Postoperative glucose metabolism in liver transplant recipients. A two-year prospective randomized study of cyclosporine versus FK506.
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Adult↗
Biomedical subjects
P McMaster
Publications and source records attributed to P McMaster.
Extended preservation of the liver with UW solution--is it justifiable?
The outcome of 228 liver grafts in 208 elective adult recipients was assessed to identify any adverse effects of extending the length of cold preservation with UW solution beyond 12 hr. A total of 114 grafts had been preserved < 12 hr--median 9.5 (group I) and 114 > 12 hr--median 14.5 (group II). Intraoperative blood and blood product usage, graft function, hospital stay, and graft and patient survival were identical in the two groups. Biliary strictures occurred in 5.7% of grafts (8 anastomotic (3 group I, 5 group II; 5 hilar/nonanastomotic: 3 group I, 2 group II). There was no graft or patient loss due to the hilar strictures but 1 patient died following reconstruction of an anastomotic stricture (0.4%). It is concluded that extending the cold preservation to approximately 15 hr does not adversely affect outcome after liver transplantation.
Adenosine↗
The role of dynamic and morphological studies in the assessment of potential liver donors.
In a prospective study, 66 donor livers were evaluated by monoethylglycinexylidide (MEGX) dynamic clearance and semiquantitative scoring of pathological changes in liver biopsies. The median MEGX level in 63 donors was 89 mcg/L (range 16-250 mcg/L); fifteen had MEGX levels < 50 mcg/L, 17 between 50 and 90 mcg/L, and 31 > 90 mcg/L. There were no cases of primary nonfunction, and no deaths were related to poor graft function. There was no statistically significant difference in peak aspartate aminotransferase (AST), day 5 AST, peak bilirubin, or lowest prothrombin time among the 3 groups. Liver biopsies were assessed in 61 donors: 33 (54%) were normal and 17 (28%) showed mild, 8 (13%) showed moderate, and 3 (5%) showed severe steatosis. Postperfusion biopsy assessing the extent of preservation injury was essentially normal or showed minimal change in 16 (26%), mild change in 29 (48%), moderate in 13 (21%) and severe abnormalities in 3 (5%). The latter 3 biopsies all had severe steatosis. There was no significant difference in early graft function or outcome between moderate/severe groups and normal/minimal groups, although the former had a higher peak AST (P < 0.02) and peak bilirubin (P < 0.004). This detailed prospective analysis suggests that MEGX and the morphological studies may assist in the assessment of potential liver donors but they do not provide a basis on which grafts should be discarded.
Adolescent↗
Peripheral neurotoxicity with tacrolimus.
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Adult↗
Donor thyroid function does not affect outcome in orthotopic liver transplantation.
Brainstem death is associated with endocrine and metabolic alterations that can result in donor hemodynamic instability. It has been suggested that these changes can be reversed through hormonal manipulation of the donor. We measured thyroid hormone levels (free triiodothyronine [fT3], free tetraiodothyronine [fT4], reverse triiodothyronine) and thyroid-stimulating hormone (TSH) in 50 consecutive adult brain dead multiorgan donors. Recipient graft function was assessed using peak and day 5 aspartate aminotransferase, peak serum bilirubin, and minimum prothrombin time during the first week after OLT. Free T3 was low in 32/50 donors and was associated with a low fT4 in 24 cases. TSH was normal in 35 donors and we found no correlation between TSH levels and fT3 or fT4. Reverse triiodothyronine was normal or high in 96% of donors. Patient and graft survival were 96% for both the low and high fT3 groups. These data suggest that euthyroid sick syndrome is the most likely cause for the endocrine and metabolic alterations seen in brainstem-dead donors. This does not appear to influence liver recipient or graft survival.
Adolescent↗
The role of orthotopic liver transplantation in the management of sclerosing cholangitis.
Our recommendations are to manage asymptomatic patients with biannual clinical and biochemical follow-up examinations. Symptomatic non-cirrhotic patients who have diffuse SC should be enrolled in trials addressing the efficacy of medical therapy such as UDCA. Patients with diffuse disease and cirrhosis of the liver should be considered for liver transplantation. Symptomatic patients with a dominant stricture should first undergo rigorous investigation to rule out CCA. Disease in those noncirrhotic patients who are deemed to have benign strictures should initially be managed by means of dilation or surgical excision, although careful monitoring and review will be needed because most will continue with progressive disease, eventually showing signs of portal hypertension and cirrhosis. Patients with dominant strictures and cirrhosis should be considered for orthotopic liver transplantation. Liver transplantation in experienced units now offers more than 80% of patients a full and effective rehabilitation, with more than 75% alive at 5 yr. A progressive, advancing decompensating cholestatic disorder with an increasing risk of underlying malignancy can be stopped, giving the patient a high quality of life. More than half of patients report an improvement in the symptoms of their inflammatory bowel disease.
Cholangitis, Sclerosing↗
Selective decontamination of the digestive tract reduces gram-negative pulmonary colonization but not systemic endotoxemia in patients undergoing elective liver transplantation.
OBJECTIVE: To examine the effect of selective antibiotic decontamination of the digestive tract in patients undergoing elective orthotopic liver transplantation. DESIGN: Prospective, randomized, concurrent allocation to either selective decontamination or standard antibiotic prophylaxis. SETTING: Operating theater and intensive care unit at a tertiary referral, university teaching hospital. PATIENTS: Fifty-nine adult patients were recruited into the study and underwent liver transplantation. INTERVENTIONS: Thirty-two patients were randomized to standard treatment (control group) and 27 patients were randomized to receive selective decontamination. After early deaths and exclusions, 31 controls and 21 decontamination patients were available for analysis. MEASUREMENTS AND MAIN RESULTS: Portal and systemic endotoxemia, colonization and infection rates, severity of illness (organ system failures, Acute Physiology and Chronic Health Evaluation II score, Therapeutic Intervention Scoring System score), antibiotic costs, and hospital survival rates were measured. Selective decontamination significantly reduced pulmonary infections and enteric, aerobic, and Gram-negative bacillary colonization without facilitating the emergence of resistant organisms, but selective decontamination had no effect on endotoxemia or the development of organ system failures. The financial costs of the selective decontamination regimen outweighed the advantages gained from an associated reduction in antibiotic usage. CONCLUSION: The failure of selective decontamination to enhance survival rates in many studies of the regimen in critically ill patients may, in part, be related to the inability of selective decontamination to abolish endotoxemia.
Adult↗
Bilateral nephrectomy for uncontrollable nephrotic syndrome in primary amyloidosis, with subsequent improvement in hepatic function.
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Amyloidosis↗
Focus on intractable rejection: 6-month results of the European multicentre liver study of FK 506 and cyclosporin A.
The incidence of intractable rejection was evaluated during the course of a multicentre, randomised, parallel-group study comparing the efficacy and safety of FK 506 and conventional cyclosporin A-based immunosuppressive regimens in patients undergoing primary liver transplantation. A diagnosis of intractable rejection was made if there was histological evidence of unchanged or worsening acute rejection, or chronic rejection after two discrete courses of antirejection therapy. Antirejection regimens were specific to each centre. Patients who experienced intractable rejection could be withdrawn from the study. Patients who were withdrawn from the cyclosporin A treatment group could subsequently receive FK 506 therapy and vice-versa. Intractable rejection was diagnosed in 32/540 patients (5.9%): 7/267 patients (2.6%) in the FK 506 treatment group and 25/273 patients (9.2%) receiving cyclosporin A therapy (P < 0.01). Of these 32 patients, 25 were withdrawn from the study: 3 and 22, from the FK 506 and cyclosporin A treatment groups, respectively. All three patients withdrawn from the FK 506 treatment group are alive: two having undergone retransplantation. Of the 22 patients withdrawn from the cyclosporin A group and converted to FK 506 therapy, 6 were retransplanted, 4 of whom subsequently died. A further two patients died without retransplantation. Thus, in 14 of the 16 patients who were still alive at 6 months, the liver graft was saved after conversion to FK 506 treatment. The reduced incidence of intractable rejection in patients receiving treatment with FK 506, together with the successful rescue of patients developing intractable rejection while receiving cyclosporin A, suggests that FK 506 is an effective immunosuppressive agent following orthotopic liver transplantation.
Adolescent↗
Corticosteroids and concomitant medication in the European multicentre study of FK 506 and cyclosporin in primary liver transplantation.
The steroid-sparing effect and the use of concomitant medication during the treatment of liver transplant patients with the novel immunosuppressant FK 506 were evaluated within the European multicentre, randomized, parallel-group study in liver transplantation. Patients undergoing primary liver transplantation were randomized to treatment with FK 506 (n = 267) or with a cyclosporin-based immunosuppressive regimen (n = 273). The total cumulative steroid usage was significantly reduced in the FK 506 treatment group, which is likely to have resulted from the lower incidence of acute rejection in these patients. The number of patients receiving antidiabetic, diuretic and antihypertensive therapy did not differ between the two treatment groups, even though the incidence of diabetes mellitus and oliguria was significantly higher in the FK 506 group. It can, therefore, be assumed that in a number of such cases the severity of these events was very mild necessitating no specific therapy.
Adrenal Cortex Hormones↗
Glucose metabolism in liver transplant recipients treated with FK 506 or cyclosporin in the European multicentre study.
From September 1990 to January 1992, 545 liver transplant patients were randomised to treatment with either FK506 and prednisolone or a conventional cyclosporin-based immunosuppressive regimen (CBIR). Eight European centres participated in the study. Adverse events were reported as defined by each centre. Hyperglycaemia was reported as an adverse event in 30.7% of patients receiving FK 506 compared with 20.5% in the CBIR group (P < 0.01). Diabetes mellitus was reported in 17.2% of patients treated with FK 506 and 9.5% of CBIR-treated patients (P < 0.05). Treatment with insulin was required in 12.0% of patients in the DK 506 treatment group and in 5% in the CBIR group at 6 months. Initially, higher doses of FK 506 were used. During the study, the protocol was changed to allow a lower dose of FK 506. When the early and late cohorts of patients were compared, the incidence of diabetes mellitus fell from 23.9% to 10.5% in FK 506-treated patients but remained relatively constant in the CBIR group (10.4% to 8.7%). The median cumulative doses of i.v. and p.o. corticosteroids were significantly greater in the CBIR group. Thus, in the overall series, the incidence of diabetes mellitus was significantly greater in the FK 506 group as compared with the CBIR group. However, when a lower FK 506 dose was used during the second half of the study, the difference in the incidence of diabetes mellitus disappeared.
Adolescent↗
Renal complications and development of hypertension in the European study of FK 506 and cyclosporin in primary liver transplant recipients.
We examined the occurrence of renal complications and hypertension in 540 primary liver recipients entered into the European liver trial comparing primary FK 506 to a cyclosporin A based immunosuppression regimen (CBIR). No difference in serious renal impairment or mean creatinine levels was observed with similar rates of "kidney failure" (FK 506 9.4% vs. CBIR 7.3%) and dialysis requirements (FK 506 12% vs. CBIR 11%). "Abnormal kidney function", a less serious parameter of renal impairment, was reported in 89 recipients (33%) in the FK 506 group versus 58 (21%) in the CBIR group (P < 0.01). Development of this complication was associated with elevated intravenous FK 506 dosing schedules, with the mean cumulative dose 43% higher than treated patients with unaffected kidney function. In a later cohort of patients where intravenous dosing was lower, no significant difference in renal complications was detectable. The 6-month prevalence rate of systemic arterial hypertension was noted to be lower in the FK 506-treated patients compared to the CBIR group [33 (17.2%) vs. 47 (25.7%)].
Adolescent↗
Neurological complications in the European multicentre study of FK 506 and cyclosporin in primary liver transplantation.
Neurological complications were examined in a multicentre, randomized, parallel-group study of 545 patients undergoing primary liver transplantation to compare the efficacy and safety of FK 506- and cyclosporin A-based immunosuppressive regimens (CBIR). In an additional analysis, patients were divided into early and late randomized cohorts to detect the influence of protocol amendements that allowed for FK 506 dose reductions. Initial follow-up was for 6 months. Tremor, headache and insomnia were the most frequently reported adverse events involving the neurological system. Whereas these neurological symptoms were observed significantly more often in FK 506-treated patients (P < 0.05 vs. CsA for the overall population), this was no longer the case for the late FK 506 and CBIR cohorts. The risk of FK 506-treated patients developing tremor was related to the initial i.v. dose, the rate of administration of the i.v. dose and the daily dose (P < 0.01). Headache was significantly correlated with the FK 506 dose (P < 0.05), and insomnia was not related to any dosing variable. Major neurological symptoms, including psychosis, convulsion, coma, aphasia and intracranial haemorrhage, were reported with a low frequency (0.4-5.2%), and differences between both treatment groups were neither significant for the overall population nor for the early and late cohorts of FK 506 and CBIR. Data from the late cohorts showed no differences in the overall incidence of neurological adverse events between FK 506- and CBIR-treated patients.
Cyclosporine↗
Patient and graft survival in the European Multicentre Liver Study--FK 506 vs cyclosporin A.
A prospective randomised study was conducted to evaluate the efficacy and safety of FK 506 administered with corticosteroids compared with a cyclosporin A-based immunosuppressive regimen in patients undergoing primary liver transplantation. 545 patients were recruited in eight European centres, of whom 267 were randomised to FK 506 therapy and 273 to cyclosporin A-based therapy. The estimated Kaplan-Meier patient and graft survival figures of 82.9% and 77.5% respectively in the FK 506 group were higher than the comparable figures in the cyclosporin A group (77.5% and 72.6%, respectively). These differences did not reach statistical significance. Retransplantation rates, time to first rejection episode and number of rejection episodes were all lower (P < 0.001) in the FK 506 group. The infection rates were comparable between the two groups. During the study, the dose of FK 506 was reduced; this did not compromise efficacy and reduced the associated toxicity. FK 506 provides effective immunosuppression in patients undergoing primary liver transplantation and is associated with a lower incidence of rejection.
Adolescent↗
Optimal FK 506 dosage in patients under primary immunosuppression following liver transplantation.
In a retrospective study, we analysed the FK 506 dosage used in primary liver graft recipients enrolled in the European FK 506 multicenter trial conducted from September 1990 to January 1992. In addition, a second cohort of patients treated more recently in a single centre was investigated. The impact of different dosing strategies on the clinical course of the patients was analysed with special emphasis on the incidence of rejection episodes and FK 506 side-effects. Among the patients enrolled in the European FK 506 multicenter trial, those patients enrolled during the "early" phase of the study received a higher oral FK 506 dose [mean oral dosage on day 7 = 0.19 mg/kg body weight (bw) per day, n = 134] compared to patients enrolled during the "late" period of the study (mean oral dosage on day 7 = 0.14 mg/kg bw per day, n = 133). This lower dosage was the result of several protocol amendments performed to reduce the incidence of FK 506 side-effects. Lowering of the FK 506 dosage was accompanied by a reduction in the long-term prevalence of side-effects such as diabetes (n. s.) or hypertension (P < 0.05), while patient survival and rejection frequency remained constant. Patients treated in centres with online FK 506 blood level monitoring experienced significantly less hypertension, less episodes of diabetes and less rejection episodes compared to patients treated in centres without. The clinical course of those patients enrolled in the multicentre trial was compared with the course of a cohort of liver-grafted patients treated with FK 506 more recently in a single centre. These patients had a further reduction in the FK 506 dosage (0.10 mg/kg bw per day p.o. or less according to whole blood levels, with no intravenous FK 506 administration). When compared to patients enrolled in the multicentre trial, these patients experienced less side-effects (nephrotoxicity, hypertension, serious early neurotoxicity) while adaequate immunosuppression was maintained.
Administration, Oral↗
FK 506 primary immunosuppression following emergency liver transplantation for fulminant hepatic failure. European FK 506 Study Liver Group.
The efficacy and safety of an FK 506-compared to a cyclosporin A based immunosuppression regimen was examined in liver recipients who underwent transplantation for fulminant hepatic failure in the European FK 506 liver study. A consistent trend towards improved patient and graft survival noted in the FK 506-treated patients was apparent from the first postoperative week (e. g. patient survival: day 7, 95.5% vs. 82.1% and month 6, 72.7% vs. 60.7%). Acute (in particular intractable) rejection was less frequent in the FK 506 group (e. g. cumulative intractable rejection rate at 6 months, 6.2% vs. 22.6%). In a single centre (Kings College Hospital), 17 patients were studied in more detail. The FK 506 treatment group had improved graft function, lower steroid requirements and episodes of infection. Accompanying these benefits, apache 111 and TISS scores were lower in this group in the early posttransplant period. Intensive care discharge was earlier and both treatment groups experienced similar toxicity.
Adolescent↗
Steroid withdrawal 3 months after liver transplantation--does FK 506 confer any advantage over cyclosporin?
Eighty-one liver recipients were randomised to FK 506 or cyclosporin (CyA) and azathioprine (AzA), both in combination with steroids. Twenty-seven FK 506 and 29 CyA/AzA patients continued in the trial 3 months after transplantation. Steroids were ceased in 23 (85%) FK 506 patients and in 27 (93%) CyA patients. After steroid withdrawal, 2 FK 506 and 4 CyA patients were excluded from the study, all for reasons other than rejection. The median follow-up was 16 months for the FK 506, and 19 months for CyA group. There were no acute rejection episodes or graft losses in the FK 506 group. None of the CyA patients lost their graft but three (13%) had episodes of acute rejection requiring steroids to be recommenced in two cases. There was no evidence of chronic rejection in any of the annual review biopsies in either group. Our results suggested no advantage of FK 506 over CyA in its steroid-sparing effect.
Adolescent↗
The immunomodulatory effects of a novel agent, leflunomide, in rat cardiac allotransplantation.
We assessed the immunomodulatory effect of leflunomide (LEF) in a heterotopic abdominal model of rat heart transplantation using a major histocompatibility mismatch (DA X LEW). The endpoint of this study was cardiac rejection assessed by abdominal palpation of the ventricular impulse and confirmed by laparotomy and histology. In this study, LF was investigated using four dosages (5, 10, 20 and 30 mg/kg per day orally) against cyclosporine (CsA) (15 mg/kg per day orally) and FK 506 (1 mg/kg per day orally). The ability of LEF to prevent rejection and reverse ongoing acute rejection was assessed. The results showed that untreated hearts were fully rejected by day 5 and that LEF at 5 mg/kg was significantly better than any other dose tested, was superior to FK 1 mg/kg, and was as effective as CsA 15 mg/kg in preventing rejection after a short course of treatment. After a longer course, 10 and 20 mg/kg LEF proved more effective than 5 mg/kg in controlling rejection and as efficacious as 1 mg/kg FK and 15 mg/kg CsA. In the control of ongoing established early rejection. LEF proved to be equally effective, even at lower doses (5 mg/kg), to CsA 15 mg/kg and FK 1 mg/kg. In the control of ongoing established late rejection, 20 mg/kg LEF proved to be superior to 10 mg/kg LEF and 15 mg/kg CsA, and was as effective as FK 1 mg/kg. However, when higher doses of CsA (25 mg/kg) and FK (2 mg/kg) were tested against 20 mg/kg LEF in this mode of rescue, LEF proved as effective as CsA and superior to FK. In the assessment of drug toxicity using body weight as a parameter, 20 mg/kg LEF proved safer than any other LEF dose tested, and safer than 15 mg/kg CsA and 1 mg/kg FK in both short- and long term administration. We conclude that LEF is a relatively safe and potent immunosuppressant with promising clinical potential.
Animals↗