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Dynamics of virus-specific T cell immunity in pediatric liver transplant recipients.
Arasaratnam, RJ, Tzannou, I, Gray, T, Aguayo-Hiraldo, PI, Kuvalekar, M, Naik, S, Gaikwad, A, Liu, H, Miloh, T, Vera, JF, et al
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018;(9):2238-2249
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Abstract
Immunosuppression following solid organ transplantation (SOT) has a deleterious effect on cellular immunity leading to frequent and prolonged viral infections. To better understand the relationship between posttransplant immunosuppression and circulating virus-specific T cells, we prospectively monitored the frequency and function of T cells directed to a range of latent (CMV, EBV, HHV6, BK) and lytic (AdV) viruses in 16 children undergoing liver transplantation for up to 1 year posttransplant. Following transplant, there was an immediate decline in circulating virus-specific T cells, which recovered posttransplant, coincident with the introduction and subsequent routine tapering of immunosuppression. Furthermore, 12 of 14 infections/reactivations that occurred posttransplant were successfully controlled with immunosuppression reduction (and/or antiviral use) and in all cases we detected a temporal increase in the circulating frequency of virus-specific T cells directed against the infecting virus, which was absent in 2 cases where infections remained uncontrolled by the end of follow-up. Our study illustrates the dynamic changes in virus-specific T cells that occur in children following liver transplantation, driven both by active viral replication and modulation of immunosuppression.
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Longitudinal assessment of T cell inhibitory receptors in liver transplant recipients and their association with posttransplant infections.
Mysore, KR, Ghobrial, RM, Kannanganat, S, Minze, LJ, Graviss, EA, Nguyen, DT, Perez, KK, Li, XC
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2018;(2):351-363
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Current immunosuppression regimens in organ transplantation primarily inhibit T cells. However, T cells are also critical in protective immunity, especially in immune-compromised patients. In this study, we examined the association of T cell dysfunction, as marked by expression of T cell exhaustion molecules, and posttransplant infections in a cohort of liver transplant patients. We focused on Programmed Death 1 (PD-1) and T cell Ig- and mucin-domain molecule 3 (Tim-3), which are potent co-inhibitory receptors, and their persistent expression often leads to T cell dysfunction and compromised protective immunity. We found that patients with the highest expression of PD-1 +Tim-3+ T cells in the memory compartment before transplantation had increased incidence of infections after liver transplantation, especially within the first 90 days. Longitudinal analysis in the first year showed a strong association between variability of PD-1 and Tim-3 expression by T cells and infectious episodes in transplant patients. Furthermore, T cells that expressed PD-1 and Tim-3 had a significantly reduced capacity in producing interferon (IFN)-γ in vitro, and this reduced IFN-γ production could be partially reversed by blocking PD-1 and Tim-3. Interestingly, the percentage of Foxp3+ regulatory T cells in liver transplant patients was stable in the study period. We concluded that the functional status of T cells before and after liver transplantation, as shown by PD-1 and Tim-3 expression, may be valuable in prognosis and management of posttransplant infections.
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Trial of complete weaning from immunosuppression for liver transplant recipients: factors predictive of tolerance.
de la Garza, RG, Sarobe, P, Merino, J, Lasarte, JJ, D'Avola, D, Belsue, V, Delgado, JA, Silva, L, Iñarrairaegui, M, Sangro, B, et al
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2013;(9):937-44
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Abstract
Recipients of liver transplantation (LT) may develop immunological tolerance. Factors predictive of tolerance are not clearly understood. Transplant recipients with normal liver function tests and without active viral hepatitis or autoimmune disease who presented with side effects of immunosuppression or a high risk of de novo malignancies were selected to participate in this prospective study. Twenty-four patients fulfilled the inclusion criteria and, therefore, underwent a gradual reduction of immunosuppression. Tolerance was defined as normal liver function tests after immunosuppression withdrawal. Basal clinical and immunological characteristics, including lymphocyte counts and subpopulations (T, B, natural killer, CD4(+) , CD8(+) , and regulatory T cells) and the phytohemagglutinin stimulation index (SI), were compared for tolerant and nontolerant patients. Fifteen of the 24 patients (62.5%) were tolerant at a median of 14 months (interquartile range = 8.5-22.5 months) after complete immunosuppression withdrawal. Tolerant patients had a longer median interval between transplantation and inclusion in the study (156 for tolerant patients versus 71 months for nontolerant patients, P = 0.003) and a lower median SI (7.49 for tolerant patients versus 41.73 for nontolerant patients, P = 0.01). We identified 3 groups of patients with different probabilities of tolerance: in the first group (n = 7 for an interval > 10 years and an SI < 20), 100% reached tolerance; in the second group (n = 10 for an interval > 10 years and an SI > 20 or an interval < 10 years and an SI < 20), 60% reached tolerance; and in the third group (n = 7 for an interval < 10 years and an SI > 20), 29% reached tolerance. In conclusion, a high proportion of select LT recipients can reach tolerance over the long term. Two simple basal variables-the time from transplantation and the SI-may help to identify these patients.
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Switch to 1.5 grams MMF monotherapy for CNI-related toxicity in liver transplantation is safe and improves renal function, dyslipidemia, and hypertension.
Orlando, G, Baiocchi, L, Cardillo, A, Iaria, G, De Liguori Carino, N, De Luca, L, Ielpo, B, Tariciotti, L, Angelico, M, Tisone, G
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2007;(1):46-54
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Although mycophenolate mofetil (MMF) monotherapy has been successfully used in liver transplant recipients suffering from calcineurin-inhibitor (CNI)-related chronic toxicity, still no consensus has been reached on its safety, efficacy and tolerability. We attempted the complete weaning off CNI in 42 individuals presenting chronic renal dysfunction and/or dyslipidemia and/or arterial hypertension and simultaneously introduced 1.5 gm/day MMF. CNI could be completely withdrawn in 41 cases. A total of 32 (75%) patients are currently on
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Alendronate in combination with calcium and vitamin D prevents bone loss after orthotopic liver transplantation: a prospective single-center study.
Millonig, G, Graziadei, IW, Eichler, D, Pfeiffer, KP, Finkenstedt, G, Muehllechner, P, Koenigsrainer, A, Margreiter, R, Vogel, W
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2005;(8):960-6
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Bone loss is a common complication in patients before and after liver transplantation (LT). The aim of this study was to investigate the efficacy of prophylactic treatment with bisphosphonates after LT in preventing progressive bone loss in LT patients. We included 136 patients with end-stage liver diseases awaiting LT. Bone mineral density (BMD) (by dual X-ray absorptiometry) and markers of bone metabolism were determined before, and 4, 12, 24, 36, and 48 months after LT. All patients received vitamin D and calcium supplementation before and after LT, those with osteopenia or osteoporosis prior to LT were additionally treated with alendronate following LT. Decreased BMD was seen in a high percentage of patients undergoing LT (osteopenia 48.5%, osteoporosis 23.5%). Reduced BMD before LT was not related to gender, underlying liver disease, or Child-Turcotte-Pugh classification. Body mass index (BMI) prior to LT, however, correlated significantly with the fracture risk. Alendronate prevented the ubiquitously observed bone loss after LT in patients with osteoporosis and osteopenia and, in addition, led to an increase in BMD in patients with osteoporosis within 24 months after LT. In conclusion, our study suggests that alendronate is efficacious in preventing the natural course of bone loss associated with LT.
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Cyclosporine absorption profiles in pediatric kidney and liver transplant patients.
Kovarik, JM, Hoyer, PF, Ettenger, R, Punch, J, Soergel, M
Pediatric nephrology (Berlin, Germany). 2003;(12):1275-9
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Abstract
Cyclosporine absorption profiling uses either the area under the concentration curve in the first 4 h post dose, AUC(0-4), or the concentration 2 h post dose (C2) to optimize immunosuppression in adult kidney and liver transplantation. We characterized C2 versus AUC(0-4) relationships over time after transplant and across transplant indications in 56 pediatric transplant patients. There were 36 kidney transplant patients aged 9.7+/-3.9 years. Nineteen of these patients were studied in the de novo period on day 7 post transplant and 17 in the maintenance phase more than 1 year post transplant. In addition, 20 liver transplant patients aged 8.9+/-4.2 years were studied in the maintenance phase. All patients had five blood samples collected over the 12-h dose interval that were analyzed by validated assay methods at a central laboratory. Pediatric C2 values were 1,463+/-658 ng/ml for de novo kidney, 954+/-322 ng/ml for maintenance kidney, and 619+/-339 ng/ml for maintenance liver transplant patients. C2 was a strong predictor of AUC(0-4) in all three pediatric groups, with coefficients of determination ( r(2)) ranging from 0.861 to 0.936. Although data were limited from the de novo period, the C2 versus AUC(0-4) regression was consistent over time after transplant and between transplant indications, with a regression slope of 2.50 in de novo kidney, 2.54 in maintenance kidney, and 2.76 in maintenance liver transplant recipients. These slopes were also comparable to that in adult maintenance kidney transplant patients (2.60). In conclusion, C2 versus AUC(0-4) relationships demonstrated consistency over time (de novo vs. maintenance phase), between transplant indications (kidney vs. liver), and across age groups (pediatric vs. adult patients). Average C2 values achieved with current pediatric cyclosporine dosing practices cluster around the target C2 ranges recommended for adults.
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Extrahepatic metabolism of sevoflurane in children undergoing orthotopic liver transplantation.
Van Obbergh, LJ, Verbeeck, RK, Michel, I, Lim, S, Veyckemans, F
Anesthesiology. 2000;(3):683-6
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BACKGROUND Sevoflurane is metabolized by cytochrome P450 and produces inorganic fluoride. The anhepatic phase of liver transplantation provides a useful tool to study the extrahepatic metabolism of drugs. The authors therefore studied the extrahepatic metabolism of sevoflurane by measuring the fluoride production in children receiving sevoflurane solely during the anhepatic phase of orthotopic liver transplantation. METHODS Children with end-stage liver disease undergoing orthotopic liver transplantation were studied. Anesthesia was provided with isoflurane, sufentanil, and pancuronium. In one group, isoflurane was replaced by sevoflurane as soon as the liver was removed from the patient and maintained until reperfusion of the new liver. Arterial blood samples were drawn at induction, before removal of the liver, 15 min and 30 min after the beginning of the anhepatic phase, at the unclamping of the new liver, and finally 60 and 120 min after the unclamping. Plasma fluoride concentrations were determined by ion-selective electrode. RESULTS No differences between the two groups (n = 10) regarding age, weight, duration of the anhepatic phase, or basal level of inorganic fluoride were found. The fluoride concentration increased significantly as soon as sevoflurane was introduced; it remained stable in the group receiving isoflurane. The peak fluoride concentration was also significantly higher in the first group (mean +/- SD: 5.5 +/- 0.8 microM (sevoflurane group) versus 1.4 +/- 0.5 microM (isoflurane group) P < 0.05). CONCLUSIONS These results demonstrate the existence of an extrahepatic metabolism of sevoflurane at least in children with end-stage liver disease.
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Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients.
Pescovitz, MD, Rabkin, J, Merion, RM, Paya, CV, Pirsch, J, Freeman, RB, O'Grady, J, Robinson, C, To, Z, Wren, K, et al
Antimicrobial agents and chemotherapy. 2000;(10):2811-5
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The pharmacokinetics of an orally administered valine ester of ganciclovir (GCV), valganciclovir (VGC), were studied. These were compared to the pharmacokinetics of oral and intravenous GCV. Twenty-eight liver transplant recipients received, in an open-label random order with a 3- to 7-day washout, each of the following: 1 g of oral GCV three times a day; 450 mg of VGC per os (p.o.) once a day (q.d.); 900 mg of VGC p.o. q.d.; and 5 mg of intravenous (i.v.) GCV per kg of body weight q.d., given over 1 h. GCV and VGC concentrations were measured in blood over 24 h. One-sided equivalence testing was performed to test for noninferiority of 450 mg of VGC relative to oral GCV (two-sided 90% confidence interval [CI] > 80%) and nonsuperiority of 900 mg of VGC relative to i.v. GCV (two-sided 90% CI < 125%). The exposure of 450 mg of VGC (20.56 microg. h/ml) was found to be noninferior to that of oral GCV (20.15 microg. h/ml; 90% CI for relative bioavailability of 95 to 109%), and the exposure of 900 mg of VGC (42.69 microg. h/ml) was found to be nonsuperior to that of i.v. GCV (47.61 microg. h/ml; 90% CI = 83 to 97%). Oral VGC delivers systemic GCV exposure equivalent to that of standard oral GCV (at 450 mg) or i.v. GCV (at 900 mg of VGC). VGC has promise for effective CMV prophylaxis or treatment with once-daily oral dosing in transplant recipients.