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\begin{document}

\title{Analysis of Clinical and Pathological Features of Omicron Variants of
SARS-CoV-2 associated Kidney Injury}



\author[1]{Xuejing Zhu}%
\author[1]{Zhiwen Qi}%
\author[1]{Shuguang Yuan}%
\author[1]{Jinying Wei}%
\author[1]{Shiyu Xia}%
\author[1]{Yao Huang}%
\author[1]{Xiaojun Chen}%
\author[1]{Yachun Han}%
\author[1]{Zheng Li}%
\author[2]{Yang Xiao}%
\author[3]{* FenghuaPeng}%
\author[1]{Xiao Fu}%
\author[1]{Lin Sun}%
\author[1]{Hong Liu}%
\affil[1]{The Second Xiangya Hospital of Central South University Department of Nephrology}%
\affil[2]{The Second Xiangya Hospital of Central South University National Clinical Research Center for Metabolic Diseases}%
\affil[3]{Second Xiangya Hospital Department of Kidney Transplantation}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Kidney injury is common in patients with Coronavirus Disease-19
(COVID-19). In this study, 49 patients with Omicron associated kidney
injury were included, 38 of whomperformed renal biopsy. Patients were
divided into 2 groups: Group A for patients developing kidney injury
afterSARS-CoV-2 infection and Group B for patients with aggravated renal
insufficiency after SARS-CoV-2 infection. The clinical, pathological and
prognostic characteristicsof the patients and theirC3 levels were
observed.In our center, the clinical diagnoses of patients with COVID-19
associated kidney injury were mainly acute kidney injury(AKI), chronic
kidney disease(CKD) and nephrotic syndrome(NS); while the pathological
diagnoses were mainly IgA nephropathy(IgAN)\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}focal segmental
glomerulosclerosis(FSGS) and membranous nephritis(MN).80\% of COVID-19
associated nephropathy (COVAN) patients had normal serum C3 complement
level, and a few patients had increased or decreased C3 level. In renal
tissue, C3 deposits were observed in 68.4\% of patients.29\% of patients
experienced deterioration of renal function after treatment, but no
patients developed to end-stage renal disease (ESRD). Among all of them,
one case presenting with thrombotic microangiopathy (TMA) had a more
severe renal pathological lesion and poorer prognosis. We observed
differences of clinical and pathological features of patients with
COVID-19associated kidney injury between races, regions and virus
variants. Asian patients with Omicron associated kidney injury have
milder kidney injury and a better renal prognosis.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Since December 2019, a new respiratory infectious disease `COVID-19' has
become a global epidemic. Kidney is one of the most frequently involved
extrapulmonary organs. The renal injury caused by SARS CoV-2 is called
COVID-19 associated nephropathy (COVAN), which is related to the poor
prognosis of patients. Renal injury usually manifests as nephritis,
recurrence or aggravation of kidney disease, transplant rejectionand
acute kidney injury (AKI). The mortality rate of COVID-19 cases with AKI
is significantly higher than those without kidney
disease\textsuperscript{{[}1{]}}. According to current reports, COVID-19
associated kidney injury has multiple pathological manifestations,
including collapsed glomerulonephritis (CG), acute interstitial
nephritis (ATI), focal segmental glomerulosclerosis(FSGS) and thrombotic
microvascular disease (TMA). CG is reported to be the most
characteristic manifestation after SARS-CoV-2
infection\textsuperscript{{[}2{]}}.

Since the first pandemic of wild-type SARS-CoV-2in 2019, the strains
have gradually mutated into Alpha, Beta, gamma, Delta and other strains.
By 2022, COVID-19 virus has been compiled into the omicron variant.
There have been plenty of reports on kidney injury caused by the early
pandemic delta strain, while at present, the reports on the clinical and
pathological characteristics of kidney injury caused by omicron
infection are relatively lacking. Although a large number of studies on
COVID-19 associated kidney injury have been reported abroad, the
clinicopathological characteristics of COVID-19 associated kidney injury
in China are different from those in foreign countries due to strain
variation and ethnic differences. This study retrospectively included 49
COVID-19 associated kidney injury patients from the Second Xiangya
Hospital of Central South University from December 2022 to March 2023,
38 of whomperformed kidney biopsy, and analyzed their clinical and
pathological features to explore the characteristics and prognosis of
COVID-19 associated kidney injury.

\textbf{Methods:}

This single center study included 49 cases of onset or aggravation of
kidney injury associated with COVID-19 infection between December 2022
and March 2023 in Nephrology Institute of the Second Xiangya Hospital
ofCentral South University. 38 of them performed kidney biopsy.Inclusion
criteria included cases with a confirmed COVID-19 infection by RNA PCR
or antigen detection within one week before or after kidney injury.
Patients were divided into 2 groups: Group A for patients with onset of
kidney injury after SARS CoV-2 infection; Group B for patients with
pre-existing kidney disease who experienced aggravation of renal
insufficiency after SARS-CoV-2 infection.

Kidney biopsy sections were stained with hematoxylin and eosin(H\&E),
Periodic acid-Schiff(PAS),Masson-Trichrome, Periodic-acid silver
methenamine (PASM), and Congo Red and examined by light microscopy.
Immunofluorescence(IF) staining was performed for IgG, IgA, IgM, C3,
C1q, Kappa light chain and Lambda light chain.All cases were diagnosed
by nephropathologist.

\textbf{Results:}

\textbf{Clinical features}

In group A, acute renal injury was the most common manifestation (35\%),
followed by nephrotic syndrome (27\%), characterized by
macroalbuminuria, hypoproteinemia, and edema, and also included simple
hematuria and/or microalbuminuria (19\%), chronic nephritis (15\%)and
lupus nephritis (4\%). (Figure 1A.) Most patients in group B presented
with CKD(55\%) and NS(40\%); Only one patient presented with lupus
nephritis(LN) (5\%).(Figure 1B.)

\textbf{Pathological features}

A total of 38 patients completed kidney biopsy, including 18 patients in
group A and 20 patients in group B. IgAN(39\%) accounted for the largest
proportion of pathological types in Group A, followed by MN(17\%),
FSGS(11\%) and Endocapillary proliferative glomerulonephritis(EPGN)
(11\%). (Figure 2A.) Among 20 patients in Group B, the most common renal
pathologic type was IgAN(45\%), followed by FSGS(25\%) and MN
(15\%).(Figure 2B)(Figure 3.)

\textbf{Serum C3 and the deposition of C3in kidney}

The serum C3 level of 25 patients with COVID-19 associated kidney injury
was measured. 80\% of them had normal C3 level. Among 38 patients with
COVID-19 associated kidney injury who performed kidney biopsy, 31.6\%
presented with C3 (-), 7.9\% presented with C3 (+), 28.9\% presented
with C3 (++), and 31.6\% presented with C3(+++).(Figure 3.)

\textbf{Prognosis}

Follow-up visits were conducted in 13 patients of Group A and 14
patients of Group B.Among the 13 patients in group A, 7 patients had
partial remission of proteinuria, 5 patients had no remission, and 1
patient had increased proteinuria. Hematuria was partially remission in
5 patients, stable in 4 patients, and increased in 4 patients. Four
patients had stable creatinine, three had increased creatinine, and one
had decreased creatinine.Among 14 patients in group B, 6 patients had
partial remission of proteinuria, 6 patients had no remission of
proteinuria, and 1 patient had remission of proteinuria. Hematuria was
partially alleviated in 6 patients, increased in 4 patients, and stable
in 4 patients. Five patients had reduced creatinine and four had stable
creatinine.(Table 1.)

\textbf{Discussion:}

In this study, 46 patients who developed kidney injury after COVID-19
infection or had an aggravation of the original kidney injury were
included.The patients with new-onset renal damage mainly present with
AKI and NS, while the patients withaggravated renal damage mainly
presents with CKD and NS. 20\% of the patients presented with impaired
renal function.A previous international meta-analysis involving 49,048
patients found that the incidence of AKI among hospitalized patients
with COVID-19 in the United States and Europe was as high as 28.6\%,
while the incidence in Asia was 5.5\%\textsuperscript{{[}3{]}}. In our
study, 19.6\% of patients developed AKI, with a significantly lower
incidence and milder clinical symptoms. The reason might be that
compared with the Delta variant in the pandemic waves before 2022, the
Omicron variantis more transmissible but lessintrinsic
virulent\textsuperscript{{[}4{]}}.

Among 38 patients with renal biopsy in this study, IgAN was the most
common pathological type, other pathological diagnoses included MN,
FSGS, acute interstitial nephritis(AIN), mesangial proliferative
glomerulonephritis(MsGPN), EPGN, henoch-schonlein purpura
nephritis(HSPN), TMA, and LN.Currently, GC has been reported as the most
common pathological manifestation of COVID-19 associated nephropathy,
which is mostly seen in patients with African ancestry and is associated
with a high-risk APOL1 genotype\textsuperscript{{[}5{]}}. The
differences of pathological type of COVID-19 associated kidney injury
may be related to race, region and strain variation. Compared with
European and American populations, the frequency and percentage of
population attributable risk (PAR\%)of the risk alleles of
IgAN-susceptible genes were significantly higher in the Chinese
population\textsuperscript{{[}6{]}}. Compared with the database of
kidney biopsies over a 10-year period prior to the pandemic in our
center, IgAN accounted for a higher proportion of COVAN patients. Ma Y
et al. speculated that SARS-CoV-2 invaded respiratory tract and
intestinal mucosa through the encoded S protein, activated antigen
presenting cells, stimulated B cells to transform into Gd-IgA1\selectlanguage{greek}λ\selectlanguage{english}B cells
and secreted Gd-IGa1through T-cell dependent and independent pathways,
and then formed immune complexes deposited in the mesangium of the
glomeruli, ultimately leading to the occurrence of
IgAN\textsuperscript{{[}7{]}}. Among other pathological types, a patient
diagnosed with TMAhada more severe renal pathological lesion and poorer
prognosis.

80\% of patients with COVID-19 associated kidney injury had normal serum
C3 complement level, a few patients had increased or decreased C3 level.
In renal tissues, C3 deposits were observed in 68.4\% of patients. Some
scholars believe that low serum C3 level indicates overactivation and
depletion of the complement system, which is related to the severity of
the disease and poor prognosis\textsuperscript{{[}8-10{]}}. It is
currently believed that complement is involved in the indirect mechanism
of COVID-19 kidney injury: SARS-CoV-2 binds to endothelial angiotensin
converting enzyme 2 (ACE2), activates the lectin pathway and classical
pathway of complement, recruits neutrophils and monocytes/macrophages,
releases proteases,cytokinesand reactive oxygen species, leads to
inflammation, subcutaneous matrix destructionand vasculitis-like
lesions\textsuperscript{{[}11{]}}.

Among the 17 patients of follow-up, 29\% of them experienced
deterioration of renal function after treatment, but no patients
developed to ESRD. However, in a cohort study of AKI in hospitalized
patients with COVID-19 in 2020, 46\% of hospitalized patients
experienced AKI, 19\% of the AKI patients entered dialysis and 50\%
died\textsuperscript{{[}12{]}}. At present, there are few international
reports on the prognosis of patients with Omicron infection. The
possible reasons for the favorable prognosis of patients in this study
are as follows: Firstly, international guidelines for treatment of
SARS-CoV-2 infection have been developed. Antiviral drugs such as
Nematovir, Azfudine and Monoravir as well as neutralizing antibody drugs
such as ambavir/Romisivirwere available for targeted antiviral therapy.
Early detection and treatment can be achieved in most patients.
Secondly, the involved patients were mainly infected with Omicron
variant. Compared to the initial strain reported internationally,
Omicron variant was less virulent and less likely to cause severe cases.

\textbf{Limitations:}

There are some limitations to this study. Due to the short follow-up
period, the long-term prognosis of patients could not be assessed.
Besides, this study failed to find direct evidence of SARS-CoV-2
infection in the patients' renal biopsy specimens. In previous studies,
SARS-CoV-2 was detected by electron microscopy
(TEM)\textsuperscript{{[}13{]}}, immunohistochemistry (IHC){[}14{]}, RNA
in situ hybridization (RNA-ISH){[}15{]} and reverse
transcription-polymerase chain
reaction(RT-PCR)\textsuperscript{{[}16{]}}, but the above positive
results were all from autopsy. SARS-CoV-2 has rarely been detected in
renal biopsy specimens. The kidney injury associated with SARS-CoV-2
infection in non-critical patients may mainly be caused through indirect
mechanisms.

\textbf{Conclusion:}

In conclusion, we present a series of native kidney biopsy in
association with the COVID-19 pandemic. Of patients in our center, the
main clinical manifestations were AKI\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}CKD and NS, while the main
pathological manifestation were IgAN\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}FSGS and MN. Generally, patients
in our center had a favorable prognosis. We observed that the clinical
and pathological features of COVID-19 associated with kidney injury vary
by race\begin{CJK}{UTF8}{gbsn}、\end{CJK}\selectlanguage{english}region and virus variant.Asian patients with the Omicron
infection have milder kidney injury and a better prognosis.

\textbf{Abbreviations}

COVID-19: Coronavirus Disease-19; COVAN: COVID-19 associated nephropathy
; AKI: acute kidney injury; CKD: chronic kidney disease; ESRD: end-stage
renal disease; NS: nephrotic syndrome; IgAN: IgA nephropathy; FSGS:
focal segmental glomerulosclerosis; MN: membranous nephritis;TMA:
thrombotic microangiopathy ; CG: collapsed glomerulonephritis ;LN: lupus
nephritis; ATI: acute interstitial nephritis; EPGN: endocapillary
proliferative glomerulonephritis; TMA: thrombotic microvascular disease;
AIN: acute interstitial nephritis; MsGPN: mesangial proliferative
glomerulonephritis; HSPN: henoch-schonlein purpura nephritis; H\&E:
hematoxylin and eosin; PAS: Periodic acid-Schiff; PASM: Periodic-acid
silver methenamine; IF: Immunofluorescence; TEM: electron microscopy;
IHC: immunohistochemistry; RNA-ISH: RNA in situ hybridization; RT-PCR:
reverse transcription-polymerase chain reaction

\textbf{Author's contributions}

Data curation, formal analysis, investigation, methodology, writing:
ZWQ. Conception or design: XJZ. Acquisition, analysis, or interpretation
of data: JYW, SYX, YCH, ZL.Provided guidance: YFL, SGY, LS, HL. All
authors contributed tomanuscript revision and read and approved the
submitted version.

\textbf{Acknowledgements}

Not applicable.

\textbf{Declaration of competing interest}

No potential conflict of interest relevant to this article was reported.

\textbf{Consent for publication}

All patients signed approved informed consent forms.

\textbf{Data availability statement}

Not applicable.

\textbf{Ethics approval and consent to participate}

This study has passed the ethical review of the Second Xiangya Hospital
(LYF2020148).

\textbf{Funding statement}

This work was supported by the Natural Science Foundation of Hunan
(2021JJ30986, 2018JJ3728, 2018JJ2596),General Project of Scientific
Research Project of Hunan Provincial Health and Family Planning
Commission(20200807), Innovation and entrepreneurship education
curriculum construction project of Central South University,The Project
of New Clinic Techniques of Central South University and National
Natural Science Foundation of China(81300600).

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\textbf{Figure legends:}

\textbf{Figure 1: Clinical characteristics of COVID-19 associated kidney
injury.} (A)Patients developing kidney injury after SARS CoV-2
infection; (B)Patients with aggravated renal insufficiency after SARS
CoV-2 infection.

\textbf{Figure 2: Pathological features of COVID-19 associated kidney
injury.} (A)Patients developing kidney injury after SARS CoV-2
infection; (B)Patients with aggravated renal insufficiency after SARS
CoV-2 infection.

\textbf{Figure 3: Renal Pathological changes in patients with COVID-19
associated kidney injury:} (A) Patient with IgAN shows IgA+++ depositing
in glomerulas (IF ×100); (B) Patient with IgAN shows segmental sclerosis
and mild mesangial proliferation (PAS×200); (C): Patient with
interstitial~nephritis shows Interstitial inflammatory cell infiltration
(HE ×200); (D) Patient with TMA shows arteriole intima edema and myxoid
degeneration (HE ×200).

\textbf{Figure4: Serum C3 and deposition of C3 in patients with COVID-19
associated kidney disease.} (A) Serum C3 levels: normal:
0.70\textasciitilde{}1.40g/L; increase: \textgreater{}1.40g/L; decrease:
\textless{}0.70g/L\textbf{;} (B) Intensity of C3 deposition by
Immunofluorescence staining in renal tissue.

\textbf{Table 1:} (A) Renal Pathology Findings and Clinical Presentation
of Patients in Group A; (B) Renal Pathology Findings and Clinical
Presentation of Patients in Group B.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/figure4A/figure4A}

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\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/figure4B/figure4B}

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\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/table1A/table1A}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/table1B/table1B}

\end{center}
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