RAPID COMMUNICATION www.jasn.

org

AKI and Collapsing Glomerulopathy Associated with

Downloaded from http://journals.lww.com/jasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW

COVID-19 and APOL1 High-Risk Genotype

Huijuan Wu,1,2 Christopher P. Larsen,3 Cesar F. Hernandez-Arroyo ,4
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/27/2023

Muner M.B. Mohamed ,4 Tiffany Caza,3 Moh’d Sharshir,5 Asim Chughtai,6 Liping Xie,7
Juan M. Gimenez,8 Tyler A. Sandow,8 Mark A. Lusco,2 Haichun Yang,2 Ellen Acheampong,9
Ivy A. Rosales,9 Robert B. Colvin,9 Agnes B. Fogo,2 and Juan Carlos Q. Velez4,10
Due to the number of contributing authors, the affiliations are listed at the end of this article.

ABSTRACT
Background Kidney involvement is a feature of COVID-19 and it can be severe in assessed apo 1 (APOL1) risk allele vari-
Black patients. Previous research linked increased susceptibility to collapsing glo- ants in affected patients and performed
merulopathy, including in patients with HIV-associated nephropathy, to apo L1 in situ hybridization (ISH) and Nano-
(APOL1) variants that are more common in those of African descent. String analysis to assess for virus in the
Methods To investigate genetic, histopathologic, and molecular features in six kidney biopsies. Our case series de-
Black patients with COVID-19 presenting with AKI and de novo nephrotic-range scribes six patients with COVID-19
proteinuria, we obtained biopsied kidney tissue, which was examined by in situ and kidney biopsy specimens in the set-
hybridization for viral detection and by NanoString for COVID-19 and acute tubular ting of AKI and proteinuria.
injury–associated genes. We also collected peripheral blood for APOL1 genotyping.
Results This case series included six Black patients with COVID-19 (four men, two
women), mean age 55 years. At biopsy day, mean serum creatinine was 6.5 mg/dl METHODS
and mean urine protein-creatinine ratio was 11.5 g. Kidney biopsy specimens
showed collapsing glomerulopathy, extensive foot process effacement, and focal/ Six patients with COVID-19 were in-
diffuse acute tubular injury. Three patients had endothelial reticular aggregates. We cluded in this case series. The diagnosis
found no evidence of viral particles or SARS-CoV-2 RNA. NanoString showed ele- of COVID-19 was confirmed with a pos-
vated chemokine gene expression and changes in expression of genes associated itive PCR test for severe acute respiratory
with acute tubular injury compared with controls. All six patients had an APOL1 high- syndrome coronavirus 2 (SARS-CoV-2)
risk genotype. Five patients needed dialysis (two of whom died); one partially re- in nasopharyngeal swabs. This study was
covered without dialysis. conducted in compliance with the Dec-
Conclusions Collapsing glomerulopathy in Black patients with COVID-19 was asso- laration of Helsinki and approved by the
ciated with high-risk APOL1 variants. We found no direct viral infection in the kid- institutional review board. Informed
neys, suggesting a possible alternative mechanism: a “two-hit” combination of consent was obtained from all patients.
genetic predisposition and cytokine-mediated host response to SARS-CoV-2 infec- Renal biopsies were processed by
tion. Given this entity’s resemblance with HIV-associated nephropathy, we propose standard light microscopy, immunoflu-
the term COVID-19–associated nephropathy to describe it. orescence (IF), and electron microscopy
(EM). Hematoxylin and eosin, Periodic
JASN 31: 1688–1695, 2020. doi: https://doi.org/10.1681/ASN.2020050558

Received May 1, 2020. Accepted May 25, 2020.

A.B.F. and J.C.Q.V. contributed equally to this work.

AKI occurs in 0.1%–29% of patients
hospitalized with coronavirus disease
2019 (COVID-19) and is associated
with an increased risk of death.1–6 The
clinical characteristics include increased
serum creatinine with variable degrees
of proteinuria and hematuria. 4,5 Re-
ports describe patients with COVID-19
with nephrotic-range proteinuria and
collapsing glomerulopathy.7–9 We have
also encountered such patients, all of
whom were of African descent. There-
fore, we hypothesized that collapsing
glomerulopathy constitutes a new renal
manifestation of COVID-19 that may
arise from genetic predisposition to in-
jurious second hits caused directly or in-
directly by COVID-19. Accordingly, we
Published online ahead of print. Publication date
available at www.jasn.org.
Correspondence: Dr. Juan Carlos Q. Velez, De-
partment of Nephrology, Ochsner Medical Center,
1514 Jefferson highway, Clinic Tower, 5th Floor,
Rm 5E328, New Orleans, LA 70121. Email: juan-
carlos.velez@ochsner.org
Copyright © 2020 by the American Society of
Nephrology

1688 ISSN : 1046-6673/3108-1688 JASN 31: 1688–1695, 2020


acid–Schiff, and Jones methenamine sil-
ver stains were performed on sections
from paraffin blocks. IF was performed
on frozen sections for IgG, IgA, IgM, C3,
C1q, k light chain, and l light chain, and
Downloaded from http://journals.lww.com/jasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
EM analysis was done.
DNA was extracted from peripheral
blood or renal biopsy tissue and geno-
typed for APOL1 risk alleles on a ViiA
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/27/2023
7 Real-Time PCR System (Thermo
Fischer, Waltham, MA) using TaqMan
assays.10
ISH was performed with RNAScope
(ACD, Newark, CA) using probes directed
against SARS-CoV-2 on formalin-fixed,
paraffin-embedded, 3-mm tissue sections
(ACDBio probes, catalog number 848561,
targeted S-gene with target region
21631–23303). 11 A negative control
probe (bacterial gene dapB) assessed
background signals and positive control
probes to the housekeeping gene pepti-
dylprolyl isomerase B confirmed RNA
integrity. The ISH sections were counter-
stained using Periodic acid–Schiff.
Three 20-mm sections from the
formalin-fixed, paraffin-embedded bi-
opsy block were deparaffinized and
RNA extracted for NanoString analy-
sis.12 RNA was analyzed on an nCounter
Max System (NanoString, Seattle. WA)
using the 770 gene Human Organ Trans-
plant Panel of probes13 supplemented
with the 10-gene probe COVID-19 Panel
Plus Beta (NanoString). Eight probes are
included for SARS-CoV-2 (envelope
protein, membrane glycoprotein, nu-
cleocapsid phosphoprotein, surface gly-
coprotein, and four open reading
frames [orf1ab, 3a, 7a, and 8]). The
complete gene list for these panels is
available at https://www.NanoString.com/
products/gene-expression-panels/
gene-expression-panels-over view/
human-organ-transplant-panel, https://
www.NanoString.com/COVID19. Nor-
malized counts of transcripts were com-
pared with those from eight control renal
biopsies processed with the Human Organ
Transplant Panel in the same way (four
with thin basement membrane disease,
two with idiopathic hematuria, one mini-
mal change disease in remission, and one
potential donor). As a positive control for
the SARS-CoV-2 probes, autopsy lung and
JASN 31: 1688–1695, 2020
kidney samples from four COVID-191 de-
cedents were analyzed.
RESULTS
Clinical Presentation
The clinical characteristics are summa-
rized in Table 1. All patients presented
with a febrile illness, with overt respira-
tory symptoms in five patients. COVID-
19 was confirmed with a positive PCR
for SARS-CoV-2 from nasopharyngeal
swabs. Three patients had CKD stage
3A at baseline, whereas no preexisting
CKD was documented for the remaining
three patients. Four patients had essen-
tial hypertension and three had type 2
diabetes mellitus. Patient 1 had an ac-
quired solitary kidney due to donation
to his sister 12 years before the encoun-
ter. Otherwise, no remarkable medical
or family history was identified. Three
patients presented with an elevated se-
rum creatinine and AKI on admission,
whereas the remaining three developed a
rise in serum creatinine during hospital-
ization. New-onset, nephrotic-range
proteinuria based on urine protein-
creatinine ratio and dipstick developed
in five patients, and with dipstick only
in one patient. All patients had adequate
urine output, and none showed hemo-
dynamic instability or shock in parallel
with or before AKI. In contrast, two
patients were hypertensive. Only two
progressed to acute hypoxic respiratory
failure requiring mechanical ventilation.
Antinuclear antibody was positive in one
patient and ANCA was negative in all six
patients. Serum complements, assessed
in five patients, were within normal
limits. AKI did not resolve, and kidney
biopsies were performed to establish a
diagnosis for the renal manifestations.
Kidney Biopsy Findings
Kidney biopsy findings are summarized
in Table 2. All patients showed collapsing
lesions with overlying hypertrophy and
hyperplasia of visceral epithelial cells
with marked eosinophilic protein drop-
lets (Figure 1). There was focal to diffuse
acute tubular injury with frequent pro-
tein droplets in tubules and very focal
COVID-19 Collapsing Glomerulopathy
www.jasn.org RAPID COMMUNICATION
Significance Statement
Kidney involvement may occur in corona-
virus disease 2019 (COVID-19), and can
be severe among Black individuals. In this
study of collapsing glomerulopathy in six
Black patients with COVID-19, the authors
found that all six had variants in the gene
encoding apo L1 (APOL1) that are more
common among those of African descent
and linked by past research to susceptibility
to collapsing glomerulopathy in non-
–COVID-19 patients. They found no evi-
dence of direct kidney viral infection
but observed changes in gene expression
in kidney biopsy samples suggesting that
the mechanism is likely driven by a host
response. These findings suggest that
Black individuals with an APOL1 high-risk
genotype and severe acute respiratory
syndrome coronavirus 2 infection are at
increased risk for experiencing an ag-
gressive form of kidney disease associ-
ated with high rates of kidney failure.
microcystic dilation (Figure 2). In pa-
tient 2, a diffuse, patchy, pleomorphic
interstitial infiltrate composed mostly
of lymphocytes with plasma cells and oc-
casional neutrophils along with tubulitis
and rare foci of neutrophilic tubular
cuffing was observed (Figure 2, case 2),
suggesting an infectious etiology. In pa-
tient 3, the biopsy showed characteristic
features of arterionephrosclerosis and
diabetic nephropathy, and also focal
acute interstitial nephritis with a lym-
phocytic infiltrate with occasional foci
of eosinophils (ten in a high-power field)
and tubulitis with acute tubular injury
and interstitial edema (Figure 2, case
3), suggesting drug-induced hypersensi-
tivity. In one patient, focal peritubular
capillaries showed red blood cell aggre-
gates but without any fibrin. IF micros-
copy showed no deposits in any of the
cases. EM was performed in five patients
and showed extensive foot process ef-
facement and microvillous transforma-
tion of podocytes (Figure 3). Endothelial
cells were swollen, with occasional small-
to-medium reticular aggregates in the cy-
toplasm in three patients (Figure 3). No
definitive viral particles were identified.
No electron-dense deposits were present.
ISH was performed in all six patients
for the presence of SARS-CoV-2 RNA
and it failed to show evidence of viral
1689
 nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/27/2023
Downloaded from http://journals.lww.com/jasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
1690

RAPID COMMUNICATION
JASN

Table 1. Clinical information of six patients with COVID-19, AKI, and nephrotic-range proteinuria
Serum

www.jasn.org
Creatinine(mg/ Urine
APOL1 dl)
Patient Age Hgb WBC Platelet Albumin Ferritin
Sex Race Risk Final Disposition
Identifier (y) WBC (mg/dl) (/ul) (/ul) (g/dl) (ng/ml)
Variants At Dipstick Blood UPCR Urine Sediment
Baseline (cells/
Biopsy Protein (cells/hpf) (g/g) Microscopy
hpf)
1 63 M B G1/G1 1.3 4.9 31 1–3 0–5 12.7 Abundant waxy 15.6 8.8 244 2.1 2147 Discharged
and muddy dependent on dialysis
brown granular
casts
2 64 F B G2/G2 1.5 4.2 31 Negative Negative 4.6 Some waxy 8.8 7.4 421 2.4 6875 Discharged
and coarse home with improving
granular casts serum creatinine,
did not need dialysis
3 65 F B G1/G1 1.3 2.9 31 Negative Negative 13.6 Many coarse 8.3 16.6 299 2.6 4934 Needed dialysis, died
granular and with suspected
some muddy brown pulmonary embolus
granular casts
4 44 M B G1/G1 1.4 11.4 31 .100 0–5 25 NP 8.1 4.1 241 2.5 443 Discharged dependent
on dialysis
5 37 M B G1/G2 1 9 31 0–2 11–20 NP NP 11.7 8 64 3 1450 Needed dialysis; then
died of ventricular
arrhythmia
6 56 M B G1/G1 1.2 6.7 31 50–100 5–10 3.6 NP 13 7 113 2.9 1620 Needed dialysis;
discharged off dialysis
Patients 1–3 were part of a 161-patient cohort of AKI in COVID-195 and patient 4 was previously reported individually.7 WBC, white blood cell; UPCR, urine protein-creatinine ratio; Hgb, hemoglobin; M, male; B,
Black; F, female; NP, not performed.
JASN 31: 1688–1695, 2020
 www.jasn.org RAPID COMMUNICATION

RNA in the kidney, with appropriate

NanoString

Negative
Negative
Negative
staining of controls. No significant signal

Additional significant findings: Patient 2 had diffuse patchy pleomorphic interstitial infiltrate with neutrophils and tubulitis; patient 3 had mild-to moderate arterionephrosclerosis, mild diabetic nephropathy, and
CoV-2
SARS-

RNA

N/A
N/A
N/A
above the control biopsies was detected
for any of the eight SARS-CoV-2 probes
by NanoString analysis. For example, the
Downloaded from http://journals.lww.com/jasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW

envelop protein RNA-normalized

Negative
Negative
Negative

Negative
Negative
Negative
CoV-2
SARS-
counts were 13.163.9 (mean6SD) for

RNA
ISH

the three FSGS cases versus 21.9616.7

for the 11 negative controls. The control
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/27/2023

COVID191 autopsy samples were

Aggregates

strongly positive, with envelop protein

Reticular

Present

Present

Present
Absent

Absent
N/A
RNA-normalized counts of 111.3676.8
for kidney samples and 6924.0613,528.7
for lung samples. Prominent differential
gene expression (more than fourfold ver-
Effacement

sus the controls) was detected for genes

Process
EM
Foot

N/A related to tubular injury (HAVCR1,

100

100
100
(%)

80
80

HIF1A, LCN2), whereas expression of sev-

eral normal tubular genes were reduced
(AQP2, ASB15, FABP1, MME, MUC1,
Particles

SLC12A3, SLC4A1), indicative of acute

None
None
None

None
None
Virus

N/A

tubular injury. Among the other nota-

ble expression increases (.43) were
IL6, numerous chemokines (CCL2,
CCL5, CCL19, CCL20, CXCL1/2, CXCL2,
Interstitial

Moderate
Moderate
moderate
Fibrosis

CXCL10, CXCL16), Fc receptors (FCER1G,

Mild to
Mild
Mild

Mild

FCGR1A, FCGR2A, FCGR2B, FCGR3A/B),

Ig (IGHG1, IGHG2, IGHG3, IGHG4,
IGHM, IGKC, IGLC1), and MHC class
II antigens (HLA-DQA1, HLA-DRA,
Diffuse
Diffuse

Diffuse
Diffuse
Diffuse
Focal

HLA-DRB1). No increase in IFNG or

ATI

IFNA1 transcripts was detected.

Follow-up Clinical Course

Collapsing
Lesions

Peripheral blood specimens or kidney

(no.)
Light Microscopy

6
3
1

2
3
3

focal acute interstitial nephritis. ATI, acute tubular injury; N/A, not available.

tissue were used to perform genotyping

for APOL1 G1 and G2 risk alleles. All
patients showed two risk alleles for
APOL1 (G1/G1 in four patients, G1/G2
Segmental
Table 2. Pathologic findings in kidney biopsies

Sclerosis

in one, and G2/G2 in one). Five (83%)

(no.)

6
4
1

2
4
4

patients progressed to require hemodial-

ysis during the hospitalization. Patients 3
and 5 died in the hospital due to suspec-
Sclerosis

ted pulmonary embolism and ventricu-

Global

(no.)

4
2
2

2
1
14

lar arrhythmia, respectively. Of the four

patients who were discharged home, two
were still dependent on hemodialysis at
discharge. Patient 1 eventually came off
Glomeruli
Total

dialysis 4 weeks later. Patient 2 did not

(no.)

7
18
25
18

24
14

require hemodialysis, had a gradual re-

covery, and was discharged with serum
creatinine of 4.2 mg/dl. At a follow-up
Identifier

visit 2 weeks later, serum creatinine im-

Patient

proved to 3.1 mg/dl, but she remained

nephrotic with a urine protein-creatinine
1
2
3

4
5
6

JASN 31: 1688–1695, 2020 COVID-19 Collapsing Glomerulopathy 1691

 RAPID COMMUNICATION www.jasn.org
Downloaded from http://journals.lww.com/jasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/27/2023
#1
#4
Figure 1. Collapsing glomerulopathy, showing collapse of glomerular tuft with overlying hypertrophy and hyperplasia of visceral epi-
thelial cells and marked protein droplets in cases 1–6. Arrow, early segmental collapsing lesion. #1–#4 and #6, Jones methenamine silver;
#5, Periodic acid–Schiff; original magnification, 3500 in #1 and 3400 in #2–#6.
ratio of 3.7 g/g. Patient 4 remains de-
pendent on dialysis 6 weeks postdi-
scharge, but hemodialysis has been
reduced from three times to twice
weekly because of increase in urine out-
put. Patient 6 has shown further improve-
ment in serum creatinine, down to
2.8 mg/dl, but his proteinuria has not
been reassessed.
DISCUSSION
AKI is relatively common in patients
with COVID-19, especially in those
with critical illness.5,14,15 This report ex-
pands on the recognition and etiology of
AKI and proteinuria in patients with
COVID-19 and strongly suggests that
SARS-CoV-2 infection may play a role
in the development of collapsing glo-
merulopathy in susceptible individuals.
Of note, three recent publications from
the United States and Europe each re-
ported a single case of collapsing glo-
merulopathy in Black patients with
COVID-19, and APOL1 G1 risk allele
homozygosity was assessed and detected
in two of the patients.7–9 Although acute
1692 JASN
#2
#5
tubular injury resulting from hemody-
namic instability is likely the main driver
for AKI in critically ill patients with
COVID-19, the possibility of direct in-
fection of kidney parenchyma by this
virus has been entertained. Angiotensin-
converting enzyme 2 (ACE2) is a
membrane-bound peptidase that acts as
protein ligand for COVID-19 binding in
humans, thus allowing viral cell entry and
damage of target organs.16 ACE2 is highly
expressed in the kidney, especially in the
proximal renal tubules, and relatively
weakly in the glomeruli.17–19 The tubular
ACE2 expression in normal kidneys is
nearly 100 times higher than that in the
respiratory tract (Z. Li, M. Wu, J. Yao,
J. Guo, X. Liao, S. Song, et al.: Caution
on kidney dysfunctions of 2019-nCoV
patients, https://doi.org/10.1101/2020.
02.08.20021212).20 Su et al.21 recently re-
ported an autopsy study of patients with
COVID-19 who died of severe respira-
tory failure with multiorgan complica-
tions. In this study, only a small number
of peritubular capillaries showed red
blood cell aggregates in one patient, a le-
sion described in the autopsy series from
China. 21 A subset of patients in the
#3
#6
Chinese autopsy series had new-onset
kidney disease, but without nephrotic
syndrome or collapsing glomerulopathy.
Tissue from a few of these patients
showed occasional viral-like particles in
podocytes and in tubules. However,
those structures were not confirmed to
be of coronavirus origin by either ISH
or immunogold EM.21 Interestingly, ab-
errantly increased ACE2 expression was
observed in some of these patients’ prox-
imal tubule cells, with mild increase in
podocytes and de novo expression in pa-
rietal epithelial cells.21 These autopsy
findings suggested the possibility that,
in some patients, SARS-CoV-2 could be
contributing directly to podocyte and tu-
bular cell injury. Recently, further evi-
dence of direct infection of the virus
into the kidneys has been reported in au-
topsy specimens without collapsing le-
sions.22 However, in our case series, we
did not find any evidence of kidney in-
fection of SARS-CoV-2 RNA by EM, ISH,
or NanoString. Thus, although the pos-
sibility that the virus was present below
the level of detection cannot be entirely
excluded, our findings indicate that direct
damage by SARS-CoV-2 is not the
JASN 31: 1688–1695, 2020
 www.jasn.org RAPID COMMUNICATION
Downloaded from http://journals.lww.com/jasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/27/2023

#1 #2 #3

#4 #5 #6

Figure 2. All biopsies show acute tubular injury with frequent tubular protein droplets. Arrow in #1, tubular protein droplets. In addition,
case 2 (#2) showed diffuse patchy pleomorphic interstitial infiltrate with neutrophils and tubulitis, and rare tubules with intratubular
neutrophils (arrows); case 3 (#3) showed focal acute interstitial nephritis with occasional foci of eosinophils (arrows), and microcystic tu-
bules were present in all cases except #3. #1, #4–#6, Periodic acid–Schiff; #2 and #3, hematoxylin and eosin; original magnification, 3400
in #1–#3 and 3200 in #4–#6.

mechanism triggering the collapsing glo-
merulopathy in this setting.
A host response—i.e., a “cytokine
storm”–induced injury—may be an al-
ternative mechanism for COVID-19–
associated collapsing glomerulopathy.
Patients with COVID-19 in the intensive-
care unit typically show elevated plasma
levels of proinflammatory cytokines in-
cluding IL-2, IL-7, IL-10, granulocyte
cell-stimulating factor, IP-10, MCP1,
MIP1A, and TNF-a versus non-ICU pa-
tients with COVID-19. 23 Moreover,
COVID-19 induced several proinflamma-
tory cytokines also induced by SARS-CoV-
2, including IL1B, IFN, IP10, and MCP1.
We also observed a marked increase in
gene expression of IL6 and numerous
chemokines including CCL2 and CXCL10
(also known as MCP1 and IP10, respec-
tively) in the kidney tissue by NanoString.
These cytokines can cause enhanced ap-
optosis of target cells, suboptimal T cell
reactions, impaired virus clearance, and
increased vascular leakage—the classic
consequences of this immune storm.23,24
In addition, occasional reticular aggregates
were observed by EM in some of the pa-
tients, although no increase in IFNG or
IFNA1 transcripts was detected by
NanoString. Reticular aggregates are a
marker associated with high levels of
the cytokine a-IFN, and they are partic-
ularly numerous in patients with SLE,
HIV infection, and IFN treatment.
Therefore, we speculate that the SARS-
CoV-2 infection could initiate a sys-
temic cytokine activation and immune
cascade. Our observation confirms the
report by Larsen et al.7 who also observed
reticular aggregates in a case of collapsing
glomerulopathy linked to SARS-CoV-2
infection.
Collapsing glomerulopathy has nu-
merous etiologies including viral infec-
tions, such as HIV, cytomegalovirus, and
parvovirus B19; severe ischemia; medi-
cations, such as pamidronate, anabolic
steroids; and IFN. 25–26 Whereas HIV
can directly infect renal parenchymal
cells (tubular epithelial cells and glomer-
ular visceral epithelial cells) in cases of
HIV-associated nephropathy,27,28 such
definitive evidence for coronavirus
glomerular infection is lacking. Increased
susceptibility to collapsing glomerulop-
athy, including HIV-associated nephrop-
athy, has been linked to risk variants of
APOL1 (G1, G2), which are increased in
those of African descent and are protec-
tive against trypanosomal disease.26,29–31
Our patients were Black with two risk
alleles for APOL1, suggesting the possi-
bility that COVID-19 may increase the
risk of collapsing glomerulopathy in
those patients with risk variants of
APOL1, i.e., a “second-hit” phenomenon.
In one patient, a single kidney status due
to living donation more than a decade ear-
lier likely further increased the risk of ad-
verse response to additional hits.
In summary, we present six Black pa-
tients with COVID-19 and two APOL1
risk alleles who presented with rapid
worsening in renal function and pro-
teinuria, with renal biopsies showing
collapsing glomerulopathy without evi-
dence of kidney parenchymal viral infec-
tion. Because collapsing glomerulopathy
can often result in irreversible kidney
damage and ESKD, this observation

JASN 31: 1688–1695, 2020 COVID-19 Collapsing Glomerulopathy 1693

 RAPID COMMUNICATION www.jasn.org
Downloaded from http://journals.lww.com/jasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/27/2023
#1
#4
Figure 3. Transmission EM shows extensive foot process effacement and moderate microvillous transformation of podocytes in all cases.
EM shows occasional reticular aggregates (arrow) in cytoplasm of endothelial cells (representative picture from #1). Original magnification,
34400 in #1, top left; 32200 in #2–#3; 36000 in #4; 38000 in #5; 314,000 in #1, bottom right.
may have important public health impli-
cations for individuals with genetic risk
factors. Further study is needed both
from biopsy and autopsy to fully inves-
tigate the renal morphologic changes in
patients with COVID-19 worldwide and
uncover potential mechanisms with im-
plications for treatment.
ACKNOWLEDGMENTS
We thank Lyndsey Buckner from the Ochsner
BioBank for facilitating blood collection
and shipping.
Dr. Agnes B. Fogo, Dr. Juan Carlos Q.
Velez, and Dr. Huijuan Wu wrote and edited
the manuscript; Dr. Tiffany Nicole Caza,
Dr. Agnes B. Fogo, Dr. Christopher Patrick
Larsen, Dr. Mark A. Lusco, Dr. Huijan Wu,
and Dr. Haichun Yang interpreted kidney
biopsies and prepared tissue for molecular
studies; Dr. Tiffany Nicole Caza and Dr. Chris-
topher Patrick Larsen performed APOL1 and
1694 JASN
#2
#5
ISH; Dr. Ellen Acheampong, Dr. Robert Colvin,
and Dr. Ivy A. Rosales performed NanoString
analysis; Dr. Asim Chughtai, Dr. Juan M.
Gimenez, Dr. Cesar F. Hernandez-Arroyo, Dr.
Muner M.B. Mohamed, Dr. Tyler A. Sandow,
Dr. Moh’d Sharshir, Dr. Juan Carlos Q. Velez,
and Dr. Liping Xie provided clinical information;
Dr. Juan M. Gimenez and Dr. Tyler A. Sandow
performed three of the kidney biopsies.
Dr. Juan Carlos Q. Velez reports personal
fees from Mallinckrodt Pharmaceuticals,
personal fees from Otsuka Pharmaceuticals,
and personal fees from Retrophin, outside
the submitted work.
DISCLOSURES
J.M. Gimenez reports he belongs to the Boston
Scientific Interventional Oncology Advisory
Board, is a Yttrium-90 proctor for Boston Scientific
Therasphere, and is a speaker for Boston Scientific
in Interventional Oncology. He does not believe
#3
#1
any of these are related to the submitted work.
His institution receives funds for these activities,
not him. I. Rosales reports consultancy for eGene-
sis. J.C. Velez has participated in advisory board
engagements with Mallinckrodt Pharmaceuticals
and Retrophin and is a member of a speaker bureau
for Otsuka Pharmaceuticals; none of the products
related those engagements are discussed in this man-
uscript. All remaining authors have nothing to
disclose.
FUNDING
None.
REFERENCES
1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He
JX, et al.: China Medical Treatment Expert
Group for Covid-19: Clinical characteristics
of coronavirus disease 2019 in China. N Engl
J Med 382: 1708–1720, 2020
2. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J,
et al.: Clinical characteristics of 138 hospitalized
JASN 31: 1688–1695, 2020

patients with 2019 novel coronavirus-infected
pneumonia in Wuhan, China. JAMA 323:
1061–1069, 2020
3. Chen N, Zhou M, Dong X, Qu J, Gong F, Han
Y, et al.: Epidemiological and clinical charac-
teristics of 99 cases of 2019 novel coronavirus
Downloaded from http://journals.lww.com/jasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AW
pneumonia in Wuhan, China: a descriptive
study. Lancet 395: 507–513, 2020
4. Cheng Y, Luo R, Wang K, Zhang M, Wang Z,
Dong L, et al.: Kidney disease is associated
with in-hospital death of patients with
nYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/27/2023
COVID-19. Kidney Int 97: 829–838, 2020
5. Mohamed MMB, Lukitsch I, Torres-Ortiz AE,
Walker JB, Varghese V, Hernandez-Arroyo CF,
et al.: Acute kidney injury associated with Co-
ronavirus disease 2019 in Urban New Orleans
[published online ahead of print May 13, 2020].
Kidney360 doi:10.34067/KID.0002652020
6. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al.:
Clinical course and outcomes of critically ill
patients with SARS-CoV-2 pneumonia in
Wuhan, China: a single-centered, retrospec-
tive, observational study [published correc-
tion appears in Lancet Respir Med 8: e26,
2020]. Lancet Respir Med 8: 475–481, 2020
7. Larsen CP, Bourne TD, Wilson JD, Saqqa O,
Sharshir MA: Collapsing glomerulopathy in a
patient with (COVID-19). Kidney Int Rep 5:
935–939, 2020
8. Kissling S, Rotman S, Gerber C, Halfon M,
Lamoth F, Comte D, et al.: Collapsing glo-
merulopathy in a COVID-19 patient [pub-
lished online ahead of print April 15, 2020].
Kidney Int doi:10.1016/j.kint.2020.04.006
9. Peleg Y, Kudose S, D’Agati V, Siddall E,
Ahmad S, Kisselev S, et al.: Acute kidney in-
jury due to collapsing glomerulopathy fol-
lowing COVID-19 infection [published online
ahead of print April 28, 2020]. Kidney Int Rep
doi:10.1016/j.ekir.2020.04.017
10. Larsen CP, Beggs ML, Saeed M, Walker PD:
Apolipoprotein L1 risk variants associate with
systemic lupus erythematosus-associated col-
lapsing glomerulopathy. J Am Soc Nephrol
24: 722–725, 2013
11. Wang F, Flanagan J, Su N, Wang LC, Bui S,
Nielson A, et al.: RNAscope: a novel in situ RNA
analysis platform for formalin-fixed, paraffin-
embedded tissues. J Mol Diagn 14: 22–29, 2012
AFFILIATIONS
1
Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China
2
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
3
Arkana Laboratories, Little Rock, Arkansas
4
Department of Nephrology, Ochsner Health System, New Orleans, Louisiana
5
Division of Nephrology, Department of Medicine, Tulane University, New Orleans, Louisiana
6
Northwest Indiana Nephrology, Hammond, Indiana
7
Ascension All Saint Nephrology, Racine, Wisconsin
8
Department of Diagnostic and Interventional Radiology, Ochsner Health System, New Orleans, Louisiana
9
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
10
Ochsner Clinical School, The University of Queensland, Brisbane, Australia
JASN 31: 1688–1695, 2020
12. Smith RN, Matsunami M, Adam BA, Rosales
IA, Oura T, Cosimi AB, et al.: RNA expression
profiling of nonhuman primate renal allograft
rejection identifies tolerance. Am J Transplant
18: 1328–1339, 2018
13. Mengel M, Loupy A, Haas M, Roufosse C,
Naesens M, Akalin E, et al.: Banff 2019 Meet-
ing Report: Molecular diagnostics in solid or-
gan transplantation – Consensus for the Banff
Human Organ Transplant (B-HOT) gene panel
and open source multicenter validation [pub-
lished online ahead of print May 19, 2020]. Am
J Transplant doi:10.1111/ajt.16059
14. Rabb H: Kidney diseases in the time of
COVID-19: major challenges to patient care.
J Clin Invest 130: 2749–2751, 2020
15. Naicker S, Yang CW, Hwang SJ, Liu BC, Chen
JH, Jha V: The novel coronavirus 2019 epidemic
and kidneys. Kidney Int 97: 824–828, 2020
16. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al.:
Genomic characterisation and epidemiology
of 2019 novel coronavirus: implications for
virus origins and receptor binding. Lancet
395: 565–574, 2020
17. Hamming I, Timens W, Bulthuis ML, Lely AT,
Navis G, van Goor H: Tissue distribution of
ACE2 protein, the functional receptor for SARS
coronavirus. A first step in understanding SARS
pathogenesis. J Pathol 203: 631–637, 2004
18. Ye M, Wysocki J, William J, Soler MJ, Cokic I,
Batlle D: Glomerular localization and ex-
pression of angiotensin-converting enzyme 2
and Angiotensin-converting enzyme: Impli-
cations for albuminuria in diabetes. J Am Soc
Nephrol 17: 3067–3075, 2006
19. Velez JC, Bland AM, Arthur JM, Raymond JR,
Janech MG: Characterization of renin-
angiotensin system enzyme activities in cul-
tured mouse podocytes. Am J Physiol Renal
Physiol 293: F398–F407, 2007
20. Zou X, Chen K, Zou J, Han P, Hao J, Han Z:
Single-cell RNA-seq data analysis on the re-
ceptor ACE2 expression reveals the potential
risk of different human organs vulnerable to 2019-
nCoV infection. Front Med 14: 185–192, 2020
21. Su H, Yang M, Wan C, Yi LX, Tang F, Zhu HY,
et al.: Renal histopathological analysis of
26 postmortem findings of patients with
COVID-19 in China [published online ahead
COVID-19 Collapsing Glomerulopathy
www.jasn.org RAPID COMMUNICATION
of print April 9, 2020]. Kidney Int doi:
10.1016/j.kint.2020.04.003
22. Puelles VG, Lütgehetmann M, Lindenmeyer
MT, Sperhake JP, Wong MN, Allweiss L, et al.:
Multiorgan and renal tropism of SARS-CoV-2
[published online ahead of print May 13, 2020].
N Eng J Med doi:10.1056/NEJMc2011400
23. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y,
et al.: Clinical features of patients infected
with 2019 novel coronavirus in Wuhan,
China. Lancet 395: 497–506, 2020
24. Channappanavar R, Perlman S: Pathogenic
human coronavirus infections: Causes and
consequences of cytokine storm and immuno-
pathology. Semin Immunopathol 39: 529–539,
2017
25. Chandra P, Kopp JB: Viruses and collapsing
glomerulopathy: a brief critical review. Clin
Kidney J 6: 1–5, 2013
26. Kopp JB: Expanding the spectrum of APOL1-
related renal disease: de novo collapsing
glomerulopathy following kidney transplant.
Kidney Int 94: 1048–1050, 2018
27. Cohen AH, Sun NC, Shapshak P, Imagawa
DT: Demonstration of human immunodefi-
ciency virus in renal epithelium in HIV-
associated nephropathy. Mod Pathol 2:
125–128, 1989
28. Winston JA, Bruggeman LA, Ross MD,
Jacobson J, Ross L, D’Agati VD, et al.: Ne-
phropathy and establishment of a renal res-
ervoir of HIV type 1 during primary infection.
N Engl J Med 344: 1979–1984, 2001
29. Abid Q, Best Rocha A, Larsen CP, Schulert G,
Marsh R, Yasin S, et al.: APOL1-Associated
collapsing focal segmental glomerulosclerosis
in a patient with stimulator of interferon genes
(STING)-Associated vasculopathy with onset in
infancy (SAVI). Am J Kidney Dis 75: 287–290,
2020
30. Genovese G, Friedman DJ, Ross MD,
Lecordier L, Uzureau P, Freedman BI, et al.:
Association of trypanolytic ApoL1 variants
with kidney disease in African Americans.
Science 329: 841–845, 2010
31. Freedman BI, Skorecki K: Gene-gene and
gene-environment interactions in apolipo-
protein L1 gene-associated nephropathy.
Clin J Am Soc Nephrol 9: 2006–2013, 2014
1695