Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, contributing to an estimated 5.3 million global deaths annually (Evans et al., 2021; Fleischmann et al., 2016). The harm not only comes from uncontrolled infection and systemic inflammation but also from complications that accelerate deterioration and increase mortality. Sepsis-associated acute kidney injury (SA-AKI) is a frequent complication among patients with sepsis. A prospective cohort study across 24 European countries revealed that the incidence of AKI in sepsis ranged from 30% to 50%, with a greater incidence observed in severe sepsis or septic shock cases (Vincent et al., 2006). Epidemiological studies from the United States and China indicate that SA-AKI occurs in approximately 20%–25% of all septic patients admitted to intensive care units, highlighting its substantial clinical burden (Wang et al., 2021; Takeuchi et al., 2025). Recent prognostic tools such as the LIP score, which integrates lymphocyte count, INR, and procalcitonin, highlight progress in sepsis risk stratification (Liu et al., 2022). Nevertheless, therapeutic strategies specifically targeting SA-AKI remain scarce. The mortality among patients with SA-AKI is significantly greater than those without kidney injury, reaching up to 41% (Pais et al., 2024). Clinically, SA-AKI often manifests as oliguria or anuria, accompanied by refractory metabolic acidosis and fluid overload, which exacerbates prognosis. Beyond the systemic inflammatory response caused by sepsis, SA-AKI involves renal injury mechanisms, including renal tubular epithelial cell damage, a decreased glomerular filtration rate, changes in renal hemodynamics, and excessive activation of inflammatory mediators within the kidney (White et al., 2023). Therefore, SA-AKI not only poses an immediate threat to patient survival but is also associated with long-term renal dysfunction and chronic kidney disease, with some survivors progressing to end-stage renal disease requiring lifelong dialysis or transplantation (Vijayan et al., 2021).

Currently, except for supportive care and timely renal replacement therapy, there is no specific treatment for SA-AKI. The primary therapeutic objectives involve preventing further renal impairment by optimizing hemodynamics and avoiding nephrotoxic agents through fluid resuscitation and anti-infection strategies (Pickkers et al., 2021). However, fluid resuscitation in patients with renal insufficiency may exacerbate fluid load, potentially worsening renal function. Studies indicate that continuous renal replacement therapy utilizing blood purification techniques, can rapidly remove inflammatory mediators from the systemic circulation, thereby attenuating renal tubular epithelial cell injury. However, there is still a lack of internationally treatment regimens for blood purification, resulting in application that often relies on local clinical expertise (Zou et al., 2022). In addition, the high cost of blood purification restricts its utilization in areas with low economic levels (Taha et al., 2024). Therefore, there is a need to investigate more cost-effective therapeutic interventions for SA-AKI.

In China, the therapeutic potential of traditional Chinese medicine in managing sepsis and its complications has garnered growing interest. Xuebijing injection, launched in 2004, is the only standardized traditional Chinese medicine formulation approved by the Chinese National Health Commission for treating sepsis and systemic inflammatory response syndrome, and it was approved for severe COVID-19 in 2020 (Hu, 2023). Mechanistically, SA-AKI involves a dual pathological process: an uncontrolled systemic inflammatory response—often termed a “cytokine storm”, marked by excessive release of TNF-α, IL-6, and IL-10—coexists with immune suppression, characterized by T cell dysfunction and reduced immune surveillance. This imbalance contributes to endothelial injury, microcirculatory dysfunction, and progressive renal parenchymal damage. Key metabolites in Xuebijing, including hydroxysafflor yellow A, paeoniflorin, ligustrazine, salvianolic acids, and ferulic acid, have demonstrated strong binding affinity to core targets within the NF-κB and related signaling pathways. Experimental investigations indicate that these metabolites not only suppress the overproduction of pro-inflammatory cytokines but also enhance T-cell-mediated immunity, improve microcirculatory perfusion, and preserve residual renal function. These pharmacological effects directly target the inflammation-immune dysregulation axis implicated in SA-AKI (Chen et al., 2023).

Since its introduction into clinical practice, Xuebijing injection has been utilized in the management of SA-AKI, and multiple randomized controlled trials (RCTs) have been conducted to evaluate its efficacy. However, the results across these trials are inconsistent and often limited by small sample sizes and inadequate statistical power. Previous systematic reviews have assessed the effects of Xuebijing injection on sepsis in general rather than specifically focusing on SA-AKI, or have assessed its role in non-septic AKI; no systematic reviews have exclusively focused on the efficacy and safety of Xuebijing injection in SA-AKI (Zheng et al., 2018; Li et al., 2023). Moreover, existing systematic reviews exhibit methodological shortcomings, including frequent absence of protocol registration, suboptimal risk-of-bias assessments, and limited appraisal of quality of evidence. Additionally, the safety profile of Xuebijing injection specifically in SA-AKI patients remains unassessed. Therefore, we conduct this systematic review of RCTs to investigate both the efficacy and safety of Xuebijing injection in SA-AKI, aiming to provide comprehensive evidence for its clinical application in this specific condition.

SA-AKI not only significantly increases the length of hospital stay, medical costs, and mortality but also raises the risk of post-discharge complications, including cardiovascular events and chronic kidney disease (Luo et al., 2022). Traditional Chinese medicine injections, known for their rapid onset of action, are suitable for critical care settings and offer a promising therapeutic option for SA-AKI. Although a previous meta-analysis investigated the use of Xuebijing injection for severe sepsis (Zhong et al., 2022), it had notable limitations: the literature search was incomplete (only seven studies were included), key methodological elements such as TSA and GRADE evaluation were lacking, and it did not specifically address kidney injury. In contrast, our systematic review included a total of 18 RCTs that specifically focused on SA-AKI and performed a comprehensive assessment that included critical care outcomes, such as the APACHE II score and inflammatory cytokines. The findings demonstrate that Xuebijing injection significantly reduced 28-day mortality and increased kidney function, immune function, and APACHE II scores in patients with SA-AKI. It also had positive effects on reducing the levels of inflammatory cytokines. Beyond sepsis, a recent systematic review demonstrated that Xuebijing also improved pulmonary ventilation parameters in acute pancreatitis (Bin et al., 2025), underscoring its systemic immunomodulatory potential.

The treatment of sepsis mainly depends on three aspects: controlling the excessive release of inflammatory cytokines, regulating the host’s septic response, and stabilizing hemodynamics (Lelubre and Vincent, 2018). Pathophysiological studies have shown that septic patients with AKI exhibit more significant systemic inflammation (e.g., increased levels of TNF-α, IL-6, and IL-10) than those without AKI (Matejovic et al., 2017). This heightened inflammatory state can cause cellular inflammatory cytokine storms and immunosuppression, promote platelet activation and aggregation, and ultimately lead to inflammatory tissue damage (Fani et al., 2018). A study based on serum pharmacochemistry revealed that Salvia miltiorrhiza, a key component of Xuebijing injection, is rich in phenolic acids such as protocatechuic acid and salvianolic acids A, B, and C (Yuan et al., 2024). These metabolites significantly inhibit the expression and release of inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6) induced by podocyte injury, which helps improve renal insufficiency caused by podocyte dysfunction and prevents renal parenchymal damage. This mechanism may explain why the Xuebijing injection group achieved greater reductions in serum creatinine and blood urea nitrogen levels.

The kidney is rich in capillaries, and sepsis-mediated microcirculatory dysfunction can lead to hypoperfusion, hypooxygenation, and a high-lactate state within the kidney (Liu et al., 2021). Animal experiments revealed that have identified 12 bioactive metabolites derived from Xuebijing injection—such as hydroxysafflower yellow A, paeoniflorin, oxypaeoniflorin, paeonifloride, and danshensu hexa—that exhibit widespread systemic distribution (Cheng et al., 2024). These metabolites not only improve the function of regulatory T cells and promote the proliferation of CD4⁺ effector T cells but also reduce levels of inflammatory cytokines in both serum and major organs, alleviate kidney damage, and improve coagulation function and vasodilation (Shen et al., 2023; Ge et al., 2023; Zhang and Wei, 2020). Comparable evidence from other flavonoids supports this notion; a meta-analysis indicated that quercetin alleviates AKI in animal models via anti-inflammatory and antioxidant mechanisms (Zeng et al., 2023). The observed increase in urine volume in the Xuebijing injection group indirectly affirms the drug’s beneficial effect on restoring renal perfusion. In addition, Xuebijing injection was shown to increase the proportion of Th1 cells and increase the percentage of CD4⁺CD25⁺ cells, thereby regulating the immune response and reversing sepsis-associated immunosuppression (Li C. et al., 2021). This timely rescue of residual renal function also contributed to the improvement in APACHE II scores in the Xuebijing injection group.

Subgroup analysis suggested that a 200 mL/day dose of Xuebijing injection had a greater effect on reducing inflammatory cytokine levels compared with a 100 mL/day regimen. This finding is similar to those of previous studies. For example, Wang et al. (2023) reported that high-dose Xuebijing injection significantly improved the coagulation status, C-reactive protein level, and lactic acid level in patients with sepsis compared with low-dose treatment. Therefore, for SA-AKI patients who exhibit adequate tolerance, we recommend a dosage of 100 ml per administration to potentially achieve better efficacy.

Only two RCTs provided safety data. Adverse events in the Xuebijing injection group are mainly mild rash and nausea (Zhu and Wu, 2020; Yu, 2021). However, owing to the limited sample size, it cannot be directly concluded that Xuebijing injection has good tolerance. A broader safety evaluation, which incorporated data from 211 publications involving 46,384 patients receiving Xuebijing injection, documented 423 adverse reactions (Li Q. et al., 2021). More than half of these affected the skin (151 cases), cardiovascular system (68 cases), or gastrointestinal system (65 cases); common manifestations included rash, pruritus, palpitations, hypotension, nausea, vomiting, and diarrhea. These reactions were generally mild and resolved after drug discontinuation or symptomatic treatment. Studies suggest that safflower yellow A and ligustrazine in Xuebijing injection may act as allergens. They could stimulate the production of antibodies or sensitize lymphocytes, potentially triggering allergic reactions upon re-exposure (Liu et al., 2019). According to the “Basic Principles of Clinical Use of Chinese Medicine Injections” promulgated by the Chinese government, factors such as infusion rate, whether the intravenous line was flushed, history of allergies, age (particularly 60 years and older), and concomitant use with other TCM injections, antibacterial agents, or immune-enhancing drugs may be associated with an increased risk of adverse reactions (Sun, 2017). Therefore, we recommend strict adherence to operational procedures during the clinical administration of Xuebijing injection, including a slow infusion rate and close monitoring for high-risk populations.

This review has several limitations. First, none of the included studies reported the specific procedures for allocation concealment and blinding, which represents a major source of risk of bias and is one of the main reasons for downgrading the certainty of evidence in the GRADE assessment. Although the sensitivity analysis excluding studies with an overall high risk of bias did not reveal important differences—suggesting that the risk of bias had a limited impact on the conclusions—the lack of these methodological safeguards may still lead to overestimation of treatment effects. For example, studies without allocation concealment and blinding have been shown to be more likely to exaggerate treatment benefits (Savović et al., 2012). Therefore, the methodological weaknesses associated with risk of bias should be taken into consideration when interpreting the findings. Second, T-cell subsets are clinically important indicators of autoimmune status in patients with SA-AKI, but the number of studies and sample size were small, and the accuracy of the results was affected. Third, although subgroup analyses stratified by age, treatment dose, and treatment duration explaining some heterogeneity, substantial unexplained heterogeneity remained across several outcomes, which limits the robustness of the pooled estimates. Some prognostic factors, such as the type and severity of infection, baseline renal function, and comorbidities (e.g., diabetes or cardiovascular disease), may contribute to heterogeneity; however, due to the limited number of studies reporting these subgroup data, we were unable to perform further analyses. Fourth, evidence of publication bias was detected for serum creatinine, which reduces confidence in the observed renal benefits of Xuebijing injection. Nevertheless, the results of the trim-and-fill analysis were consistent with the direction of the primary analysis, implying that unpublished studies would not substantially alter the conclusions. Fifth, all included RCTs were conducted in China, raising concerns regarding external validity and generalizability. Variations in healthcare systems, clinical practice patterns, patient demographics, and ancillary treatment strategies across regions may limit the applicability of our findings to non-Chinese populations. Therefore, further multicenter trials across diverse populations are necessary before the applicability of Xuebijing injeciton can be confirmed internationally.

Xuebijing injection, when used as an adjunctive therapy for SA-AKI, may improve renal function, immune responses, and inflammatory status, and ultimately reduce mortality. However, as the certainty of evidence is limited by risk of bias, heterogeneity, and publication bias, high-quality, large-scale, double-blind RCTs are needed to validate these findings.