Peripheral Transcriptomics in Acute and Long-Term Kidney Dysfunction in SARS-CoV2 Infection

Background Acute kidney injury (AKI) is common in hospitalized patients with SARS-CoV2 infection despite vaccination and leads to long-term kidney dysfunction. However, peripheral blood molecular signatures in AKI from COVID-19 and their association with long-term kidney dysfunction are yet unexplored. Methods In patients hospitalized with SARS-CoV2, we performed bulk RNA sequencing using peripheral blood mononuclear cells(PBMCs). We applied linear models accounting for technical and biological variability on RNA-Seq data accounting for false discovery rate (FDR) and compared functional enrichment and pathway results to a historical sepsis-AKI cohort. Finally, we evaluated the association of these signatures with long-term trends in kidney function. Results Of 283 patients, 106 had AKI. After adjustment for sex, age, mechanical ventilation, and chronic kidney disease (CKD), we identified 2635 significant differential gene expressions at FDR<0.05. Top canonical pathways were EIF2 signaling, oxidative phosphorylation, mTOR signaling, and Th17 signaling, indicating mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Comparison with sepsis associated AKI showed considerable overlap of key pathways (48.14%). Using follow-up estimated glomerular filtration rate (eGFR) measurements from 115 patients, we identified 164/2635 (6.2%) of the significantly differentiated genes associated with overall decrease in long-term kidney function. The strongest associations were ‘autophagy’, ‘renal impairment via fibrosis’, and ‘cardiac structure and function’. Conclusions We show that AKI in SARS-CoV2 is a multifactorial process with mitochondrial dysfunction driven by ER stress whereas long-term kidney function decline is associated with cardiac structure and function and immune dysregulation. Functional overlap with sepsis-AKI also highlights common signatures, indicating generalizability in therapeutic approaches. SIGNIFICANCE STATEMENT Peripheral transcriptomic findings in acute and long-term kidney dysfunction after hospitalization for SARS-CoV2 infection are unclear. We evaluated peripheral blood molecular signatures in AKI from COVID-19 (COVID-AKI) and their association with long-term kidney dysfunction using the largest hospitalized cohort with transcriptomic data. Analysis of 283 hospitalized patients of whom 37% had AKI, highlighted the contribution of mitochondrial dysfunction driven by endoplasmic reticulum stress in the acute stages. Subsequently, long-term kidney function decline exhibits significant associations with markers of cardiac structure and function and immune mediated dysregulation. There were similar biomolecular signatures in other inflammatory states, such as sepsis. This enhances the potential for repurposing and generalizability in therapeutic approaches. ### Competing Interest Statement DISCLOSURES GNN and SGC report grants, personal fees, and non-financial support from Renalytix. GNN reports non-financial support from Pensieve Health, personal fees from AstraZeneca, personal fees from BioVie, personal fees from GLG Consulting, and personal fees from Siemens Healthineers from outside the submitted work. IP receives personal fees from Character Biosciences. ELT reports personal fees from Predigen and Biomeme and is currently employed by Danaher Diagnostics. None of the other authors have any other competing interests to declare. ### Clinical Protocols ### Funding Statement FUNDING This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant UL1TR004419 from the National Center for Advancing Translational Sciences. The research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD026880 and S10OD030463. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was funded by R01DK127139 and R01DK127139-S1. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This research was reviewed and approved by the Icahn School of Medicine at Mount Sinai Program for the Protection of Human Subjects (PPHS) under study number 20 00341 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability This research was reviewed and approved by the Icahn School of Medicine at Mount Sinai Program for the Protection of Human Subjects (PPHS) under study number 20 00341. The clinical data tables and analysis data are available in the Synapse repository syn35874390. Synapse can be accessed at https://www.synapse.org/#!Synapse:syn35874390. Subject IDs in the Supplementary Tables are public deidentified ids from the synapse repository