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

Abstract

Background: Acute kidney injury (AKI) is common in SARS-CoV-2 infection and COVID-19, often leading to long-term kidney dysfunction. However, the transcriptomic features of AKI severity and its long-term effects are underexplored.

Methods: We performed bulk RNA sequencing on peripheral blood mononuclear cells (PBMCs) from hospitalized SARS-CoV-2 patients and complemented these findings with proteomic data from the same cohort. We compared the functional enrichment findings with historical sepsis-AKI data and subsequently examined the association between molecular signatures and long-term kidney function changes.

Results: In 283 patients, 57 had mild AKI (stage 1) and 49 had severe AKI (stage 2 or 3). Following adjustments for age, sex, severity of infection, and pre-existing chronic kidney disease (CKD), we identified 6,432 differentially expressed genes (DEGs) in the severe AKI vs. control comparison, 840 in the mild AKI vs. control, and 1,213 in the severe vs. mild AKI comparison (FDR<0.05). Common pathways included unfolded protein response, cellular response to stress via eIF2, and IFN-g-mediated inflammatory response. Severe AKI was linked to pathways involved in mitochondrial dysfunction and endoplasmic reticulum stress. Proteomic analysis confirmed 40 established AKI and inflammation biomarkers, while gene-set enrichment of transcription regulators revealed additional biomarkers for severe AKI. Comparison with PBMC transcriptomics from sepsis-related AKI showed significant functional overlap (30%). Analysis of post-discharge eGFR data in 115 patients identified 177 DEGs for severe vs. control, 106 for mild vs. control, and 46 for severe vs. mild AKI. Key associations included kidney function decline related to carbohydrate and mitochondrial metabolism, inflammatory-response, and cardiovascular regulation.

Conclusions: We demonstrate that severe AKI in SARS-CoV-2 infection is linked to mitochondrial dysfunction and ER stress. The functional overlap with sepsis-AKI suggests potential broader therapeutic applicability. Long-term kidney dysfunction is influenced by disruptions in cellular energy metabolism and immune response.