DISCUSSION
In this study, the mean ages of the three groups were 45, 50, and 52 years, respectively, which were much higher than those of the general population (see Table 1). This was because the investigated patients were hospitalized with pneumonia rather than patients with only COVID-19. Moreover, pneumonia mostly occurs in older infected individuals. Although the three groups differed significantly in terms of age (P=0.025), patients with severe symptoms who needed medications were mostly older individuals (Table 1). COVID-19 infection in KTR occurred later than it did in healthy people; furthermore, we indicated the duration of medication and time needed to reveal negative results (Supplementary Table 2).
The Montefiore Medical Center in New York reported 36 KTR confirmed with COVID-19 [21]. Moreover, 15 KTR who required hospitalization due to confirmed COVID-19 were reported by the Columbia University Kidney Transplantation Project [22]. The most common complications were hypertension, diabetes, smoking history, and heart disease. The overall performance of KTRs with COVID-19 was similar to that of the general population. The most common symptoms were fever, cough, dyspnea, fatigue, diarrhea, and myalgia. More than 50% of patients had bilateral or multiple focal ground-glass shadows on the initial chest radiograph. Laboratory examination showed that lymphocyte and platelet counts were decreased, and CD3, CD4, and CD8 cell counts were decreased. Inflammatory markers such as ferritin, C-reactive protein, procalcitonin, and D-dimer had increased [21-22]. In our study, 125 (89.29%) patients had fever, 114 (81.43%) had cough, and 66 (47.1%) had malaise. Ninety percent of patients had a combination of two or more symptoms. There was no significant difference in the frequency of symptoms between the treatment groups, except for nausea and vomiting, which were more common in the two drug combination groups and was statistically different (Supplementary Table 2).
KTRs may face more severe challenges than non-transplant patients. Based on a recent meta-analysis, transplant patients with COVID-19 had a higher risk (+57%) of ICU admission than non-transplant patients [20]. Therefore, there is a need to pay more attention to medication for KTRs with COVID-19. The lymphatic system is rebuilt after an increase in lymphocytes, after which the viral load is decreased. Therefore, the application of small-molecule antiviral drugs is of significance and beneficial for better prognosis.
Small-molecule drugs for the treatment of patients with COVID-19 mainly include two types: those that inhibit COVID-19 and those that control the human cytokine storm. Among these, RdRp and Mp-ro are the main targets of COVID-19 small-molecule drugs. Among the COVID-19 therapeutic drugs currently on the market, Azvudine and Paxlovid are small-molecular drugs targeting RdRp and Mp-ro [Gordon D E, Jang G M, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing[J]. Nature, 2020, 583(7816):1-13.].
We administered azvudine, paxlovid, or a combination of both. Paxlovid acts on the main protease of COVID-19, inhibits the processing of protein precursors mediated by this enzyme and viral replication, and significantly reduces mortality. On the other hand, nirmatrelivr has a significant antiviral activity, and is currently reported to reduce viral load most rapidly [16]. However, paxlovid is contraindicated in patients with severe liver and kidney injury. According to the diagnosis and treatment modality of COVID-19 (Version X), patients with moderate kidney injury should be administered half of nirmatrelivr, whereas patients with severe liver and kidney injury should not use paxlovid because its usage may increase the blood concentration of calcineurin inhibitors, which are essential for KTRs is one aspect. Moreover, paxlovid may cause renal injury. This is consistent with our study. AKI in the paxlovid group was much higher than that in the other two groups (P=0.010), as shown in Table 4. However, to treat COVID-19, small-molecule antiviral drugs are urgently needed. Therefore, we used azvudine as a substitute, when a calcineurin inhibitor acted as an immunosuppressant after kidney transplantation.
The target of Azvudine is RdRp, which is a pathway that increases the indications for anti-HIV drug-based COVID-19 treatment. In a phase III clinical trial, 40% patients with COVID-19 showed alleviated clinical symptoms 1 week after receiving azvudine treatment, whereas the proportion of patients receiving placebo was only 11% [23]. Azvudine does not directly inhibit viral replication. It performs triphosphorylation in cells to produce FNC triphosphate, which then produces broad-spectrum inhibitory activity against not only COVID-19, but also hepatitis C virus (HCV) and enterovirus 71 (EV71). FNC triphosphate has been proven to effectively inhibit COVID-19 in cell cultures and animal models. Azvudine’s triphosphorylation product is used as a substrate that combines with the RdRp of COVID-19, resulting in the termination of viral RNA chain synthesis and generation of non-functional viral genomic RNA, thus inhibiting viral replication [24]. However, KTRs infected with COVID-19 present with quite severe symptoms, and azvudine alone is insufficient to achieve treatment outcomes; therefore, we administered paxlovid immediately after the calcineurin inhibitor was withdrawn. Therefore, we grouped the patients into A+P and paxlovid groups (Table 2).
The period of medication for KTRs receiving any of the three groups of small-molecule drugs lasted longer than the recommended time of diagnosis and treatment scheme of COVID-19 (Version X), and was also longer than that of patients with simple pneumonia. This, on the other hand, proves that KTRs with COVID-19 infection presents with more severe symptoms than those pneumonia patients with infection.
According to the changes in laboratory test data before and after treatment with the novel coronavirus (Figures 2 ), differences between the three groups were found in absolute T-lymphocyte levels 7 days after admission and at discharge (P= 0.015, P=0.004) and lymphocyte counts at admission, 7 days after admission, and at discharge (P=0.032, P=0.000, P=0.000), with no significant differences in other clinical data between the three groups. This showed that there were no differences between the three groups of small-molecule drugs after the removal of the interference factors. In other words, the small-molecule drugs we used were suitable and safe for kidney transplant patients with COVID-19. However, the specific choice of azvudine, paxlovid, or a combination of both must be determined based on the use of immunosuppressants and the patient’s symptoms.
We also administered intravenous hormones to improve the treatment effect in patients with severe conditions (Table 2). For the immunosuppressive therapeutic modality, we used triple immunosuppressive agents and antimetabolic drugs for most patients. During the course of treatment, the rate of withdrawal of antimetabolic drugs was higher than that of calcineurin inhibitors, whereas the use of calcineurin inhibitors in the paxlovid and A+P groups was discontinued (Table 2).