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Post-hoc analysis of a randomized controlled trial on the impact of pre-transplant use of probiotics on outcomes after liver transplantation.
Grąt, M, Grąt, K, Krawczyk, M, Lewandowski, Z, Krasnodębski, M, Masior, Ł, Patkowski, W, Zieniewicz, K
Scientific reports. 2020;(1):19944
Abstract
Perioperative use of probiotics serves as efficient prophylaxis against postoperative infections after liver transplantation, yet data on long-term effects of pre-transplant probiotic intake is lacking. The aim of this study was to assess the effects of pre-transplant probiotic administration on long-term results of liver transplantation. This was secondary analysis of a randomized trial. Patients were randomized to receive either 4-strain probiotic or placebo before liver transplantation. Five year graft survival was set as the primary end-point. Secondary end-points comprised serum bilirubin and C-reactive protein (CRP) concentration, international normalized ratio (INR), serum transaminases and gamma-glutamyl transferase (GGT) activity. Study group comprised 44 patients, of whom 21 received probiotics and 23 received placebo with 5-year graft survival of 81.0% and 87.0%, respectively (p = 0.591). Patients in the probiotic arm exhibited lower INR (p = 0.001) and CRP (p = 0.030) over the first 6 post-transplant months. In the absence of hepatitis B or C virus infection, pre-transplant administration of probiotics also reduced aspartate transaminase activity (p = 0.032). In the intervention arm, patients receiving probiotics for under and over 30 days had 5-year graft survival rates of 100% and 66.7%, respectively (p = 0.061). Duration of probiotic intake > 30 days was additionally associated with increased INR (p = 0.031), GGT (p = 0.032) and a tendency towards increased bilirubin (p = 0.074) over first 6 post-transplant months. Pre-transplant administration of probiotics has mild positive influence on 6-month allograft function, yet should not exceed 30 days due to potential negative effects on long-term outcomes. (ClinicalTrials.gov Identifier: NCT01735591).
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Effect of the proton-pump Inhibitor pantoprazole on MycoPhenolic ACid exposure in kidney and liver transplant recipienTs (IMPACT study): a randomized trial.
Sunderland, A, Russ, G, Sallustio, B, Cervelli, M, Joyce, D, Ooi, E, Jeffrey, G, Boudville, N, Chakera, A, Dogra, G, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(6):1060-1070
Abstract
BACKGROUND Mycophenolic acid (MPA) is widely utilized as an immunosuppressant in kidney and liver transplantation, with reports suggesting an independent relationship between MPA concentrations and adverse allograft outcome. Proton-pump inhibitors (PPIs) may have variable effects on the absorption of different MPA formulations leading to differences in MPA exposure. METHODS A multicentre, randomized, prospective, double-blind placebo-controlled cross-over study was conducted to determine the effect of the PPI pantoprazole on the MPA and its metabolite MPA-glucuronide (MPA-G) area under the curve (AUC) >12 h (MPA-AUC12 h) in recipients maintained on mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). We planned a priori to examine separately recipients maintained on MMF and EC-MPS for each pharmacokinetic parameter. The trial (and protocol) was registered with the Australian New Zealand Clinical Trials Registry on 24 March 2011, with the registration number of ACTRN12611000316909 ('IMPACT' study). RESULTS Of the 45 recipients screened, 40 (19 MMF and 21 EC-MPS) were randomized. The mean (standard deviation) recipient age was 58 (11) years with a median (interquartile range) time post-transplant of 43 (20-132) months. For recipients on MMF, there was a significant reduction in the MPA-AUC12 h [geometric mean (95% confidence interval) placebo: 53.9 (44.0-65.9) mg*h/L versus pantoprazole: 43.8 (35.6-53.4) mg*h/L; P = 0.004] when pantoprazole was co-administered compared with placebo. In contrast, co-administration with pantoprazole significantly increased MPA-AUC12 h [placebo: 36.1 (26.5-49.2) mg*h/L versus pantoprazole: 45.9 (35.5-59.3) mg*h/L; P = 0.023] in those receiving EC-MPS. Pantoprazole had no effect on the pharmacokinetic profiles of MPA-G for either group. CONCLUSIONS The co-administration of pantoprazole substantially reduced the bioavailability of MPA in patients maintained on MMF and had the opposite effect in patients maintained on EC-MPS, and therefore, clinicians should be cognizant of this drug interaction when prescribing the different MPA formulations.
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Combined Flush With Histidine-Tryptophan-Ketoglutarate and University of Wisconsin Solutions in Liver Transplantation: Preliminary Results.
León Díaz, FJ, Fernández Aguilar, JL, Nicolás de Cabo, S, Pérez Reyes, M, Sánchez Pérez, B, Montiel Casado, C, Pérez Daga, JA, Aranda Narváez, JM, Suárez Muñoz, MA, Arenas González, F, et al
Transplantation proceedings. 2018;(2):539-542
Abstract
INTRODUCTION Ischemia reperfusion injury (IRI) is the main cause of early allograft dysfunction (EAD) and subsequent primary allograft failure (PAF). OBJECTIVES The purpose of this study is to compare IRI, EAD, and PAF in liver transplantation in a cohort of patients perfused with histidine-tryptophan-ketoglutarate (HTK) solution and University of Wisconsin (UW) solution versus HTK alone. METHODS A randomized trial was performed to compare outcomes in liver recipients who underwent transplantation surgery in the University Regional Hospital of Malaga, Spain. Forty patients were randomized to two groups. Primary endpoints included IRI, EAD, PAF, re-intervention, acute cellular rejection, retransplantation, arterial complications, and biliary complications at postoperative day 90. RESULTS Postoperative glutamic oxaloacetic transaminase (1869.15 ± 1559.75 UI/L vs. 953.15 ± 777.27 UI/L; P = .004) and glutamic pyruvic transaminase (1333.60 ± 1115.49 U/L vs. 721.70 ± 725.02 U/L; P = .023) were significantly higher in patients perfused with HTK alone. A clear tendency was observed in recipients perfused with HTK alone to present moderate to severe IRI (7 patients in the HTK + UW solution group vs. 15 patients in the HTK-alone solution group; P = .06), EAD (0 patients in the HTK + UW solution group vs. 0 patients in the HTK-alone solution group; P = .76), and PAF (3 patients in the HTK + UW solution group vs. 8 patients in the HTK-alone solution group; P = .15). CONCLUSIONS Initial perfusion with HTK solution followed by UW solution in liver transplantation improves early liver function as compared to perfusion with HTK alone.
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N-Acetylcysteine inhalation improves pulmonary function in patients received liver transplantation.
Li, X, Wei, X, Chen, C, Zhang, Z, Liu, D, Hei, Z, Yao, W
Bioscience reports. 2018;(5)
Abstract
Postoperative pulmonary complications (PPCs) following orthotopic liver transplantation (OLT) are associated with high morbidity and mortality rates. The effect of N-acetylcysteine (NAC) inhalation on the incidence of PPCs and the outcomes of patients undergoing OLT is unknown. This prospective randomized controlled clinical trial was conducted to investigate the effect of NAC inhalation during OLT on PPCs. Sixty patients were randomly assigned to the NAC group (n = 30) or the control group (n = 30) to receive inhaled NAC or sterilized water, respectively, for 30 min before surgery and 3 h after reperfusion. The incidence of early PPCs and outcomes including survival rate were assessed. Biomarkers including tumor necrosis factor (TNF)-α, interleukin (IL)-8, Clara cell secretory protein (CC16), intercellular adhesion molecule (ICAM)-1, and superoxide dismutase (SOD) were measured in exhaled breath condensate (EBC) at T1 (before surgery) and T2 (at the end of operation) as well as in serum at T1, T2, T3 (12 h after operation), and T4 (24 h after operation). A total of 42 patients (20 in the NAC group and 22 in the control group) were enrolled in the final analysis. Atomization inhaled NAC significantly reduced the incidence of PPCs after OLT. The levels of TNF-α, IL-8, CC16, and ICAM-1 in EBC were significantly lower, and SOD activity was higher, at T2 in the NAC group; similar data were found in serum at T2, T3, and T4. In summary, perioperative NAC inhalation may reduce the incidence of PPCs and improve patient outcomes after OLT.
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Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial.
Saliba, F, Duvoux, C, Gugenheim, J, Kamar, N, Dharancy, S, Salamé, E, Neau-Cransac, M, Durand, F, Houssel-Debry, P, Vanlemmens, C, et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2017;(7):1843-1852
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Abstract
SIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. -13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3-21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR.
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A Pilot Study of Mesenchymal Stem Cell Therapy for Acute Liver Allograft Rejection.
Shi, M, Liu, Z, Wang, Y, Xu, R, Sun, Y, Zhang, M, Yu, X, Wang, H, Meng, L, Su, H, et al
Stem cells translational medicine. 2017;(12):2053-2061
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Abstract
Acute allograft rejection remains common after liver transplantation despite modern immunosuppressive agents. In addition, the long-term side effects of these regimens, including opportunistic infections, are challenging. This study evaluated the safety and clinical feasibility of umbilical cord-derived mesenchymal stem cell (UC-MSC) therapy in liver transplant patients with acute graft rejection. Twenty-seven liver allograft recipients with acute rejection were randomly assigned into the UC-MSC infusion group or the control group. Thirteen patients received one infusion of UC-MSCs (1 × 106 /kg body weight); one patient received multiple UC-MSC infusions; 13 patients were used as controls. All enrolled patients received conventional immunosuppressive agents with follow-up for 12 weeks after UC-MSC infusions. No side effects occurred in treated patients. Four weeks after UC-MSC infusions, alanine aminotransferase levels had decreased markedly and remained lower throughout the 12-week follow-up period. Importantly, allograft histology was improved after administration of UC-MSCs. The percentage of regulatory T cells (Tregs) and the Treg/T helper 17 (Th17) cell ratio were significantly increased 4 weeks after infusions; in contrast, the percentage of Th17 cells showed a decreasing trend. In controls, the percentages of Tregs and Th17 cells and the Treg/Th17 ratio were statistically unchanged from the baseline measurements. Transforming growth factor beta 1 and prostaglandin E2 were increased significantly after UC-MSC infusions; by contrast, there were no significant changes in controls. Our data suggest that UC-MSC infusion for acute graft rejection following liver transplantation is feasible and may mediate a therapeutic immunosuppressive effect. Stem Cells Translational Medicine 2017;6:2053-2061.
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Sodium bicarbonate infusion in patients undergoing orthotopic liver transplantation: a single center randomized controlled pilot trial.
Weinberg, L, Broad, J, Pillai, P, Chen, G, Nguyen, M, Eastwood, GM, Scurrah, N, Nikfarjam, M, Story, D, McNicol, L, et al
Clinical transplantation. 2016;(5):556-65
Abstract
BACKGROUND Liver transplantation-associated acute kidney injury (AKI) carries significant morbidity and mortality. We hypothesized that sodium bicarbonate would reduce the incidence and/or severity of liver transplantation-associated AKI. METHODS In this double-blinded pilot RCT, adult patients undergoing orthotopic liver transplantation were randomized to an infusion of either 8.4% sodium bicarbonate (0.5 mEq/kg/h for the first hour; 0.15 mEq/kg/h until completion of surgery); (n = 30) or 0.9% sodium chloride (n = 30). PRIMARY OUTCOME AKI within the first 48 h post-operatively. RESULTS There were no significant differences between the two treatment groups with regard to baseline characteristics, model for end-stage liver disease and acute physiology and chronic health evaluation (APACHE) II scores, and pre-transplantation renal function. Intra-operative factors were similar for duration of surgery, blood product requirements, crystalloid and colloid volumes infused and requirements for vasoactive therapy. Eleven patients (37%) in the bicarbonate group and 10 patients (33%) in the sodium chloride group developed a post-operative AKI (p = 0.79). Bicarbonate infusion attenuated the degree of immediate post-operative metabolic acidosis; however, this effect dissipated by 48 h. There were no significant differences in ventilation hours, ICU or hospital length of stay, or mortality. CONCLUSIONS The intra-operative infusion of sodium bicarbonate did not decrease the incidence of AKI in patients following orthotopic liver transplantation.
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Long-term follow-up of five yr shows superior renal function with everolimus plus early calcineurin inhibitor withdrawal in the PROTECT randomized liver transplantation study.
Sterneck, M, Kaiser, GM, Heyne, N, Richter, N, Rauchfuss, F, Pascher, A, Schemmer, P, Fischer, L, Klein, CG, Nadalin, S, et al
Clinical transplantation. 2016;(6):741-8
Abstract
BACKGROUND The 12-month (M) PROTECT study showed that de novo liver transplant recipients (LTxR) who switched from a calcineurin inhibitor (CNI)-based immunosuppression to a CNI-free everolimus (EVR)-based regimen showed numerically better renal function. Here, we present the five-yr follow-up data. METHODS PROTECT was a randomized controlled study in which LTxR received basiliximab and CNI-based immunosuppression ± corticosteroids. Patients were randomized 1:1 to receive EVR or continue CNI. Patients completing the core study could enter the extension study on their randomized treatment. RESULTS A total of 81 patients entered the extension study (41, EVR; 40, CNI). At M59 post-randomization, the adjusted mean eGFR was significantly higher in the EVR group, with a benefit of 12.4 mL/min using Cockcroft-Gault (95% CI: 1.2; 23.6; p = 0.0301). Also, there was a significant benefit for adjusted and unadjusted eGFR using the four-variable Modification of Diet in Renal Disease (MDRD4) or Nankivell formula. During the extension period, treatment failure rates were similar. SAEs occurred in 26 (63.4%) and 28 (70.0%) of the patients in EVR and CNI groups, respectively. CONCLUSION Compared with the CNI-based treatment, EVR-based CNI-free immunosuppression resulted in significantly better renal function and comparable patient and graft outcomes after five-yr follow-up.
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Multicentre, randomised, placebo-controlled trial of extract of Japanese herbal medicine Daikenchuto to prevent bowel dysfunction after adult liver transplantation (DKB 14 Study).
Kaido, T, Shimamura, T, Sugawara, Y, Sadamori, H, Shirabe, K, Yamamoto, M, Uemoto, S
BMJ open. 2015;(9):e008356
Abstract
INTRODUCTION This multicentre randomised controlled clinical trial will aim to determine the ability of an extract (TJ-100) of Daikenchuto (traditional Japanese herbal medicine; Kampo) to prevent bowel dysfunction in at least 110 patients after liver transplantation (LT). METHODS AND ANALYSIS The following co-primary end points will be evaluated on postoperative day 7: total oral and enteral caloric intake, abdominal distension and abdominal pain. The secondary end points will comprise sequential changes of total oral and enteral caloric intake after LT, sequential changes in numeric rating scales for abdominal distension and pain, elapsed time to the first postoperative passage of stool, quality of life assessment using the Gastrointestinal Symptom Rating Scale score (Japanese version), postoperative liver function, liver regeneration rate, incidence of bacteraemia and bacterial strain, trough level of immunosuppressants, occurrence of acute cellular rejection, discharge or not within 2 months after LT, sequential changes of portal venous flow to the graft and ascites discharge. The two arms of the study will comprise 55 patients per arm. ETHICS AND DISSEMINATION The study has been conducted according to the CONSORT statement. All participants signed a written consent form, and the study has been approved by the institutional review board of each participating institute and conducted in accordance with the Declaration of Helsinki of 1996. The findings will be disseminated through scientific and professional conferences, and in peer-reviewed journals. TRIAL REGISTRATION NUMBER The DKB 14 Study was registered in the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan (registration number: UMIN000014326) during 2014.
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Evaluation of the Effect of Ascorbic Acid Administration on Gene Expression Level of IL-6 and TNF-α Cytokines in Deceased Donors.
Kazemi, M, Tabei, SM, Najafizadeh, K, Mehrabi Sisakht, J, Milani, S, Khosravi, MB
Iranian journal of allergy, asthma, and immunology. 2015;(2):149-57
Abstract
Brain death is associated with increased inflammatory cytokines levels and poor graft quality to transplant. We aimed to evaluate the impact of Ascorbic Acid (AA) on the inflammatory status of Brain-Dead Donors (BDDs). Forty BDDs were randomly divided into two groups. Donor treatment (n=20) consisted of 100 mg/kg AA infusion 6 hours before donor operation and subsequent infusion of 100 mg/kg/p6h until organ removal. Blood samples were taken at three times, 6 hours before donor surgery (TP(1)), immediately after laparotomy (TP(2)), and before organ removal (TP(3)). Gene expression level and serum concentration of IL-6 and TNF-α cytokines were assessed by real-time PCR and ELISA methods. To investigate transplanted liver function, serum values of Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and Billirubin-Total were evaluated on the 1(st), 3(rd), and 10(th) postoperative days. We found a significant reduction in IL-6 mRNA expression ratio of TP(3) to TP(1) following AA application among BDDs. Despite the considerable decrease in treated donors regarding IL-6 mRNA expression ratio of TP(2) to TP(1), TP(3) to TP(2), and also TNF-α variations in these periods, the results were not significant. Regarding serum concentration of these cytokines, particularly IL-6, there was a decrease between TP(2) and TP(3) following AA application in the treated donors. Furthermore, a significant reduction was found in serum AST and ALT levels in the recipients of treated group on the 3(rd) day compared to the 1(st) day after transplantation. It seems that AA beneficially affects the inflammatory status of BDDs, resulting in improved primary allograft function.