A Head-to-head Comparison of De Novo Sirolimus or Everolimus Plus Reduced-dose Tacrolimus in Kidney Transplant Recipients: A Prospective and Randomized Trial.

BACKGROUND: Mammalian target of rapamycin inhibitors (mTORi), sirolimus (SRL) and everolimus (EVR), have distinct pharmacokinetic/pharmacodynamics properties. There are no studies comparing the efficacy and safety of de novo use of SRL versus EVR in combination with reduced-dose calcineurin inhibitor. METHODS: This single-center prospective, randomized study included first kidney transplant recipients receiving a single 3 mg/kg antithymocyte globulin dose, tacrolimus, and prednisone, without cytomegalovirus (CMV) pharmacological prophylaxis. Patients were randomized into 3 groups: SRL, EVR, or mycophenolate sodium (MPS). Doses of SRL and EVR were adjusted to maintain whole blood concentrations between 4 and 8 ng/mL. The primary endpoint was the 12-mo incidence of the first CMV infection/disease. RESULTS: There were 266 patients (SRL, n = 86; EVR, n = 90; MPS, n = 90). The incidence of the first CMV event was lower in the mTORi versus MPS groups (10.5% versus 7.8% versus 43.3%, P < 0.0001). There were no differences in the incidence of BK polyomavirus viremia (8.2% versus 10.1% versus 15.1%, P = 0.360). There were no differences in survival-free from treatment failure (87.8% versus 88.8% versus 93.3%, P = 0.421) and incidence of donor-specific antibodies. At 12 mo, there were no differences in kidney function (75 ± 23 versus 78 ± 24 versus 77 ± 24 mL/min/1.73 m 2 , P = 0.736), proteinuria, and histology in protocol biopsies. Treatment discontinuation was higher among patients receiving SRL or EVR (18.6% versus 15.6% versus 6.7%, P = 0.054). CONCLUSIONS: De novo use of SRL or EVR, targeting similar therapeutic blood concentrations, shows comparable efficacy and safety. The reduced incidence of CMV infection/disease and distinct safety profile of mTORi versus mycophenolate were confirmed in this study.

Conversion to mTOR Inhibitor to Reduce the Incidence of Cytomegalovirus Recurrence in Kidney Transplant Recipients Receiving Preemptive Treatment: A Prospective, Randomized Trial.

BACKGROUND: Although mammalian target of rapamycin inhibitors (mTORi) are associated with a lower incidence of the first episode of cytomegalovirus (CMV) infection/disease in kidney transplant recipients receiving calcineurin inhibitors (CNIs), the efficacy and safety of the conversion from the antimetabolite to an mTORi for the prevention of CMV recurrence are unknown. METHODS: In this single-center prospective randomized trial, low-immunological-risk, CMV-positive kidney transplant recipients receiving preemptive therapy were randomized to be converted (sirolimus [SRL]) or not (control [CTR]) immediately after the treatment of the first episode of CMV infection/disease and were followed for 12 mo. A sample size of 72 patients was calculated to demonstrate a 75% reduction in the incidence of CMV recurrence (80% power, 95% confidence level). RESULTS: Of 3247 adult kidney transplants performed between September 13, 2015, and May 7, 2019, 1309 (40%) were treated for the first CMV infection/disease, and 72 were randomized (35 SRL and 37 CTR). In the SRL group, there were no episodes of CMV recurrence, compared with 16 patients in the CTR group (0% versus 43%; P < 0.0001). Four patients had a second and 1 a third recurrent CMV event. Three of them were converted to SRL and did not develop any further CMV events. There were no differences in the incidence of acute rejection, drug discontinuation, kidney function, and patient and graft survival at 12 mo. CONCLUSIONS: These data suggest that, in CMV-positive kidney transplant recipients, the conversion from an antiproliferative drug to SRL after the first CMV episode is an effective and safe strategy for recurrent episodes.

Immunogenicity After a Heterologous BNT262b2 Versus Homologous Booster in Kidney Transplant Recipients Receiving 2 Doses of CoronaVac Vaccine: A Prospective Cohort Study.

BACKGROUND: Comparative studies of third heterologous doses following the CoronaVac vaccine against coronavirus disease 2019 (COVID-19) in kidney transplant recipients are lacking. METHODS: This prospective, single-center cohort study included kidney transplant recipients without previous COVID-19. Patients received a third heterologous (BNT162b2 mRNA) or homologous dose at least 4 wk after 2 doses of the CoronaVac vaccine. Immunoglobulin G antibody response and seroprevalence for neutralizing anti-severe acute respiratory syndrome coronavirus 2 antibodies immediately before and 28 d after third doses were compared between the groups. RESULTS: There were 307 patients in the heterologous group and 777 in the homologous group. Patients in the heterologous group were older (54 versus 50 y; P < 0.0001), with a longer time since transplant (11 versus 6 y; P < 0.0001). Immediately before the third dose, immunoglobulin G seroprevalence (36% versus 34%; P = 0.597) and antibody titers (246 versus 268 AU/mL; P = 0.279) were similar. After booster, seroconversion was higher in the heterologous group (49% versus 32%; P < 0.0001), resulting in a higher seroprevalence (67% versus 55%; P = 0.0003); however, 42% of all patients remained seronegative. Antibody titers after booster in seropositive patients were higher in the heterologous group (7771 versus 599 AU/mL; P < 0.0001). These results persisted after adjusting for confounding variables. Lastly, a similar proportion of patients became seropositive for neutralizing antibodies (98% versus 94%; P = 0.098). CONCLUSIONS: In kidney transplant recipients fully vaccinated with CoronaVac, a third dose with an mRNA vaccine produced a higher seroconversion rate and antibody titers than a third homologous dose. However, both boosters achieved equivalent seroprevalence for neutralizing antibodies. The high proportion of still seronegative patients indicates the need for alternative strategies of protection.

Inactivated Whole-virus Vaccine Triggers Low Response Against SARS-CoV-2 Infection Among Renal Transplant Patients: Prospective Phase 4 Study Results.

BACKGROUND: Anti-severe acute respiratory syndrome coronavirus 2 mRNA vaccines elicit lower humoral responses in solid-organ transplant recipients. This is the first prospective trial investigating the effect of an inactivated whole-virion vaccine in kidney transplant recipients. METHODS: Prospective, single-center, phase 4, interventional study. Kidney transplant recipients aged 30-69 y with >30 d of transplantation received two 3 µg intramuscular doses of CoronaVac 28 d apart and are being followed for 6 mo. Primary outcomes: (1) reactogenicity after first dose; (2) antibody responses 28 d after each dose; and (3) incidence/severity of confirmed coronavirus disease 2019 (COVID-19) and 28-d lethality rate. For this analysis, clinical effectiveness was assessed for 3 mo, starting 15 d after the second dose, and compared with 3-mo period before vaccination. RESULTS: Of the 3371 individuals who received the first dose, 99% completed vaccination schedule. Mild/local adverse reactions were reported by 33% of the patients. In the immunogenicity cohort (n = 942), the proportion of patients with IgG antibodies to severe acute respiratory syndrome coronavirus 2 increased from 15.2% after first dose to 43% after second dose. Increase in antibody values after second dose was associated with higher proportion of patients with detected neutralizing antibodies. A significant reduction in the incidence of COVID-19 was observed (6.4% versus 4.2%; P < 0.0001), although the 28-d lethality rate remained unchanged (25% versus 22%; P = 0.534). In 45 patients from the immunogenicity cohort who developed COVID-19, all the 6 deaths occurred among those without antibody response (n = 22; 49%). CONCLUSIONS: CoronaVac vaccine was associated with low reactogenicity, low immunogenicity but reduced incidence of COVID-19 among kidney transplant recipients. The lack of reduction in lethality rates is perhaps associated with the low percentage of patients developing humoral response after the second dose.

Inactivated whole-virus vaccine triggers low response against SARS-CoV-2 infection among renal transplant patients: prospective phase 4 study results

Background. Anti-severe acute respiratory syndrome coronavirus 2 mRNA vaccines elicit lower humoral responses in solid-organ transplant recipients. This is the first prospective trial investigating the effect of an inactivated whole-virion vaccine in kidney transplant recipients. Methods. Prospective, single-center, phase 4, interventional study. Kidney transplant recipients aged 30–69 y with >30 d of transplantation received two 3 µg intramuscular doses of CoronaVac 28 d apart and are being followed for 6 mo. Primary outcomes: (1) reactogenicity after first dose; (2) antibody responses 28 d after each dose; and (3) incidence/severity of confirmed coronavirus disease 2019 (COVID-19) and 28-d lethality rate. For this analysis, clinical effectiveness was assessed for 3 mo, starting 15 d after the second dose, and compared with 3-mo period before vaccination. Results. Of the 3371 individuals who received the first dose, 99% completed vaccination schedule. Mild/local adverse reactions were reported by 33% of the patients. In the immunogenicity cohort (n = 942), the proportion of patients with IgG antibodies to severe acute respiratory syndrome coronavirus 2 increased from 15.2% after first dose to 43% after second dose. Increase in antibody values after second dose was associated with higher proportion of patients with detected neutralizing antibodies. A significant reduction in the incidence of COVID-19 was observed (6.4% versus 4.2%; P < 0.0001), although the 28-d lethality rate remained unchanged (25% versus 22%; P = 0.534). In 45 patients from the immunogenicity cohort who developed COVID-19, all the 6 deaths occurred among those without antibody response (n = 22; 49%). Conclusions. CoronaVac vaccine was associated with low reactogenicity, low immunogenicity but reduced incidence of COVID-19 among kidney transplant recipients. The lack of reduction in lethality rates is perhaps associated with the low percentage of patients developing humoral response after the second dose.