Morning administration enhances humoral response to SARS-CoV-2 vaccination in kidney transplant recipients.

Although severe acute respiratory syndrome coronavirus 2 messenger ribonucleic acid (SARS-CoV-2 mRNA) vaccines are effective in kidney transplant recipients (KTRs), their immune response to vaccination is blunted by immunosuppression. Other tools enhancing vaccination response are therefore needed. Interestingly, aligning vaccine administration with circadian rhythms (chronovaccination) has been shown to boost immune response. However, its applicability in KTRs, whose circadian rhythms are likely disrupted by immunosuppressants, remains unclear. To assess the impact of vaccination timing on seroconversion in the KTRs population, we analyzed data from 553 virus-naïve KTRs who received 2 doses of messenger ribonucleic acid (mRNA) vaccine. Bayesian logistic regression was employed, adjusting for previously identified predictors of seroconversion, including allograft function, maintenance immunosuppressants, or time since transplantation. SARS-CoV-2 immunoglobulin G (IgG) levels were measured with a median of 47 days after the second dose. The results did not reveal a reliable effect of timing of the first dose but did indicate that earlier timing for the second dose brings a notable benefit-every 1-hour delay in the application was associated with a 16% reduction in the odds of seroconversion (OR 0.84, 95% CI 0.71, 0.998). Similar results were obtained from quantile regression modeling IgG levels. In conclusion, morning vaccination is emerging as a promising and easily implementable strategy to enhance vaccine response in KTRs.

Tacrolimus After rATG and Infliximab Induction Immunosuppression-RIMINI Trial.

BACKGROUND: Infliximab selectively targets recently activated effector cells and, as an induction agent, might enable the safe elimination of mycophenolate from maintenance immunosuppression in kidney transplantation. METHODS: This is a phase II international multicenter open-label single-arm confidence interval (CI)-based clinical trial of the BIO-DrIM EU consortium aimed at assessing the efficacy and safety of rabbit antithymocyte globulin and infliximab induction in kidney transplantation. Sixty-seven primary kidney transplant recipients at low risk (panel-reactive antibodies <20%, no donor-specific antibodies [DSA]) received rabbit antithymocyte globulin (2 × 1.5 mg/kg, postoperative days 0 and 1) and infliximab (5 mg/kg, postoperative day 2), followed by mycophenolate-free tacrolimus-based immunosuppression for 12 mo. The primary endpoint was efficacy failure, defined as a composite of acute rejection, graft loss, or poor graft function (estimated glomerular filtration rate <40 mL/min) at 12 mo and was based on the endpoint of the comparator study. Additionally, a historical propensity-matched control cohort was established. RESULTS: Primary endpoint occurred in 22 of 67 patients (32.84%), with upper bound of an exact 1-sided 95% CI of 43.47%, which met the predefined criteria (efficacy failure of <40% and upper-bound 95% CI of <50%) and was similar in the historical matched cohort. By 12 mo, 79.1% of patients remained on the study protocol. Lower rates of BK replication (6% versus 22.4%; P = 0.013) but higher rates of de novo DSAs (11.9% versus 1.5%; P = 0.039) were observed in the study cohort. CONCLUSIONS: A similar efficacy of the study immunosuppression regimen to the comparator study and the historical matched cohort was found. However, a higher de novo DSA emergence points to an increased risk of antibody-mediated rejection (NCT04114188).

Early referring saved lives in kidney transplant recipients with COVID-19: a beneficial role of telemedicine.

Introduction: There is a strong impetus for the use of telemedicine for boosting early detection rates and enabling early treatment and remote monitoring of COVID-19 cases, particularly in chronically ill patients such as kidney transplant recipients (KTRs). However, data regarding the effectiveness of this practice are lacking. Methods: In this retrospective, observational study with prospective data gathering we analyzed the outcomes of all confirmed COVID-19 cases (n = 955) in KTRs followed at our center between March 1, 2020, and April 30, 2022. Risk factors of COVID-19 related mortality were analyzed with focus on the role of early referral to the transplant center, which enabled early initiation of treatment and remote outpatient management. This proactive approach was dependent on the establishment and use of a telemedicine system, which facilitated patient-physician communication and expedited diagnostics and treatment. The main exposure evaluated was early referral of KTRs to the transplantation center after confirmed or suspected COVID-19 infection. The primary outcome was the association of early referral to the transplantation center with the risk of death within 30 days following a COVID-19 diagnosis, evaluated by logistic regression. Results: We found that KTRs who referred their illness to the transplant center late had a higher 30-day mortality (4.5 vs. 13.6%, p < 0.001). Thirty days mortality after the diagnosis of COVID-19 was independently associated with late referral to the transplant center (OR 2.08, 95% CI 1.08-3.98, p = 0.027), higher age (OR 1.09, 95% CI 1.05-1.13, p < 0.001), higher body mass index (OR 1.06, 95% CI 1.01-1.12, p = 0.03), and lower eGFR (OR 0.96, 95% CI 0.94-0.98, p < 0.001) in multivariable logistic regression. Furthermore, KTRs who contacted the transplant center late were older, had longer time from transplantation, lived farther from the center and presented with higher Charlson comorbidity index. Discussion: A well-organized telemedicine program can help to protect KTRs during an infectious disease outbreak by facilitating pro-active management and close surveillance. Furthermore, these results can be likely extrapolated to other vulnerable populations, such as patients with chronic kidney disease, diabetes or autoimmune diseases requiring the use of immunosuppression.

Novel transcriptomic signatures associated with premature kidney allograft failure.

BACKGROUND: The power to predict kidney allograft outcomes based on non-invasive assays is limited. Assessment of operational tolerance (OT) patients allows us to identify transcriptomic signatures of true non-responders for construction of predictive models. METHODS: In this observational retrospective study, RNA sequencing of peripheral blood was used in a derivation cohort to identify a protective set of transcripts by comparing 15 OT patients (40% females), from the TOMOGRAM Study (NCT05124444), 14 chronic active antibody-mediated rejection (CABMR) and 23 stable graft function patients ≥15 years (STA). The selected differentially expressed transcripts between OT and CABMR were used in a validation cohort (n = 396) to predict 3-year kidney allograft loss at 3 time-points using RT-qPCR. FINDINGS: Archetypal analysis and classifier performance of RNA sequencing data showed that OT is clearly distinguishable from CABMR, but similar to STA. Based on significant transcripts from the validation cohort in univariable analysis, 2 multivariable Cox models were created. A 3-transcript (ADGRG3, ATG2A, and GNLY) model from POD 7 predicted graft loss with C-statistics (C) 0.727 (95% CI, 0.638-0.820). Another 3-transcript (IGHM, CD5, GNLY) model from M3 predicted graft loss with C 0.786 (95% CI, 0.785-0.865). Combining 3-transcripts models with eGFR at POD 7 and M3 improved C-statistics to 0.860 (95% CI, 0.778-0.944) and 0.868 (95% CI, 0.790-0.944), respectively. INTERPRETATION: Identification of transcripts distinguishing OT from CABMR allowed us to construct models predicting premature graft loss. Identified transcripts reflect mechanisms of injury/repair and alloimmune response when assessed at day 7 or with a loss of protective phenotype when assessed at month 3. FUNDING: Supported by the Ministry of Health of the Czech Republic under grant NV19-06-00031.

The impact of frailty syndrome on humoral response to SARS-CoV-2 mRNA vaccines in older kidney transplant recipients.

PURPOSE: Advanced age is associated with an impaired humoral immune response to SARS-CoV-2 mRNA vaccination in kidney transplant recipients (KTR). The mechanisms are, however, poorly understood. Frailty syndrome assessment may determine the most vulnerable population. METHODS: This study is a secondary analysis of a prospective study (NCT04832841) regarding seroconversion after BNT162b2 vaccination, including 101 SARS-CoV-2 naïve KTR 70 years and older. The Fried frailty components were evaluated, and antibodies against S1 and S2 subunits of SARS-CoV-2 were examined > 14 days after the second dose of BNT162b2 vaccine. RESULTS: Seroconversion was observed in 33 KTR. Male gender, eGFR, MMF-free immunosuppression, and a lower frailty score were associated with higher seroconversion rates in univariable regression. Concerning frailty components, physical inactivity had the most negative effect on seroconversion (OR = 0.36, 95% CI 0.14-0.95, p = 0.039). In a multivariable regression adjusted for eGFR, MMF-free immunosuppression, time from transplant and gender, pre-frail (OR = 0.27, 95% CI 0.07-1.00, p = 0.050), and frail status (OR = 0.14, 95% CI 0.03-0.73, p = 0.019) were associated with an increased risk of unresponsiveness to SARS-CoV-2 vaccines. CONCLUSION: Frailty was associated with an impaired humoral response to SARS-CoV-2 mRNA vaccination in older SARS-CoV-2 naïve KTR. TRAIL REGISTRATION: This study is registered under the identifier NCT04832841 on ClinicalTrials.gov.

Association Between SARS-CoV-2 Messenger RNA Vaccines and Lower Infection Rates in Kidney Transplant Recipients : A Registry-Based Report.

BACKGROUND: The real-world protection provided by SARS-CoV-2 messenger RNA (mRNA) vaccines to kidney transplant recipients (KTRs) remains uncertain. OBJECTIVE: To study the association between mRNA vaccination and SARS-CoV-2 infection rate in KTRs. DESIGN: Retrospective observational cohort study. SETTING: The Czech Republic (17 February to 16 May 2021). PATIENTS: 2101 KTRs followed in the Department of Nephrology at the Institute for Clinical and Experimental Medicine. MEASUREMENTS: Positive result for SARS-CoV-2 on polymerase chain reaction test and vaccination status of KTRs. RESULTS: The incidence rate in the vaccinated group was 0.474 per 1000 person-days (33 cases in 69 672 days at risk). The incidence rate in the unvaccinated group was 1.370 per 1000 person-days (79 cases in 57 658 days at risk). The unadjusted incidence rate ratio (IRR; incidence rate of vaccinated/incidence rate of unvaccinated) for KTRs was 0.346 (95% CI, 0.227 to 0.514). The multivariable adjusted IRR for KTRs was 0.544 (CI, 0.324 to 0.876). LIMITATION: Retrospective observational design, uneven follow-up of patient groups, and different exposition to SARS-CoV-2 stemming from strong temporal trends and differences in clinical and probably behavioral characteristics. CONCLUSION: Vaccination of KTRs is associated with lower risk for SARS-CoV-2 infection. PRIMARY FUNDING SOURCE: The Ministry of Health of the Czech Republic.

Determinants of Immune Response to Anti-SARS-CoV-2 mRNA Vaccines in Kidney Transplant Recipients: A Prospective Cohort Study.

BACKGROUND: Immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has been recently shown to be impaired in kidney transplant recipients (KTRs), but the underlying factors affecting vaccine effectiveness need to be further elucidated. METHODS: In this prospective cohort study, antibodies against S1 and S2 subunits of SARS-CoV-2 were evaluated using an immunochemiluminescent assay (cutoff 9.5 AU/mL, sensitivity 91.2%, and specificity 90.2%) in 736 KTRs, who were previously either naive or infected with SARS-CoV-2 and vaccinated before or after transplantation. Cellular response was analyzed in a subset of patients using an interferon gamma release assay (cutoff 0.15 IU/mL, sensitivity 92%, and specificity 100%). RESULTS: Seroconversion was significantly more impaired in SARS-CoV-2-naive KTRs than in those previously infected (40.1% versus 97.1%; P < 0.001). Mycophenolate use (odds ratio, 0.15; 95% confidence interval, 0.09-0.24; P < 0.001) and depleting therapy in the past year (odds ratio, 0.19; 95% confidence interval, 0.05-0.8; P = 0.023) were found to be among independent factors associated with impaired humoral response. Similarly, the interferon gamma release assay tested in 50 KTRs (cutoff 0.15 IU/mL, sensitivity 92%, specificity 100%) showed that specific T-cell responses against spike protein epitopes are impaired in SARS-CoV-2-naive KTRs, as compared to previously infected KTRs (9.4% versus 90%, P < 0.001). All 35 KTRs vaccinated on the waiting list before transplantation exhibited sustained seroconversion persisting after transplantation. CONCLUSIONS: Survivors of coronavirus disease 2019 and those vaccinated while on the waiting list exhibited a marked immune response to mRNA vaccines, contrary to poor response in naive KTRs vaccinated after transplantation (NCT04832841).

Humoral response to SARS-CoV-2 is well preserved and symptom dependent in kidney transplant recipients.

Data on the immune response to SARS-CoV-2 in kidney transplant recipients are scarce. Thus, we conducted a single-center observational study to assess the anti-SARS-CoV-2 IgG seroprevalence in outpatient kidney transplant recipients (KTR; n = 1037) and healthcare workers (HCW; n = 512) during the second wave of the COVID-19 pandemic in fall 2020 and evaluated the clinical variables affecting antibody levels. Antibodies against S1 and S2 subunit of SARS-CoV-2 were evaluated using immunochemiluminescent assay (cut off 9.5 AU/ml, sensitivity of 91.2% and specificity of 90.2%). Anti-SARS-CoV-2 IgG seroprevalence was lower in KTR than in HCW (7% vs. 11.9%, p = .001). Kidney transplant recipients with SARS-CoV-2 infection were younger (p = .001) and received CNI-based immunosuppression more frequently (p = .029) than seronegative KTR. Anti-SARS-CoV-2 IgG positive symptomatic KTR had a higher BMI (p = .04) than asymptomatic KTR. Interestingly, anti-SARS-CoV-2 IgG levels were higher in KTR than in HCW (median 31 AU/ml, IQR 17-84 vs. median 15 AU/ml, IQR 11-39, p < .001). The presence of moderate to severe symptoms in KTR was found to be the only independent factor affecting IgG levels (Beta coefficient = 41.99, 95% CI 9.92-74.06, p = .011) in the multivariable model. In conclusion, KTR exhibit a well-preserved symptom-dependent humoral response to SARS-CoV-2 infection.