Department of Nephrology, The First Hospital Affiliated to Jinan University, No. 613 Huangpu West Road, Guangzhou, 510630, China.
Central Laboratory, The Fifth Hospital Affiliated to Jinan University, Heyuan, China.
Syst Rev. 2022 Sep 8;11(1):197. doi: 10.1186/s13643-022-02003-5.
Acute kidney injury (AKI) induced by ischemia/reperfusion injury significantly contribute to the burden of end-stage renal disease. Extracellular vesicles (EVs), especially for stem/progenitor cell-derived EVs (stem/progenitor cell-EVs), have emerged as a promising therapy for ischemia/reperfusion injury-induced AKI. However, their regulatory effects remain poorly understood, and their therapeutic efficiency in clinical trials is controversial. Here, we performed this systematic review and meta-analysis to assess the stem/progenitor cell-EV efficacy in treating ischemia/reperfusion injury-induced AKI in preclinical rodent models.
A literature search was performed in PubMed, Embase, Scopus, and Web of Science to identify controlled studies about the therapeutic efficiency of stem/progenitor cell-EVs on ischemia/reperfusion injury-induced AKI rodent models. The level of SCr, an indicator of renal function, was regarded as the primary outcome. Meta-regression analysis was used to reveal the influential factors of EV therapy. Sensitivity analysis, cumulative meta-analysis, and assessment of publication bias were also performed in our systematic review and meta-analysis. A standardized mean difference (SMD) was used as the common effect size between stem/progenitor cell-EV-treated and control groups, with values of 0.2, 0.5, 0.8, and 1.0 defined as small, medium, large, and very large effect sizes, respectively.
A total of 30 studies with 985 ischemia/reperfusion injury-induced AKI rodent models were included. The pooled results showed that EV injection could lead to a remarkable sCr reduction compared with the control group (SMD, - 3.47; 95%CI, - 4.15 to - 2.80; P < 0.001). Meanwhile, the EV treatment group had lower levels of BUN (SMD, - 3.60; 95%CI, - 4.25 to - 2.94; P < 0.001), indexes for tubular and endothelial injury, renal fibrosis (fibrosis score and α-SMA), renal inflammation (TNF-α, IL-1β, iNOS, and CD68 + macrophages), but higher levels of indexes for tubular proliferation, angiogenesis-related VEGF, and reactive oxygen species. However, our meta-regression analysis did not identify significant associations between sCr level and cell origins of EVs, injection doses, delivery routes, and therapy and outcome measurement time (all P values > 0.05). Significant publication bias was observed (Egger's test, P < 0.001).
Stem/progenitor cell-EVs are effective in improving renal function in rodent ischemia/reperfusion injury-induced AKI model. These vesicles may help (i) reduce cell apoptosis and stimulate cell proliferation, (ii) ameliorate inflammatory injury and renal fibrosis, (iii) promote angiogenesis, and (iv) inhibit oxidative stress. However, the current systematic review and meta-analysis did not identify significant influential factors associated with treatment effects. More preclinical studies and thoughtfully designed animal studies are needed in the future.
缺血/再灌注损伤引起的急性肾损伤（AKI）显著增加了终末期肾病的负担。细胞外囊泡（EVs），特别是干细胞/祖细胞衍生的 EV（干细胞/祖细胞-EVs），已成为治疗缺血/再灌注损伤诱导的 AKI 的一种很有前途的疗法。然而，其调节作用仍知之甚少，其在临床试验中的治疗效果存在争议。在这里，我们进行了这项系统评价和荟萃分析，以评估干细胞/祖细胞-EV 在治疗缺血/再灌注损伤诱导的 AKI 啮齿动物模型中的疗效。
在 PubMed、Embase、Scopus 和 Web of Science 中进行文献检索，以确定关于干细胞/祖细胞-EVs 治疗缺血/再灌注损伤诱导的 AKI 啮齿动物模型的疗效的对照研究。肾功能指标血清肌酐（SCr）水平被视为主要结局。采用元回归分析来揭示 EV 治疗的影响因素。我们的系统评价和荟萃分析还进行了敏感性分析、累积荟萃分析和发表偏倚评估。标准化均数差（SMD）被用作干细胞/祖细胞-EV 治疗组与对照组之间的共同效应大小，0.2、0.5、0.8 和 1.0 分别定义为小、中、大、非常大效应大小。
共有 30 项研究纳入了 985 个缺血/再灌注损伤诱导的 AKI 啮齿动物模型。汇总结果显示，与对照组相比，EV 注射可显著降低 sCr 水平（SMD，-3.47；95%CI，-4.15 至-2.80；P<0.001）。同时，EV 治疗组的 BUN（SMD，-3.60；95%CI，-4.25 至-2.94；P<0.001）、肾小管和内皮损伤、肾纤维化（纤维化评分和α-SMA）、肾炎症（TNF-α、IL-1β、iNOS 和 CD68+巨噬细胞）水平也较低，但肾小管增殖、血管生成相关 VEGF 和活性氧的水平较高。然而，我们的元回归分析并未发现 sCr 水平与 EV 细胞起源、注射剂量、给药途径以及治疗和结局测量时间之间存在显著相关性（所有 P 值均>0.05）。观察到显著的发表偏倚（Egger 检验，P<0.001）。
干细胞/祖细胞-EVs 可有效改善缺血/再灌注损伤诱导的 AKI 模型中肾功能。这些囊泡可能有助于：（i）减少细胞凋亡并刺激细胞增殖；（ii）改善炎症损伤和肾纤维化；（iii）促进血管生成；（iv）抑制氧化应激。然而，目前的系统评价和荟萃分析未发现与治疗效果相关的显著影响因素。未来需要更多的临床前研究和精心设计的动物研究。
