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Abstract: FR-PO116

Integration of Human Kidney Transcriptome and Plasma Proteome Identifies Novel Biomarkers of Proximal Tubule Maladaptation to Injury

Session Information

  • AKI: Mechanisms - II
    November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Wen, Yumeng, Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Su, Emily, Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Xu, Leyuan, Yale School of Medicine, New Haven, Connecticut, United States
  • Menez, Steven, Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Moledina, Dennis G., Yale School of Medicine, New Haven, Connecticut, United States
  • Palevsky, Paul M., University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Cantley, Lloyd G., Yale School of Medicine, New Haven, Connecticut, United States
  • Cahan, Patrick, Johns Hopkins Medicine, Baltimore, Maryland, United States
  • Parikh, Chirag R., Johns Hopkins Medicine, Baltimore, Maryland, United States

Group or Team Name

  • for the Kidney Precision Medicine Project (KPMP) and Translational Research in Biomarker Endpoints of Acute Kidney Injury (TRIBE-AKI) consortia
Background

There are no non-invasive approaches to identify maladaptive responses in proximal tubule (PT) after kidney injury.

Methods

We performed single nucleus RNA sequencing (snRNA-seq) analysis of kidney biopsy tissues from 6 participants with AKI and 7 healthy controls from the KPMP and HuBMAP consortia. We integrated differentially expressed genes in PT maladaptation with the plasma proteome (SomaScan) in cardiac surgery patients in the TRIBE-AKI cohort. We evaluated the association between post-operative plasma proteins of maladaptive and healthy PT with KDIGO stage 2-3 AKI after surgery. We also performed reverse translational studies and confirmed these findings in a mouse model of maladaptive kidney repair following unilateral ischemia-reperfusion injury.

Results

SnRNA-seq analysis of kidney biopsy tissue in participants with AKI identified the subgroup of maladaptive PT cells characterized by advanced dedifferentiation and enrichment of pro-fibrotic pathways. Integrating 923 differentially expressed genes in PT maladaptation in participants from KPMP with the post-operative plasma proteome on 4040 protein aptamers in participants from TRIBE-AKI, we identified 4 proteins whose genes were specifically upregulated, and 5 proteins whose genes were specifically downregulated by PT maladaptation. The increases in COL23A1, TGFB2 and NLGN4X, and decreases in ENPP6 and PLG protein aptamers post-operatively were strongly associated with development of severe AKI during hospitalization. (Figure 1) The upregulation in Col23a1 and Tgfb2, and the downregulation in Enpp6 were associated with kidney atrophy in the mouse model of maladaptive kidney repair.

Conclusion

A multiomics approach of human kidney tissue interrogation discovered multiple novel protein markers to assess PT maladaptation and health with severe AKI.

Funding

  • NIDDK Support