This observational retrospective study was conducted at the Lausanne University Hospital (Lausanne, Switzerland), a 1500-bed tertiary care hospital and one of the six kidney transplantation centers in Switzerland. Our institution performs around 60 kidney transplantations per year and regularly follows around 1000 KTR. The study was approved by the institutional ethics review board (Swissethics Project-ID 2022-00324) for the retrospective use of clinical data.

All adult (≥18 years old) KTR followed at our Transplantation Center who were diagnosed with a microbiologically-proven SARS-CoV-2 infection by real-time PCR between March 1st, 2020 and May 20th, 2022, were included in the analysis. Subsequent episodes of COVID-19 were included if they occurred at least 3 months after the previous one, based on reappearance of typical COVID-19 symptoms and de novo positive SARS-CoV-2 real-time PCR. Patients that had previously refused the institution’s general consent and those with graft loss (re-initiation of dialysis at the time of the study) were excluded. Patients were identified by the preexistent database including all KTR followed at our center. All patients were instructed to contact the transplantation center in case of COVID-19-compatible symptoms and following a positive antigenic test or PCR for SARS-CoV-2 irrespective of symptoms. Nephrologists responsible for the care of patients in other associated centers were additionally instructed to communicate with our center in the event of a positive case. Data were prospectively collected for all cases of COVID-19 in KTR in a secured database.

Depending on their immunological risk, KTR received basiliximab or anti-thymocyte globulins induction therapy (Thymoglobulin®). Maintenance immunosuppressive protocol generally consisted of the combination of a calcineurin inhibitor (CNI; mainly tacrolimus, TAC), mycophenolic acid (MPA), and prednisone following a tapering protocol during the first year. Beyond the first year, prednisone (5 mg/day) was only maintained in high immunological risk recipients. TAC doses were adjusted according to therapeutic drug monitoring and MPA according to digestive and haematological tolerability. All patients received co-trimoxazole prophylaxis during the first 6 months, and valgancyclovir or valacyclovir during the first 3 to 6 months according to donor/recipient serostatus.

Prevention and treatment of COVID-19 in KTR varied over time according to the availability of the different drugs and vaccines. From March 2020 to June 2020, only investigational drugs were used via the inclusion in clinical trials (hydroxychloroquine, lopinavir, remdesivir). Since June 2020, dexamethasone was used in all patients needing supplemental oxygen therapy. Tocilizumab was administered in selected patients not responding to dexamethasone. Remdesivir was not used in hospitalized patients on a routine basis. The vaccination campaign started in January 2021 and KTR were considered as a priority group for vaccination. Two doses of an mRNA vaccine (mRNA-1273 or BNT162b2) were proposed initially, with a third dose proposed from September 2021. Casirivimab/imdevimab (2400 mg) was available since July 2021. Sotrovimab (500 mg) was available in Switzerland since September 2021, although it was used at our institution only from end of December 2021, based on data regarding the reduced activity on the omicron variant of casirivimab/imdevimab as compared to sotrovimab (19, 20). Anti-Spike mAbs were proposed to all KTR with documented mild or moderate COVID-19 within 5–7 days of onset of symptoms (considered in this study as “early treatment”). From March 15th^, 2022, the dose of administered sotrovimab was doubled to increase its activity against the predominant omicron BA.2 variant (21). In addition, casirivimab/imdevimab was used in selected patients with severe COVID-19 and negative SARS-CoV-2 serology, according to the Recovery study (22). In this case, we used the term “late treatment” with mAbs. Following a positive SARS-CoV-2 test, MPA dosage was reduced by 50% or even stopped depending on the severity of the disease and/or concomitant administration of high dose corticosteroids. TAC trough levels were also decreased by around 30%.

The primary outcome was death or hospitalization for COVID-19-related symptoms within 28 days from the diagnosis of infection. The secondary outcome was defined as need for oxygen therapy within 28 days. Data regarding demographics (age, sex), comorbidities, transplantation characteristics (date of transplantation, immunosuppression, graft function), vaccination status (BNT162b2 or mRNA-1273), SARS-CoV-2 serology, specific anti-SARS-CoV-2 treatments including mAbs (casirivimab/imdevimab and sotrovimab), and complications were collected in the patients’ electronic health records. SARS-CoV-2 serology (IgG) was performed using a previously described Luminex-based (Luminex Corp) assay quantifying antibody binding to the trimeric form of the SARS-CoV-2 S-protein and divided by the negative control; a ratio of ≥5.9 was considered positive (23).

All data were collected, stored and managed using REDCap electronic data capture tools hosted at Lausanne University Hospital. REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed to support data capture for research studies (24, 25).

The date of the first positive SARS-CoV-2 PCR was defined as infection onset. Acute kidney injury (AKI) was defined according to the 2012 Kidney Disease Improving Global Outcome (KDIGO) guidelines. Reduction of immunosuppressive treatment was defined as at least 50% MPA or 30% TAC dose decrease. Adequate vaccination was defined as having received three doses before infection or developing infection within 4 months after two doses. By using the data from the Swiss Federal Office of Public Health (26) that monitored the circulation and prevalence of SARS-CoV-2 variants, we divided the study in four periods: Period 1 (March to December 2020): pre-vaccination period, with the initial virus or alpha variant; Period 2 (January to June 2021): vaccination available but before mAbs, with the alpha and delta variants; Period 3 (July to December 2021): vaccination available and mAbs, with the delta variant; and Period 4 (January to May 2022): vaccination available and mAbs, with the omicron variant.

The SPSS version 26.0 (SPSS, Chicago, IL, United States) software was used for data analysis. Categorical variables were analyzed using the chi-square or Fisher exact test and continuous variables with Mann-Whitney U test. Two multivariate logistic regression analyses were performed with primary and secondary outcomes, respectively, as the dependent variables. Four variables from the univariate analysis with p < 0.05 (Charlson Comorbidity Index, adequate vaccination, mAbs as early treatment, Period 4) that did not contribute to multicollinearity were used in multivariate logistic regression model. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to evaluate the strength of any association. The primary and secondary outcomes trends during the pandemic periods were assessed using Spearman’s correlation analysis. All statistic tests were 2-tailed and p < 0.05 was considered statistically significant.

Overall, 246 KTR with at least one episode of COVID-19 were identified, for whom 243 episodes were included in the study corresponding to 237 patients (6 patients had two episodes of COVID-19 during the study period). Among the 9 patients that were excluded, 4 patients were excluded for refusal of general consent and 5 due to graft loss at the time of study initiation. Patients’ characteristics according to the time-period of SARS-CoV-2 diagnosis are shown in Table 1. Overall, there was no significant difference in the demographic characteristics of the infected patients during the different pandemic periods. The majority of patients were middle-aged men with 22% suffering from obesity, 24% from diabetes, and/or 14% from coronary heart disease, representative of the general KTR population. The majority were on CNI-based (mainly TAC) triple immunosuppressive therapy, including prednisone (70%) and MPA (77%). No patient was on belatacept maintenance immunosuppressive therapy and only a minority of the study population (4%) had received T- or B-cell depleting agents in the previous year before suffering from COVID-19, and one patient received eculizumab every 3 weeks for the treatment of recurrent glomerulonephritis.

In total, 77 patients (32%) were hospitalized within 28 days from diagnosis; 66 patients were hospitalized due to COVID-19 symptoms and 44 patients needed oxygen therapy. Eight patients (3%) died within 28 days from the diagnosis of infection. Sixty-eight patients (28%) developed the primary outcome (hospitalization for COVID-19-related symptoms or death within 28 days from infection diagnosis) and 44 (18%) the secondary endpoint (need for oxygen therapy within 28 days). Hospitalization for COVID-19-related symptoms or death was seen in 45% (39/87) of patients during Period 1 and 2 and 19% (29/156) of patients during Period 3 and 4. A significant decrease in the incidence of primary (p < 0.001, r −0.342) and secondary outcomes (p < 0.001, r −0.311) was observed during the consecutive study periods. Overall, AKI (≥ AKIN stage I) was observed in 8% of KTR, and the same proportion (10–14%) of patients had persisting moderate to severe graft dysfunction at 28 days. Four patients lost their graft and returned to dialysis following severe COVID-19. Among 112 patients in whom anti-HLA Abs could be screened after the episode of SARS-CoV-2 infection, 5 (4%) developed de novo donor-specific anti-HLA Abs (DSA). There was however no episode of acute cellular or antibody-mediated rejection that could be associated with the infection.

In total, mAbs were administered as early treatment in 101 patients (14 with casirivimab/imdevimab and 87 with sotrovimab), and 6 (3%) additional patients received casirivimab/imdevimab as a late treatment (Table 1). Double dose of sotrovimab was administered in 17 patients, of whom two were hospitalized due to COVID-19 symptoms and one needed oxygen therapy.

Among 145 patients that had received at least one vaccination dose before infection, 109 (45% of all infection episodes) were considered as adequately vaccinated. Figure 1 shows the number of patients with the primary outcome depending on adequate vaccination and timing of SARS-CoV-2 infection. Serology was performed in 109 patients at the time of SARS-CoV-2 infection diagnosis and it was positive in 83 (76%). Among 108 patients for whom serology was performed after two or three doses (without documented prior infection), 83 (77%) had positive serology. Figure 2 shows the results of SARS-CoV-2 serology depending on the timing of sampling (after vaccination and/or SARS-CoV-2 infection). Serology results of patients with two or three vaccine doses and with prior SARS-CoV-2 infection (median ratio of 71.7) were significantly higher (p < 0.001) than for those who received two (median ratio of 18.5) or three doses (median ratio of 27.4) without prior infection.

Multivariate analysis revealed that the Charlson Comorbidity Index (P 0.001; OR 1.28, CI 1.11–1.48) was associated with the primary outcome, while administration of mAbs as early treatment (P 0.032; OR 0.39, CI 0.16–0.92) was associated with a better outcome (Table 2). Of note, adequate vaccination and infection during Period 4 were associated with improved primary outcome in the univariate analysis, but this was not confirmed in the multivariate analysis. In the multivariate analysis for the secondary outcome (hospitalization for need of oxygen), the Charlson Comorbidity Index (P 0.001; OR 1.30, CI 1.11–1.51) increased the risk of secondary outcome, while administration of mAbs as early treatment (P 0.009; OR 0.19, CI 0.06–0.66) was associated with a reduced risk for the secondary outcome. Similarly, adequate vaccination and infection during Period 4 were not associated with the secondary outcome.