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).