Acute kidney injury in severe COVID-19 has similarities to sepsis-associated kidney injury- a multi-Omics study

Alexander, Mariam P.; Mangalaparthi, Kiran K.; Madugundu, Anil K.; Moyer, Ann M.; Adam, Benjamin A.; Mengel, Michael; Singh, Smrita; Herrmann, Sandra M.; Rule, Andrew D.; Cheek, E. Heidi; Herrera Hernandez, Loren P.; Graham, Rondell P.; Denic, Aleksander; Aubry, Marie-Christine; Roden, Anja C.; Hagen, Catherine E.; Quinton, Reade A.; Bois, Melanie C.; Lin, Peter T.; Maleszewski, Joseph J.; Cornell, Lynn D.; Sethi, Sanjeev; Pavelko, Kevin D.; Charlesworth, Jon; Narasimhan, Ramya; Larsen, Christopher P.; Rizza, Stacey A.; Nasr, Samih H.; Grande, Joseph P.; McKee, Trevor D.; Badley, Andrew D.; Pandey, Akhilesh; Taner, Timucin

Objective To compare COVID-19 acute kidney injury (AKI) to sepsis-AKI (S-AKI) the morphology, transcriptomic and proteomic characteristics of autopsy kidneys were analyzed. Patients and methods Individuals 18 years and older who died from COVID-19 and had an autopsy performed at Mayo Clinic between April 2020 to October 2020 were included. Morphological evaluation of the kidneys of 17 individuals with COVID-19 was performed. In a subset of 7 COVID-19 cases with post-mortem interval of ≤20 hours, ultrastructural and molecular characteristics (targeted transcriptome & proteomics analyses of tubulointerstitium) were evaluated. Molecular characteristics were compared to archived cases of S-AKI and non-sepsis causes of AKI (NS-AKI). Results The spectrum of COVID-19 renal pathology included macrophage dominant microvascular inflammation (glomerulitis and peritubular capillaritis), vascular dysfunction (peritubular capillary congestion & endothelial injury), tubular injury with ultrastructural evidence of mitochondrial damage. Investigation of the spatial architecture using a novel imaging mass cytometry revealed enrichment of CD3+CD4+ T cells in close proximity to antigen-presenting cells, and macrophage-enriched glomerular and interstitial infiltrates, suggesting an innate and adaptive immune tissue response. COVID-19 AKI and S-AKI, as compared to NS-AKI, had an enrichment of transcriptional pathways involved in inflammation (apoptosis, autophagy, MHC class I and II, and Th1 differentiation). Proteomic pathway analysis demonstrated that COVID-19 AKI & to a lesser extent S-AKI was enriched in necroptosis and sirtuin signaling pathways, both involved in regulatory response to inflammation. Upregulation of ceramide signaling pathway and downregulation of oxidative phosphorylation in COVID-19 AKI was noted. Conclusions This data highlights the similarities between S-AKI and COVID-19 AKI and suggests that mitochondrial dysfunction may play a pivotal role in COVID-19 AKI. This data may allow the development of novel diagnostic and therapeutic targets.