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 transplantant (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 < 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 < 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.

Cyclosporine vs. tacrolimus after liver transplantation for primary sclerosing cholangitis - a propensity score-matched intention-to-treat analysis.

BACKGROUND & AIMS: There is controversy regarding the optimal calcineurin inhibitor type after liver transplant(ation) (LT) for primary sclerosing cholangitis (PSC). We compared tacrolimus with cyclosporine in a propensity score-matched intention-to-treat analysis based on registries representing nearly all LTs in Europe and the US. METHODS: From the European Liver Transplant Registry (ELTR) and Scientific Registry of Transplant Recipients (SRTR), we included adult patients with PSC undergoing a primary LT between 2000-2020. Patients initially treated with cyclosporine were propensity score-matched 1:3 with those initially treated with tacrolimus. The primary outcomes were patient and graft survival rates. RESULTS: The propensity score-matched sample comprised 399 cyclosporine-treated and 1,197 tacrolimus-treated patients with PSC. During a median follow-up of 7.4 years (IQR 2.3-12.8, 12,579.2 person-years), there were 480 deaths and 231 re-LTs. The initial tacrolimus treatment was superior to cyclosporine in terms of patient and graft survival, with 10-year patient survival estimates of 72.8% for tacrolimus and 65.2% for cyclosporine (p <0.001) and 10-year graft survival estimates of 62.4% and 53.8% (p <0.001), respectively. These findings were consistent in the subgroups according to age, sex, registry (ELTR vs. SRTR), time period of LT, MELD score, and diabetes status. The acute rejection rates were similar between groups. In the multivariable Cox regression analysis, tacrolimus (hazard ratio 0.72, p <0.001) and mycophenolate use (hazard ratio 0.82, p = 0.03) were associated with a reduced risk of graft loss or death, whereas steroid use was not significant. CONCLUSIONS: Tacrolimus is associated with better patient and graft survival rates than cyclosporine and should be the standard calcineurin inhibitor used after LT for patients with PSC. IMPACT AND IMPLICATIONS: The optimal calcineurin inhibitor to use after liver transplantation in patients with primary sclerosing cholangitis has yet to be firmly established. Since randomized trials with long follow-up are unlikely to be performed, multicontinental long-term registry data are essential in informing clinical practices. Our study supports the practice of using tacrolimus instead of cyclosporine in the initial immunosuppressive regimen after liver transplantation for patients with primary sclerosing cholangitis. The retrospective registry-based design is a limitation.

End-ischemic hypothermic oxygenated machine perfusion does not improve renal outcome following liver transplantation from aged donors: A single-center retrospective report.

BACKGROUND: Organ transplantation using grafts from elderly donors entails a higher risk for severe ischemia-reperfusion injury (IRI). Advanced IRI after liver transplantation (LT) seems to be associated with the development of acute kidney injury (AKI). We studied if end-ischemic hypothermic oxygenated machine perfusion (HOPE) of liver grafts, aimed at mitigating liver IRI, impacts on the frequency and severity of AKI after LT. METHODS: LTs performed at our center between January 2017 and December 2022 using organs from deceased brain-dead donors aged 70 or older were reviewed. From November 2020 on, HOPE was performed routinely in this donor category. The frequency and severity of AKI (KDIGO criteria) within 48 hours of graft reperfusion and the model of early allograft function (MEAF) were compared between HOPE-LTs (n = 30) and control LTs (n = 71). RESULTS: AKI developed in 23/30 (77%) HOPE-LTs and in 40/71 (56%) control LTs (p = n.s.), with no difference in severity and timing between groups. Renal replacement therapy was required in 3/30 (10%) HOPE-LTs and 6/71 (8%) control LTs. In addition, transaminase leak during the first week (marker of IRI) and MEAF were similar between groups. These findings persisted after propensity matching. Histology showed more hepatocyte vacuolization and higher Suzuki score in HOPE-LTs. Although this analysis could have been underpowered, no trends supporting the benefit of HOPE on liver and renal injury after LT were ever identified. CONCLUSIONS: In conclusion, HOPE in this group of older donors does not seem to improve either graft IRI, or the incidence of early AKI after LT.

Shear wave elastography and shear wave dispersion correlated to biopsy at the scheduled follow-up of pediatric liver grafts.

BACKGROUND: It is unknown how shear wave dispersion (SWD) is displayed in pediatric liver transplant recipients and not fully elucidated how ultrasound shear wave elastography (2D-SWE) display within this cohort, which is important to determine to improve noninvasive surveillance of these patients. The study aimed to compare SWE and SWD values with histopathology in pediatric liver recipients. METHODS: Forty-eight pediatric liver recipients were examined with SWE in conjunction with an elective liver biopsy (clinically without complication). Additionally, SWD values were measured in 21 children. SWE and SWD values were compared to histologically determined fibrosis graded as none-to-mild (F0-1) and moderate-to-severe (F2-4), and inflammation graded as low (grade 0-1) and high (grade 2-4). RESULTS: Two children were excluded due to SWE IQR/median > 30% kPa. The mean age across 46 included patients was 10.9 years (range 1.4-18). The number of patients and median (range) SWE value (kPa) for each stage of fibrosis were: F0-1 [n = 23; 5.8 (3.2-16.1)], F2 [n = 22; 6.0 (4.5-25.9)], F3 [n = 1; 33.3], and F4 [n = 0]. Significantly higher SWE values and greater variability were registered in F2-4 vs. F0-1 (p = .05). Grade of fibrosis correlated weakly to SWE values (r = .3; p = .05), but not to SWD values (r = .2; p = .27). In patients with low-grade inflammation, median SWD was 13.7 m/s KHz (10.7-17.6). Only one patient had high-grade inflammation. CONCLUSIONS: Uncomplicated transplanted liver grafts in a small pediatric cohort revealed slightly increased SWE and SWD values compared to previously reported values in healthy children. This likely reflect both the fibrotic and inflammatory elements in the grafts; however, other confounders impacting the liver's viscoelastic properties are also probable factors.

Abnormal Calcium Levels are Associated With Worse Maternal and Fetal Outcomes; Results From an Exploratory Study.

CONTEXT: Precise estimates of the incidence of hyper- and hypocalcemia in pregnancy are unknown. Abnormal calcium levels have been associated with unfavorable pregnancy-related outcomes. OBJECTIVE: Determine frequency of hypercalcemia and hypocalcemia in pregnancy when tested and their associations with maternal and fetal outcomes. DESIGN: Exploratory retrospective cohort study. SETTING: Single tertiary care maternity unit. PATIENTS: Pregnant women with expected delivery date between 2017 and 2019 and a second additional cohort of pregnant women with hypercalcemia between 2014 and 2016 and 2020 and 2021. INTERVENTIONS: Observational. MAIN OUTCOMES MEASURED: (1) Incidence of hyper- and hypocalcemia when calcium tested; (2) maternal outcomes: incidence of preterm delivery, emergency cesarean section, and blood loss during delivery; and (3) fetal outcomes: fetal loss (miscarriage/stillbirth), neonatal intensive care unit admission, and fetal birth weight (for term deliveries). RESULTS: Total number of gestations and livebirths recorded were 33 118 and 20 969, respectively, with median [interquartile range] age of 30.1 [25.6-34.3] years. A total of 15.7% (n = 5197) of all gestations had albumin-adjusted calcium tested, and incidence of hypercalcemia and hypocalcemia when tested was 0.8% (n = 42) and 9.5% (n = 495), respectively. Both hypercalcemia (including additional cohort n = 89) and hypocalcemia were associated with increased incidence of preterm delivery (P < .001), emergency cesarean section (P < .001 and .019), blood loss (P < .001), and neonatal intensive care unit admission (P < .001). A total of 27% in the hypercalcemic group had an established diagnosis of primary hyperparathyroidism. CONCLUSIONS: Abnormal calcium levels during pregnancy are common and associated with worse pregnancy-related outcomes, which raises the possible need for routine calcium testing. Prospective studies to confirm the incidence, etiology, and effects of abnormal calcium in pregnancy are recommended.

Long-term survival after liver transplantation for alcohol-related liver disease in the Nordic countries.

OBJECTIVES: Alcohol-related liver disease (ALD) is among the most common indications for liver transplantation (LTX) in Europe and North America, with good five-year survival rates post-LTX. Here we evaluated survival up to and beyond 20 years after LTX for patients with ALD compared to a comparison group. METHODS: Patients with ALD and a comparison group transplanted in the Nordic countries between 1982 and 2020 were included. Data were analyzed using descriptive statistics, Kaplan-Meier curves and predictors of survival were assessed with Cox-regressions. RESULTS: 831 patients with ALD and 2979 patients in the comparison group were included in the study. Patients with ALD were older at the time of LTX (p < .001) and more likely to be male (p < .001). The estimated median follow-up time was 9.1 years for the ALD-group and 11.1 years for the comparison group. 333 (40.1%) patients with ALD and 1010 (33.9%) patients in the comparison group died during follow-up. The overall survival was impaired for patients with ALD compared to the comparison group (p < .001) and was evident for male and female patients, patients transplanted before and after 2005, and observed in all age-groups except patients over 60 years. Age at transplant, waiting time, year of LTX and country of LTX were associated with decreased survival after LTX for patients with ALD. CONCLUSIONS: Patients with ALD have a decreased long-term survival following LTX. This difference was evident in most sub-groups of patients and warrants close follow-up of liver transplanted patients with ALD with focus on risk reduction.

Primary hyperparathyroidism in pregnancy: experience of a tertiary centre.

BACKGROUND AND PURPOSE: The management of primary hyperparathyroidism (PHPT) during pregnancy is challenging and there is no clear consensus on whether it increases the risk of complications in pregnancy. We conducted this study to review the maternal and fetal outcomes of pregnant women treated for PHPT in a single centre. METHODS: Data on relevant clinical parameters, demographics, management strategies, maternal and fetal outcomes were collected from the medical records of pregnant patients with PHPT diagnosed between 2012 and 2019. RESULTS: Of 15 pregnant women with PHPT, 6 were managed medically and 9 underwent surgery. The median age at their index pregnancy was 28 years [range 19-42]. The median highest adjusted calcium level in the medical group was 2.90 [range 2.61-3.25] mmol/L vs. 3.11 [2.78-4.95] mmol/L in the surgical group. There was one miscarriage and the stillbirth of twins in the medical group, but no such outcomes in the surgical group. The median gestational ages were 39 + 3 weeks [range 24 + 2-41 + 2 weeks] and 39 + 4 weeks [range 37 + 1-39 + 5 weeks] in the medical and surgical groups, respectively. No birth was complicated by neonatal tetany or convulsions. CONCLUSION: More complications developed in the pregnant PHPT patients who were managed medically than in those who underwent surgery. Surgery performed during the second trimester resulted in good outcomes. Multi-centre prospective studies are required to ascertain the risk of various complications in women with PHPT during pregnancy.

Hypertonic saline for severe symptomatic hyponatraemia: real-world findings from the UK.

Objective: To evaluate 'real-world' safety and efficacy of the European Society of Endocrinology guidelines for the treatment of severe symptomatic hyponatraemia using hypertonic saline (HTS). Design: Retrospective, observational, cohort study, examining the use of HTS for severe symptomatic hyponatraemia at Sheffield Teaching Hospitals between 2017 and 2020. Methods: Patients were identified from pharmacy records and demographic, clinical, and treatment data extracted. Results: Out of 112 patients (females:males = 61:51), the mean age ± s.d. was 66.3± 16.0 years and mean pre-treatment serum sodium ± s.d. was 113.8 ± 6.4 mmol/L. Overall, overcorrection rates at 24 and 48 h (>10 and >18 mmol/L) were 44.9 and 19.6%, respectively, while 19.6% of patients were treated for overcorrection. Above-target rise in sodium (>5 mmol/L) after first and second boluses was noted in 22.6 and 34.6% of patients, respectively. In-hospital and 12-month mortality was 7.1 and 18.7%, respectively, with no cases of osmotic demyelination. The mean venous blood gas (VBG) sodium was 1.9 mmol/L lower than paired serum sodium (n = 36) (113.6 ± 6.6 vs 115.7 ± 7.8 mmol/L). Conclusion: We report real-world data demonstrating that a significant number of patients overcorrected using current guidelines. Also, several patients had above-target rise in sodium after one bolus of HTS, and sodium measurement should be considered before the second bolus unless ongoing severe symptoms persist. A point of care VBG sodium concentration was useful for this purpose. In addition to careful monitoring, a cautious but anticipatory overcorrection prevention strategy should be considered in the first 24 h.

Perioperative kidney injury in liver transplantation: a prospective study with renal histology and measured glomerular filtration rates.

BACKGROUND: Acute kidney injury (AKI) is frequent after liver transplantation (LT), with impact on graft function, morbidity and mortality. Although multifactorial, the pathophysiology of perioperative kidney injury remains unclear. Our aims were to analyze the frequency, evolution and risk factors for kidney impairment during the peri- and early post-operative period. METHODS: In a prospective, single-center study of 27 adult patients undergoing first single-organ LT, we analyzed measured glomerular filtration rate (mGFR) pre-transplant, at post-operative day (POD) 10, and at 1, 3, 12 and 36 months. Kidney and liver graft biopsies were performed during LT. RESULTS: A median mGFR decline of 45% was detected from pre-transplant to POD 10, correlating strongly with the mGFR evolution from baseline to 12 months (rs = 0.80, p<.001) and baseline to 36 months (rs = 0.82, p<.001). AKI occurred in 59% of recipients within 48 h of LT, notably before the introduction of calcineurin inhibitors on POD 3. AKI was strongly associated with mGFR at 12 and 36 months. Kidney and liver graft biopsies showed only minor histological changes. Donor and recipient body mass index, recipient age, model of end-stage liver disease score, diagnosis of hepatitis C, donor cause of death, as well as bleeding, transfusions and duration of the anhepatic phase correlated with early kidney dysfunction. CONCLUSION: The greatest decline in mGFR was evident within 10 days and AKI within hours of LT, irrespective of baseline mGFR and before introduction of calcineurin inhibitors. Very early post-LT kidney injury has substantial consequences for long-term kidney function.

Excellent outcome following emergency deceased donor ABO-incompatible liver transplantation using rituximab and antigen specific immunoadsorption.

BACKGROUND: The acceptance of ABO-incompatible (ABOi) liver grafts will expand the donor pool for a patient in urgent need for a liver transplantation (LT). Here we report our results with emergency ABOi DD (deceased donor) LT using rituximab and antigen specific immunoadsorption. PATIENTS AND METHODS: 2009 to 2019 we performed 20 ABOi DD LTs (adults n = 17, children n = 3) for patients in urgent need for a LT. Immunosuppression consisted of rituximab (n = 20) and basiliximab (n = 15) or anti-thymocyte globuline (n = 4), intravenous immunoglobulin (IVIG; n = 6), tacrolimus, prednisolone and mycophenolate mofetil. Fifteen patients were treated with IA (n = 14) or both IA and plasmapheresis (PP; n = 1) pre-transplant and 18 patients were treated with IA (n = 15) or both IA and PP (n = 3) post-transplant. The median pre-transplant MELD- score was 40 (range 18-40). Patient and graft survival and complications were compared to a 1:4 case matched control group of ABO-identical or compatible (ABOid/c) DDLT. RESULTS: The 1-, 3- and 5-year patient and graft survival rates were 85, 85 and 78% for the ABOi recipients and not significantly different compared to ABOid/c controls. Only one ABOi patient developed antibody-mediated rejection. CONCLUSION: Patient and graft survival after emergency ABOi DDLT using rituximab and immunoadorption was equal to ABOid/DDLT. ABOi DD LT was a successful approach to expand the donor pool for patients in urgent need for a liver graft.

Renal function after liver transplantation: Real-world experience with basiliximab induction and delayed reduced-dose tacrolimus.

BACKGROUND: Routine use of delayed reduced-dose calcineurin-inhibitor treatment with induction immunosuppression in liver transplantation to minimize post-operative kidney injury is still scarce. AIM: To evaluate real-world experience of basiliximab induction with delayed reduced-dose tacrolimus. METHODS: In a retrospective cohort study, kidney function was evaluated pre- and postoperatively by measured glomerular filtration rate (mGFR). Adult patients undergoing liver transplantation between 2000 and 2017 were divided into a conventional treatment group (immediate-introduction of tacrolimus, target trough levels 10-15 ng/mL, and corticosteroids, n = 203) and a revised treatment group (basiliximab induction, reduced-dose tacrolimus, target through levels 5-8 ng/mL, delayed until day three, and mycophenolate mofetil 2000 mg/day, n = 343). RESULTS: Mean mGFR was similar between groups at wait-listing (85.3 vs 84.1 ml/min/1.73m², p = 0.60), but higher in the revised treatment group at 3 (56.8 vs 63.4 ml/min/1.73m², p = 0.004) and 12 months post-transplant (60.9 vs 69.7 ml/min/1.73m², p<0.001); this difference remained after correcting for multiple confounders and was independent of pre-transplant mGFR. In the revised treatment group, biopsy proven acute rejection rate was lower (38% vs. 21%, p<0.001), and graft-survival better (p = 0.01). CONCLUSION: Basiliximab induction with delayed reduced-dose tacrolimus is associated with less kidney injury when compared to standard-dose tacrolimus, without increased risk of rejection, graft loss or death.

Impact of muscle mass on survival of patients with hepatocellular carcinoma after liver transplantation beyond the Milan criteria.

BACKGROUND: Access to the liver transplant waitlist for patients with hepatocellular carcinoma (HCC) depends on tumour presentation, biology, and response to treatments. The Milan Criteria (MC) represent the benchmark for expanded criteria that incorporate additional prognostic factors. The purpose of this study was to determine the added value of skeletal muscle index (SMI) in HCC patients beyond the MC. METHOD: Patients with HCC that were transplanted beyond the MC were included in this retrospective multicentre study. SMI was quantified using the Computed Tomography (CT) within 3 months prior to transplantation. Cox regression models were used to identify predictors of overall survival (OS). The discriminative performance of SMI extended Metroticket 2.0 and AFP models was also assessed. RESULTS: Out of 889 patients transplanted outside the MC, 528 had a CT scan within 3 months prior to liver transplantation (LT), of whom 176 (33%) were classified as sarcopenic. The median time between assessment of the SMI and LT was 1.8 months (IQR: 0.77-2.67). The median follow-up period was 5.1 95% CI [4.7-5.5] years, with a total of 177 recorded deaths from any cause. In a linear regression model with SMI as the dependent variable, only male gender (8.55 95% CI [6.51-10.59], P < 0.001) and body mass index (0.74 95% CI [0.59-0.89], P < 0.001) were significant. Univariable survival analysis of patients with sarcopenia versus patients without sarcopenia showed a significant difference in OS (HR 1.44 95% CI [1.07 - 1.94], P = 0.018). Also the SMI was significant (HR 0.98 95% CI [0.96-0.99], P = 0.014). The survival difference between the lowest SMI quartile versus the highest SMI quartile was significant (log-rank: P = 0.005) with 5 year OS of 57% and 71%, respectively. Data from 423 patients, describing 139 deaths, was used for multivariate analysis. Both sarcopenia (HR 1.45 95% CI [1.02 - 2.05], P = 0.036) and SMI were (HR 0.98 95% CI [0.95-0.99], P = 0.035) significant. On the survival scale this translates to a 5 year OS difference of 11% between sarcopenia and no sarcopenia. Whereas for SMI, this translates to a survival difference of 8% between first and third quartiles for both genders. CONCLUSIONS: Overall, we can conclude that higher muscle mass contributes to a better long-term survival. However, for individual patients, low muscle mass should not be considered an absolute contra-indication for LT as its discriminatory performance was limited.

The RETREAT score provides valid predictions regarding hepatocellular carcinoma recurrence after liver transplantation.

Prediction of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) with knowledge of explant data is important for guiding post-LT surveillance and treatment. The RETREAT score was recently introduced for this purpose, but has not been validated outside the USA. In a retrospective single-center study of 169 consecutive patients undergoing LT in Gothenburg, through 2000-2017 (mean age 57 years, 80% men), there were 34 HCC recurrences during a median 4.6-year follow-up. The 5-year cumulative incidence of HCC recurrence was 0% with RETREAT scores of 0-1 (18%), 11-22% with scores of 2-4 (58%), and 65% with scores of 5-8 (24%). The C-statistic, as a measure of discrimination for prediction of HCC recurrence was 0.762, 0.664, 0.616, and 0.717, for the RETREAT score, Milan criteria, UCSF criteria, and post-MORAL criteria. The RETREAT score had no significant impact on patient survival after HCC recurrence (HR 1.00, P = 0.97). In conclusion, the RETREAT score provided valid predictions of post-LT HCC recurrence in a European setting, with the ability to discriminate between high, intermediate, and low risk for HCC recurrence in a clinically important way. Prognosis after recurrence did not differ according to the RETREAT score in our study.

Characteristics, Trends, and Outcomes of Liver Transplantation for Primary Sclerosing Cholangitis in Female Versus Male Patients: An Analysis From the European Liver Transplant Registry.

BACKGROUND: The influence of sex on primary sclerosing cholangitis (PSC), pre- and postliver transplantation (LT) is unclear. Aims are to assess whether there have been changes in incidence, profile, and outcome in LT-PSC patients in Europe with specific emphasis on sex. METHODS: Analysis of the European Liver Transplant Registry database (PSC patients registered before 2018), including baseline demographics, donor, biochemical, and clinical data at LT, immunosuppression, and outcome. RESULTS: European Liver Transplant Registry analysis (n = 6463, 32% female individuals) demonstrated an increasing number by cohort (1980-1989, n = 159; 1990-1999, n = 1282; 2000-2009, n = 2316; 2010-2017, n = 2549) representing on average 4% of all transplant indications. This increase was more pronounced in women (from 1.8% in the first cohort to 4.3% in the last cohort). Graft survival rate at 1, 5, 10, 15, 20, and 30 y was 83.6%, 70.8%, 57.7%, 44.9%, 30.8%, and 11.6%, respectively. Variables independently associated with worse survival were male sex, donor and recipient age, cholangiocarcinoma at LT, nondonation after brain death donor, and reduced size of the graft. These findings were confirmed using a more recent LT population closer to the current standard of care (LT after the y 2000). CONCLUSIONS: An increasing number of PSC patients, particularly women, are being transplanted in European countries with better graft outcomes in female recipients. Other variables impacting outcome include donor and recipient age, cholangiocarcinoma, nondonation after brain death donor, and reduced graft size.

Everolimus and long-term decline in renal function after liver transplantation: real-life experience with measured GFR.

Switching from calcineurin-inhibitors (CNI) to everolimus >6-12-months after liver transplantation (LT) seems inefficient in improving renal function, but whether everolimus halts further renal-function decline compared to low-dose CNI remains unclear. In a retrospective single-center study of everolimus after LT (2008-2016) with routine measured glomerular filtration rates (mGFR; 51Cr-EDTA- or iohexol clearance), we compared by propensity-score matching everolimus therapy to low-dose CNI therapy. The study comprised 36 patients with everolimus introduced on average 22 months post-LT (range 2-105 months, median follow-up 3.4 years), and 36 matched controls. Everolimus introduction was associated with a mean improvement in mGFR of 7 mL/min up to 1 year (p = .003), restricted to patients switched <1-year post-transplant and at tacrolimus trough levels >5 ng/mL. The differences between the everolimus group and controls in delta-mGFR from baseline to 1 year (7.3 vs 4.3 mL/min, p = .25) or 1-year to last follow-up (-0.8 vs -0.2 mL/min/year, p = .71) were non-significant. Proportions with mGFR decline >3 mL/min/year were similar between groups (11% and 14%, p = 1.00). Everolimus was stopped in three patients (8%), and acute rejection occurred in 17%. In conclusion, despite an early improvement in renal function after everolimus introduction, we found no evidence that everolimus halts the long-term mGFR decline compared to continued low-dose CNI therapy. Due to retrospective design, small sample size and heterogenous characteristics, definite conclusions require prospective studies.

Improved Survival in Liver Transplant Patients Receiving Prolonged-release Tacrolimus-based Immunosuppression in the European Liver Transplant Registry (ELTR): An Extension Study.

BACKGROUND: We compared, through the European Liver Transplant Registry, long-term liver transplantation outcomes with prolonged-release tacrolimus (PR-T) versus immediate-release tacrolimus (IR-T)-based immunosuppression. This retrospective analysis comprises up to 8-year data collected between 2008 and 2016, in an extension of our previously published study. METHODS: Patients with <1 month follow-up were excluded; patients were propensity score matched for baseline characteristics. Efficacy measures included: univariate/multivariate analyses of risk factors influencing graft/patient survival up to 8 years posttransplantation, and graft/patient survival up to 4 years with PR-T versus IR-T. Overall, 13 088 patients were included from 44 European centers; propensity score-matched analyses comprised 3006 patients (PR-T: n = 1002; IR-T: n = 2004). RESULTS: In multivariate analyses, IR-T-based immunosuppression was associated with reduced graft survival (risk ratio, 1.49; P = 0.0038) and patient survival (risk ratio, 1.40; P = 0.0215). There was improvement with PR-T versus IR-T in graft survival (83% versus 77% at 4 y, respectively; P = 0.005) and patient survival (85% versus 80%; P = 0.017). Patients converted from IR-T to PR-T after 1 month had a higher graft survival rate than patients receiving IR-T at last follow-up (P < 0.001), or started and maintained on PR-T (P = 0.019). One graft loss in 4 years was avoided for every 14.3 patients treated with PR-T versus IR-T. CONCLUSIONS: PR-T-based immunosuppression might improve long-term outcomes in liver transplant recipients than IR-T-based immunosuppression.

A prospective clinical trial on sorafenib treatment of hepatocellular carcinoma before liver transplantation.

BACKGROUND: Patients with hepatocellular carcinoma waiting for liver transplantation are commonly treated with locoregional treatments, such as TACE and ablation, to prevent tumor progression and dropout and to improve long-term outcome after transplantation. We wanted to prospectively assess feasibility of systemic antitumor treatment with sorafenib as neoadjuvant treatment for hepatocellular carcinoma while waiting for liver transplantation, evaluating tolerability, toxicity and posttransplant morbidity. We also wanted to evaluate perfusion CT parameters to assess tumor properties and response early after start of sorafenib treatment in patients with early hepatocellular carcinoma. METHODS: Twelve patients assigned for liver transplantation due to hepatocellular carcinoma, within the UCSF and who fulfilled other criteria, were included January 2012-August 2014. After baseline evaluation, sorafenib treatment was started. Treatment was evaluated by perfusion CT at 1, 4 and 12 weeks and thereafter every 8 weeks. Toxicity and quality of life was assessed at 1 and 4 weeks and every 4 weeks thereafter during treatment. Treatment was stopped when patients were prioritized on the transplantation waiting list or when intolerable side effects or tumor progress warranted other treatments. Posttransplant morbidity after 90 days was registered according to Clavien-Dindo. RESULTS: Baseline perfusion CT parameters in the tumors predicted the outcome according to RECIST/mRECIST at three months, but no change in CTp parameters was detected as a result of sorafenib. Sorafenib as neoadjuvant treatment was associated with intolerability and dose reductions. Therefore the prerequisites for evaluation of the sorafenib effect on both CT parameters and tumor response were impaired. CONCLUSIONS: This study failed to show changes in CTp parameters during sorafenib treatment. Despite the curative treatment intention, tolerability of neoadjuvant sorafenib treatment before liver transplantation was inadequate in this study. TRIAL REGISTRATION: EudraCT number: 2010-024306-36 (date 2011-04-07).

The Effect of Donor Age and Recipient Characteristics on Renal Outcomes in Patients Receiving Prolonged-Release Tacrolimus After Liver Transplantation: Post-Hoc Analyses of the DIAMOND Study.

BACKGROUND The DIAMOND study of de novo liver transplant patients showed that prolonged-release tacrolimus exposure in the acute post-transplant period maintained renal function over 24 weeks of treatment. To assess these findings further, we performed a post-hoc analysis in patients according to baseline kidney function, Model for End-stage Liver Disease [MELD] scores, and donor age. MATERIAL AND METHODS Patients received prolonged-release tacrolimus (initial-dose, Arm 1: 0.2 mg/kg/day, Arm 2: 0.15-0.175 mg/kg/day, Arm 3: 0.2 mg/kg/day delayed until Day 5), mycophenolate mofetil and 1 steroid bolus. Arms 2 and 3 also received basiliximab. The recommended tacrolimus target trough levels to Day 42 post-transplantation were 5-15 ng/mL in all arms. In this post-hoc analysis, change in renal outcome, based on estimated glomerular filtration rate (eGFR), Modified Diet in Renal Disease-4 (MDRD4), values from baseline to Week 24 -post-transplantation, were assessed according to baseline patient factors: eGFR (≥60 and ˂60 mL/min/1.73 m²), MELD score (˂25 and ≥25) and donor age (˂50 and ≥50 years). RESULTS Baseline characteristics were comparable (Arms 1-3: n=283, n=287, n=274, respectively). Patients with baseline renal function, eGFR ≥60 mL/min/1.73 m², experienced a decrease in eGFR in all tacrolimus treatment arms. In patients with lower baseline renal function (eGFR ˂60 mL/min/1.73 m²), an advantage for renal function was observed with both the early lower-dose and delayed higher-dose tacrolimus regimens compared with the early introduction of higher-dose tacrolimus. At Week 24, renal function was higher in the early-lower tacrolimus arm with older donors, and the delayed higher-dose tacrolimus arm with younger donors, both compared with early higher-dose tacrolimus. CONCLUSIONS Pre-transplantation factors, such as renal function and donor age, could guide the choice of prolonged-release tacrolimus regimen following liver transplantation.