Long-term, Prolonged-release Tacrolimus-based Immunosuppression in De Novo Liver Transplant Recipients : 5-year Prospective Follow-up of Patients in the DIAMOND Study

Background. Immunosuppression with calcineurin inhibitors (CNIs) is reportedly associated with risk of renal impairment in liver transplant recipients. It is believed that this can be mitigated by decreasing initial exposure to CNIs or delaying CNI introduction until 3-4 d posttransplantation. The ADVAGRAF studied in combination with mycophenolate mofetil and basili ximab in liver transplantation (DIAMOND) trial evaluated different administration strategies for prolonged-release tacrolimus (PR-T). Methods. DIAMOND was a 24-wk, open-label, phase 3b trial in de novo liver transplant recipients randomized to: PR-T 0.2 mg/kg/d (Arm 1); PR-T 0.15-0.175 mg/kg/d plus basiliximab (Arm 2); or PR-T 0.2 mg/kg/d delayed until day 5 posttransplant plus basiliximab (Arm 3). In a 5-y follow-up, patients were maintained on an immunosuppressive regimen according to standard clinical practice (NCT02057484). Primary endpoint: graft survival (Kaplan-Meier analysis). Results. Follow-up study included 856 patients. Overall graft survival was 84.6% and 73.5% at 1 and 5 y post transplant, respectively. Five-year rates for Arms 1, 2, and 3 were 74.7%, 71.5%, and 74.5%, respectively. At 5 y, death-censored graft survival in the entire cohort was 74,7%. Overall graft survival in patients remaining on PR-T for z30 d was 79.1%. Graft survival in patients who remained on PR-T at 5 y was 87.3%. Patient survival was 86.6% at 1 y and 76.3% at 5 y, with survival rates similar in the 3 treatment arms at 5 y. Estimated glomerular filtration rate at the end of the 24-wk initial study and 5 y posttransplant was 62.1 and 61.5 mi./min/1.73 m(2), respectively, and was similar between the 3 treatment arms at 5 y. Overall, 18 (2.9%) patients had z1 adverse drug reaction, considered possibly related to PR-T in 6 patients. Conclusions. In the DIAMOND study patient cohort, renal function, graft survival, and patient survival were similar between treatment arms at 5 y posttransplant.Peer reviewe

Type of calcineurin inhibitor and long-term outcomes following liver transplantation in patients with primary biliary cholangitis – an ELTR study

Background &amp; Aims: Tacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the association between the type of calcineurin inhibitor used and long-term outcomes following LT in patients with PBC. Methods: Survival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the European Liver Transplant Registry. Patients who received a donation after brain death graft between 1990 and 2021 with at least 1 year of event-free follow-up were included. Results: In total, 3,175 patients with PBC were followed for a median duration of 11.4 years (IQR 5.9–17.9) after LT. Tacrolimus (Tac) was registered in 2,056 (64.8%) and cyclosporin in 819 (25.8%) patients. Following adjustment for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (adjusted hazard ratio [aHR] 1.07, 95% CI 0.92-1.25, p = 0.402) or death (aHR 1.06, 95% CI 0.90-1.24, p = 0.473) over cyclosporin. In this model, maintenance mycophenolate mofetil (MMF) was associated with a lower risk of graft loss (aHR 0.72, 95% CI 0.60-0.87, p &lt;0.001) or death (aHR 0.72, 95% CI 0.59-0.87, p &lt;0.001), while these risks were higher with use of steroids (aHR 1.31, 95% CI 1.13-1.52, p &lt;0.001, and aHR 1.34, 95% CI 1.15-1.56, p &lt;0.001, respectively). Conclusions: In this large LT registry, type of calcineurin inhibitor was not associated with long-term graft or recipient survival, providing reassurance regarding the use of Tac post LT in the population with PBC. Patients using MMF had a lower risk of graft loss and death, indicating that the threshold for combination treatment with Tac and MMF should be low. Impact and implications: This study investigated the association between immunosuppressive drugs and the long-term survival of patients with primary biliary cholangitis (PBC) following donation after brain death liver transplantation. While tacrolimus has previously been related to a higher risk of PBC recurrence, the type of calcineurin inhibitor was not related to graft or patient survival among patients transplanted for PBC in the European Liver Transplant Registry. Additionally, maintenance use of mycophenolate was linked to lower risks of graft loss and death, while these risks were higher with maintenance use of steroids. Our findings should provide reassurance for physicians regarding the continued use of Tac after liver transplantation in the population with PBC, and suggest potential benefit from combination therapy with mycophenolate.</p

ADHERE: randomized controlled trial comparing renal function in de novo kidney transplant recipients receiving prolonged-release tacrolimus plus mycophenolate mofetil or sirolimus

ADHERE was a randomized, open-label, Phase IV study comparing renal function at Week 52 postkidney transplant, in patients who received prolongedrelease tacrolimus-based immunosuppressive regimens. On Days 0?27, patients received prolonged-release tacrolimus (initially 0.2 mg/kg/day), corticosteroids, and mycophenolate mofetil (MMF). Patients were randomized on Day 28 to receive either prolonged-release tacrolimus plus MMF (Arm 1) or prolongedrelease tacrolimus (?25% dose reduction on Day 42) plus sirolimus (Arm 2). The primary endpoint was glomerular filtration rate by iohexol clearance (mGFR) at Week 52. Secondary endpoints included eGFR, creatinine clearance (CrCl), efficacy failure (patient withdrawal or graft loss), and patient/graft survival. Tolerability was analyzed. The full-analysis set comprised 569 patients (Arm 1: 287; Arm 2: 282). Week 52 mean mGFR was similar in Arm 1 versus Arm 2 (40.73 vs. 41.75 ml/min/1.73 m2; P = 0.405), as were the secondary endpoints, except composite efficacy failure, which was higher in Arm 2 versus 1 (18.2% vs. 11.5%; P = 0.002) owing to a higher postrandomization withdrawal rate due to adverse events (AEs) (14.4% vs. 5.2%). Results from this study show comparable renal function between arms at Week 52, with fewer AEs leading to study discontinuation with prolonged-release tacrolimus plus MMF (Arm 1) versus lower dose prolonged-release tacrolimus plus sirolimus (Arm 2)

The Influence of Pharmacological Preconditioning with Sevoflurane on Incidence of Early Allograft Dysfunction in Liver Transplant Recipients

Background. Pharmacological preconditioning is one of the tools used to diminish preservation injury. We investigated the influence of sevoflurane preconditioning of liver grafts on postoperative graft function. Methods. Consecutive 60 deceased brain donors were randomized into sevoflurane group or control group. In sevoflurane group donors were treated with endexpiratory 2,0 volume% of sevoflurane during procurement. Primary endpoint was postoperative liver injury. Secondary endpoint was incidence of early allograft dysfunction (EAD). Results. The groups were not different in median DRI, donor age, graft steatosis, and MELD score. Peak AST and ALT levels were lower in sevoflurane group than in control group: 792 and 1861 (=0,038) for AST and 606 and 1191 for ALT (=0,117). Incidence of EAD was 16,7% in sevoflurane group and 50% in control group (Fisher test, =0,013). In subgroups without steatosis preconditioning with sevoflurane did not have influence on incidence of EAD. In subgroups with mild and moderate steatosis incidence of EAD was lower in recipients of liver grafts treated with sevoflurane. Conclusions. Preconditioning with sevoflurane during organ procurement improves graft function by lowering incidence of early allograft dysfunction, particularly in recipients of steatotic liver grafts

Diagnostic value of sepsis biomarkers in hematopoietic stem cell transplant recipients in a condition of high prevalence of gram-negative pathogens

Objective/background: A decision about the need for antimicrobial therapy in a patient with febrile neutropenia after hematopoietic stem cell transplantation (HSCT) is often complicated because of the low frequency of culture isolation and reduced clinical manifestation of infection. Usefulness and choice of sepsis biomarkers to distinguish bloodstream infection (BSI) from other causes of febrile episode is still argued in HSCT recipients in modern epidemiological situations characterized by the emergence of highly resistant gram-negative microorganisms. In this study a comparative analysis of diagnostic values of presepsin, procalcitonin (PCT), and C-reactive protein (CRP) was performed as sepsis biomarkers in adult patients after HSCT in a condition of high prevalence of gram-negative pathogens. Methods: A prospective observational clinical study was performed at the Center of Hematology and Bone Marrow Transplantation in Minsk, Republic of Belarus. The biomarkers (presepsin, PCT, and CRP) were assessed in a 4-hour period after the onset of febrile neutropenia episode in adult patients after HSCT. Microbiologically-confirmed BSI caused by a gram-negative pathogen was set as a primary outcome. Results: Clinical and laboratory data were analyzed in 52 neutropenic patients after HSCT aged 18–79 years. Out of the biomarkers assessed, the best diagnostic value was shown in presepsin (area under the curve [AUC]: 0.889, 95% confidence interval [CI]: 0.644–0.987, p < .0001) with 75% sensitivity and 100% specificity, then in PCT (AUC: 0.741, 95% CI: 0.573–0.869, p = .0037) with 62% sensitivity and 88% specificity. The optimal cut-off value for CRP was set as 165 mg/L, while it had an average diagnostic value (AUC: 0.707, 95% CI: 0.564–0.825, p = .0049) with low sensitivity (40%) and should not be routinely recommended as a biomarker in adult patients with suspected BSI after HSCT. Conclusion: Presepsin may be recommended in adult patients with suspected gram-negative BSI after HSCT as a possible additional supplementary test with a cut-off value of 218 pg/mL. PCT is inferior to presepsin in terms of sensitivity and specificity, but still shows a good quality of diagnostic value with an optimal cut-off value of 1.5 ng/mL. CRP showed an average diagnostic value with low sensitivity (40%) and should not be routinely recommended as a biomarker in adult patients with suspected BSI after HSCT in a condition of high prevalence of gram-negative pathogens. Keywords: Bloodstream infections, C-reactive protein, Hematopoietic stem cell transplantation, Presepsin, Procalcitoni

Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients

The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m2 at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice.status: publishe

Recent outcome of liver transplantation for Budd Chiari syndrome - analysis of the european liver transplant registry (ELTR) and affiliated centres

..

Recent outcomes of liver transplantation for Budd-Chiari syndrome:A study of the European Liver Transplant Registry (ELTR) and affiliated centers

Background and Aims: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplant (post-LT) outcomes in Europe. Approach and Results: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients &lt; 16 years, with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 (p &lt; 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02-1.06) and MELD score (aHR:1.04,95%CI:1.01-1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41-0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00-1.03) and GS (aHR:1.02,95%CI:1.01-1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16-0.54) and GS (aHR:0.48,95%CI:0.29-0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%). Conclusions: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes. 2024 American Association for the Study of Liver Diseases. Published by Wolters Kluwer Health, Inc.</p