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Abstract: TH-PO083

AKI in Patients With SARS-CoV-2 Is Significantly Associated With Mitochondrial Dysfunction and ER Stress

Session Information

  • AKI: Mechanisms - I
    November 03, 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

  • Jayaraman, Pushkala, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Paranjpe, Ishan, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Vasquez-Rios, George, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Dellepiane, Sergio, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Nadkarni, Girish N., Icahn School of Medicine at Mount Sinai, New York, New York, United States

Group or Team Name

  • Augmented Intelligence in Medicine at Mount Sinai Group (AIMS group at D3M, MSSM)
Background

AKI is a common complication of COVID-19. The peripheral blood molecular signatures are unknown and could unveil potential therapeutic targets.

Methods

We enrolled a prospective patient cohort of 283 patients with COVID-19 (Mar 24-Aug 26, 2020), with blood samples from Mount Sinai Biobank. We determined AKI severity using KDIGO criteria on admission parameters. 31 patients with severe AKI (AKI 2-3) were defined as cases. We then performed bulk peripheral RNA sequencing and fit a multivariate linear regression model adjusting for key covariates. We also performed cell-type deconvolution following to adjust for neutrophils, and whole blood cells. We considered a significant p-value (0.05) after Bonferroni correction and then used ingenuity pathway analysis (IPA) to analyze differentially expressed genes.

Results

Patients who developed AKI were significantly older (67 vs. 60 yrs.) and had a greater prevalence of type 2 diabetes (37% vs 20%), and chronic kidney disease (20% vs 4%) vs. controls. Of the 18539 genes in the analysis, 1597 were upregulated and 1267 were downregulated after Bonferroni correction. Top canonical pathways (Fig 1) showed significantly downregulated genes including EIF2, eIF4, and p70S6K via activation of ATF6, a marker of ER stress. Potential mechanisms displayed by our analyses include upregulation of the NF-KB inhibitor and IL6 pathways. Genes involved in oxidative Phosphorylation and mitochondrial dysfunction were heavily downregulated and there was upregulation of markers of kidney cell necrosis. In contrast, upregulated genes CRK and TIMP2 have been previously implicated in kidney injury and progression. Downregulated mTOR pathway is responsible for the activation of the ER stress response via the eIF2/4 complex which is also supported by our finding of upregulated NRF2-transcriptional pathway.

Conclusion

Transcriptomic analysis of AKI in COVID-19 revealed evidence of mitochondrial dysfunction driven by ER stress and immune-mediated pathways. Addressing these pathways could aide development of targeted therapies.

Funding

  • NIDDK Support