S Petruccelli

Conversion to everolimus monotherapy in maintenance liver transplantation: feasibility, safety, and impact on renal function.

We present the 12‐month results of a prospective trial of conversion from calcineurin inhibitors (CNI) to everolimus (EVL) in maintenance liver transplant (LT) recipients. Forty (M:F = 28:12; 54.9 ± 11 years) patients were enrolled at a mean interval of 45.5 ± 31.2 months from transplantation. Conversion was with EVL at a dosage of 0.75 mg b.i.d., withdrawal of antimetabolites, and a 50%‐per‐week reduction of CNI to a complete stop within 4 weeks. The treatment success was conversion to EVL monotherapy at 12 months while failure was presence of CNI, death, and graft loss. Indication to conversion was deteriorating renal function in 36 (90%). At 12 months, patient‐ and graft survival were 100% and the success rate was 75% (30/40). Ten patients (25%) were failures: four (10%) for acute rejection; three hepatitis C virus‐RNA positive patients (7.5%) for hypertransaminasemia; one (2.5%) for acute cholangitis; and two (5%) due to persistent pruritus and oral ulcers. In patients on EVL monotherapy, at 12 months the mean change of calculated creatinine clearance (cCrCl) was 4.03 ± 12.6 mL/min and the only variable correlated with the probability of improvement was baseline cCrCl (P < 0.0001). Conversion from CNI to EVL is feasible in 75% of the cases and associated with improvement in renal function for patients with higher baseline cCrCl.

THE ROLE OF IMMUNOMODULATION IN ABO-INCOMPATIBLE ADULT LIVER TRANSPLANT RECIPIENTS

ABO‐incompatible (ABO‐i) liver transplantation (LT) is a high‐risk procedure due to the potential for antibody‐mediated rejection (AMR) and cell‐mediated rejection. The aim of the current report is to illustrate the results of a retrospective comparison study on the use of immunomodulation with therapeutic plasma exchange (TPE) associated to high‐dose immunoglobulins (IVIg) and extracorporeal photopheresis (ECP) in ABO‐i adult LT patients.

Viral load 1 week after liver transplantation, donor age and rejections correlate with the outcome of recurrent hepatitis C

Background: Early identification of patients at a higher risk of rapidly progressive recurrent hepatitis post liver transplantation (LT) could help to tailor antiviral therapy.

The impact of everolimus on renal function in maintenance liver transplantation

We retrospectively investigated the impact on renal function (RF) of conversion from calcineurin inhibitors (CNI) to everolimus (EVL) monotherapy in orthotopic liver transplant (OLT) recipients. Between January 2006 and July 2007, 70 deceased donor OLT recipients including 51 men and 19 women of overall mean age of 55.9 +/- 11 years were enrolled into a program of conversion to EVL monotherapy at a mean interval of 45 +/- 35.9 months from transplantation (range, 7-192 months). The indication for conversion was deteriorating RF in 64 (91.4%). Efficacy failure was defined as the persistence of CNI, EVL discontinuation, death, graft loss, loss to follow-up, or need for dialysis at 12 months. Twelve months after switching, 53 patients (75.7%) were on EVL monotherapy. Their mean change in creatinine clearance (CrCl) from baseline (day 1 before EVL introduction) to endpoint (12 months) was 5.8 +/- 13.1 mL/min. On univariate and multivariate analyses, the clinical variable correlated with the greatest probability of improvement was the baseline CrCl (P < .0001). Conversion from CNI to EVL monotherapy was successful in 75.7% of cases with improvement in RF correlated with baseline CrCl. These data supported preemptive minimization of CNI in the posttransplant course, seeking to delay the decline in RF.

Transjugular intrahepatic portosystemic shunt for hepatitis C virus-related portal hypertension after liver transplantation.

Ghinolfi D, De Simone P, Catalano G, Petruccelli S, Coletti L, Carrai P, Marti J, Tincani G, Cicorelli A, Cioni R, Filipponi F. Transjugular intrahepatic portosystemic shunt for hepatitis C virus‐related portal hypertension after liver transplantation.

Quality assurance, efficiency indicators and cost‐utility of the evaluation workup for liver transplantation

We report the results of a retrospective review of the outpatient pretransplantation workup for United Network for Organ Sharing (UNOS) 3 patients adopted at a liver transplantation (LT) center and illustrate the efficiency indicators used for quality evaluation and cost‐analysis. A single‐center, pre‐LT evaluation workup was performed on an outpatient basis at a cost per patient evaluation of 2,770 Euros (€). Objective measures were: the number of patients admitted to and excluded from each phase of the algorithm; the rate of patients admitted to pre‐LT evaluation out of the total of referred patients (the referral efficiency rate); the rate of waitlisted patients out of those admitted to pre‐LT evaluation (the evaluation efficiency rate); the rate of waitlisted patients out of those referred for LT (the process efficiency rate); and the cost per waitlisted patient, as the ratio of the cost per patient evaluation to the evaluation efficiency rate. From January 1, 1996, to October 1, 2004, 1,837 patients were referred for LT on an outpatient basis. Based on preemptive evaluation of the available clinical data, 412 patients (22.4%) were excluded from pre‐LT evaluation and 1,425 (77.6%) were admitted to preliminary consultation. Among these, 603 (42.3%) were excluded from and 822 (57.7%) were admitted to pre‐LT evaluation with a referral efficiency rate of 44.7% (822 of 1,837). Out of the patients evaluated for LT, 484 were waitlisted with a cost‐utility and evaluation efficiency rate of 58.8% each (484 of 822). Of the 1,837 patients originally addressed for LT 484 were waitlisted, yielding a process efficiency rate of 26.3% (484 of 1,837) and a cost per waitlisted patient of €4,710.8. In conclusion, the 3 indicators allowed monitoring of the efficiency of the pre‐LT evaluation algorithm. The current process efficiency rate at our center is low (26.3%), but avoiding early referrals we might increase it to 31.6%, with a 12% net saving on costs per waitlisted patient (from €4,710.8 to €4,165.4). (Liver Transpl 2005;11:1080–1085.)

A single-staggered dose of calcineurin inhibitor may be associated with neurotoxicity and nephrotoxicity immediately after liver transplantation

Abstract:  The aim of the present work was to assess the incidence of neuro‐nephrotoxicity after a single‐staggered dose of calcineurin inhibitors (CI) with different immunosuppressive approaches. From January to December 2006, all liver transplantation (LT) recipients at risk of renal or neurological complications treated with extracorporeal photopheresis (ECP) + mycophenolate mofetil + steroids and staggered introduction of CI (ECP group) were compared with a historical control group on standard CI‐based immunosuppression. The ECP group included 24 patients with a mean model for end‐stage liver disease (MELD) score of 19.9 ± 11.1. The control group consisted of 18 patients with a mean MELD score of 12.5 ± 5.2 (p = 0.012). In the ECP group CI were introduced at a mean of 9.2 ± 6.2 d (4–31 d) after LT. Five patients in the ECP group presented acute neuro‐nephrotoxicity after the first CI administration on post‐transplant d 4, 5, 6, 6, and 14. Overall patient survival at one, six, and 12 months was 100%, 95.8%, and 95.8% in the ECP group vs. 94.4%, 77.7%, and 72.2% in the control group (p < 0.001). In conclusion, we showed that CI toxicity may occur after a single‐staggered dose administration, ECP seems to be a valuable tool for managing CI‐related morbidity regardless of the concomitant immunosuppressive regimen, being associated with a lower mortality rate in the early post‐transplant course.

Dual aortic and portal perfusion at procurement prevents ischaemic-type biliary lesions in liver transplantation when using octogenarian donors: a retrospective cohort study

Several risk factors for ischaemic‐type biliary lesions (ITBL) after liver transplantation (LT) have been identified, but the role of portal vein perfusion at graft procurement is still unclear. This was a prospective study on double aortic and portal perfusion (DP) of liver grafts stratified by donors decade (<60 yo; 60–69 yo; 70–79 yo and ≥80 yo) versus similar historical cohorts of primary, adult grafts procured with single aortic perfusion (SP) only. The primary study aim was to assess the role of DP on the incidence of ITBL. There was no difference in the incidence of overall biliary complications according to procurement technique for recipients of grafts <80 years. A higher incidence of ITBL was observed for patients receiving grafts ≥80 years and perfused through the aorta only (1.9 vs. 13.4%; P = 0.008). When analysing octogenarian grafts, donor male gender (HR = 6.4; P = 0.001), haemodynamic instability (HR = 4.9; P = 0.008), and type‐2 diabetes mellitus (DM2) (HR = 3.0; P = 0.03) were all independent risk factors for ITBL, while double perfusion at procurement (HR = 0.1; P = 0.04) and longer donor intensive care unit (ICU) stay (HR = 0.7; P = 0.04) were protective factors. Dual aortic and portal perfusion has the potential to reduce post‐transplant ITBL incidence for recipients of octogenarian donor grafts. Larger series are needed to confirm this preliminary experience.

Modification of immunosuppressive therapy as risk factor for complications after liver transplantation

Management of complications post-liver transplantation (LT) includes immunosuppressive manipulations with the aim to reduce the overall burden of immunologic suppression and compensate for renal, cardiovascular, metabolic toxicities, and for the increased oncologic risk. Two approaches can be implemented to reduce immunosuppression-related adverse events: upfront schedules tailored to the pretransplant individual patients risk profile versus downstream modifications in the event of immunosuppression-related complications. Upfront strategies are supported by evidence originating from prospective randomized trials and consist of triple/quadruple schedules whereby calcineurin inhibitors (CNI)-exposure is reduced with combination of anti-CD25 monoclonal antibodies, antimetabolites and corticosteroids. Quadruple regimens allow for staggering of CNI introduction and higher renal function in the early term, but their superiority in the long term has not yet been established. A more recent upfront schedule contemplates early (4 weeks) introduction of mammalian target of rapamycin inhibitor (mTORi) everolimus and allows for reduction of CNI up to 4 years posttransplantation. Incorporation of mTORi has the potential to prolong time to recurrence for patients with hepatocellular carcinoma. However, as suggested by the available evidence, downstream immunosuppressive manipulations are more frequently adopted in clinical practice. These encompass CNI replacement and immunosuppression withdrawal. Switching CNI to mTORi monotherapy is the option most commonly adopted to relieve renal function and compensate for posttransplant malignancies. Its impact is dependent on interval from transplantation and underlying severity of renal impairment. Introduction of mTORi is associated with longer overall survival for patients with extrahepatic posttransplant malignancies, but results are awaited for recurrences of hepatocellular carcinoma. Immunosuppression withdrawal seems feasible (70%) in very long term survivors (>10 years), but is not associated with reversal of immunosuppression-related complications. Awaiting novel immunosuppressive drug categories, integration of upfront strategies with the aim to reduce CNI-exposure and a low threshold for adjustment in the posttransplant course are both advisable to improve long-term outcomes of LT.