The COVID-19 pandemic has created unprecedented challenges for solid organ transplant (SOT) programs. During the first months of the pandemic, most organ donation and transplantation programs reduced their activity, or suspended it altogether, due to the collapse of intensive care units and the almost exclusive dedication to the care of patients with COVID-19, especially severe in immunosuppressed individuals. Subsequently, activity has been recovering, and the transplant units have been adapting their programs to the new reality1,2 until the practical normalization of the activity.

It is well known that the incidence and mortality rate due to COVID-19 in the renal transplant population is higher than in the general population, and this worse prognosis has been associated with variables such as advanced age or severe pneumonia.3,4 For this reason, this was one of the groups prioritized to receive the first vaccines against SARS-CoV-2 in Spain.5 However, they have developed suboptimal immunization due to their inherent characteristics (immunosuppression, advanced age, chronic kidney disease [CKD]).6–8 This has meant that, despite high vaccination rates, renal transplant (RT) patients continue to have a higher rate of severe disease and even mortality due to SARS-CoV-2.9

This manuscript aims to update the recommendations already published in 202010 on SARS-CoV-2 infection in the RT-bearing population taking into account the current epidemiological context.

One of the most important concerns of those responsible for RT is the need for safety of living donors, recipients and healthcare personnel involved in this activity.11 Transmission of COVID-19 infection through organ transplantation is exceptional, and there is increasing experience with the use of kidneys from COVID-19 positive donors, with no adverse reactions reported in recipients.12,13

The National Transplant Organization (ONT), in collaboration with the Autonomous (Regional) Transplant Coordination Offices and the Corona-SOT Group, have prepared a document14 containing recommendations regarding organ donation and transplantation in relation to COVID-19 infection.

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  The use of face masks (preferably FFP2) is recommended in closed spaces or in crowded areas.

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  Maintain proper hygiene:

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    Wash hands frequently with soap and water for at least 20s, or else with an alcohol-based hand sanitizer (at least 60% alcohol), especially: after using the toilet, before eating, after blowing the nose, coughing or sneezing, and after direct contact with sick people or their environment.

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    Avoid touching eyes, nose and mouth before washing hands.

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  Avoid contact or maintain a distance of at least two meters with people suffering from symptoms of respiratory infection (fever, cough, generalized muscle pain, sore throat or respiratory distress), and do not share personal belongings with them.

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  Follow a correct diet. Avoid sharing food and utensils (cutlery, glasses, napkins, handkerchiefs, etc.) and other objects without cleaning them properly.

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  Avoid tobacco and alcohol consumption. In addition to being harmful to health, these substances weaken the immune system, making the body more vulnerable to infectious diseases.

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  Avoid large crowds. It is recommended not to attend places where there may be crowds or excessive contact with other people.

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  It is recommended to periodically ventilate the rooms with fresh air, open the windows.

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  When SARS-CoV-2 infection is suspected in a renal transplant patient, a diagnostic test for active infection should be performed: a rapid antigen detection test or a viral RNA detection test by RT-PCR in nasopharyngeal exudate.

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  In case of asymptomatic or mild infection, they should consult their transplant physician or primary care physician (preferably by telephone communication) for appropriate care.

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  In case of severe infection, the patient should go to the emergency department of the hospital of reference.

Despite the new treatments against SARS-CoV-2, which we will discuss later, patients receiving RT continue to be a very vulnerable group, with rates of progression to severe COVID-19 and mortality much higher than the general population.15 Therefore, it is essential to develop preventive measures in this group of patients.

Until recently, vaccination was the only immunization option available. However, the effect of immunosuppression has a negative impact on the serologic response to vaccination in transplant recipients.16–19 Data from the SENCOVAC study reveal that up to 37.6% of RT recipients did not develop antibodies after 2 doses of an mRNA vaccine, leading to the administration of a third and fourth dose.20–23 The recent development of monoclonal antibodies capable of blocking viral entry into host cells has provided a promising alternative in the immunization of transplant recipients.16,24

Monoclonal antibodies

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  Tixagevimab/cilgavimab (Evusheld®): It is a combination of two long-acting IgG1k monoclonal antibodies, cilgavimab and tixagevimab, derived from B cells from convalescent patients with SARS-CoV-2 infection that are indicated as pre-exposure prophylaxis in groups at risk of developing severe disease. In Spain, it has been included in the Vaccination Strategy against COVID-19 as a complement to vaccination in persons aged ≥ 12 years and weighing at least 40kg with a high degree of immunosuppression and who do not respond adequately to vaccination, among whom are SOT recipients.24 They should be administered as separate sequential intramuscular injections at different injection sites in two different muscles, preferably in the buttocks. The efficacy and safety of Evusheld® has been evaluated in the Phase 3 PROVENT trial,43 demonstrating an 83% reduction in the risk of severe disease. In this study, participants in the Evusheld® group suffered more serious cardiovascular events than those in the placebo group, although a causal relationship between Evusheld® and these events has not been established.43 Prior to administration, the person must have received at least 3 doses of the vaccine, unless it was contraindicated, and preferably have a serological test performed at least 15 days after administration. Until now, it had been established that an antibody titer to protein S of less than 260BAU/ml was considered an inadequate response to vaccination. However, since the threshold against the new variants of interest has not been validated, this figure can be considered indicative and the degree of immunosuppression of the patient and individual risk of infection should be taken into account. Additional candidates would be those persons at risk in whom it is not possible to complete the vaccination regimen, either because of contraindication to vaccines against COVID-19 or because they have developed serious adverse reactions associated with vaccination. In the case of recent SARS-CoV-2 infection, they can receive Evusheld® at least 6 months after infection.43 In the latest recommendations of the European Union Vaccination Registry and Program Panel, following the review performed in September 2022, the dose in pre-exposure prophylaxis is maintained at 300mg of Evusheld® (150mg tixagevimab and 150mg cilgavimab) recommending administration of new doses also of 150mg tixagevimab/150mg cilgavimab after 6 months of the first administration.42

Vaccination and passive immunization with monoclonal antibodies are not mutually exclusive (Fig. 1). Administration of monoclonal antibodies is advised at least 15 days after vaccination, whereas COVID-19 vaccines can be administered at the same time or at any time after administration of Evusheld®.42,44

Fig. 1.

Recommendations on the prevention and treatment of SARS-CoV-2 infection.

MAB: monoclonal antibodies; IL-6: Interleukin-6; JAK: Janus kinase.

1Vaccination and passive immunization with MAB are not mutually exclusive. At least 15 days after vaccination is advised to administer MAB; COVID-19 vaccines can be administered simultaneously or at any time after MAB.

2Avoid it if there are pharmacological interactions, so it is not usually indicated as a first option in transplant recipients. There are proposals for dose adjustment in GFR<30ml/min/1.73m2, that are not supported in clinical practice.52

3Although limited, some published experiences do not show greater toxicity in advanced CKD.54,55 Some guidelines propose its use with GFR<30ml/min/1.73m2, evaluating the risks-benefits.45

4Indicated, in general, if the anti-S IgG antibody response is considered inadequate for the patient's degree of immunosuppression (Table 2).

5Lower efficacy than other anti-COVID-19 therapies.

(0.19MB).

Information on the treatment of COVID-19 is continuously evolving. There are many ongoing randomized controlled studies of different therapies for SARS-CoV-2 infection, so the evidence in this field is rapidly changing. Currently, treatments widely recommended a few months ago, such as hydroxychloroquine, lopinavir/ritonavir, azithromycin or interferon, have been discarded due to lack of efficacy.15,16 The use of hyperimmune plasma is also increasingly discussed and was considered not to be indicated before the arrival of Omicron, however in the current epidemiological situation there is not enough data and therefore its use could be considered, together with other strategies, in situations of severe immunosuppression.15,16,45,46

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  Nirmatrelvir/ritonavir (Paxlovid®): Nirmatrelvir co-administered with ritonavir has demonstrated to produce a 89% reduction in hospitalization or death in patients with mild to moderate COVID-19 at risk of progression to severe disease when administered within 5 days of the onset of symptoms.48 However, ritonavir is a potent inhibitor of cytochrome P450 (CYP A3) and P-glycoprotein, leading to a strong interaction with calcineurin inhibitors and mTOR inhibitors, requiring temporary discontinuation and/or dose reduction of these immunosuppressants. Once treatment with ritonavir has been completed, CYP A3 activity needs a few days to recover. For these reasons, the administration of nirmatrelvir/ritonavir requires adjustment of the doses of immunosuppressants and monitoring the levels of these drugs, which may complicate their use in transplant patients with COVID-19, although it does not contraindicate it.49 The New York Presbyterian Hospital group has proposed a protocol for the management of tacrolimus and cyclosporine in patients treated with nirmatrelvir/ritonavir, and the published results are acceptable.49,50 However, the experience published so far in transplant recipients is very limited. The American Society of Transplantation recommends other treatments (MAB or remdesivir) in preference to nirmatrelvir/ritonavir, due to the mentioned risks associated with this drug, nevertheless it also suggests strategies for its use in case it is chosen.51 Moreover, in patients with moderate renal insufficiency the dose of this medication should be reduced (with a dose adjustment that has not been clinically tested) and is not recommended with estimated glomerular filtration rate (eGFR) below 30ml/min/1.73m2. Based on the pharmacology of nirmatrelvir, Hiremath et al make a proposal for dose adjustment in patients with eGFR less than 30ml/min/1.73m2 or on dialysis.52 However, so far there are no studies that support this proposal, so its use in these cases should be carried out with extreme caution, closely assessing risks and benefits and giving priority to other therapeutic options that are not contraindicated in advanced CKD.

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  Remdesivir (Veklury®): It is a viral RNA-dependent RNA polymerase inhibitor that inhibits virus replication, with in vitro activity against SARS-CoV-2. It has been shown to accelerate healing in hospitalized patients with COVID-19 pneumonia, especially in those who do not require oxygen or who require low-flow oxygen.45,46 More recently, the PINETREE study showed that a 3-day course of treatment in outpatients reduced the risk of hospitalization or death by 87% as compared to placebo.53 Based on this, a 3-day course of treatment with this antiviral is considered indicated in immunosuppressed patients at risk of progression to severe disease, such as transplant recipients, in the first 7 days from the onset of symptoms, if effective MAB treatments are not available.45–47 Clinical trials have excluded patients with eGFR less than 30ml/min/1.73m2. It has been proposed that remdesivir could cause dose-dependent tubular damage or by accumulation of the excipient sulfobutylether-beta-cyclodextrin in patients with decreased renal function, so it is considered contraindicated in these cases.15,16,45,46 However, the results are contradictory and recent experiences do not show greater toxicity when used in patients with advanced CKD.54,55 Therefore, the U.S. National Institute of Health (NIH) guidelines, raise the possibility of its use in patients with GFR less than 30ml/min/1.73m2 if it is considered that the benefits may outweigh the risk, and it should be discontinued if there is a greater than 10-fold increase in ALT values or other evidence of hepatic inflammation is detected.45

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  Molnupiravir (Lagevrio®): A ribonucleoside antiviral that has also been approved for patients with non-severe COVID-19, within 5 days of symptom onset; however it appears to be less effective than other antivirals and sotrovimab.56,57 It is not excreted through kidneys so it is considered safe for use regardless of renal function. It is contraindicated in pregnancy because it is teratogenic, and patients should be warned about this.45,46 Experience in transplant recipients is limited.58 It is recommended in those cases in which nirmatrelvir/ritonavir, sotrovimab or remdesivir cannot be used.15,16,45–47

In transplant patients the response to the vaccine is very poor, especially after 1 or 2 doses. In fact, the data from the COVID-19 registry of the Spanish Society of Nephrology showed no improvement of survival in renal transplant patients who had received two doses of vaccine versus those that did not receive the vaccine.9 This has generated great interest in passive immunization. MABs directed against the SARS-CoV-2 spike protein have emerged as a new therapy to reduce viral load and decrease the risk of progression to severe disease. Several formulations have been emerging in recent months (bamlanivimab, casirivimab/imdevimab, bamlanivimab-etesevimab, sotrovimab, bebtelovimab, tixagevimab/cilgavimab). They are anti-spike MABs designed to block the receptor-binding domain of the virus, thus interfering with its entry into the cell. They have demonstrated efficacy in hospitalized seronegative patients requiring low-flow oxygen.15,16,45,46 Some studies suggest an adverse effect if administered to patients who have developed endogenous neutralizing antibodies, although the possible mechanisms of this damage and whether or not it is specific to some MABs are unknown.45 In non-hospitalized patients with recent infection (3–7 days from symptom onset) and with risk factors for progression to severe forms of COVID-19, have been observed to significantly reduce this progression and reduce hospitalizations. However, the rapid emergence of mutations has meant that most of these MABs lack efficacy against new strains of the virus. Only sotrovimab, bebtelovimab and tixagevimab/cilgavimab have maintained potential activity against omicron, although with limitations that will be discussed below.15,16,45–47

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  Sotrovimab (Xevudy®): It is approved in Spain for the treatment COVID-19 in patients with negative or low titers antibodies against SARS-CoV-2 who present mild-moderate or severe disease, recent onset (5 days from the onset of symptoms) and risk factors for poor outcome (such as transplant recipients).47 We have recently reported experience with this MAB in 82 renal transplant recipients with COVID-19.59 We observed excellent tolerance even in patients with very high comorbidity or advanced stages of CKD, and administration in the early stages of the disease was associated with a decrease in the need for ventilatory support and less ICU admissions and mortality.

Sotrovimab has been designed to bind to a more conserved region of the receptor-binding domain present in other sarbecoviruses, conferring potential protection to maintain its activity against new mutations.47,59 However, its efficacy against the BA.2 subvariant is under discussion. Although in vitro studies show less neutralizing activity against these recent omicron sublineages, the in vivo effects are under investigation. Recent data reveal that, despite decreased neutralizing activity in cell culture, sotrovimab reduced virus and proinflammatory cytokine levels in the lung of BA.2-infected mice demonstrating these differences between loss of potency in vitro and protection maintained in vivo.60 However, the Food and Drug Administration (FDA) withdrew the authorization for use in the USA in April 2022.61 In contrast, in Europe, the European Medicines Agency (EMA) has maintained the authorization of sotrovimab based on the lack of knowledge about the clinical relevance of the decrease in neutralizing activity against omicron BA.2.62 A recent French multicenter study compared the efficacy of sotrovimab in preventing severe COVID-19 in high-risk patients infected with omicron BA.1 or BA.2, showing a low rate of hospitalizations and a similar reduction in nasopharyngeal viral load in both groups.63 The impact of the new omicron sublineages BA.2.11, BA.2.12.1 and BA.4/5 on the neutralizing capacity of Sotrovimab does not appear to be superior to that observed with BA.2. Early data on the recent BA.2.75 (centaurus) subvariant are contradictory: some results point to a loss of neutralizing activity that is lower than that detected with the previous omicron sublineages while other studies find very little activity.64,65 Updated information on the susceptibility of the different variants and subvariants of the virus to MAB can be found at https://covdb.stanford.edu/page/susceptibility-data/.

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  Bebtelovimab: in vitro data on this MAB suggest that it maintains its neutralizing activity against the new omicron subvariants, but there are no controlled studies available that evaluate its use in patients at high risk of progression to severe COVID-19.45,64 So far it has been evaluated only in low-risk patients showing good tolerance and a more rapid decrease in viral load as compared to placebo.45 It has been approved in the U.S. the use in the first 7 days of symptoms and only if nirmatrelvir/ritonavir or remdesivir are not considered appropriate. Initial experience in transplant patients shows results that appear similar to those obtained with other MABs.66,67 At the time of this review in September 2022, it has not been approved in Europe.

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  Tixagevimab/cilgavimab (Evusheld®): Tixagevimab shows significant loss in its neutralizing capacity against the new Omicron variants while for cilgavimab and the tixagevimab/cilgavimab combination the reduction of neutralizing capacity appears to be mild-moderate (https://covdb.stanford.edu/page/susceptibility-data/). Very recently the results of the TACKLE study have been published, this is a randomized versus placebo study in which patients, unvaccinated, with mild-moderate COVID-19 without oxygen requirement were treated with 600mg of tixagevimab/cilgavimab (2 consecutive intramuscular injections of 300mg cilgavimab and 300mg tixagevimab) in the first 7 days from onset of symptoms. The variants of virus preceded the omicron. Severe COVID-19 or death occurred in 4% of those treated with tixagevimab/cilgavimab vs. 9% in the placebo group, with a 50.5% decrease in relative risk (P=.0096).68 The number of patients in the study included in the category of “immunosuppressed” was very small (5%). The reported experience in transplantation is still very limited.69 The EMA has approved the use of tixagevimab/cilgavimab for treatment while the FDA maintains the use only for pre-exposure.70

Due to immunosuppression, RT patients have an altered immune response, particularly the T-cell mediated immune response, thus patients are exposed to a higher risk of infections.53 The first step in the treatment of any infectious disease of viral origin is prevention, through strategies such as vaccination, antiviral prophylaxis and control of the disease with general measures.74 However, if this fails and the patient develops infection, treatment of the infection includes not only targeted antiviral treatment but also reduction or modulation of immunosuppression.

In this regard, the accumulated evidence on the management of immunosuppression in kidney transplant patients with SARS-CoV-2 infection in these first 2 years of the pandemic has focused on the publication of observational, retrospective, non-randomized studies that have helped to clarify initial doubts about the immunosuppressive strategy to be followed and its medium-term repercussions.75–84 All published information recognizes that the reduction of immunosuppression has been one of the pillars of therapeutic management, in the absence of specific antiviral treatment, and this reduction has been carried out according to the clinical situation of the patient, the period of time after transplantation, the immunological risk of the patient and always under the supervision of a nephrologist.

In a Spanish multicenter study,82 which collected the experience of immunosuppression management of the majority of COVID-19 infected RT patients in Spain during the first and second waves of the pandemic. It was observed that immunosuppression management was mainly based on discontinuation of mycophenolic acid and very discrete reductions or discontinuations of calcineurin inhibitors. These supervised and intentional changes in immunosuppressive therapy did not influence renal function or HLA sensitization at 6 months after COVID-19 diagnosis. In another French multicenter study84 it was also observed that, after modulation of immunosuppression during coronavirus infection, the incidence of de novo donor-specific antibodies (de novo DSA) after SARS-CoV-2 infection was 4%, which was very similar to the incidence of de novo DSA in non-COVID-19 RT patients (5%) and renal function remained stable in all of them, This indicates that this practice of reducing immunosuppression in situations of severe infection does not seem to imply a greater immunological risk for the graft and allows the patient to acquire, in a short period of time, the cellular immunity necessary to control the infection and thus avoid its progression and its vital complications.

In the above mentioned Spanish study82 there was no common protocol for the management of immunosuppression; however, in all centers immunosuppression was progressively reduced as the patient's clinical situation worsened. Based on this study, which brings together the clinical practice of most of the RT units in Spain, we should recommend the following immunosuppression management guideline during SARS-CoV-2 infection:

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  In cases of SARS-CoV-2 infection with mild or asymptomatic symptoms, it is not necessary to modify the patient's baseline immunosuppression.

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  In cases of moderate infection with pneumonia and hypoxemia requiring oxygen therapy with nasal goggles. If the patient is at low immunological risk it is recommended to suspend immunosuppressive treatment with mycophenolic acid or m-TOR inhibitors, reduce the dose of calcineurin inhibitor (by 30%) and associate or increase the dose of steroids (prednisone or methylprednisolone to 20mg/day).

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  In cases of severe infection with pneumonia requiring mechanical ventilation or ICU admission, it is recommended a complete and temporary suspension of immunosuppression and increased steroids (prednisone or methylprednisolone at 20−40mg/per day). In highly sensitized patients with severe infection, they could receive intravenous nonspecific immunoglobulin every 15 days if possible, until recovery of immunosuppression.

Regarding the re-instauration of immunosuppressive therapy, it should be done once the patient has shown clinical, analytical and radiological improvement, which will depend on the baseline situation of each patient and the associated comorbidity. The full dose of calcineurin inhibitors should be reestablished first, and if the patient remains clinically stable, immunosuppressive treatment with antimetabolites or m-TOR inhibitors should then be restarted, and reduce progressively the dose of steroid to its usual dose.

The authors declare that they have no conflicts of interest related to the contents of the article.