Li Sheng, Zhou Xing, Liu Chengmeng, Wang Yijie, Zhou Qianhui, Sun Ting
Department of Nephrology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, China.
Department of Urology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, China.
Int Urol Nephrol. 2025 Jun;57(6):1907-1917. doi: 10.1007/s11255-024-04350-9. Epub 2024 Dec 30.
Nephrotic syndrome, a debilitating manifestation of kidney disease, often arises from diverse glomerular disorders and is accompanied by notable comorbidities. Despite indications of an immunological etiology, the precise role of immune cells in its pathogenesis remains unclear. This study aimed to elucidate the causal relationships between circulating immune cell phenotypes and nephrotic syndrome using a rigorous bidirectional Mendelian randomization approach.
We conducted a bidirectional Mendelian randomization analysis leveraging public genome-wide association studies (GWAS) datasets to investigate the causal links between 731 immune cell features and nephrotic syndrome. Our primary analysis employed inverse variance weighting (IVW), complemented by MR-Egger regression, simple model, weighted median method, and weighted model techniques to ensure robustness. Sensitivity analyses were performed to address potential biases arising from heterogeneity, horizontal pleiotropy, and single-nucleotide polymorphism (SNP) instability in nephrotic syndrome.
Among traits examined, 13 immune cell phenotypes were identified to have significant causal impacts on nephrotic syndrome (adjusted P > < 0.05). Among these phenotypes, CD25 on unswitched memory B cell, CD25 on memory B cell, CD25 on CD24 + CD27 + B cell, CD25 on IgD-CD38-B cell, CD33dim HLA DR-Absolute Count, and CD127 on granulocyte emerged as causal risk factors, while seven circulating immune cell phenotypes, predominantly monocyte subsets, exhibited protective effects. Furthermore, the reverse Mendelian randomization analysis demonstrated significant effects of nephrotic syndrome on 27 immune phenotypes (P < 0.05).
The genetic predictions indicate that multiple circulating immune cell phenotypes, particularly CD25 on specific B-cell subsets, serve as independent risk factors for the onset and progression of nephrotic syndrome. Conversely, monocytes expressing specific phenotypes may exert protective effects against the development of nephrotic syndrome. These findings offer a novel therapeutic approach for the prevention and treatment of nephrotic syndrome.
肾病综合征是一种使人衰弱的肾脏疾病表现形式，通常由多种肾小球疾病引起，并伴有显著的合并症。尽管有迹象表明其病因与免疫有关，但免疫细胞在其发病机制中的确切作用仍不清楚。本研究旨在使用严格的双向孟德尔随机化方法阐明循环免疫细胞表型与肾病综合征之间的因果关系。
我们利用公开的全基因组关联研究（GWAS）数据集进行了双向孟德尔随机化分析，以研究731种免疫细胞特征与肾病综合征之间的因果联系。我们的主要分析采用逆方差加权（IVW），辅以MR-Egger回归、简单模型、加权中位数法和加权模型技术以确保稳健性。进行敏感性分析以解决肾病综合征中异质性、水平多效性和单核苷酸多态性（SNP）不稳定性引起的潜在偏差。
在所检查的性状中，鉴定出13种免疫细胞表型对肾病综合征有显著因果影响（校正P > < 0.05）。在这些表型中，未转换记忆B细胞上的CD25、记忆B细胞上的CD25、CD24+CD27+B细胞上的CD25、IgD-CD38-B细胞上的CD25、CD33dim HLA DR绝对计数以及粒细胞上的CD127成为因果危险因素，而七种循环免疫细胞表型，主要是单核细胞亚群，表现出保护作用。此外，反向孟德尔随机化分析表明肾病综合征对27种免疫表型有显著影响（P < 0.05）。
遗传预测表明，多种循环免疫细胞表型，特别是特定B细胞亚群上的CD25，是肾病综合征发病和进展的独立危险因素。相反，表达特定表型的单核细胞可能对肾病综合征的发展发挥保护作用。这些发现为肾病综合征的预防和治疗提供了一种新的治疗方法。
