197 results on '"van den Berg AP"'
Search Results
2. Increased incidence of azathioprine-induced toxicity in inflammatory bowel diseases compared to other diseases
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Weersma, RK, Peters, FT, Oostenbrug, LE, van den Berg, AP, van Haastert, M, Ploeg, RJ, Posthumus, MD, van der Heide, JJH, Jansen, PLM, and van Dullemen, HM
- Published
- 2016
3. No increased risk of hepatocellular carcinoma in cirrhosis due to Wilson disease during long-term follow-up
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van der Meer, S, de Man, Rob, van den Berg, AP, Houwen, RHJ, Linn, FHH, van Oijen, MGH, Siersema, PD, van Erpecum, KJ, and Gastroenterology & Hepatology
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digestive system diseases - Abstract
Background and AimsData on risk of hepatocellular carcinoma (HCC) in patients with Wilson disease are scarce. We determine HCC risk in a well-defined cohort of Wilson patients. MethodsAll patients with a confirmed diagnosis of Wilson disease (Leipzig score4) in three Dutch university referral hospitals were included in this retrospective cohort study. End of follow-up was defined as date of diagnosis of HCC, liver transplantation, death, or last available hospital visit. Also, a meta-analysis was performed to determine incidence and mortality rate of HCC in Wilson disease based on all published cohorts. ResultsIn total, 130 patients with Wilson disease were followed during a median follow-up of 15 years (range 0.1-51.2). At baseline, cirrhosis was present in 74 patients (57% of total: 64% compensated, and 36% decompensated). At end of follow-up, liver disease severity was improved, stable or deteriorated in 20%, 46%, and 24% of all cases (10% unknown), respectively. Two patients developed HCC (one despite excellent decoppering after 50 years follow-up, the other with newly diagnosed Wilson disease). Estimated annual HCC risk for all patients was 0.09% (95% confidence interval [CI]: 0.01-0.28). Subgroup analysis in cirrhotic patients revealed an annual HCC risk of 0.14% (95% CI: 0.02-0.46). The meta-analysis showed an annual HCC risk of 0.04% (95% CI: 0.01-0.10) and HCC mortality rate of 2.6/10000 person-years (95% CI: 0.7-7.0). ConclusionsEven in case of cirrhosis, HCC risk is low in Wilson disease. Our data do not support regular HCC surveillance in Wilson disease.
- Published
- 2015
4. Effect of age on radiation-induced early changes of rat rectum. A histological time sequence
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Acht, Manouk, van den Berg, AP (Aad), Quint, S, de Boer, H, Seven, M, Sornsen de Koste, J, Creutzberg, CL, Visser, A, Radiation Oncology, and Erasmus MC other
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Pathology ,medicine.medical_specialty ,Physiology ,Rectum ,Radiation induced ,Radiation Dosage ,Sensitivity and Specificity ,Vascular occlusion ,Culture Techniques ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Rats, Wistar ,Radiation injury ,Analysis of Variance ,business.industry ,Incidence (epidemiology) ,Age Factors ,Dose-Response Relationship, Radiation ,Histology ,Hematology ,Rat Rectum ,Rats ,Disease Models, Animal ,Radiation Injuries, Experimental ,Logistic Models ,medicine.anatomical_structure ,Oncology ,Analysis of variance ,medicine.symptom ,business - Abstract
Background and purpose : Radiation treatment of the elderly (>75 years) is often modified due to an assumed decrease in normal tissue tolerance in this age group. Since more radiobiological data concerning normal tissue toxicity as a function of age are needed, a histological study of age-related radiation changes of the rectum was performed. Materials and methods : The rectum of young and old female Wistar rats (12 and 78 weeks, respectively) was irradiated with single doses of 22 and 39 Gy. The field size was 1.5×2.0 cm. The animals were sacrificed at 1, 2, 4 and 10 weeks after treatment. To evaluate radiation damage, 12 histological parameters were scored in four areas of the rectum. A total radiation injury score was calculated. The number of proliferative epithelial cells was evaluated by 5-bromo-2′-deoxyuridine labeling. Results : Some age-related histological differences were observed; especially, the incidence of ulceration and vascular occlusion was higher in the older group. In the low dose group of the older animals, 60% showed ulceration, which was 0% for the young low dose animals. Severe vascular changes occurred early and were more extensive in older animals (4 weeks) than in the younger group (10 weeks). In the area adjacent to the treatment field, cell proliferation increased significantly in older rats at 1 week after 22 Gy, which did not occur in the young group. Conclusions : Discrete radiation-induced histological differences were observed between the rectum of young and old Wistar rats, especially in the development of ulceration and vascular changes. Although the survival of these Wistar rats in earlier studies was not affected by age, the impact of the observed histological differences for their importance in the long-term is currently being investigated.
- Published
- 2001
5. Patients with isolated polycystic liver disease referred to liver centres: clinical characterization of 137 cases
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van Keimpema, L, de Koning, DB, van Hoek, B, van den Berg, AP (Aad), van Oijen, MGH, de Man, Rob, Nevens, F, Drenth, JPH, Groningen Institute for Organ Transplantation (GIOT), Radiotherapy, and Gastroenterology & Hepatology
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PCLD ,MUTATIONS ,SEC63 ,PROLIFERATION ,WOMEN ,KIDNEY-DISEASE ,clinical characterization ,HEPATIC CYSTS ,polycystic liver disease ,RENAL-DISEASE ,VOLUME ,MANAGEMENT ,liver cyst ,PRKCSH - Abstract
Background and aim: Isolated polycystic liver disease (PCLD) is characterized by the presence of multiple cysts in the liver in the absence of polycystic kidneys. The clinical profile of PCLD is poorly defined and we set up a study for the clinical characteristics of PCLD. Methods: We collected clinical data on 188 PCLD patients (defined as 410 liver cysts) from five tertiary referral centres, and 137 patients were selected for the purpose of this study. We performed molecular analysis of the PCLD associated genes PRKCSH and SEC63 in 91 patients. Results: A total of 118 (86%) patients were female. The majority of patients (88%) had 420 cysts. The median age at diagnosis was 47 years (range 23-84). 37 (41%) patients carried a mutation. Clinical symptoms at presentation were present in 111 (84%) patients. gamma-glutamyl transferase was elevated to 1.4 times upper limit of normal (interquartile range 1.0-2.7). The presence of a mutation and female gender predicted a more severe course: female patients were 9 years younger at the time of diagnosis (47 years; range 23-84) and 91% had symptoms (P < 0.01); likewise, mutation carriers were younger at presentation (39 years; range 35-48) and 95% of this cohort had symptoms (P < 0.01). During follow-up [median 8.2 years (range 0-35)], 10% of untreated and 51% of treated patients developed complications. Mortality in this cohort was 8%, but only 2% died of PCLD-related causes. 58% of patients were treated a median of 2 years (range 0-25) after diagnosis. Conclusion: Symptomatic PCLD patients are mainly females. Females and mutation carriers were younger at diagnosis and had a more severe course of disease.
- Published
- 2011
6. Inflammatory bowel disease after liver transplantation: the effect of different immunosuppressive regimens
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Haagsma, EB, Van den Berg, AP, Kleibeuker, JH, Slooff, MJH, Dijkstra, G, Faculteit Medische Wetenschappen/UMCG, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Groningen Institute for Organ Transplantation (GIOT), and Translational Immunology Groningen (TRIGR)
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RECIPIENTS ,MICE ,surgical procedures, operative ,ULCERATIVE-COLITIS ,FEATURES ,AUTOIMMUNITY ,TACROLIMUS ,PRIMARY SCLEROSING CHOLANGITIS - Abstract
Background: Seemingly conflicting results have been reported on the prevalence and severity of inflammatory bowel disease after liver transplantation. Regimens with different combinations of drugs can be used for immunosuppression after transplantation. Aim: To study retrospectively the prevalence of inflammatory bowel disease after liver transplantation, and the possible relationship with maintenance immunosuppressive regimens. Methods: All 78 patients with end-stage primary sclerosing cholangitis (48 patients) or autoimmune cirrhosis (30 patients), transplanted between 1979 and July 2001, and with a follow-up of at least 1 year, were eligible for this study. In addition to patient and transplant characteristics, data on inflammatory bowel disease and immunosuppression before and after transplantation were collected. The Kaplan-Meier method was used for survival analysis. Possible risk factors for inflammatory bowel disease after transplantation were analysed by Cox univariate and multivariate regression. Results: The median follow-up after transplantation was 7.2 years (range, 1.1-22.3 years). Nine of 25 patients with pre-transplant inflammatory bowel disease experienced flare-ups after transplantation. Six of 53 patients without pre-transplant inflammatory bowel disease developed de novo inflammatory bowel disease after transplantation. The cumulative risks (standard errors in parentheses) for inflammatory bowel disease were 6% (3%), 12% (4%) and 20% (5%) at 1, 3 and 5 years after transplantation, respectively. The inflammatory bowel disease-free survival was significantly higher in patients not receiving tacrolimus vs. those receiving tacrolimus, in patients receiving azathioprine vs. those not receiving azathioprine and in patients taking the regimen prednisolone-azathioprine-ciclosporin A vs. those taking tacrolimus-prednisolone. Pre-transplant inflammatory bowel disease and the use of tacrolimus were found to be independent predictors for inflammatory bowel disease after transplantation. Conclusions: The prevalence of inflammatory bowel disease after liver transplantation is affected by the immunosuppression used. Azathioprine seems to have a protective effect and tacrolimus a promoting effect.
- Published
- 2003
7. Autoimmune hepatitis: Pathogenesis, diagnosis and treatment
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van den Berg, AP and Groningen Institute for Organ Transplantation (GIOT)
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autoimmune hepatitis ,treatment ,diagnosis ,pathogenesis ,CHRONIC ACTIVE HEPATITIS ,ANTIBODIES ,VIRUS ,SUSCEPTIBLE INDIVIDUALS ,TRIGGER - Abstract
Background: Autoimmune hepatitis (AIH) is a chronic necro-inflammatory disease of the liver. Early recognition is important in order to prevent the development of cirrosis. This review discusses recent developments in the fields of diagnosis, pathophysiology and management of AIH. Methods: Relevant manuscripts were identified using an electronic database, and by hand search of a personal library. Results and conclusions: Description of new auto-antibodies, and formulation of diagnostic criteria and a scoring system by an international panel constitute important advances that may help diagnosis of the disease at an early stage. While a satisfying animal model of the disease is lacking, clinical observations have led to the formulation of a pathophysiological model. Current treatment has a failure rate of about 13%, and is unable to induce a permanent remission in most patients. New immunosuppressive agents (cyclosporine, tacrolimus and mycophenolate mofetil) appear promising, and should be evaluated in controlled trials.
- Published
- 2002
8. The significance of parenchymal changes of acute cellular rejection in predicting chronic liver graft rejection
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Gouw, ASH, van den Heuvel, MC, van den Berg, AP, Slooff, NJH, de Jong, KP, Poppema, S, Groningen Institute for Organ Transplantation (GIOT), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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TRANSPLANTATION ,RISK-FACTORS ,BIOPSIES ,ALLOGRAFT-REJECTION ,CENTRILOBULAR NECROSIS - Abstract
Background. Chronic rejection (CR) in liver allografts shows a rapid onset and progressive course, leading to graft failure within the first year after transplantation. Most cases are preceded by episodes of acute cellular rejection (AR), but histological features predictive for the transition toward CR are not well documented. Methods. We assessed the predictive value of centrilobular necrosis, central vein endothelialitis (CVE), central vein fibrosis, and lobular inflammation in the development of CR. One-week and one-month biopsy specimens of 12 patients with CR were compared with those of a control group consisting of 17 patients, who experienced AR without developing CR. The progress of the histological changes was further evaluated in follow-up biopsy specimens of the CR group taken at 2 months and beyond 3 months after transplantation. Results. Centrilobular necrosis, CVE, central vein fibrosis, and lobular inflammation were common features in both groups at 1 week. At 1 month, the incidence declined in the control group. The CR group showed an increased incidence and persistence of these features in the follow-up biopsy specimens. The incidence and median grade of severity of CVE was significantly higher in the CR group (P=0.04 and P Conclusion. The shift from a predominantly portal-based process toward lobular graft damage represents the early transition of AR to CR, for which a modification of immunosuppression might be necessary to prevent graft loss.
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- 2002
9. Hepatitis C virus infection
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de Knegt, RJ, van den Berg, AP, Faculteit Medische Wetenschappen/UMCG, and Groningen Institute for Organ Transplantation (GIOT)
- Published
- 2001
10. Rapid decreases in donor-specific cytotoxic T lymphocyte precursor frequencies and graft outcome after liver and lung transplantation
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de Haan, A, van den Berg, AP, van der Bij, W, Hepkema, BG, Bruin-van Dijk, E, van der Gun, [No Value], Lems, SPM, Slooff, MJH, Haagsma, EB, de Leij, LFMH, Prop, J, Faculteit Medische Wetenschappen/UMCG, University of Groningen, and Groningen Institute for Organ Transplantation (GIOT)
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KIDNEY ALLOGRAFT ,surgical procedures, operative ,LIMITING DILUTION ,FUNCTIONAL DELETION ,ANTIGEN-SPECIFIC HYPOREACTIVITY ,BRONCHIOLITIS OBLITERANS SYNDROME ,ALLOGRAFT RECIPIENTS ,CHRONIC REJECTION ,PERIPHERAL-BLOOD ,SUPPRESSOR CELLS ,TOLERANCE INDUCTION - Abstract
Background. A decrease in donor-specific T cell precursor frequencies as seen late, one or more years, after transplantation is assumed to reflect transplantation tolerance, a condition important for long term acceptance of the allograft. However, such late decreases also occur in recipients that developed chronic transplant dysfunction questioning its relevance in transplantation tolerance, We investigated whether early, i.e., the first 6 months, decreases in donor-specific T cell precursor frequencies reflect transplantation tolerance and predict graft outcome after liver and lung transplantation. Methods. Donor and third party specific cytotoxic (CTLp) and helper T lymphocyte precursor (Rnp) frequencies were analyzed in pretransplant and 1 (or 2) and 6-month blood samples taken from liver and lung recipients and were correlated with graft outcome. Results. In liver allograft recipients with good graft function (n = 7), mean donor-specific CTLp frequencies decreased as early as 1 month after transplantation and remained low thereafter, In contrast, mean CTLp frequencies did not decrease in liver allograft recipients with chronic transplant dysfunction (n = 6). In lung allograft recipients, donor-specific CTLp frequencies remained relatively high and frequencies were not different between recipients without (n = 6) or with (n = 6) chronic transplant dysfunction. Donor-specific HTLp frequencies did not change significantly after liver or lung transplantation and did not differ between recipients without or with chronic transplant dysfunction, Conclusions, An early decrease in donor-specific CTLp correlates with good graft outcome after liver transplantation. Such rapid decreases in alloreactivity do not occur after lung transplantation illustrating the unique capacity of liver allografts to induce transplantation tolerance.
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- 2001
11. A moderate elevation of blood glucose level increases the effectiveness of thermoradiotherapy in a rat tumor model. I. Relative contributions of glucose and heating to tumor acidification
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van den Berg, AP (Aad), van den Berg-Blok, AE, Kal, HB, Reinhold, HS (Huib), and Radiation Oncology
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- 2001
12. Single dose irradiation response of pig skin: a comparison of brachytherapy using a single, high dose rate iridium-192 stepping source with 200 kV X-rays
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Hamm, PCJ, Bakker, EJ, van den Berg, AP (Aad), Aardweg, GJMJ, Visser, AG (Andries), Levendag, Peter, and Radiation Oncology
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- 2000
13. Towards standardization of the human cytomegalovirus antigenemia assay
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Verschuuren, EAM, Harmsen, MC, Limburg, PC, van der Bij, W, van den Berg, AP, Meedendorp, AMKDB, van Son, WJ, Hauw, T, Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Groningen Institute for Organ Transplantation (GIOT), and Vascular Ageing Programme (VAP)
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standardization ,TRANSPLANTATION ,antigenemia ,INFECTION ,virus diseases ,VIRUS ,PERIPHERAL-BLOOD LEUKOCYTES ,VIREMIA ,cytomegalovirus ,IMMEDIATE EARLY ANTIGEN ,PP65 - Abstract
The Human Cytomegalovirus antigenemia (HCMV-Agemia) test has been accepted worldwide as a clinical tool in the diagnosis and management of HCMV-associated syndromes in immunocompromised patients. The many modifications proposed since the first description by our laboratory make standardisation of the HCMV-Agemia assay necessary to enable multicenter clinical trials. We report the initial work for standardization of the HCMV-Agemia ia assay. A sta nda rd protocol is proposed, the optimal distribution conditions are investigated and the results of the shipment of positive and negative test slides as well as of two sets of coded internal standard slides are discussed. The main conclusions are that standard slides can be distributed at room temperature and that the results of participating laboratories with the coded internal standard slides were strikingly similar in spite of differences in HCMV-Agemia protocols used by participating laboratories. Copyright (C) 2000 S. Karger AG, Basel.
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- 1999
14. Repair mechanisms of radiation-induced DNA damage
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van den Berg, AP (Aad), Kanaar, Roland, Radiation Oncology, and Molecular Genetics
- Published
- 1999
15. Donor-specific hyporeactivity after liver transplantation - Prominent decreases in donor-specific cytotoxic T lymphocyte precursor frequencies independent of changes in helper T lymphocyte precursor frequencies or suppressor cell activity
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de Haan, A, van den Berg, AP, Hepkema, BG, van Dijk, E, Haagsma, EB, The, TH, Slooff, MJH, Lems, SPM, de Leij, LFMH, Prop, J, Faculteit Medische Wetenschappen/UMCG, and Groningen Institute for Organ Transplantation (GIOT)
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LIMITING DILUTION ,FUNCTIONAL DELETION ,KIDNEY ,REJECTION ,ALLOGRAFT RECIPIENTS ,RAT ,TOLERANCE INDUCTION ,RESPONSES ,APOPTOSIS - Abstract
Background. The development of immunological donor-specific hyporeactivity may account for the low incidence of chronic rejection after clinical liver transplantation. We investigated whether hyporeactivity commonly develops after liver transplantation by analyzing precursor frequencies of donor-reactive cytotoxic (CTLp) and helper (HTLp) T lymphocytes and mixed lymphocyte culture (MLC) reactivity in liver allograft recipients. We further studied whether CTLp hyporeactivity correlated with changes in donor-specific HTLp frequencies or suppressor cell activity. Methods. CTLp and HTLp frequencies and MLC reactivity against donor and third-party spleen cells were determined in pre- and posttransplantation peripheral blood samples from 18 recipients with good graft function 2 years after transplantation. By mixing posttransplantation samples (with "putative" suppressor cell activity) with pretransplantation samples tin which normal CTL activity with no suppressor cell activity is expected), the presence of suppressor cell activity in peripheral blood was analyzed. Results. Two years after transplantation, all but one (94%) of the recipients had developed CTLp hyporeactivity as evidenced by reduced donor-specific CTLp frequencies. The development of hyporeactivity was not specific for any particular underlying disease. The occurrence of HTL hyporeactivity, however, was less frequent: 38% and 20% of recipients were HTLp and MLC hyporeactive, respectively. Decreases in CTLp frequencies did not correlate with decreased donor-specific HTL function or suppressor cell activity in peripheral blood samples. Conclusions. Donor-specific CTLp hyporeactivity can develop in the majority of liver allograft recipients, irrespective of underlying disease. Donor-specific HTL hyporeactivity, however, occurs infrequently. A reduction in donor-specific CTLp frequencies was found to be independent of changes in donor-specific HTLp or suppressor cell activity, suggesting that other mechanisms (e.g., clonal deletion) are operative in the reduction of donor-specific CTLp after liver transplantation.
- Published
- 1998
16. Routine Doppler ultrasound for the detection of clinically unsuspected vascular complications in the early postoperative phase after orthotopic liver transplantation
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Kok, T, Slooff, MJH, Thijn, CJP, Peeters, PMJG, Verwer, R, Bijleveld, CMA, van den Berg, AP, Haagsma, EB, Klompmaker, IJ, and Groningen Institute for Organ Transplantation (GIOT)
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liver transplantation ,ultrasound ,hepatic artery ,cardiovascular system ,HEPATIC-ARTERY THROMBOSIS ,DUPLEX US ,SONOGRAPHY ,DIAGNOSIS - Abstract
To assess the role of routine Doppler ultrasound in the detection of clinically unsuspected vascular complications in the early postoperative phase after orthotopic liver transplantation (OLT), the findings of 858 routinely performed Doppler ultrasound examinations were analyzed in 268 transplants. At various time intervals after OLT, we encountered 46 abnormal Doppler findings: hepatic artery (thrombosis), portal vein [anastomotic stenosis, (non)occlusive thrombosis or reversed flow], inferior vena cava [anastomotic stenosis with reversed flow, no flow or (non)occlusive thrombosis], and hepatic veins (to-and-fro flow or stenosis with reversed flow) in 14, 20, 9, and 2 transplants, respectively. Most of these abnormal Doppler findings were confirmed by angiography, cavography, or surgery. The positive predictive value for hepatic artery thrombosis (HAT) was 12 out of 14, or 86 %. In the first 2 weeks after OLT, routine Doppler ultrasound revealed 20 of the 46 abnormal findings (43 %). Clinically unsuspected complications of the hepatic artery, portal vein, inferior vena cava, and hepatic veins were found in 9 of the 14 (64 %), 6 of the 20 (30 %), 3 of the 9 (33 %), and 2 of the 2 (100 %) transplants, respectively. The highest incidence nine vascular complications - was found on the 1st day. On each of the remaining days (except for the 2nd and 9th days), one or two vascular complications were detected. HAT was found mainly in the Ist week. Vascular complications developed independently or concomitantly. We conclude that routine Doppler ultrasound is very important for the detection of clinically unsuspected vascular complications, particularly HAT, in the first 2 weeks after OLT. We recommend routine Doppler ultrasound of all hepatic vessels every 3 days in the early postoperative phase after OLT Special attention should be paid to the Ist day.
- Published
- 1998
17. Quantitation of immunosuppression by flow cytometric measurement of the capacity of T cells for interleukin-2 production
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van den Berg, AP, Twilhaar, WN, Mesander, G, van Son, WJ, van der Bij, W, Klompmaker, IJ, Slooff, MJH, The, TH, de Leij, LHFM, Faculteit Medische Wetenschappen/UMCG, and Groningen Institute for Organ Transplantation (GIOT)
- Subjects
BLOOD ,ANTIGENEMIA ,CHRONIC REJECTION ,CYTOKINES ,CYCLOSPORINE ,LIVER-TRANSPLANTATION ,CALCINEURIN ACTIVITY ,CYTOMEGALOVIRUS-INFECTION ,LEUKOCYTES - Abstract
Background. Methods to quantitate the effects of immunosuppressive drugs on immune reactivity might be helpful for monitoring immunosuppressive treatment. Cyclosporine (CsA) inhibits the induction of cytokine synthesis in T cells, and measurement of interleukin (IL)-2 production might constitute a parameter of this drug's effect. Methods. We determined the percentages of CD4(+) and CD8(+) lymphocytes producing IL-2 upon stimulation by phorbol myristate acetate and calcium ionophore in whole blood culture, using immunostaining of intracytoplasmatic and membrane markers, followed by multiparameter flow cytometry. A total of 38 clinically stable transplant patients on various immunosuppressive protocols were studied. Results. The percentage of CD4(+) T cells producing IL-2 was strongly reduced in patients compared with healthy controls (23% [range, 3-68%] vs. 59.0% [range, 41-70%]; P=0.000035). The percentage of CD4(+) T cells producing IL-2 was negatively correlated with the CSA level (R-c=-0.0821, P=0.00002297) but not with prednisolone or azathioprine doses. Fewer CD8(+) T cells produced IL-2 in transplant patients compared with controls, but the difference failed to reach statistical significance. The percentage of CD8(+) T cells capable of producing IL-2 was inversely correlated to CsA levels (R-c= -0.0375, P=0.0011). Conclusions. These data suggest that the functional effects of CsA in transplant recipients can be quantitatively determined and that the capacity of CD4(+) T cells to produce IL-2 upon stimulation constitutes a functional parameter of CsA effects on the immune system. Prospective studies are required to determine whether this method is useful for clinical monitoring.
- Published
- 1998
18. Relationship between monitoring the viral load in blood, human cytomegalovirus pathophysiology and management strategies of patients after transplantation
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The, TH, Harmsen, MC, van der Bij, W, van den Berg, AP, van Son, WJ, Scholz, M, Rabenau, HF, Doerr, HW, Cinatl, J, Faculteit Medische Wetenschappen/UMCG, Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Groningen Institute for Organ Transplantation (GIOT), and Vascular Ageing Programme (VAP)
- Subjects
VIRUS INFECTION ,ORGAN-TRANSPLANTATION ,CMV INFECTION ,ACQUIRED IMMUNODEFICIENCY SYNDROME ,BONE-MARROW TRANSPLANTATION ,ALLOGRAFT-REJECTION ,PERIPHERAL-BLOOD ,MONOCLONAL-ANTIBODIES ,LIVER-TRANSPLANTATION ,ENDOTHELIAL-CELLS - Published
- 1998
19. Anastomotic biliary strictures after liver transplantation: prevalence, presentation, management and outcome
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Verdonk, RC, primary, Buis, CI, additional, Porte, RJ, additional, van der Jagt, EJ, additional, Limburg, AJ, additional, van den Berg, AP, additional, Slooff, MJH, additional, Kleibeuker, JH, additional, and Haagsma, EB, additional
- Published
- 2006
- Full Text
- View/download PDF
20. Actual non-estimated ten-year survival in adults after liver transplantation (LT)
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van der Hilst, CS, primary, IJtsma, AJC, additional, Boelstra, TJ, additional, Haagsma, EB, additional, van den Berg, AP, additional, TenVergert, EM, additional, and Slooff, MJH, additional
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- 2006
- Full Text
- View/download PDF
21. Thermal enhancement of both tumour necrosis factor alpha-induced systemic toxicity and tumour cure in rats
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van der Zee, J, primary, van den Aardweg, GJMJ, additional, van Rhoon, GC, additional, van den Berg, AP, additional, and de Wit, R, additional
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- 1995
- Full Text
- View/download PDF
22. In memoriam: Ruud A.F. Krom, MD, PhD (1941-2024).
- Author
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Alwayn IPJ, van den Berg AP, Guichelaar MMJ, van Hoek B, Janssen H, Kootstra G, de Meijer VE, Porte RJ, Slooff MJ, and Wiesner RH
- Published
- 2024
- Full Text
- View/download PDF
23. An open-label randomised-controlled trial of azathioprine vs. mycophenolate mofetil for the induction of remission in treatment-naive autoimmune hepatitis.
- Author
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Snijders RJALM, Stoelinga AEC, Gevers TJG, Pape S, Biewenga M, Tushuizen ME, Verdonk RC, de Jonge HJM, Vrolijk JM, Bakker SF, Vanwolleghem T, de Boer YS, Baven Pronk MAMC, Beuers U, van der Meer AJ, Gerven NMFV, Sijtsma MGM, van Eijck BC, van IJzendoorn MC, van Herwaarden M, van den Brand FF, Korkmaz KS, van den Berg AP, Guichelaar MMJ, Levens AD, van Hoek B, and Drenth JPH
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- Humans, Female, Male, Mycophenolic Acid adverse effects, Prospective Studies, Treatment Outcome, Immunosuppressive Agents adverse effects, Prednisolone adverse effects, Remission Induction, Azathioprine therapeutic use, Hepatitis, Autoimmune drug therapy
- Abstract
Background & Aims: Patients with autoimmune hepatitis (AIH) almost invariably require lifelong immunosuppressive treatment. There is genuine concern about the efficacy and tolerability of the current standard combination therapy of prednisolone and azathioprine. Mycophenolate mofetil (MMF) has emerged as an alternative option. The aim of this study was to compare MMF to azathioprine as induction therapy for AIH., Methods: In this 24-week, prospective, randomised, open-label, multicentre superiority trial, 70 patients with treatment-naive AIH received either MMF or azathioprine, both in combination with prednisolone. The primary endpoint was biochemical remission defined as normalisation of serum levels of alanine aminotransferase and IgG after 24 weeks of treatment. Secondary endpoints included safety and tolerability., Results: Seventy patients (mean 57.9 years [SD 14.0]; 72.9% female) were randomly assigned to the MMF plus prednisolone (n = 39) or azathioprine plus prednisolone (n = 31) group. The primary endpoint was met in 56.4% and 29.0% of patients assigned to the MMF group and the azathioprine group, respectively (difference, 27.4 percentage points; 95% CI 4.0 to 46.7; p = 0.022). The MMF group exhibited higher complete biochemical response rates at 6 months (72.2% vs. 32.3%; p = 0.004). No serious adverse events occurred in patients who received MMF (0%) but serious adverse events were reported in four patients who received azathioprine (12.9%) (p = 0.034). Two patients in the MMF group (5.1%) and eight patients in the azathioprine group (25.8%) discontinued treatment owing to adverse events or serious adverse events (p = 0.018)., Conclusions: In patients with treatment-naive AIH, MMF with prednisolone led to a significantly higher rate of biochemical remission at 24 weeks compared to azathioprine combined with prednisolone. Azathioprine use was associated with more (serious) adverse events leading to cessation of treatment, suggesting superior tolerability of MMF., Impact and Implications: This randomised-controlled trial directly compares azathioprine and mycophenolate mofetil, both in combination with prednisolone, for the induction of biochemical remission in treatment-naive patients with autoimmune hepatitis. Achieving complete remission is desirable to prevent disease progression. Patients assigned to the mycophenolate mofetil group reached biochemical remission more often and experienced fewer adverse events. The findings in this trial may contribute to the re-evaluation of international guidelines for the standard of care in treatment-naive patients with autoimmune hepatitis., Trial Registration Number: #NCT02900443., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
24. Effects of interrupting the enterohepatic circulation in amatoxin intoxications.
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Varekamp J, Tan JL, Stam J, van den Berg AP, van Rheenen PF, Touw DJ, and Dekkers BGJ
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- Humans, Amanitins, Enterohepatic Circulation, Liver, Charcoal therapeutic use, Mushroom Poisoning diagnosis, Mushroom Poisoning drug therapy
- Abstract
Background: Interruption of the enterohepatic circulation is regarded as an effective way to treat patients with amatoxin poisoning. Nonetheless, its effectiveness has not yet been systematically evaluated. Therefore, we performed a systematic review to investigate the role of enterohepatic circulation on patient outcome and clinical laboratory values. We specifically sought to evaluate the effect of activated charcoal, which absorbs drugs and toxins in the gastrointestinal tract., Methods: A previously established database with data extracted from case reports and series from literature, supplemented with recent publications, was used. Patient characteristics, outcome, and laboratory values were evaluated., Results: We included 133 publications describing a total of 1,119 unique cases. Survival was 75 per cent in the control group ( n = 452), whereas in the group treated with single or multiple doses of activated charcoal ( n = 667) survival was 83 per cent ( P < 0.001, odds ratio 1.89 [95 per cent confidence interval 1.40-2.56]). Furthermore, no difference in peak values of alanine aminotransferase and aspartate aminotransferase activities were observed, whereas peak values of total serum bilirubin concentration and international normalized ratio were statistically significantly reduced in patients treated with activated charcoal., Discussion: The ability of activated charcoal to enhance the elimination of amatoxin through interruption of the enterohepatic circulation offers a potentially safe and inexpensive therapy for patients in the post-absorptive phase., Limitations: Limitations include the potential for publication bias, the lack of universal confirmation of amatoxin concentrations, and the inability to directly measure enterohepatic circulation of amatoxin., Conclusion: Treatment with activated charcoal in patients with amatoxin poisoning was associated with a greater chance of a successful outcome. Additionally, activated charcoal was associated with a reduction in markers of liver function, but not markers of liver injury.
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- 2024
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25. Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial.
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Stoelinga AEC, Tushuizen ME, van den Hout WB, Girondo MDMR, de Vries ES, Levens AD, Moes DAR, Gevers TJG, van der Meer S, Brouwer HT, de Jonge HJM, de Boer YS, Beuers UHW, van der Meer AJ, van den Berg AP, Guichelaar MMJ, Drenth JPH, and van Hoek B
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- Humans, Quality of Life, Retrospective Studies, Treatment Outcome, Immunosuppressive Agents adverse effects, Mycophenolic Acid adverse effects, Enzyme Inhibitors therapeutic use, Liver Cirrhosis drug therapy, Randomized Controlled Trials as Topic, Multicenter Studies as Topic, Clinical Trials, Phase III as Topic, Tacrolimus adverse effects, Hepatitis, Autoimmune diagnosis, Hepatitis, Autoimmune drug therapy
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Background: Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH., Methods: The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness., Discussion: This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines., Trial Registration: ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021., (© 2024. The Author(s).)
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- 2024
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26. Prolonged hypothermic machine perfusion enables daytime liver transplantation - an IDEAL stage 2 prospective clinical trial.
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Brüggenwirth IMA, Lantinga VA, Lascaris B, Thorne AM, Meerdink M, de Kleine RH, Blokzijl H, van den Berg AP, Reyntjens KMEM, Lisman T, Porte RJ, and de Meijer VE
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Background: Liver transplantation is traditionally performed around the clock to minimize organ ischemic time. However, the prospect of prolonging preservation times holds the potential to streamline logistics and transform liver transplantation into a semi-elective procedure, reducing the need for nighttime surgeries. Dual hypothermic oxygenated machine perfusion (DHOPE) of donor livers for 1-2 h mitigates ischemia-reperfusion injury and improves transplant outcomes. Preclinical studies have shown that DHOPE can safely extend the preservation of donor livers for up to 24 h., Methods: We conducted an IDEAL stage 2 prospective clinical trial comparing prolonged (≥4 h) DHOPE to conventional (1-2 h) DHOPE for brain-dead donor livers, enabling transplantation the following morning. Liver allocation to each group was based on donor hepatectomy end times. The primary safety endpoint was a composite of all serious adverse events (SAE) within 30 days after transplantation. The primary feasibility endpoint was defined as the number of patients assigned and successfully receiving a prolonged DHOPE-perfused liver graft. Trial registration at: WHO International Clinical Trial Registry Platform, number NL8740., Findings: Between November 1, 2020 and July 16, 2022, 24 patients were enrolled. The median preservation time was 14.5 h (interquartile range [IQR], 13.9-15.5) for the prolonged group (n = 12) and 7.9 h (IQR, 7.6-8.6) for the control group (n = 12; p = 0.01). In each group, three patients (25%; 95% CI 3.9-46%, p = 1) experienced a SAE. Markers of ischemia-reperfusion injury and oxidative stress in both perfusate and recipients were consistently low and showed no notable discrepancies between the two groups. All patients assigned to either the prolonged group or control group successfully received a liver graft perfused with either prolonged DHOPE or control DHOPE, respectively., Interpretation: This first-in-human clinical trial demonstrates the safety and feasibility of DHOPE in prolonging the preservation time of donor livers to enable daytime transplantation. The ability to extend the preservation window to up to 20 h using hypothermic oxygenated machine preservation at a 10 °C temperature has the potential to reshape the landscape of liver transplantation., Funding: University Medical Center Groningen, the Netherlands., Competing Interests: Vincent E. de Meijer reports a VENI research grant by the Dutch Research Council (NWO; grant #09150161810030), a Research grant from the Dutch Ministry of Economic Affairs (Health ∼ Holland Public Private Partnership grant #PPP-2019-024), and a Research grant from the Dutch Society for Gastroenterology (NVGE #01-2021), all outside the submitted work. Other authors declare that they have no competing interests., (© 2023 The Author(s).)
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- 2024
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27. Incidence and predictors of hepatocellular carcinoma in patients with autoimmune hepatitis.
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Colapietro F, Maisonneuve P, Lytvyak E, Beuers U, Verdonk RC, van der Meer AJ, van Hoek B, Kuiken SD, Brouwer JT, Muratori P, Aghemo A, Carella F, van den Berg AP, Zachou K, Dalekos GN, Di Zeo-Sánchez DE, Robles M, Andrade RJ, Montano-Loza AJ, van den Brand FF, Slooter CD, Macedo G, Liberal R, de Boer YS, and Lleo A
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- Humans, Incidence, Liver Cirrhosis complications, Liver Cirrhosis epidemiology, Obesity complications, Retrospective Studies, Risk Factors, Carcinoma, Hepatocellular epidemiology, Carcinoma, Hepatocellular etiology, Carcinoma, Hepatocellular diagnosis, Hepatitis, Autoimmune complications, Hepatitis, Autoimmune epidemiology, Hepatitis, Autoimmune diagnosis, Liver Neoplasms epidemiology, Liver Neoplasms etiology, Liver Neoplasms diagnosis
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Background and Aims: Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown aetiology; the risk of hepatocellular carcinoma (HCC) remains unclear and risk factors are not well-defined. We aimed to investigate the risk of HCC across a multicentre AIH cohort and to identify predictive factors., Methods: We performed a retrospective, observational, multicentric study of patients included in the International Autoimmune Hepatitis Group Retrospective Registry. The assessed clinical outcomes were HCC development, liver transplantation, and death. Fine and Gray regression analysis stratified by centre was applied to determine the effects of individual covariates; the cumulative incidence of HCC was estimated using the competing risk method with death as a competing risk., Results: A total of 1,428 patients diagnosed with AIH from 1980 to 2020 from 22 eligible centres across Europe and Canada were included, with a median follow-up of 11.1 years (interquartile range 5.2-15.9). Two hundred and ninety-three (20.5%) patients had cirrhosis at diagnosis. During follow-up, 24 patients developed HCC (1.7%), an incidence rate of 1.44 cases/1,000 patient-years; the cumulative incidence of HCC increased over time (0.6% at 5 years, 0.9% at 10 years, 2.7% at 20 years, and 6.6% at 30 years of follow-up). Patients who developed cirrhosis during follow-up had a significantly higher incidence of HCC. The cumulative incidence of HCC was 2.6%, 4.6%, 5.6% and 6.6% at 5, 10, 15, and 20 years after the development of cirrhosis, respectively. Obesity (hazard ratio [HR] 2.94, p = 0.04), cirrhosis (HR 3.17, p = 0.01), and AIH/PSC variant syndrome (HR 5.18, p = 0.007) at baseline were independent risk factors for HCC development., Conclusions: HCC incidence in AIH is low even after cirrhosis development and is associated with risk factors including obesity, cirrhosis, and AIH/PSC variant syndrome., Impact and Implications: The risk of developing hepatocellular carcinoma (HCC) in individuals with autoimmune hepatitis (AIH) seems to be lower than for other aetiologies of chronic liver disease. Yet, solid data for this specific patient group remain elusive, given that most of the existing evidence comes from small, single-centre studies. In our study, we found that HCC incidence in patients with AIH is low even after the onset of cirrhosis. Additionally, factors such as advanced age, obesity, cirrhosis, alcohol consumption, and the presence of the AIH/PSC variant syndrome at the time of AIH diagnosis are linked to a higher risk of HCC. Based on these findings, there seems to be merit in adopting a specialized HCC monitoring programme for patients with AIH based on their individual risk factors., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
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- 2024
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28. Health-related Quality of Life and Fatigue in Liver Transplant Recipients Receiving Tacrolimus Versus Sirolimus-based Immunosuppression: Results From a Randomized Trial.
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Mulder MB, Busschbach JV, van Hoek B, van den Berg AP, Polak WG, Alwayn IPJ, de Winter BCM, Verhey-Hart E, Erler NS, den Hoed CM, and Metselaar HJ
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- Humans, Tacrolimus adverse effects, Surveys and Questionnaires, Immunosuppression Therapy, Fatigue diagnosis, Health Status, Quality of Life, Liver Transplantation adverse effects
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Background: The impact of different immunosuppression regimes on the health-related quality of life (HRQoL) and the severity of fatigue in liver transplant recipients is largely unknown. We investigated the impact of a sirolimus-based regimen compared with a tacrolimus (TAC)-based regimen on the HRQoL and the severity of fatigue., Methods: In this multicenter, open-label, randomized, controlled trial, 196 patients were randomized 90 d after transplantation to (1) once daily normal-dose TAC or (2) once daily combination therapy of low-dose sirolimus and TAC. HRQoL was measured with the EQ-5D-5L questionnaire, the EQ-visual analog scale, and the severity of fatigue questionnaire Fatigue Severity Score (FSS). The EQ-5D-5L scores were translated to societal values. We examined the HRQoL and the FSS over the course of the study by fitting generalized mixed-effect models., Results: Baseline questionnaires were available for 87.7% (172/196) of the patients. Overall, patients reported the least problems in the states of self-care and anxiety/depression and the most problems in the states of usual activities and pain/discomfort. No significant differences in HrQol and FSS were seen between the 2 groups. During follow-up, the societal values of the EQ-5D-5L health states and the patient's self-rated EQ-visual analog scale score were a little lower than those of the general Dutch population in both study arms., Conclusions: The HRQoL and FSS were comparable in the 36 mo after liver transplantation in both study groups. The HRQoL of all transplanted patients approximated that of the general Dutch population, suggesting little to no residual symptoms in the long term after transplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2023
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29. Randomized Trial of Ciclosporin with 2-h Monitoring vs. Tacrolimus with Trough Monitoring in Liver Transplantation: DELTA Study.
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Ruijter BN, Inderson A, van den Berg AP, Metselaar HJ, Dubbeld J, Tushuizen ME, Porte RJ, Polak W, van der Helm D, van Reeven M, Rodriguez-Girondo M, and van Hoek B
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Background and Aims: Previous trials comparing cyclosporine and tacrolimus after liver transplantation (LT) showed conflicting results. Most used trough monitoring for cyclosporine (C0), leading to less accurate dosing than with 2-h monitoring (C2). Only one larger trial compared C2 with tacrolimus based on trough level (T0) after LT, with similar treated biopsy-proven acute rejection (tBPAR) and graft loss, while a smaller trial had less tBPAR with C2 compared to T0. Therefore, it is still unclear which calcineurin inhibitor is preferred after LT. We aimed to demonstrate superior efficacy (tBPAR), tolerability, and safety of C2 or T0 after first LT., Methods: Patients after first LT were randomized to C2 or T0. tBPAR, patient- and graft survival, safety and tolerability were the main endpoints, with analysis by Fisher test, Kaplan-Meier survival analysis and log-rank test., Results: In intention-to-treat analysis 84 patients on C2 and 85 on T0 were included. Cumulative incidence of tBPAR C2 vs. T0 was 17.7% vs. 8.4% at 3 months ( p =0.104), and 21.9% vs. 9.7% at 6 and 12 months ( p =0.049). One-year cumulative mortality C2 vs. T0 was 15.5% vs. 5.9% ( p =0.049) and graft loss 23.8% vs. 9.4% ( p =0.015). Serum triglyceride and LDL-cholesterol was lower with T0 than with C2. Incidence of diarrhea in T0 vs, C2 was 64% vs. 31% ( p ≤0.001), with no other differences in safety and tolerability., Conclusions: In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2., Competing Interests: BvH has been an editorial board member of Journal of Clinical and Translational Hepatology since 2022. The other authors have no conflict of interests related to this publication., (© 2023 Authors.)
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- 2023
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30. Qualifying the suitability of living donor livers for pediatric liver transplantation: are we doing the right thing?
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Verkade HJ, Cuperus FCJ, and van den Berg AP
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Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-219/coif). The authors have no conflicts of interest to declare.
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- 2023
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31. Three-year results of renal function in liver transplant recipients on low-dose sirolimus and tacrolimus: a multicenter, randomized, controlled trial.
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Mulder MB, van Hoek B, van den Berg AP, Polak WG, Alwayn IPJ, de Jong KP, de Winter BCM, Verhey-Hart E, Erler NS, den Hoed CM, and Metselaar HJ
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- Humans, Tacrolimus therapeutic use, Sirolimus adverse effects, Immunosuppressive Agents therapeutic use, Kidney physiology, Graft Rejection epidemiology, Graft Rejection prevention & control, Graft Rejection drug therapy, Graft Survival, Liver Transplantation adverse effects, Kidney Transplantation adverse effects, Renal Insufficiency, Chronic diagnosis, Renal Insufficiency, Chronic chemically induced
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The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade ≥3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%-59.9%) vs. 43.7%, 95% CI: 32.8%-52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1±15 vs. 67.6±16 mL/min/1.73 m2, p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade ≥3 at 36 months compared to normal-dose extended-release TAC., (Copyright © 2023 American Association for the Study of Liver Diseases.)
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- 2023
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32. Waitlist mortality of young patients with biliary atresia: Impact of allocation policy and living donor liver transplantation.
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Esmati H, van Rosmalen M, van Rheenen PF, de Boer MT, van den Berg AP, van der Doef HPJ, Rayar M, de Kleine RHJ, Porte RJ, de Meijer VE, and Verkade HJ
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- Humans, Living Donors, Cohort Studies, Risk Assessment, Retrospective Studies, Treatment Outcome, Liver Transplantation adverse effects, Biliary Atresia surgery
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Patients with biliary atresia (BA) below 2 years of age in need of a transplantation largely rely on partial grafts from deceased donors (deceased donor liver transplantation [DDLT]) or living donors (living donor liver transplantation [LDLT]). Because of high waitlist mortality in especially young patients with BA, the Eurotransplant Liver Intestine Advisory Committee (ELIAC) has further prioritized patients with BA listed before their second birthday for allocation of a deceased donor liver since 2014. We evaluated whether this Eurotransplant (ET) allocation prioritization changed the waitlist mortality of young patients with BA. We used a pre-post cohort study design with the implementation of the new allocation rule between the two periods. Participants were patients with BA younger than 2 years who were listed for liver transplantation in the ET database between 2001 and 2018. Competing risk analyses were performed to assess waitlist mortality in the first 2 years after listing. We analyzed a total of 1055 patients with BA, of which 882 had been listed in the preimplementation phase (PRE) and 173 in the postimplementation phase (POST). Waitlist mortality decreased from 6.7% in PRE to 2.3% in POST ( p = 0.03). Interestingly, the proportion of young patients with BA undergoing DDLT decreased from 32% to 18% after ET allocation prioritization ( p = 0.001), whereas LDLT increased from 55% to 74% ( p = 0.001). The proportional increase in LDLT decreased the median waitlist duration of transplanted patients from 1.5 months in PRE to 0.85 months in POST ( p = 0.003). Since 2014, waitlist mortality in young patients with BA has strongly decreased in the ET region. Rather than associated with prioritized allocation of deceased donor organs, the decreased waitlist mortality was related to a higher proportion of patients undergoing LDLT., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2023
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33. Calcineurin Inhibitors in the Treatment of Adult Autoimmune Hepatitis: A Systematic Review.
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Baven-Pronk MA, Hew JM Jr, Biewenga M, Tushuizen ME, van den Berg AP, Bouma G, Brouwer JT, and van Hoek B
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Background and Aims: A considerable number of autoimmune hepatitis (AIH) patients completely or partially fail on first-line treatment. Several studies on the use of calcineurin inhibitors (CNIs) in the treatment of AIH have been published without focusing on indication. The aim was to assess the efficacy of CNIs in the treatment of adult AIH patients, specifically focusing on indication: first-line intolerant and with first-line insufficient response (failure to achieve or maintain remission), and with second versus third-line treatment., Methods: A literature search included studies on the use of CNIs in adult AIH. Patients with past or present use of CNIs from the Dutch AIH group cohort were added. The primary endpoint was biochemical remission while using CNIs. Secondary endpoints were biochemical response, treatment failure, and adverse effects., Results: Twenty studies from the literature and nine Dutch patients were included describing the use of cyclosporine in 59 and tacrolimus in 219 adult AIH patients. The CNI remission rate was 53% in patients with insufficient response to first-line treatment and 67% in patients intolerant to first-line treatment. CNIs were used as second-line treatment in 73% with a remission rate of 52% and as third-line treatment in 22% with a remission rate of 26%. Cyclosporine was discontinued in 13% and tacrolimus in 11% of patients because of adverse events., Conclusions: CNIs as rescue treatment in adult AIH patients are reasonably effective and safe both with insufficient response or intolerance to previous treatment. Prospective studies are needed., Competing Interests: ME Tushuizen has been an editorial board member of Journal of Clinical and Translational Hepatology since 2021, and B van Hoek has been an editorial board member of Journal of Clinical and Translational Hepatology since 2022. The other authors have no conflict of interests related to this publication., (© 2022 Authors.)
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- 2022
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34. Assessing the efficacy and safety of mycophenolate mofetil versus azathioprine in patients with autoimmune hepatitis (CAMARO trial): study protocol for a randomised controlled trial.
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Snijders RJALM, Stoelinga AEC, Gevers TJG, Pape S, Biewenga M, Verdonk RC, de Jonge HJM, Vrolijk JM, Bakker SF, Vanwolleghem T, de Boer YS, Pronk MAMCB, Beuers UHW, van der Meer AJ, van Gerven NMF, Sijtsma MGM, Verwer BJ, Gisbertz IAM, Bartelink M, van den Brand FF, Sebib Korkmaz K, van den Berg AP, Guichelaar MMJ, Soufidi K, Levens AD, van Hoek B, and Drenth JPH
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- Adult, Humans, Mycophenolic Acid adverse effects, Azathioprine adverse effects, Quality of Life, Immunosuppressive Agents adverse effects, Treatment Outcome, Severity of Illness Index, Prednisolone adverse effects, Randomized Controlled Trials as Topic, Multicenter Studies as Topic, Hepatitis, Autoimmune diagnosis, Hepatitis, Autoimmune drug therapy, End Stage Liver Disease
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Background: Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH., Methods: CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks., Discussion: The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases., Trial Registration: EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016., (© 2022. The Author(s).)
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- 2022
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35. Amanitin intoxication: effects of therapies on clinical outcomes - a review of 40 years of reported cases.
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Tan JL, Stam J, van den Berg AP, van Rheenen PF, Dekkers BGJ, and Touw DJ
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- Humans, Amanita, Alanine Transaminase, Acetylcysteine therapeutic use, Silybin therapeutic use, Penicillin G therapeutic use, Amanitins, Mushroom Poisoning drug therapy, Mushroom Poisoning complications
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Background and Aims: Amanita phalloides poisoning causes severe liver damage which may be potentially fatal. Several treatments are available, but their effectiveness has not been systematically evaluated. We performed a systematic review to investigate the effect of the most commonly used therapies: N-acetylcysteine (NAC), benzylpenicillin (PEN), and silibinin (SIL) on patient outcomes. In addition, other factors contributing to patient outcomes are identified., Methods: We searched MEDLINE and Embase for case series and case reports that described patient outcomes after poisoning with amanitin-containing Amanita mushrooms. We extracted clinical characteristics, treatment details, and outcomes. We used the liver item from the Poisoning Severity Score (PSS) to categorize intoxication severity., Results: We included 131 publications describing a total of 877 unique cases. The overall survival rate of all patients was 84%. Patients receiving only supportive care had a survival rate of 59%. The use of SIL or PEN was associated with a 90% (OR 6.40 [3.14-13.04]) and 89% (OR 5.24 [2.87-9.56]) survival rate, respectively. NAC/SIL combination therapy was associated with 85% survival rate (OR 3.85 [2.04, 7.25]). NAC/PEN/SIL treatment group had a survival rate of 76% (OR 2.11 [1.25, 3.57]). Due to the limited number of cases, the use of NAC alone could not be evaluated. Additional analyses in 'proven cases' (amanitin detected), 'probable cases' (mushroom identified by mycologist), and 'possible cases' (neither amanitin detected nor mushroom identified) showed comparable results, but the results did not reach statistical significance. Transplantation-free survivors had significantly lower peak values of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total serum bilirubin (TSB), and international normalized ratio (INR) compared to liver transplantation survivors and patients with fatal outcomes. Higher peak PSS was associated with increased mortality., Conclusion: Based on data available, no statistical differences could be observed for the effects of NAC, PEN or SIL in proven poisonings with amanitin-containing mushrooms. However, monotherapy with SIL or PEN and combination therapy with NAC/SIL appear to be associated with higher survival rates compared to supportive care alone. AST, ALT, TSB, and INR values are possible predictors of potentially fatal outcomes.
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- 2022
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36. Outcomes after primary and repeat thermal ablation of hepatocellular carcinoma with or without liver transplantation.
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Serbanescu-Kele Apor de Zalán CMC, Ruiter SJS, van den Berg AP, Pennings JP, and de Jong KP
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- Hepatectomy methods, Humans, Neoplasm Recurrence, Local pathology, Recurrence, Retrospective Studies, Treatment Outcome, Carcinoma, Hepatocellular pathology, Liver Neoplasms pathology, Liver Transplantation methods
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Objectives: Thermal ablation (TA) is an established treatment for early HCC. There is a lack of data on the efficacy of repeated TA for recurrent HCC, resulting in uncertainty whether good oncologic outcomes can be obtained without performing orthotopic liver transplantation (OLTx). This study analyses outcomes after TA, with a special focus on repeat TA for recurrent HCC, either as a stand-alone therapy, or in relationship with OLTx., Methods: Data from a prospectively registered database on interventions for HCC in a tertiary hepatobiliary centre was completed with follow-up until December 2020. Outcomes studied were rate of recurrence after primary TA and after its repeat interventions, the occurrence of untreatable recurrence, OS and DSS after primary and repeat TA, and complications after TA. In cohorts matched for confounders, OSS and DSS were compared after TA with and without the intention to perform OLTx., Results: After TA, 100 patients (56·8%) developed recurrent HCC, of whom 76 (76·0%) underwent up to four repeat interventions. During follow-up, 76·7% of patients never developed a recurrence unamenable to repeat TA or OLTx. OS was comparable after primary TA and repeat TA. In matched cohorts, OS and DSS were comparable after TA with and without the intention to perform OLTx., Conclusions: We found TA to be an effective and repeatable therapy for primary and recurrent HCC. Most recurrences can be treated with curative intent. There are patients who do well with TA alone without ever undergoing OLTx., Key Points: • Recurrent HCC after primary TA can often be treated effectively with repeat TA. Survival after repeat TA is comparable to primary TA. • In matched cohorts, outcomes after TA with and without subsequent waitlisting for OLTx are comparable. • There are patients who do well for many years with primary and repeat TA alone; some despite multiple recurrences., (© 2022. The Author(s).)
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- 2022
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37. Sequential hypothermic and normothermic machine perfusion enables safe transplantation of high-risk donor livers.
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van Leeuwen OB, Bodewes SB, Lantinga VA, Haring MPD, Thorne AM, Brüggenwirth IMA, van den Berg AP, de Boer MT, de Jong IEM, de Kleine RHJ, Lascaris B, Nijsten MWN, Reyntjens KMEM, de Meijer VE, and Porte RJ
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- Hemoglobins, Humans, Liver, Living Donors, Organ Preservation methods, Oxygen, Perfusion methods, Prospective Studies, Liver Transplantation methods
- Abstract
Ex situ normothermic machine perfusion (NMP) is increasingly used for viability assessment of high-risk donor livers, whereas dual hypothermic oxygenated machine perfusion (DHOPE) reduces ischemia-reperfusion injury. We aimed to resuscitate and test the viability of initially-discarded, high-risk donor livers using sequential DHOPE and NMP with two different oxygen carriers: an artificial hemoglobin-based oxygen carrier (HBOC) or red blood cells (RBC). In a prospective observational cohort study of 54 livers that underwent DHOPE-NMP, the first 18 procedures were performed with a HBOC-based perfusion solution and the subsequent 36 procedures were performed with an RBC-based perfusion solution for the NMP phase. All but one livers were derived from extended criteria donation after circulatory death donors, with a median donor risk index of 2.84 (IQR 2.52-3.11). After functional assessment during NMP, 34 livers (63% utilization), met the viability criteria and were transplanted. One-year graft and patient survival were 94% and 100%, respectively. Post-transplant cholangiopathy occurred in 1 patient (3%). There were no significant differences in utilization rate and post-transplant outcomes between the HBOC and RBC group. Ex situ machine perfusion using sequential DHOPE-NMP for resuscitation and viability assessment of high-risk donor livers results in excellent transplant outcomes, irrespective of the oxygen carrier used., (© 2022 The Authors. American Journal of Transplantation published by Wiley Periodicals LLC on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)
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- 2022
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38. Protocol for a randomized controlled multicenter trial assessing the efficacy of leuprorelin for severe polycystic liver disease: the AGAINST-PLD study.
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Aapkes SE, Bernts LHP, van den Berg AP, van den Berg M, Blokzijl H, Cantineau AEP, van Gastel MDA, de Haas RJ, Kappert P, Müller RU, Nevens F, Torra R, Visser A, Drenth JPH, and Gansevoort RT
- Subjects
- Female, Humans, Cysts, Multicenter Studies as Topic, Prospective Studies, Randomized Controlled Trials as Topic, Leuprolide therapeutic use, Liver Diseases drug therapy
- Abstract
Background: In patients with severe polycystic liver disease (PLD), there is a need for new treatments. Estrogens and possibly other female sex hormones stimulate growth in PLD. In some patients, liver volume decreases after menopause. Female sex hormones could therefore be a target for therapy. The AGAINST-PLD study will examine the efficacy of the GnRH agonist leuprorelin, which blocks the production of estrogen and other sex hormones, to reduce liver growth in PLD., Methods: The AGAINST-PLD study is an investigator-driven, multicenter, randomized controlled trial. Institutional review board (IRB) approval was received at the University Medical Center of Groningen and will be collected in other sites before opening these sites. Thirty-six female, pre-menopausal patients, with a very large liver volume for age (upper 10% of the PLD population) and ongoing liver growth despite current treatment options will be randomized to direct start of leuprorelin or to 18 months standard of care and delayed start of leuprorelin. Leuprorelin is given as 3.75 mg subcutaneously (s.c.) monthly for the first 3 months followed by 3-monthly depots of 11.25 mg s.c. The trial duration is 36 months. MRI scans to measure liver volume will be performed at screening, 6 months, 18 months, 24 months and 36 months. In addition, blood will be drawn, DEXA-scans will be performed and questionnaires will be collected. This design enables comparison between patients on study treatment and standard of care (first 18 months) and within patients before and during treatment (whole trial). Main outcome is annualized liver growth rate compared between standard of care and study treatment. Secondary outcomes are PLD disease severity, change in liver growth within individuals and (serious) adverse events. The study is designed as a prospective open-label study with blinded endpoint assessment (PROBE)., Discussion: In this trial, we combined the expertise of hepatologist, nephrologists and gynecologists to study the effect of leuprorelin on liver growth in PLD. In this way, we hope to stop liver growth, reduce symptoms and reduce the need for liver transplantation in severe PLD. Trial registration Eudra CT number 2020-005949-16, registered at 15 Dec 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-005949-16 ., (© 2022. The Author(s).)
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- 2022
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39. Controlled DCD Liver Transplantation Is Not Associated With Increased Hyperfibrinolysis and Blood Loss After Graft Reperfusion.
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Karangwa SA, Adelmeijer J, Burgerhof JGM, Lisman T, de Meijer VE, de Kleine RH, Reyntjens KMEM, van den Berg AP, Porte RJ, and de Boer MT
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- Adult, Blood Component Transfusion, Brain Death, Death, Graft Survival, Humans, Plasma, Reperfusion, Retrospective Studies, Tissue Donors, Liver Transplantation adverse effects, Tissue and Organ Procurement
- Abstract
Background: The specific effect of donation after circulatory death (DCD) liver grafts on fibrinolysis, blood loss, and transfusion requirements after graft reperfusion is not well known. The aim of this study was to determine whether transplantation of controlled DCD livers is associated with an elevated risk of hyperfibrinolysis, increased blood loss, and higher transfusion requirements upon graft reperfusion, compared with livers donated after brain death (DBD)., Methods: A retrospective single-center analysis of all adult recipients of primary liver transplantation between 2000 and 2019 was performed (total cohort n = 628). Propensity score matching was used to balance baseline characteristics for DCD and DBD liver recipients (propensity score matching cohort n = 218). Intraoperative and postoperative hemostatic variables between DCD and DBD liver recipients were subsequently compared. Additionally, in vitro plasma analyses were performed to compare the intraoperative fibrinolytic state upon reperfusion., Results: No significant differences in median (interquartile range) postreperfusion blood loss (1.2 L [0.5-2.2] versus 1.3 L [0.6-2.2]; P = 0.62), red blood cell transfusion (2 units [0-4] versus 1.1 units [0-3]; P = 0.21), or fresh frozen plasma transfusion requirements (0 unit [0-2.2] versus 0 unit [0-0.9]; P = 0.11) were seen in DCD compared with DBD recipients, respectively. Furthermore, plasma fibrinolytic potential was similar in both groups., Conclusions: Transplantation of controlled DCD liver grafts does not result in higher intraoperative blood loss or more transfusion requirements, compared with DBD liver transplantation. In accordance with this, no evidence for increased hyperfibrinolysis upon reperfusion in DCD compared with DBD liver grafts was found., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2022
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40. Prolonged dual hypothermic oxygenated machine preservation (DHOPE-PRO) in liver transplantation: study protocol for a stage 2, prospective, dual-arm, safety and feasibility clinical trial.
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Brüggenwirth IMA, Lantinga VA, Rayar M, van den Berg AP, Blokzijl H, Reyntjens KMEM, Porte RJ, and de Meijer VE
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- Feasibility Studies, Humans, Living Donors, Prospective Studies, Liver Transplantation adverse effects, Organ Preservation adverse effects
- Abstract
Introduction: End-ischaemic preservation of a donor liver by dual hypothermic oxygenated machine perfusion (DHOPE) for 2 hours prior to transplantation is sufficient to mitigate ischaemia-reperfusion damage and fully restore cellular energy levels. Clinical studies have shown beneficial outcomes after transplantation of liver grafts preserved by DHOPE compared with static cold storage. In addition to graft reconditioning, DHOPE may also be used to prolong preservation time, which could facilitate logistics for allocation and transplantation globally., Methods and Analysis: This is a prospective, pseudo-randomised, dual-arm, IDEAL-D (Idea, Development, Exploration, Assessment, Long term study-Framework for Devices) stage 2 clinical device trial designed to determine safety and feasibility of prolonged DHOPE (DHOPE-PRO). The end-time of the donor hepatectomy will determine whether the graft will be assigned to the intervention (16:00-3:59 hour) or to the control arm (4:00-15:59 hour). In total, 36 livers will be included in the study. Livers in the intervention group (n=18) will undergo DHOPE-PRO (≥4 hours) until implantation the following morning, whereas livers in the control group (n=18) will undergo regular DHOPE (2 hours) prior to implantation. The primary endpoint of this study is a composite of the occurrence of all (serious) adverse events during DHOPE and up to 30 days after liver transplantation., Ethics and Dissemination: The protocol was approved by the Medical Ethical Committee of Groningen, METc2020.126 in June 2020, and the study was registered in the Netherlands National Trial Registry (https://www.trialregister.nl/) prior to initiation., Trial Registration Number: NL8740., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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41. Maintenance immunosuppressive therapy in autoimmune hepatitis: To stop or not to stop, that is the question.
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Stolk MFJ, van den Berg AP, and van Erpecum KJ
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- Azathioprine therapeutic use, Humans, Immunosuppressive Agents therapeutic use, Hepatitis, Autoimmune drug therapy
- Published
- 2021
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42. Development and validation of a prognostic score for long-term transplant-free survival in autoimmune hepatitis type 1.
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Biewenga M, Verhelst XPDMJ, Baven-Pronk MAMC, Putter H, van den Berg AP, van Nieuwkerk KCMJ, van Buuren HR, Bouma G, de Boer YS, Simoen C, Colle I, Schouten J, Sermon F, van Steenkiste C, van Vlierberghe H, van der Meer AJ, Nevens F, and van Hoek B
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Belgium epidemiology, Child, Child, Preschool, Cohort Studies, Disease Progression, Disease-Free Survival, Female, Hepatitis, Autoimmune complications, Hepatitis, Autoimmune therapy, Humans, Liver Cirrhosis etiology, Male, Middle Aged, Multivariate Analysis, Netherlands epidemiology, Prognosis, Proportional Hazards Models, Reproducibility of Results, Risk Assessment, Risk Factors, Time Factors, Young Adult, Decision Support Techniques, Hepatitis, Autoimmune mortality, Liver Cirrhosis mortality, Liver Transplantation statistics & numerical data
- Abstract
Background: No prognostic score is currently available for long-term survival in autoimmune hepatitis (AIH) patients., Objective: The aim of this study was to develop and validate such a prognostic score for AIH patients at diagnosis., Methods: The prognostic score was developed using uni- & multivariate Cox regression in a 4-center Dutch cohort and validated in an independent 6-center Belgian cohort., Results: In the derivation cohort of 396 patients 19 liver transplantations (LTs) and 51 deaths occurred (median follow-up 118 months; interquartile range 60-202 months). In multivariate analysis age (hazard ratio [HR] 1.045; p < 0.001), non-caucasian ethnicity (HR 1.897; p = 0.045), cirrhosis (HR 3.266; p < 0.001) and alanine aminotransferase level (HR 0.725; p = 0.003) were significant independent predictors for mortality or LT (C-statistic 0.827; 95% CI 0.790-0.864). In the validation cohort of 408 patients death or LT occurred in 78 patients during a median follow-up of 74 months (interquartile range: 25-142 months). Predicted 5-year event rate did not differ from observed event rate (high risk group 21.5% vs. 15.7% (95% CI: 6.3%-24.2%); moderate risk group 5.8% versus 4.3% (95% CI: 0.0%-9.1%); low risk group 1.9% versus 5.4% (95% CI: 0.0%-11.4%); C-statistic 0.744 [95% CI 0.644-0.844])., Conclusions: A Dutch-Belgian prognostic score for long-term transplant-free survival in AIH patients at diagnosis was developed and validated., (© 2021 The Authors. UEG Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)
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- 2021
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43. Machine Perfusion of Donation After Circulatory Death Liver and Lungs Before Combined Liver-lung Transplantation.
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van Leeuwen OB, Brüggenwirth IMA, de Kleine RHJ, van den Berg AP, Verschuuren EAM, Erasmus ME, and Porte RJ
- Abstract
Shortage of deceased donor organs for transplantation has led to the increased use of organs from donation after circulatory death (DCD) donors. There are currently no reports describing outcomes after multiorgan transplantation with DCD livers. The use of DCD organs for multiorgan transplantation can be enhanced if the detrimental effects of prolonged cold ischemia and subsequent ischemia-reperfusion injury are overcome. We present a case in which the liver and lungs of a DCD donor were preserved using ex situ machine perfusion for combined liver-lung transplantation. The recipient was a 19-year-old male patient requiring bilateral lung transplantation for severe progressive pleural parenchymal fibroelastosis and portal hypertension with portal vein thrombosis. The donor liver was preserved with dual hypothermic oxygenated machine perfusion, whereas the lungs were perfused using ex vivo lung perfusion. With ex vivo lung perfusion, total preservation time of right and left lung reached 17 and 21 h, respectively. Now, 2 y after transplantation, liver function is normal and lung function is improving. To conclude, we suggest that combined transplantation of DCD liver and lungs is feasible when cold ischemia is reduced with ex situ machine perfusion preservation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)
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- 2021
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44. Hypothermic Machine Perfusion in Liver Transplantation - A Randomized Trial.
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van Rijn R, Schurink IJ, de Vries Y, van den Berg AP, Cortes Cerisuelo M, Darwish Murad S, Erdmann JI, Gilbo N, de Haas RJ, Heaton N, van Hoek B, Huurman VAL, Jochmans I, van Leeuwen OB, de Meijer VE, Monbaliu D, Polak WG, Slangen JJG, Troisi RI, Vanlander A, de Jonge J, and Porte RJ
- Subjects
- Adult, Cold Temperature, Constriction, Pathologic prevention & control, Female, Humans, Male, Middle Aged, Perfusion, Reperfusion Injury prevention & control, Biliary Tract pathology, Cold Ischemia, Liver Transplantation, Organ Preservation methods
- Abstract
Background: Transplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited., Methods: In this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications., Results: A total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval [CI], 0.14 to 0.94; P = 0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups., Conclusions: Hypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage. (Funded by Fonds NutsOhra; DHOPE-DCD ClinicalTrials.gov number, NCT02584283.)., (Copyright © 2021 Massachusetts Medical Society.)
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- 2021
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45. Donor diabetes mellitus is a risk factor for diminished outcome after liver transplantation: a nationwide retrospective cohort study.
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Brüggenwirth IMA, van Reeven M, Vasiliauskaitė I, van der Helm D, van Hoek B, Schaapherder AF, Alwayn IPJ, van den Berg AP, de Meijer VE, Darwish Murad S, Polak WG, and Porte RJ
- Subjects
- Adult, Cohort Studies, Graft Survival, Humans, Retrospective Studies, Risk Factors, Tissue Donors, Treatment Outcome, Diabetes Mellitus epidemiology, Diabetes Mellitus etiology, Liver Transplantation adverse effects
- Abstract
With the growing incidence of diabetes mellitus (DM), an increasing number of organ donors with DM can be expected. We sought to investigate the association between donor DM with early post-transplant outcomes. From a national cohort of adult liver transplant recipients (1996-2016), all recipients transplanted with a liver from a DM donor (n = 69) were matched 1:2 with recipients of livers from non-DM donors (n = 138). The primary end-point included early post-transplant outcome, such as the incidence of primary nonfunction (PNF), hepatic artery thrombosis (HAT), and 90-day graft survival. Cox regression analysis was used to analyze the impact of donor DM on graft failure. PNF was observed in 5.8% of grafts from DM donors versus 2.9% of non-DM donor grafts (P = 0.31). Recipients of grafts derived from DM donors had a higher incidence of HAT (8.7% vs. 2.2%, P = 0.03) and decreased 90-day graft survival (88.4% [70.9-91.1] vs. 96.4% [89.6-97.8], P = 0.03) compared to recipients of grafts from non-DM donors. The adjusted hazard ratio for donor DM on graft survival was 2.21 (1.08-4.53, P = 0.03). In conclusion, donor DM is associated with diminished outcome early after liver transplantation. The increased incidence of HAT after transplantation of livers from DM donors requires further research., (© 2020 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)
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- 2021
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46. Screening for abnormal glycosylation in a cohort of adult liver disease patients.
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Jansen JC, van Hoek B, Metselaar HJ, van den Berg AP, Zijlstra F, Huijben K, van Scherpenzeel M, Drenth JPH, and Lefeber DJ
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- Adult, Aged, Case-Control Studies, Cohort Studies, Congenital Disorders of Glycosylation diagnosis, Female, Glycosylation, Humans, Liver metabolism, Male, Middle Aged, Transferrin metabolism, Congenital Disorders of Glycosylation metabolism, End Stage Liver Disease metabolism, Mass Spectrometry methods, Transferrin analysis
- Abstract
Congenital disorders of glycosylation (CDG) are a rapidly expanding group of rare genetic defects in glycosylation. In a novel CDG subgroup of vacuolar-ATPase (V-ATPase) assembly defects, various degrees of hepatic injury have been described, including end-stage liver disease. However, the CDG diagnostic workflow can be complex as liver disease per se may be associated with abnormal glycosylation. Therefore, we collected serum samples of patients with a wide range of liver pathology to study the performance and yield of two CDG screening methods. Our aim was to identify glycosylation patterns that could help to differentiate between primary and secondary glycosylation defects in liver disease. To this end, we analyzed serum samples of 1042 adult liver disease patients. This cohort consisted of 567 liver transplant candidates and 475 chronic liver disease patients. Our workflow consisted of screening for abnormal glycosylation by transferrin isoelectric focusing (tIEF), followed by in-depth analysis of the abnormal samples with quadruple time-of-flight mass spectrometry (QTOF-MS). Screening with tIEF resulted in identification of 247 (26%) abnormal samples. QTOF-MS analysis of 110 of those did not reveal glycosylation abnormalities comparable with those seen in V-ATPase assembly factor defects. However, two patients presented with isolated sialylation deficiency. Fucosylation was significantly increased in liver transplant candidates compared to healthy controls and patients with chronic liver disease. In conclusion, a significant percentage of patients with liver disease presented with abnormal CDG screening results. However, the glycosylation pattern was not indicative for a V-ATPase assembly factor defect. Advanced glycoanalytical techniques assist in the dissection of secondary and primary glycosylation defects., (© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)
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- 2020
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47. Immediate impact of COVID-19 on transplant activity in the Netherlands.
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de Vries APJ, Alwayn IPJ, Hoek RAS, van den Berg AP, Ultee FCW, Vogelaar SM, Haase-Kromwijk BJJM, Heemskerk MBA, Hemke AC, Nijboer WN, Schaefer BS, Kuiper MA, de Jonge J, van der Kaaij NP, and Reinders MEJ
- Subjects
- Adolescent, Betacoronavirus isolation & purification, COVID-19, Child, Child, Preschool, Humans, Netherlands, Pandemics, SARS-CoV-2, Tissue and Organ Procurement, Transplant Recipients, Coronavirus Infections epidemiology, Coronavirus Infections transmission, Organ Transplantation statistics & numerical data, Pneumonia, Viral epidemiology, Pneumonia, Viral transmission
- Abstract
The rapid emergence of the COVID-19 pandemic is unprecedented and poses an unparalleled obstacle in the sixty-five year history of organ transplantation. Worldwide, the delivery of transplant care is severely challenged by matters concerning - but not limited to - organ procurement, risk of SARS-CoV-2 transmission, screening strategies of donors and recipients, decisions to postpone or proceed with transplantation, the attributable risk of immunosuppression for COVID-19 and entrenched health care resources and capacity. The transplant community is faced with choosing a lesser of two evils: initiating immunosuppression and potentially accepting detrimental outcome when transplant recipients develop COVID-19 versus postponing transplantation and accepting associated waitlist mortality. Notably, prioritization of health care services for COVID-19 care raises concerns about allocation of resources to deliver care for transplant patients who might otherwise have excellent 1-year and 10-year survival rates. Children and young adults with end-stage organ disease in particular seem more disadvantaged by withholding transplantation because of capacity issues than from medical consequences of SARS-CoV-2. This report details the nationwide response of the Dutch transplant community to these issues and the immediate consequences for transplant activity. Worrisome, there was a significant decrease in organ donation numbers affecting all organ transplant services. In addition, there was a detrimental effect on transplantation numbers in children with end-organ failure. Ongoing efforts focus on mitigation of not only primary but also secondary harm of the pandemic and to find right definitions and momentum to restore the transplant programs., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)
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- 2020
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48. Donor hepatectomy time influences ischemia-reperfusion injury of the biliary tree in donation after circulatory death liver transplantation.
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van Leeuwen OB, van Reeven M, van der Helm D, IJzermans JNM, de Meijer VE, van den Berg AP, Darwish Murad S, van Hoek B, Alwayn IPJ, Porte RJ, and Polak WG
- Subjects
- Adult, Bile Ducts pathology, Biliary Tract Diseases pathology, Female, Humans, Male, Middle Aged, Perfusion, Retrospective Studies, Biliary Tract Diseases etiology, Hepatectomy, Liver Transplantation, Operative Time, Reperfusion Injury etiology
- Abstract
Background: Donor hepatectomy time is associated with graft survival after liver transplantation. The aim of this study was to identify the impact of donor hepatectomy time on biliary injury during donation after circulatory death liver transplantation., Methods: First, bile duct biopsies of livers included in (pre)clinical machine perfusion research were analyzed. Secondly, of the same livers, bile samples were collected during normothermic machine perfusion. Lastly, a nationwide retrospective cohort study was performed including 273 adult patients undergoing donation after circulatory death liver transplantation between January 1, 2002 and January 1, 2017. Primary endpoint was development of non-anastomotic biliary strictures within 2 years of donation after circulatory death liver transplantation. Cox proportional-hazards regression analyses were used to assess the influence of hepatectomy time on the development of non-anastomotic biliary strictures., Results: Livers with severe histological bile duct injury had a higher median hepatectomy time (P = .03). During normothermic machine perfusion, livers with a hepatectomy time >50 minutes had lower biliary bicarbonate and bile pH levels. In the nationwide retrospective study, donor hepatectomy time was an independent risk factor for non-anastomotic biliary strictures after donation after circulatory death liver transplantation (Hazard Ratio 1.18 per 10 minutes increase, 95% Confidence Interval 1.06-1.30, P value = .002)., Conclusion: Donor hepatectomy time negatively influences histological bile duct injury before normothermic machine perfusion and bile composition during normothermic machine perfusion. Additionally, hepatectomy time is a significant independent risk factor for the development of non-anastomotic biliary strictures after donation after circulatory death liver transplantation., (Copyright © 2020 Elsevier Inc. All rights reserved.)
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- 2020
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49. Selected liver grafts from donation after circulatory death can be safely used for retransplantation - a multicenter retrospective study.
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van Reeven M, van Leeuwen OB, van der Helm D, Darwish Murad S, van den Berg AP, van Hoek B, Alwayn IPJ, Polak WG, and Porte RJ
- Subjects
- Brain Death, Death, Graft Survival, Humans, Liver, Netherlands, Reoperation, Retrospective Studies, Tissue Donors, Tissue and Organ Procurement
- Abstract
Due to the growing number of liver transplantations (LTs), there is an increasing number of patients requiring retransplantation (reLT). Data on the use of grafts from extended criteria donors (ECD), especially donation after circulatory death (DCD), for reLT are lacking. We aimed to assess the outcome of patients undergoing reLT using a DCD graft in the Netherlands between 2001 and July 2018. Propensity score matching was used to match each DCD-reLT with three DBD-reLT cases. Primary outcomes were patient and graft survival. Secondary outcome was the incidence of biliary complications, especially nonanastomotic strictures (NAS). 21 DCD-reLT were compared with 63 matched DBD-reLTs. Donors in the DCD-reLT group had a significantly lower BMI (22.4 vs. 24.7 kg/m
2 , P-value = 0.02). Comparison of recipient demographics and ischemia times yielded no significant differences. Patient and graft survival rates were comparable between the two groups. However, the occurrence of nonanastomotic strictures after DCD-reLT was significantly higher (38.1% vs. 12.7%, P-value = 0.02). ReLT with DCD grafts does not result in inferior patient and graft survival compared with DBD grafts in selected patients. Therefore, DCD liver grafts should not routinely be declined for patients awaiting reLT., (© 2020 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.)- Published
- 2020
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50. Post-transplant obesity impacts long-term survival after liver transplantation.
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van Son J, Stam SP, Gomes-Neto AW, Osté MCJ, Blokzijl H, van den Berg AP, Porte RJ, Bakker SJL, and de Meijer VE
- Subjects
- Adult, Body Mass Index, Cohort Studies, End Stage Liver Disease complications, End Stage Liver Disease mortality, End Stage Liver Disease surgery, Female, Follow-Up Studies, Humans, Liver Function Tests, Male, Middle Aged, Obesity etiology, Overweight complications, Overweight mortality, Postoperative Complications mortality, Risk Factors, Survival Analysis, Liver Transplantation adverse effects, Liver Transplantation mortality, Obesity mortality
- Abstract
Background: Short-term survival after orthotopic liver transplantation (OLT) has improved over the past decades, but long-term survival remains impaired. The effects of obesity on long-term survival after OLT are controversial. Because pre-transplant body mass index (BMI) can be confounded by ascites, we hypothesized that post-transplant BMI at 1 year could predict long-term survival., Methods: A post-hoc analysis was performed of an observational cohort study consisting of adult recipients of a first OLT between 1993 and 2010. Baseline BMI was measured at 1-year post-transplantation to represent a stable condition. Recipients were stratified into normal weight (BMI < 25 kg/m
2 ), overweight (25 ≤ BMI ≤ 30 kg/m2 ), and obese (BMI > 30 kg/m2 ). Kaplan-Meier survival analyses were performed with log-rank testing, followed by multivariable Cox proportional hazards regression analysis., Results: Out of 370 included recipients, 184 had normal weight, 136 were overweight, and 50 were obese at 1-year post-transplantation. After median follow-up for 12.3 years, 107 recipients had died, of whom 46 (25%) had normal weight, 39 (29%) were overweight, and 22 (44%) were obese (log-rank P = 0.020). Obese recipients had a significantly increased mortality risk compared to normal weight recipients (HR 2.00, 95% CI 1.08-3.68, P = 0.027). BMI was inversely associated with 15 years patient survival (HR 1.08, 95% CI 1.03-1.14, P = 0.001 per kg/m2 ), independent of age, gender, muscle mass, transplant characteristics, cardiovascular risk factors, kidney- and liver function., Conclusion: Obesity at 1-year post-transplantation conveys a 2-fold increased mortality risk, which may offer potential for interventional strategies (i.e. dietary advice, lifestyle modification, or bariatric surgery) to improve long-term survival after OLT., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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