Journal Pre-proof

COVID-19 and glomerular diseases

Nattawat Klomjit, M.D., Ladan Zand, M.D., Lynn D Cornell, M.D, Mariam Priya
Alexander, M.D.

PII: S2468-0249(23)01234-2
DOI: https://doi.org/10.1016/j.ekir.2023.03.016
Reference: EKIR 2289

To appear in: Kidney International Reports

Received Date: 10 February 2023

Revised Date: 13 March 2023
Accepted Date: 20 March 2023

Please cite this article as: Klomjit N, Zand L, Cornell LD, Alexander MP, COVID-19 and glomerular
diseases, Kidney International Reports (2023), doi: https://doi.org/10.1016/j.ekir.2023.03.016.

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 COVID-19 and glomerular diseases

Nattawat Klomjit, M.D.1, Ladan Zand, M.D.2, Lynn D Cornell, M.D3, Mariam Priya Alexander, M.D.3
1
Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, MN, USA
2
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
3
Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA

Running title: COVID-19 and glomerular disease

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Keywords: COVID-19, SARS-CoV 2, glomerulonephritis, glomerular disease, collapsing focal segmental
glomerulonephritis, COVAN, focal segmental glomerulonephritis, FSGS

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Correspondence:
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Nattawat Klomjit, M.D.
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Division of Nephrology and Hypertension

Department of Medicine
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University of Minnesota
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Minneapolis, MN, USA

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Figure: 3

Table: 1

Word count: 5767

Conflict of interest: None

Abstract

COVID (Coronavirus disease)-19 is a systemic disease and the kidney is one of the target organs of
infection. Kidney injury is common and can occur in up to 40% of patients. Several glomerular diseases
have been reported in association with COVID-19. Some are likely related to COVID-19 whereas many
are likely coincidental. Glomerular diseases that are frequently reported in COVID-19 and have a
plausible mechanistic explanation, are likely to be related to COVID-19. On the other hand, glomerular
diseases that are seldom reported and have no known plausible mechanism, are likely to be unrelated.
Collapsing glomerulopathy (CG) is by far the most prevalent. Its association with COVID-19, resembling
human immunodeficiency virus (HIV) and CG, led to the newly proposed term “COVID-19 associated
nephropathy” or “COVAN”. High-risk APOL1 genotypes are the major risk factor in COVAN patients.
Podocytopathy, membranous nephropathy, pauci-immune crescentic glomerulonephritis, and
thrombotic microangiopathy are also reported. In kidney allografts, CG remains the most common
glomerular pathology. Patients typically present with acute kidney injury (AKI) or abnormal urinary

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findings at the time of or shortly after COVID-19 diagnosis. Treatment of glomerular disease in COVID-19

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patients is challenging. Providers should cautiously consider balancing risks and benefit of
immunosuppression, particularly in patients with active diseases. Short-term outcomes vary but

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generally remain poor with high morbidity and mortality. Future study of long-term outcomes is needed
to improve our understanding of glomerular disease associated with COVID-19.
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Introduction

Since the coronavirus disease 2019 (COVID-19) pandemic began, over 680 million people have been
infected, with a mortality of 6.8 million. COVID-19 is a systemic disease and extra-pulmonary
manifestations are common.1 Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is an
enveloped single stranded RNA virus that belongs to the family Coronaviridae.2 SARS-CoV-2 imposes
tissue injury via several mechanisms including direct viral invasion, endothelial cell damage, immune
dysregulation, and renin angiotensin aldosterone system (RAAS) dysfunction.1 Angiotensin- converting
enzyme (ACE) 2 is the membrane-bound receptor that binds to the receptor binding site (RBD) located
at the spike region of SARS-CoV-2.3 A disintegrin and metalloproteinase domain-containing protein
(ADAM) 10, ADAM 17 and transmembrane protease serine 2 (TMPRSS2) are required for ACE2-SARS-
CoV-2 complex to enter target cells via proteolytic cleavage.4 ACE2 is widely expressed in many tissues
including type 2 pneumocytes, nasal mucosa, nasopharynx, and enterocytes of small intestines, skin,
bone marrow, spleen, liver, brain and kidney.3, 5 Although the kidney appears to be one of the target

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organs affected by SARS-CoV-2, supported by the presence of SARS-CoV-2 in the urine and favorable

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distribution of ACE2,6-8most kidney biopsies from COVID-19 patients do not demonstrate the presence
of SARS-CoV-2 in the tissue.9-12 Acute kidney injury (AKI) is prevalent in COVID-19 patients.13, 14 Earlier

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published studies, which predated mass vaccination enrollment, showed a high rate of AKI ranging from
20-40% with the rate of renal replacement therapy (RRT) as high as 31%.13 A more recent study
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demonstrated a lower rate of AKI with a pooled incidence of 12.3% with 5% requiring RRT. SARS-CoV-2
can cause AKI via direct and indirect effects. Directly, SARS-CoV-2 can cause cellular toxicity,
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complement activation, immune dysregulation and coagulopathy.15, 16 Immune dysregulation in COVID-

19 is one of the key features in many kidney pathologies and it involves various mechanisms including
molecular mimicry, upregulation of inflammatory cytokines, alteration in immune profile and auto-
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antibody production.17 On the other hand, SARS-CoV-2 can indirectly induce AKI via hemodynamic
instability, organ cross-talk or exposure to nephrotoxic agents.15 Although acute tubular injury is
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common in a kidney biopsy of COVID-19 patients, several other kidney pathologies have been
reported.9, 18, 19
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In this review, we searched peer-reviewed literature through PUBMED on COVID-19 associated kidney
pathology in kidney biopsy series published since the beginning of the pandemic until February 2023.
We emphasize only those series with available clinical outcomes and relevance to clinical practice. We
focus on de-novo glomerular disorders. Details of clinical presentation, treatments, clinical courses, and
outcomes that are available in the published articles, are included. We also provide examples of kidney
pathology images of unpublished cases from our institution.

Kidney biopsy and autopsy series in COVID-19 patients

Since the onset of the COVID-19 pandemic until February 2023, there have been 76 kidney pathology-
related studies. These studies included 511 native kidney cases and 85 transplant cases. Of the 76
studies, 36 (47.4%) studies are from North America, 16 (21.1%) from Europe, 22 (28.9%) from Asia, 1
(1.3%) from Africa, and 1 (1.3%) from South America.

Of 511 biopsy cases, 410 cases (80.2%) have glomerular lesions, 99 cases (19.4%) have tubulointerstitial
lesions, and 2 cases (0.4%) have no significant pathology. Of glomerular pathologies, collapsing
glomerulopathy (CG) is the most common pathology (n=148, 36.1%) followed by, primary
podocytopathy (n=45, 11.0%), diabetic nephropathy (DN) (n=37, 9.0%), pauci-immune crescentic
glomerulonephritis (GN) (n=31, 7.6%), membranous nephropathy (MN) (n=23, 5.6%) and IgA
nephropathy (IgAN) (n=23, 5.6 %). The remaining 103 (25.1 %) cases have other glomerular pathologies.
The detail of glomerular pathologies is shown in Table 1 and Figure 1A.

There are several glomerular diseases reported in COVID-19 patients; however, some glomerular
diseases are likely simply coincidental. These lesions are mostly being diagnosed while COVID-19
patients seek medical attentions for other issues. While establishing a causal-relationship between
COVID-19 and glomerular diseases remains challenging, some clues may suggest the possibility of the
association. Glomerular diseases that are likely to have a causal relationship with COVID-19 are
frequently reported in the literature, more prevalent in the COVID-19 era compared to pre-COVID-19
era,9 or have plausible mechanistic explanations such as immune dysregulation, auto -antibody
production, cytokine upregulation, complement activation or direct viral toxicity.15 These entities may
include CG, primary podocytopathy, pauci-immune crescentic GN, MN, IgA nephropathy, etc. On the
other hand, some glomerular lesions that are likely coincidental with no other plausible mechanistic

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links include diabetic nephropathy, AL amyloidosis, AA amyloidosis, among others, etc (Figure 2).

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Glomerular diseases in native kidneys

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1. Kidney pathology potentially related to COVID-19

1.1 Collapsing glomerulopathy

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CG is the major pathological finding in the biopsy series of COVID-19 patients.9, 19 It was first reported by
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Larsen et al. in a Black patient who presented with COVID-19.20 The patient developed stage 3 AKI and
nephrotic range proteinuria. A kidney biopsy revealed CG and diffuse acute tubular injury. Genetic
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testing showed homozygous G1 apolipoprotein L1 (APOL1) variant.20 Subsequent studies have reported
similar finding of CG in COVID-19 and high-risk variant APOL1.19, 21-26 May et al. showed that 91.7% of
African American or Hispanic descents whose kidney biopsy showed CG harbored 2 risk alleles APOL1
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variant.9 On the other hand, only 35.6% of patients with non-CG possessed 2 risk alleles of the APOL1
variant.9
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This association of high-risk APOL1 genotype and kidney disease has been previously reported in several
viral infections such as cytomegalovirus, parvovirus B19, Epstein-Barr virus and particularly HIV.27 HIV-
associated nephropathy (HIVAN) is an aggressive form of kidney disease that occurs in HIV patients
particularly in patients with uncontrolled disease. The biopsy findings in HIVAN typically show diffuse
CG, tubular injury and distended tubules containing proteinaceous cast forming “tubular microcysts”.
Electron microscopy shows collapsed capillaries with wrinkled glomerular basement membrane and
diffuse foot process effacement. Tubulo-reticular inclusions, known as “interferon footprint”, are often
observed in glomerular endothelium.28 The similarity of clinical and pathological findings in HIVAN and
CG in COVID-19 led to the newly proposed term of COVAN or COVID-19-associated nephropathy.27
Pathophysiology of COVAN is thought to be related to immune dysregulation in COVID-19 patients.
Several cytokines such as interleukin (IL)-1β, IL-6, IL-10, and interferon (IFN)-γ are upregulated in the
setting of SARS-CoV-2 infection.29 IFN interact with APOL1 risk variant culminating in glomerular
epithelial cell autophagy, mitochondrial dysfunction, and cell injury.27 Although COVAN shares several
similarities, including pathological findings and upregulation of IFN, with HIVAN, viral detection in
kidneys appears to be more common in HIVAN than in COVAN.30 To date, there are 148 cases of CG in
COVID-19, of these, 86 cases have detailed clinical data available.
Clinical presentation

The median age was 57 years [interquartile range (IQR) 49, 63]. The majority of patients were men (75.6
%) and nearly all the patients were of African ancestry.19 Cardiovascular co-morbidities such as diabetes,
hypertension and obesity were common. About 80% of patients had a kidney biopsy within 1 month of
COVID-19 diagnosis.19 Patients often presented with acute kidney injury with median serum creatinine
of 7.4 mg/dl. Almost 90% of patients had AKI stage 3. Severe proteinuria was a hallmark of CG with
median 24 hour urine protein of 10 g/d and 96% of patients have nephrotic syndrome.19 About half of
patients have hematuria (Supplementary table 1).

Pathological findings (Figure 3A)

Glomeruli demonstrates glomerular tuft collapse with overlying reactive glomerular epithelium in the
Bowman space.20 Features of tubular injury include diffuse simplification with denudation of the brush
border. The degree of tubulo-interstitial scarring seems to be associated with the time of CG and COVID-

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19 diagnosis. Moderate to severe tubulointerstitial scarring tends to be more common if a kidney biopsy

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is performed after 1 month of the COVID-19 diagnosis.19

Some patients may have interstitial edema with a predominantly lymphocytic infiltrate.20

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Immunofluorescence is typically negative for immune reactants. Electron microscopy typically showed
diffuse foot process effacement and cytoplasmic vaculolization.20, 31 Tubuloreticular inclusions are
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occasionally found in the glomerular endothelial cell cytoplasm.31 Overall, these features are not
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different than CG in non-COVID-19 patients. Thus far, there has been no evidence of viral detection in
kidney biopsy of patients with CG.
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Treatment and outcome

About a third of patients received steroids for COVID-19 and a quarter of patients received either
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monoclonal antibodies or immunomodulators agents for COVID-19. However, only 6% of patients

received antiviral therapy. A quarter of the patients received immunosuppression for CG. These
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treatments included prednisone alone, calcineurin inhibitor (cyclosporine) and cyclophosphamide.

Overall, CG portends poor prognosis. Approximately 70% of patients required dialysis, but half of the
patients were able to come off dialysis. The rate of end-stage kidney disease (ESKD) was higher than CG
in non-COVID-19 in which the rate of ESKD was approximately 30%.32 About 7.0% of the patients died
during follow-up. Supplementary table 1.

1.2 Non-collapsing podocytopathy

Podocytopathy refers to a group of glomerular diseases caused by podocyte injury. This often leads to
severe proteinuria and nephrotic syndrome as a result of diffuse foot process effacement.33, 34
Podocytopathy can be classified based on their pathogenesis into permeability-factor mediated, toxic, or
genetic.34 Non-collapsing primary podocytopathy (Minimal Change Disease [MCD] and non-collapsing
FSGS) is the second most common reported glomerular pathology in COVID-19 patients following CG.
Pathophysiology of podocytopathy may be related to upregulation of interferon in COVID-19 rather than
direct toxicity from viral invasion as most patients did not have viral particles detected in their biopsy.9,
35
Although, the relationship between APOL1 high risk genotype and non-collapsing FSGS is less defined
compared to CG, about 86% of African American and Hispanic patients with primary podocytopathy had
APOL1 high risk genotypes.9 There were total of 45 cases, of which 23 cases (51.1%) were MCD and 22
cases (48.9%) were non-collapsing FSGS. Of these 45 cases, only 21 cases have detailed clinical history
available.10, 18, 19, 35-38

Clinical presentation

Similar to podocytopathy in non-COVID-19 setting, patients typically presented with significant

proteinuria. The median urine protein was 12 g per day. About two-third of patients have evidence of
hematuria. The majority (75%) of patients were African American. The median age at presentation was
54 years and 57% were male. About two-third of patients presented with stage 3 AKI with median serum
creatinine of 4.5 mg/dl. A kidney biopsy is often performed within 2-4 weeks of COVID-19 diagnosis.19, 35
Most patients had mild to moderate COVID-19.19 Summary of clinical characteristics is shown in
Supplementary table 2.

Pathological findings

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Kidney pathology may vary depending on the degree of injuries. Light microscopy may show no
significant abnormalities as in MCD. Subtle changes such as mild mesangial hypercellularity may be

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reported. Tip or not otherwise specified (NOS) lesions are reported in patients with FSGS. Acute tubular
injury is very common and seen in almost every cases. The degree of interstitial fibrosis and tubular

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atrophy (IFTA) is usually mild but some cases may show severe changes19 which raises suspicion of
possible undiagnosed podocytopathy preceding COVID-19. Microcysts may present in small number of
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patients.19 Immunofluorescence is typically negative for immunoreactants. EM findings demonstrate
diffuse foot process effacement (FPE) with occasional TRIs.35 Phagolysosomal activity may be observed
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by electron microscopy (EM).10

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Treatment and outcome

Twenty seven percent of patients received steroids therapy for COVID-19 and 18% received antiviral
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therapy. The majority of patients did not receive immunosuppression. Approximately one-third of
patients received immunosuppression, all of which were prednisone. Unlike CG, only 37.5 % of patients
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required dialysis. Patients had a better prognosis compared to CG. Twenty-five percent of patients had
complete renal recovery and only 6% required long term dialysis (Supplementary table 2).

1.3 Membranous nephropathy

Membranous nephropathy (MN) is the most common adult nephrotic syndrome in western world.39
Approximately 80% of cases are associated with phospholipase A2 receptor (PLA2R) antibody.39 Other
antigens associated with MN include thrombospondin 7A (THSD7A), neural epidermal growth factor-like
1 protein (NELL-1), Exostosin (EXT)1/2, or protocadherin FAT140, 41 which have expanded our
understanding of MN. However, some viral infections primarily hepatitis B virus can be associated with
MN.42 There are reports of MN cases that occurred in temporal relationship with COVID-19 (23 cases)
but only 7 cases have clinical information available.18, 43-47 Pathophysiology of MN in COVID-19 remains
unclear but may be related to immune dysregulation resulting in auto-antibodies production.46

Clinical presentation

The median age on presentation was 72 years (IQR 63, 81 years). Almost all patients (85.7%) were male.
There were 33% Asian, 33% Hispanic,17% Black and 17% White. Median time of onset was within 1
week of COVID-19 diagnosis. Median serum creatinine upon biopsy was 1.8 mg/dl (IQR 1.0, 7.0). The
median proteinuria was 6.8 (IQR 4.6, 8.7) g/d and nearly all patients (83.3%) had hematuria. PLA2R
antigen was tested in all 7 patients and detected in 4 (57.1%) patients. No other antigen has been
reported in the literature thus far (Supplementary table 3).

Pathological findings

Glomeruli typically showed segmental mild to moderate mesangial hypercellularity and matrix
expansion.44, 46 Diffuse thickening of basement membrane is common. There was no report of
endocapillary hypercellularity, crescents or thrombi in these cases. Glomerulosclerosis and IFTA were
typically mild to moderate.18 Microcysts were observed in some cases.18 ATI was reported in some
cases.46, 47 IF showed typical granular peripheral capillary wall staining of IgG similar to non-COVID-19
MN cases. EM generally demonstrated diffuse foot process effacement with primarily subepithelial
immune deposits.46 Mesangial and intramembranous immune deposits were sometimes reported.44
Abundant tubuloreticular inclusions were identified in the endothelial cell cytoplasm of one case.46

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Treatment and outcome

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The treatment and outcome are limited due to scarcity of reports and short-term follow-up. Two out of
patients received steroids for COVID-19 and only 1 patient received antiviral therapy. There were 4

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patients (66.7%) that received immunosuppression: one with tacrolimus, one with cyclophosphamide,
one with methylprednisolone, and one with rituximab.18, 44-46 Two patients received conservative
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management. Two patients (40%) required dialysis and eventually died. Four patients (66.6%) had
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persistent kidney dysfunction. Of these, 3 patients received cyclophosphamide, tacrolimus or rituximab

(Supplementary table 3).18, 44, 45
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1.4 IgA nephropathy (IgAN)

IgAN is the most common GN globally, and is more common in the East and Pacific Asian countries.48
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Patients typically present with microscopic or gross hematuria. Proteinuria is common, and is associated
with progression of kidney disease. The risk of progression to ESKD varies from 5-15% at 5 years and 10-
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50% at 20 years.49 Some patient may present with rapidly progressive GN (RPGN) with high burden of
glomerular crescents.50 Pathophysiology of IgAN in COVID-19 remains to be elucidated but it is possible
that upregulated IgA may result in development of IgAN. In fact, IgA is the dominant immunoglobulin in
the early course of COVID-19, and is associated with clinical severity.51, 52Similar to a report of IgAN post
COVID-19 vaccine, COVID-19 itself may unmask subclinical IgAN in asymptomatic patients.53 There were
total of 23 patients with IgAN in association with COVID-19. Of these, 13 patients had clinical data
available.47, 54-63

Clinical presentation

COVID-19 patients with IgAN tended to be older with median age of 64.5 years (IQR 41, 79.5 years)
compared to 34 years for IgAN in general population.64 The median onset of IgAN was 3 weeks (IQR 0,
7) post COVID-19. One patient had hematuria and proteinuria 14 months prior to COVID-19. However,
this patient had worsened proteinuria and hematuria after COVID-19 and a kidney biopsy showed
IgAN.56 Majority (69.2 %) of patients were male, and 63.6 % were White. The median serum creatinine
upon biopsy was 3.1 mg/dl (IQR 1.9, 4.0). Of the 13 patients, 2 patients did not have AKI, 1 patient had
AKI stage 1, 5 patients had stage 2 AKI and 5 patient had stage 3 AKI. Nearly all patients (91.7%) had
hematuria and the median proteinuria was 3.7 g/d (IQR 1.3, 4.9) (Supplementary table 4). Interestingly,
7 of 13 patients (53.8%) also had concomitant cutaneous vasculitis.47, 57, 59, 60, 62

Pathological findings

Kidney pathology of IgAN in COVID-19 was similar to IgAN in non-COVID-19 cases including segmental
sclerosis, mesangial hypercellularity and endocapillary hypercellularity. However, COVID-19 IgAN cases
may exhibit more active features such as diffuse endocapillary hypercellularity with neutrophilic
exudation, and crescents.47, 56, 59, 62 Of 13 patients, 7 patients (53.8%) had crescentic lesions.47, 55, 56, 59, 60,
62, 63
IF showed granular mesangial staining for IgA, C3, kappa and lambda light chain.61 EM displayed
mesangial, para-mesangial and rare subendothelial electron deposits.61 Significant podocyte foot
process effacement was observed in some cases.47, 62 Perez et al. also reported the presence of
coronavirus particles in the cytoplasm of tubular cells via immunohistochemistry. However, PCR for
SARS-CoV-2 was negative. 61 Figure 3B & C.

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Treatment and outcome

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Thirty percent and 15% of patients received steroids and anti-viral for COVID-19, respectively. Only one
patient required dialysis. This patient had serum creatinine of 7.8 upon presentation. A kidney biopsy

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showed concomitant acute interstitial nephritis and crescentic lesions. This patient had epidural abscess
which precluded the patieent from receiving aggressive immunosuppression but received high dose
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steroids with improvement in serum creatinine but remained on dialysis at the time of the report.55
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Nine patients required immunosuppression and all of which received steroids. Three patients received
additional treatment with rituximab, cyclophosphamide or tonsillectomy.60, 62, 63 . Of patients with
immunosuppression, 2 patients had complete renal recovery, 6 patients had partial renal recovery (one
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with negative proteinuria but with partial creatinine improvement; five with partial improvement in
proteinuria ranging between 40-90%) 57, 59, 60, 62, 63, and one patient remained on dialysis. Three patient
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were treated conservatively with RAAS inhibitor.54, 56, 58 Of these, one had complete recovery of
proteinuria and the other two had improvement in serum creatinine but the amount of proteinuria were
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not reported.54, 56, 58 (Supplementary table 4).

1.5 Pauci-immune crescentic GN

Pauci-immune crescentic GN is a group of vasculitis that involves kidneys and extra-renal organs.
Majority of patients (90%) are associated with anti-neutrophil cytoplasmic antibody (ANCA) including
proteinase-3 (PR3) and myeloperoxidase (MPO).65 ANCA-negative pauci-immune glomerulonephritis
accounts for 10% of cases.65 In patients with genetic predisposition for ANCA-associated GN, exposure to
certain triggers (e.g. infections, drugs, or environmental factors) may lead to neutrophilic activation and
ANCA production.66 There is growing evidence to support the role of infections in both ANCA-associated
and ANCA-negative GN.67, 68 Cytomegalovirus, Ebstein-Barr virus and dengue virus are reported to be
associated with ANCA-associated GN.67 The underlying mechanism of developing pauci-immune
crescentic GN may be related to molecular mimicry, ANCA auto-antibody production, and formation of
neutrophil extracellular traps (NETs).69, 70 Thus far, there are a total of 31 reports of COVID-19 associated
pauci-immune crescentic GN; of these, 16 patients had clinical data available.38, 70-80

Clinical presentation
The median age was 62.5 years (IQR 38.5, 76.4). Majority of patients were female (56.5 %) and majority
were white (37.5 %). The median serum creatinine was 4.3 mg/dl (IQR 2.5, 6.1). Patients typically
presented with severe AKI with 73.3 % of patients developing stage 3 AKI. All patients had proteinuria
and the median proteinuria was 3.3 g/d (IQR 1.8, 5.0). This was quite high comparing to non-COVID-19
ANCA patients.81 There were heterogeneity in reporting ANCA antibody. MPO accounted for 43.7% of
cases followed by PR3 (25.0 %) and C-ANCA (12.5%), C and P-ANCA (6.3%), MPO+PR3 (6.3%) and ANCA-
negative 6.3%). Onset typically within 1 week of COVID-19 diagnosis (IQR 0, 2.5). Of 13 patients that
reported onset information, 9 patients were diagnosed within 1 week of COVID-19. Four patients were
diagnosed at least 2 weeks after COVID-19 diagnosis, of these, 3 patients had MPO antibody.
(Supplementary table 5).71, 72, 74, 78

Pathological findings

Light microscopy shows moderate to diffuse cellular to fibrocellular crescents associated with ruptured

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Bowman’s capsule. 48-54 The degrees of glomerulosclerosis ranges from mild to severe.72 ATI is common
with inflammatory infiltrates in some cases, and tubulitis may be observed.75 Inflammatory infiltrates

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are non-specific and include T-cells, B-Cells, plasma cells and macrophages.74, 75 Red blood cell cast may
be observed in severe hematuria.71 Necrotizing arteritis with fibrinoid necrosis and peritubular

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capillaritis are noted.74 IF shows minimal to no staining of immunoreactants except fibrinogen in areas of
crescents and necrosis. Electron microscopy shows no or few electron-dense deposits, and shows no
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viral particles.75, 79 Uppal et al. were the only investigators who tried to detect the presence of SARS-CoV
in the kidney, which was negative by immunohistochemistry.79 As expected, patients who had a kidney
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biopsy done more than 1 month after COVID-19 appeared to have a greater degree of IFTA.71, 72, 74 Figure
3D.
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Treatment and outcome

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Although patients typically presented at the time of COVID-19 diagnosis, only 12.5% received steroids
and 18.8% received antiviral agents for COVID-19. Of 16 patients, 15 patients required
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immunosuppression for the vasculitis. Thirteen patients received steroids plus other agents whereas
two patients received steroids alone. Three patients received plasmapheresis, of these 2 patients
received cyclophosphamide and 1 received rituximab.70, 71, 76 Five patients (31.3%) required dialysis and
two patients were able to discontinue dialysis after treatment. Of 16 patients, only 2 patient achieved
complete recovery, 10 patients with persistent renal dysfunction and 3 patients were dialysis
dependent. One patient died. (Supplementary table 5).

1.6 Thrombotic microangiopathy

Thrombotic microangiopathy (TMA) is a systemic disease characterized by endothelial injury. Clinical

manifestations of TMA are diverse and vary greatly from organ-limited symptoms to systemic features
including thrombocytopenia and microangiopathic hemolytic anemia.82 Kidney pathology shows
endothelial swelling with or without thrombi. Intraluminal schistocytes may be present in the vessels.
EM typically shows endothelial swelling and subendothelial lucency.83 There are several factors
associated with TMA including drug-induced TMA, atypical hemolytic uremic syndrome (aHUS),
autoimmune diseases, glomerular diseases, bone marrow transplant, malignancies, genetic disorders
and infections.82 Many infections have been reported to induce TMA such as E.coli (Shiga toxin)84, HIV85,
influenza86, CMV, EBV, and others.87 Pathogenesis of infection related TMA may be related to a second
hit from infections in patients with predisposing complement gene mutations.86, 87 In COVID-19, direct
viral toxicity to vascular endothelium, immune dysregulation, hyper-inflammatory state and
uncontrolled complement pathway activation may play a role in pathogenesis of TMA in COVID-19.88, 89
There were total of 21 patient reports of renal TMA, of these, 16 patients had clinical data available.
However, there were additional five cases with evidence of TMA along with other glomerular
pathologies, of these four had CG and one had FSGS.35

Clinical presentation

The median age was 43 years (IQR 35.8, 67.5). The majority were male (56.3%) and White (44.4%). All
patients suffered severe AKI, all stage 3 with median serum creatinine of 4.8 mg/dl (IQR 3.0, 7.4).
Patients typically have subnephrotic range proteinuria, median urine protein 1.4 g/d (0.7, 3.9). Seventy
percent of patients have hematuria. Nearly 80% of patients have systemic features of TMA. Three
patients have evidence of alternative complement dysregulation. One patient had low complement

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factor H and elevated CBb, one had CFHR1 and 3 gene mutations and one had variance of unknown
significance in complement factor I and risk polymorphism in complement factor H gene.90-92

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(Supplementary table 6).

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Pathological findings

Light microscopy shows endothelial swelling with glomeruli and arterial thrombi. GBM remodeling with
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double contouring and cross-linked fibrin aggregated in glomerular capillaries can be observed in
electron microscopy.25 ATI and interstitial inflammation can be seen. In a case with severe TMA, diffuse
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coagulative cortical necrosis ensued.90

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Treatment and outcome

Patients with TMA tended to received specific therapy for COVID-19 more than other type of glomerular
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diseases: steroids (46.2%), monoclonal antibodies or immunomodulators (33.3%) or antiviral agents

(15.4%). The outcome and prognosis of patients with TMA in COVID-19 are grim. Two third of patients
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required dialysis. Three patients received immunosuppression (two with steroids and one with
rituximab).35, 77, 93 Eight patients received eculizumab. However, there were no difference in the rate of
renal recovery or dialysis between patients with or without eculizumab. Twenty three percent of
patients died. (Supplementary table 6).

1.7 Other immune-complex GN

There have been 8 reports of infection-associated GN as part of a large pathology cohort in COVID-19
patients. However, there was no detailed clinical data available.9 There were 3 reports of immune
complex GN and 2 case had clinical data available.94, 95 Sethi et al. reported on a 25-year-old White
female with history of genetic FSGS due to SMARCAL1 gene mutation. The patient was admitted due to
diarrhea and was found to have Escherichia coli O157:H7-associated hemolytic uremic syndrome. She
was also positive for SARS CoV-2. She was treated with eculizumab with improvement in serum
creatinine but her proteinuria increased to 13 g/d from baseline of 3.7 g/d leading to a kidney biopsy. A
kidney biopsy revealed a membranoproliferative GN pattern of injury. There were subendothelial wire-
loop lesions. No crescents or fibrinoid necrosis was detected. IF showed bright staining for full-house
immunoreactions and also C4d. EM showed numerous large subendothelial and mesangial immune
deposits. TRIs were absent. Interestingly, there was no evidence of endothelial injury.95 Given “full
house” appearance, an extensive autoimmune panel was checked, and was negative. The patient was
given high-dose methylprednisone followed by prednisone taper and mycophenolate mofetil. Three
weeks after treatment, the patient still had significant proteinuria with slightly worsening kidney
function.95 Danis et al. reported on a 59 year-old male who developed nephrotic syndrome and AKI 2
months post COVID-19. Serum creatinine upon presentation was 5.2 mg/dl and 4.2 g/d of proteinuria.
Serological testing was negative. A kidney biopsy showed immune complex glomerulonephritis with
positive IgG and C3 immunoreactants. The patient was treated with cyclophosphamide and high dose
steroids with kidney function returned to normal at 2 weeks.94 Etiology of immune complex GN in
COVID-19 remains elusive but may be related to B-cell activation and hypergammaglobulinemia similar
to HIV-associated immune-complex GN.95 Pathophysiology of immune complex GN in COVID-19 may be
similar to immune complex GN in HIV patients whereby polyclonal B-cell activation and
hypergammglobulinemia contributing to immune complex.95 In fact, COVID-19 has been associated with
interleukin-6 upregulation which is an important growth factor for B-cell differentiation and

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maturation.96

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1.8 Lupus nephritis

There were a total of 10 cases of LN in COVID-19 patients but only one case had available clinical data.

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Kudose et al reported a 27-year-old Asian female with a history of class 2 LN who developed AKI with a
serum creatinine of 2.5 mg/dL from a baseline of 0.9 mg/dL. The patient also developed nephrotic
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syndrome with 9.2 g/d of proteinuria, albumin 2.0 g/dL, and microscopic hematuria. A kidney biopsy was
performed which showed evidence of LN class 4 and 5. There was endocapillary and mesangial
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hypercellularity associated with crescents. There was diffuse interstitial inflammation. EM showed
diffuse foot process effacement without evidence of TRIs or viral particles.18 The patient received
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steroids but subsequently expired due to multi-organ failure from COVID-19. The pathogenesis of lupus
and other auto-immune disease and COVID-19 may be related to molecular mimicry between SARs-CoV-
2 and self-antigens and immune dysregulations.97
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1.9 Anti-glomerular basement membrane (Anti-GBM) disease

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There were a total of 9 cases of anti-GBM disease but only 7 cases with reported clinical data.18, 98-100 Of
7 patients, 6 patients were Asian, and 1 patient was African American. The median age was 48 years
(IQR 32, 57). Four patients (57.1%) were male. A kidney biopsy typically showed crescentic GN with
evidence of anti-GBM GN with all glomeruli affected.18 Figure 3E & F. Patients typically present with very
high serum creatinine, median 9.5 mg/dl (4.5, 17.0).18, 98-100 All patients received immunosuppression
with cyclophosphamide and steroids. Five patients received plasmapheresis and two patients declined
the therapy. Six patients required dialysis upon presentation but only 2 patients were able to
discontinue dialysis.

1.10 Proliferative glomerulonephritis with monoclonal immunoglobulin deposit (PGNMID)

May et al. demonstrated that PGNMID was more enriched in COVID-19 native kidney biopsies compared
to the pre-COVID-19 era.9 There were a total of 5 cases of PGNMID in the literature. Four cases were
from May et al. and one case was reported by Shieh et al.9, 101 This patient was the only patient with
detail clinical information. The patient was a 71-year-old woman with normal baseline serum creatinine,
0.7-0.9 mg/dl. She was diagnosed with COVID-19 and was treated with remdesivir and dexamethasone.
One month post COVID-19, respiratory status improved but she developed generalized swelling. She had
AKI with increased serum creatinine at 3.3 mg/dl but progressed to peak at 8.5 mg/dl before dialysis
initiation. She has nephrotic syndrome with 24-hour urine protein of 5.2 g/d and serum albumin 1.9
g/dl. Kidney biopsy showed PGNMID with monoclonal IgG3 kappa deposits and only 10-20% interstitial
fibrosis. Serum and urine monoclonal protein were negative. She was treated with cylocphosphamide,
bortezomib and dexamethasone (CyBORD) for 2 cycles with an improvement in kidney function (serum
creatinine 2.1 mg/dl) and subsequent discontinuation of dialysis. However, she developed recurrent AKI
with serum creatinine up to 6.7 mg/dl shortly after stopping anti-plasma cell therapy, requiring re-
initiation of dialysis. A repeat kidney biopsy showed similar finding of PGNMID. CyBORD was reinitiated
with good response and she was able to come off of dialysis. At the last follow-up, her serum creatinine
were stabilized at less than 2.0 mg/dl with over 80% reduction in proteinuria.9, 101 There was a report
that COVID-19 may cause an acute monoclonal gammopathy in patients without previous evidence of
monoclonal gammopathy similar to other viral infections.102 Upregulation of interleukin 6 in COVID-19
may promote B-cell differentiation and maturation into plasma cell resulting in monoclonal

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gammopathy.102 It is also possible that other immune response to viral infection may explain the
association with PGNMID similarly to previous reports.103, 104

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2. Kidney pathology potentially unrelated to COVID-19

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There were reports of monoclonal protein-related lesions in COVID-19 patients including
cryoglobulinemic GN, AL amyloidosis, light chain deposition disease (LCDD), proliferative
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glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and membranous-like
glomerulopathy with masked IgG kappa deposit (MGMID).9, 19 Other lesions include AA amyloidosis, thin
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glomerular basement membrane disease, and sickle cell nephropathy. 9, 19, 105 It is less likely that these
lesions are associated with COVID-19 but rather a coincidental finding due to rarity of these lesions even
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in the COVID-19 era and lack of plausible pathophysiological association.

Glomerular diseases in kidney allografts

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There are a total of 85 kidney transplant patients. Of these, 58 cases (68.2%) have glomerular
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pathologies, 23 cases (27.1%) have tubulointerstitial lesions and 4 cases (4.7%) have no significant
pathologies. Of 58 cases, 37 cases (63.8%) have acute or chronic rejections whereas the remaining 21
cases (36.2%) have other glomerular lesions. The detail of glomerular lesions in kidney allografts is
shown in Figure 1B. The increase in percentage of rejection in allograft biopsy was noted in a large
series from May et al. and Daniel et al.9, 11 Majority of cases did not detect any evidence of viral invasion
in the kidneys.11 Pathophysiology of allograft rejection in COVID-19 is possibly related to immune
dysregulation and reduction in anti-rejection medication in the setting of active COVID-19.35 It is also
possible that COVID-19 acting as a second hit in patients with pre-existing donor specific antibodies.11 In
this section, we will focus only glomerular lesions excluding allograft rejections. Of 21 cases, collapsing
glomerulopathy is the most common reported lesions (n=8, 38%).

Collapsing glomerulopathy

There were 8 cases of CG in allografts with available clinical data.10, 11, 22, 24 Of five cases, 3 cases received
living donor kidneys whereas four cases received deceased donor kidneys. There was no report about
donor in one patient.106 Median age was 49 years (IQR 45.8, 60). About 50% of patients were African
American, 16.3%, 33.3% White and 16.7% Hispanic. The median serum creatinine was 6.2 mg/dl (IQR
3.1, 11.3) with proteinuria 7.6 g/d (IQR 4.414.2). There were 3 cases that had APOL1 risk genotype
analyzed, one was G1/G2,107 one was G0/G222 and another one was G0/G1.10 This is different than
native kidney CG where high risk APOL1 were more common than allograft CG.9 Similar to native
kidneys, light microscopy typically revealed collapsing glomerular capillary loops accompanied by
reactive/hypertrophic glomerular epithelial and mesangial hypercellularity. Patients typically had severe
ATN with microcystic dilation containing proteinaceous content.10, 22, 24 IF was typically negative for
immunoreactants. EM showed diffuse foot process effacement.11 Six patients had a reduction in
immunosuppression.10, 11, 22, 107 One patient required dialysis and remained dialysis dependent at the
time of the report.24 Three patients had graft failure and three patients had persistent kidney
dysfunction. Only one patient had recovered kidney function. The patient with kidney function recovery
also received bamlanivimab therapy.11

Other lesions

There were several other lesions reported in the literature including calcineurin toxicity, TMA with

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cortical necrosis, IgA nephropathy, diabetic nephropathy, LN, and PGNMID.11, 18, 43 The frequency of each
of these lesions is low, however, and some are possible coincidental.

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Future directions

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Although there are several case series and reports of glomerular diseases in COVID-19 patients since the
pandemic began, there is still a need for large population based studies exploring incidence and
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prevalence of glomerular diseases post COVID-19 similar to studies of glomerular diseases post COVID-
19 vaccination.108 Many glomerular diseases are likely coincidental to COVID-19 rather than having true
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association. We need studies with control groups in order to compare the difference in clinical,
pathological and prognostication between non-COVID-19 and COVID-19 patients. Importantly, clinicians
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lack the data regarding treatment particularly how to navigate immunosuppression therapy in the
setting of active COVID-19 infection. It also remains unknown whether the outcomes of glomerular
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diseases associated with COVID-19 would improve with simply COVID-19 therapy or would require
additional immunosuppression. Last but not least, the type of therapeutic agents, dosage, duration of
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immunosuppression, and long term outcomes are the pivotal areas that need to be further explored.

Conclusion

There are various forms of glomerular diseases reported in native and allograft kidneys of patients who
recently had COVID-19 (Figure 2). The underlying mechanisms for each disease process remain unclear
but likely are varied and multifactorial. A hyper-inflammatory state and direct viral cytotoxicity may be
responsible for CG, podocytopathy particularly in high risk APOL1 genotypes. Immune dysregulation may
incite or unmask some autoimmune process such as ANCA-associated GN, anti-GBM disease, IgA
nephropathy or lupus nephritis. Endothelial injury in conjunction with complement activation may
precipitate TMA. On the other hand, there are several renal pathologies that are like unrelated to
COVID-19 but are discovered when the patients sought care due to COVID-19. These lesions include
certain monoclonal protein related kidney diseases, sickle cell nephropathy, AA amyloidosis, etc.
Clinicians should take into consideration the onset of kidney manifestations, types of lesions, chronicity
of lesions and pathophysiological plausibility in deciding which lesions are likely causally related to
COVID-19. Treatments of glomerular diseases in the setting of active or recent COVID-19 is challenging.
Many patients were managed conservatively. However, immunosuppression may be beneficial in
selected patients whose glomerular diseases that, outside of the setting of COVID-19 infection, typically
require immunosuppression such as pauci-immune crescentic GN. Although long-term outcomes remain
elusive, short-term outcomes generally are guarded. Larger and prospective studies are needed to
better understand the epidemiology and outcomes of glomerular diseases following COVID-19,
particularly with emerging variants.

Supplementary Material

Supplementary information is available at KI Report's website.

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Table 1: Glomerular pathologies from native kidney biopsy studies since from start of COVID-19
pandemic until February 2023.

Pathology Number Percentage

Collapsing glomerulopathy 148 36.1%
Podocytopathy 45 11.0%
Diabetic nephropathy 37 9.0%
Pauci-immune crescentic GN 31 7.6%
Membranous nephropathy 23 5.6%
IgA nephropathy 23 5.6%
Thrombotic microangiopathy 21 5.1%
Secondary FSGS 15 3.7%

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Lupus nephritis 10 2.4%
Anti-GBM GN 9 2.2%

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Infection-associated GN 8 2.0%
AL amyloidosis 5 1.2%

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PGNMID 5 1.2%
Cryoglobulinemic GN 3 0.7%
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Immune complex GN 3 0.7%
MGMID 1 0.3%
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Fibrillary glomerulonephritis 1 0.3%

Light chain deposition disease 1 0.3%
AA amyloidosis 1 0.3%
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Other
- Nephrosclerosis (chronic changes) 17 4.1%
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- Thin basement membrane disease 1 0.3%

- Sickle cell nephropathy 1 0.3%
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Total 410 100.0%

Abbreviations: FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; GBM, glomerular

basement membrane; PGNMID, proliferative glomerulonephritis with monoclonal immunuoglobulin
deposition; MGMID, membranous-like glomerulopathy with masked IgG kappa deposits
Figure legends

Figure 1: Glomerular pathology in native kidney and allograft biopsy

Abbreviations: CG, collapsing glomerulopathy; DN, diabetic nephropathy; GN, glomerulonephritis; MN,
membranous nephropathy; FSGS, focal segmental glomerulosclerosis; IgAN, IgA nephropathy; LN, lupus
nephritis; TMA, thrombotic microangiopathy; ABMR, antibody-mediated rejection; ATN, acute tubular
necrosis; TCMR, T-cell mediated rejection

Figure 2: Approach to glomerular pathology in COVID-19 patients

Abbreviations: CG: collapsing glomerulopathy; FSGS, focal segmental glomerulosclerosis; MCD, minimal

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change disease; GN, glomerulonephritis; GBM, glomerular basement membrane; ATN, acute tubular
necrosis; TMA, thrombotic microangiopathy; TBMD, thin basement membrane disease; PGNMID,

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proliferative glomerulonephritis with monoclonal immunoglobulin deposit; MGMID, membranous-like
glomerulopathy with masked IgG kappa deposits; CNI, calcineurin inhibitor

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Figure 3: Kidney pathology in native kidney biopsy in COVID-19 patients
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A) The glomerulus shows collapsed capillary tufts with florid parietal epithelial cells hyperplasia, typical
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of COVID-19 associated nephropathy (COVAN) (Jones methenamine silver, 400X); B) A segmental cellular
crescent and mesangial proliferation are noted in the glomerulus of a patient who had COVID-19 and IgA
nephropathy (Jones methenamine silver, 400X); C) IgA dominant staining of the mesangium confirms a
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diagnosis of IgA nephropathy. D) A PR3 positive pauci-immune glomerulonephritis characterized by a

focal segmental cellular crescent and lack of mesangial or endocapillary proliferation (PAS, 400X) E) A
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biopsy of anti-glomerular basement membrane nephritis in a patient with COVID-19 shows a

circumferential cellular crescent and glomeruli without proliferative histology (PAS, 400X); F) The IgG
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stain demonstrates bright linear staining of the glomerular basement membrane, without staining of
tubular basement membranes.
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