medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120.

The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Human Kidney is a Target for Novel Severe Acute Respiratory

Syndrome Coronavirus 2 (SARS-CoV-2) Infection

Running title: SARS-CoV-2 infects human kidney

Bo Diao1#, Chenhui Wang2#, Rongshuai Wang3#, Zeqing Feng2, Yingjun Tan1,

Huiming Wang4, Changsong Wang5, Liang Liu6, Ying Liu1, Yueping Liu1, Gang
Wang1, Zilin Yuan1 , Liang Ren3#, Yuzhang Wu2#, Yongwen Chen2#

1. Department of Medical Laboratory Center, General Hospital of Central Theat

er Command, Wuhan, Hubei province, 430015, People’s Republic of China

2. Institute of Immunology, PLA, Third Military Medical University, Chongqing,

400038, People’s Republic of China

3. Department of Forensic Medicine, Tongji Medical College, Huazhong Univers

ity of Science and Technology, No. 13 Hangkong Road, Wuhan, Hubei
province, 430030, People’s Republic of China

4. Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan,

Hubei province, 430060, People’s Republic of China

5. Department of Pathology, 989th Hospital of PLA, Luoyang, 471000, Henan

Province, People’s Republic of China

6. Hubei Chongxin Judicial Expertise Center, Wuhan, Hubei province, 430415,

People’s Republic of China

# Equally to this work

*Corresponding author: Yongwen Chen (Ph. D.), Institute of Immunology, PLA, Third
Military Medical University, Chongqing, 400038, People’s Republic of China. Fax:
+8602368752228; Phone: +8602368752228. E-mail: [email protected] or
Yuzhang Wu (Prof. & Chair). Email: [email protected]
medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Summary

BACKGROUND The outbreak of a novel coronavirus (SARS-CoV-2, previously

provisionally named 2019 novel coronavirus or 2019-nCoV) since December 2019 in
Wuhan, China, has become an emergency of major international concern. Apart from
the respiratory system, it is unclear whether SARS-CoV-2 can also directly infect other
tissues such as the kidney or induce acute renal failure.

METHODS We conducted a retrospective analysis of estimated glomerular filtration

rate (eGFR) along with other clinical parameters from 85 patients with laboratory-
confirmed COVID-19 admitted to a hospital in Wuhan from January 17, 2020 to March
3, 2020. Kidney tissues from six patients with postmortem examinations in the other
hospital were analyzed by Hematoxylin and Eosin (H&E) and in situ expression of viral
nucleocaspid protein (NP) antigen, immune cell markers (CD8, CD68 and CD56) and
the complement C5b-9 was detected by immunohistochemistry.

RESULTS 27.06% (23/85) patients exhibited acute renal failure (ARF). The eldery
patients and cases with comorbidities such as hypertension and heart failure more easily
developed ARF (65.22% vs 24.19%, p< 0.001; 69.57% vs 11.29%, p< 0.001,
respectively). H&E staining demonstrated kidney tissues from postmortems have
severe acute tubular necrosis and lymphocyte infiltration. Immunohistochemistry
showed that SARS-CoV-2 NP antigen was accumulated in kidney tubules. Viral
infection not only induces CD68+ macrophages infiltrated into tubulointerstitium, but
also enhances complement C5b-9 deposition on tubules.

CONCLUSIONS SARS-CoV-2 induces ARF in COVID-19 patients. Viruses directly

infect human kidney tubules to induce acute tubular damage. The viruses not only have
direct cytotoxicity, but also initiate CD68+ macrophage together with complement C5b-
9 deposition to mediate tubular pathogenesis.
medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Introduction

In December 2019, a cluster of pneumonia cases caused by a novel severe acute

respiratory syndrome coronavirus 2 (SARS-CoV-2) were reported in Wuhan, Hubei
Province, China.1-3 This disease, now designated as coronavirus disease 2019 (COVID-
19) by the WHO, rapidly spread to other cities of China and around the world.4-6 By
March 3, 2020, 80270 cases were laboratory confirmed with 2981 deaths in China based
on CCDC (Chinese Center For Disease Control And Prevention) reports.7

Some studies have suggested that SARS-CoV-2, SARS-CoV (Severe acute

respiratory syndrome-Coronavirus) and MERS-CoV (Middle East Respiratory
Syndrome-Coronavirus) share a common ancestor resembling the bat coronavirus
HKU9-1.8,9 Recently, Shi et al., reported that SARS-CoV-2 interacts with human ACE2
(angiotensin converting enzyme-II) molecules via its Spike protein.10 In addition to
respiratory organs, the expression of ACE2 protein has also been observed in human
kidneys,11,12 and Cheng et al., reported that some COVID-19 patients had an elevated
level of proteinuria.13 However, no evidence directly demonstrates that SARS-CoV-2
can infect the kidney to cause acute renal failure.

We retrospectively analyzed the clinical data on kidney function from 85 cases of

COVID-19 who were admitted into the General Hospital of Central Theatre Command
in Wuhan, Hubei Province, from January 17, 2020 to March 3, 2020. To elucidate the
mechanism of renal injury, we also used H&E staining and immunohistochemistry to
visually assess tissue damage and viral presence in kidney tissues from six biopsies.

Methods

Patients Medical records from 85 COVID-19 patients (aged from 21 years to 92 years)
with dynamic observation of renal function in General Hospital of Central Theatre
Command in Wuhan from January 17, 2020 to March 3, 2020 were collected and
retrospectively analyzed. Postmortem autopsies were conducted on six patients who
had been admitted in Hospital. Diagnosis of COVID-19 was based on the New
medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Coronavirus Pneumonia Prevention and Control Program (5th edition) published by the
National Health Commission of China. All the patients were laboratory-confirmed
positives for SARS-CoV-2 by use of quantitative RT-PCR (qRT-PCR) on throat swab
samples. This study was approved by the National Health Commission of China and
Ethics Commission of General Hospital of Central Theatre Command ([2020]017-1)
and Jinyintan Hospital (KY-2020-15.01). Written informed consent was waived by the
Ethics Commission of the designated hospital for emerging infectious diseases.

Data collection and definitions We reviewed clinical records and laboratory findings
for all the patients. All information was obtained and curated with a customized data
collection form. eGFR was calculated by the CKD-EPI equation based on serum
creatinine level, sex, race and age. Acute renal impairment was defined as a decline of
eGFR by at least 30% of the baseline value on admission or below 90mL/min on
admission. Three investigators (C Wang, Z Fen and Y Chen) independently reviewed
the data collection forms to verify data accuracy.

Tissue morphology detection and immunohistochemistry Due to the special

infection-control precaution of handling deceased subjects with COVID-19,
postmortem examination was performed in a designated pathology laboratory. Kidney
specimens from autopsy were retrieved for standard examination via light microscopy.
Briefly, paraffin-embedded tissue blocks were cut into 3 μm slices and mounted onto
poly-lysine-coated glass slides, and tissue injury was stained for by H&E. Sections were
also used for immunohistochemistry as following: Antigen retrieval was performed by
microwaving these sections in citrate buffer (10 mM, pH 6.0). The sections were then
incubated in 3% BSA plus 0.1% H2O2 for 1h at RT to block nonspecific binding. The
sections were then incubated overnight at 4 °C with primary anti-SARS-CoV-2
nucleocaspid protein (NP) antibodies (clone ID: 019, 1:100, rabbit IgG; Sino Biological,
Beijing), anti-CD8 (Clone ID:4B11, 1:100, mouse IgG2b; BIO-RAD), anti-CD68
(Clone ID:KP1, 1:100, mouse IgG1; BIO-RAD), anti-CD56 (Clone ID:123C3, 1:100,
mouse IgG1; BIO-RAD), anti-C5b-9 (clone ID: aE11, 1:100, mouse IgG;
Dakocytomation) or rabbit-isotype antibody controls (1:100; Dako). Sections were
further incubated with the HRP-anti-Rabbit secondary antibodies for 1h at RT.
medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Peroxidase activity was visualized with the DAB Elite kit (K3465, DAKO), and the
brown coloration of tissues represented positive staining as viewed by a light
microscope (Zeiss Axioplan 2, Germany).

Statistical analysis Statistical analyses were performed using GraphPad Prism version
8.0 (GraphPad Software, Inc., San Diego, CA, USA). Categorical variables were
expressed as numbers (%). p values are from χ2.

Role of the funding source The funding agencies did not participate in study design,
data collection, data analysis, or manuscript writing. The corresponding authors were
responsible for all aspects of the study to ensure that issues related to the accuracy or
integrity of any part of the work were properly investigated and resolved. The final
version was approved by all authors.

Results

1. SARS-CoV-2 induces ARF in COVID-19 patients

We retrospectively analyzed laboratory kidney functions from 85 cases of COVID-

19 patients, and focusing on eGFR. Results showed that 27.06% (23/85) COVID-19
patients exhibited acute renal failure. Patients who are elderly (≥60 years) or carry
comorbidities (65.22% vs 24.19%, p<0.001, 69.57% vs 11.29%, p<0.001, respectively),
such as hypertension (39.13% vs 12.90%, p=0.0007) and coronary heart disease (21.74%
vs 4.84%, p=0.018) more easily developed ARF (Table1), suggesting renal function
impairment is relatively common in COVID-19 patients.

2. SARS-CoV-2 induces human kidney tubular injury

Next, the histopathological examination was performed by H&E- staining in kidney

specimens from autopsy of six COVID-19 subjects with observed renal function
impairment. Varying degrees of acute tubular necrosis, luminal brush border sloughing
and vacuole degeneration, were found in different areas of all six renal specimens.
Severe infiltration of lymphocytes in the tubulointerstitium was observed in two
patients, and moderate infiltration was seen in three cases, and the remaining one case
manifested absence of lymphocyte infiltration. Moreover, viral infection associated-
medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

syncytia were also observed in three cases. At the same time, dilated capillary vessels
were observed in the glomeruli of these 6 cases. Nevertheless, severe glomerular injury
was absent in all of these six cases, although benign hypertensive glomerulosclerosis
and autolysis were noted in three hypertensive patients (Figure 1, Table 2). Collectively,
these results demonstrated that SARS-CoV-2 infection mainly induces severe acute
tubular necrosis and lymphocyte infiltration.

3. SARS-CoV-2 directly infects human kidney tubules

To confirm that SARS-CoV-2 might directly infect kidney tubules thus lead to tubular
damage, the viral NP antigen was assessed by immunohistochemistry. Results showed
that SARS-CoV-2 NP antigens could be seen in kidney tissues from all of these six
samples, with NP expression restricted to kidney tubules, and NP- positive inclusion
body was also observed. The NP- positive expression was observed in cytoplasm, but
nuclear signals were not observed (Figure 2A). Some NP-positive tubular epithelial
cells were dropped from normal tubules (Figure 2B), while NP- antigen was also absent
in the glomerulus (Figure 2C). The expression of NP protein in lung tissues from
COVID-19 patients was used as positive controls (Figure 2D), whereas normal kidney
tissues (Figure 2E) or renal sections from unrelated autopsies treated with rabbit
isotype control antibodies (Figure 2F) were used as negative controls. Collectively,
these data suggest that SARS-CoV-2 directly infects kidney tubules.

4. SARS-CoV-2 induces CD68+ macrophage infiltration and complement C5b-9

deposition

Since the infiltration of proinflammatory cells can significantly accelerate tubular

damage, we next examined the identity of these infiltrated cells. Immunohistochemistry
showed strong presence of CD68+ macrophages were in the tubulointerstitium of these
six cases, while moderate numbers of CD8+ T cells were also observed in two cases,
whereas, CD4+ T cells and CD56+ natural killer (NK) cells were seldom found in the
examined tissues (Figure 3A, Table 2), suggesting that SARS-CoV-2 might cause
further tubular damage through recruiting macrophages to infiltrate into the
medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

tubulointerstitium.

As the deposition of the complement membrane-attack complex (MAC, also named

C5b-9) on tubules or glomeruli may also cause renal damage,14 we further analyzed
C5b-9 status in kidney tissues from these postmortems. Interestingly, strong C5b-9
depositions on tubules were observed in all of these six cases. Very low levels of C5b-
9 deposition on glomeruli and capillaries were also seen in two cases. However, C5b-9
expression is absent in normal kidney tissue (Figure 3B, Table 2), suggesting that
SARS-CoV-2 infection induces acute tubular necrosis and ARF through triggering C5b-
9 deposition.

Discussion

In this study, we found that 27.06% of patients with COVID-9 had abnormal eGFR,
and patients who are aged or have comorbidities more commonly developed ARF
(Table 1), suggesting that ARF is relatively common following SARS-CoV-2 infection.
This phenomenon is different from the 2003 outbreak of SARS, in which ARF was
uncommon, despite being one of the top risk factors for mortality. 15 Recently, Yan
et al., reported that 63% (32/51) of COVID-19 patients had an elevated level of
proteinuria.13 Collectively, these results illustrate that SARS-CoV-2 mediated ARF may
be one of the major causes of multiorgan failure and eventual death in COVID-19
patients.

The extents of tubular atrophy and interstitial disease are the strongest histological
parameters which correlate with renal function and predict progression. To further
analyze how SARS-CoV-2 affects renal function, we focused on analyzing renal tissue
morphology from autopsies. H&E staining showed that acute renal tubular damage and
lymphocyte infiltration was observed in all six cases during postmortem examinations,
while the glomeruli were intact, except for some cases with slight glomerulosclerosis,
suggesting that other conditions such as hypertension and diabetic nephropathy may

have been involved in the pathogenesis（Figure 1). It has been shown that the ACE-2

receptor of SARS-CoV-2 is highly expressed in renal tubules.12,16 We used

medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

immunohistochemistry to analyze the expression of viral NP antigen in situ in kidney

tissues, and found that viral NP antigen was restricted to the renal tubular cells of the
infected tissues (Figure 2). This phenomenon is consistent with SARS-CoV and
MERS-CoV, both of which can also infect human kidneys. 17,18 Recently, some
researchers have reported they have successfully isolated SARS-CoV-2 virus particles
from the urine of COVID-19 patients, suggesting that kidney-originated viral particles
may enter the urine through glomerular filtration. Taken together with our study, these
results demonstrate that the kidney is also a site of viral infection and replication outside
of the lungs.

While SARS-CoV-2 is a cytopathic virus which can also directly induce renal tubular
injury during infection and replication, the occurrence of such injury may also initiate
complex immune responses. After all, although host immune cells can infiltrate into
infected tissue to counteract viral replication, hyperactivation of immune cells may
instead promote fibrosis, induce epithelial cell apoptosis, and cause microvasculature
changes.19-21 We report here that SARS-CoV-2 virus recruits high levels of CD68+
macrophages to infiltrate into the tubulointerstitium (Figure 3A), suggesting that
proinflammatory cytokines derived from macrophages would induce tubular damage.
Both clinical and experimental models suggest that the abnormal presence of serum-
derived complement components in the tubular lumen leads to the assembly of the
complement C5b-9 (via the alternative pathway) on the apical brush border of tubular
epithelial cells (TECs), and that this is an important factor in the pathogenesis of
tubulointerstitial damage.22-24 We here observed that SARS-CoV-2 initiates
complement C5b-9 assembly and deposition on tubules (Figure 3B). We therefore
demonstrate that SARS-CoV-2 causes tubular damage through direct cytotoxicity, but
also initiates immune- mediates tubule pathogenesis.

One limitation of this paper is that due to the high infectivity and the complexity of
specimen preparation, we were unable to present electron microscopy imaging to
further clarify the subcellular distribution of virus particles in kidney in situ. In the next
step, we will cooperate with other laboratories to carry out this work.
medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

In conclusion, we have demonstrated that the SARS-CoV-2 virus can directly infect
human renal tubules and consequently lead to acute renal tubular injury. Moreover,
improvement of eGFR would increase the survival of COVID-19 patients who have
ARF. We strongly suggest that applying potential interventions including continuous
renal replacement therapies (CRRT) for protecting kidney function in COVID-19
patients, particularly for ARF cases, maybe a key method to preventing fatality.

Conflict of interest: The authors declare no financial or commercial conflict of

interest.

Authors' contributions:

Yuzhang Wu, and Yongwen Chen were involved in the final development of the project
and manuscript preparation; Zilin Yuan, Chenghui Wang and Zeqing Feng analyzed the
data; Bo Diao and Huiming Wang performed most of experiments; Yin Liu, Gang Wang,
Yinjun Tan and Yueping Liu did H&E staining and immunohistochemistry; Changsong
Wang evaluated H&E and immunohistochemistry results; Liang Liu, Rongshuai Wang
and Liang Ren provided autopsies and analyzed H&E staining.

Ethics committee approval: This study was approved by the National Health
Commission of China and Ethics Commission of General Hospital of Central Theatre
Command and Jinyintan Hospital.

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is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Figure and figure legends

Figure 1 Representative H&E staining of kidney tissues from 6 cases of COVID-

19 patients undergoing postmortem examination. Sections were stained by H&E,
arrow indicated infiltrated lymphocytes; arrow head indicated viral infection
associated- syncytia. Scale bar= 100 μM.
medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Figure 2 Immunohistochemistry analyzed SARS-CoV-2 NP antigen in kidney

tissues. The expression of viral NP antigen was detected in kidney (A～C) and lung
(D) tissues from COVID-19 patients undergoing postmortem examination. A: arrow
indicated NP positive tubules and arrow head indicated viral inclusion body. B: arrow
indicated viral NP positive cells dropped from normal tubule; C: arrow indicated NP

positive cells and circle indicated glomerulus; E: Absence expression of viral NP

protein in normal kidney tissues; F: Sections incubated with rabbit IgG1 isotype control
antibodies. Scale bar= 100 μM.
medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Figure 3 Immunohistochemistry analyzed lymphocytes and the complement C5b-

9 in kidney tissues. The expression of (A) CD68, CD8 and CD56; (B) C5b-9 in kidney
tissues from COVID-19 patients undergoing postmortem examination or normal
healthy was detected by immunohistochemistry. Arrow indicated positive cells. Scale
bar= 100 μM.
medRxiv preprint doi: https://doi.org/10.1101/2020.03.04.20031120. The copyright holder for this preprint (which was not peer-reviewed)
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .

Table1 Clinical Characteristics of COVID-19 patients.

Group ARF Non-ARF p value

(N=23) (N=62)
Age
≥60yr 15（65.22） 15（24.19） <0.001
<60yr 8(34.78) 47(75.81)
Sex
Male 15（65.22） 33（53.23） 0.322
Female 8(34.78) 29(46.77)
Coexisting Disorder
Any 16（69.57） 7（11.29） <0.001
Hypertension 9（39.13） 8（12.90） 0.007
Coronary heart disease 5（21.74） 3（4.84） 0.018
other heart disease 4（17.39） 4（6.45） 0.125
Diabetes 3（13.04） 4（6.45） 0.326
COPD 2（8.70） 0（0.00） 0.019
Chronic renal disorder 2（8.70） 3（4.80） 0.502
Cerebrovascular
disease 1（4.35） 2（3.23） 0.803
Cancer 1（4.35） 2（3.23） 0.803
Hepatitis B infection 0（0.00） 3（4.84） 0.283
Data are n（%），p values are from χ2 . ARF=acute renal failure
 Table 2 The pathologic findings and protein expression of kidney tissues from COVID-19 patients undergoing postmortem examination.

SASR-CoV-2
Coexisting H&E staining Immunohistochemistry confirmed by
Case Gender Age disorder PCR
number
Benign Tubular Intestinal Autolysis Viral NP C5b-9 on CD68 CD8 CD56
glomerulosclerosis necrosis infiltration antigen tubules

1 male 70 Hypertension + +++ +++ ++ +++ ++ ++ - - Yes

>10 years

2 female 86 Hypertension + +++ +++ + ++++ ++++ ++++ ++ + Yes

>10 years;
coronary
disease >10 year

3 male 62 None - ++ ++ + +++ ++ +++ ++ + Yes

4 male 51 Hypertension + ++ ++ + +++ + ++ - +/- Yes

>10 years

5 male 78 Hypertension + ++ ++ + +++ ++ ++ +- - Yes

>5 years; Gout

6 female 67 None - ++++ - + +++ + +- - - Yes

# Expression levels: Negative:-; slightly: +; Moderate: ++; Severe: +++; Extremely severe ++++.

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