Cellular and Spatial Drivers of Unresolved Injury and Functional Decline in the Human Kidney

Area of Science:

• Nephrology
• Genomics
• Systems Biology

Background:

• Kidney disease pathogenesis involves complex interactions between injured kidney cells and their environment.
• Understanding cellular repair mechanisms is crucial for distinguishing recovery from chronic disease progression.

Purpose of the Study:

• To create a multi-modal atlas of human kidney disease, defining spatial and molecular features of repair and non-repair states.
• To identify key cellular transitions, gene regulatory networks, and biomarkers associated with kidney injury and repair.

Main Methods:

• Integrated single-cell and spatial multi-omics data from human kidney biopsies and mouse models.
• Analyzed ~1.7 million human cells and >300,000 mouse cells, including spatial transcriptomics from >150 human biopsies.
• Performed gene regulatory network analysis and linked molecular signatures to clinical outcomes.

Main Results:

• Delineated spatially resolved repair states and mechanisms in human kidney disease.
• Identified distinct cellular states and spatial niches associated with acute kidney injury (AKI) and chronic kidney disease (CKD).
• Prioritized key transcription factors (e.g., SOX4, SOX9) and identified biomarkers predictive of AKI-to-CKD progression.

Conclusions:

• The developed atlas provides a comprehensive resource for understanding kidney disease progression and repair.
• Identified druggable targets and molecular signatures crucial for therapeutic development in kidney disease.
• Established links between gene regulatory programs, cellular states, spatial niches, and clinical outcomes in kidney disease.