The document discusses management of kidney transplant recipients during the COVID-19 pandemic. It notes that transplantation programs have been reduced due to shortages of facilities and personnel devoted to COVID-19 care. Kidney transplant recipients are at high risk for COVID-19 infection due to immunosuppression. The challenge is controlling infection while maintaining immunosuppression to protect the transplant. The document reviews medications used to treat COVID-19 and potential interactions with immunosuppressive drugs in kidney transplant patients.

2.  Infection with atypical form of pneumonia in a large scale of
population was reported in Wuhan on December 31, 2019 .
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)
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2019. N Engl J Med 2020. DOI: 10.1056/NEJMoa2001017

3.  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
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4.  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.

5.  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
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kidney disease. Kidney Int 2020. DOI: 10.1016/j. kint.2020.03.001

6. 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
 . In Middle East, including Egypt, transplantation rates have been decreased significantly
in comparison with 2019
 Zidan A, Alabbad S, Tariq A. Position statement of transplant activity in the Middle East
in era of COVID-19 pandemic, transplantation. June 9, 2020. DOI:
10.1097/TP.0000000000003348

7. 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

8. 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].

9.  Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P. et al... In vitro antiviral activity and projection of
optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory
syndrome coronavirus 2 (SARS-CoV2). Clin Infect Dis 2020. DOI: 10.1093/cid/ciaa237
 27 Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M. et al... Hydroxychloroquine and
azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int
J Antimicrob Agents 2020. DOI: 10.1101/2020.03.16.20037135
 28 Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D. et al... Efficacy of hydroxychloroquine in patients
with COVID-19: results of a randomized clinical trial. MedRxiv 2020. DOI:
10.1101/2020.03.22.20040758
 29 Heckman-Stoddard BM, DeCensi A, Sahasrabuddhe VV, Ford LG. Repurposing metformin for the
prevention of cancer and cancer recurrence. Diabetologia 2017. 60:1639–1647. DOI:
10.1007/s00125- 017-4372-6
 30 Mehra MR. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of
COVID-19: a multinational registry analysis. Lancet 2020. DOI: 10.1016/S0140-6736(20)31180-6

10. Hydroxychloroquine
 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]

11.  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

12.  The COVID-19 treatment Guidelines Panel recommends against using lopinavir/ritonavir or other HIV protease inhibitors for the treatment of COVID-19,except in a clinical trial.
 raise concerns about whether it is possible to achieve drug concentrations that can inhibit the SARS-CoV-2 proteases.
 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 Table 1 Difference between
COVID-19, Pneumocystis jirovecii, and CMV infection among kidney transplant recipients (21–24) COVID-19 Pneumocystis jirovecii CMV Risky group All KTrs. Elderly, diabetic, cancer patients Severely
immunosuppressed patients with low CD4 count CMV IgG negative recipients with IgG positive donors Clinical data Fever is mild Cough, chest tightness Fever is mild to high, cough, chest tightness Fever, cough
chest tightness Extrapulmonary Acute kidney injury CMV can involve all organs Laboratory investigations Leucopenia Lymphocytopenia Positive throat and nasopharyngeal swabs for SARS-Cov-2 RNA Leucopenia
Lymphocytopenia Low CD4 count LDH increased Trophozites and cysts in BAL Leucopenia Neutopenia CMV inclusion bodies CMV RNA detection in blood Radiological findings Peripheral consolidation and ground
glass appearance Diffuse ground glass appearance which may be central and sparing periphery, rare consolidation Diffuse ground galss appearance and large consolidation Specific treatment No specific treatment
Sulfamethoxazole Pentamidine Clindamycin Caspofungin Ganciclovir, Valgancyclovir, Foscarnet, Cidofovir CMV, cytomegalovirus; IgG, immunoglobulin G; KTRs, kidney transplant recipients. 226 Journal of The
Egyptian Society of Nephrology and Transplantation, Vol. 20 No. 4, October-December 2020 [Downloaded free from http://www.jesnt.eg.net on Wednesday, October 28, 2020, IP: 196.154.141.223]
immunosuppressive medications (tacrolimus, cyclosporine and sirolimus) is needed to reach accepted trough level when combined with RTVboosted proteinase inhibitors [43,44]
Lopinavir/Ritonavir

13. Lopinavir/Ritonavir
 . 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]

14. Tocilizumab
 A hummanized 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 hyperactivated immune system [49–51]. However, there are no data to
prove a drug-drug interaction between tocilizumab and immunosuppressive
medications [40]

15. Remdesivir
 Remdesivir binds to the viral RNA-dependent RNA polymerase, inhibiting viral replication through
premature termination of RNA transcription.
 It has been studied in several clinical trials for the treatment of COVID-19.
 It is available through the Food and Drug Administration (FDA) Emergency Use Authorization (EUA) for
people
 with severe COVID-19

16.  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

17. Remdesivir
 Remdesivir COVID-19 Emergency Use Authorization Expanded
 Remdesivir was FDA-approved for the treatment of coronavirus disease 2019 (COVID-19) in
hospitalized adult and pediatric patients (≥12 years of age and weighing ≥40 kg).
 The emergency use (EUA) authorization continues to allow for remdesivir (lyophilized
powder only) to be used by licensed health care providers for the treatment of suspected
or laboratory-confirmed COVID-19 in hospitalized pediatric patients weighing ≥3.5 kg.

18. Remdesivir
Drug – drug interactions
 Concomitant Use With Chloroquine or Hydroxychloroquine
 The FDA is warning health care providers that co-administration of remdesivir and chloroquine
phosphate or hydroxychloroquine sulfate is not recommended as it may result in reduced antiviral
activity of remdesivir.
 Health care providers should review the most up-to-date fact sheet when prescribing remdesivir.

19. Remdesivir
 Infusion-related and anaphylactic reactions
 Slowing infusion rate (maximum infusion time: 120 minutes) may be considered to
potentially prevent these reactions.

20. 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 .

21.  In the early days of the SARS-CoV-2 pandemic, based on experience in both SARS and
MERS, recommendations cautioned against the use of systemic corticosteroids due to
risk of worsening clinical status, delayed viral clearance, and adverse events.
 The Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial, a multicenter,
randomized, open-label trial in hospitalized patients with COVID-19, showed that the
mortality from COVID-19 was lower among patients who were randomized to receive
dexamethasone than among those who received the standard of care also the
duration of mechanical ventilation.

22. 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.

23. Suggested proposal for immunosuppressive
medications modulations in COVID-19 infected
kidney transplant recipients.