Causal association of circulating immune cells with nephrotic syndrome: evidence from a two-sample Mendelian randomization study.

Objective: 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.

Methods: 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.

Results: 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).

Conclusion: 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.