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Abstract: FR-OR09

A Spatially Anchored Transcriptomic Atlas of the Human Kidney Papilla Identifies Significant Immune Injury and Matrix Remodeling in Stone Disease Patients

Session Information

Category: Bone and Mineral Metabolism

  • 402 Bone and Mineral Metabolism: Clinical

Authors

  • Sabo, Angela R., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Canela, Victor Hugo, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Bowen, William S., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Melo ferreira, Ricardo, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Barwinska, Daria, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Winfree, Seth, University of Nebraska Medical Center, Omaha, Nebraska, United States
  • Lake, Blue, University of California San Diego Department of Bioengineering, San Diego, California, United States
  • Cheng, Ying-Hua, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • LaFavers, Kaice Arminda, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Zhang, Kun, University of California San Diego Department of Bioengineering, San Diego, California, United States
  • Coe, Fredric L., University of Chicago Department of Medicine, Chicago, Illinois, United States
  • Worcester, Elaine M., University of Chicago Department of Medicine, Chicago, Illinois, United States
  • Jain, Sanjay, Washington University in St Louis School of Medicine, St Louis, Missouri, United States
  • Eadon, Michael T., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Williams, James C., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • El-Achkar, Tarek M., Indiana University School of Medicine, Indianapolis, Indiana, United States

Group or Team Name

  • KPMP
Background

Kidney stone disease causes significant morbidity and health care utilization. The pathogenesis of this disease is incompletely understood. This is partly due to the poor characterization of the cellular and molecular makeup of the human papilla and its alteration with disease.

Methods

We utilized renal papillary biopsies obtained from calcium oxalate stone formers and non-stone formers. Specimens underwent single nuclear RNA sequencing (snRNAseq), spatial transcriptomics and/or high-resolution large-scale multiplexed 3D and Co-detection by indexing (CODEX) imaging. snRNAseq data from the Kidney Precision Medicine Project was used for comparison. A cohort including 58 patients and healthy volunteers was used for urine studies.

Results

We define and localize a complete landscape of papillary cells, which include surface epithelial cells, stromal and immune cells, unique subtypes of principal cells, and an undifferentiated epithelial cell type that was enriched in specimens from stone patients. Despite the focal nature of mineral deposition, we show that injury pathways such as immune activation, oxidative stress and matrix remodeling are globally upregulated across multiple cell types within the papilla of stone patients. We also characterize Randall’s plaque as an active immune zone with inflammatory macrophages and T cells and demonstrate the presence of an immune lifespan around mineral deposition ranging from inflammation to fibrosis. Finally, we show that two matrix metalloproteinase, MMP7 and MMP9, are linked to active stone disease and mineralization within the papilla, and that their levels in the urine correlate with disease activity.

Conclusion

Our integrated multiomics approach reveals the complexity of the human kidney papilla and provides insights into the role of immune system activation and matrix remodeling in mineral deposition and stone disease. We also identify MMP7 and MMP9 as potential noninvasive markers of kidney stone disease course and activity.

Funding

  • NIDDK Support