Key words : COVID-19, COVID-19 vaccine, Immuno-suppression, Renal transplantation, SARS-CoV-2

Introduction
Kidney transplant (KT) recipients with viral infections are at serious risks of morbidity and mortality. Elevated creatinine levels and corresponding decreases in glomerular filtration rate (GFR) occur in 25.5% of KT recipients with COVID-19; the presence of both is associated with acute kidney injury, the need for hemodialysis, an increased risk of developing community-acquired and nosocomial pneumonia, and approximately 3 times increased risk of death.¹ Patients with chronic kidney disease have a 14- to 16-fold higher risk of death due to lung tissue inflammation than the general population; therefore, chronic kidney disease can be considered as an important factor in the system of risk stratification of poor prognosis in patients with COVID-19.^2,3 A follow-up analysis of 7184 dialysis patients in 61 Wuhan city centers demonstrated the need for longer isolation to prevent the spread of infection. Indicators of cellular immunity, including interleukin 4, interleukin 6 (IL-6), and tumor necrosis factor α, showed that a weakened immune system could not effectively respond to the invasion of SARS-CoV-2, thus leading to a “cytokine storm” and serious organ damage.^4,5 COVID-19 progresses faster in immunosuppressed people, requiring more frequent intensive care unit hospitalizations and leading to more deaths.⁶ Kidney transplant recipients should take all necessary measures to prevent infection.

Immunosuppression, which is crucial for preventing alloimmune reactions and prolonging the function of the graft in the recipient, can impair the host’s defense mechanisms. In case series from Europe and the United States, the mortality rates of these patients ranged from 23% to 28%, which is significantly higher than the mortality among general patients infected with COVID-19 (?5%).^7,8 The investigators described different management strategies based on a gradual decrease of immunosuppression depending on the severity of the disease, taking into account the risk of acute rejection and graft loss.

Patients with chronic kidney disease and COVID-19 should continue treatment and receive hydroxychloroquine on the days following a hemodialysis session. Interestingly, there was no information about the last in any of the reports, probably because the observation period was short. However, serious concerns remain that the withdrawal of immunosuppressants may exacerbate the hyperinflammatory response that develops in the late stages of COVID-19. In addition, antiviral drugs in the standard protocols for patients with COVID-19 have been shown to have interactions with various immunosuppressants (Figure 1).⁹ There are a number of global problems that have arisen for healthcare centers and for transplant experts during the COVID-19 pandemic. First, the possibility of transmitting the virus with a donor organ, as well as transplant to the recipient in the incubation period, has so far not been described. Second, donors and potential recipients must be tested for SARS-CoV-2. Third, there is no clear understanding in the benefit-to-risk ratio of postponing transplant and performing only emergency surgeries (KT can be delayed in most patients, but patients on the liver and heart wait lists, for example, should be stratified). Fourth, transplant programs in many countries, including because of lack of resources, had to be suspended. Fifth, health of donor teams and transplant center staff need protection from COVID-19, and there is a need for rapid testing in cases of contact or the appearance of even minor symptoms. Sixth, outpatient care required reorganization, including reducing the number of visits to the center, remote counseling, and temporary refusal of planned hospitalization. Seventh, recruitment of patients into clinical trials was suspended, postponing the start of new trials in transplant. Finally, there are psychological problems associated with the pandemic, in both patients and doctors.

The Developing Education Science and Care for Renal Transplantation in European States working group of the European Kidney Association after intensive discussions, based on the expert opinions from publications and recommendations from relevant communities of France,¹⁰ Spain,⁹ Great Britain,¹¹and the United States,¹² formulated proposals for the management of KT recipients with COVID-19 (with transplant duration more than 6 months) (Table 1).¹³ When available, risk stratification may additionally benefit from the results of laboratory parameters indicating severe inflammatory disease at risk of rapid progression, such as a high level of C-reactive protein, IL-6, ferritin, and D-dimer.

The aim of our study was to examine the course and occurrence of new coronavirus infections in patients who underwent KT from a living related donor during a global pandemic in Uzbekistan.

Materials and Methods
From 2017 to 2022 at our center, 609 KT procedures were performed from living related donors. During the pandemic (from the beginning of pandemic in our country [March 2020] until the end of 2021), there were 320 (52.55%) KTs. There were 228 patients who had COVID-19 infection and COVID-19-associated pneumonia after transplant (37.4%). 40 patients (12.5%) (40?320) from the total number of operated during the pandemic were infected with the virus before transplant and successfully cured and prepared for further surgery. These patients were successfully cured and prepared for further surgery. Of 320 patients, the number of patients infected with the virus during their stay in the transplant department was 2 (0.625%) out of the total number operated during the pandemic. The number of patients who died in the pandemic period was 8/320 (2.5%) out of the total number operated during the pandemic; and in 4/320 patients (1.25%), the results of polymerase chain reactions tests could not confirm COVID-19 infection.

Results
The characteristics of the KT recipients included in the study are presented in Table 2. The average age of patients was 27 years (from 25 to 29 ± 11 years). Among the KT recipients, 97 were treated for COVID-19 infection on an outpatient basis, which accounted for 42.5% (97?228) of the total number of those infected with this virus during the pandemic. Of 228 recipients, 89 (39%) received treatment in a hospital, and 34 (14.9%) were hospitalized in the intensive care unit because of more serious disease. As shown in computed tomography scans, recipients had characteristic lung damage of varying severity, with lung damage of 13% in patients treated on an outpatient basis, 51% lung damage in patients hospitalized for inpatient treatment, and more than 55% lung damage in patients treated in the intensive care unit and in patients who died. Patients with computed tomography 3rd and 4th stage had progressive respiratory failure and needed oxygen support.

Discussion
When we consider the course ofCOVID-19 infection in relatively healthy people, patients who have undergone KT are at particular risk, since this disease can proceed with lightning speed, with life-threatening complications to the recipient. In our patients, the incidence of moderate severity of the disease was 71%, and pneumonia associated with COVID-19infection accounted for approximately 42% of patients who underwent KT. Kidney transplant recipients, after lung damage was confirmed by multislice computed tomography of the lungs, were sent to the intensive care unit for appropriate treatment and a speedy recovery to avoid possible complications to the graft.

Patients who had COVID-19 but did not die from COVID-19 included those who were diagnosed with the disease when presenting to a medical organization. In addition, a patient was considered to have had COVID-19 if at least 1 positive PCR test was obtained and/or specific antibodies to the SARS-CoV-2 virus were identified and/or there was a typical scan that showed COVID-19 pneumonia on computed tomography. Diagnosis included the results of all tests, including those conducted at the initiative of the patients themselves. For a more accurate interpretation of medical data, patients were asked for electronic copies of the results of laboratory and instrumental tests, discharge summaries, and if they required inpatient treatment.

Possible drugs are available for treatment, which have been used by specialists in our country in accordance with the above recommendations. These include hydroxychloroquine (400 mg, 2 times on day 1, then 200 mg 2 times) or chloroquine (500 mg, 2 times/day); lopinavir/ritonavir (200/50 mg twice per day, although it causes a sharp increase in the concentration of tacrolimus); corticosteroids (not widely used); interferon 1β (may cause acute rejection); remdesivir (200 mg intravenously on day 1, then 100 mg intravenously until day 10); tocilizumab (up to 8 mg/kg, 1-3 injections with an interval of 8-12 hours); ascorbic acid (very little data in favor of this drug);intravenous immunoglobulin (1 g/kg for 2 days or 400 mg/kg for 5 days; no clear rationale for use in all patients); and antibiotics (especially azithromycin; in combination with hydroxychloroquine, dose of azithromycin of 500 mg on day 1, then 250 mg for 4 days).

There is some debate as to whether to cancel cyclosporine and tacrolimus. The Brescia Renal Covid Task Force recommends discontinuation of cyclosporine even in asymptomatic KT recipients. This is largely done to avoid dangerous drug interactions with lopinavir/ritonavir (a protease inhibitor). On the other hand, renowned Italian nephrologists^14,15 believed that the effects of lopinavir/ritonavir were not yet proven and that withdrawal of cyclosporine because of this drug is not justified, as it increases the risk of graft loss. Analogies of the cytokine storm in COVID-19 with hemophagocytic syndrome, in the treatment of which cyclosporine is used, are also being drawn. Apparently, in patients with mild or moderate COVID-19 disease course, only a decrease in the dose of cyclosporine is necessary; however, in patients with severe disease, cancellation is still necessary.

Vaccination in the Republic of Uzbekistan
Vaccination of KT recipients and those in constant contact with them is a mandatory, life-saving measure that effectively reduces the risk of death from COVID-19. Until more new data become available, the vaccination regimen should strictly comply with the instructions for medical use of the drug. Before vaccination, the patient should be examined according to the screening protocol and also consulted by a transplant doctor, nephrologist, and other specialists, if necessary.

With regard to the estimated timeframe required for vaccination against COVID-19 infection, the recom-mendation is to delay vaccination for at least 1month after transplant and at least 3 months in patients who are given T-lymphocyte-depleting agents such as antithymocyte globulin or rituximab. If transplant is performed between vaccine doses, the recommendation is to delay the second dose until at least 1 month after transplant surgery unless a T-cell/B-cell depleting agent was used for induction or at least 3 months after transplant surgery if a T-cell/B-cell-depleting agent was used for induction. To date, for the population of our country, the types of vaccines presented in Table 3 are available, which, according to indications, can also be used for our KT recipients.

Conclusions
When the first symptoms of a viral infection appeared, our specialists recommended the following types of tests to almost all recipients: complete blood count, coagulogram, biochemical blood test, in which special attention was paid to the indicators of D-dimer, ferritin, procalcitonin, and immunologic tests (C-reactive protein, IL-6, determination of immunoglobulin M/immunoglobulin G antibodies to the SARS-CoV-2 virus by immunochemiluminescent assay or enzyme-linked immunoassay methods). The recommendations of the Ministry of Health of the Republic of Uzbekistan indicate the possibility of administering drugs based on monoclonal antibodies that block IL-6 receptors (tocilizumab and sarilumab) in patients with moderate and severe COVID-19. However, immunosuppressive therapy is indicated as contraindications in organ transplant, although many large transplant centers in Western countries use tocilizumab in this group of patients. There are no direct contraindications to the use of these drugs after organ transplant. It must be remembered that patients on immunosuppressive therapy should not be given live attenuated vaccines. There is a lot of research to be done, new protocols to be developed for patients on wait lists, and prevention and treatment strategies to be considered and implemented for solid-organ transplant recipients with new infections.

Timely detection of symptoms of COVID-19 infection, treatment, and preventative measures in patients who underwent KT from living related donors resulted in decreased numbers of complications of COVID-19 at our center.

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