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\begin{document}

\title{Evaluation of the relationship between KIM-1 and suPAR level in COVID-19
patients and a different perspective on suPAR}



\author[1]{Buğra  Kerget}%
\author[2]{Ferhan Kerget}%
\author[2]{Alperen Aksakal}%
\author[2]{Seda Aşkın}%
\author[2]{Elif Yilmazel Ucar}%
\author[1]{Leyla Sağlam}%
\affil[1]{Ataturk Universitesi}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Objective: COVID-19 is one of the most important health problems
concerning the last century and our knowledge of the disease is still
limited. In our study, we aimed to compare serum-soluble urokinase
plasminogen activator receptor (suPAR) and kidney injury molecule-1
(KIM-1) level with clinical course in COVID-19 patients. Methods: Our
study included 102 patients over the age of 18 who were diagnosed with
Covid-19 between September 2020 and December 2020 by taking
nasopharyngeal swap and using real time PCR method and 30 volunteer
medical personnel over the age of 18 who were PCR negative after the
nasopharyngeal swap. K\selectlanguage{polish}İ\selectlanguage{english}M-1 and suPAR were measured by enzyme-linked
immunosorbent assay. Results: NLR, LDH, prothrombin time, CRP,
PaO2/FiO2, D-Dimer, ferritin and fibrinogen levels, which have been
mentioned in previous studies to be of prognostic importance for
COVID-19, were observed to be higher in the severely ill group (p=0,001,
0,001, 0,05, 0,001, 0,001, 0,005, 0,001, 0,001 respectively). suPAR and
KIM-1 levels were statistically significantly higher in patient groups
compared to the control group (p=0.001 for all). While suPAR level was
statistically significantly lower in severe patients compared to
moderate patients (p=0.034), KIM-1 level was observed to be higher in
severe patients (p=0.001). Conclusion: The increased level of KIM-1 in
severe patients, which is thought to play an important role in the
endocytosis of SARS-CoV-2 to the cell, may have an important place for
the therapeutic target in the future. SuPAR can be considered to play an
important role especially in the defense mechanism and fibrinolysis and
its decreased level in severe patients may be associated with poor
prognosis in the early period. However, extensive studies are needed to
reach a definitive opinion about suPAR.%
\end{abstract}%



\sloppy


\textbf{Evaluation of the relationship between KIM-1 and suPAR level in
COVID-19 patients and a different perspective on suPAR}

\textbf{Short title:} KIM-1 and suPAR level in COVID-19

Bu\selectlanguage{polish}ğ\selectlanguage{english}ra Kerget\textsuperscript{1}, Ferhan Kerget\textsuperscript{2},
Alperen Aksakal\textsuperscript{3}, Seda A\selectlanguage{polish}ş\selectlanguage{english}k\selectlanguage{polish}ı\selectlanguage{english}n\textsuperscript{4}, Elif
Y\selectlanguage{polish}ı\selectlanguage{english}lmazel U\selectlanguage{ngerman}çar\textsuperscript{1}, Leyla Sa\selectlanguage{polish}ğ\selectlanguage{english}lam\textsuperscript{1}

\textsuperscript{1} Depertment of Pulmonary Diseases, Ataturk University
School of Medicine, Yakutiye, Erzurum, Turkey

\textsuperscript{2} Depertmant of Infection Diseases and Clinical
Microbiology, Health Sciences University Erzurum Regional Education and
Research Hospital, Yakutiye, Erzurum, Turkey

\textsuperscript{3} Depertmant of Pulmonary Diseases, Health Sciences
University Erzurum Regional Education and Research Hospital, Yakutiye,
Erzurum, Turkey

\textsuperscript{4} Depertmant of Biochemistry, Ataturk University
School of Medicine, Yakutiye, Erzurum, Turkey

All authors disclosure no Conflict of Interest.

*Corresponding Author:

Bu\selectlanguage{polish}ğ\selectlanguage{english}ra Kerget,MD

Yakutiye Medical Research Center

Chest Disease Department

25240, Yakutiye

Erzurum, TURKEY

Tel: +904423447446

Fax: +904423446528

bjkerget1903@gmail.com

\textbf{Evaluation of the relationship between KIM-1 and suPAR level in
COVID-19 patients and a different perspective on suPAR}

\textbf{Abstract}

\textbf{Objective:} COVID-19 is one of the most important health
problems concerning the last century and our knowledge of the disease is
still limited. In our study, we aimed to compare serum-soluble urokinase
plasminogen activator receptor (suPAR) and kidney injury molecule-1
(KIM-1) level with clinical course in COVID-19 patients.

\textbf{Methods:} Our study included 102 patients over the age of 18 who
were diagnosed with Covid-19 between September 2020 and December 2020 by
taking nasopharyngeal swap and using real time PCR method and 30
volunteer medical personnel over the age of 18 who were PCR negative
after the nasopharyngeal swap. K\selectlanguage{polish}İ\selectlanguage{english}M-1 and suPAR were measured by
enzyme-linked immunosorbent assay.

\textbf{Results:} NLR, LDH, prothrombin time, CRP,
PaO\textsubscript{2}/FiO\textsubscript{2}, D-Dimer, ferritin and
fibrinogen levels, which have been mentioned in previous studies to be
of prognostic importance for COVID-19, were observed to be higher in the
severely ill group (p=0,001, 0,001, 0,05, 0,001, 0,001, 0,005, 0,001,
0,001 respectively). suPAR and KIM-1 levels were statistically
significantly higher in patient groups compared to the control group
(p=0.001 for all). While suPAR level was statistically significantly
lower in severe patients compared to moderate patients (p=0.034), KIM-1
level was observed to be higher in severe patients (p=0.001).

\textbf{Conclusion:} The increased level of KIM-1 in severe patients,
which is thought to play an important role in the endocytosis of
SARS-CoV-2 to the cell, may have an important place for the therapeutic
target in the future. SuPAR can be considered to play an important role
especially in the defense mechanism and fibrinolysis and its decreased
level in severe patients may be associated with poor prognosis in the
early period. However, extensive studies are needed to reach a
definitive opinion about suPAR.

\textbf{Keywords:} COVID-19, KIM-1, suPAR

\textbf{What's already known about this topic?}

The KIM-1 molecule, which was previously associated with acute kidney
damage, is synthesized in proximal tubules after kidney damage and plays
an important role in inflammation and immune response. Research has
shown that the KIM-1 molecule, which is significantly synthesized in the
lung and kidney, can be a receptor that facilitates the binding of
SARS-CoV-2 to the cell surface through the IgV field and have put
forward that it may be the cause of acute kidney damage in patients with
Covid-19. Soluble urokinase plasminogen activator (suPAR), the dissolved
form of urokinase plasminogen activator, has been another molecule
thought to be responsible for acute kidney damage that may develop in
Covid-19. However, suPAR may also play a role in fetal complications
that may occur in the lungs and heart. suPAR plays an important role in
the remodeling of tissues under inflammation and immune cell migration
and activation.

\textbf{What does this article add?}

KIM-1/TIM-1 acts as an important gateway to the entry of the virus into
the cell and its increased level of severely ill patients seems to
confirm this. Treatments for this gateway can play an important role in
treatment in COVID-19. In addition, the falling level of suPAR, which
plays a role in body defense and fibrinolisis, with the weight of the
disease may be the cause of parenchymal fibrosis development in
patients, increased predisposition to thromboembolic events and
increased virulence. This issue seems to need to be confirmed through
more extensive research.

\textbf{Introduction}

The pandemic has been a frequently used medical term for our world in
the last year and whose meaning is known to everyone. Although pandemics
have not left our world since the existence of humanity, the
sociocultural, economic and psychological effects they create leave
lasting damage to people. Covid-19 is the latest pandemic that our world
has experienced, and while most affected people are prevalent with mild
symptoms such as loss of taste and smell, sore throat, joint pain and
headache, especially in individuals over 65 who have comorbidity, it can
progress with morbidity and mortality comorbidity 1.

Acute respiratory failure syndrome has been one of the most important
causes of mortality since the beginning of Covid-19 infection. With
increased experience in patients, more frequent observance of thrombotic
events and renal failure compared to known viral infections in followed
patients has resulted in deepening of research 2, 3.

Initially, the angiotensin-converting enzyme 2 (ACE2) receptor was
considered the most important receptor in the introduction of the virus
into the cell and medical treatments were moving in this direction.
However, later the discovery of the transmembrane protein serine
protease-2 (TMPRSS2), which facilitates the introduction of the virus
into the cell, and kidney injury molecule-1 (KIM-1), which is highly
synthesized especially in the lung, and kidney, has caused the direction
of treatment and target to change 4, 5.

The KIM-1 molecule, which was previously associated with acute kidney
damage, is synthesized in proximal tubules after kidney damage and plays
an important role in inflammation and immune response. Research has
shown that the KIM-1 molecule, which is significantly synthesized in the
lung and kidney, can be a receptor that facilitates the binding of
SARS-CoV-2 to the cell surface through the IgV field and have put
forward that it may be the cause of acute kidney damage in patients with
Covid-19 5, 6 . Soluble urokinase plasminogen activator (suPAR), the
dissolved form of urokinase plasminogen activator, has been another
molecule thought to be responsible for acute kidney damage that may
develop in Covid-19 7. However, suPAR may also play a role in fetal
complications that may occur in the lungs and heart 8. suPAR plays an
important role in the remodeling of tissues under inflammation and
immune cell migration and activation. It also balances tissue and organ
damage that may develop due to excessive inflammatory response 9.
Therefore, its importance increases even more, especially in a disease
such as Covid-19, where the abnormal inflammatory response is involved.
In our study, we aimed to investigate the role of serum suPAR and KIM-1
level in determining the relationship with clinical course in Covid-19
patients who did not develop acute renal failure in their follow-up.

\textbf{Material and methods}

Study design

As the standard, high-resolution computed tomography (HRCT) was
performed for high-risk patients with COVID-19. In line with HRCT
results, while patients who have observed opacity in bilateral frosted
glass density showing peripheral placement in the foreground, sub
segmental consolidation or linear opacities, paving stone view, inverse
halo sign were evaluated as typical findings; patients with concordant
clinical complaints, even if they had radiologically atypical findings,
were hospitalized. After the hospitalization of the patients,
hematological parameters, biochemical parameters to include liver and
kidney function tests, clotting parameters, ferritin, D-Dimer,
troponin-i, CRP, and arterial blood gas parameters were analysed. The
current parameters of the patients were repeated daily.

Study group

The 132 people included in our study were divided into 3 groups. Group
1; Asymptomatic volunteering health employees who came out negative as a
result of PCR for Covid-19 (n:30), Group 2; Moderately ill patients with
clinical signs of pneumonia with no signs of severe pneumonia (severe
pneumonia: Pneumonia fitting any one of the following conditions:
respiratory rate [?] 30 breaths/min; SpO2 [?] 92\%; patients with
\textgreater{} 50\% of lung infiltration rate) (n:62), Group 3: Severely
ill patients who are admitted with severe pneumonia and develop
macrophage activation syndrome in their follow-up (n:40).

Exclusion Criteria

Exclusion criteria were determined as the presence of chronic or
clinically significant infectious or inflammatory conditions in the last
month, asthma, chronic obstructive pulmonary disease (COPD), malignancy,
invasive surgical intervention in the last month, uncontrolled
hypertension, patients with high fasting blood sugar, diabetes,
cerebrovascular disease, kidney disease and coronary artery disease.
Anamnesis information and laboratory parameters taken during
hospitalization were used in the evaluation of patients in terms of
exclusion criteria. In terms of coronary artery disease, asthma, KOAH
presence and diabetes, cardiology, chest diseases and internal medicine
were consulted by clinics.

Definitions and Treatment

In patients, temperatures taken as axillary and found to be above 37.3 C
were defined as fever. In patients with high fever observed under
treatment for Covid-19, blood, urine and culture of sputum for possible
bacterial, fungal superinfections were taken and empirically given
antibio therapies were revised according to culture results. Diagnosis
and rating of acute respiratory failure was made according to Berlin
2015 diagnostic criteria \textsuperscript{10}. If the cardiological
specific troponin level of patients was observed above normal, it was
evaluated in terms of cardiological pathologies that may have just
developed with echocardiography. Coagulopathy was defined as 3 seconds
above normal at the time of prothrombin and 5 seconds above normal at
the level of partial thromboplastin. Treatment strategy according to the
weight of the patients was made according to the Covid-19 adult
diagnosis and treatment guide of the Ministry of Health of the Republic
of Turkey. in case of symptoms such as resistant fever, which continues
despite treatment, CRP and ferritin values, which are constantly high or
continue to increase, cytopenias in the form of lymphopenia and
thrombocytopenia, impaired liver function tests, pitofibrinogenemia or
elevation in triglyceride values, patients were followed up for MAS
D-dimer height. In case of increase in daily sequential measurements in
these parameters and when this situation cannot be explained by
secondary bacterial infections, 400 mg of tosilizumab was applied to
patients if there was no contraindication for MAS. After 24 hours, the
appropriate clinical and laboratory response was not repeated in the
patients received. However, the appropriate clinic and laboratory were
repeated in the same dose in case of no response.

\textbf{Measurement of biochemical markers}

After 15 minutes of semi-supine rest, blood samples were obtained from
an antecubital vein into tubes containing ethylenediaminetetraacetic
acid (EDTA) to prevent coagulation. Troponin I concentrations were
measured by chemiluminescent immunoassay using an Immulite 2500 (Siemens
Medical Solutions, Erlangen, Germany). K\selectlanguage{polish}İ\selectlanguage{english}M-1 and suPAR were measured by
enzyme-linked immunosorbent assay (Elabscience human ELISA kit, UK).

\textbf{Statistical analysis}

The data were analyzed using IBM SPSS Statistics for Windows version
20.0 (IBM Corp., Armonk, NY). Pearson's chi-square test and
Mann--Whitney U test were used for intergroup comparisons of parametric
data and nonnormally distributed numerical data, respectively.
Independent-samples t test was used to compare demographic data and
laboratory parameters between the groups. Wilcoxon analysis was used for
intragroup comparisons of laboratory values during follow-up. Pearson
correlation analysis was used to evaluate relationships between KIM-1
and suPAR levels and CRP, ferritin, D-dimer, lymphocyte,
neutrophil/lymphocyte ratio, troponin-I, and
PaO\textsubscript{2}/FiO\textsubscript{2}. A p-value less than 0.05 was
considered statistically significant.

\textbf{Results}

The mean age of the 102 patients included in our study was 56.1 \selectlanguage{ngerman}± 14.9
percent. The mean age of the patients in the control group was 53.1 ±
18.1 percent. No statistically significant difference was observed
between the patient and the control group (p=0.34) 59 of the patients
were male and 43 were female. The mean age of male patients was 56.3 ±
15.8 and female patients were 55.9 ± 13.8 percent. Statistical analysis
of the mean age of patients by gender showed no significant difference
between average age (p=0.9).

While we did not have patients who developed mortality during the
follow-up, the need for mechanical ventilators in severe patients did
not occur in the following process. Only 2 severe pneumonia patients
developed a massive pulmonary thromboembolism setting in spite of the
application of enoxaparin sodium at 12-hour intervals in accordance with
weight.

Evaluation of laboratory parameters according to the disease severity
belonging to COVID-19 patients included in our study was carried out in
Table 1. NLR, LDH, prothrombin time, CRP, PaO2/FiO2, D-Dimer, ferritin
and fibrinogen levels which have been mentioned in previous studies to
have prognostic importance for COVID-19, were observed to be higher in
the severely ill group (p=0.001, 0.001, 0.05, 0.001, 0.001, 0.005,
0.001, 0.001 respectively). Comparison of the patient groups among
themselves and the control group with suPAR and KIM-1 levels is shown in
Table 2. Accordingly, suPAR and KIM-1 levels were statistically
significantly higher to the control group in patient groups (p=0.001 for
all). While suPAR level was statistically significantly lower in severe
patients compared to middle patients (p=0.034), KIM-1 level was observed
to be higher in severely ill patients (p=0.001).

Comparison of the suPAR and KIM-1 levels of patient groups among
themselves and the control group is shown in Table 2. Accordingly, suPAR
and KIM-1 levels were statistically significantly higher to the control
group in patient groups (p=0.001 for all). While suPAR level was
statistically significantly lower in severe patients compared to middle
patients (p=0.034), KIM-1 level was observed to be higher in severe
patients (p=0.001).

While negative directional correlation was observed in the correlation
analysis of suPAR level with age (r=-0.197, p=0.05), positive
directional correlation was observed in correlation analysis with
PaO2/FiO2 level (r=0.316, p=0.01) (Figure 1). Statistically significant
difference was not observed in the correlational analysis of suPAR level
with D-Dimer (r=-0, 114, p=0,255). While negative directional
correlation was observed in the correlation analysis of KIM-1 level with
PaO2/FiO2 level (Figure 1), it was observed that it showed positive
correlation with parameters associated with prognosis such as NLR and
LDH (r=-0,319, p=0.01, r=0.336, p=0.01, r=0.466, p=0.01 respectively).

\textbf{Discussion}

In our study, it was observed that laboratory parameters that have been
observed to have prognostic importance in COVID-19 patients increased in
correlation with the severity of the disease. In the evaluation of suPAR
and KIM-1 levels, it was observed that suPAR level was low compared to
moderate patients in severe patients, while KIM-1 level increased in
line with the severity of the disease. In the correlation of PaO2/FiO2
level with the parameters subject to our research, positive directional
correlation was observed with suPAR level, while negative directional
correlation was found with KIM-1 level.

SARS-CoV-2 is closely related to SARS-CoV and MERS-CoV, which are
responsible for past outbreaks with significant morbidity and mortality.
The rapid spread of COVID-19 has caused the pandemic and is now
spreading globally. So far, the number of people infected due to
COVID-19 is said to be over a hundred million, and the number is
increasing day by day \textsuperscript{11.}

Observing lymphopenia in most patients in the examination of laboratory
parameters of COVID-19 patients suggested that 2019nCoV similar to
SARS-CoV could have an effect on lymphocytes, especially T lymphocytes.
Virus particles emanating from the respiratory mucosa and infecting
other cells cause abnormal cytokine discharge in the body, which is
called a cytokine storm. T lymphocyte damage is also important in
cytokine storm formation \textsuperscript{12}. After the cytokine storm,
many proinflammatory cytokines, especially TNF-alpha, IL-1, IL-2, IL-6,
nitric oxide, are released. These cytokines can cause increased vascular
permeability, causing deterioration in tissue perfusion, as well as
endothelial damage and microtombus formation. This increase in vascular
permeability causes fluid accumulation in lung tissue and the
interstitial area, resulting in an acute setting of respiratory failure.
Positive results have been reported that IL-1 and IL-6 antagonists can
be used to control this setting \textsuperscript{13, 14}.

The dense presence of the KIM-1 molecule in T cells gave it a different
name: T cell/transmembrane, immunoglobulin, and mucin (TIM-1). The
interaction of KIM-1/TIM-1 with T cells has played an important role in
immune response, allergy, asthma, autoimmune diseases and response to
viral infections \textsuperscript{5.} In the preliminary evaluation of
clinical interaction between KIM-1/TIM-1 and COVID-19 patients, the
relationship with acute kidney damage was evaluated in the
foreground\textsuperscript{15}. Kim-1/TIM-1 has been observed to
facilitate the entry of the virus into the cell, such as ACE-2 receptors
via IgV. It has been observed that increased proinflammatory cytokine
levels as a result of increased virulence may cause further progression
of kidney damage \textsuperscript{6}. In studies with SARS-CoV and
MERS-CoV, it was also determined that the IgV unit provides ease of
entry for other members of the family \textsuperscript{16}. In another
publication, which is also in the evaluation phase, it has been
suggested that KIM-1/TIM-1 receptors are high in the lungs and kidneys
and that the observed TW-37 molecule, which can inhibit anth-KIM-1/TIM-1
antibody and endocytosis, can be used as a therapeutic target
\textsuperscript{5}.

Humoral immunity plays an important role in controlling infection after
the development of viremia. One of the chemotactic agents that plays an
important role in the migration of these cells is uPAR. uPAR and its
serum-dissolved form, suPAR, mediate the transformation of plasminogen
into a plasmin.

By enabling a number of proteolytic activities to take place in the
placenum extracellular matrix, it facilitates the migration of cells
that play a role in the immune response \textsuperscript{8}. Studies
investigating the relationship of suPAR level with inflammatory diseases
found that the level of diabetes mellitus, coronary artery disease,
community origin, ventilator-related pneumonias, smoking, acute
enflaming of chronic obstructive pulmonary disease and sepsis increased
compared to the healthy control group \textsuperscript{17, 18, 19, 20,
21, 22, 23, 24, 25}. It has also been shown that early mortality may
have an important place in the pre-examination and survey in patients
with sepsis. In the study evaluating patients with COVID-19, it was also
assessed that there may be an early biomarker in patients who may
require hospitalization in intensive care \textsuperscript{26}.

In our study, it was observed that the laboratory parameters examined in
hospitalization such as NLR, LDH, prothrombin time, CRP, PaO2/FiO2,
D-Dimer, ferritin and fibrinogen levels were higher in severe patients
in line with previous studies conducted in patients with COVID-19. It
was also observed that the KIM-1 level taken care of during
hospitalization was high compared to moderately ill patients compared to
severely ill patients. This can be assessed as the KIM-1, which mediates
the endocytology of the virus in the cell, increases viremia.

In addition, increased viremia may have led to the development of MAS
with abnormal cytokine discharge in these patients later on. In the
evaluation of suPAR levels, we obtained a different observation with
previous studies. Compared to the healthy control group, it was observed
that the rising suPAR level in both moderate and severe COVID-19
patients was lower in severely ill patients than in moderate COVID-19
patients. SuPAR, which plays an important role in the migration of cells
involved in body defense, can be evaluated as aggravating the disease
due to the inability to create a low level adequate immune response in
severe patients. In addition, the decreased level of this molecule,
which plays a role in fibrinolytic activity, may have led to
hypofibrinolytic activity, causing acute respiratory distress.

The most important limit observed in our study was that the number of
our severely ill patients was small compared to the number of moderately
ill patients. However, due to the effects of the level of parameters
subject to our research on comorbidities, the exclusion of these
patients caused our number to be small.

As a result, KIM-1/TIM-1 acts as an important gateway to the entry of
the virus into the cell and its increased level of severely ill patients
seems to confirm this. Treatments for this gateway can play an important
role in treatment in COVID-19. In addition, the falling level of suPAR,
which plays a role in body defense and fibrinolisis, with the weight of
the disease may be the cause of parenchymal fibrosis development in
patients, increased predisposition to thromboembolic events and
increased virulence. This issue seems to need to be confirmed through
more extensive research.

\textbf{References}

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6. Yang C, Zhang Y, Chen H, et al. Kidney injury molecule-1 is a
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7. Azam TU, Shadid HR, Blakely P, et al. Soluble Urokinase Receptor
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\textbf{Figure legends}

\textbf{Figure 1.} Correlation analysis of serum suPAR and KIM-1 levels
of patients followed up due to COVID-19 done with PaO2/FiO2

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