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Kidney Week

Abstract: FR-PO017

Proximal Tubule Neighborhood in AKI, CKD, and Healthy Control Kidney Tissue Using Spatial Transcriptomics

Session Information

Category: Augmented Intelligence, Digital Health, and Data Science

  • 300 Augmented Intelligence, Digital Health, and Data Science

Authors

  • Asghari, Mahla, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Melo Ferreira, Ricardo, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Cheng, Ying-Hua, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Gisch, Debora L., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Barwinska, Daria, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Sabo, Angela R., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Himmelfarb, Jonathan, University of Washington School of Medicine, Seattle, Washington, United States
  • Dagher, Pierre C., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Winfree, Seth, University of Nebraska Medical Center, Omaha, Nebraska, United States
  • Jain, Sanjay, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
  • El-Achkar, Tarek M., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Eadon, Michael T., Indiana University School of Medicine, Indianapolis, Indiana, United States

Group or Team Name

  • KPMP.
Background

The interaction of proximal tubules (PTs) with neighboring immune, stromal, and endothelial cells may impact their physiological functions. Using spatial transcriptomics (ST), we sought to establish the spatially anchored microenvironments of the PT across kidney samples in chronic kidney disease (CKD), acute kidney injury (AKI) and healthy human kidney biopsy samples.

Methods

We interrogated 23 samples from the HuBMAP, Kidney Precision Medicine Project (KPMP) and Biopsy Biobank Cohort of Indiana with Visium ST. Cell labeling was performed using a transfer score methodology of the publicly available snRNAseq atlas. Label score vectors were utilized to cluster and identify niches in R. Pathway analysis was performed in PathfindR.

Results

Clustering revealed 33 distinct PT neighborhood clusters with colocalization of injured PTs, stromal cell and immune cell dominant PT neighborhoods. The adjusted p-value of 0.05 was considered as the significance threshold. Adaptive PT (aPT) enriched clusters in AKI revealed increases in injury, repair, and immune responses compared to normal PTs. Pathway enrichment displayed activation of ERK1/2 cascade, TOR signaling, neutrophil chemotaxis, positive regulation of interleukin−2 production and T cell receptor signaling pathways. CKD samples were enriched for B and plasma cell niches. Upregulation of immunoglobulin genes and pathways contributing to activation of complement cascade were observed in CKD.

Conclusion

Distinct cell type compositions were identified within normal and disease cell clusters. ST facilitated spatial anchoring of cells within the kidney. The neighborhood analyses of PTs in disease and health provide insights into alteration of cell networks in kidney disease.

Funding

  • NIDDK Support