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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.

The fundamental tenet of modern biological understanding is therelationship between structure and function. That is, what something does is directly related to its shape, what it is made of, and the arrangement of its parts. This is true at each size scale from the organ system, to the tissue, the cell, the organelle, and finally at the molecular level. In order to decode mechanism in biology one must understand these relationships. Moreover, for this, it is especially important to appreciate cell and tissue context, macomolecular organization, organelle structure, function and integrity, and the relationship between formed elements in the cytoplasm with cell polarity, and the machinery of cell motility and division to name just a few.Recent advances in serial block face electron microscope imaging provide game-changing progress important for the understanding of diverse public health problems including aging, neurodegenerative disease, cancer, diabetes, kidney and liver disease, and developmental disorders, to name just a few. These techniques allow investigators to image macromolecular features and cell- and tissue-specific relationships at extremely high resolution in 3-D and in large overall volumes, which previously have been unattainable by conventional means. This information can then be digitally sampled, much like clinical MRI data sets. This approach allows gives the researcher an unparalleled view of biological structures at high resolution in 3-dimensional space bridging the gap between optical microscopy and standard transmission electron microscopy. In this presentation, we will discuss our Cores' experience with establishing a serial block face electron microscope service and the cyberinfrastructure to store, manage and analyze extremely large image data files forunderstanding cell and tissue architecture in human disease processes.