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\begin{document}

\title{How Slovak Kidney Transplant Program Worked and How COVID-19 Crisis
Influenced Kidney Transplant Recipients in Slovakia}



\author[1]{Zuzana Žilinská}%
\author[1]{Martin Chrastina}%
\author[1]{Marcela Žitňáková}%
\author[2]{Eva Lacková}%
\author[3]{Ľuboslav Beňa}%
\author[3]{Tatiana Baltesová}%
\author[4]{Jaroslav Rosenberger}%
\author[5]{Karol Graňák}%
\author[5]{Matej Vnučák}%
\author[5]{Ivana Dedinská}%
\affil[1]{Comenius University in Bratislava Faculty of Medicine}%
\affil[2]{F D Roosevelt Teaching Hospital with Policlinic Banska Bystrica}%
\affil[3]{Pavol Jozef Stafarik University in Kosice Faculty of Medicine}%
\affil[4]{FMC-dialysis services Slovakia}%
\affil[5]{Comenius University in Bratislava Jessenius Faculty of Medicine in Martin}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: The aim of our analysis was to evaluate the impact of the
COVID-19 pandemic on the procurement program and kidney transplantation
in Slovakia and to identify the risk factors for a severe course of
COVID-19 disease, as well as the risk factors for COVID-19 fatalities,
with focus on the parameters preceding the infection. Methods: 305 KTRs
(68.8\% males) with confirmed SARS-CoV-2 positivity were included in the
multicentric retrospective analysis. Results: The procurement program
and kidney transplants in Slovakia dropped in the observed period by
28.6\% (P\textless{}0.0001) and by 33.5\% (P\textless{}0.0001)
respectively. Age over 59 years (OR=1.03, P=0.0088) and diabetes
mellitus (OR=2.04, P=0.0106) were identified as independent risk factors
for severe course of the disease. Risk factors for death were age over
59 years (OR=1.05, P=0.0003) and graft dysfunction with
CKD-EPI\textless{}0.5 mL/s (OR=4.87, P=0.0029). The prevalence of the
alpha variant in Slovakia was associated with a severe course in KTRs
treated with corticoids (OR=5.72, P=0.0273) and in graft dysfunction
with CKD-EPI\textless{}0.5 mL/s (OR=2.94, P=0.0076); the risk of death
was higher in KTRs over 59 years (OR=1.07, P=0.0173) and again with
CKD-EPI\textless{}0.5 mL/s (OR=4.42, P=0.0393). KTRs had a 3.7 times
lower risk of infection compared to hemodialysis patients (14\% vs 52\%,
P\textless{}0.0001), with mortality of 9.8\% vs 30\%
(P\textless{}0.0001). Conclusion: The procurement and transplant program
is sustainable even during a pandemic, provided that measures are set up
quickly. Morbidity and mortality from COVID-19 in KTRs was comparable to
the situation in EU countries.%
\end{abstract}%



\sloppy


\textbf{How Slovak Kidney Transplant Program Worked and How COVID-19
Crisis Influenced Kidney Transplant Recipients in Slovakia}

Zuzana \selectlanguage{polish}Ž\selectlanguage{english}ilinsk\selectlanguage{ngerman}á\textsuperscript{1,2}, Martin
Chrastina\textsuperscript{1}, Marcela \selectlanguage{polish}Ž\selectlanguage{english}it\selectlanguage{polish}ň\selectlanguage{ngerman}áková\textsuperscript{1}, Eva
Lacková\textsuperscript{3}, \selectlanguage{polish}Ľ\selectlanguage{english}uboslav Be\selectlanguage{polish}ň\selectlanguage{english}a\textsuperscript{4}, Tatiana
Balt\selectlanguage{ngerman}ésová\textsuperscript{4}, Jaroslav Rosenberger\textsuperscript{4,5},
Karol Gra\selectlanguage{polish}ň\selectlanguage{ngerman}ák\textsuperscript{6}, Matej Vnu\selectlanguage{polish}č\selectlanguage{ngerman}ák\textsuperscript{6}, Ivana
Dedinská\textsuperscript{6}

\textsuperscript{1}Comenius University Faculty of Medicine Department of
Urology with The Center for Kidney Transplantation, University Hospital
Bratislava, Bratislava, Slovakia

\textsuperscript{2}Comenius University Faculty of Medicine,
5\textsuperscript{th} Department of Internal Medicine, University
Hospital Bratislava, Bratislava, Slovakia

\textsuperscript{3}Department of Internal Medicine II, Slovak Medical
University and University Hospital Banska Bystrica, Slovakia

\textsuperscript{4}Transplant Department, University Hospital of Luis
Pasteur, Ko\selectlanguage{polish}š\selectlanguage{english}ice, Slovakia

\textsuperscript{5}FMC-dialysis services Slovakia

\textsuperscript{6}Transplantation Center, Jessenius Faculty of Medicine
of Comenius University and University Hospital Martin, Slovakia

\textbf{Address for correspondence:}

Assoc. prof. Ivana Dedinsk\selectlanguage{ngerman}á, MD., Ph.D.

Transplantation Center

Jessenius Faculty of Medicine of Comenius University and University
Hospital Martin

Kollárova 2

036 01 Martin

Slovak Republic

Email: idedinska@yahoo.co.uk,\emph{dedinska@unm.sk}

Phone number: +421 43 4203 920

\textbf{Conflict of interest statement:}

The authors below declare that the research was conducted with no
commercial or financial affiliations which could be construed as a
potential conflict of interest.

\textbf{Author contribution statement:}

Assoc. prof. Zuzana \selectlanguage{polish}Ž\selectlanguage{english}ilinsk\selectlanguage{ngerman}á, MD, Ph.D, MPH, MHA: participated in
writing the paper, conducting the research, and analysing the data

Assoc. prof. Ivana Dedinská, MD, Ph.D: participated in conducting the
research, and analysing the data

Martin Chrastina, MD, Ph.D, CETC: participated in donor data collection

Marcela \selectlanguage{polish}Ž\selectlanguage{english}it\selectlanguage{polish}ň\selectlanguage{ngerman}áková, MD: participated in data collection

Eva Lacková, MD, Ph.D: participated in data collection

\selectlanguage{polish}Ľ\selectlanguage{english}uboslav Be\selectlanguage{polish}ň\selectlanguage{english}a, MD, Ph.D, CETC: participated in data collection

Tatiana Baltesov\selectlanguage{ngerman}á, MD, Ph.D: participated in data collection

Jaroslav Rosenberger, MD, Ph.D: participated in hemodialysis data
collection

Karol Gra\selectlanguage{polish}ň\selectlanguage{ngerman}ák, MD, Ph.D: participated in data collection

Matej Vnu\selectlanguage{polish}č\selectlanguage{ngerman}ák, MD, PhD.: participated in data collection

\textbf{CONTRIBUTION TO THE FIELD}

The aim of our analysis was to evaluate the impact of the COVID-19
pandemic on the donor program and kidney transplantation in Slovakia and
to identify the risk factors for a severe course of COVID-19 disease, as
well as the risk factors for COVID-19 fatalities, with focus on the
parameters preceding the infection. We compared morbidity and mortality
from COVID-19 before and after the proliferation of the alpha variant of
the virus and the same among transplant and hemodialysis patients in
Slovakia.

\textbf{ETHICS STATEMENTS}

\textbf{Studies involving animal subjects}

Generated Statement: No animal studies are presented in this manuscript.

\textbf{Studies involving human subjects}

Generated Statement: The studies involving human participants were
reviewed and approved by the ethical committees of the University
Hospital in Bratislava and Jessenius Faculty of Medicine in Martin. The
patients/participants provided their written informed consent to
participate in this study.

\textbf{Inclusion of identifiable human data}

Generated Statement: No potentially identifiable human images or data
are presented in this study.

\textbf{DATA AVAILABILITY STATEMENT}

Generated Statement: The raw data supporting the conclusions of this
article will be made available by the authors, without undue
reservation.

\par\null

\textbf{ABSTRACT}

\textbf{Background:} The aim of our analysis was to evaluate the impact
of the COVID-19 pandemic on the procurement program and kidney
transplantation in Slovakia and to identify the risk factors for a
severe course of COVID-19 disease, as well as the risk factors for
COVID-19 fatalities, with focus on the parameters preceding the
infection.

\textbf{Methods:} 305 KTRs (68.8\% males) with confirmed SARS-CoV-2
positivity were included in the multicentric retrospective analysis.

\textbf{Results:} The procurement program and kidney transplants in
Slovakia dropped in the observed period by 28.6\% (P\textless{}0.0001)
and by 33.5\% (P\textless{}0.0001) respectively. Age over 59 years
(OR=1.03, P=0.0088) and diabetes mellitus (OR=2.04, P=0.0106) were
identified as independent risk factors for severe course of the disease.
Risk factors for death were age over 59 years (OR=1.05, P=0.0003) and
graft dysfunction with CKD-EPI\textless{}0.5 mL/s (OR=4.87, P=0.0029).
The prevalence of the alpha variant in Slovakia was associated with a
severe course in KTRs treated with corticoids (OR=5.72, P=0.0273) and in
graft dysfunction with CKD-EPI\textless{}0.5 mL/s (OR=2.94, P=0.0076);
the risk of death was higher in KTRs over 59 years (OR=1.07, P=0.0173)
and again with CKD-EPI\textless{}0.5 mL/s (OR=4.42, P=0.0393). KTRs had
a 3.7 times lower risk of infection compared to hemodialysis patients
(14\% \emph{vs} 52\%, P\textless{}0.0001), with mortality of
9.8\%\emph{vs} 30\% (P\textless{}0.0001).

\textbf{Conclusion:} The procurement and transplant program is
sustainable even during a~pandemic, provided that measures are set up
quickly. Morbidity and mortality from COVID-19 in KTRs was comparable to
the situation in EU countries.

\textbf{KEYWORDS}

COVID-19, Kidney Transplantation, Dialysis, Immunosuppresion, Steroid,
Obesity, Diabetes Mellitus

\textbf{ABBREVIATIONS}

ACE-I, angiotensin-converting enzyme inhibitor

BMI, body mass index

CKD, chronic kidney disease

CKD-EPI, chronic kidney disease epidemiology collaboration

COVID-19, coronavirus disease 2019

CNI, calcineurin inhibitor

DBD, donation after brain death

ERACODA, the European Renal Association COVID-19 Database

ERA-EDTA, the European Renal Association

EuClid5, Nephrocare European Clinical Database

EU, European Union

eGFR, estimated glomerular filtration rate

HD, hemodialysis

IV, intravenously

KTRs, kidney transplant recipients

LKD, living kidney donor

MMF, mycophenolate mofetil

MPA, mycophenolic acid

mTOR-I, inhibitor of mammalian target of rapamycine

RT PCR, real-time polymerase chain reaction

SARS-CoV-2, severe acute respiratory syndrome coronavirus-2

TAC, tacrolimus

\emph{vs} , versus

\textbf{INTRODUCTION}

Since the initial outbreak in Wuhan, China, in December 2019, the
Coronavirus Disease 2019 (COVID-19) has spread across the world,
prompting a global pandemic. The disease caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) was seen as a pulmonary
and infectious problem (1).

The other conditions initially identified as risk factors for a severe
course of COVID-19 were cardiovascular disease, diabetes, and
hypertension. Only later in the process came the realization that kidney
disease is a leading risk factor for death. Ultimately, it appeared that
the population of patients with chronic kidney disease (CKD), especially
those treated with dialysis or transplantation, is one of the
highest-risk groups for hospitalization and death (2, 3, 4). Dialysis
and transplant patients represent a vulnerable population as all of them
suffer from multiple pre-existing medical conditions. COVID-19 causes
substantial mortality in both dialysis and kidney transplant population
due to their underlying chronic kidney disease and a high prevalence of
comorbid conditions such as hypertension, diabetes mellitus, and
cardiovascular disease (5, 6). Immunosuppressive treatment is also a
precondition for a more severe course of the disease. However, the
potential effect of its long-term use is a matter of debate (7, 8). Some
argue that the transplant patients might be at a higher risk of severe
infection resulting from their impaired immune system, while others
speculate that immunosuppressive therapy might be protective as it could
address the COVID-19 induced cytokine storm (9, 10, 11, 12, 13).

Large European data became available later, after the first wave. Recent
data show that CKD patients are at a higher risk than those with other
known risk factors, including chronic heart and lung disease. According
to the European Renal Association COVID-19 registry which included 4,298
kidney failure patients, 28-day mortality was 20\% in 3,285 patients
receiving dialysis and 19.9\% in 1,013 recipients of a~transplant (7).
The ERACODA database (1,073 patients) reported a 28-day case fatality
rate of 25\% in 768 dialysis patients and 21.3\% in 305 kidney
transplant recipients during the first wave (5). Other reports based on
regional or national registries have also suggested lower mortality in
kidney transplant patients than in hemodialysis patients (14, 15).

COVID-19 reported case fatality rates vary greatly between countries
owing to differences in public health policy, case ascertainment, and
testing capacity. During the pandemic, a substantial number of patients
died while waitlisted, due to dramatic reductions in organ donation and
transplantation, reaching as high as 80\% in some countries of the
European Union (4, 16). The early days of the pandemic came with plenty
of unknowns affecting the healthcare community's ability to prepare for
and perform transplants. At the beginning, hospitals were limiting
surgical procedures to emergencies only in an effort to free up staff
for COVID-19 patients and to preserve scarce resources such as personal
protective equipment. Testing capacity was also limited. Additionally,
there was an effort to avoid the risk of further infections which could
arise from admitting more patients into hospitals than necessary.
Transplants from deceased donors were limited to urgent situations only;
while living donation programs were suspended amid the lockdown and fear
of infection. However, it was shown that during the outbreak, the risk
of being infected by SARS-CoV-2 was more than 4 times lower for kidney
transplant recipients than for hemodialysis patients, mainly because
transplant patients can be managed at home, while hemodialysis still
mostly takes place in hospital settings (4, 17). In-center hemodialysis
patients were at a higher risk for COVID-19 related mortality,
independently from the known risk factors such as obesity, ischemic
heart disease and lung disease (2). Data from Spain and Italy have shown
a 30\% mortality of dialysis patients (18, 19). Recently published
French data showed that the 30-day Covid-19-related mortality was
significantly higher in kidney transplant recipients (KTRs) compared to
non-transplant patients (17.9\% \emph{vs} 1.4\%, P=0.038) (20).

\emph{Short summary of the impact of the COVID-19 pandemic on donation
and kidney transplant program in Slovakia:}

The first patient to test positive for SARS-CoV-2 virus in Slovakia was
reported on 6.3.2020. It was a~52-year-old healthy man with a~mild
course of the disease. The last DBD (donation after brain death) donor
and transplantation of two kidneys and one liver before the state of
emergency was declared (15.3.2020) were performed on 11.3.2020. Twelve
days later, measures were taken to limit the transplant program to
urgent life-saving procedures (heart, liver), and kidney transplants
from living and deceased donors were stopped. Due to the favorable
development of the pandemic in Slovakia, kidney transplants from living
and deceased donors were resumed since 14.4.2020, the transplant program
was cleared for all procedures, provided that donors were RT-PCR tested
and strict epidemiological measures were observed. During the summer
months, procurement and transplantation activity intensified to the
average level of 2019, which was the most successful year in the number
of organ transplants in the history of Slovakia. All of the postponed
kidney transplants from living donors were performed. The second wave of
the COVID-19 crisis began in September 2020. For the purposes of our
analysis, the COVID-19 morbidity/mortality in the group of patients
after kidney transplantation was divided in two phases: the first phase
of the second wave (hereinafter ''first period'') from 1.9.2020 to
31.12.2020, and the second phase of the second wave, connected with
proliferation of the alpha variant as confirmed by sequencing
(hereinafter referred to as the ''second period'') from 1.1.2021 to
31.3.2021, when the data collection for this analysis was concluded.
While all four Slovak kidney transplant centers (the University Hospital
in Bratislava, Banská Bystrica, Martin and Ko\selectlanguage{polish}š\selectlanguage{english}ice) proceeded uniformly
during the first wave of COVID-19, during the second wave, when the new
precautionary measures were enacted in an effort to avoid stopping the
transplant program, the individual transplant centers proceeded
according to their individual possibilities, taking into account the
regional epidemic situation.

We present our experience with the development and impact of COVID-19
pandemic on patients after kidney transplantation in Slovakia. We
focused on morbidity and mortality during the two waves of the COVID-19
crisis and tried to identify the risk factors for developing a severe
course of the disease in KTRs. We compared morbidity and mortality of
KTRs with the hemodialysis population.

\textbf{MATERIALS AND METHODS}

In a retrospective multicentric analysis, we included SARS-CoV-2
positively tested patients after kidney transplantation monitored in all
four transplant centers in Slovakia -- the University Hospital in
Bratislava, Bansk\selectlanguage{ngerman}á Bystrica, Martin, and Ko\selectlanguage{polish}š\selectlanguage{english}ice. The data were collected
for the period from March 6, 2020 to March 31, 2021. Positivity was
confirmed by real-time polymerase chain reaction (RT-PCR) test. We
recorded age, time (months) after transplantation, diabetes mellitus and
arterial hypertension history, BMI (body mass index) and graft function
at the time of the test positivity, and telephone consultation with the
transplant center by the patient or the treating physician from the
hospital where the infected patient was admitted in relation to COVID-19
and its treatment. We evaluated the type and doses/levels of
immunosuppression and treatment with angiotensin-converting enzyme
inhibitors (ACE-I) at the time of the test positivity.

The group of patients was divided into three subgroups according to the
COVID-19 pandemic period:

Subgroup 1: the first wave of COVID-19 crisis (March 6, 2020 -- August
31, 2020).

Subgroup 2: the first period of the second wave (September 1, 2020 --
December 31, 2020).

Subgroup 3: the second period of the second wave -- prevalence of the
alpha variant of SARS-CoV-2 as confirmed by sample sequencing (January
1, 2021 -- March 31, 2021).

Further division based on the clinical course of the disease was into
asymptomatic or moderate course -- patients were treated at home; and
severe course requiring hospitalization.

For the purposes of the analysis, the doses were unified and
mycophenolic acid (MPA) was recalculated to mycophenolate mofetil (MMF).
Similar approach was used in recalculation of methylprednisolone to
prednisolone.

To compare the mortality rate to that of the hemodialysis patients, we
employed information from 34 dialysis clinics reporting data to
Nephrocare European Clinical Database (EuClid5).

\emph{Immunosuppression:}

Immunosuppressive treatment of the patients consisted of cyclosporine
(n=33 patients, 10.8\%) or tacrolimus (n=261, 85.6\%); mycophenolate
mofetil/mycophenolic acid (n=272, 89.2\%) and prednisone (n=266,
87.2\%). Cyclosporine was administered at a starting dose of 6--8 mg/kg
per day (twice daily) for the first 24 hours after transplantation, with
a~later dosage adjustment to maintain the following blood concentration
levels: 200--400 ng/ml in month 1, 200--300 ng/ml in months 2--3,
150--250 ng/ml in months 4--6, and 100--200 ng/ml in months 6--12.
Tacrolimus was administered for the first 1--2 days after
transplantation at a dose of 0.2 mg/kg per day, aiming to target whole
blood concentration at 10 to 15 ng/ml in month 1, 7 to 10 ng/ml in
months 2--3, 6 to 8 ng/ml in months 4--6, and 5 to 7 ng/ml in months
6--12. Mycophenolate mofetil/mycophenolic acid was given at an induction
dose of 2000 mg/1440 mg per day and a maintenance dose of 1000--2000
mg/760--1440 mg per day, later reduced according to the immunology risk
status of the patient. The initial dose of 500 mg of
6-methylprednisolone was administered intra-operatively intravenously
(IV), then 250--500 mg IV 1 or 2 days post-transplant, followed by oral
prednisolone acetate tapering to 20 mg during the first month after
transplantation, then 10 mg during months 2--3, and later 5 to 2.5 mg
per day.

Cyclosporine A, sirolimus and azathioprine were used in a small group of
patients with longer time since transplant.

\textbf{STATISTICAL ANALYSIS}

We used a certified statistical program, MedCalc version 13.1.2. (VAT
registration no. BE 0809 344 640, Member of International Association of
Statistical Computing, Ostend, Belgium), to perform statistical
analyses. Continuous data were compared using the Student's t-test or
the Wilcoxon rank-sum test as appropriate. The \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} test
and Fisher's exact test were used for categorical variables. Univariate
and multivariate logistic regressions were used to assess monitored
parameters in order to predict the risk of severe course and death.
Statistically significant parameters assessed in the univariate analysis
were entered in the multivariate model. Statistically significant
parameters were also further analysed by the means of probit regression.
We considered the P-value of \textless{} 0.05 to be statistically
significant.

\textbf{ETHICAL APPROVAL}

All procedures involving human participants have been approved according
to the ethical standards of the institutional research committee,
including the 1964 Helsinki Declaration and its later amendments of
comparable ethical standards. Informed consent for participants included
in the analysis was checked and approved by the University Hospital's
and Jessenius Faculty of Medicine's ethical committees and all the
signed informed consents are being archived for at least 20 years after
conclusion of the research. The reported clinical and research
activities are consistent with the Principles of the Declaration of
Istanbul as outlined in the Declaration of Istanbul on Organ Trafficking
and Transplant Tourism.

\textbf{RESULTS}

In the pandemic year 2020, the donation program in Slovakia dropped by
28.6\% (P\textless{}0.0001) compared to 2019 which was the most
successful year for organ transplants in the history of Slovakia. The
number of kidney transplantations decreased by 33.5\%
(P\textless{}0.0001), kidney transplantations from living donors were at
a comparable level (P=0.0767). Compared to 2018, kidney transplantations
decreased by 10.3\% (P=0.0001) during the COVID-19 crisis in Slovakia
(Figure 1).

A total of 305 patients (210 men, 68.8\%) with confirmed SARS-CoV-2
positivity between March 6, 2020 and March 31, 2021 were included in our
analysis. Basic characteristics of the group are shown in Table 1. The
median age was 54 years (52.7 \selectlanguage{ngerman}± 12), the median body mass index was 29
kg/m\textsuperscript{2} (29.6 ± 18.3), 291 recipients (95.4\%) suffered
from hypertension and 109 (35.7\%) from diabetes mellitus. Patients who
were longer after the kidney transplantation became ill more frequently,
with a~median of 68 months (84.8 ± 64.3). Excellent graft function
(eGFR; CKD-EPI \selectlanguage{english}[?] 1.5 mL/s/1.73 m\textsuperscript{2}) at the time of the
first positive test was found in 27 cases (8.9\%), 121 patients (39.7\%)
were in the second stage of chronic kidney disease (eGFR; CKD-EPI 1.49
-- 1.0 mL/s/1.73 m\textsuperscript{2}), 120 (39.3\%) in the third stage
(eGFR; CKD-EPI 0.99 -- 0.5 mL/s/1.73 m\textsuperscript{2}), and 37
(12.1\%) with advanced graft dysfunction (eGFR; CKD-EPI \textless{} 0.5
mL/s/1.73 m\textsuperscript{2}).

In the first wave of COVID-19 crisis only three positively tested
patients (1\%) for SARS-CoV-2 were identified in Slovakia, the course of
the disease was asymptomatic/moderate. During the second wave, the
COVID-19 morbidity rose significantly, SARS-CoV-2 was identified in 302
KTRs (99\%), of which, in the first period of the second wave, it was
147 KTRs (48.2\%), followed by 155 (50.8\%) positively tested KTRs in
the second period of the second pandemic wave (Tab. 1).

Criteria for the asymptomatic/moderate course of the disease were met by
206 patients (67.5\%), admission to the hospital was indicated in 99
KTRs (32.5\%) (Tab. 1). 192 positively tested patiens (63\%) called the
transplant centers and consulted the symptoms and the treatment (Tab.
1), more frequently during the second period of the second wave
(54.9\%\emph{vs} 71.6\%; P=0.0028), more commonly with
asymptomatic/moderate course of the disease (72.1\% \emph{vs} 46.9\%);
P\textless{}0.0001) (Tab. 2). In 92 hospitalized patients (92.9\%), the
physicians from the hospitals/COVID-19 departments to which the patients
were admitted consulted the treatment with experienced nephrologists
from the transplant centers, especially discontinuation of
immunosuppressants, doses of steroids, and supportive antimicrobial
treatment and prevention of thrombosis (Tab. 2). There were no deaths
recorded during the first wave, thirty patients (9.8\%) died during the
second wave of COVID-19 pandemic, there was no significant difference
between both periods of the second wave (Tab. 1). Elderly patients were
hospitalized more frequently (P=0.0059); for the whole set, in both
univariate and multivariate analysis (Tab. 3), the age over 59 years was
a~risk factor for a~more severe course and death. Another risk factor
for hospitalization and death in the whole set, according to the
univariate analysis, was diabetes mellitus, while in the multivariate
analysis (Tab. 3), diabetes mellitus was only associated with a more
severe course of the disease (OR {[}95\% CI{]}: 2.0433
{[}1.1812-3.5346{]}; P=0.0106). Patients with advanced graft dysfunction
defined by eGFR \textless{} 0.5 mL/s (Tab. 3), OR {[}95\% CI{]} had a
worse prognosis associated with the risk of death: 4.8668
{[}1.7182-13.7849{]}; P=0.0029). In contrast, better graft function was
more common in patients with a mild course (45.9\% \emph{vs} 27.6\%,
P=0.0028).

We did not find any effect of arterial hypertension, BMI, time since
transplantation, CNI, MMF/MPA, mTOR-I and ACE-I on the incidence and
clinical course of COVID-19 in KTRs during the first and second waves of
the pandemic (Tab. 2). At the time of finding of the infection, patients
with a more severe course and need for hospitalization (93.9
\emph{vs}85.8; P=0.0419) were more frequently treated with
corticosteroids at a higher mean dose than the mild course group
(7.3+-5.3 \emph{vs} 5.9+-3.1; P=0.0056). While according to a univariate
analysis, a lower dose of prednisolone (\textless{}10mg) was a
protective factor at the onset of infection, the protective effect of
low doses of corticosteroids was not confirmed by the multivariate
analysis (Tab. 3).

We focused our interest in whether the proliferation of the alpha
variant of the SARS-CoV-2 virus affected the course and risk factors of
COVID-19 in kidney transplant patients. By comparing subgroup 2 (09/2020
- 12/2020) and subgroup 3 (01/2021 - 03/2021), we did not find any
significant differences in the screened parameters depending on the
period when patients became ill or tested positive for SARS-CoV-2 virus
(Tab. 2, Tab. 4, Tab. 5).

Finally, we compared COVID-19 morbidity and mortality rates between KTRs
and patients on hemodialysis (HD). While among the patients after kidney
transplantation, 14\% tested positive, in the hemodialysis cohort, there
was up to 52\% positivity (P\textless{}0.0001). Mortality among the
infected kidney recipients was 9.8\% \emph{vs} 30\% (P
\textless{}0.0001) in HD patients. Of the total set of KTRs in
dispensary, a total of 1.4\% died in Slovakia during the COVID-19
pandemic by the end of March 2021, while in the population of HD
patients it was up to 15.6\% (P\textless{}0.0001).

\textbf{DISCUSSION}

Our analysis confirmed that the risk group for a~severe course of
COVID-19 infection, as well as for death, are patients over 59 years,
diabetes mellitus was found to be an independent risk factor for
hospital admission. Our data correspond with the conclusions of the
ERACODA register in which a 28-day mortality was primarily associated
with elderly kidney transplant patients (5). An analysis by French
authors comparing the course of COVID-19 infection in patients after
kidney transplantation with a non-transplant group also confirmed the
significantly worse outcome of COVID-19 in the group of transplant
patients over 60 years of age (19). Diabetes mellitus was confirmed as
an independent risk factor for a serious course of COVID-19 in the group
of patients after kidney transplantation (21). Advanced impairment of
graft function at the time of infection was identified as another risk
factor for poor outcome in the studied group of patients. The prevalence
of the alpha variant in Slovakia did not affect the development of
morbidity and mortality in patients after kidney transplantation.

The pandemic heavily impacted both the dialysis care and organ
procurement and transplantation activities: hemodialysis centers became
a source of infections owing to the model of repetitive treatment in a
closed community; peritoneal dialysis insertions which could have
protected CKD patients as they allow dialysis outside the hospital were
postponed as non-urgent procedures (4, 15).

These factors also affected the situation in Slovakia. A quick
understanding that restricting or stopping kidney transplants from
deceased and living donors could lead to unnecessary deaths of the
waitlisted patients led to setting the rules so that the procurement and
transplantation program in Slovakia did not stop during the second wave
of the COVID-19 crisis. Claims that transplant patients are at a high
risk of infection and it is better to keep them on the hemodialysis
program have proved to be unsubstantiated. All the more so, given that
the morbidity and mortality of patients in hemodialysis centers in
Slovakia was 52\% and 30\%, which was a~higher rate compared to the
ERA-EDTA Registry (7) and the ERACODA database (5) data, where 28-day
mortality was 19.9\% and 25\%. The onset of morbidity and mortality in
Slovakia during the second wave of the COVID-19 pandemic was also
reflected in the increase in the number of infected KTRs, but compared
to the hemodialysis population, the risk of infection and death was 3.7
times lower. According to the data of ERA-EDTA a~EU National Competent
Authorities on Organ donation and transplantation the risk of being
infected by SARS-CoV-2 was more than 4 times lower for kidney transplant
recipients than for hemodialysis patients, mainly because transplant
patients can be managed at home, while hemodialysis still takes place
mostly in hospital settings (4, 17). It should be noted that
hemodialysis patients are generally older and have a higher prevalence
of comorbid conditions than kidney transplant recipients (16). At the
Slovak hemodialysis units, screening for COVID-19 was performed not only
in symptomatic patients and as a~post-contact screening, but also as a
part of routine surveillance, whereas transplant patients only underwent
testing when they presented with symptoms or after the contact with a
positive person. On the other hand, lower morbidity and mortality among
transplant patients may be explained by better habits to protect oneself
from infection and by better opportunities to manage the treatment at
home and remotely during the critical period of the pandemic
(telemedicine, e-prescription), while hemodialysis still mostly takes
place in hospital settings. Therefore, promoting transplantation is
integral to fostering future preparedness for other mass infectious
disease emergencies (4).

Unlike the first wave, the second wave in Slovakia was marked by slow
enacting of the precautions, greater benevolence, misinterpretation of
negative test results (as being a ''freedom pass'') and also pandemic
fatigue. Nevertheless, Slovakia was able to maintain the procurement and
transplantation program. While donation and organ transplants in some
European Union countries dropped by more than 80\% (7), in Slovakia it
was only up to 33.5\%. Kidney transplants from living donors, with the
exception of the first wave, continued without restriction and at the
same level as in 2018 and 2019. No transmission of infection from the
donor to the recipient or infection in the hospital during the short
post-transplant period was observed. The first wave of the COVID-19
pandemic in Slovakia has shown that clear rules and strict anti-epidemic
measures and their observance by kidney transplant patients as well as
their family members are an efficient way to protect against the
disease. Increased vigilance during a pandemic and the prevention of
infectious diseases should be maintained not only shortly after
transplantation, but also later, as patients being longer
post-transplantation became infected more frequently (median: 5.7
years).

In January 2021, vaccination started in Slovakia for health
professionals and at-risk groups of the population, including patients
with CKD, especially patients on dialysis and transplant patients.

The limitation of our analysis lies in the absence of data regarding the
treatment of patients during hospitalization, since the patients were
not hospitalised in a specialized COVID-19 center, consultation timing
varied and thus, the treatment data would not be homogeneous. On the
other hand, our analysis deals with the risk factors for a severe course
of COVID-19 before the infection onset.

\textbf{CONCLUSION}

The COVID-19 pandemic has had a substantial effect on morbidity and
mortality in kidney replacement therapy patients affected by the
disease, peaking in elderly and diabetic patients. Despite the higher
risk of morbidity and mortality due to impaired immunity, kidney
transplantation from a deceased or living donor appears to be a safe
treatment modality for patients with end-stage renal failure even during
the COVID-19 pandemic. Mortality of the kidney transplant patients from
COVID-19 is significantly lower than the risk of infection and death
during a hemodialysis treatment. It is of vital importance that in
future pandemics the nephrology community has a crisis management and
protocols in place and be able to act swiftly to increase the safety of
their patients and mitigate the damage to their health as much as
possible. Transplant centers need to be flexible during a pandemic,
adopting both short-term and long-term changes along the way. Important
precautionary measures include early vaccination of at-risk groups,
including kidney transplant patients.

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