1-mediated anti-inflammatory and anti-necrotic effects, volatile anesthesia presents protective effects on the kidney [68‒70]. Recently, it was reported that miRNAs play a key role in renal diseases and the regulation of IRI [86]. Data from Yamamoto et al. [71] suggested that pretreatment anesthesia and ischemic preconditioning with sevoflurane could affect different miRNAs that can similarly regulate the chromosome 10 (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway (suppressed PTEN and increased phosphorylated Akt), resulting in renal protection. PTEN blocks the downstream activity of the PI3K/Akt pathway, while Akt activation can promote cell survival through anti-apoptosis [87]. This means sevoflurane can reduce renal IRI by inhibiting miRNAs, which would be a good target to prevent AKI. However, these animal studies have not yet been translated into human studies, so further human studies are needed.

The use of sedative and antiemetic drugs is often necessary for the perioperative care of patients. Many studies have reported the different effects and protective mechanisms of these drugs against AKI (Table 4, Fig. 3). The risk of AKI is further reduced by providing a tailored dosing regimen that ensures optimal comfort.

Midazolam is a benzodiazepine that can be used for the management of palliative sedation. It is mainly metabolized in the liver by cytochrome P450 (CYP) and excreted by the kidneys. In the case of inflammation and organ failure, midazolam clearance is reduced which could cause drug accumulation in the kidneys [97, 98]. Kirwan et al. suggested that increased severity and duration of AKI were associated with reduced elimination of midazolam. This may be caused by impaired CYP3A activity secondary to AKI [99]. The structures of propofol and midazolam both have phenol, but the experimental data did not show that midazolam had any antioxidant effect similar to propofol on the kidneys of rats after IR [100]. In patients with renal impairment, excretion of midazolam-active metabolites and parent drugs is prolonged. Midazolam should be used with caution in patients with acute renal failure [101]. Currently, studies on midazolam and AKI are scarce, thus further elaborations are also needed.

DEX, a class of fast-onset sedative drugs with proven neuroprotective and nephroprotective effects, has been widely introduced in the perioperative period due to its beneficial physiological effects and limited adverse effects [102]. Previous experiments have shown that DEX causes diuresis by inhibiting vasopressin secretion and increasing urine output [88], and protects against AKI by inhibiting inflammation, oxidation, and apoptosis [6]. Currently, an increasing number of studies confirm its protective effects against perioperative AKI. Shan et al. [13] found that DEX treatment attenuated renal insufficiency and reduced the incidence of AKI after endovascular aortic repair, which may be due to the reduction of sympathy-adrenal hyperactivity and stable maintenance of hemodynamic variables caused by DEX, resulting in enhanced GFR and increased urine output. Superoxide dismutase, which can reduce the risk of free radical overproduction, plays an important role in reducing oxidative stress [103]. In another cardiac valve replacement under CPB study, DEX was found to alleviate renal injury by increasing superoxide dismutase activity [12]. Besides, early intervention of DEX before ischemic injury appears to be essential for its organ-protective effect against IRI. In Cho’s research, preemptive DEX administration during an initial period lasting 24 h after surgery is effective in preventing AKI after cardiac surgery [104]. Similarly, data from Soh et al. [14] presented a lower incidence of AKI in an aortic operation under CPB after 24 h of preemptive DEX administration starting after anesthetic induction.

DEX is a selective α2 adrenergic receptor (α2-AR) agonist, and its protection mechanism of tissue damage through antioxidant, anti-apoptotic, and anti-inflammatory pathways [6] has been demonstrated by several animal studies. In a surgical bilateral renal IR model, DEX attenuated renal fibrosis after renal IR by reducing inflammation and premature cellular senescence mainly through α2-AR, which effectively prevented the renal IR-induced AKI-CKD transition [89]. One study on lipopolysaccharide‐induced AKI noted that the nephroprotective effect of DEX is to reduce inflammation and oxidative stress through glycogen synthase kinase‐3β (GSK-3β)/nuclear factor erythroid 2‐related factor 2 (Nrf2) signaling mediated by α2-AR pathway [90]. Nrf2 is thought to be crucial in the prevention of oxidative stress diseases [105‒107]. In pathological state, Nrf2 binds to antioxidant response elements in gene promoters, initiates Nrf2-mediated transcription process, regulates downstream gene expression such as heme oxygenase-, and promotes cytoprotective mechanisms such as anti-oxidative stress, anti-inflammatory, and anti-apoptosis [108]. GSK-3β is widely found in the kidney [109], which regulates Nrf2 activity by inhibiting GSK-3β [110]. GSK-3β/Nrf2 pathway may be an emerging therapeutic target for AKI. Furthermore, DEX can also ameliorate AKI through various pathways such as inducible nitric oxide synthase/nitric oxide pathway and toll‐like receptor 4 (TLR4)/NADPH oxidase 4/NF-κB pathway [91, 92]; however, they were not listed here due to few relevant studies.

Setrons are competitive antagonists of serotonin receptors (5-HT₃R), which are effective in preventing nausea and vomiting induced by chemotherapy and radiotherapy [111]. Cisplatin is a highly emetogenic anticancer drug with nephrotoxicity, which has been recommended for use with 5-HT₃R antagonists [112, 113]. Therefore, protecting the renal function during administration is needed. However, a study indicated that the first-generation 5-HT₃R antagonists (ondansetron, granisetron, tropisetron) exacerbated cisplatin-induced renal injury, whereas the second-generation 5-HT₃R antagonists (palonosetron) showed greater anti-cisplatin-induced nephrotoxicity than other 5-HT₃R antagonists [114, 115]. A study reported that ondansetron is associated with an increasing risk of AKI [116]. But interestingly, in a recent study, ondansetron was found to be correlated with lower mortality among AKI patients in intensive care unit. In addition, by comparing the gene expression characteristics, this effect may be induced by nuclear factor-kappa B pathway and Janus kinases-signal transducer and activator of transcription pathway [93]. In another retrospective cohort study, ondansetron use was also found to be associated with lower risk-adjusted mortality among patients with AKI, possibly due to the anti-inflammatory, antiplatelet aggregation, and anti-apoptosis effects [94]. However, it is worth noting that differences in the number of subjects and age groups as well as experimental indicators may contribute to different experimental results. Some animal studies have shown that the combination of ondansetron and cisplatin increases nephrotoxicity [117], while some other studies demonstrated tropisetron treatment ameliorated the cisplatin-induced nephrotoxicity [95]. These results are consistent with Kou’s clinical trial [118]. At present, few studies have been conducted to investigate the protective effect of setron drugs against AKI. Different types and doses of therapeutic drugs can cause different effects of setrons on renal function, which needs further clinical studies.

The renoprotective effects of the abovementioned anesthetic agents have been studied in several studies, but there is no single anesthetic agent that is widely accepted and included in standard perioperative anesthetic regimens. Therefore, whether or not an anesthetic agent of choice is used in the perioperative period or whether it is included as an add-on therapy for patients at high risk for AKI depends on a combination of factors. For example, when selecting an anesthetic agent during surgery, factors such as the type of surgery, the patient’s underlying health status, drug effects, and metabolic pathways are taken into account, in addition to other anesthesia-related factors such as blood pressure control and analgesic needs. Overall, more research is needed to confirm these findings and to find the best way to use them, based on a comprehensive assessment of the patient's overall condition and other clinical conditions, in order to fully protect renal function.

A single anesthetic (or treatment for that matter) may not change AKI outcomes, and multiple small interventions are needed to improve outcomes. AKI's “care bundle” concept has been proposed as a structured approach aimed at improving care processes and outcomes [119]. Care bundle is not a single intervention but a number of independent elements (usually between three and six) delivered together as a complex intervention designed to change clinician behavior [120]. The biomarker-guided KDIGO bundle has been shown in previous Prev-AKI trials to be effective in reducing AKI in cardiac surgery patients [121, 122]. Moreover, multiple BIGPAC trials have shown that early biomarker-based prediction of AKI after implementation of the KDIGO care package reduces the risk of postoperative AKI [123, 124]. Anesthetics can improve the level of traditional biomarkers, while the new biomarkers applied by care bundle can be diagnosed earlier. The study of pairing certain anesthetics with care bundles may provide a new direction for AKI prevention.

In fact, the application of perioperative medication of anesthesia on perioperative AKI in clinics still has many challenges. On the one hand, many studies are still at the animal level and the results have not been translated to humans, such as few clinical studies have explored the renal protection effects of DEX by modulating Nrf2 activity. On the other hand, regarding animal models (or humans), there may be sex differences in response to drugs. Due to the higher incidence of postoperative AKI in female gender, the gender ratio of patients needs to be carefully considered in clinical studies. In addition, there are a few basic studies using male rodents, however, gender is an under-researched factor in this population. Moreover, the interactions between the various anesthetics and other cells, tissues, and organs of the body have not been very clearly studied. Therefore, the selection of clinical anesthetics needs a comprehensive evaluation of various factors and more experimental support.

AKI is very common in surgical patients, and the influence of anesthetic drugs on renal function is particularly important during the perioperative period. In recent years, some anesthetic drugs seem to have therapeutic value for AKI through anti-inflammatory, antioxidant, anti-apoptotic, and other mechanisms, which is a hot topic of intense research. However, there are also many researchers studying the clinical effect of anesthetic drugs, with mixed results. The underlying mechanism of renal protection is still unclear; further studies are needed to clarify the molecular mechanisms of anesthetics and to resolve discrepant findings.

In this study, we reviewed the protective mechanism of various anesthetic drugs on AKI and the latest clinical research, in order to better understand anesthetic administration for perioperative AKI. Intravenous anesthetics (e.g., propofol), volatile anesthetics (e.g., sevoflurane), and sedatives (e.g., DEX) seem to be outstanding in the prevention or treatment of AKI. These drugs achieve anti-inflammatory, antioxidant, and cell protection through expression regulation and signal transduction, such as propofol and sevoflurane can both reduce IL-6 level. However, the effect of other drugs such as setrons and midazolam on AKI is still controversial. Nowadays, there are still many challenges to the clinical application of perioperative medication of anesthesia on perioperative AKI. Therefore, we also present relevant basic studies to further elucidate the renal protective mechanisms of anesthetic drugs.

In any case, there is no doubt that studies on the renal protection of anesthetic agents will be continued, and these studies will help further evaluate and improve the administration of anesthetic agents in perioperative AKI. This paper not only provides a theoretical basis for perioperative anesthesia but also provides a reference for the precise treatment of AKI. More importantly, we hope that the above summary can provide a better choice of anesthesia drugs during the perioperative period and provide future direction for the treatment of AKI.

The graphical abstracts were created with BioRender software (BioRender.com).

The authors have no conflicts of interest to declare.

This work was supported by the Natural Science Foundation of Jiangxi Province (No. 20224ACB216009); the National Natural Science Foundation of China (Grant No. 82160371, No. 82100869, No. 82360162, No. 81960669); the Jiangxi Province Thousands of Plans (No. jxsq2023201105); and the Hengrui Diabetes Metabolism Research Fund (No. Z-2017-26-2202-4).

Bin Zeng: Conceptualization, Writing - Original Draft, Writing - Review & Editing Preparation, Supervision, Funding acquisition.

Yi-Nuo Liu: Conceptualization, Writing - Original Draft, Writing - Review & Editing Preparation.

Jia-Wei Xua: Writing - Original Draft, Writing - Review & Editing Preparation.

Li-Yan Niu: Visualization, Writing - Review & Editing Preparation.

Yuting Wu: Writing - Review & Editing Preparation.

De-Ju Zhang: Writing - Review & Editing Preparation.

Xiao-Yi Tang: Writing - Review & Editing Preparation.

Zi-Cheng Zhu: Visualization.

Yi-Xuan Chen: Visualization.

Lei-Lei Hu: Visualization.

Shu-Chun Yu: Visualization.

Peng Yu: Conceptualization, Writing - Review & Editing Preparation, Supervision, Project administration, Funding acquisition.

Wen-Ting Wang: Conceptualization, Supervision.

Jing Zhang: Conceptualization, Supervision, Funding acquisition.

Bin Zeng, Yinuo Liu, and Jiawei Xu are co-first authors.