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\begin{document}

\title{Renal consequences of the novel coronavirus disease 2019 (COVID-19) and
hydrogen sulfide as a potential therapy}



\author[1]{GEORGE DUGBARTEY}%
\affil[1]{Western University}%


\vspace{-1em}



  
  \date{May 20, 2024}


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\selectlanguage{english}
\begin{abstract}
The novel coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is
a global pandemic which is primarily considered a respiratory illness.
However, emerging reports show that the virus exhibits both pulmonary
and extra-pulmonary manifestations in humans, with the kidney as a major
extra-pulmonary target due to its abundant expression of
angiotensin-converting enzyme 2 and transmembrane protease serine 2,
which facilitate entry of the virus into cells. Acute kidney injury has
become prevalent in COVID-19 patients without prior any history of
kidney dysfunction. In addition, the virus also worsens kidney
conditions and increases mortality of COVID-19 patients with
pre-existing chronic kidney disease, renal cancer, diabetic nephropathy,
end-stage kidney disease as well as dialysis and kidney transplant
patients. In the search for antiviral agents for the treatment of
COVID-19, hydrogen sulfide (H2S), the third established member of
gasotransmitter family, is emerging as a potential candidate, possessing
important therapeutic properties including antiviral, anti-inflammatory,
anti-thrombotic and antioxidant properties. A recent clinical study
revealed higher serum H2S levels in survivors of COVID-19 pneumonia with
reduced interleukin-6 levels compared to fatal cases. In this review, we
summarize the global impact of COVID-19 on kidney conditions and discuss
the emerging role of H2S as a potential COVID-19 therapy.%
\end{abstract}%



\sloppy


\textbf{1. Introduction}

The global outbreak of the novel coronavirus disease 2019 (COVID-19)
caused by severe acute respiratory syndrome corona virus-2 (SARS-CoV-2)
has rapidly evolved into a global pandemic with enormous consequences.
It has caused significant mortality and loss of capital, with a
struggling global economy to contain the pandemic (Douglas et al.,
2020). This virus, which is the third zoonotic virus next to SARS-CoV
and Middle East Respiratory Syndrome (MERS-CoV), was first identified in
Wuhan, Hubei Province in China in December 2019, from where it has
spread to all countries and territories of the globe (Velavan and Meyer,
2020). The initial signs of SARS-CoV-2 infection such as pneumonia,
multiple organ failure and acute respiratory distress syndrome are
elicited through the actions of the immune system (Douglas et al., 2020;
Velavan and Meyer, 2020). Various immunopathological changes in patients
with SARS-CoV-2 infection have been documented in which lymphopenia,
abnormalities in granulocytes and monocytes in serum as well as increase
in cytokine production have been reported. These pathological changes
seen in the upper respiratory tract is due to uncontrollable viral
replication, leading to influx of neutrophils, macrophages and monocytes
and elevated production of pro-inflammatory cytokines, the so-called
cytokine storm syndrome (Douglas et al., 2020; Velavan and Meyer, 2020).

Current studies have shown that the kidneys are badly affected during
SARS-CoV-2 infection, leading to kidney injury especially in patients
with comorbidities, and worsening kidney conditions with increased
mortality of COVID-19 patients with pre-existing chronic kidney disease,
renal cancer, diabetic nephropathy, end-stage kidney disease as well as
dialysis and kidney transplant patients (Carriazo et al., 2020; Kudose
et al., 2020; Pei et al., 2020; Wald and Bagshaw, 2020). In the search
for antiviral agents for the treatment of COVID-19, hydrogen sulfide
(H\textsubscript{2}S), a gas known for its distinct ``rotten-egg'' smell
and established as the third member of a family of gaseous signaling
molecules, is emerging as a potential candidate. In this review, we
summarize the global impact of COVID-19 on pathological conditions
involving the kidney and discuss the emerging role of
H\textsubscript{2}S as a potential COVID-19 therapy.

\textbf{2.0 Impact of COVID-19 on kidney conditions}

The global spread of COVID-19 has left nephrologists and their patients
with challenging decisions in the treatment and management of kidney
conditions such as acute kidney injury, chronic kidney disease, diabetic
nephropathy, renal cancer, kidney infarction, end-stage kidney disease,
nephrotic syndrome, dialysis and kidney transplantation. It has been
widely reported that SARS-CoV-2 enters its host cell by binding to
angiotensin-converting enzyme 2 (ACE2), a cell-surface protein found in
a host of tissues and organs including the kidney (Kuba et al., 2005;
Alhene-Gelas and Drueke, 2020). In addition, transmembrane protease
serine 2 (TMPRSS2), which is also expressed in the kidney, facilitates
the fusion of the virus and cellular membranes by cleaving the spike (S)
protein of the virus (Pan et al., 2020). In the kidney, colocalization
of ACE2 and TMPRSS were found in the podocytes and the proximal straight
tubule cells as the host cells for COVID-19 infection due to their
increased expression of these proteins (Pan et al., 2020; Wu et al.,
2021). Interestingly, RNA-sequencing data revealed that ACE2 expression
in the kidneys was almost 100-fold greater than in the lungs, suggesting
that COVID-19-related kidney injury is significantly through
ACE2-dependent pathways (Cheng et al., 2020). ACE2 is an enzyme of the
renin-angiotensin-aldosterone-system that converts angiotensin II to
angiotensin I, a vasodilator which counteracts the effects of
angiotensin II. As illustrated in figure 1, the attachment and
proliferation of the virus in the kidneys lead to an increase in kidney
function parameters such as creatinine, along with hematuria,
proteinuria and other urine abnormalities. Furthermore, kidney
structures such as the glomeruli are also inflamed and destroyed. These
changes in the kidneys progressively lead to renal failure, needing
kidney replacement therapy such as dialysis and transplantation in
patients with renal manifestations of COVID-19 infection.



\section*{2.1 COVID-19 infection and acute kidney
injury}

{\label{covid-19-infection-and-acute-kidney-injury}}

Progressive acute kidney injury (AKI) is common among hospitalized
COVID-19 patients, and is an independent risk factor for mortality. It
has been reported that AKI was one of the complications observed in
hospitalized COVID-19 patients with its occurrence ranging between 0.5\%
and 80\% (Ng et al., 2020a). The mechanisms underlying
COVID-19--associated AKI are unknown. However, proposed mechanisms of
kidney injury range from direct viral infection to effects on the
renin-angiotensin-aldosterone system, hemodynamic instability,
coagulopathy, and cytokine storm. In a systematic review and
meta-analysis of outcomes for patients with COVID-19 and AKI among 20
cohorts covering 13,137 hospitalized COVID-19 patients, prevalence of
AKI was found to be 17\%, out of which 77\% experienced severe COVID-19
infection and 52\% died (Robbins-Juarez et al., 2020). AKI was
associated with increased odds of death among COVID-19 patients (pooled
odds ratio 15.27, 95\% CI 4.82-48.36), although there was considerable
heterogeneity across studies and among different regions in the world.
About 5\% of all patients in the study required the use of kidney
replacement therapy. The study concluded that kidney dysfunction was
common among patients with COVID-19, and patients who develop AKI have
inferior outcomes (Robbins-Juarez et al., 2020).

Proteinuria and hematuria were common features observed in about 40\% of
COVID-19 patients on hospital admission (Perico et al., 2020). In one
observational study of 5,449 hospitalized patients, the incidence of AKI
was 36.6\% with 14.3\% of patients requiring dialysis and this was even
higher in patients admitted at the intensive care unit (Benedetti et
al., 2020). Autopsy reports from kidneys of COVID-19 deceased patients
revealed acute tubular injury and collapsing glomerulopathy as the most
prominent damage to the kidneys (Cheruiyot et al., 2020; Su et al.,
2020). Electron microscopy of kidney biopsies revealed viral-like
particles in the glomeruli and renal tubules although the particles were
not conclusively that of SARS-CoV-2 (Perico et al., 2020; Su et al.,
2020). The incidence of AKI in COVID-19 patients was also highlighted in
15 separate studies, with an odds ratio (OR) of 18.5\% based on COVID-19
severity (Cheruiyot et al., 2020). The OR for COVID-19 patients with
AKI-associated mortality was reported to be as high as 23.95\%. In some
710 COVID-19 patients who reported to the hospital, prevalence of
elevated markers of renal function such as serum creatinine and blood
urea nitrogen (BUN) was 15.5\% and 14.1\% respectively, with 26.9\% of
these patients coming in with microscopic hematuria and 44\% having
proteinuria although the incidence of AKI in these patients was reported
as 3.2\% (Swai et al., 2020). According to this and other supporting
data, AKI is likely associated with worse prognosis in COVID-19 patients
and increases their mortality rates (Izzedine and Jhaveri 2021; Taher et
al., 2020). In a related retrospective analysis of medical records from
85 COVID-19-positive patients in Wuhan from January 17 to March 3, 2020,
27.06\% of the patients developed AKI especially among the elderly
(59-92 years old) (Diao et al., 2021). During this study, varying
degrees of tubular necrosis, luminal brush border sloughing and vacuole
degeneration was observed in a Hematoxylin and Eosin staining of 6
kidney samples as well as the presence of CD68\textsuperscript{+}
macrophages, CD8\textsuperscript{+} T cells, CD4\textsuperscript{+} T
cells and CD56\textsuperscript{+} natural killer cells from deceased
COVID-19 patients (Diao et al., 2021). In conclusion, COVID-19 infection
likely accelerates the development of AKI, especially among elderly
patients.

\section*{2.2 COVID-19 infection and chronic kidney
disease}

{\label{covid-19-infection-and-chronic-kidney-disease}}

Patients with chronic kidney disease (CKD) are predisposed to COVID-19
(Yang et al., 2020). Emerging reports suggest that patients with
pre-existing kidney injuries got worse after testing positive and being
admitted to the hospital for COVID-19. In one study, there was an
elevation in markers of renal function, elevation of serum D-dimer,
pro-inflammatory cytokines particularly interleukin-6 as well as
neutrophilia (Yang et al., 2020). It is currently unclear as to the
extent the virus directly damages renal tubular epithelial cells or
whether the kidney injury is secondary to the cytokine storm syndrome
(Cheng et al., 2020; Qian et al., 2020). In a study involving 1,603
patients with COVID-19, 21\% presented with increased serum creatinine
levels while 43.5\% of them had a previously diagnosed CKD stage 3 or
higher and with higher mortality rates than in the non-CKD group
(Portoles et al., 2020). In these CKD patients (n = 146), urea, serum
potassium, urinary proteins, D-dimer, procalcitonin, lactate and
troponins levels were elevated while hemoglobin, platelets, albumin and
estimated glomerular filtration rate were decreased. Mortality was high
in COVID-19 patients with elevated serum creatinine (32.4\%) and those
with previously diagnosed CKD (41.1\%) than those with normal serum
creatinine levels (5.8\%) (Portoles et al., 2020). In summary, COVID-19
infection appears to damage the kidney and may accelerate the death of
patients with CKD.

\section*{2.3 COVID-19 infection and diabetic
nephropathy}

{\label{covid-19-infection-and-diabetic-nephropathy}}

COVID-19 patients with comorbidities are more likely to show a more
severe clinical picture of the infection with high mortality rate. Most
of the available data highlight diabetes mellitus as one exceptional
comorbidity associated with more severe COVID-19 and mortality (D'Marco
et al., 2020). A survey done in the United Kingdom showed that out of
23,804 patients with COVID-19 dying in hospitals, 1.5\% had type 1
diabetes mellitus and 32\% had type 2 diabetes mellitus, with 3.5 and
2.03 times the odds of dying compared to patients without diabetes
mellitus respectively (Apicella et al., 2020). It has been observed that
patients with diabetes mellitus have a severe and fatal manifestation of
COVID-19 disease with increased ACE2 production as an adaptive response
to elevated levels of angiotensin I and II, which in effect facilitates
the entry of SARS-CoV-2 into host cells (Pal and Bhansali, 2020). This
phenomenon enhances a progressive decline in renal function in diabetic
patients characterized by an increase in serum creatinine, uric acid,
BUN, proteinuria and a decrease in estimated glomerular filtration rate
(D'Marco et al., 2020). A molecular study revealed that the enhanced
progressive decline in renal function in COVID-19 patients with diabetes
mellitus could be due to upregulation of genes that influence viral
infection pathways in diabetic nephropathy (Menon et al., 2020). For
example, proximal tubular epithelial cell (PTEC) gene, which is
co-expressed with ACE2, may exhibit cellular interplay between mechanism
that enhance viral infection and host immune responses (Menon et al.,
2020). Thus, COVID-19 increases the severity of the manifestations of
diabetes mellitus, which may then contribute to death of the diabetic
patient.

\section*{2.4 COVID-9 infection and renal
cancer}

{\label{covid-9-infection-and-renal-cancer}}

Cancer patients undergoing cancer chemotherapy are among those likely to
be easily infected with SARS-CoV-2 due to drug-related immunosuppression
(Ofori-Asenso et al., 2020; Mihalopoulos et al., 2020). Globally, renal
cell carcinoma (RCC) represents the 6\textsuperscript{th} and
10\textsuperscript{th} most diagnosed cancer in men and women, and
accounts for 5\% and 3\% of all cancers in males and females
respectively (Wallis et al., 2020). A recent study revealed predominant
expression of coronavirus receptors (CoV; DPP4, ANPEP, ENPEP) in clear
cell RCC and also in other forms of renal cancers such as papillary and
chromophobe subtypes (Tripathi et al., 2020). This finding confirms
increased risk of SARS-CoV-2 infection in these groups of patients.
Hence, a number of strategies have been proposed and employed to provide
care for these patients in this COVID-19 era, including postponing
chemotherapy, minimizing elective surgical procedures in patients with
stable cancer as well as in those patients at high risk for ending up in
the intensive care units following surgery (Al-Quteimat and Amer, 2020).
In the light of these strategies, recommendations for the deferment for
cytoreductive nephrectomy in patients with metastatic RCC in this
COVID-19 era and replacement with systemic therapy for patients with
intermediate to poor-risk disease has been made (Ged et al., 2020).
Current data from a study gives both medical practitioners and patients
some hope, as surgery can be safely delayed in a subgroup of patients
with RCC to between 3 and 6 months without significant sacrifice in
overall survival (Srivastava et al., 2021). Overall, patients with RCC
and other forms of renal cancer, who are undergoing cancer chemotherapy
are at a higher risk of COVID-19 infection, which could further
exacerbate their kidney condition.

\section*{2.5 COVID-19 infection and kidney
infarction}

{\label{covid-19-infection-and-kidney-infarction}}

An increased risk of the formation of blood clot has previously been
noted with SARS and MERS, and this is one proposed cause of pre-renal
injury in COVID-9 patients (Bandyopadhyay et al., 2020; Dobesh and
Trujillo, 2020). The lodging of thrombi in the renal vessels and kidneys
increases the likelihood of kidney damage and possibly kidney death due
to kidney infarction. This finding supports the observation where
platelet-rich fibrin microthrombi scattered in peritubular capillaries
and tubules in kidneys of deceased COVID-19 patients (Rapkiewicz et al.,
2020). In some COVID-19-positive patients, changes in blood coagulation
parameters have been observed (Iba et al., 2020; Post et al., 2020).
Disseminated intravascular coagulopathy (DIC; a condition of overactive
clotting factors) is observed in COVID-19 patients, particularly in the
critically ill patients. DIC arises from cytokine storm syndrome-induced
hemophagocytosis and acute consumptive coagulopathy, which leads to
enhanced platelet activation, fibrin and thrombus formation (Ortega-Paz
et al., 2021). A cross-sectional study from April 13-24 in 2020 revealed
elevation of markers of endothelial cells and platelet activation such
as von Willebrand factor antigen, coagulation factors and fibrinolytic
enzymes (Goshua et al., 2020). These coagulation anomalies were reported
in a 71-year-old COVID-19-positive patient, who exhibited thromboembolic
events such as ascending aortic thrombosis, renal infarction and a
corresponding hypercoagulable state (Mukherjee et al., 2020). However,
this may seem a little presumptuous given that the coagulation anomalies
were reported in only one patient and over a short period (10 days). In
a nutshell, COVID-19 infection increases the likelihood of formation of
blood clots in the renal vessels and kidney, which may lead to kidney
infarction and possibly death of the patient.

\section*{2.6 COVID-19 infection and end-stage renal
disease}

{\label{covid-19-infection-and-end-stage-renal-disease}}

Information on COVID-19 in end-stage renal disease (ESRD) is limited but
rapidly evolving. ESRD patients have a higher chance of contracting
COVID-19 due to suppression of the immune system, which is associated
with ESRD (Fu et al., 2020; Kunutsor and Laukkanen, 2020). While there
is no evidence-based solution to this concern, patients who are at high
risk of progressing to ESRD without immediate treatment are being
advised to postpone treatment until their local transmission rates of
COVID-19 are low. Further evidence of the impact of COVID-19 on ESRD
patients was reported where a higher rate of in-hospital death of
COVID-19 patients with ESRD compared to those without ESRD in a
retrospective study in the United States (Ng et al., 2020b). This
observation was in agreement with that of an independent study, where
the researchers evaluated clinical characteristics, laboratory measures
and clinical outcomes in 759 hospitalized COVID-19 patients out of which
45 had ESRD (Kamel et al., 2021). The authors reported that COVID-19
patients with ESRD had significantly increased leucocyte count,
C-reactive protein, lactate dehydrogenase and ferritin, and markedly
reduced serum albumin and thrombocytopenia with a higher in-hospital
mortality (18\%) compared to their counterparts without ESRD (10\%)
(Kamel et al., 2021). Another study also reported that COVID-19-positive
patients who had ESRD and on dialysis had better outcomes than ESRD
patients who were not on dialysis (Naaraayan et al., 2020). They
attributed their observation to a possible ``pre-conditioning'', where
underlying chronic inflammation in ESRD patients on dialysis attenuates
the inflammatory response from the COVID-19 infection. It is important
to note that the spread of COVID-19 in some dialysis centers is on the
rise (e.g. Italy), which is partly due to the difficulty in applying
social distancing protocols (La Milla et al., 2020) while it is lower in
other centers (e.g. Abu Dhabi, United Arab Emirates) due to rapid
isolation of COVID-19 patients within their dialysis centers (Ahmed et
al., 2021). Taken together, COVID-19 worsens kidney condition of ESRD
patients, and thus leads to increased mortality.

\section*{2.7 COVID-19 infection and kidney
transplantation}

{\label{covid-19-infection-and-kidney-transplantation}}

Kidney transplant patients are currently at a higher risk of COVID-19
infection and its associated mortality, as these patients have a
spectrum of kidney diseases and comorbidities such as hypertension,
diabetes, obesity that requires kidney transplantation (Cravedi et al.,
2020; Gonzalez and Ciancio, 2020). Hence, kidney transplant surgeons
have been advised to suspend kidney transplantation during this pandemic
due to poor outcomes, especially in high-risk older recipients with
comorbidities. This unfortunate obstacle to such an important
life-saving procedure is due to possible donor to recipient viral
transmission or members of the transplant team serving as vectors of the
SARS-CoV-2. Suspension of kidney transplantation during the pandemic
will have a negative impact on the transplant waiting list, thereby
increasing morbidity and mortality (Abu Jawdeh, 2020). SARS-CoV-2 has a
higher tropism for the kidney, where it has been shown to replicate in
about 30\% of COVID-19 patients (Fisher and Carson, 2020). In 12
transplant centers in the United States, Italy, and Spain, Cravedi et
al. (2020) reported a high COVID-19-related mortality and AKI rate in
adult kidney transplant recipients. This observation supports previous
findings in which a very high early mortality (28\%) was recorded among
kidney transplant recipients with COVID-19 in the United States compared
to 8-15\% mortality of COVID-19 mortality among the general population
(Akalin et al., 2020) and dialysis patients on the waiting list for
kidney transplantation (Hilbrands et al., 2020). The high
COVID-19-related mortality in this group of patients is mainly due to
advanced age and frailty (Hilbrands et al., 2020). In conclusion,
patients who have undergone kidney transplantation have a high
COVID-19-related mortality risk, which are driven by factors such as
immunosuppression therapy, comorbidities, advanced age and frailty.

\textbf{3. A special case of COVID-19-associated nephropathy in people
of African ancestry}

Genetic variants of apolipoprotein L1 (APOL1), which greatly increases
the risk of kidney diseases, are found only in people of African descent
(Genovese et al., 2010). The APOL1 alleles became common in Sub-Saharan
Africa due to protection conferred by these alleles against the pathogen
that causes African sleeping sickness (trypanosomiasis). Studies in
recent times suggest that black people living in Sub-Saharan Africa have
high predisposition to kidney disease as do African Americans, and that
these two groups (African Americans and Black Africans) have common
genetic susceptibilities. Two APOL1 susceptibility gene variants (G1 and
G2) are linked with hypertension-associated CKD, collapsing focal
segmental glomerulosclerosis and HIV-associated nephropathy (Kopp et
al., 2011; Tayo et al., 2013; Ulasi et al., 2013). The APOL1 kidney risk
variants encode circulating APOL1, which functions as a trypanolytic
factor capable of killing the trypanosome parasites in the human serum
(Genovese et al., 2010). These APOL1 risk variants developed some 10,000
years ago in Sub-Saharan Africa where trypanosomiasis was endemic. Thus,
APOL1 gene is an innate immunity gene common in people of African
ancestry.

Recent studies suggest that people with high/low renal risk alleles for
APOL1, who are COVID-19-positive, may have a high risk of developing
renal failure, proteinuria and hematuria. There are six case reports of
collapsing glomerulopathy among COVID-19 patients of African ancestry,
with severe AKI and nephrotic range proteinuria, two of whom carried
APOL1 renal risk genotypes (Kissling et al., 2020; Larsen et al., 2020;
Mohamed et al., 2020; Peleg et al., 2020). APOL1 coding variants have
been associated with collapsing glomerulopathy among individuals with
untreated HIV infection or undergoing interferon treatment. There is a
high frequency of APOL1 risk genotypes among African Americans
(\textasciitilde{}13\%) and West Africans (\textasciitilde{}25\%), with
lower frequencies found in East and South Africans (Genovese et al.,
2010; Dummer et al., 2015; Kasembeli et al., 2015). Collapsing
glomerulopathy has been described in 24 cases of COVID-19 infection; 23
out of the 24 (95.8\%) cases were Africans or African American and 1 was
Indian, 18 patients had APOL1 gene variants (12 were G1:G1 and 6 were
G1:G2) (Ng et al., 2020a). This suggests that one of the major risk
factors for AKI in patients with COVID-19 infection is black race
(Hirsch et al., 2020). Individuals with high renal risk alleles for
APOL1 who have COVID-19 infection may be at increased risk of developing
AKI, proteinuria and hematuria and consequent chronic kidney disease. A
likely mechanism may be upregulation of APOL1 mediated by cytokines
resulting from the SARS CoV-2 infection. This hypothesis requires
investigation. In addition, innate immune response to SARS CoV-2
infection can drive the APOL1 kidney disease in patients with APOL1 high
risk genotypes. The later argument is based a case series of collapsing
glomerulopathy linked to interferon therapy (Nichols et al., 2015).



\textbf{4.0 Hydrogen sulfide as a potential therapy against COVID-19
infection}

There is currently no drug for effective treatment of COVID-19.
Investigations into the search for drugs to combat COVID-19 are
underway. In the meantime, remdesivir, an orphan antiviral drug
originally developed to treat Ebola virus disease and Marburg virus
infections (via inhibition of the viral RNA-dependent RNA polymerase),
is the only drug approved by United States Food and Drug Administration
(FDA) for the treatment of COVID-19 in symptomatic patients (Wang et
al., 2020). This antiviral drug is administered along with convalescent
plasma. In addition to remdesivir, a host of vaccine candidates have
been approved and distributed for global use to curb the spread of SARS
CoV-2.

\emph{4.1 Endogenous and exogenous sources of hydrogen sulfide}

In the search for antiviral agents for effective treatment of COVID-19,
hydrogen sulfide (H\textsubscript{2}S), a pungent-smelling gas which
gained notoriety for several centuries for its toxicity and death among
industrial and agricultural workers, is emerging as a potential
candidate drug. Over the last two decades, however, H\textsubscript{2}S
has moved past its historic notorious label as a gas which was once
feared, to a volatile intracellular messenger molecule that plays
important roles in cellular homeostasis and impact physiological and
pathophysiological conditions, including regulation of the renal system
(Wang, 2002). H\textsubscript{2}S possesses important therapeutic
properties including antiviral, anti-inflammatory, anti-thrombotic and
antioxidant properties, which are important for any drug candidate
against COVID-19. Endogenous H\textsubscript{2}S is produced in
mammalian cells by four enzymatic pathways. The first two pathways
involve the use of the substrate L-cysteine, a sulfur-containing amino
acid, in the presence of two cytosolic enzymes cystathionine \selectlanguage{greek}β-\selectlanguage{english}synthase
(CBS) and cystathionine \selectlanguage{greek}γ-\selectlanguage{english}lyase (CSE) while the third pathway uses the
mitochondrial enzyme 3-mecaptopyruvate sulfurtransferase (3-MST) and the
intermediate product 3-mecaptopyruvate (from L-cysteine). The fourth
enzymatic pathway uses D-cysteine, an enantiomer of L-cysteine, and the
peroxisomal enzyme D-amino acid oxidase (DAO) (Xia et al., 2009; Mikami
et al., 2011; Modis et al., 2013; Shibuya et al., 2013). Reduced
production of endogenous H\textsubscript{2}S and expression of these
H\textsubscript{2}S-producing enzymes have been associated with various
pathologies of the organ system including the renal system. Whereas the
distribution of these H\textsubscript{2}S-producing enzymes are tissue
specific, we and others have previously reported that all the four
enzymes are abundantly expressed in the glomerular and tubular
compartments of the kidney (Shibuya et al., 2013; Yamamoto et al., 2013;
Dugbartey et al., 2015a; Tomita et al., 2016). This makes the kidney is
a richer source of endogenous H\textsubscript{2}S production compared to
other organs.

In addition to its endogenous production, H\textsubscript{2}S is also
administered exogenously in its gaseous form (though less ideal) and via
H\textsubscript{2}S donor compounds. These H\textsubscript{2}S donors
include water-soluble, fast-releasing but short-lasting
H\textsubscript{2}S donors such as the inorganic sulfide salts, sodium
hydrosulfide (NaHS) and sodium sulfide (Na\textsubscript{2}S) (Kulkarni
et al., 2009). There is also water-soluble, slow- and
controlled-releasing, long-lasting H\textsubscript{2}S donor donor
GYY4137 (Li et al., 2008), and mitochondrially-targeted slow-releasing
donors AP39 and AP123 (Gero et al., 2016), which augment mitochondrial
H\textsubscript{2}S production by 3-MST and provide an effective and
longer treatment time in experimental models of kidney diseases
including acute kidney injury, chronic kidney disease, diabetic
nephropathy, hypertensive kidney injury, renal cancer, drug-induced
nephropathy, renal ischemia-reperfusion injury and kidney
transplantation. As already discussed in previous sections, all these
pathological conditions involving the kidney are worsened by COVID-19
infection. While these H\textsubscript{2}S donors are limited to only
preclinical studies, thiosulfate, a major H\textsubscript{2}S oxidation
product in the form of sodium thiosulfate (STS), is an FDA-approved drug
already in clinical use for treatment of calciphylaxis in ESRD patients
and other clinical situations (Strazzula et al., 2013). Other clinically
viable H\textsubscript{2}S donor drugs such as ATB-346
(H\textsubscript{2}S-generating naproxen molecule) and zofenopril
(FDA-approved antihypertensive drug that increases H\textsubscript{2}S
release) are currently in human clinical trials for gastric ulcer,
osteoarthritis, chronic pain, cardiovascular diseases and type 2
diabetes mellitus (www.clinicaltrials.gov).

\emph{4.2 Antiviral action of H\textsubscript{2}S and its underlying
mechanisms in relation to COVID-19 infection}

Burgeoning evidence shows that H\textsubscript{2}S donors such as NaHS
and GYY4137 exhibit excellent effects against the family of enveloped
RNA viruses of which SARS-CoV-2 is a member (Li et al., 2015; Ivanciuc
et al., 2016; Bazhanov et al., 2017; Bazhanov et al., 2018) Also,
natural sources of exogenous H\textsubscript{2}S such as diallyl
sulfide, diallyl disulfide and diallyl trisulfide, which are derived
from garlic, have been reported to reduce viral load of cytomegalovirus
(another enveloped virus) in infected organs of humans and rodents (Fang
et al., 1999). Furthermore, sinigrin, a precursor of the
H\textsubscript{2}S donor allyl isothiocyanate, and obtained from the
root extract of \emph{Isatis indigotica} plant for Chinese traditional
medicine (Martelli et al., 2020), inhibited the function of
3-chymotrypsin-like protease, the main protease of SARS-CoV, which
caused the 2002--2004 outbreak of severe acute respiratory syndrome (Lin
et al., 2005).

There are several mechanisms that underlie the antiviral action of
H\textsubscript{2}S. Firstly, the antiviral activity of
H\textsubscript{2}S has been suggested to be partly linked to its
antioxidant property - activating and increasing the levels of other
antioxidant enzymes including glutathione (GSH), the most abundant
naturally occurring antioxidant in the body, which inhibits
overproduction of reactive oxygen species (ROS; a destructive mediator
in tissue injury) and its consequent oxidative stress (Palamara et al.,
1995; Kim et al., 2020). Interestingly, ROS-induced oxidative stress has
been associated with viral infection in the kidney (Horoz et al., 2006),
impairing the kidney's antioxidant defense system. Moreover, Kim et al.
(2020) recently predicted in their study involving high-throughput
artificial intelligence-based binding affinity that GSH interacts with
and possibly inhibits the action of ACE2 and TMPRSS2, the two proteins
that facilitate SARS-COV-2 entry into the kidney. Secondly, findings
from a recent study also suggested that H\textsubscript{2}S may also
exhibit its antiviral activity against SARS-CoV-2 by interfering with
ACE2 and TMPRSS2 and blocking the attachment of the virus to these host
proteins (Yang et al., 2019), and thereby inhibiting entry of the virus
into the host cell (Fig. 2). Besides, administration of
H\textsubscript{2}S via its donor molecule NaHS has been reported to
upregulate carotid ACE2 expression and reduced organ damages in a mouse
model of carotid artery ligation (Lin et al., 2017). A recent molecular
dynamics simulation study showed that reduction of disulfides in ACE2
and S protein of SARS-CoV-2 into sulfydryl groups impairs the binding of
the S protein of SARS-CoV-2 to ACE-2 (Hati et al., 2020). Interestingly,
administration of N-acetylcysteine (NAC; an antioxidant
H\textsubscript{2}S donor and a source of cysteine for endogenous GSH
production) disrupted the disulfides, leading to inhibition of
SARS-CoV-2 into the host cell (Man\selectlanguage{polish}č\selectlanguage{english}ek-Keber et al., 2021). Moreover, NAC
is a known mucolytic agent that breaks disulfide bonds in mucus, making
it less viscous and easier to be expelled by other mucoactive agents
(expectorants and mucokinetics) together with the action of the ciliary
apparatus of the respiratory system. Thus, H\textsubscript{2}S
facilitates elimination of potentially harmful viruses such as
SARS-CoV-2, suggesting its antiviral action in COVID-19.

Thirdly, the antiviral action of H\textsubscript{2}S involves Toll-like
receptors (TLRs), a class of pattern recognition receptors (PRRs) that
initiate innate immune response for early immune recognition of a
pathogen. Following release of viral RNA (i.e. pathogen-associated
molecular pattern) into host cells, it is recognized by PRRs such as
TLRs in the host immune cells, which activates production and secretion
of large amounts of proinflammatory cytokines and chemokines responsible
for cytokine storm and organ damage as seen in the various kidney
conditions discussed in previous sections (Sallenave and Guillot, 2020).
Chen and colleagues (2021) recently reported that deficiency in
endogenous H\textsubscript{2}S level contributes to sepsis-induced
myocardial dysfunction (SIMD) in humans and mice via increased
expression of TLRs. However, administration of NaHS in SIMD mice
inhibited TLR pathway and prevented TLR-mediated inflammation. Although
this study was not in relation to viruses, it is likely that antiviral
action of H\textsubscript{2}S involves the same mechanism. Besides,
H\textsubscript{2}S has been reported to inhibit activation and nuclear
translocation of nuclear factor-kappaB (NF-\selectlanguage{greek}κ\selectlanguage{english}B; an inflammatory-related
transcription factor) and thereby suppressing the transcription of
pro-inflammatory genes, leading to inhibition of the secretion of
virus-induced chemokines and cytokines (Li et al., 2015). Fourthly,
post-mortem examination of transplanted kidney, lungs and heart of
COVID-19 deceased patients revealed endotheliitis and accumulation of
apoptotic bodies (Varga et al., 2020), suggesting that inflammation of
the endothelium (an important gatekeeper of cardiovascular health and
homeostasis) and apoptotic cell death contributed to dysfunction or
malfunction of these organs in the COVID-19 patients, which resulted in
death of these patients. As a potential therapy for COVID-19 patients,
there are studies showing the ameliorative effect of H\textsubscript{2}S
endothelial dysfunction in cardiovascular disorders such as
hypertension, atherosclerosis, hyperhomocysteinemia as well as in
diabetes (Citi et al., 2020; Sun et al., 2020). Besides, overactivation
of the sympathetic nervous system has recently been implicated in
COVID-19 patients with pre-existing chronic lung diseases, kidney
diseases, cardiovascular pathologies, obesity and diabetes mellitus
through factors including ACE2 imbalance, which contributes to organ
damage in these patients (Porzionato et al., 2020). Interestingly,
H\textsubscript{2}S donors such as NaHS are well-known to suppress
sympathetic activation (Kulkarni et al., 2009; Guo et al., 2011; Duan et
al., 2015; Salvi et al., 2016), and therefore inhibition of sympathetic
outflow could be a potential therapeutic mechanism by
H\textsubscript{2}S donors for COVID-19 patients.

Another mechanism underlying the antiviral action of H\textsubscript{2}S
in relation to COVID-19 involves interaction with endoplasmic reticulum
(ER) stress-related proteins. A recent preliminary virtual screening
study in patients with COVID-19 pneumonia revealed higher gene
expression and serum concentrations of glucose-regulated protein 78
(GRP78; an ER stress protein and the host cell surface protein to which
the Spike protein of SARS-CoV-2 binds as revealed by molecular docking)
compared to pneumonia patients without COVID-19 (Palmeira et al., 2020).
There are studies showing the inhibitory action of H\textsubscript{2}S
donors on GRP78 and other ER stress-related proteins in experimental
models of human diseases. Yi et al. (2018) reported that administration
of NaHS downregulated the expression of GRP78 and other ER
stress-related proteins in uranium-induced rat renal proximal tubular
epithelial cells and mitigated ER stress via activation of
Akt/GSK-3\selectlanguage{greek}β/\selectlanguage{english}Fyn-Nrf2 pathway, a protective molecular pathway.
This\emph{in vitro} result supports a previous result by Wei et al.
(2010) who observed attenuation of hyperhomocysteinemia-induced
cardiomyocyte injury following H\textsubscript{2}S administration in
rats. Administration of NaHS also markedly inhibited cigarette
smoke-induced overexpression GRP78 and other markers of ER
stress-mediated apoptosis and prevented lung tissue damage (Lin et al.,
2017). These pieces of experimental evidence suggest that
H\textsubscript{2}S donors could be potential antiviral agents that
serve to treat COVID-19 patients by preventing entry of SARS-CoV-2 into
host cells via inhibition or downregulation of the expression of GRP78
and other ER stress-related proteins, thereby preventing apoptosis and
organ damage. In addition to all these mechanisms, we also reported that
H\textsubscript{2}S decreases renal expression of kidney injury molecule
(KIM-1; a biomarker of human renal proximal tubular injury) (Dugbartey
et al., 2015a; Dugbartey et al., 2015b), which has recently been found
to be associated with COVID-19 nephropathy and potential receptor for
SARS-CoV-2 entry into renal and lung cells (Wan et al., 2021). Renal and
lung epithelial cells of humans and mice co-expressed KIM-1 and
SARS-CoV-2 Spike protein (Ichimura et al., 2020), suggesting that KIM-1
could directly bind to SARS-CoV-2 Spike protein following its induction
by AKI or other pathological conditions involving the kidney, as this
interaction was inhibited by anti-KIM-1 antibodies and the KIM-1
inhibitor, TW-37 (Ichimura et al., 2020). Yang et al. (2021) also
implicated KIM-1 and ACE2 in a synergistic interaction which mediated
the invasion of SARS-CoV-2 in kidney cells and worsened COVID-19
infection in the kidney. We recently showed that activation of
endogenous H\textsubscript{2}S production by dopamine administration
increases renal expression of H\textsubscript{2}S-producing enzymes
(CBS, CSE and 3-MST) and serum H\textsubscript{2}S level and decreases
renal KIM-1 expression, leading to increased kidney protection in a rat
model of deep hypothermia/rewarming-induced AKI (Dugbartey et al.,
2015a). We also observed decreased expression of KIM-1 in renal tubules
and preservation of renal structures following administration of
5'-adenosine monophosphate, which correlated with increased renal
H\textsubscript{2}S-producing enzymes and serum H\textsubscript{2}S
level in a hamster model of therapeutic hypothermia (Dugbartey et al.,
2015b). These observations together with other potential mechanisms that
decrease KIM-1 expression in kidney and lung tissues suggest that
H\textsubscript{2}S may offer a new therapy for COVID-19-associated
nephropathy and pneumopathy. Other mechanisms underlying the antiviral
action of H\textsubscript{2}S or H\textsubscript{2}S donors include
inhibition of gene transcription along with antiviral immunosuppressive
effect, as was reported in human cytomegalovirus (Zhen et al., 2006) and
alterations of the viral membrane, as XM-01 (an H\textsubscript{2}S
donor) inhibited the activities of enveloped viruses but had no effect
on non-enveloped viruses (Pacheco et al., 2017). The findings from all
these studies strongly suggest that H\textsubscript{2}S donors could
serve a therapeutic purpose in COVID-19 and its complications including
COVID-19-associated nephropathy (Fig. 2).

\emph{4.3 H\textsubscript{2}S as a potential biomarker in determining
final outcome of COVID-19 infection}

Although there is currently no studies on effect of H\textsubscript{2}S
on COVID-19-associated nephropathy, recent clinical study in a cohort of
patients with COVID-19 pneumonia showed that circulating
H\textsubscript{2}S level was significantly higher along with increased
lymphocyte count and reduced serum interleukin-6 (IL-6; an inflammatory
marker) in survivors of the disease compared to healthy controls and
those who died of the disease (Renieris et al., 2020). This observation
suggests that H\textsubscript{2}S could be a potential biomarker to
determine the final outcome of pneumonia caused by COVID-19. It is
important to note that IL-6 is considered a major pro-inflammatory
mediator in the cytokine-storm syndrome that causes respiratory failure
and COVID-19-associated mortality (Gubernatorova et al., 2020). There
are studies including ours, showing that H\textsubscript{2}S is a potent
inhibitor of pro-inflammatory pathway by inhibiting pulmonary and renal
IL-6 and several other pro-inflammatory mediators such as IL-2, tumor
necrosis factor-alpha (TNF-\selectlanguage{greek}α\selectlanguage{english}), interferon-gamma (IFN-\selectlanguage{greek}γ\selectlanguage{english}), intercellular
adhesion molecule-1 (ICAM-1) and NF-\selectlanguage{greek}κ\selectlanguage{english}B while simultaneously increasing
the levels of anti-inflammatory cytokines (Lobb et al., 2014; Zhang et
al., 2016). Therefore, the findings by Renieris et al. (2020) may
suggest that the increased serum H\textsubscript{2}S level in the
COVID-19 survivors could be due to increased endogenous
H\textsubscript{2}S production from the lungs and perhaps the kidneys
and other tissues to suppress production of IL-6 and other
pro-inflammatory mediators which are yet to be investigated. This is in
agreement with the a study by Li and colleagues (2015) who observed
reduced endogenous H\textsubscript{2}S production and downregulation of
CSE mRNA and protein expression (H\textsubscript{2}S-producing enzyme)
in airway epithelial cells infected with respiratory syncytial virus,
the virus commonly associated with upper and lower respiratory tract
infections in children of which there is no vaccine or effective
treatment. Further evidence of the involvement of H\textsubscript{2}S in
virus-induced respiratory condition was reported when increased viral
replication and airway inflammation was observed in CSE knockout mice
infected with respiratory syncytial virus compared to wild-type mice
(Ivanciuc et al., 2016). Interestingly, treatment with the
H\textsubscript{2}S donor, GYY4137, markedly reduced the viral
replication of not only respiratory syncytial virus but also human
metapneumovirus and Nipah virus, which correlated with decreased
production of pro-inflammatory mediators and improvement in airway
dysfunction (Ivanciuc et al., 2016). These findings provide strong
evidence of the antiviral property of H\textsubscript{2}S, which could
be a potential therapeutic agent against COVID-19. In addition,
administration of NAC to 10 patients with severe COVID-19 significantly
improved clinical and biochemical parameters (Ibrahim et al., 2020) as
well as clinical improvement in two critically ill COVID-19 patients
with multisystem organ dysfunction, who were treated with intravenous
administration of NAC (75 mg/kg over 4 hours, then 35 mg/kg over 16
hours, followed by 17 mg/kg over 24 hours on day 2) along with low-dose
hydroxychloroquine (Puyo et al., 2020). This finding is supported by
another case of a severely ill COVID-19 patient who was cured and
discharged following administration of NAC inhalation solution (Liu et
al., 2020). However, a recent double-blind, randomized controlled trial
in which intravenous administration of NAC (14 g/kg in the first 4 hours
and 7 g/kg in the next 16 hours) to severe COVID-19 patients in late
stage of the disease showed no clinical benefits compared to placebo
group (de Alencar et al., 2021). This contradictory result could be
attributable to differences in the dose of NAC and treatment regimen,
synergistic effect with hydroxychloroquine, and the timing of NAC
administration, as the latter study administered NAC later than 7--10
days after the onset of COVID-19 symptoms compared to the former study.
It further suggests that the aforementioned factors are crucial in the
treatment of COVID-19 patients with NAC or other H\textsubscript{2}S
donors, and should be matched with concurrent medical treatments. These
clinical outcomes have led to conduction of several clinical trials with
NAC to determine the most appropriate timing of administration in
various stages of COVID-19. In the face of the potential positive role
of H\textsubscript{2}S in COVID-19 cases, Dominic et al. (2021) recently
refuted the report of Renieris et al. (2020) by showing low circulating
H\textsubscript{2}S levels in Caucasian and African American COVID-19
patients compared to healthy controls and fatal cases. This conflicting
finding could be due to important determinants such as age, race, sex,
comorbidities (e.g. diabetes and hypertension) and stage of COVID-19
infection, which were not reported in the former study. Another
important factor for consideration is the differences in the method of
serum H\textsubscript{2}S measurement, as H\textsubscript{2}S decay was
so fast in the latter study and may not have been very accurate.
Besides, the authors of the latter study did not include high
performance liquid chromatography (a new method of H\textsubscript{2}S
quantification in biological systems) in their serum H\textsubscript{2}S
measurement, which their counterparts in the former study did, although
both studies used the common monobromobimane method of
H\textsubscript{2}S measurement. This discrepancy in the two studies
requires additional investigations, and should take into consideration
all important determining factors of H\textsubscript{2}S, to establish
the exact role of H\textsubscript{2}S in determining the final outcome
of COVID-19 infection.

The pathological characteristics of COVID-19 also includes coagulopathy,
during which there is progression of thrombosis and generation of DIC
with increased platelet--leukocyte aggregates, which promote coagulation
and vascular inflammation in the glomeruli of critically ill patients,
and partly accounts for COVID-19-related mortality (Pfister et al.,
2021). Hence, inhibiting platelet--leukocyte aggregates is a therapeutic
interest in COVID-19 patients, especially those with kidney conditions.
Emerging evidence using animal and human whole blood shows that
H\textsubscript{2}S donors such as NaHS and GYY4137 inhibit the
coagulation system by preventing DIC formation and platelet-leukocyte
aggregation, and facilitate thrombolysis, leading to impairment in
thrombus stability (Lu et al., 2015; Grambow et al., 2017). Therefore,
these findings about the thrombolytic or anti-thrombotic property of
H\textsubscript{2}S could advance its potential clinical utility by
COVID-19 patients.

\textbf{5. Conclusion}

Symptomatic COVID-19 patients develop renal complications and patients
with pre-existing renal conditions also have a high chance of disease
progression and mortality. Currently, there are no approved drugs that
offer renal protection in COVID-19 patients although a number of
vaccines have been approved by FDA for emergency use. With a new viral
pandemic which has significant renal involvement, there is a need for
future studies to determine the risk factors of kidney disease among
COVID-19 patients. It is important to also determine the link between
genetic polymorphisms and the risk of developing kidney diseases among
certain races of people including those of African ancestry, who have
genetic polymorphisms to kidney diseases, and to know whether there is
an association between APOL1 high-risk carriers and risk of developing
COVID-19-associated nephropathy. As the search for pharmacological
agents for effective treatment of COVID-19 is underway, there are
studies that are suggesting the potential clinical use of
H\textsubscript{2}S donors, as these agents fall under all three
classifications of COVID-19 treatment - antiviral treatment, cytokine
storm treatment, and thrombosis treatment. A growing body of evidence
show that H\textsubscript{2}S donors interact with ACE2, TMPRSS2 and
other potential SARS-CoV-2 receptors on the host cell surface, alter
SARS-CoV-2 membrane, thereby inhibiting the entry of the virus into the
host cell and consequently preventing its replication (assembly and
release). This mechanism is thought to suppress SARS-CoV-2-induced
inflammatory pathway, leading to organ protection (Fig. 2). Other
studies also suggest inhibition of gene transcription by
H\textsubscript{2}S donors along with antiviral immunosuppressive
effect. In the light of these mechanisms of the antiviral action of
H\textsubscript{2}S donors, more experimental and clinical studies with
H\textsubscript{2}S donors, especially those that are already
FDA-approved and are in human clinical trials such as STS, NAC, ATB-346
and zofenopril, should be considered for preventive treatment or
effective therapy against COVID-19 infection, and should include their
use in nebulizer for aerosol inhalation into the lungs and dissemination
to extra-pulmonary organs such as the kidney.

\textbf{Conflict of Interest}

The authors have no conflict of interest to declare

\textbf{Funding Sources}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

\textbf{Author Contributions}

GJD conceived and designed the research; GJD, KKA, BOO and VB drafted
the manuscript; GJD prepared the figures; GJD, SA, MOM, DA and AS
reviewed and edited the manuscript; All authors approved the final
version of the manuscript.

\textbf{Figure Legend}

\textbf{Figure 1.} \textbf{A diagram showing the attachment of
SARS-CoV-2 to the ACE2 receptors expressed on the surface of renal
cells.} Invasion of the kidneys by SARS-CoV-2 leads to proteinuria,
hematuria, elevation in kidney function parameters (urea, creatinine,
uric acid and albumin), and occlusion of renal arteries and veins as
well as collapsing glomerulopathy as a result of local cytokine storm
syndrome.

\textbf{Figure 2. Possible mechanism of action of H\textsubscript{2}S
against SARS-CoV-2.} Administration of H\textsubscript{2}S donors
increases endogenous production of H\textsubscript{2}S by cystathionine
\selectlanguage{greek}β-\selectlanguage{english}synthase (CBS), cystathionine \selectlanguage{greek}γ-\selectlanguage{english}lyase (CSE), 3-mecaptopyruvate
sulfurtransferase (3-MST) and D-amino acid oxidase (DAO).
H\textsubscript{2}S interacts with angiotensin-converting enzyme 2
(ACE2) and blocks the binding of SARS-CoV-2 to these host cell proteins,
thereby inhibiting entry of the virus into the host cell.
H\textsubscript{2}S also alters SARS-CoV-2 membrane and inhibits its
gene transcription including inhibiting the activation of nuclear
factor-kappaB (NF-\selectlanguage{greek}κ\selectlanguage{english}B). In addition, H\textsubscript{2}S activates
antioxidant pathway, leading to increased levels of antioxidant enzymes
such as glutathione (GSH), nuclear factor-erythroid factor 2-related
factor 2 (Nrf2) and superoxide dismutase (SOD), and suppressing
overproduction of reactive oxygen species (ROS). Furthermore,
H\textsubscript{2}S inhibits pro-inflammatory pathway, resulting in
reduced production of pro-inflammatory mediators such as
interleukin-1beta (IL-1\selectlanguage{greek}β\selectlanguage{english}), IL-6, tumor necrosis factor-alpha (TNF-\selectlanguage{greek}α\selectlanguage{english}),
interferon-gamma (IFN-\selectlanguage{greek}γ\selectlanguage{english}) and intercellular adhesion molecule-1 (ICAM-1)
while activating anti-inflammatory pathway which increases production of
IL-10.

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