Renal microthrombosis and thrombomodulin deficiency in COVID-19-associated acute kidney injury.

BACKGROUND: Severe COVID-19 frequently involves multi-organ dysfunction, including acute kidney injury (AKI), which affects up to 85% of critically ill patients. While both direct viral infection and systemic effects are implicated, the role of renal microthrombosis remains poorly defined in COVID-19 and AKI. Angiopoietin-2, a pro-inflammatory cytokine, and cleaved thrombomodulin is elevated in plasma in severe COVID-19 and has been linked to endothelial dysfunction and hypercoagulability. We hypothesize that renal microthrombi can contribute to decreased kidney function in critically ill COVID-19 patients. METHODS: We performed histopathological and molecular analyses of postmortem kidney tissue from seven critically ill COVID-19 patients. Control tissue was obtained from nephrectomy specimens (n = 6) and postmortem tissue (n = 7). We assessed microthrombi, tubular necrosis, glomerulosclerosis, fibrosis, and expression of angiopoietin-2 and thrombomodulin. Immunofluorescence and SARS-CoV-2 nucleoprotein staining were used alongside clinical data. RESULTS: AKI was observed in six of seven COVID-19 patients. Compared to controls, COVID-19 kidneys showed a significant reduction in tubular nuclear area (P < 0.0003), presence of viral antigen in tubular epithelium, and marked glomerular and peritubular microthrombi (15.2 vs. 1.3 thrombi/mm²; P < 0.0001). THBD expression was significantly reduced bith peritubular capillaries and glomeruli in COVID-19 kidneys. Glomerulosclerosis, glomerular area, and tubulointerstitial fibrosis were variable in both control and COVID-19 patients with no significant differences. CONCLUSIONS: This study identifies widespread renal microthrombi, tubular necrosis, and reduced THBD expression in COVID-19 patients with AKI, supporting a role for endothelial dysfunction and microvascular thrombosis in COVID-19-associated renal injury. The data implicates the disruption of endothelial anticoagulant signaling through thrombomodulin as a contributing mechanism.