1. Introduction

As the first wave of the coronavirus disease 2019 (COVID-19) pandemic is continuing with different effects in different countries, our knowledge about disease features and outcomes of this novel coronavirus in the general population has grown substantially ^[1].

Kidney transplant (KTx) recipients have been recently classified by the Center for Disease Control and Prevention (CDC) as a high-risk group for severe COVID-19 ^[2]. Emerging evidence suggests 10-fold higher rates of early case fatality rate (CFR) in transplanted patients compared to that in the general population (GP) ^[3][4], due to the immunocompromised status resulting in impaired immunological response to pathogens ^[5] and to the almost universal presence of comorbidities ^[6][7].

The body of literature regarding COVID-19 infection in kidney transplantation is growing every day; however, it comprises mostly case reports, small case series, and small cohorts.

There is a broad variation in studies among different countries across the globe. The reported KTx recipients are heterogeneous in terms of race, ethnicity, time from transplantation, and baseline status at the time of COVID-19 infection. 

We performed a systematic review of all studies reporting on kidney transplant recipients with confirmed COVID-19 infection.

2. Patients’ Demographics and Baseline Characteristics

The mean and median age of the 169 patients, for whom individual patient data were available, were 55 ± 15 years and 55 years (range 21–80) respectively. The reported median age from available aggregated data ranged from 57 to 60 years. There was a male predominance of 67%.

The majority of KTx recipients (74%) had received a deceased donor transplant (DBD in 95% of cases), while 26% had been transplanted from a living donor. In 156 cases, the donor source was not reported.

Seven out of 420 patients (2%) were multiple organ transplant recipients: 2 had received liver and kidney, 2 had received heart and kidney, and 3 had received pancreas and kidney, respectively.

From the total cohort, only 2% of patients had undergone subsequent kidney transplantations. Median time from KTx to COVID-19 infection was 6.5 years (range 0–33) while 23% of the patients were transplanted for less than one year.

The majority of patients (81%) suffered from hypertension (HTN), while only 12% had no comorbidities. The second most frequent associated medical condition was diabetes mellitus (DM) (36%), followed by cardiovascular disease (CVD) (21%), obesity (OB) (15%), chronic obstructive pulmonary disease (COPD) (5%), malignancy (4%), and chronic viral infection (2%).

Out of 162 patients with comorbidities, 41% had one, 29% had two, and 18% suffered from three comorbidities.
Baseline renal function was relatively well-preserved with a median serum creatinine of 1.47 mg/dL in 91 patients. Baseline eGFR was assessed in a few studies (16 out of 63) with a mean of 40 ± 23 mL/min/1.73 m². The median peak serum creatinine during hospitalization was 2.2 mg/dL (range 0.62–10.94) and returned to 1.4 mg/dL at discharge.

The patients’ clinical features and outcomes as well as management strategies are depicted in Table 1.

Table 1. Demographic and baseline characteristics, clinical outcomes, and treatment of kidney transplant recipients with coronavirus disease 2019 (COVID-19) infection.

3. Major Clinical Outcomes after COVID-19 Infection

The infection rate in our study ranged from 0.27% to 1.67% and was calculated in those studies where the number of the total cohort of KTx recipients was available.

Of the total cohort, 93% of patients were hospitalized. The median duration of hospitalization was 16 days (range 1–100). From 391 hospitalized patients, 118 (30%) were admitted to the intensive care unit (ICU). In 32 out of 118 patients, the median duration of the ICU stay was 8.5 days (range 1–34). Non-invasive mechanical ventilation (NIV) was applied to 7% and invasive mechanical ventilation (IMV) to 23% of patients. Acute respiratory distress syndrome (ARDS) was reported in (175/391) 45% of patients. A substantial proportion of patients, (150/345) 44% developed acute kidney injury (AKI), with the need for renal replacement therapy (RRT) reported in 23%. Death was recorded in (93/420) 22% of patients. Most patients, (232/391) 59% were discharged; 29 patients remained hospitalized when the studies were published, 14 of whom were still in the ICU.

Case fatality rates in the case series including more than ten patients ranged from 6% up to 67%.

4. Baseline Immunosuppression and Modifications during COVID-19 Infection

The most frequently applied immunosuppressive regimen at baseline consisted of a calcineurin inhibitor (CNI), an antimetabolite, and corticosteroids (CS) in 73% of patients.

In total, 64% (147/230) of patients were receiving tacrolimus (TAC), 10% (18/176) cyclosporine (CsA), 68% (217/319) mycophenolic acid (MPA), 14% (26/184) everolimus, 4% (9/211) azathioprine (AZA), and a minority (<2%) of patients other agents such as belatacept, mizoribine, or leflunomide.

Overall, immunosuppression was reduced in 27% (97/357), discontinued in 31% (66/212), and remained unchanged in 5% (14/275) of patients. The most frequently discontinued drug was the antimetabolite in 91% (227/250) of patients. Calcineurin inhibitors were reduced in 32% (65/204) and discontinued in 58% (118/204) of patients. Switch from TAC or mammalian target of rapamycin inhibitor (mTORi) to CsA occurred in 7% (24/358) of patients. The mTORi was reduced in 7% (2/27) and discontinued in 67% (18/27) of cases.

5. COVID-19-Targeted Therapies

The main agents used for COVID-19 infection were antivirals, antibiotics, hydroxychloroquine (HCQ), anti-IL monoclonal antibodies, and steroid boluses. In total, 30% (123/414) of patients received antivirals. The most frequently used antiviral was lopinavir/ritonavir, administered to 76% (94/123) of those. Other antivirals included darunavir/ritonavir (13%), ritonavir-darunavir/lopinavir (4%), oseltamivir or arbidol (11%), umifenovir (7%), and darunavir/cobicistat (2%).Hydroxychloroquine was administered to 78% (320/409) of patients. The majority of patients (73%, 290/399) received antibiotics: azithromycin was administered to 53% (155/290) and other broad-spectrum antibiotics to 17% (50/290) of cases. Corticosteroid (CS) boluses or dexamethasone were used in 25% (83/331) of patients. Anti-IL agents were introduced in 28% (59/213) of patients with more severe illness; tocilizumab was the preferred agent in 56 of 59 patients.Less frequently used agents were immunoglobulin in 8%, colchicine in 0.5%, interferon in 0.5%, and leronlimab in 1.4% of patients.

In conclusion, the main finding of our analysis is the high rate of all major adverse outcomes among hospitalized patients with COVID-19 infection.