In our case series, we discussed the clinical characteristics and the outcomes of the first six kidney recipients with COVID-19 in our Hospital. The mortality rate in our patients was in line with similar previous studies [6, 7]. Kidney recipients with COVID-19 developed even higher AKI than critically ill patients in Wuhan, China [8]. Besides, we found that respiratory involvement may be the main cause of the disease progression in patients with COVID-19 who had received kidney transplantation.
The 2019 novel coronavirus enters human cells by binding its spike to the angiotensin-converting enzyme 2 (ACE2) receptor. Proximal tubular cells and podocytes express the ACE2 receptor, resulting in AKI by virus-induced cytopathic effect, which is manifested by hematuria, proteinuria, elevated levels of blood urea nitrogen (BUN), and serum creatinine [2]. In our case-series, AKI was defined according to kidney disease improving global outcomes (KDIGO) guideline [9]. In addition, the baseline Cr was determined as the last serum Cr within 8 to 365 days prior to admission. Overall, AKI is reported to develop in 58.5% of kidney recipients with COVID-19 during admission [10]. Wang and colleagues [11] studied two patients with COVID-19 and chronic renal disease. They found AKI in both patients and concluded that COVID-19 may contribute to accelerated renal impairment. Besides, a recent meta-analysis suggested that there is an association between severe AKI and high mortality in patients with COVID-19 [12]. We found all patients developed AKI (100%) during hospitalization, which may prove that transplant recipients are at higher risk of AKI compared with 29% AKI in critically ill patients in Wuhan, China [8]. Therefore, close monitoring of patients with abnormal kidney indicators may prevent the progression of COVID-19.
Strikingly, in this study, the progression of COVID-19 was not associated with the severity of pulmonary involvement on chest CT scan on admission. Several patients with moderate pulmonary involvement recovered with-out any complications; however, patient 4 deceased despite moderate involvement on chest CT scan. According to a study conducted by Tan, et al. [13] patients with severe COVID-19 had an elevated CRP level at the early stage of the disease, even before CT scan findings. Also, we found that CRP level was elevated in all patients. These results indicate that despite the diagnostic value of CT scan at admission, it may not provide prognostic information in transplant recipients and other factors including inflammatory biomarkers may help us to detect the COVID-19 progression.
Since the outbreak of this disease in December 2019, it has been discussed that the novel coronavirus acts on lymphocytes, particularly T lymphocytes, resulting in T cell reduction. Besides, antimetabolite drugs work by suppressing the adhesion and proliferation of T lymphocytes [14, 15]. Of note, the number of T lymphocytes was clearly decreased in our patients, with the median of .36×109/L (range: 0.12-0.82×109/L), which is in line with that of Santeusanio, et al. [16] who found absolute lymphocyte count ≤ 600 cells/mL among all patients at admission. Given this experience, anti-proliferative agents (MMF, sirolimus, and azathioprine) were withdrawn at the time of admission in all patients. The role of antiviral therapies has been disputed since the outbreak of COVID-19; however, some studies suggest an effective role for hydroxychloroquine and lopinavir/ritonavir in reducing the viral load [17, 18]. Zhang H, et al. [19] studied five transplant recipients and reported that they administrated antiviral therapy (arbidol or oseltamivir) for all patients in line with immunosuppressants reduction in four patients. In addition, in a study conducted by Alberici F, et al. [6] the general management of COVID-19 was similar to the mentioned studies with the use of HCQ (95%), methylprednisolone (100%), and immunosuppression withdrawn (100%). Interestingly, although patients in this study were treated with anti-IL 6 drugs such as tocilizumab, the final outcome was not significantly different from other studies. In our patients, in accordance with previous studies, we started antiviral therapies in all patients. It is noteworthy to note that the treatment approach is in line with the standard protocols at the time of patients’ admission.
The essential role of inflammation and cytokine storm in the progression of COVID-19 has been revealed so far [20]; therefore, urgently needed treatments based on suppressing the inflammation such as glucocorticoids are demanded to control COVID-19; so, we elevated the dose of prednisolone to 15 mg daily. It is believed that cyclosporine may have effective roles in COVID-19 treatment by inhibiting the replication of the virus [21]; although, the same strategy did not work in the fourth case of our report who continued her cyclosporine. In addition, this patient developed sepsis during follow-up, which warrants more careful use of glucocorticoids in patients with COVID-19. Overall, it is important to note that the risk of rejection may increase with a reduction in immunosuppression; however, with regard to the high in-hospital mortality of COVID-19, clinicians should make different decisions based on patients’ conditions.
Most notably, the mortality rate in our patients was 33.3%, which nearly is consistent with previous studies [6, 7]. According to a recent review study, Moris, et al. [10] reported a cumulative mortality rate of 19.9% in kidney recipients with COVID-19. Pereira and colleagues [3] studied 90 solid-organ transplant (SOT) recipients including 46 patients with a history of kidney transplantation; they concluded that mortality (24%) and severity (39%) were significantly higher in transplant recipients compared with other patients. Moreover, according to a study conducted by Fernández-Ruiz, et al. [22] SOT recipients developed more ARDS compared with others (38.9% vs. 5.6%). In a recent study in Wuhan, China, the mortality rate among patients with ARDS was 52.4%, which has been described to be the leading cause of death on COVID-19 [23]. One of the essential characteristics of ARDS is the cytokine storm cascade, which has been proved to be the cause of sepsis, and can contribute to multi-organ failure [20]. In our study, the poor outcome in patient 4 may be related to the patient’s ARDS, which was followed by sepsis. Additionally, patient 6 deceased as a result of deterioration in respiratory status, which may indicate that respiratory involvement is the main cause of poor outcomes in patients with COVID-19; so, more supportive care must be considered in these patients.
Limitations
We would like to emphasize that our study has several limitations; however, we believe our study population is representative of patients diagnosed in our hospital. First, it is a single-center study on the Iranian population, and future multicenter studies on different ethnicities are demanded. Second, the small sample size of our study may affect the findings, and our results should be confirmed in larger studies.
Conclusions
In summary, in our case series of six kidney transplant recipients with COVID-19, two patients deceased (33.3%) and all the patients developed AKI, which indicates that immunosuppression after kidney transplantation may be a risk indicator for poor outcomes in COVID-19.