Ever since the severe acute respiratory syndrome virus causing coronavirus disease 2019 (COVID-19) struck the world, global health strategies have changed significantly. According to the Centers for Disease Control and Prevention, kidney transplant recipients are stratified as being high risk of developing fatal illness from COVID-19 infection. Kidney transplant is the gold-standard treatment for end-stage kidney disease subjects. During the pandemic, significant concerns have emerged regarding continuation of kidney transplant surgeries and management of kidney transplant recipients post-transplant. The added risk of immunosuppression in this cohort was and remains a theoretical concern, posing a potential risk of transplantation rather than benefit. This comprehensive review aims to cover most of the faced challenges in kidney transplantation in different stages of the pandemic. In addition, it will elucidate the epidemiology, nature, course of the disease, surgical consideration in donors and recipients as well as role of immunosuppression and management of COVID-19 infected kidney transplant recipients during these extraordinary circumstances.

Coronavirus disease 2019 (COVID-19) has had a substantial international impact as the world is trying to learn how to manage this deadly disease. The virus was initially identified in Wuhan, China in 2019 and was thought to originate from a zoonotic etiology. It has now spread across borders and the United States of America alone has had over 25 million people infected, causing 400000 deaths[1]. One of the more deadly aspects of COVID-19, which has also led to many hospitalizations, is that it can cause a severe respiratory disease known as severe acute respiratory disease syndrome coronavirus 2 (SARS-CoV-2). The virus enters its host via the angiotensin-converting enzyme 2 receptors, which are very prominent in the lung's alveolar cells. The virus then causes pneumonia, which may lead to the often-fatal acute respiratory disease syndrome. Another possible complication of COVID-19 is a cytokine storm syndrome caused by a hypersensitive response to the virus, leading to multiorgan damage and failure, which may also be fatal[2,3].

In patients with end-organ damage, organ transplantation has become very common in treatment. Kidney failure is a prevalent complication of uncontrolled diabetes mellitus and hypertension. Many patients with chronic kidney disease progress to an end-stage renal disease characterized by a glomerular filtration rate of less than 15 mL/min. During this state, the body is unable to remove urinary substances and toxins. The only treatment in these situations is hemodialysis, which allows for extracorporeal renal replacement, or renal transplantation. Renal transplantation is more cost-effective and provides a higher quality of life to patients, but the major limitation would be obtaining a compatible kidney[4,5] and organ donation supply.

After kidney transplantation, post-transplant immunosuppressive therapy is the gold standard of treatment. The induction therapy generally starts with either lymphocyte depleting antibodies or non-depleting antibodies. This is then followed by a triple-drug regimen consisting of steroids, a calcineurin inhibitor, and an antiproliferative agent. This treatment reduces the risk of rejection and increases infection risk; hence, balance is essential between the risks and benefits. It is unclear if this level of immunosuppression would decrease the chance of a cytokine storm flair.

Kidney transplant recipients are considered to carry a higher risk for complicated COVID-19 viral infection. Other significant comorbidities including obesity, diabetes mellitus, and chronic obstructive lung disease are predisposing factors for higher risk of getting COVID-19 disease[6].

Upon literature review, many case series had shown a particularly higher mortality rate in kidney recipient patients with COVID-19 disease (e.g., a case series of 36 patients reported in Montefiore Medical Center in New York[7] and another 15 kidney transplant recipients reported in Columbia University[8]. Moreover, multiple case series were reported in Europe (e.g., 7 patients reported by St. George's University Hospital in London, United Kingdom)[9]. In these reports, mortality rates ranged between 20% and 28% compared to the general population's general mortality reports, which fluctuate between < 1% to 5%.

Almost all the previous studies revealed that the COVID-19 viral loads and the mortality rates were significantly higher in kidney transplant patients who had moderate to severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome as compared to immunocompetent people[10].

Fever, shortness of breath, and cough were the most common presenting symptoms, while portable chest x-ray abnormality was the main radiological finding. Other common features included elevated C-reactive protein, low lymphocyte count (lymphopenia), and increased ferritin level[11].

The World Health Organization has recommended using personal protective equipment in addition to recommending against routine or nonemergent procedures during COVID-19 pandemic. The use of procedures causing aerosolization, such as endotracheal intubation, high flow respirators, and suction, poses an imminent risk of spreading the disease. The increasing mechanical ventilation requirement in intensive care units may limit the number of ventilators for routine procedures[21]. Despite the limitations mentioned above, some procedures, including emergency surgeries, transplant surgeries, and cancer surgeries, should be continued as lack of such services would increase morbidity and mortality. The anecdotal evidence of routine surgeries, including cholecystectomy in COVID-19 patients, have shown unfavorable outcomes[22]. Careful planning for anesthesia may help mitigate the spread during the procedure. Filtering face piece during intubation, use of disposable equipment, rapid sequence intubation avoiding manual ventilation, and the closed suction system are some of the proposed ways to prevent the spread of COVID-19[23]. The use of agents containing 62%-71% ethanol, 0.5% hydrogen peroxide, or 0.1% sodium hypochlorite effectively decreases transmission of COVID-19 in operating theatres[24]. The American Red Cross recommends a 28-d delay for donors traveling to high-risk regions or contact with COVID-19 patients[15]. The presence of a false-negative reverse transcription-PCR for COVID-19 causes the missing COVID-19 infection in both donors and recipients. Transplanted patients in the immediate postoperative period are immunocompromised and thus have a higher susceptibility of COVID-19[25]. The requirement to monitor COVID-19 cases and restrict transplants to emergencies in case of increasing COVID-19 cases has also been proposed to decrease the spread of COVID-19[26]. Further research has to be undertaken to assess postoperative complications and risk stratification strategies in COVID-19 patients[27].

Kidney transplant recipients pose a particular risk because of their steady-state of immunosuppression[28]. Kidney transplant patients who contract COVID-19 are at a higher risk of developing acute kidney injury and mortality[17]. There is no global consensus on the ideal management of kidney transplant recipients with COVID-19 disease, so patients are dealt with individually from case to case. Essential aspects of the treatment are managing immunosuppression medications and considering drug-drug interactions. In kidney transplant patients, the most commonly used immunosuppressive drugs [mycophenolate mofetil (MMF), tacrolimus, and cyclosporine] have a narrow therapeutic index and fluctuating pharmacokinetics[29,30]. Mycophenolate, which inhibits T and B cell proliferation, is always withheld[31,32]. Calcineurin inhibitors (CNIs) are substrates for cytochrome P450 3Y4. Moreover, cyclosporine further inhibits cytochrome P450 (CYP) 2C9, CYP3A4, and organic anion-transporting peptides (OATP) 1B1/1B3. MMF is a substrate of OATP and uridine diphosphate-glucuronosyltransferase enzymes. Significant drug-drug interactions are tabulated in Table 1.

Remdesivir and favipiravir are analogs of adenosine that inhibit SARS-CoV-2 RNA-dependent RNA polymerase, which is needed to replicate the virus[33]. Remdesivir is beneficial, especially in severe cases of COVID-19 infection. However, its effect is not studied in those patients with estimated glomerular filtration rate < 30 mL/min per 1.73 m², and it serves as an exclusion criterion for treatment[33,34]. As of February 2021, remdesivir is the only Food and Drug Administration-approved antiviral drug used for hospitalized adults and children with severe infection (low O₂ saturations, requiring significant supplemental oxygen, needing mechanical ventilation) for reducing time to recovery[35]. In vitro, remdesivir serves as a substrate of CYP3A4 and the drug carriers OATP1B and P-glycoprotein. It also acts as an inhibitor of multiple enzymes, including OATP1B1, CYP3A4, OATP1B3, and multidrug and toxin extrusion protein 1[36]. Favipiravir is more beneficial at least than lopinavir–ritonavir, and its use is authorized in China from February 2020[37]. Although there are no clear drug-drug interactions between remdesivir and other immunosuppressive agents, careful monitoring of the drug levels is needed given the lack of sufficient data.

Transferring a passive immunity from a healed patient through convalescent plasma has shown promising results, and more trials are underway[51,52].

The first COVID-19 vaccines were given in the United States in December of 2020. The vaccines used new technology with messenger RNA. These vaccines were initially targeted for the geriatric population and later to those of high risk, eventually making it down to the general public. Amongst this population of high-risk patients was where those with organ transplants reside.

Many studies were published regarding this population. Renal function should be closely monitored after the vaccine as there is an increased chance of rejection, especially if booster vaccines may be required[53]. Because this group is immunocompromised, there was concern that their body would not be able to elicit an appropriate response to make antibodies. A study published in kidney international showed that 85% of patients had made the appropriate antibodies 6 mo after the vaccines[54]. Another study in Germany demonstrated that 22% of the post-renal transplant patients had antibodies but were only tested 2 wk after vaccination[55]. The efficacy is not very clear in this immunocompromised population. In patients who have received the vaccine and had worsening kidney function, pulsatile steroids were given to a patient whose creatinine was increased and showed marked improvement[53]. The best solution would appear to be to get the vaccine but still abide by other appropriate precautions such as social distancing, face coverings, and hand hygiene[56].

Patients on immunosuppression are generally advised to spend as much time at home as possible unless it is essential to go outside. The patient should also play their role in spreading awareness among their community about physical distancing and personal hygiene such as frequent hand washing. If needed to go outside at all, they must wear facemasks and get vaccinated when possible. If a transplant recipient has tested positive for COVID but having mild or no symptoms, staying home and have a telephonic follow-up every 24-48 h is recommended. Patients should have frequent temperature checks and observe symptoms. If symptoms are progressing, patients must contact a healthcare worker as soon as possible for an assessment. Generally, patients are advised to reduce prednisone to 0.2 mg/kg per day but not stop it abruptly. Similarly, consideration should be given to stopping/reducing antimetabolites[32].

Immunocompromised patients are considered to be at high risk for severe disease from COVID-19 infection. Solid organ transplant recipients are of particular concern given the need to balance the potential for acute rejection and compromised immune response to a viral infection. There is currently inconclusive literature available to guide the optimal management of COVID-19 infection and baseline immunosuppression in renal transplant patients.

Ramoz et al[57] summarized 40 published cases detailing immunosuppression regimen management in renal transplant recipients with COVID-19 infection. Calcineurin inhibitors and antiproliferative therapy were discontinued in 75% of patients, whereas only 7.5% of patients were managed with no change in their baseline regimen. None of the patients treated without modification in their immunosuppressive therapy required mechanical ventilation[58-60].

Before the publication of the RECOVERY trial, which demonstrated lower 28-d mortality with the use of dexamethasone, a select group of patients were successfully managed with corticosteroid-sparing regimens. An example of such regimens consisted of dose-reduced antiproliferative therapy from mycophenolic acid 540 mg twice daily to 360 mg twice daily and decreased tacrolimus target trough levels from 6-8 ng/mL to 4-6 ng/mL[57,61]. The rationale for avoiding corticosteroids in these patients was based on the inconclusive evidence at the time supporting the use of corticosteroids coupled with the potential for decreased immune response, reduced pathogen clearance, promotion of secondary infections, and increased viral shedding.

An alternative strategy to manage immunosuppression is to follow a stepwise approach to reducing or holding the antimetabolite in moderate to severe COVID-19 infection[6]. Preference is generally given to the calcineurin inhibitor as they inhibit IL-6, IL-1, and tumor necrosis factor-α, inflammatory cytokines thought to contribute to the dysregulated immune response cytokine storm observed in severe COVID-19 infections[62]. According to recommendations from the American Society of Transplantation, patients receiving maintenance corticosteroids have generally been maintained during therapy[63]. In patients with unstable severe COVID-19 disease requiring mechanical ventilation, cessation of all immunosuppressive agents can be considered to initiate or continue corticosteroids[64]. For patients on dual therapy with an antimetabolite and calcineurin inhibitor, it may be reasonable to replace the antimetabolite with low-dose corticosteroids[64]. Although the optimal timing has yet to be established, immunosuppression can be cautiously resumed 5-15 d after resolving symptoms, starting with the calcineurin inhibitor[64].

The narrow therapeutic indexes and variable pharmacokinetic parameters of immunosuppressive medications used for renal transplant patients require careful screening and monitoring when used with specific agents[29,30]. Tacrolimus and cyclosporine are substrates of CYP3A4 and the P-glycoprotein efflux pump. Besides, cyclosporine weakly inhibits CYP2C9, CYP3A4, and OATP1B1/1B3, as well as P-glycoprotein. Mycophenolate is a substrate of specific OATP and uridine diphosphate-glucuronosyltransferase enzymes. As of January 2021, currently recommended therapies for COVID-19 include remdesivir and corticosteroids[65].

This comprehensive review covered most of the faced challenges in kidney transplantation in different stages of the pandemic. In addition, it elucidated the epidemiology, nature, course of the disease, surgical consideration in donors and recipients, as well as role of immunosuppression and management of COVID-19 infected kidney transplant recipients during these extraordinary circumstances.