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Static cold storage (SCS) remains the gold standard for preserving donor hearts before transplantation but is associated with ischaemia, anaerobic metabolism, and organ injuries, leading to patient morbidity and mortality. We aimed to evaluate whether continuous, hypothermic oxygenated machine perfusion (HOPE) of the donor heart is safe and superior compared with SCS. We performed a multinational, multicentre, randomised, controlled, open-label clinical trial with a superiority design at 15 transplant centres across eight European countries. Adult candidates for heart transplantation were eligible and randomly assigned in a 1:1 ratio. Donor inclusion criteria were age 18–70 years with no previous sternotomy and donation after brain death. In the treatment group, the preservation protocol involved the use of a portable machine perfusion system ensuring HOPE of the resting donor heart. The donor hearts in the control group underwent ischaemic SCS according to standard practices. The primary outcome was time to first event of a composite of either cardiac-related death, moderate or severe primary graft dysfunction (PGD) of the left ventricle, PGD of the right ventricle, acute cellular rejection at least grade 2R, or graft failure (with use of mechanical circulatory support or re-transplantation) within 30 days after transplantation. We included all patients who were randomly assigned, fulfilled inclusion and exclusion criteria, and received a transplant in the primary analysis and all patients who were randomly assigned and received a transplant in the safety analyses. This trial was registered with ClicalTrials.gov (NCT03991923) and is ongoing. A total of 229 patients were enrolled between Nov 25, 2020, and May 19, 2023. The primary analysis population included 204 patients who received a transplant. There were no patients who received a transplant lost to follow-up. All 100 donor hearts preserved with HOPE were transplantable after perfusion. The primary endpoint was registered in 19 (19%) of 101 patients in the HOPE group and 31 (30%) of 103 patients in the SCS group, corresponding to a risk reduction of 44% (hazard ratio 0·56; 95% CI 0·32–0·99; log-rank test p=0·059). PGD was the primary outcome event in 11 (11%) patients in the HOPE group and 29 (28%) in the SCS group (risk ratio 0·39; 95% CI 0·20–0·73). In the HOPE group, 63 (65%) patients had a reported serious adverse event (158 events) versus 87 (70%; 222 events) in the SCS group. Major adverse cardiac transplant events were reported in 18 (18%) and 33 (32%) patients in the HOPE and SCS group (risk ratio 0·56; 95% CI 0·34–0·92). Although there was not a significant difference in the primary endpoint, the 44% risk reduction associated with HOPE was suggested to be a clinically meaningful benefit. Post-transplant complications, measured as major adverse cardiac transplant events, were reduced. Analysis of secondary outcomes suggested that HOPE was beneficial in reducing primary graft dysfunction. HOPE in donor heart preservation addresses the existing challenges associated with graft preservation and the increasing complexity of donors and heart transplantation recipients. Future investigation will help to further elucidate the benefit of HOPE. XVIVO Perfusion.

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

Renal-transplant recipients were given alemtuzumab induction therapy or conventional induction therapy as part of a program of early glucocorticoid withdrawal. Acute rejection was less frequent with alemtuzumab during the first year. In the United States between 1998 and 2007, a total of 78% of renal-transplant recipients received antibody induction therapy. The most frequently used agents have been rabbit antithymocyte globulin (Thymoglobulin, Genzyme), a lymphocyte-depleting polyclonal antibody, and basiliximab (Simulect, Novartis Pharmaceuticals), a non–lymphocyte-depleting monoclonal antibody targeting the interleukin-2 receptor. 1 More recently, alemtuzumab (Campath-1H, Berlex Laboratories), an anti-CD52 T-cell and B-cell–depleting monoclonal antibody, has been used for induction in renal transplantation. 2 – 5 Although a number of trials of early glucocorticoid withdrawal and calcineurin-inhibitor minimization have been conducted in renal-transplant recipients over the past decade, it is not clear which induction agent is . . .

Standard practice for immunosuppressive therapy after renal transplantation is quadruple therapy using antibody induction, low-dose tacrolimus, mycophenolate mofetil, and corticosteroids. Long-term steroid intake significantly increases cardiovascular risk factors with negative effects on the outcome, especially post-transplantation diabetes associated with morbidity and mortality. In this trial, we examined the efficacy and safety parameters of rapid steroid withdrawal after induction therapy with either rabbit antithymocyte globulin (rabbit ATG) or basiliximab in immunologically low-risk patients during the first year after kidney transplantation. In this open-label, multicentre, randomised controlled trial, we randomly assigned renal transplant recipients in a 1:1:1 ratio to receive either basiliximab induction with low-dose tacrolimus, mycophenolate mofetil, and steroid maintenance therapy (arm A), rapid corticosteroid withdrawal on day 8 (arm B), or rapid corticosteroid withdrawal on day 8 after rabbit ATG (arm C). The study was done in 21 centres across Germany. Only participants aged between 18 and 75 years with a low immunological risk who were scheduled to receive a single-organ renal transplant from either a living donor or a deceased donor were considered for enrolment. Patients receiving a second renal transplant were eligible, provided that the first allograft was not lost due to acute rejection within the first year after transplantation. Donor and recipient had to be ABO compatible. Grafts with pre-transplant existing donor-specific human leukocyte antigen (HLA) antibodies were not eligible and the recipients had to have a panel-reactive antibody concentration of 30% or less. Pregnant women and nursing mothers were excluded from the study. The primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) at 12 months. All analyses were done by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00724022. Between Aug 7, 2008, and Nov 30, 2013, 615 patients were randomly assigned to arm A (206), arm B (189), and arm C (192). BPAR rates were not reduced by rabbit ATG (9·9%) compared with either treatment arm A (11·2%) or B (10·6%; A versus C: p=0·75, B versus C p=0·87). As a secondary endpoint, rapid steroid withdrawal reduced post-transplantation diabetes in arm B to 24% and in arm C to 23% compared with 39% in control arm A (A versus B and C: p=0·0004). Patient survival (94·7% in arm A, 97·4% in arm B, and 96·9% in arm C) and censored graft survival (96·1% in arm A, 96·8% in arm B, and 95·8% in arm C) after 12 months were excellent and equivalent in all arms. Safety parameters such as infections or the incidence of post-transplantation malignancies did not differ between the study arms. Rabbit ATG did not show superiority over basiliximab induction for the prevention of BPAR after rapid steroid withdrawal within 1 year after renal transplantation. Nevertheless, rapid steroid withdrawal after induction therapy for patients with a low immunological risk profile can be achieved without loss of efficacy and is advantageous in regard to post-transplantation diabetes incidence. Investigator Initiated Trial; financial support by Astellas Pharma GmbH, Sanofi, and Roche Pharma AG.

Nonadherence to immunosuppressive therapy after renal transplantation is associated with poor graft outcomes. We aimed to evaluate whether the use of the Adhere4U mobile medication manager application could improve adherence among renal transplant recipients ≥1 year posttransplantation. Adhere4U can provide medication reminders, monitor medication use, and provide information on immunosuppressants. We conducted a prospective randomized controlled study to compare the rate of nonadherence to index immunosuppressant (tacrolimus or cyclosporine) in a group using the Adhere4U app (mobile group) and in another group receiving conventional care (control group). The primary outcome was the nonadherence rate, which was evaluated using an electronic medication event monitoring system during the 6-month intervention period. Our secondary outcome included self-reported adherence using the Basel Assessment of Adherence to Immunosuppressive Medication Scale (BAASIS) and the visual analog scale (VAS) based on a 4-week recall on days 28, 90, and 180. Longitudinal data of repeated measures of self-rated adherence were analyzed using generalized estimating equations (GEE) to compare the between-group difference in adherence change over time. Between November 2013 and May 2015, 138 renal transplant recipients were randomly allocated to the control (n = 67) or the mobile group (n = 71). The overall nonadherence rate over the 6-month study period by electronic monitoring was 63.6%, with no between-group difference [mobile group, 65.0% (n = 39/60); control group, 62.1% (n = 36/58); odds ratio 1.14; 95% confidence interval 0.53-2.40; p = 0.89]. Self-rated nonadherence assessed using the BAASIS and VAS at baseline was 53.7% and 51.5%, respectively. Although the self-rated nonadherence by BAASIS of the mobile group was lower than the control group throughout the study period, there was no between-group difference in the change of nonadherence over time (χ2 = 2.82, df = 3, p = 0.42 by logistic GEE). There also was no significant between-group difference in the nonadherence by VAS (χ2 = 1.71, df = 3, p = 0.63 by logistic GEE) over time. The main limitation of this study was the low rate of patient engagement with the app among the mobile group. The rate of app use was 47.6% (31/65) at 28 days, 33.9% (19/56) at 90 days, and 11.5% (6/52) at 180 days. The Adhere4U application did not improve adherence to immunosuppressive therapy. Our evidence is limited by the high rate of attrition. Further studies on strategies to facilitate patient engagement with mobile interventions are warranted.

Background Chronic active antibody-mediated rejection (AMR) is a major cause of graft loss with no approved drugs for its treatment. Currently, off-label regimens are used, reflecting the high unmet need for effective therapies based on well-controlled trials. Clazakizumab is a high-affinity, humanized monoclonal antibody that binds interleukin-6 and decreases donor-specific antibody (DSA) production and inflammation. Phase 2 pilot studies of clazakizumab in kidney transplant recipients with chronic active AMR suggest modulation of DSA, stabilization of glomerular filtration rate (GFR), and a manageable safety profile. We report the design of the Phase 3 IMAGINE study (NCT03744910) to evaluate the safety and efficacy of clazakizumab for the treatment of chronic active AMR. Methods IMAGINE is a multicenter, double-blind trial of approximately 350 kidney transplant recipients with chronic active AMR (Banff chronic glomerulopathy [cg] >0 with concurrent positive human leukocyte antigen DSA) randomized 1:1 to receive clazakizumab or placebo (12.5 mg subcutaneous once every 4 weeks). The event-driven trial design will follow patients until 221 occurrences of all-cause graft loss are observed, defined as return to dialysis, graft nephrectomy, re-transplantation, estimated GFR (eGFR) <15 mL/min/1.73m 2 , or death from any cause. A surrogate for graft loss (eGFR slope) will be assessed at 1 year based on prior modeling validation. Secondary endpoints will include measures of pharmacokinetics/pharmacodynamics. Recruitment is ongoing across North America, Europe, Asia, and Australia. Discussion IMAGINE represents the first Phase 3 clinical trial investigating the safety and efficacy of clazakizumab in kidney transplant recipients with chronic active AMR, and the largest placebo-controlled trial in this patient population. This trial includes prognostic biomarker enrichment and uniquely utilizes the eGFR slope at 1 year as a surrogate endpoint for graft loss, which may accelerate the approval of a novel therapy for patients at risk of graft loss. The findings of this study will be fundamental in helping to address the unmet need for novel therapies for chronic active AMR. Trial registration ClinicalTrials.gov NCT03744910 . Registered on November 19, 2018.

BackgroundRandomized controlled trials in pediatric kidney transplantation are hampered by low incidence and prevalence of kidney failure in children. Real-World Data from patient registries could facilitate the conduct of clinical trials by substituting a control cohort. However, the emulation of a control cohort by registry data in pediatric kidney transplantation has not been investigated so far.MethodsIn this multicenter comparative analysis, we emulated the control cohort (n = 54) of an RCT in pediatric kidney transplant patients (CRADLE trial; ClinicalTrials.gov NCT01544491) with data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, using the same inclusion and exclusion criteria (CERTAIN cohort, n = 554).ResultsMost baseline patient and transplant characteristics were well comparable between both cohorts. At year 1 posttransplant, a composite efficacy failure end point comprising biopsy-proven acute rejection, graft loss or death (5.8% ± 3.3% vs. 7.5% ± 1.1%, P = 0.33), and kidney function (72.5 ± 24.9 vs. 77.3 ± 24.2 mL/min/1.73 m2P = 0.19) did not differ significantly between CRADLE and CERTAIN. Furthermore, the incidence and severity of BPAR (5.6% vs. 7.8%), the degree of proteinuria (20.2 ± 13.9 vs. 30.6 ± 58.4 g/mol, P = 0.15), and the key safety parameters such as occurrence of urinary tract infections (24.1% vs. 15.5%, P = 0.10) were well comparable.ConclusionsIn conclusion, usage of Real-World Data from patient registries such as CERTAIN to emulate the control cohort of an RCT is feasible and could facilitate the conduct of clinical trials in pediatric kidney transplantation.

This study examines the toxicity of immunosuppressive regimens in renal-transplant recipients. A regimen containing mycophenolate mofetil, daclizumab, low-dose tacrolimus, and corticosteroids appeared to be the most effective with respect to the glomerular filtration rate, allograft survival, and acute rejection, as compared with regimens containing dacluzimab induction plus either low-dose cyclosporine or low-dose sirolimus and with standard-dose cyclosporine without induction. A regimen containing mycophenolate mofetil, daclizumab, low-dose tacrolimus, and corticosteroids appeared to be the most effective with respect to the glomerular filtration rate, allograft survival, and acute rejection. Despite improved short-term outcome in renal transplantation, 3 to 5% of allografts per year are still lost; the leading causes are long-term allograft nephropathy and death with a functioning allograft. 1 As patients have fewer acute rejection episodes, adverse events associated with long-term immunosuppression have become increasingly evident. Accordingly, reducing the toxic effects of immunosuppressive regimens has become a major goal in the treatment of transplant recipients. Cyclosporine, a calcineurin inhibitor in use for many years, is still the basis of many immunosuppressive regimens because of its clinical success. However, standard recommended doses are associated with nephrotoxicity, resulting in long-term renal . . .

We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression. ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design. In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression. ClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.

Tacrolimus is the most commonly used immunosuppression drug after solid organ transplantation; however, its dosing is challenging due to substantial inter-individual variability, often resulting in blood levels that deviate from the target therapeutic range. We explored whether a dynamically customized, phenotypic-outcome-guided drug dosing method could improve maintenance of drug trough levels within pre-determined target ranges, focusing on tacrolimus immediately after liver transplantation. This single-center, partially blinded, completed clinical trial involved 62 adults undergoing liver transplantation, block randomized into parallel groups: standard-of-care (SOC) clinician-determined or Phenotypic Personalized Medicine (PPM)-guided tacrolimus dosing. The primary outcome was percentage of post-transplant days with large (>2 ng/mL) deviations from the target range. At trial completion, analysis found statistically significant improvement in the PPM group ( n  = 27): 24.2% of days showing large deviations compared to 38.4% in the SOC group ( n  = 29) (difference −14.2%, 95% CI: −26.7 to −1.5 %, P  = 0.029) with no increase in adverse events. These results demonstrate that PPM-guided tacrolimus dosing more effectively maintains drug levels within the target range compared to SOC, suggesting a promising approach to improving drug dosing. The trial was registered at ClinicalTrials.gov with the identifier NCT03527238. Tacrolimus is a critical immunosuppressant for liver transplant recipients, but its dosing is challenging due to individual variability. Here, the authors show that a phenotypic personalized medicine approach improves tacrolimus dosing precision, reducing large deviations from target levels and shortening hospital stays in a Phase 2 randomized trial.