The correlation between serum angiopoietin-2 levels and acute kidney injury (AKI): a meta-analysis

Background

Acute kidney injury (AKI) is emerging as a burgeoning burden on global health. Globally, one out of every five adults and one out of every three children encounter AKI during a hospital admission, accompanied by a high comorbidity rate, elevated mortality, and an extended hospital stay [1, 2]. AKI impacts 40–60 % of individuals admitted to the intensive care unit (ICU) [3], leading to unfavorable short- and long-term results [4]. In the ICU, AKI manifests as a sudden drop in renal function, indicated by elevated serum creatinine and/or diminished urine output. The occurrence of AKI in septic individuals prolongs ICU stays, escalates hospitalization costs, and leads to substantial long-term morbidity and mortality, particularly in cases of severe AKI. AKI is associated with poor outcomes; even in non-ICU hospitalized patients with AKI, mortality is typically 10–20 % [5, 6]. Timely identification and proactive intervention are crucial to avert unfavorable consequences. Thus, the identification of outcome-specific biomarkers in this patient population would be of great value for ICU physicians [7, 8].

Angiopoietin-2 is a protein involved in vascular formation and endothelial function regulation. Elevated levels of serum angiopoietin-2 are associated with the occurrence and severity of AKI. Angiopoietin-2 is believed to play a role in endothelial barrier disruption, inflammation, and impaired renal blood flow, all of which are key factors in the pathogenesis of AKI [9]. Angiopoietin-2, situated within the angiopoietin-Tie-2 signaling axis, is acknowledged for its dynamic contribution to the modulation of vascular stability and inflammation [10]. The maintenance of endothelial quiescence relies on the coordinated efforts of angiopoietin-1 and angiopoietin-2 in physiological conditions. In pathological conditions, such as inflammation or hypoxia, angiopoietin-2 disrupts the delicate balance, driving endothelial activation and resultant vascular leakage [11]. Early evidence from experimental studies in animal models revealed an upsurge in angiopoietin-2 expression in renal tissues during ischemic and nephrotoxic AKI [12]. A seminal study by Roviezzo et al. [11] demonstrated a notable upregulation of angiopoietin-2 expression within renal tissues during ischemic AKI. Experimental studies conducted by Fiedler et al. [13] revealed that elevated angiopoietin-2 levels were associated with increased vascular permeability and inflammation in the renal microenvironment following nephrotoxic insults. Robinson-Cohen et al. [14] reported plasma levels of endothelial biomarkers, especially angiopoietin-2, were significantly increased in critically ill patients with AKI, independent of inflammation, and angiopoietin-2 remained associated with the development of later onset AKI. These discoveries suggested a potential connection between angiopoietin-2 and the vascular disruptions observed in AKI. Over the course of research development, the focus transitioned from isolated assessments of angiopoietin-2 in AKI to a more holistic understanding of its clinical significance. Allegretti et al. [15] showed that angiopoietin-2 was associated with mortality and other clinically relevant outcomes in the patients with AKI. Liu et al. [16] also found that the levels of angiopoietin-2 may play an important role in development of AKI in patients with acute myocardial infarction. However, the intricate relationship between angiopoietin-2 levels and AKI development remains incompletely understood, necessitating a comprehensive investigation. This meta-analysis aims to bridge this gap by systematically synthesizing existing evidence to evaluate the correlation between serum angiopoietin-2 levels and the risk of AKI. By doing so, we seek to contribute valuable insights that can inform clinical practice and guide future research endeavors.

Methods

The systematic review and meta-analysis were executed following the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [17]. The protocol was registered in the International Prospective Register of Systematic Reviews with registration number CRD42023471523.

Results

Study selection

Initial retrieval through electronic search yielded 380 papers, with contributions from PubMed (80), Embase (155), Web of Science (129), and Cochrane Library (16). After deduplication, 276 studies persisted, and subsequent assessment of titles and abstracts led to the exclusion of 187 studies. A total of 71 studies were excluded after a careful assessment of the full texts due to non-compliance with eligibility criteria. Finally, 18 articles [14], [15], [16, 22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36] were deemed suitable for inclusion in the meta-analysis (Figure 1).

Figure 1:

PRISMA flow chart of literature selection.

Comparison of angiopoietin-2 levels between patients with and without AKI

There were 11 studies investigating the relationship between angiopoietin-2 levels and acute kidney injury. Significant heterogeneity (I²=93.2 %, p<0.001) is observed and a random effects model is applied. Serum angiopoietin-2 levels were significantly different between patients with and without AKI (WMD: 4.85; 95 % CI: 0.75–0.27) (Figure 2A). In subgroup analysis, serum angiopoietin-2 levels were significantly higher in adults with AKI (WMD: 5.17; 95 % CI: 3.51–6.83; I²=82.6 %, p<0.001) (Figure 2B), but not children with AKI. The results of subgroup analysis based on study type (Supplemental Figure S1) were completely consistent with the overall analysis results.

Figure 2:

Forest plots of angiopoietin-2 levels between patients with and without AKI. (A) Overall comparison; (B) subgroup analysis.

Association between angiopoietin-2 level and risk of AKI

Thirteen studies provided sufficient information about the correlation of angiopoietin-2 levels and risk of AKI. Significant heterogeneity (I²=89.1 %, p<0.001) is observed and a random effects model is applied. In this meta-analysis, high angiopoietin-2 levels are associated with an increased risk of AKI (OR: 1.58; 95 % CI: 1.39–1.8) (Figure 3A). The results of subgroup analysis based on study type (Figure 3B), endpoint (Figure 3C) and age (Figure 3D) were completely consistent with the overall analysis results.

Figure 3:

Forest plots of angiopoietin-2 level and risk of AKI. (A) Overall comparison; (B) subgroup analysis based on study type; (C) subgroup analysis based on endpoint; (D) subgroup analysis based on age.

Sensitivity analysis

In the sensitivity analysis, it was observed that excluding individual studies had negligible effects on the overall effect size (Figure 4).

Figure 4:

Sensitivity analysis examining the influence of individual studies on pooled results. (A) Angiopoietin-2 levels between patients with and without AKI; (B) angiopoietin-2 level and risk of AKI.

Publication bias

Publication bias was assessed through visual inspection of the funnel plot and Egger’s test. There was obvious asymmetry in the results of the funnel plot analysis for publication bias in the figure, as shown below (Figure 5). Egger’s test revealed evidence of publication bias for angiopoietin-2 levels between patients with and without TKI (Egger’s test: p<0.001) (Figure 5A) and angiopoietin-2 levels and the risk of AKI (Egger’s test: p=0.033) (Figure 5B). The ‘trim and fill’ analysis for angiopoietin-2 levels between patients with and without TKI indicated an estimated three missing studies, with the corresponding pooled mean difference estimate being 5.775 (95 % CI: 4.248, 7.851) (Supplemental Figure S2). For the ‘trim and fill’ analysis concerning angiopoietin-2 level and the risk of AKI, six missing studies were estimated, yielding a pooled odds ratio estimate of 1.189 (95 % CI: 1.165, 1.212) (Supplemental Figure S3).

Figure 5:

Funnel plot for publication bias. (A) Angiopoietin-2 levels between patients with and without AKI; (B) angiopoietin-2 level and risk of AKI.

Discussion

This meta-analysis focused on the correlation between angiopoietin-2 and acute kidney injury (AKI). The results revealed a significant difference in serum angiopoietin-2 levels between patients with and without AKI. Subgroup analysis highlighted elevated angiopoietin-2 levels in adults with AKI, but not in children. Furthermore, high angiopoietin-2 levels were associated with an increased risk of AKI. The association between endothelial dysfunction and AKI is multifaceted, reflecting the intricate interplay between vascular dynamics and renal function [37]. The endothelium, a key regulator of vascular homeostasis, plays a crucial role in maintaining renal perfusion and glomerular filtration [38]. Endothelial injury, as evidenced by elevated levels of von Willebrand factor (vWF) and soluble thrombomodulin (sTM), has been implicated in the pathogenesis of AKI [26]. Our meta-analysis focuses on angiopoietin-2, a vascular modulator with a dual role in maintaining endothelial quiescence and promoting vascular leakage under pathological conditions [10]. The observed elevation in serum angiopoietin-2 levels among individuals with AKI suggests its potential involvement in the endothelial dysfunction observed in AKI. This aligns with experimental evidence demonstrating increased angiopoietin-2 expression in renal tissues during ischemic and nephrotoxic AKI [11]. The observed elevation in serum angiopoietin-2 levels aligns with its recognized role as a key regulator of endothelial function. Angiopoietin-2 is intricately involved in the regulation of vascular permeability and inflammation, both pivotal aspects of endothelial dysfunction [39]. The consistent findings across clinical and experimental domains underscore the molecular basis of angiopoietin-2 in mediating endothelial responses during AKI. The connection between angiopoietin-2 and endothelial dysfunction is particularly relevant in the context of AKI, where disruption of renal microvascular integrity plays a central role in disease progression [14]. Angiopoietin-2’s ability to sensitize endothelial cells to inflammatory stimuli contributes to the dysregulation of vascular homeostasis observed in AKI [40]. The consistent elevation in angiopoietin-2 levels reinforces the notion that endothelial dysfunction is a central player in AKI pathogenesis. While these findings support the link between endothelial dysfunction and AKI, the specific mechanisms underlying angiopoietin-2-mediated effects warrant further exploration.

In endothelial cells, angiopoietin-2 is generated and stored within the Weibel-Palade bodies, where it coexists with von Willebrand factor (vWF). According to Kümpers et al., the glomerular endothelium of patients with lupus nephritis exhibited prominent protein expression of angiopoietin-2 in contrast to healthy subjects. Furthermore, they established a significant correlation between serum levels of angiopoietin-2 and the severity of systemic lupus erythematosus [41]. In ANCA-associated vasculitis with renal involvement, serum levels of angiopoietin-2 were significantly higher compared to patients with active limited granulomatous disease restricted to the respiratory tract or healthy subjects [42]. Taken together, these results suggest that the release of angiopoietin-2 from the renal endothelium is associated with inflammatory injury to the kidneys. In the context of sepsis, angiopoietin-2 is released into the circulation, leading to autocrine effects such as the disruption of the endothelial barrier and an elevation in microvascular permeability [43]. AKI stands as one of the prevailing organ dysfunctions associated with sepsis [12, 44]. According to Robinson-Cohen et al., plasma levels of endothelial biomarkers, especially angiopoietin-2, were significantly elevated in critically ill patients with AKI, independent of inflammation. Moreover, angiopoietin-2 retained its association with the subsequent onset of AKI 24 h later [14]. The observed elevation of serum angiopoietin-2 levels in patients with AKI suggests its potential as a clinically relevant biomarker for diagnostic and prognostic purposes. Our findings align with these efforts, emphasizing the clinical significance of angiopoietin-2 in identifying individuals at heightened risk for AKI. Moreover, the differential association between adults and children warrants attention, indicating that angiopoietin-2 may have age-specific implications that merit further investigation for refined clinical application. The renal response to injury varies across age groups, influenced by developmental factors, immune system maturation, and differences in nephron number and function. These age-specific dynamics may contribute to variations in the expression and response to angiopoietin-2 in the context of AKI [45]. Additionally, the underlying etiologies of AKI in adults and children often differ, with ischemic events and sepsis being more prevalent in adults, while congenital anomalies and infections are common in the pediatric population [46]. These distinct etiologies may further contribute to the observed differences in angiopoietin-2 levels in AKI.

Hypertension is a widespread medical condition with a high global prevalence [47]. The Renin-Angiotensin-Aldosterone System (RAAS), particularly the involvement of angiopoietin-2, holds a central role in the regulation of hypertension, emphasizing the intricate interrelationships between these elements [48]. The study by Lin et al. [26] delves into the relationship between hypertension, angiopoietin-2, and the development of AKI through regression analysis. Their findings illuminate the complex interplay between these factors, suggesting a potential contributory role of angiopoietin-2 in the pathogenesis of AKI, particularly in the context of hypertension (OR=3.79, 95 % CI 0.81–17.79). Additionally, the work of Liu et al. [16] further supports this association, revealing a significantly higher incidence of hypertension in patients with AKI compared to those without (84.6 vs. 44.5 %, p=0.008). Considering the intricate connections between RAAS, angiopoietin-2, hypertension, and AKI, our research serves as a stepping stone to unravel the underlying complexities of these relationships. However, it is crucial to acknowledge the limitations of the current statistical approach due to the scarcity of original research in this domain. While our study provides a foundation, there exists a critical need for more extensive original investigations employing robust statistical methodologies to further elucidate and quantify the associations between RAAS, angiopoietin-2, hypertension, and AKI.

While our meta-analysis provides valuable insights, it is imperative to acknowledge its inherent limitations. Firstly, this meta-analysis included studies with diverse designs, patient populations, and clinical contexts, introducing inherent heterogeneity. Variability in AKI etiologies, severity, and patient demographics may limit the generalizability of the findings. Secondly, the analysis may be susceptible to publication bias, as studies with statistically significant results are more likely to be published. Thirdly, variability in the methods used to measure angiopoietin-2 levels across studies, including differences in assay sensitivity, specificity, and standardization, introduces a potential source of bias. Fourthly, the included studies may employ different criteria for defining AKI, such as variations in serum creatinine thresholds or urine output criteria. This heterogeneity in AKI definitions could impact the accuracy and reliability of the meta-analysis results. Finally, the study is limited because of including data from one or more small studies. However, smaller studies are more likely to present superior findings. Because this phenomenon has been thoroughly documented in other fields [49].

Conclusions

In conclusion, our meta-analysis provides robust evidence supporting the correlation between elevated angiopoietin-2 levels and the risk of AKI. The clinical implications of this association are profound, offering potential avenues for early intervention and risk stratification. However, the complexity of AKI pathophysiology demands a nuanced understanding of angiopoietin-2’s role, considering its multifaceted involvement in angiogenesis, inflammation, and endothelial function. Future research should delve into the mechanistic aspects, exploring how angiopoietin-2 interacts with key pathways in renal injury. Additionally, prospective studies are warranted to validate angiopoietin-2 as a prognostic biomarker and assess its utility in guiding therapeutic interventions.