Acute Kidney Injury in Severe COVID-19 Has Similarities to Sepsis-Associated Kidney Injury

Abstract

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.

Kidney Injury in COVID-19: Epidemiology, Molecular Mechanisms and Potential Therapeutic Targets

“…More recent data suggest that, though not entirely overlapping, ATI in COVID-19 may share similar molecular mechanisms as septic AKI. A recent multi-omics study of seven COVID-19 kidney autopsy specimens demonstrated a similar transcriptomic and proteomic profile to that of seven control samples with non-COVID-19 septic AKI, with both profiles prominently featuring the presence of mitochondrial dysfunction [62].…”

“…3.1. Tubular Injury and Tubular Dysfunction as Primary Features of COVID-19-Associated AKI Multiple case series, including autopsy and biopsy studies, have shown that kidney disease in the setting of COVID-19 is most commonly due to acute tubular injury (ATI), often somewhat less severe than would be expected for the clinical severity of AKI; however, multiple glomerular pathologies, especially collapsing glomerulopathy, have also been reported [17,[60][61][62][63][64][65][66][67][68][69][70][71][72][73][74]. Collapsing glomerulopathy appears to occur most commonly in patients expressing high-risk APOL1 alleles [65][66][67][68][69][70][71].…”

Diffuse C4d staining of peritubular capillaries in renal allograft following bamlanivimab therapy

“…In kidney transplant recipients, mortality rate ranged between 24%−32% 14 . Acute tubular injury is one of the most common pathology in SARS‐CoV2 infection 15,16 . In kidney transplantation, acute rejection is found in 9.2% of the kidney transplant tranrecipients 17 .…”

Multi-Omics Techniques Make it Possible to Analyze Sepsis-Associated Acute Kidney Injury Comprehensively

“…Mariam P. Alexander et al. ( 128 ) compared COVID-19 AKI with SA-AKI, and analyzed the morphological, transcriptome, and proteomic characteristics of postmortem kidneys. Transcriptomics found that COVID-19 AKI and SA-AKI have a rich transcriptional pathway associated with inflammation (apoptosis, autophagy, major histocompatibility complex I and II, and Type 1 T-assisted cell differentiation) compared to non-infectious AKI; Proteomic pathway analysis showed that both of them were enriched to a lesser extent in necrotic apoptosis and Sirtuin signaling pathways, both of which are involved in the regulatory response of inflammation.…”