The coronavirus is a human and animal pathogen. At the end of 2019, a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as a cause of pneumonia in a group of patients in Wuhan, a city in Hubei province (China).1 The SARS-CoV-2 virus, previously known as 2019-nCoV, is the agent responsible for coronavirus disease 2019 (COVID-19).2 The pathogenesis of respiratory damage in COVID-19 is similar to severe acute respiratory syndromes in its clinical spectrum and epidemiology.1–3 It can manifest as an asymptomatic or symptomatic infection, with a spectrum ranging from mild to severe pneumonia. Infection can be divided into three phases: mild infection, the pulmonary phase and the inflammatory phase.4 Given the spread of the disease, as well as the current epidemiological situation, various treatments for the infection are being studied. Remdesivir is the only antiviral drug that has been shown to be useful against SARS-CoV-2 in the pulmonary phase, shortening hospitalisation time as compared to placebo.3

Kidney transplant (KT) patients are especially vulnerable to this disease, not just because they are immunosuppressed, but also because they are patients with different degrees of renal insufficiency. In the aforementioned studies assessing the efficacy of remdesivir, KT patients were not included. The effect in this population being limited to some published cases.5 In an observational study that included 46 patients with SARS-CoV-2 pneumonia with chronic kidney failure (16), kidney transplant recipients (8) and with acute kidney failure (22), the median number of days from admission to start of remdesivir was five (1–26) days, with 36 patients (78.2%) on dialysis at the start of remdesivir therapy. Of these, treatment was not completed in six patients due to death following clinical progression of the disease, and treatment was stopped in two patients due to clinical improvement. A single patient manifested a reaction to the infusion; transient behavioural changes were observed in five cases and acute gout was observed in one patient while undergoing treatment. In this study, good tolerance to remdesivir was observed in patients with chronic kidney disease, even in patients on dialysis.6

There are no reported cases of interaction between remdesivir and immunosuppressive therapy. However, given the limited experience in the field of interaction of both treatments, it is advisable to exercise caution and closely monitor the concentration of immunosuppression when administering with remdesivir due to the lack of knowledge and safety assessment studies.7

Given the limited evidence on the use of remdesivir in KT patients, it would be necessary to include this vulnerable group of patients in randomised clinical trials, but in the meanwhile, it is essential to describe the effect of remdesivir in this population.

The objective of our study was to retrospectively describe the clinical course of KT patients with SARS-CoV-2 infection who received treatment with remdesivir.

Of a total of 37 KT patients admitted with SARS-CoV-2 pneumonia, seven received treatment with remdesivir with a median of six (3–9) days elapsed since the onset of symptoms. The rest of the patients were excluded because of a CKD-EPI less than 30 ml/min or because they did not meet the clinical criteria. The median age was 59 (53–71) years. Demographic characteristics and the immunosuppression patients received are given in Table 1. The median post-transplant time was 43 (16–82) months, with the median renal function at admission being CKD-EPI 47 (40–75) ml/min/1.73 m2. The most common clinical manifestation was dyspnoea (6/7), followed by dry cough (5/7), tachypnoea (5/7) and fever (4/7). All patients showed bilateral infiltrates in the chest X ray and required low-flow oxygen therapy on admission with a baseline PaO2/FiO2 of 325 (206–373), with three patients requiring high-flow oxygen therapy throughout admission. In all patients, immunosuppressive therapy was suspended on the day of admission, only maintaining dexamethasone 6 mg. The median time to reintroduction of tacrolimus was 10 (8−18) days. Mycophenolic acid (MPA) was started in only two patients two months after discharge. Table 2 shows the laboratory characteristics of the patients. Two patients presented with impaired graft function due to acute tubular necrosis of multifactorial origin secondary to hypovolaemia, nephrotoxic agents and SARS-CoV-2 infection at the time of admission, prior to starting remdesivir, with peak creatinine of 2.2 mg/dl on the day of admission in the first case, and peak creatinine of 2 mg/dl in a recently transplanted patient, neither case requiring haemodialysis and both cases recovered normal kidney function on the 10th day of admission (Fig. 1A). The degree of lymphocytopenia mas maximal on admission, subsequently it recovered progressively (Fig. 1B). ALT increased progressively, it being considered a mild adverse effect secondary to treatment with remdesivir. It did not reach levels that double the normal limit in any case (Fig. 1C), while CRP decreased progressively during admission (Fig. 1D). No patient died, required admission to the intensive care unit or suffered other side effects to the treatment. The median length of hospital stay was 12 (10–18) days.

Fig. 1.

A. Evolution of creatinine in the laboratory tests of kidney transplant patients (n = 7) based on baseline creatinine and its evolution during admission (day 0, day +7 and day +14). The creatinine median and interquartile range show kidney function stability during admission.

B. Evolution of lymphocytes in the laboratory tests of kidney transplant patients (n = 7) from admission (day 0, day +7 and day +14). The lymphocytes median and interquartile range show a progressive increase from admission, with the start of recovery without reaching normality on day 14.

C. Evolution of the ALT enzyme in the laboratory tests of kidney transplant patients (n = 7) from admission (day 0, day +7 and day +14). The ALT median and interquartile range show a progressive increase during admission. The horizontal red lines show normal values.

D. Evolution of CRP in the laboratory tests of kidney transplant patients (n = 7) from admission (day 0, day +7 and day +14). The CRP median and interquartile range show a decrease during the first seven days of admission.

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There is currently no known treatment for COVID-19, so different treatment lines have been tried, including remdesivir.3 This study describes the clinical course of a group of KT patients with COVID-19 treated with remdesivir.

Remdesivir is a nucleoside analogue with antiviral activity. As a ribonucleic acid (RNA) polymerase inhibitor, it can inhibit the replication of multiple coronaviruses in respiratory epithelial cells. In monkey models infected with Middle East respiratory syndrome (MERS-CoV), treatment with remdesivir 24 h prior to infection achieved complete prevention of symptoms by inhibiting viral replication in the respiratory tract and preventing the formation of lung lesions. By administering remdesivir 12 h after infection, clear clinical benefits were observed, with reduced symptoms, virus replication in the lungs and pulmonary lesions.12 In human studies, remdesivir resulted in a shorter hospital stay compared to placebo when administered on day nine (7–12) of infection.3 In our study, it was started a median of six (3–9) days after the onset of symptoms. Therefore, it would be expected that the shorter the progression of the disease should reflect a more effective the treatment with remdesivir.

One study focused on the detection of side effects. The study included eight KT patients and found no serious adverse effects.6 We have not found other studies that assess the efficacy of remdesivir on KT patients with COVID-19.

Regarding the management of immunosuppression, it is a complex issue in the context of a severe infection, not only because of the infection itself, but also because of the possible interaction with the drugs used to treat SARS-CoV-2 pneumonia. It is important to mention that, to date, remdesivir has shown no interactions with calcineurin inhibitors, antimetabolites or mTORi.13,14 However, remdesivir can induce cytochrome p450 enzymes, including CYP1A2, CYP2B6 and CYP3A4.13,14 In our study, immunosuppression with calcineurin inhibitors and antimetabolites was suspended in all patients at diagnosis prior to starting remdesivir. None of the patients had previously suffered from rejection and therefore, to assess the benefit against the potential risk, only treatment with steroids was maintained.

The main side effects of remdesivir are hepatotoxicity and nephrotoxicity.3 Remdesivir is currently contraindicated in patients with ALT five times the upper limit of normal and in patients with a glomerular filtration rate less than 30 ml/min/1.73 m2. Beigel et al. published a cohort of 155 patients with SARS-CoV-2 infection treated with remdesivir, in which only 1% had to discontinue treatment due to acute kidney failure.3 Natasha et al. did not find a higher incidence of adverse effects, impaired kidney function or elevated transaminases among patients with a glomerular filtration rate higher or lower than 30 ml/min/1.73 m2.15 In our study, there were only two cases of impaired kidney function prior to the administration of remdesivir. Regarding hepatotoxicity, there was a slow but progressive increase in ALT, but transaminase values barely doubled normal levels.

Remdesivir is the only antiviral therapy that has been shown to be useful against SARS-CoV-2 in the pulmonary phase, and it shows a shortening of recovery time compared to placebo (median 10 days vs 15 days)3 and shortening hospital stay in patients who received this treatment versus placebo (median 12 days versus 17 days).3 In a review that included 420 cases from the first wave, where no patient received treatment with remdesivir, the length of hospitalisation was 16 (1–100) days.16 During the same period in Spain, the duration of hospital stay was 14 (8–21) days.17 In our study, the median days of admission and recovery in KT patients with SARS-CoV-2 pneumonia was 12 (10–18) days, suggesting a decrease in the length of hospital stay in KT patients when they receive treatment with remdesivir.

The results of different studies show a mortality rate of 28% at three weeks in KT patients compared to 1%–5% of the general population prior to the approval of remdesivir.18 In the study by Villanego et al., of the 1,011 cases included, 548 were from the first wave and 463 from the second (93.6% and 80.4%, respectively, of the total number of patients included in the registry). In the second wave, KT patients were younger, 18.4% were asymptomatic and had fewer cases of pneumonia (49.7% vs 80.5%). During the first wave, there were changes in treatment with increased use of remdesivir and steroids. Ritonavir/lopinavir, hydroxychloroquine and azithromycin were hardly used in the second wave. Hospitalisation decreased (63.3% in the second wave compared to 90% in the first), but more KT recipients were admitted to the ICU, when patients hospitalised during the second wave were analysed. Overall mortality in this cohort was lower (even excluding asymptomatic cases) during the second wave (15.1%) compared to the first wave (27.4%) (p < 0.001). Mortality of hospitalised patients was also lower (22.9% in the second wave compared to 29.5% in the first wave, p < 0.04). However, in critical KT patients, mortality was 66.7%, not significantly different from that reported in the first wave (58.1%).17 In our series of patients treated with remdesivir for five days, clinical course was favourable without need of admission to the intensive care unit, and patients were discharged with a mortality rate of 0%, which suggests that remdesivir could be an effective treatment.

Regarding prognosis, Beigel et al. suggest that treatment with remdesivir in the general population may have prevented progression to more severe respiratory disease, and it may have decreased the use of the scarce healthcare resources during the pandemic.3 In our study, all patients showed with bilateral infiltrates on x-ray scans and required low-flow oxygen therapy at diagnosis. After starting treatment with remdesivir, only three patients required high-flow oxygen therapy, without admission to the intensive care unit or invasive mechanical ventilation being required in any of the cases.

With respect to the incidence of acute kidney failure, the aforementioned review, which includes kidney transplant recipients from the first wave, reports an incidence of 44%, compared to 29% in the general population.16 A substantial proportion of those who developed kidney failure (23%) required renal replacement therapy. Of the remaining patients, most cases recovered kidney function at discharge.16 In our study of patients treated with remdesivir, there were two cases of impaired kidney function that worsened 1.5 times the baseline value at diagnosis. The cause of impaired kidney function was attributed to acute tubular necrosis secondary to hypovolaemia, nephrotoxic agents and SARS-CoV-2 infection (no kidney biopsy performed in any case). It was not attributed to a side effect to remdesivir in any of the cases, with progressive recovery during admission, reaching baseline creatinine on the 10th day of admission.

On one hand, our study is one of the first published including cohorts of KT with COVID-19 pneumonia treated with remdesivir, analysing its efficacy and safety. On the other hand, it is a retrospective observational study with a small sample size with its consequent biases.

Our study suggests that KT patients with SARS-CoV-2 infection undergoing treatment with remdesivir show a good clinical course with no adverse effects and low mortality. Remdesivir is well tolerated in kidney transplant patients, with no evidence of nephrotoxicity related to the drug. More controlled studies with a larger number of patients are needed to broaden our understanding the effect of this drug on SARS-CoV-2 infection in kidney transplant patients.

None.

The authors have no conflicts of interest.