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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 20  |  Issue : 4  |  Page : 224-231

COVID-19 and kidney transplantation: how to face the disaster?


Nephrology Department, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt

Date of Submission21-Jun-2020
Date of Acceptance25-Jun-2020
Date of Web Publication16-Oct-2020

Correspondence Address:
Dr. Hussein A Sheashaa
Department of Nephrology and Internal Medicine, Urology and Nephrology Center, Mansoura University, Mansoura, 35516
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jesnt.jesnt_23_20

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  Abstract 


There is no doubt that pandemic of COVID-19 caused by SARS-CoV-2 virus is a real disaster, which has affected all aspects of medical field. Kidney transplantation program has faced many problems during COVID-19 pandemic. The program has been cut down in many centers all over the world. Shortage of medical facilities, which have been directed to COVID-19 care, unavailability of ICU beds, and redirection of medical personnel to combat against COVID-19 are restrictions against continuity of the transplantation program. Transplantation is surrounded by many safety issues, as donor–recipient COVID-19 transmission is not well defined till now. Being immunocomprised, kidney transplant recipients are at high risk for infection. The immune state may alter the presentation and prognosis of disease in that particular population. The challenge is to keep the graft well functioning while the patient recovers rapidly from infection which requires meticulous manipulation of immunosuppressive medications. Herein, we discuss the effect of COVID-19 pandemic on kidney transplantation and the available treatment plans for infected kidney transplant recipients.

Keywords: COVID-19, kidney transplantation, pneumonia, post renal transplantation complications, viral infection


How to cite this article:
Elmowafy AY, Denewar AA, Mashaly ME, Osama M, Donia AF, Refaie AF, Sheashaa HA. COVID-19 and kidney transplantation: how to face the disaster?. J Egypt Soc Nephrol Transplant 2020;20:224-31

How to cite this URL:
Elmowafy AY, Denewar AA, Mashaly ME, Osama M, Donia AF, Refaie AF, Sheashaa HA. COVID-19 and kidney transplantation: how to face the disaster?. J Egypt Soc Nephrol Transplant [serial online] 2020 [cited 2020 Oct 23];20:224-31. Available from: http://www.jesnt.eg.net/text.asp?2020/20/4/224/298253




  Introduction Top


Infection with atypical form of pneumonia in a large scale of population was reported in Wuhan on December 31, 2019 [1]. The suspected organism causing pneumonia was discovered as coronavirus, and then it was named severe acute respiratory syndrome type 2 (SARS-CoV-2), causing a disease called Coronavirus Disease 2019 (COVID-19) [2].

The pandemic of COVID-19 emerged very fast, and limited data about the disease are present. It is supposed that immunocompromised patients and patients with multiple comorbidities are at high risk for infection and disease progression. The disease has incubation period ranging from 1 to 14 days with an average of 5–6 days. Symptoms vary from mild (fever, cough, and malaise) to severe (pneumonia and hypoxemia). Patients with mild symptoms may be home isolated and those with severe symptoms need hospitalization. Pregnant women, newborns, the elderly, immunocompromised, and patients with comorbidities such as diabetes mellitus, hypertension, and cardiovascular disease, are more to be infected by COVID-19, and they are more likely to experience severe illness that often requires being admitted to ICU [3].

Kidney transplantation is known to be the best treatment modality for dialysis patients. However, during pandemics, many safety issues will be raised. Immunosuppressive state of kidney transplant recipients will alter the presentation of COVID-19 and the prognosis will be more unpredictable. For example, lymphopenia is present in 63% of patients with COVID-19. However, in kidney transplant recipients (KTRs), it may be drug induced. The state of immunosuppression may worsen the condition. Immunosuppressive medications need special manipulation during this pandemic. So, special concerns should be raised for those particular populations [4].

This review focuses on the effect of COVID-19 on renal transplantation in the following domains: first, concerns about transplantation program; second, concerns about SARS-CoV-2 and kidney transplant recipients; third, concerns about treatment of COVID-19 among kidney transplant recipients; and fourth, concerns about COVID-19 and kidney donation.

Cut down of transplantation program during COVID-19 outbreaks

Transplantation program faces many difficulties during this pandemic. These difficulties included shortage in hospital facilities as most facilities are directed to treat COVID-19, prioritization of ICU for COVID-19 patients, unknown risk of donor–recipient transmission, unknown method for immunosuppressive medication modulation. and the risk versus benefit of adding new immunocompromised patient to the society [5]. Kidney transplantation is not a safe procedure in pandemic areas except in emergencies as in case of difficult vascular access [6].

Transplant center should weigh the risk versus benefit from continuing transplantation. For example, Ospedale Maggiore Policlinico in Milan adapted local policy for liver transplantation, limiting liver transplantation to the most urgent cases [7]. In the USA, a report by Boyarsky et al. [8] studied the effect of COVID-19 on transplant program. They found that 71.8% of living donor kidney transplant programs were fully suspended, whereas 80.2% of deceased donor programs were operating with major restrictions. Examples of living donor kidney transplantation restrictions included transplanting only preemptive KTs, well-recipients, and those with lack of dialysis access. Some restrictions were driven by limited operating room staffing. Common deceased donor kidney transplantation (DDKT) restrictions included transplanting only highly sensitized patients, those with negative cross-match, higher acuity patients, and those without dialysis access. Transplantation needs faced many limitations. Overall, 98.2% of outpatient visits were limited. There were deficiencies in personal protective equipment (PPEs), blood products, negative pressure wards, and ICU beds [8]. In Middle East, including Egypt, transplantation rates have been decreased significantly in comparison with 2019 [9].

Transplantations may add some burden to the society during pandemics such as introducing immunosuppression into patients in the midst of a pandemic, rationing of healthcare resources including both inpatient and outpatient resources, and also may cause deficiency in ventilator capacities. Transplant level activities may be reduced by 25 up to 100% according to the extent to which the healthcare system is overwhelmed by COVID-19 outbreak [10].

The transplant team is also at risk (teams traveling for donor procurement to areas of high risk, team performing high-risk procedures such a bronchoscopies on deceased donors, and team exposures to transplant recipients). Anxiety and distress related to COVID-19 among transplant team will be associated with poor outcome [10].

Effect of SARS-CoV-2 on kidney transplant recipients

SARS-CoV-2 is characterized by its high virulence with increased risk of developing pneumonia after infection. It may also invade other organs of gastrointestinal system [11],[12].

Detection methods for SARS-CoV-2 among kidney transplant recipients are similar to that for general population. Virus nucleic acid detection via real-time PCR (RT-PCR) has the highest sensitivity and specificity. Samples could be obtained from throat swabs and nasopharyngeal swabs. Its sensitivity varies according to the site of sampling (32% for throat swabs, 63% for nasal swabs, 72% for sputum, and 93% for broncho-alveolar lavage). Virus nucleic acid could be also detected by antigen tests (sensitivity about 70–90%). Moreover, it offers rapid detection (within 4–6 h). Virus culture takes about 2–3 weeks. Detection of SARS-Cov-2 antibodies (immunoglobulin G and immunoglobulin M) is another method for detection with less sensitivity and specificity (30%). Detection of inclusion bodies in lung tissue is possible but needs invasive technique [13],[14].

SARS-CoV-2 incubation period ranges from 3 to 7 days, but some in some cases, it was 1 day, and in other cases, it was 24 days. That is why it is recommended to closely observe or isolate those who travel to endemic areas or who get in contact with infected person for 14 days [15]. Viral pneumonia among kidney transplant recipients has weak seasonality, as it can occur throughout the year [16]. COVID-19 pneumonia among kidney transplant recipients is characterizes by variability of symptoms. Dry cough is a common symptom. Fever is present in most of the cases. Diarrhea and other gastrointestinal symptoms have been association with the incidence of COVID-19 among kidney transplant recipients. Other symptoms include easy fatigability, bone aches, bone aches, and anosmia. In general, COVID-19 pneumonia among kidney transplant recipients is characterized by cough, chest tightness, progressive shortness of breath, and fever [17]. Symptoms may be very mild, but the patient shows rapid deterioration [18]. Incidence of pneumonia is relatively higher in patients infected with SARS-CoV-2 than other respiratory viruses as this virus has high pathogenicity, and this may be the cause for the poor prognosis and delayed recovery. Moreover, kidney transplant recipients are liable to increased incidence of complications such as extensive pneumonia and respiratory failure when compared with general population [19].

Early after transplantation, respiratory viral infections may cause rejection among renal transplant recipients owing to molecular cross reactivity [20].

Radiological findings of SARS-CoV-2 among kidney transplant recipients are varied. The findings may be ground glass appearance, patches of consolidation, or pleural effusion. Infiltrations may be multiple and peripheral [21],[22].

[Table 1] illustrates the differences between COVID-19-, Pneumocystis Jirovecii-, and CMV-induced pneumonia [23],[24],[25].
Table 1 Difference between COVID-19, Pneumocystis jirovecii, and CMV infection among kidney transplant recipients (21–24)

Click here to view


Management of kidney transplant recipients infected with SARS-CoV-2

There is no specific prophylaxis against COVID-19 in general till now. The best prophylaxis is to avoid coming in contact with the virus [25].

Hydroxychloroquine

Mechanism of action of hydroxychloroquine against COVID-19 is not well established. However, it may induce changes in pH of cell membrane surface, thus preventing viral fusion. Other theories suggest that it inhibit nucleic acid replication, viral assembly, and release [26]. Since the beginning of the pandemic, hydroxychloroquine became a basic medication in any treatment plan. A recent French clinical trial reported significant reduction of viral load with hydroxychloroquine [27]. Other reports showed conflicting results [28],[29].

A report was published in Lancet on May 22, 2020 against the use of hydroxychloroquine, containing data from a large registry. However, it was retracted soon after owing to significant methodology defect [30]. Hydroxychloroquine may lead to different types of arrhythmias such as prolonged QT interval and torsades de pointes. The incidence of arrhythmias reached 10% of population in many studies [31]. The studies comparing between hydroxychloroquine and placebo as prophylaxis showed no difference between both groups, and patients who received hydroxychloroquine had more adverse events [32],[33].

Hydroxychloroquine undergoes hepatic metabolism as a substrate of CYP2D6 and undergoes renal excretion via urine (15–25%) in metabolits and unchanged drug forms [34].

Hydroxychloroquine has no direct interaction with calcineurin inhibitors (CNI) inhibitors, and no effect on drug doses or trough level has been observed, but hydroxychloroquine is N-dealkylated by CYP3A4 to the active metabolites, so interaction with cyclosporine is possible. Both hydroxychloroquine and mycophenolate mofetil have common hematopoietic adverse effects including leucopenia and bone marrow failure. The most important dug-drug interaction is QT prolongation and torsade de pointes with tacrolimus, cyclosporine, and sirolimus [35],[36].

Lopinavir/ritonavir and darunavir

Protease inhibitors inhibit important enzyme in CoV protein processing called proteinase, and low concentrations of SARS-CoV-1 were reported with lopinavir [37],[38]. The results of different studies about the use of anti-HIV in treating COVID-19 are conflicting. Some researchers suggested that darunavir inhibits COVID-19 in vitro, whereas others found no beneficial effect in treating patients with lopinavir and ritonavir (RTV) [39],[40],[41].

Lopinavir is boosted by RTV and cobicistat (COB), which inhibit cytochrome P3A4, thus affecting the trough level of different immunosuppressive medications [42]. Dramatic lowering of immunosuppressive medications (tacrolimus, cyclosporine and sirolimus) is needed to reach accepted trough level when combined with RTV-boosted proteinase inhibitors [43],[44]. No changes in the dose of antiproliferatives are needed when combined with ritonavir. However, it is suggested to stop antiproliferative during infection episodes in general [45].

Favipravir

Favipiravir (T705), a purine nucleic acid analog, is considered to be tested in clinical trials [46]. Faviprevir was tested against lopinavir/RTV in one study, including 80 patients, and favipiravir group showed faster viral clearance [47]. In another trial, no difference was found between a group that received favipiravir and another group that received arabidol, except for faster relieve of symptoms with favipiravir [48]. Favipiravir has no significant interaction with immunosuppressive medications.

Tocilizumab

A humanized monoclonal antibody called tocilizumab used in treating autoimmune diseases can bind to interleukin-6 receptors (membrane type); thus, it inhibits the release of inflammatory mediators and suppresses cytokine storm triggered by hyper-activated immune system [49],[50],[51]. However, there are no data to prove a drug-drug interaction between tocilizumab and immunosuppressive medications [40].

Remdesivir

This is the prodrug of a nucleotide analog with potent activity in vitro against a broad spectrum of virus RNA. It performs its action by disruption of RNA transcription [52]. It can be given at a dose of 200 mg loading dose for 1 day and then maintenance for 9 days at 100 mg intravenously [3]. Wang and his colleagues in February 2020 reported that remdesivir and chloroquine have potent effect against novel coronavirus (2019-nCoV) in vitro [53]. However, they did not find a clinical difference between remdesivir and placebo in treating severely ill patients with COVID-19 in a randomized clinical trial including 237 divided into two groups [54]. Grein et al. [55] reported significant improvement in some cases of COVID-19.

Intravenous immunoglobulin

Up to date, there is no strong evidence for the use of IVIG in treating COVID-19 kidney transplant recipients except in a case report [56].

Convalescent plasma

The use of convalescent plasma from recovered patients has been approved by US Food and Drug Administration as a treatment for severe ill patients on an individual basis [57]. Duan et al. [58] suggested therapeutic effect of convalescent plasma in treating severely ill patients. The exact dose and timing is not well defined. Another study by Shen et al. [59] reported that treatment of critical ill cases responded to convalescent plasma. However, a large randomized clinical trial (103 patients into two groups) by Ling et al. [60] found no statistical significant improvement in time to clinical improvement between a group that used convalescent plasma in addition to standard treatment and a control group that used standard plasma alone.

Dexamthasone

Dexamethasone has been shown to reduce mortality in critically ill patients necessitating ICU admission at a percent of average 17% and also has been shown to reduce hospitalization by ∼5%. It has been noted that its application was mainly for oxygen-dependent patients with respiratory failure [61].

Immunosuppressive medication modulations in COVID-19 kidney transplant recipients

Having anti-inflammatory effects, from decreasing of cytokine release to preservations of endothelium integrity and permeability, it is suggested to continue methyl prednisilone at dose of 20–40 mg/day [62].

Till now, there is little evidence regarding minimizing immunosuppressive medication doses. Tacrolimus doses could be maintained on the same doses if the patient is not severely ill and can be decreased or halved in critically ill patients. Precautions must be taken regarding tacrolimus, cyclosporine, and sirolimus trough levels when administering hydroxychloroquine or RTV. Antiproliferative medications are supposed to be suspended during illness [3].

Sanchez and colleagues suggest cyclosporine A as a treatment of COVID-19 and to be tested in randomized clinical trials owing to its protective effect against COVID-19-induced cytokine storm in patients with COVID-19 [62].

Belatacept causes blockade of massive cytokine/chemokine production. So, infected patients receiving belatacept showed mild symptoms [63]. To decrease nosocomial infection during outbreaks, some suggest giving belatacept monthly [64]. In another case report, belatacept was replaced with cyclosporine A during outbreaks [65]. Sirolimus should be suspended during COVID-19 outbreaks, as it may cause pneumonitis, which could be misdiagnosis as suspicious for COVID-19. All immunosuppressive medications should be suspended in critical ill patients.

[Figure 1] represents a suggested proposal for immunosuppressive medication modulation in COVID-19 kidney transplant recipients.
Figure 1 Suggested proposal for immunosuppressive medications modulations in COVID-19 infected kidney transplant recipients.

Click here to view


Vaccination of kidney transplantation during COVID-19 outbreak

There is no evidence about the protective effect of streptococcus vaccine against SARS-CoV-2. Up to date, there are no recommendations against giving the immune-compromised patients the routine vaccines during COVID-19 outbreak [66].

Kidney donation in the era of COVID-19

The risk of donor–recipient transmission is still unknown. The risk of transmission is dependant mainly on the state of infection in donor side. In general, viability of virus in specific organ determines its ability to be transmitted via different organs [64].

UK National Health Service Blood and Transplant Organ Donation and Transplantation have recommended in their guidelines screening the donors for SARS-CoV-2, as one of the risk factors for developing COVID among renal transplant recipients is donor transmission. This represents a big problem in pandemic areas; thus, they suspended transplantation program and suggested that careful selection of donor–recipient pairs is not applicable during pandemics [67].

Each country should adopt its policy for kidney donation during COVID-19. In Saudi Arabia, they accepted deceased donation during the outbreak. The donors were screened for COVID-19 by nasopharyngeal and throat swab before donation. Live donors were rejected. In Egypt, live donation decreased significantly [9].

The risk for developing COVID-19 or other serious illness will not increase by kidney donation as the ability to combat against infection will not be affected by the process of kidney donation. The National Health Service for Blood and Transplant published against any false information about the additional risk of living kidney donation for COVID-19, and donors are not in need for additional protection, only if they have other risk factors than donation [68].


  Conclusion Top


Every transplant center should put its local policy about transplantation depending on the state of epidemic in the country. Nowadays, transplantation program in Egypt should be limited to urgent cases. We suggest lowering the threshold for diagnosis of COVID-19 among renal transplant recipient. Handling and manipulation of immunosuppressant during COVID-19 infection is an art, and it is the key for recovery from infection with preservation of graft function. We suggest stopping antiproliferatives in mild cases with other comorbidities and in severe cases and low trough level (2–4 ng/dl) for infected kidney transplant recipients. Our recommendation is toward shifting from sirolimus to calcineurin inhibitors during the outbreak as sirolimus may cause pneumonitis which may be misdiagnosed as suspicious for COVID-19. Treatment choice should be individualized according to infection state, presence of comorbidities, immunosuppressive medications, and drug availability in each country. Future randomized clinical trials are needed to determine the risk of donor–recipient transmission.

Acknowledgements

Ahmed Y. Elmowafy wrote the article; Ahmed A.-F. Denewar edited the article; and Mohamed E. Mashaly and Mohamed Osama retrieved and collected the literatures; Ahmed F. Donia and Ayman F. Refaie are responsible for the integrity of the article; Hussein A. Sheashaa revised and edited the article; The manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met, and that each author believes that the manuscript represents honest work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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