Kidney Week

Abstract: FR-OR20

Proximal Tubular Epithelial Cell States in KPMP Protocol Kidney Biopsies Are Linked to Short-Term AKI Patient Outcomes

Session Information

• AKI Research: Mechanisms
  November 04, 2022 | Location: W230, Orange County Convention Center‚ West Building
  Abstract Time: 05:51 PM - 06:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Schaub, Jennifer A., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Jennifer A. Schaub, MD

• Menon, Rajasree, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Rajasree Menon,

• Bhatraju, Pavan K., Washington University in St Louis, St Louis, Missouri, United States

Pavan K. Bhatraju,

• Melo ferreira, Ricardo, Indiana University, Bloomington, Indiana, United States

Ricardo Melo ferreira,

• Lake, Blue, University of California San Diego, La Jolla, California, United States

Blue Lake,

• Otto, Edgar A., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Edgar A. Otto,

• Sealfon, Rachel S., Princeton University, Princeton, New Jersey, United States

Rachel S. Sealfon,

• Troyanskaya, Olga, Princeton University, Princeton, New Jersey, United States

Olga Troyanskaya,

• Hodgin, Jeffrey B., University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Jeffrey B. Hodgin,

• Barisoni, Laura, Duke University School of Medicine, Durham, North Carolina, United States

Laura Barisoni,

• Eadon, Michael T., Indiana University, Bloomington, Indiana, United States

Michael T. Eadon,

• Zhang, Kun, University of California San Diego, La Jolla, California, United States

Kun Zhang,

• Victoria Castro, Angela Maria, Yale School of Medicine, New Haven, Connecticut, United States

Angela Maria Victoria Castro,

• Wilson, Francis Perry, Yale School of Medicine, New Haven, Connecticut, United States

Francis Perry Wilson,

• Murugan, Raghavan, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Raghavan Murugan,

• Rosengart, Matthew Randall, University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Matthew Randall Rosengart,

• Palevsky, Paul M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States

Paul M. Palevsky,

• Jain, Sanjay, Washington University in St Louis, St Louis, Missouri, United States

Sanjay Jain,

• Himmelfarb, Jonathan, Washington University in St Louis, St Louis, Missouri, United States

Jonathan Himmelfarb,

• Kretzler, Matthias, University of Michigan Michigan Medicine, Ann Arbor, Michigan, United States

Matthias Kretzler,

Group or Team Name

• KPMP

Background

Acute Kidney Injury (AKI) is a heterogeneous syndrome making it challenging to identify biological underpinnings for poor outcomes. Linking sub-phenotypes, such as resolving and non-resolving AKI, with single cell RNA sequencing data may help identify relevant biologic signatures. As part of Kidney Precision Medicine Project (KPMP), we performed an integrated tissue level analysis from 19 participating AKI patients.

Methods

Clinical assessment of AKI resolution 72 hours post diagnosis was performed on the AKI patients, classified as ‘resolving’ versus ‘non-resolving’. Resolving AKI was defined as “decrease in the concentration of sCr of 0.3 mg/dl or more or 25% or more from maximum in the first 72 hours after AKI diagnosis” (PMC7154800). Single cell and single nucleus analyses (sc/sn) (10x Chromium) and spatial transcriptomic data (visium) were performed on biopsy samples from AKI patients. Cell clusters were annotated using the integrated analysis of AKI sc/sn datasets per KPMP atlas (bioRxiv 2021.07.28.454201).

Results

107,119 sc/sn post QC from the 19 AKI samples clustered to 71 cell types/states. A global differential expression analysis across all cell types/states between resolving (n=6) and non-resolving (n=13) samples resulted in 231 genes that were significantly differentially expressed (adj p value < 0.05). Majority of these genes were enriched in the degenerative (5,990 sc, 4,177 sn) and adaptive (6,134 sc, 13,237 sn) states of the proximal tubular epithelial cell; Immune-related processes were enriched for these genes. Ligand receptor analysis indicated multiple potential interactions between T cells and these two proximal tubular cell states. Moreover, we were able to identify a similar adaptive proximal cell state using spatial transcriptomic technology in resolving AKI kidney biopsy tissue.

Conclusion

Using integrated analysis of single cell expression data with a clinical assessment variable, we identified a molecular signature enriched in adaptive and degenerative cell states of proximal epithelial cells linked to short term outcomes in AKI.

Funding

• NIDDK Support