Main Texts
SARS-CoV-2 infection can lead to diverse clinical pathologies that
involve multiple organ systems (2). The virus mainly targets pneumocytes
and endothelial cells in the respiratory tract that can lead to
pulmonary tissue damage and acute respiratory syndrome. In some severe
cases, acute kidney injury has also been associated with an unfavorable
prognosis for the patients (3). Previous studies have established that
human kidney cells express cellular factors, e.g., the
angiotensin-converting enzyme II (ACE2) that serves as the main receptor
of SARS-CoV-2 and the transmembrane protease serine 2 (TMPRSS2) that
cleaves the viral spike protein into the S1 and S2 subunits to form the
virion envelope structure, which are needed to mediate virus entry into
cells (4,5).
The authors of the current study (1) used histopathological and
immunofluorescence methods to provide evidence of direct viral infection
and tissue damage of renal parenchymal and tubular epithelial cells in
anonymized postmortem kidney specimens of four adult COVID-19 cases that
were overseen by the autopsy service at the Icahn School of Medicine at
Mount Sinai, New York, USA. Additional details of these fatal COVID-19
cases have been published elsewhere (6). Using the conventional
hematoxylin-eosin (H&E) staining and indirect immunofluorescence (IF)
assay, the authors showed various degrees of acute tubular necrosis,
segmental glomerulosclerosis, and autolysis of the renal tubular cells
in 3 of the 4 cases. These findings are consistent with a previous
report (7), which also showed evidence of kidney injury in some fatal
COVID-19 cases. On the contrary, none of these histopathological
findings were noted in renal tissues of healthy individuals in the
current study.
Since there were clear evidence of kidney tissue damage in some of the
COVID-19 cases under examination, it was important to know whether this
was due to a direct virus infection of the kidney and which cell types
were involved. Toward this end, the authors used IF assay with antibody
that was known to react to the viral S1 protein to show S1 presence in
groups of cells in the renal parenchyma in all four fatal COVID-19 cases
but not in healthy controls. To determine which renal cell types were
infected by the virus, the authors performed dual-IF staining for the
viral S1 protein along with other known markers of some of the major
kidney cell types, such as tubular epithelial cells, vascular
endothelial cells, and mesangial cells, and found viral S1-positive
staining only in the tubular epithelial cells in COVID-19 cases but not
in healthy controls. These findings are consistent with previous reports
of SARS-CoV-2’s distinct tropism for this cell type in the kidney (8,9).
To ensure that the detection of the S1 viral protein in kidney cells was
due to authentic viral infection, the authors cleverly stained kidney
tissues with a different antibody that is known to react to the viral
nonstructural protein 8 (NSP8) that is only expressed following viral
genome replication and protein translation and processing. Accordingly,
the authors observed NSP8 staining in similar groups of cells in the
renal parenchyma in all four fatal COVID-19 cases but not in healthy
controls, confirming active SARS-CoV-2 replication in renal cells.
As a previous report (6) has provided evidence of infiltration and
infection of various immune cells in the lung tissue of severe COVID-19
cases, the authors decided to perform dual-IF staining of the viral S1
protein and some known markers of innate immune cells (i.e., monocytes,
macrophages, and natural killer cells) and of adaptive immune cells
(i.e., B cells, CD8 T cells) as well as of the T-cell activation marker
in COVID-19 kidney tissues. They found a limited number of immune cell
infiltrates in 3 of 4 cases and more immune cells in the kidney tissues
of a patient who was known to suffer from chronic kidney disease. Among
the immune cell types examined, the authors clearly observed S1-positive
staining only in a very small number of monocytes, macrophages, and NK
cells, but not in any of the lymphocytes (B and T cells) examined. In a
couple of the cases, the authors only observed infiltration of monocytes
and macrophages, but failed to detect any S1 positivity. Similarly, only
a few NK cells in the kidney tissues stained positive for the S1
protein. This aspect of the study requires some careful interpretations.
Whereas the authors attributed the relatively low levels of S1 staining
for limited virus-replication capacity in these immune cells, it might
be important to correlate it with the level of NSP8 staining, which was
not performed. It might also be possible that some of these rare and
seldomly infected innate immune cells in the kidney represented
bystander cells that got infected as they infiltrated the kidney in
response to kidney injury.
In summary, the authors of the current study (1) provided strong
evidence of SARS-CoV-2 infection of renal tubular cells that might
explain the potential role of those cells in COVID-19-associated renal
disease pathology. The biological and physiological significance of
these findings lie in the fact that renal tubular cells are known to be
involved in the renin-angiotensin-aldosterone-system (RAAS), which plays
an important role in blood pressure regulation as well as in maintaining
the body’s water-salt balance (10). This RAAS system is regulated by
angiotensin II (Ang II), which acts on both the type 1 and type 2
angiotensin receptors (AT1R and AT2R) to regulate blood pressure and
renal sodium and water resorption by stimulating vasoconstriction. The
ACE2 protein acts as a counteractive regulator to RAAS activation to
lower blood pressure and to promote vasodilation of blood vessels and
preventing tissue-associated oxidative stress and inflammation. Thus, it
is possible that binding of the ACE2 receptor to the viral spike protein
during SARS-CoV-2 infection process could lead to dysregulated RAAS
pathway and might result in hypertension and renal failure (10).
However, it remains to be determined whether ACE2 serves as the
predominant cellular receptor for SARS-CoV-2 in the kidney and whether
viral infection of the renal tubular cells can directly or indirectly
contribute to RAAS system dysregulation and/or cardio-renal dysfunctions
in severe and fatal COVID-19.