PMC:7464116 / 34401-39777 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7464116","sourcedb":"PMC","sourceid":"7464116","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7464116","text":"6. Histopathology\nAs mentioned before, the virus gains access to the kidney via the ACE-2receptor for which it uses to enter entrance to target cells [62,86,87] and it has been shown that the ACE-2 receptor of SARS-CoV-2 is highly expressed in renal proximal tubule cells [63,88,89]. Possible mechanisms for kidney injury in COVID-19 include direct infection of the renal parenchyma [47].\nDiao et al. [65] retrospectively analyzed the clinical data on renal function from 85 cases of COVID-19; a similar analysis on kidney abnormalities in 26 autopsies of COVID-19 patients was conducted by Su et al. [66]. Using light microscopy, ultrastructural observation and immunostaining have been very informative to understand the extent of kidney injury.\nLight microscopy examination using Hematoxylin and Eosin staining may show the extent of tubular atrophy and interstitial disease, these are strong histological markers of renal damage and may also predict progression of renal failure. Using light microscopy, proximal tubule injurywas observed with the loss of brush border and vacuolar degeneration with necrosis and detachment of the epithelium observed in the lumen of the tubules; dilatation of the tubular lumen was also noted together with cellular debris resulting from necrosed cells. Erythrocyte aggregates were also observed, causing obstruction of peritubular and glomerular capillary loops, with no obvious erythrocyte or platelet fragmentation or any fibrin thrombi, and less erythrocyte aggregation was observed in peritubular capillaries in those cases with predominantly glomerular loop obstruction [65,66].\nHemosiderin granules were identified in the renal tubular epithelium of a few patients, while pigmented casts were found in a small number of patients who had high levels of creatine phosphokinase, indicating the presence of rhabdomyolysis. Su et al. noted some cellular swelling of the renal distal tubules and collecting ducts, with some edematous expansion of the interstitial space, but without any significant inflammation. They also noted infiltration of lymphocytesin areas of nonspecific fibrosis, including subcapsular areas. Glomeruli were intact, with various degrees of morphologic changes: nodular mesangial expansion and arteriolar hyalinosis; endothelial cell swelling and degeneration was observed in a small number of COVID-19 patients but these were older individuals with a history of diabetes and hypertension; in other cases podocyte vacuolation and detachment from the glomerular basement membrane was seen; in 2 patients with proteinuria and diabetes, focal segmental glomerulosclerosis was also noted.\nImmunohis to chemical studies utilizing an anti-SARS-CoV nucleoprotein antibody against the viral nucleocapsid protein (NP) and indirect fluorescence microscopy, showed the NP antigen was present in the renal tubular cells of the infected tissues, suggesting that SARS-CoV-2 can directly infect kidney tubules. Moreover, Diao et al. observed that the presence ofSARS-CoV-2 virus resulted in the infiltration of high levels of CD68+ macrophages into the tubulo-interstitium, and it is feasible that these macrophages could release proinflammatory cytokines which in turn would cause renal tubular damage. In contrast, CD8+ T cells were observed only in moderate numbers in the examined tissues, while CD4+ T cells and CD56+ natural killer (NK) cells were seldom found.\nDiao et al. also observed the deposition of the C5b-9 complement complex (also known as the membrane attack complex pathway) on the apical brush border of renal tubular epithelial cells, whereas C5b-9 expression was absent in normal kidney tissue. The complex may cause cell death and therefore renal injury and may be an important factor in the pathogenesis of tubulo-interstitial damage [90,91]. All these findings suggest that SARS-CoV-2 infection causes acute tubular necrosis not only through direct cytotoxicity, but also via immune mediated mechanisms.\nObservations using transmission electron microscopy (EM) of kidney tissue from autopsies of COVID-19 cases has shown the presence of coronavirus-like particles in the cytoplasm of proximal and distal tubular cells; as well as in podocytes, podocyte foot processes and the glomerular basement membrane. In two autopsy specimens observed by Diao et al., it was noted that the cells in infected kidney tissue were swollen, with enlargement of mitochondria and lysosomes, and viral particles were observed in the broken lysosomes in the cytoplasm. These findings demonstrate SARS-CoV-2 can directly infect kidneys and why patients with COVID-19 often present with proteinuria, hematuria and AKI.\nAs has already been mentioned with the light microscopy observations, EM also showed erythrocytic obstruction of peritubular capillary lumens with injury of the endothelium. Aggregation of erythrocytes in segmental glomerular capillary loops was frequent, but without inflammation or necrosis. Intriguingly, according to a recent study [14] about endothelial cell infection and endothelitis in COVID-19, endothelial dysfunction is probably one of the main causes of microvascular dysfunction by causing vasoconstriction leading to organ ischemia, inflammation with associated tissue edema and a procoagulant state. The principal findings of light microscopy, immunofluorescence and EM are shown in Figure 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