Machine Learning Analysis of Single-Cell Transcriptomics Identifies a B-Cell-Associated Fibroblast Signature Predictive of Renal Fibrosis Severity.

Background: Renal fibrosis represents the final common pathway of chronic kidney disease (CKD); however, both its definitive diagnostic biomarkers and the principal cellular mediators driving its progression remain incompletely characterized. Objective: To derive a machine-learning-based transcriptomic signature from single-cell RNA-sequencing data that predicts kidney fibrosis severity and elucidates the underlying immune-stromal cellular interactions. Methods: A machine-learning approach incorporating Random Forest and Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to identify a sparse transcriptomic signature. Cell-cell communication networks and pseudotime trajectories were reconstructed to characterize the fibrotic niche. The five-gene signature (CXCL13, CCL19, TNFSF13B, IL6, and TGFB1) was then correlated with eGFR, UACR, and Banff scores, and externally validated in the independent human kidney scRNA-seq dataset GSE183276. Results: The fibrotic kidney microenvironment exhibited a marked expansion of fibroblasts and CD19+ B-cells. Machine-learning feature selection identified a highly predictive five-gene molecular signature comprising CXCL13, CCL19, TNFSF13B (encoding BAFF), IL6, and TGFB1. Intercellular network analysis revealed dominant B-cell-fibroblast signaling that was significantly associated with fibroblast transdifferentiation into extracellular matrix-producing myofibroblasts. The signature score correlated with eGFR, UACR, and Banff scores. External validation in the independent dataset GSE183276 confirmed the diagnostic robustness of this signature. Conclusion: We present a validated machine-learning -derived transcriptomic signature that reflects the immune-stromal dynamics of renal fibrosis. This five-gene signature accurately predicts CKD severity and, importantly, implicates B-cell-mediated fibroblast activation as a promising diagnostic biomarker and a potential therapeutic target.