Combined Liver-Kidney Transplantation With Preformed Anti-human Leukocyte Antigen Donor-Specific Antibodies

Introduction: the impact of preformed donor-specific anti-human leukocyte antigen (HLA) antibodies (pDSAs) after combined liver-kidney transplantation (CLKT) is still uncertain. Methods: we conducted a retrospective study in 8 European high-volume transplant centers and investigated the outcome of 166 consecutive CLKTs, including 46 patients with pDSAs. Results: patient survival was lower in those with pDSAs (5-year patient survival rate of 63% and 78% with or without pDSA, respectively; P = 0.04). The presence of pDSAs with a mean fluorescence intensity (MFI) ≥ 5000 (hazard ratio 4.96; 95% confidence interval: 2.3-10.9; P < 0.001) and the presence of 3 or more pDSAs (hazard ratio 6.5; 95% confidence interval: 2.5-18.8; P = 0.05) were independently associated with death. The death-censored liver graft survival was similar in patients with or without pDSAs. Kidney graft survival was comparable in both groups. (The 1- and 5-year death-censored graft survival rates were 91.6% and 79.5%, respectively, in patients with pDSAs and 93% and 88%, respectively, in the donor-specific antibody [DSA]-negative group, P = not significant). Despite a higher rate of kidney graft rejection in patients with pDSAs (5-year kidney graft survival rate without rejection of 87% and 97% with or without pDSAs, respectively; P = 0.04), kidney function did not statistically differ between both groups at 5 years post-transplantation (estimated glomerular filtration rate 45 ± 17 vs. 57 ± 29 ml/min per 1.73 m2, respectively, in patients with and without pDSAs). Five recipients with pDSAs (11.0%) experienced an antibody-mediated kidney rejection that led to graft loss in 1 patient. Conclusion: our results suggest that CLKT with pDSAs is associated with a lower patients' survival despite good recipients', liver and kidney grafts' outcome

Combined Liver-Kidney Transplantation With Preformed Anti–human Leukocyte Antigen Donor-Specific Antibodies

International audienceIntroduction:The impact of preformed donor-specific anti–human leukocyte antigen (HLA) antibodies(pDSAs) after combined liver-kidney transplantation (CLKT) is still uncertain.Methods:We conducted a retrospective study in 8 European high-volume transplant centers and inves-tigated the outcome of 166 consecutive CLKTs, including 46 patients with pDSAs.Results :Patient survival was lower in those with pDSAs (5-year patient survival rate of 63% and 78% with orwithout pDSA, respectively;P¼0.04). The presence of pDSAs with a meanfluorescence intensity (MFI)$5000(hazard ratio 4.96; 95% confidence interval: 2.3–10.9;P<0.001) and the presence of 3 or more pDSAs (hazardratio 6.5; 95% confidence interval: 2.5–18.8;P¼0.05) were independently associated with death. The death-censored liver graft survival was similar in patients with or without pDSAs. Kidney graft survival was compa-rable in both groups. (The 1- and 5-year death-censored graft survival rates were 91.6% and 79.5%, respectively,in patients with pDSAs and 93% and 88%, respectively, in the donor-specific antibody [DSA]-negative group,P¼not significant). Despite a higher rate of kidney graft rejection in patients with pDSAs (5-year kidney graft survivalrate without rejection of 87% and 97%with or without pDSAs, respectively;P¼0.04), kidney function did notstatistically differ between both groups at 5 years post-transplantation (estimated glomerularfiltration rate 4517 vs. 5729 ml/min per 1.73 m2, respectively, in patients with and without pDSAs). Five recipients with pDSAs(11.0%) experienced an antibody-mediated kidney rejection that led to graft loss in 1 patient.Conclusion:Our results suggest that CLKT with pDSAs is associated with a lower patients’survival despitegood recipients’, liver and kidney grafts’outcome

Five‐year outcomes in liver transplant patients receiving everolimus with or without a calcineurin inhibitor: Results from the CERTITUDE study

BACKGROUND AND AIMS: To report 5‐year outcomes of the CERTITUDE study. METHODS: An observational study in patients with liver transplantation (LTx) compared the long‐term impact of immunosuppression (with/without a calcineurin inhibitor) on renal function, cancers, major cardiovascular events (MACEs) and other safety parameters. All patients completing the 6‐month SIMCER study were recruited and analysed according to treatment received at randomization and actual treatment received during the follow‐up. RESULTS: Of the 143 enrolled patients, 119 completed the 5‐year follow‐up (everolimus [EVR], n = 55; tacrolimus [TAC], n = 64). The mean absolute change in estimated glomerular filtration rate was not statistically different between both groups (TAC, −15.53 ml/min/1.73 m(2) and EVR, –14.56 ml/min/1.73 m(2)). In the treatment subgroups based on actual treatment received, renal function was preserved better in the EVR subgroup compared with other subgroups (p = .051). Treated biopsy‐proven acute rejection was higher in the EVR group (15.4% vs. 6.4%); however, the majority of events were mild in severity. MACE occurred in 9.2% vs. 14.1% of patients in the EVR and TAC groups respectively (p = .370). De novo cancer was reported in 14 and 5 patients in EVR and TAC groups respectively. Hepatocellular carcinoma (HCC) recurrence was observed in the TAC group alone (n = 4). Adverse events and treatment discontinuation owing to an adverse event were higher in the EVR group. CONCLUSIONS: The CERTITUDE study demonstrated that EVR‐ and TAC‐based regimens have comparable efficacy, safety and tolerability up to 5 years post‐LTx

Corticosteroid-Sparing and Optimization of Mycophenolic Acid Exposure in Liver Transplant Recipients Receiving Mycophenolate Mofetil and Tacrolimus

International audienceBACKGROUND:We conducted a randomized multicenter open-label trial in de novo liver transplant recipients to assess the feasibility and potential benefit of a corticosteroid (CS)-free regimen coupled with tacrolimus (Tac) and dose-intensified mycophenolate mofetil (MMF) further adjusted individually.METHODS:Adult liver transplant recipients were randomized on the day of transplantation to a CS-free regimen with Tac and MMF starting at 3 g/d and dose adjusted from day 5 according to mycophenolic acid (MPA) exposure (arm A) or a regimen with CS maintained up to 6 months, Tac and fixed-dose MMF (2 g/d) (arm B). The primary end point was the proportion of patients who experienced treated biopsy-proven acute rejection (BPAR) during the first year posttransplant.RESULTS:One hundred eighty-seven patients were randomized, and 174 comprised the per-protocol population (87 in each arm). The primary objective of noninferiority was met: 7 patients in arm A (8%) and 8 in arm B (9%) experienced treated BPAR in the first year. Two patients in arm A (2%) and 5 in arm B (6%) lost their graft, and 12-month patient survival was similar in both arms (90.8% vs 89.8%; P = 0.86). Adverse events were comparable between arms, except for a lower incidence of de novo diabetes (19.8% vs 32.6%, P = 0.049) and a higher incidence of leukopenia less than 2000/mm (28.6% vs 9.8%; P = 0.001) and neutropenia (26.7% vs 7.9%; P < 0.001) in arm A.CONCLUSIONS:Mycophenolate mofetil at intensified and individually adjusted dose in combination with Tac in de novo liver transplant recipients allows CS discontinuation from day 1 posttransplant with good tolerance and very low rejection incidence

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial

International audienceSIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. −13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3–21.3]; p 3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR

Non-invasive diagnosis and follow-up in liver transplantation

International audienceThe field of liver transplantation directly or indirectly embodies all liver diseases, in addition to specific ones related to organ rejection (cellular and humoral). The recommended non-invasive methods for determining the indication for liver transplantation are the Model for End-stage Liver Disease score, and the alpha-foetoprotein score in case of hepatocellular carcinoma. Radiological methods are the cornerstones for the diagnosis of vascular and biliary complications after liver transplantation. The possible diseases of the liver graft after transplantation are multiple and often intertwined. Non-invasive diagnostic methods have been poorly evaluated in this context, apart from the recurrence of hepatitis C. Liver biopsy remains the gold standard for evaluating graft lesions in the majority of cases, especially graft rejection

Time to Conversion to an Everolimus‐Based Regimen: Renal Outcomes in Liver Transplant Recipients From the EVEROLIVER Registry

International audienceLongterm use of a calcineurin inhibitor (CNI)-based regimen is one of the major reasons for chronic renal failure in liver transplantation recipients (LTRs). The Everolimus Liver registry (EVEROLIVER) evaluated renal function in LTRs who were converted to everolimus (EVR). This observational registry included all LTRs receiving EVR across 9 centers from France. Data are being collected in an electronic database over 10 years (12 visits/patient) to evaluate efficacy, renal function (estimated glomerular filtration rate [eGFR]), and safety of EVR use in clinical practice, and the current analysis is reporting up to 60 months of findings. Until September 2017, 1045 patients received EVR after a mean time of 3.6 ± 5.1 years. CNI withdrawal was feasible in 57.7% of patients as of month 60. Mean eGFR improved in patients with baseline eGFR <60 mL/minute/1.73 m2 and was maintained in those with baseline eGFR ≥60 mL/minute/1.73 m2 . Among patients with chronic kidney disease (CKD; baseline eGFR <60 mL/minute/1.73 m2 ), 55% converted to EVR within 3 months (early conversion) and 39.4% converted between 4 and 12 months after transplantation (mid-conversion) experienced improvement in eGFR (≥60 mL/minute/1.73 m2 ) at month 36. Only 20.9% and 17.4% among those converted beyond 12 months (late conversion) experienced improvement respectively at month 36 and 60. A logistic regression analysis in patients with CKD stage ≥3 demonstrated that late conversion, age, and female sex were associated with nonimprovement of eGFR (≥60 mL/minute/1.73 m2 ). Data from this real-life use of EVR indicate that renal function was maintained from the preconversion period until month 36 even in patients with advanced CKD. However, early rather than late conversion appears to be a safe approach to preserve longterm renal function in LTRs