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Abstract: SA-OR51

A Multimodal Single Cell and Spatial Atlas of the Human Kidney in Health and Disease Delineates Cell States Associated with CKD Outcomes

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Jain, Sanjay, Washington University in St Louis, St Louis, Missouri, United States
  • Lake, Blue, University of California System, San Diego, California, United States
  • Menon, Rajasree, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Winfree, Seth, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Hu, Qiwen, Harvard Medical School, Boston, Massachusetts, United States
  • Melo ferreira, Ricardo, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Otto, Edgar A., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Barwinska, Daria, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Kalhor, Kian, University of California System, San Diego, California, United States
  • Ferkowicz, Michael J., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Naik, Abhijit S., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Murray, Evan, Broad Institute, Cambridge, Massachusetts, United States
  • Eddy, Sean, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Williams, James C., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Balderrama, Karol S., Broad Institute, Cambridge, Massachusetts, United States
  • Parikh, Chirag R., Johns Hopkins University, Baltimore, Maryland, United States
  • Kim, Eric H., Washington University in St Louis, St Louis, Missouri, United States
  • Kharchenko, Peter, Broad Institute, Cambridge, Massachusetts, United States
  • Gaut, Joseph, Washington University in St Louis, St Louis, Missouri, United States
  • Hodgin, Jeffrey B., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States
  • Eadon, Michael T., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Dagher, Pierre C., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • El-Achkar, Tarek M., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Zhang, Kun, University of California System, San Diego, California, United States
  • Kretzler, Matthias, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Group or Team Name

  • KPMP, HuBMAP
Background

The knowledge of the complexity of cell types, states and their interactions during homeostasis or disease is needed to identify the mechanisms of kidney disease.

Methods

We have applied multiple single cell or nucleus omic assays (>400,000 nuclei/cells) that capture gene regulation, expression and their spatial relationships to a broad spectrum of healthy reference (35) and disease kidney tissues (50, AKI or CKD) to establish a robust atlas of the cellular diversity representing kidney function or dysfunction.

Results

We identified 100 cell clusters including rare and novel cell populations and their spatial locations spanning the entire kidney. Among these, we define cellular states associated with kidney injury alterations that represent cycling, adaptive or maladaptive repair and degenerative states, their associated regulatory factors, and genes and pathways underlying these transitions. Molecular signatures of these states permit their classification and spatial localization within injury neighborhoods, allowing discovery of intercellular signaling relevant to acute or chronic injury. Large scale 3D imaging linked glomerular, proximal tubule and thick ascending limb injured cells to an active immune response that is uniquely associated with tubular cells. The altered state gene signatures were negatively associated with a decline in eGFR in patients with chronic kidney disease in two separate cohorts.

Conclusion

This comprehensive molecular, cellular and spatial atlas serves as a benchmark to identify nascent and altered kidney cell states, define therapeutic targets in individual patient samples and engineer healthy kidneys.

Funding

  • NIDDK Support