DIAMOND: multicenter, 24‐week, randomized trial investigating the effect of different once‐daily, prolonged‐release tacrolimus dosing regimens on renal function after de novo liver transplantation. ...Arm 1: prolonged‐release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged‐release tacrolimus (0.15–0.175mg/kg/day) plus basiliximab; Arm 3: prolonged‐release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). Primary endpoint: eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan–Meier estimates of composite efficacy failure‐free survival were 72.0%, 77.6%, 73.9% in Arms 1–3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged‐release tacrolimus (0.15–0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged‐release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher‐dose prolonged‐release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable.
The DIAMOND study demonstrates that an initial lower dose or a delayed higher dose of prolonged‐release tacrolimus significantly reduces renal function impairment versus a higher initial dose of prolonged‐release tacrolimus administered immediately posttransplant, over 24 weeks of treatment in de novo liver transplant recipients.
Towards tolerance in liver transplantation Toti, L.; Manzia, T.M.; Sensi, B. ...
Baillière's best practice & research. Clinical gastroenterology,
October-December 2021, 2021-10-00, 20211001, Letnik:
54-55
Journal Article
Recenzirano
Life-long immunosuppression has always been considered the key in managing liver graft protection from recipient rejection. However, it is associated with severe adverse effects that lead to ...increased morbidity and mortality, including infections, cardiovascular diseases, kidney failure, metabolic disorders and de novo malignancies.
This explains the great interest that has developed in the concept of tolerance in recent years. The liver, thanks to its marked tolerogenicity, is to be considered a privileged organ: up to 60% of selected patients undergoing liver transplantation could safely withdraw immunosuppression.
•Long-term survival in liver transplant patients is still low: the side effects of immunosuppression are the one main reason for this deficiency.•The liver is immunologically privileged over other organs: for this reason, many studies have been carried out in recent decades to understand the best way to achieve complete tolerance.•Withdrawal of immunosuppression can be safely achieved in up to 40% of selected liver transplant recipients.•There is a need to define valid and safe biomarkers able to predetermine tolerance.
Liver biopsy is a very important investigation in Hepatology. The aim of this retrospective study was to assess the prevalence of complications after Percutaneous Liver Biopsy (PLB), performed in ...two groups of patients with liver transplantation or with liver disease. We compared our results with those most representative of the literature and discussed about indications, advantages and disadvantages in relation to the different modes for the execution of this procedure, with particular regard to the use of ultrasound guidance.
We analyzed the results of 847 PLB performed with the Menghini technique between January 2004 and December 2013 at the Transplant Unit of the University of Rome Tor Vergata. The indications for biopsy were: follow-up liver transplantation, HBV, HCV and HBV/HCV related liver disease, alcohol related liver disease and HIV coinfected with HBV or HCV. Our patients were classified into two groups according to specific indication: patients with liver transplantation (group A) and patients with liver disease (group B). The procedure was always performed in the Day Hospital regimen. After the biopsy, the patients remained in bed for about 4-6 hours. In absence of complications, they were then discharged in the same day.
The most frequent complication was pain after biopsy (group A n. 45, 7.9%; group B n. 85, 30.9%), requiring analgesics administration, hypotension as a result of a vasovagal reaction resolved spontaneously (group A n. 6, 1.0%; group B n. 6, 2.2%), and bleeding (group A n. 1, 0.2%; group B n. 6, 2.2%), which, however, has never necessitated surgery, except in one case of hemothorax. Two cases of pneumothorax were resolved with chest tube. Other complications did not have a significant impact.
Liver biopsy is not replaceable investigation to diagnose several liver diseases and their course and also to monitor the condition of the hepatic parenchyma after transplantation. Among the various methods we preferred the Menghini technique with percutaneous transcostal approach, because less traumatic. This procedure presents low occurrence of various problems. We reviewed the literature regarding the major complications related to the technique and the use of ultrasound guidance. Based on our case series and data reported by the main Authors, we believe that ultrasound guidance is not decisive in the prevention of major complications. It is useful if done in the days or weeks prior to biopsy only in order to know any anatomical abnormalities or rather diseases that may pose a specific indication for the procedure with ultrasound guidance.
Transarterial chemoembolization (TACE) in patients with hepatocellular cancer (HCC) on the waiting list for liver transplantation may be associated with an increased risk for hepatic artery ...complications. The present study aims to assess the risk for, primarily, intraoperative technical hepatic artery problems and, secondarily, postoperative hepatic artery complications encountered in patients who received TACE before liver transplantation.
Available data from HCC liver transplantation recipients across six European centres from January 2007 to December 2018 were analysed in a 1 : 1 propensity score-matched cohort (TACE versus no TACE). Incidences of intraoperative hepatic artery interventions and postoperative hepatic artery complications were compared.
Data on postoperative hepatic artery complications were available in all 876 patients (425 patients with TACE and 451 patients without TACE). Fifty-eight (6.6 per cent) patients experienced postoperative hepatic artery complications. In total 253 patients who had undergone TACE could be matched to controls. In the matched cohort TACE was not associated with a composite of hepatic artery complications (OR 1.73, 95 per cent c.i. 0.82 to 3.63, P = 0.149). Data on intraoperative hepatic artery interventions were available in 825 patients (422 patients with TACE and 403 without TACE). Intraoperative hepatic artery interventions were necessary in 69 (8.4 per cent) patients. In the matched cohort TACE was not associated with an increased incidence of intraoperative hepatic artery interventions (OR 0.94, 95 per cent c.i. 0.49 to 1.83, P = 0.870).
In otherwise matched patients with HCC intended for liver transplantation, TACE treatment before transplantation was not associated with higher risk of technical vascular issues or hepatic artery complications.
Immunosuppressive drugs can be completely withdrawn in up to 20% of liver transplant recipients, commonly referred to as ‘operationally’ tolerant. Immune characterization of these patients, however, ...has not been performed in detail, and we lack tests capable of identifying tolerant patients among recipients receiving maintenance immunosuppression. In the current study we have analyzed a variety of biological traits in peripheral blood of operationally tolerant liver recipients in an attempt to define a multiparameter ‘fingerprint’ of tolerance. Thus, we have performed peripheral blood gene expression profiling and extensive blood cell immunophenotyping on 16 operationally tolerant liver recipients, 16 recipients requiring on‐going immunosuppressive therapy, and 10 healthy individuals. Microarray profiling identified a gene expression signature that could discriminate tolerant recipients from immunosuppression‐dependent patients with high accuracy. This signature included genes encoding for γδ T‐cell and NK receptors, and for proteins involved in cell proliferation arrest. In addition, tolerant recipients exhibited significantly greater numbers of circulating potentially regulatory T‐cell subsets (CD4+CD25+ T‐cells and Vδ1+ T cells) than either non‐tolerant patients or healthy individuals. Our data provide novel mechanistic insight on liver allograft operational tolerance, and constitute a first step in the search for a non‐invasive diagnostic signature capable of predicting tolerance before undergoing drug weaning.
Microarray profiling of peripheral blood on 16 operationally tolerant liver recipients identified some candidate features that could identify patients in which drug weaning is more likely to be successful.
This study was a retrospective analysis of the European Liver Transplant Registry (ELTR) performed to compare long‐term outcomes with prolonged‐release tacrolimus versus tacrolimus BD in liver ...transplantation (January 2008–December 2012). Clinical efficacy measures included univariate and multivariate analyses of risk factors influencing graft and patient survival at 3 years posttransplant. Efficacy measures were repeated using propensity score‐matching for baseline demographics. Patients with <1 month of follow‐up were excluded from the analyses. In total, 4367 patients (prolonged‐release tacrolimus: n = 528; BD: n = 3839) from 21 European centers were included. Tacrolimus BD treatment was significantly associated with inferior graft (risk ratio: 1.81; p = 0.001) and patient survival (risk ratio: 1.72; p = 0.004) in multivariate analyses. Similar analyses performed on the propensity score‐matched patients confirmed the significant survival advantages observed in the prolonged‐release tacrolimus‐ versus tacrolimus BD‐treated group. This large retrospective analysis from the ELTR identified significant improvements in long‐term graft and patient survival in patients treated with prolonged‐release tacrolimus versus tacrolimus BD in primary liver transplant recipients over 3 years of treatment. However, as with any retrospective registry evaluation, there are a number of limitations that should be considered when interpreting these data.
The authors perform a retrospective analysis of European Liver Transplant Registry data and identify significant improvements in graft and patient survival in patients treated with prolonged‐ versus immediate‐release tacrolimus over three years of treatment. See editorial by Asrani and O'Leary on page 1135.
Fabry's disease (FD) is a genetic disorder of lysosomal storage characterized by the intralysosomal accumulation of globotriaosylceramide (Gb3). This genetic mutation causes a total or partial ...deficit of the α-galactosidase (GAL) enzyme activity. FD has an incidence of 1:40000-60000 born alive. Its prevalence is higher in specific pathological conditions like chronic kidney disease (CKD). The aim of this study was to evaluate the FD prevalence in Italian renal replacement therapy (RRT) patients from Lazio region.
485 patients in RRT (hemodialysis, peritoneal dialysis, and kidney transplantation) were recruited. The screening test was performed on venous blood sample. The latter was analyzed using specific FD diagnostic kit, based on the analysis of dried blood spots on filter paper.
We found 3 cases of positivity to FD (1 female and 2 males). In addition, 1 male patient was identified with biochemical alteration indicative of GAL enzyme deficiency with a genetic variant of the GLA gene of unknown clinical significance. The FD prevalence in our population was 0.60% (1 case out 163), it rises to 0.80% (1 case out of 122) if the genetic variant of unknown clinical significance is considered. Comparing the three subpopulations, we observed a statistically significant difference in GAL activity in transplanted patients compared to dialysis patients (p<0.001).
Considering the presence of an enzyme replacement therapy able to modify FD clinical history, it is essential to try to implement FD early diagnoses. However, the screening is too expensive to be extended on large scale, due to the low prevalence of the pathology. The screening should be performed on high-risk populations.
In the last decades, liver biopsy was the reference procedure for the diagnosis and follow-up of liver disease. Aim of present retrospective analysis was to assess the prevalence of complications and ...risk factors after Percutaneous Liver Biopsy (PLB) performed for diagnosis and staging in patients with chronic liver disease and for monitoring the graft in liver transplanted patients
Data were collected from a total of 1.011 PLB performed with the Menghini technique between January 2004 and December 2014 at the Hepatology and Transplant Units of the University of Rome Tor Vergata. The indications for biopsy were: follow-up of liver transplantation, chronic Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV), with or without Human Immunodeficiency Virus (HIV) and alcohol-related liver disease. Our patients were divided into two groups according to the biopsy indication: follow-up of liver transplantation (Group A) and chronic liver disease (Group B). All the procedures were performed in Day Hospital regimen. After the biopsy, patients remained in bed for about 4-6 hours. In the absence of complications, they were then discharged on the same day.
The most frequent complication after biopsy was pain (Group A n. 57, 8.8%; Group B n. 105, 29.0%), hypotension as a result of a vasovagal reaction resolved spontaneously (Group A n. 7, 1.1%; Group B n. 6, 1.7%), and intrahepatic bleeding resolved with conservative therapy (Group A n. 1, 0.2%; Group B n. 6, 1.7%). Two cases of pneumothorax in the Group A (0.3%) were treated with a chest tube. Other complications did not have a significant impact. Also, we did not observe statistically significant differences in patients who underwent PLB without and with ultrasound guidance.
Liver biopsy is not a replaceable tool in diagnosis and follow-up of several chronic liver diseases. The Menghini technique with the percutaneous trans costal approach, might be preferred because less traumatic and related with a low occurrence of minor and major complications. According to our case load and comparing our findings with the previous published data, we speculate that ultrasound guidance is not crucial in the prevention of major complications.
Donor–recipient match is a matter of debate in liver transplantation. D‐MELD (donor age × recipient biochemical model for end‐stage liver disease MELD) and other factors were analyzed on a national ...Italian database recording 5946 liver transplants. Primary endpoint was to determine factors predictive of 3‐year patient survival. D‐MELD cutoff predictive of 5‐year patient survival <50% (5yrsPS<50%) was investigated. A prognosis calculator was implemented (http://www.D‐MELD.com). Differences among D‐MELD deciles allowed their regrouping into three D‐MELD classes (A < 338, B 338–1628, C >1628). At 3 years, the odds ratio (OR) for death was 2.03 (95% confidence interval CI, 1.44–2.85) in D‐MELD class C versus B. The OR was 0.40 (95% CI, 0.24–0.66) in class A versus class B. Other predictors were hepatitis C virus (HCV; OR = 1.42; 95% CI, 1.11–1.81), hepatitis B virus (HBV; OR = 0.69; 95% CI, 0.51–0.93), retransplant (OR = 1.82; 95% CI, 1.16–2.87) and low‐volume center (OR = 1.48; 95% CI, 1.11–1.99). Cox regressions up to 90 months confirmed results. The hazard ratio was 1.97 (95% CI, 1.59–2.43) for D‐MELD class C versus class B and 0.42 (95% CI, 0.29–0.60) for D‐MELD class A versus class B. Recipient age, HCV, HBV and retransplant were also significant. The 5yrsPS<50% cutoff was identified only in HCV patients (D‐MELD ≥ 1750). The innovative approach offered by D‐MELD and covariates is helpful in predicting outcome after liver transplantation, especially in HCV recipients.
D‐MELD, the product of donor age and MELD, remains the main determinant of survival in liver transplantation and its use, along with the covariates, supports the intentional balancing of donor and recipient risk factors.
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