Polyomavirus Nephropathy in ABO Blood Group-Incompatible Kidney Transplantation: Torque Teno Virus and Immunosuppressive Burden as an Approximation to the Problem.

Introduction: Earlier reports suggest that patients after ABO-incompatible kidney transplantation (ABOi) are at enhanced risk of developing BK-virus (BKV, also known as BK polyomavirus [BKPyV]) nephropathy (BKPyVAN). It remains elusive whether this is a result of more intense immunosuppression or an ABOi-associated "intrinsic attribute." To address this question, we measured Torque Teno virus (TTV) loads as a quantitative proxy for immunosuppressive depth in ABOi recipients and compared them to human leukocyte antigen-incompatible (HLAi, i.e. pretransplant donor-specific antibody-positive) and standard-risk transplant recipients. Methods: Our retrospective study screened 2256 consecutive kidney transplantations performed between 2007 and 2020 at the Medical University of Vienna. Out of 629 in-principle eligible transplantations, we were able to include 465 patients: 42 ABOi, 106 HLAi, and 317 control recipients. Longitudinal TTV- polymerase chain reaction (PCR) and BKV-PCR was carried out at predefined timepoints and ranged from pretransplant until month 24 posttransplantation. TTV loads and immunosuppression were evaluated in the context of BKV-associated complications. Results: ABOi recipients had a higher TTV load compared to HLAi and controls both at month 3 (median 1.5 × 109 vs. 2.4 × 108 vs. 9.1 × 107; P = 0.010) and at month 6 (3.1 × 109 vs. 1.4 × 107 vs. 6.4 × 107; P = 0.014) posttransplantation. Tacrolimus exposure was significantly higher in ABOi patients compared to HLAi and control patients (ABOi vs. HLAi: P = 0.007; ABOi vs. controls: P < 0.0001). Biopsy-proven BKPyVAN was more frequent in ABOi recipients when compared to HLAi and control recipients (11.9% vs. 2.8% vs. 4.1%; P = 0.046). Conclusion: Our data support the assumption that ABOi patients are indeed at higher risk to develop BKPyVAN. A higher TTV load and immunosuppressive burden suggest that intense immunosuppression, rather than an "intrinsic attribute" conferred by ABOi, may contribute to this finding.

The association of Torque Teno viral load with CMV and BKV infection in pediatric and adolescent kidney transplant patients.

BACKGROUND: Long-term allograft and patient survival after kidney transplantation (KTX) depends on the balance between over- and under-immunosuppression (IS). High levels of IS predispose to opportunistic infections. Plasma load of Torque Teno Virus (TTV), a non-pathogenic highly prevalent Annellovirus, is associated with its hosts immune status, especially after solid organ transplantation. OBJECTIVES: To investigate the association of plasma TTV load and opportunistic viral infections after pediatric KTX. STUDY DESIGN: This retrospective study includes all pediatric KTX patients followed at the Medical University of Vienna 2014-2020. PCR for Cytomegalovirus (CMV), Epstein-Barr virus (EBV), BK virus (BKV), and TTV was performed every 4-8 weeks at routine follow-up visits. RESULTS: 71 pediatric KTX patients were followed with TTV measurements for a median of 2.7 years. TTV plasma load was associated with CMV DNAemia at the next visit with an OR of 2.37 (95 % CI 1.15-4.87; p = 0.03) after adjustment for time after KTX and recipient age. For a cut-off of 7.68 log10 c/mL TTV a sensitivity of 100 %, a specificity of 61 %, a NPV 100 %, and a PPV of 46 % to detect CMV DNAemia at the next visit was calculated. TTV plasma loads were also associated with BKV DNAuria and BKV DNAemia at the next visit, but not with EBV DNAemia. CONCLUSIONS: This is the first study to analyse associations between TTV plasma loads and opportunistic viral infections in pediatric KTX. We were able to present a TTV cut-off for the prediction of clinically relevant CMV DNAemia that might be useful in clinical care.

The kinetics of Torque Teno virus plasma load following calcineurin inhibitor dose change in kidney transplant recipients.

Torque Teno virus (TTV) is nonpathogenic, highly prevalent, and reflects the immune status of its host. Thus, TTV plasma load was suggested for the guidance of immunosuppression post solid organ transplantation. The present study was designed to determine the kinetics of TTV following changes in calcineurin inhibitor (CNI) dose. A total of 48 adult recipients of a kidney graft transplanted at the Medical University of Vienna between 2018 and 2019 with isolated changes in CNI dose were selected from the prospective TTV-POET trial. TTV plasma load was quantified by in-house PCR. At Day 30 following CNI dose adaptation (median 33% of daily dose) no changes in TTV load were noted. However, at Day 60, following CNI dose reduction a lower TTV load of 6.4 log10 c/mL (median; interquartile range [IQR] 4.9-8.1) compared with the baseline of 7.1 log10 c/mL (IQR 5.3-8.9) was noted (p = 0.001); there was also a trend toward a higher TTV load following CNI increase (6.6 log10 c/mL, IQR 4.1-9.7 vs. 5.2 log10 c/mL, IQR 4.5-6.8; p = 0.09). The data suggested that TTV load changes become noticeable only 2 months after CNI dose adaptation, which might be the ideal time point for TTV load monitoring.

Prediction of humoral and cellular immune response to COVID-19 mRNA vaccination by TTV load in kidney transplant recipients and hemodialysis patients.

BACKGROUND: Immunosuppressed individuals such as kidney transplant recipients (KTR) and hemodialysis patients (DP) show impaired immune responses to COVID-19 vaccination. Plasma Torque Teno Virus (TTV) DNA load is used as surrogate for the individual degree of immunosuppression. We now assessed the association of TTV load at time of COVID-19 vaccination with humoral and cellular immune response rates to vaccination in KTR, DP, and healthy medical personnel (MP). METHODS: A total of 100 KTR, 115 DP and 54 MP were included. All were SARS-CoV-2 seronegative at the time of vaccination with either BNT162b2 or mRNA-1273. Plasma TTV loads were assessed at the time of first vaccination. After two-dose vaccination, seroconversion (de novo detection of SARS-CoV-2 S1-IgA and/or IgG) was determined. In addition, cellular responses as assessed by interferon γ release and neutralizing antibodies were assessed in a subset of participants. ROC analyses were performed to define TTV load cut-offs predicting specific immune responses to vaccination. RESULTS: Plasma TTV loads at the time of first vaccination were negatively associated with seroconversion after two-dose vaccination in KTR (OR 0.87, 95% CI 0.76-0.99). TTV loads were significantly lower in KTR who developed humoral and cellular immune responses to vaccination compared to non-responders (p = 0.0411 and 0.0030, respectively). Of patients with TTV loads above 106 copies/ml, none developed cellular immune responses against SARS-CoV-2, and only 2 of 17 (12%) seroconverted in response to vaccination. CONCLUSION: Plasma TTV loads at the time of first vaccination in immunosuppressed individuals may be useful to predict individual vaccine-specific immune responses.

A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation: TTVguideIT.

BACKGROUND: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. METHODS: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. DISCUSSION: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents. TRIAL REGISTRATION: EU CT-Number: 2022-500024-30-00.

Validation of plasma Torque Teno viral load applying a CE-certified PCR for risk stratification of rejection and infection post kidney transplantation.

BACKGROUND: Torque Teno virus (TTV) is non-pathogenic, highly prevalent and reflects the immune status of its host. TTV plasma load was suggested for risk stratification of graft rejection and infection post kidney-transplantation, for which most studies applied an in-house PCR. Recently, a commercial PCR was CE-certified for clinical use. The present study was designed to assess the performance of TTV load as quantified by the commercial PCR in the prediction of graft rejection and infection. METHODS: Patients and events were selected from the prospective TTV-POET trial, including 683 consecutive adult recipients of a kidney-graft transplanted at the Medical University Vienna, 2016-2020. TTV was quantified in plasma drawn in Months 4-12 post-transplant by in-house and commercial PCR and associated with consecutive infections and graft rejections until Month 12 post-transplantation. RESULTS: A total of 342 samples from 314 patients with 85 biopsies (rejection, n = 18) and 79 infectious events were assessed. The two PCRs were highly associated (estimate 0.91, 95%CI 0.89-0.93), with a mean difference of 1.38 log10 copies/mL (95%CI 1.46-1.30). The risk of rejection decreased by 25% with every log10 increase in TTV load as quantified by commercial PCR (RR 0.75, 95%CI 0.67-0.85), and the risk of infection increased by 6% (RR 1.06, 95%CI 1.00-1.12). CONCLUSION: These data support the value of TTV quantification by commercial PCR for the risk stratification of graft rejection and infection in the first year post kidney-transplantation. The test performance determined within this study may serve to design clinical trials and subsequently, support application in clinical routine.

Obesity is associated with a higher Torque Teno viral load compared to leanness.

Introduction: Obesity affects a rising proportion of the population and is an important risk factor for unfavorable outcomes in viral disease including severe acute respiratory syndrome coronavirus 2- associated diseases. Torque Teno virus (TTV) is a ubiquitous and apathogenic virus which reflects the immune function of its host. The aim of this study was to investigate the association between obesity and TTV load - an indirect marker of compromised viral immune response. Methods: TTV was quantified by TTV R-GENE® PCR in a total of 89 participants of which 30 were lean (BMI <25 kg/m2) and 59 were obese (BMI >30 kg/m2). For 38 subjects, follow-up was available after bariatric surgery. Results: TTV load was higher in individuals with obesity (median 2.39, IQR: 1.69-3.33 vs. 1.88, IQR 1.08-2.43 log10 copies/mL; p = 0.027). Multivariable linear modeling revealed an independent association between TTV load and obesity. TTV was positively correlated with waist-to-hip ratio and inversely with 25OH vitamin D levels. Interleukin 6 and fasting insulin resistance were confounders of the association between TTV and obesity, while age was an effect modifier. TTV load increased by 87% (95% CI 2-243%) in the year following bariatric surgery. Discussion: A higher TTV load in obese individuals may reflect compromised immune function and thus might serve for risk stratification of unfavorable outcomes during infectious disease, including coronavirus disease 2019, in this population. Our data warrant further analysis of TTV-based risk assessment in obese individuals in the context of infectious disease-associated outcomes.

SARS-CoV-2 IgG spike protein antibody response in mRNA-1273 Moderna® vaccinated patients on maintenance immunoapheresis - a cohort study.

Background: The SARS-CoV-2 pandemic increased mortality and morbidity among immunocompromised populations. Vaccination is the most important preventive measure, however, its effectiveness among patients depending on maintenance immunoglobulin G (IgG) apheresis to control autoimmune disease activity is unknown. We aimed to examine the humoral immune response after mRNA-1273 Moderna® vaccination in immunoapheresis patients. Methods: We prospectively monitored SARS-CoV-2 IgG spike (S) protein antibody levels before and after each IgG (exposure) or lipid (LDL) apheresis (controls) over 12 weeks and once after 24 weeks. Primary outcome was the difference of change of SARS-CoV-2 IgG S antibody levels from vaccination until week 12, secondary outcome was the difference of change of SARS-CoV-2 IgG S antibody levels by apheresis treatments across groups. Results: We included 6 IgG and 18 LDL apheresis patients. After 12 weeks the median SARS-CoV-2 IgG S antibody level was 115 (IQR: 0.74, 258) in the IgG and 1216 (IQR: 788, 2178) in the LDL group (p=0.03). Median SARS-CoV-2 IgG S antibody reduction by apheresis was 76.4 vs. 23.7% in the IgG and LDL group (p=0.04). The average post- vs. pre-treatment SARS-CoV-2 IgG S antibody rebound in the IgG group vs. the LDL group was 46.1 and 6.44%/week from prior until week 12 visit. Conclusions: IgG apheresis patients had lower SARS-CoV-2 IgG S antibody levels compared to LDL apheresis patients, but recovered appropriately between treatment sessions. We believe that IgG apheresis itself probably has less effect on maintaining the immune response compared to concomitant immunosuppressive drugs. Immunization is recommended independent of apheresis treatment.

Stopping of Mycophenolic Acid in Kidney Transplant Recipients for 2 Weeks Peri-Vaccination Does Not Increase Response to SARS-CoV-2 Vaccination-A Non-randomized, Controlled Pilot Study.

Introduction: Kidney transplant recipients (KTR) are at high risk of developing severe COVID-19. However, vaccine response in this population is severely impaired with humoral response rates of 36-54 and 55-69% after two or three doses of SARS-COV-2 vaccines, respectively. Triple immunosuppression and specifically the use of anti-proliferative agents such as mycophenolic acid (MPA) or azathioprine (AZA) have been identified as risk factors for vaccine hypo-responsiveness. Methods: We hypothesized that in vaccine non-responders to at least three previous vaccine doses, pausing of MPA or AZA for 1 week before and 1 week after an additional vaccination would improve humoral response rates. We conducted an open-label, non-randomized controlled pilot study including 40 KTR with no detectable humoral response after three or four previous vaccine doses. Primary endpoint was seroconversion following SARS-CoV-2 vaccination. MPA and AZA was paused in 18 patients 1 week before until 1 week after an additional vaccine dose while immunosuppression was continued in 22 patients. Results: There was no difference in the humoral response rate between the MPA/AZA pause group and the control group (29 vs. 32%, p > 0.99). Absolute antibody levels were also not statistically significantly different between the two groups (p = 0.716).Renal function in the MPA/AZA pause group remained stable and there was no detection of new onset donor-specific antibodies or an increase of donor-derived cell-free DNA serving as a marker of allograft damage throughout the study period. Conclusion: Pausing of MPA/AZA for 2 weeks peri-vaccination did not increase the rate of seroconversion in kidney transplant. However, one in three KTR without humoral immune response to at least three previous vaccinations developed antibodies after an additional vaccine dose supporting continued vaccination in non-responders.

Early Estimated Glomerular Filtration Rate Trajectories After Kidney Transplant Biopsy as a Surrogate Endpoint for Graft Survival in Late Antibody-Mediated Rejection.

Background: Late antibody-mediated rejection (ABMR) after kidney transplantation is a major cause of long-term allograft loss with currently no proven treatment strategy. Design for trials testing treatment for late ABMR poses a major challenge as hard clinical endpoints require large sample sizes. We performed a retrospective cohort study applying commonly used selection criteria to evaluate the slope of the estimated glomerular filtration rate (eGFR) within an early and short timeframe after biopsy as a surrogate of future allograft loss for clinical trials addressing late ABMR. Methods: Study subjects were identified upon screening of the Vienna transplant biopsy database. Main inclusion criteria were (i) a solitary kidney transplant between 2000 and 2013, (ii) diagnosis of ABMR according to the Banff 2015 scheme at >12 months post-transplantation, (iii) age 15-75 years at ABMR diagnosis, (iv) an eGFR > 25 mL/min/1.73 m2 at ABMR diagnosis, and (v) a follow-up for at least 36 months after ABMR diagnosis. The primary outcome variable was death-censored graft survival. A mixed effects model with linear splines was used for eGFR slope modeling and association of graft failure and eGFR slope was assessed applying a multivariate competing risk analysis with landmarks set at 12 and 24 months after index biopsy. Results: A total of 70 allografts from 68 patients were included. An eGFR loss of 1 ml/min/1.73 m2 per year significantly increased the risk for allograft failure, when eGFR slopes were modeled over 12 months [HR 1.1 (95% CI: 1.01-1.3), p = 0.020] or over 24 months [HR 1.3 (95% CI: 1.1-1.4), p = 0.001] after diagnosis of ABMR with landmarks set at both time points. Covariables influencing graft loss in all models were histologic evidence of glomerulonephritis concurring with ABMR as well as the administration of anti-thymocyte globulin (ATG) at the time of transplantation. Conclusion: Our study supports the use of the eGFR slope modeled for at least 12 months after biopsy-proven diagnosis of late ABMR, as a surrogate parameter for future allograft loss. The simultaneous occurrence of glomerulonephritis together with ABMR at index biopsy and the use of ATG at the time of transplantation-likely representing a confounder in pre-sensitized recipients-were strongly associated with worse transplant outcomes.

Integrated Immunologic Monitoring in Solid Organ Transplantation: The Road Toward Torque Teno Virus-guided Immunosuppression.

Potent immunosuppressive drugs have been introduced into clinical care for solid organ transplant recipients. It is now time to guide these drugs on an individual level to optimize their efficacy. An ideal tool simultaneously detects overimmunosuppression and underimmunosuppression, is highly standardized, and is straightforward to implement into routine. Randomized controlled interventional trials are crucial to demonstrate clinical value. To date, proposed assays have mainly focused on the prediction of rejection and were based on the assessment of few immune compartments. Recently, novel tools have been introduced based on a more integrated approach to characterize the immune function and cover a broader spectrum of the immune system. In this respect, the quantification of the plasma load of a highly prevalent and apathogenic virus that might reflect the immune function of its host has been proposed: the torque teno virus (TTV). Although TTV control is driven by T cells, other major immune compartments might contribute to the hosts' response. A standardized in-house polymerase chain reaction and a conformité européenne-certified commercially available polymerase chain reaction are available for TTV quantification. TTV load is associated with rejection and infection in solid organ transplant recipients, and cutoff values for risk stratification of such events have been proposed for lung and kidney transplantation. Test performance of TTV load does not allow for the diagnosis of rejection and infection but is able to define at-risk patients. Hitherto TTV load has not been used in interventional settings, but two interventional randomized controlled trials are currently testing the safety and efficacy of TTV-guided immunosuppression.

Proteinuria in Deceased Kidney Transplant Donors for Prediction of Chronic Lesions in Pretransplant Biopsies: A Prospective Observational Study.

BACKGROUND: Pretransplant kidney graft biopsies have been suggested for organ quality assessment. Data on the association between donor proteinuria and organ quality of deceased donors are not available. METHODS: In this prospective study, we analyzed 147 pretransplant kidney biopsies from 88 deceased adult donors procured and transplanted consecutively at the Medical University Vienna between July 2017 and May 2020. Lesions in each renal compartment were scored from 0 to 5 with each ascending score representing a 20% increase in organ damage. A chronic lesions score was calculated including glomerulosclerosis, intima fibrosis, hyalinosis, interstitial fibrosis, and tubular atrophy. RESULTS: The median chronic lesion score was 2 (interquartile range [IQR] 1-4) and the median donor urinary protein to creatinine ratio (UPCR) was 382 mg/dL (IQR 222-703). There was a positive correlation between UPCR and number of chronic lesions (ß 0.15, 95% confidence interval, 0.03-0.28; P = 0.019). Biopsies with 2 or more lesions had a median UPCR of 486 mg/dL (IQR 251-717) compared with 274 mg/dL (IQR 211-556; P = 0.016) in biopsies with <2 lesions. The risk for detection of 2 or more lesions rose by 18% for every log increase in UPCR (risk ratio 1.18, 95% confidence interval, 1.03-1.25; P = 0.017). Multivariable and sensitivity analysis revealed an independent and robust association between chronic lesions and UPCR. CONCLUSIONS: Donor UPCR is associated with chronic lesions in pretransplant deceased donor kidney graft biopsies. This finding justifies further investigation of donor proteinuria for the assessment of organ quality and outcome.

Torque Teno Virus quantification for monitoring of immunomodulation with biologic compounds in the treatment of rheumatoid arthritis.

OBJECTIVES: RA patients who fail to respond to MTX can receive biologic dMARDs (bDMARDs). The Torque Teno Virus (TTV) is a potential novel candidate for monitoring of immunosuppression. We explore TTV in these patients and its association with clinical response to bDMARDs. METHODS: The BioBio Study is a multicentre randomized open-label trial, including RA patients with insufficient response to MTX. Patients were randomized to either TNFi (infliximab, INF), anti-IL-6 (tocilizumab, TCZ), CTLA4-Ig (abatacept, ABA) or anti-CD20 (rituximab, RTX) in addition to MTX. PCR was used to quantify TTV in the peripheral blood. RESULTS: TTV was measured in 95 patients (INF, n = 23; TCZ, n = 22; ABA, n = 27; RTX; n = 23). TTV increased by a median of 4.5 × 104 copies/ml [c/ml; interquartile range (IQR) 0-7.5 × 105] after 3 months. TTV levels at month 3 were associated with the Simplified Disease Activity Index (SDAI) (P = 0.03) and the Clinical Disease Activity Index (CDAI) response (P = 0.026) at month 6. A TTV cut-off level of 1.2 × 106 c/ml at month 3 had a positive likelihood ratio of 2.7 for prediction of an 85% reduction in SDAI at month 6. CONCLUSION: Our data suggest that TTV levels increase upon TNF, CD20 and costimulation blockade and are associated with the clinical response to bDMARDs in RA patients. TRIAL REGISTRATION: ClinicalTrials.gov; https://clinicaltrials.gov; NCT01638715.

Comparison of SARS-CoV-2 Antibody Response 4 Weeks After Homologous vs Heterologous Third Vaccine Dose in Kidney Transplant Recipients: A Randomized Clinical Trial.

Importance: Fewer than 50% of kidney transplant recipients (KTRs) develop antibodies against the SARS-CoV-2 spike protein after 2 doses of an mRNA vaccine. Preliminary data suggest that a heterologous vaccination, combining mRNA and viral vector vaccines, may increase immunogenicity. Objective: To assess the effectiveness of a third dose of an mRNA vs a vector vaccine in KTRs who did not have antibodies against the SARS-CoV-2 spike protein after 2 doses of an mRNA vaccine. Design, Setting, and Participants: This was a single center, single-blinded, 1:1 randomized clinical trial of a third dose of vaccine against SARS-CoV-2, conducted from June 15 to August 16, 2021, in 201 KTRs who had not developed SARS-CoV-2 spike protein antibodies after 2 doses of an mRNA vaccine. Data analyses were performed from August 17 to August 31, 2021. Interventions: mRNA (BNT162b2 or mRNA-1273) or vector (Ad26COVS1) as a third dose of a SARS-CoV-2 vaccine. Main Outcomes and Measures: The primary study end point was seroconversion after 4 weeks (29-42 days) following the third vaccine dose. Secondary end points included neutralizing antibodies and T-cell response assessed by interferon-γ release assays (IGRA). In addition, the association of patient characteristics and vaccine response was assessed using logistic regression, and the reactogenicity of the vaccines was compared. Results: Among the study population of 197 kidney transplant recipients (mean [SD] age, 61.2 [12.4] years; 82 [42%] women), 39% developed SARS-CoV-2 antibodies after the third vaccine. There was no statistically significant difference between groups, with an antibody response rate of 35% and 42% for the mRNA and vector vaccines, respectively. Only 22% of seroconverted patients had neutralizing antibodies. Similarly, T-cell response assessed by IGRA was low with only 17 patients showing a positive response after the third vaccination. Receiving nontriple immunosuppression (odds ratio [OR], 3.59; 95% CI, 1.33-10.75), longer time after kidney transplant (OR, 1.44; 95% CI, 1.15-1.83, per doubling of years), and torque teno virus plasma levels (OR, 0.92; 95% CI, 0.88-0.96, per doubling of levels) were associated with vaccine response. The third dose of an mRNA vaccine was associated with a higher frequency of local pain at the injection site compared with the vector vaccine, while systemic symptoms were comparable between groups. Conclusions and Relevance: This randomized clinical trial found that 39% of KTRs without an immune response against SARS-CoV-2 after 2 doses of an mRNA vaccine developed antibodies against the SARS-CoV-2 spike protein 4 weeks after a third dose of an mRNA or a vector vaccine. The heterologous vaccination strategy with a vector-based vaccine was well tolerated and safe but not significantly better than the homologous mRNA-based strategy. Trial Registration: EudraCT Identifier: 2021-002927-39.

Torque Teno Virus Load Is Associated With Subclinical Alloreactivity in Kidney Transplant Recipients: A Prospective Observational Trial.

BACKGROUND: Nonpathogenic torque teno viruses (TTVs) are highly prevalent in transplant recipients and associated with immunosuppression. Studies in kidney transplant patients have proposed assessment of TTV load for risk stratification of clinically overt graft rejection. The value of TTV quantification in the context of subclinical rejection has not been evaluated. METHODS: In this prospective trial, 307 consecutive kidney transplant recipients were subjected to per-protocol monitoring of plasma TTV. TTV was analyzed in the context of protocol biopsies (n = 82), scheduled 1 year posttransplantation. RESULTS: TTV load at the time of biopsy was lower in recipients with rejection (n = 19; according to Banff, including borderline changes suspicious for acute T cell-mediated rejection) than those without rejection (n = 63) whereby each log increase in TTV copies/mL decreased the risk for rejection by 9% (risk ratio 0.91, 95% confidence interval, 0.85-0.97; P = 0.004). Development of chronic lesions (cg, cv, ci, ct, ah, ptcml) was associated with the number of days with a TTV load <1 × 106 copies/mL between months 3 and 12 posttransplant (ß 0.07, 95% confidence interval, 0.01-0.14; P = 0.02). CONCLUSIONS: This trial demonstrates an association between TTV and subclinical graft rejection in kidney transplant recipients. A TTV load <1 × 106 copies/mL suggests suboptimal immunosuppression.

A Randomized Clinical Trial of Anti-IL-6 Antibody Clazakizumab in Late Antibody-Mediated Kidney Transplant Rejection.

BACKGROUND: Late antibody-mediated rejection (ABMR) is a leading cause of transplant failure. Blocking IL-6 has been proposed as a promising therapeutic strategy. METHODS: We performed a phase 2 randomized pilot trial to evaluate the safety (primary endpoint) and efficacy (secondary endpoint analysis) of the anti-IL-6 antibody clazakizumab in late ABMR. The trial included 20 kidney transplant recipients with donor-specific, antibody-positive ABMR ≥365 days post-transplantation. Patients were randomized 1:1 to receive 25 mg clazakizumab or placebo (4-weekly subcutaneous injections) for 12 weeks (part A), followed by a 40-week open-label extension (part B), during which time all participants received clazakizumab. RESULTS: Five (25%) patients under active treatment developed serious infectious events, and two (10%) developed diverticular disease complications, leading to trial withdrawal. Those receiving clazakizumab displayed significantly decreased donor-specific antibodies and, on prolonged treatment, modulated rejection-related gene-expression patterns. In 18 patients, allograft biopsies after 51 weeks revealed a negative molecular ABMR score in seven (38.9%), disappearance of capillary C4d deposits in five (27.8%), and resolution of morphologic ABMR activity in four (22.2%). Although proteinuria remained stable, the mean eGFR decline during part A was slower with clazakizumab compared with placebo (-0.96; 95% confidence interval [95% CI], -1.96 to 0.03 versus -2.43; 95% CI, -3.40 to -1.46 ml/min per 1.73 m2 per month, respectively, P=0.04). During part B, the slope of eGFR decline for patients who were switched from placebo to clazakizumab improved and no longer differed significantly from patients initially allocated to clazakizumab. CONCLUSIONS: Although safety data indicate the need for careful patient selection and monitoring, our preliminary efficacy results suggest a potentially beneficial effect of clazakizumab on ABMR activity and progression.