Safety and Outcomes in 100 Consecutive Donation After Circulatory Death Liver Transplants Using a Protocol That Includes Thrombolytic Therapy.

Donation after circulatory death (DCD) liver transplantation (LT) reportedly yields inferior survival and increased complication rates compared with donation after brain death (DBD). We compare 100 consecutive DCD LT using a protocol that includes thrombolytic therapy (late DCD group) to an historical DCD group (early DCD group n = 38) and a cohort of DBD LT recipients (DBD group n = 435). Late DCD LT recipients had better 1- and 3-year graft survival rates than early DCD LT recipients (92% vs. 76.3%, p = 0.03 and 91.4% vs. 73.7%, p = 0.01). Late DCD graft survival rates were comparable to those of the DBD group (92% vs. 93.3%, p = 0.24 and 91.4% vs. 88.2%, p = 0.62). Re-transplantation occurred in 18.4% versus 1% for the early and late DCD groups, respectively (p = 0.001). Patient survival was similar in all three groups. Ischemic-type biliary lesions (ITBL) occurred in 5%, 3%, and 0.2% for early DCD, late DCD, and DBD groups, respectively, but unlike in the early DCD group, in the late DCD group ITBL was endoscopically managed and resolved in each case. Using a protocol that includes a thrombolytic therapy, DCD LT yielded patient and graft survival rates comparable to DBD LT.

Excellent liver retransplantation outcomes in hepatitis C-infected recipients.

UNLABELLED: Survival outcomes for liver retransplantation (LRTx) after graft loss in HCV patients (HCV-LRTx) are generally considered inferior to those after non-HCV-LRTx. Between January 1, 2005 and June 30, 2011, our center performed 663 LTx, including 116 (17.5%) LRTx, 41 (35.3%) of which were more than 90 d after the LTx. Twenty-nine (70.7%) LRTx were performed in HCV antibody-positive individuals. We compared patient demographics, baseline characteristics and outcomes of our HCV-LRTx group with the HCV-LRTx patients from the most recent OPTN database covering the same time period. Our Kaplan-Meier HCV-LRTx one-, three-, and five-yr HCV-LRTx patient survival rates were 86.2%, 79.0%, and 72.4%, respectively compared with the OPTN one-, three-, and five-yr HCV-LRTx survival rates of 73.3%, 59.0%, and 51.3% respectively. Likewise, our graft survival rates were higher than OPTN rates at all time points studied. We performed a higher percentage of HCV-LRTx as simultaneous liver/kidney transplants (SLK) (37.9% vs. 21.8%) and recorded shorter warm (30 ± 4 vs. 45 ± 23 min) and cold ischemic times (5:44 ± 1:53 vs. 7:36 ± 3:12 h:min). CONCLUSION: In our experience, HCV-LRTx patient and graft survival rates are comparable to LTx survival rates and are higher than the rates described by OPTN.

Adult living liver donors have excellent long-term medical outcomes: the University of Toronto liver transplant experience.

Right lobe living donor liver transplantation is an effective treatment for selected individuals with end-stage liver disease. Although 1 year donor morbidity and mortality have been reported, little is known about outcomes beyond 1 year. Our objective was to analyze the outcomes of the first 202 consecutive donors performed at our center with a minimum follow-up of 12 months (range 12-96 months). All physical complications were prospectively recorded and categorized according to the modified Clavien classification system. Donors were seen by a dedicated family physician at 2 weeks, 1, 3 and 12 months postoperatively and yearly thereafter. The cohort included 108 males and 94 females (mean age 37.3 +/- 11.5 years). Donor survival was 100%. A total of 39.6% of donors experienced a medical complication during the first year after surgery (21 Grade 1, 27 Grade 2, 32 Grade 3). After 1 year, three donors experienced a medical complication (1 Grade 1, 1 Grade 2, 1 Grade 3). All donors returned to predonation employment or studies although four donors (2%) experienced a psychiatric complication. This prospective study suggests that living liver donation can be performed safely without any serious late medical complications and suggests that long-term follow-up may contribute to favorable donor outcomes.

Reduced mortality with right-lobe living donor compared to deceased-donor liver transplantation when analyzed from the time of listing.

Right lobe living donor liver transplantation (RLDLT) is not yet a fully accepted therapy for patients with end-stage liver failure in the Western hemisphere because of concerns about donor safety and inferior recipient outcomes. An outcome analysis from the time of listing for all adult patients who were listed for liver transplantation (LT) at our center was performed. From 2000 to 2006, 1091 patients were listed for LT. One hundred fifty-four patients (LRD; 14%) had suitable live donors and 153 (99%) underwent RLDLT. Of the remaining patients (DD/Waiting List; n = 937), 350 underwent deceased donor liver transplant (DDLT); 312 died or dropped off the waiting list; and 275 were still waiting at the time of this analysis. The LRD group had shorter mean waiting times (6.0 months vs. 9.8 months; p < 0.001). Although medical model for end-stage liver disease (MELD) scores were similar at the time of listing, MELD scores at LT were significantly higher in the DD/Waiting List group (15.4 vs. 19.5; p = 0.002). Patients in Group 1 had a survival advantage with RLDLT from the time of listing (1-year survival 90% vs. 80%; p < 0.001). To our knowledge, this is the first report to document a survival advantage at time of listing for RLDLT over DDLT.

Selective use of older adults in right lobe living donor liver transplantation.

Many centers are reluctant to use older donors (>44 years) for adult right-lobe living donor liver transplantation (RLDLT) due to concerns about possible increased morbidity in donors and poorer outcomes in recipients. Since 2000, 130 adult RLDLTs have been performed at our institution. Recipients were divided into those who received a right lobe graft from a donor 44 (n = 41, 32%; mean age 52). The two donor and recipient populations had similar demographic and operative profiles. With a median follow-up of 29 months, the severity and number of complications in older donors were similar to those in younger donors. No living donor died. Older donor allografts had initial allograft dysfunction compared to younger donors. Complication rates were similar among recipients in both groups but there was a higher bile duct stricture rate with older donor grafts (27% vs. 12%; p = 0.04). One-year recipient graft survival was 86% for older donors and 85% for younger donors (p = 0.95). Early experience with the use of selected older adults (>44 years) for RLDLT is encouraging, but may be associated with a higher rate of biliary complications in the recipient.

Biliary strictures in 130 consecutive right lobe living donor liver transplant recipients: results of a Western center.

Biliary strictures remain the most challenging aspect of adult right lobe living donor liver transplantation (RLDLT). Between 04/2000 and 10/2005, 130 consecutive RLDLTs were performed in our center and followed prospectively. Median follow-up was 23 months (range 3-67) and 1-year graft and patient survival was 85% and 87%, respectively. Overall incidence of biliary leaks (n = 19) or strictures (n = 22) was 32% (41/128) in 33 patients (26%). A duct-to-duct (D-D) or Roux-en-Y (R-Y) anastomosis were performed equally (n = 64 each) with no difference in stricture rate (p = 0.31). The use of ductoplasty increased the number of grafts with a single duct for anastomosis and reduced the biliary complication rate compared to grafts >/=2 ducts (17% vs. 46%; p = 0.02). Independent risk factors for strictures included older donor age and previous history of a bile leak. All strictures were managed nonsurgically initially but four patients ultimately required conversion from D-D to R-Y. Ninety-six percent (123/128) of patients are currently free of any biliary complications. D-D anastomosis is safe after RLDLT and provides access for future endoscopic therapy in cases of leak or stricture. When presented with multiple bile ducts, ductoplasty should be considered to reduce the potential chance of stricture.

The cardiac response to exercise in cirrhosis.

BACKGROUND: Impaired exercise capacity and oxygen consumption are common in cirrhosis. AIM: To explore the relationship between possible myocardial dysfunction and exercise tolerance in cirrhosis. METHODS: Cardiac responses to exercise, using radionuclide angiography and graded upright cycle ergometry with oxygen consumption, were assessed before and after exercise in 39 cirrhotics patients and compared with 12 age and sex matched healthy volunteers. Baseline cardiac chamber dimensions and wall thickness, ejection fraction, and diastolic function were measured using two dimensional echocardiography is all subjects. RESULTS: Baseline diastolic dysfunction with prolonged isovolumic relaxation times (p=0.02), left atrial enlargement, and left ventricular wall thickening were present in all cirrhotics (p=0.02), despite increased mean ejection fraction. With graded exercise, cirrhotics achieved 71 (4)% (p=0.03) (pre-ascitics) and 46 (3)% (p<0.001) (ascitics) of predicted work loads, respectively, without significant increases in ejection fraction. The smaller absolute and percentage increases in cardiac output (p=0.003) in the cirrhotics were associated with significantly reduced oxygen consumption (p=0.003) and anaerobic threshold (p<0.001), and correlated significantly with work and metabolic parameters. CONCLUSIONS: Impaired exercise capacity in cirrhosis is associated with myocardial thickening and ventricular stiffness leading to decreased diastolic function, inotropic and chronotropic incompetence under conditions of stress, with metabolic consequences. This picture is compatible with the condition now known as cirrhotic cardiomyopathy.

ACE inhibitor-induced angioedema of the intestine: Case report, incidence, pathophysiology, diagnosis and management.

A case report of fosinopril-induced angioedema of the intestine with a chronic course accompanied by multiple acute exacerbations is described. Angiotensin-converting enzyme (ACE) inhibitor-induced angioedema of the intestine (AIAI) occurs in a minority of patients taking an ACE inhibitor. The clinical presentation encompasses acute abdominal symptoms, pronounced bowel edema and ascites with occasional facial and/or oropharyngeal swelling. AIAI is diagnosed based on the temporal relationship between the symptomatic presentation and drug use, absence of alternative diagnoses including other causes of angioedema, and the prompt resolution of symptoms upon discontinuation of the ACE inhibitor. Prompt radiological investigation (abdominal computerized tomography and/or ultrasound) is critical in making an early diagnosis and in preventing unnecessary surgical intervention. There is a female predominance of AIAI, which may reflect the interaction of estradiol with the various pathways involved in the pathophysiology of AIAI. Management of AIAI consists mainly of conservative measures and discontinuation of the ACE inhibitor. Angiotensin II receptor antagonists should not be considered as appropriate alternatives. Awareness and knowledge of AIAI are important because of the increasing use of ACE inhibitors, current delays in making the diagnosis, obvious management strategies once the diagnosis is made and the dysutility of alternative diagnoses, which may lead to considerable morbidity. AIAI must be considered in patients taking ACE inhibitors who develop gastrointestinal complaints irrespective of the duration of the therapy.

The University of Toronto Liver Transplant Program: Toronto General Hospital, Hospital for Sick Children.

The University of Toronto Liver Transplant Program began in 1985 at a time when the procedure had already evolved from an experimental form of surgery to an accepted treatment for many forms of liver failure. The program was established not only to provide clinical care for patients but also to address academically the barriers that impeded success. The program brought together experts in medicine, surgery, pathology, and the basic sciences of immunology, virology and molecular biology. Significant advances over the past decade and a half in immunosuppressive drugs and monitoring, patient selection, and infectious management have contributed to markedly improved patient and graft survival rates. Nevertheless, we continue to face 2 major challenges: a growing scarcity of donor organs, a problem partially addressed through development of living-related liver donation, and recurrent viral hepatitis. We expect to remain on the forefront of ongoing research to provide solutions to these and other barriers to the full deployment of liver transplantation in the year 2000.

Haemodynamic, renal sodium handling, and neurohormonal effects of acute administration of low dose losartan, an angiotensin II receptor antagonist, in preascitic cirrhosis.

BACKGROUND: The renin-angiotensin system may be implicated in the subtle sodium handling abnormality in preascitic cirrhosis. AIMS: To assess the role of angiotensin II in sodium homoeostasis in preascitic cirrhosis, using losartan, its receptor antagonist. PATIENTS: Nine male, preascitic cirrhotic patients, and six age matched, healthy male controls. METHODS: A dose response study using 2.5, 5, 7.5, and 10 mg of losartan was performed on a daily 200 mmol sodium intake, followed by repeat studies with the optimal dose, 7.5 mg of losartan, to determine its effects on systemic and renal haemodynamics, renal sodium handling, and neurohumoral factors. RESULTS: Preascitic cirrhotic patients had significantly reduced baseline urinary sodium excretion compared with controls (154 (8) versus 191 (12) mmol/day, p<0.05), associated with significantly reduced systemic angiotensin II levels (6.0 (1.7) versus 39.5 (10.0) pmol/l, p=0.002). Losartan 7.5 mg normalised renal sodium handling in the preascitic cirrhotic patients (202 (12) mmol/day, p=0.05 versus baseline), without any change in systemic or renal haemodynamics, but with significantly increased systemic angiotensin II levels (7.8 (2.3) pmol/l, p=0.05 versus baseline). Losartan had no effect on renal sodium handling in controls. CONCLUSIONS: In preascitic cirrhotic patients, the subtle renal sodium retention, paradoxically associated with low systemic neurohumoral factor levels, is improved with low dose losartan, suggesting the involvement of angiotensin II via its direct action on the renal tubule.

Reliability of a Crohn's disease clinical classification scheme based on disease behavior.

Classification of Crohn's disease (CD) by disease behavior--either inflammatory (INF), fibrostenotic (FS), or fistulizing/perforating (FP)--has been proposed as a means of assisting management decisions and predicting outcomes for subgroup analysis in clinical trials and for making phenotype/genotype associations in molecular genetic studies. Accurate and reproducible classification of CD patient subgroups is of paramount importance in such studies but to be useful, the classification scheme must have good interrater agreement. We sought to assess the interrater agreement associated with the disease-behavior classification scheme of CD. Twelve patients with CD were randomly selected from a database of 964 patients with CD undergoing medical or surgical treatment or both. Clinical details of the 12 cases, along with their radiographs and surgical and pathological reports, were presented to a panel of 20 experts who were asked to classify each case based on the patient's overall disease course (scenario A) and as if the patient were being entered into a clinical trial on that day (scenario B). Calculations of strength of interrater agreement were made and were expressed as the kappa statistic (kappa), with kappa < 0.2 = poor strength of agreement; kappa 0.21 - 0.4 = fair; kappa 0.41 - 0.6 = moderate; kappa 0.61 - 0.8 = good; and kappa 0.81 - 1.0 = very good. Five panel participants did not complete the study, and three clinical vignettes were excluded because of incomplete scoring, leaving a total of 15 panel experts assessing nine cases. Overall interrater agreement was only fair with kappa = 0.353 for scenario A and kappa = 0.291 for scenario B. Interrater agreement was less when only the most straightforward case in each disease category was evaluated. Classification of CD by pattern of disease behavior yields only fair interrater agreement. This raises concerns regarding its applicability, particularly in ongoing studies of genotype/phenotype associations. Further refinement of disease subtypes and clear operational definitions are required.

Review: the controversy over the pathophysiology of ascites formation in cirrhosis.

The pathogenesis of renal sodium retention and ascites formation in cirrhosis is a subject of much controversy. The generally accepted 'peripheral arterial vasodilatation hypothesis' seems to best explain the mechanism of sodium retention and other clinical findings, such as the hyperdynamic circulation of cirrhosis. However, recent data in pre-ascites and in early ascites do not seem to conform to the peripheral arterial vasodilatation hypothesis. Sodium handling abnormalities can be demonstrated in pre-ascitic cirrhosis when patients are challenged with a sodium load, in the absence of systemic vasodilatation or arterial underfilling. Therefore, an alternative hypothesis with a direct hepatorenal interaction, acting via sinusoidal portal hypertension and/or hepatic dysfunction as the affector mechanism, is proposed to be the initiating event in renal sodium retention in cirrhosis. The second and later process is the development of systemic arterial vasodilatation, possibly due to the presence of excess systemic vasodilators and/or decreased responsiveness of the vasculature to endogenous vasoconstrictors. This, in turn, will lead to a relatively underfilled circulation with consequent activation of neurohumoral systems, promoting further renal sodium retention as described by the peripheral arterial vasodilatation hypothesis and ultimately leading to ascites. When compensatory natriuretic mechanisms fail, refractory ascites develops and hepatorenal syndrome sets in. Thus, renal sodium retention in cirrhosis is the result of interplay of many factors, with direct hepatorenal interaction predominating in earlier stages of the cirrhotic process, while systemic vasodilatation becomes a more important pathogenetic factor as the disease progresses.

Localization of the CD44 glycoprotein to fibrous astrocytes in normal white matter and to reactive astrocytes in active lesions in multiple sclerosis.

The CD44 antigen is a proteoglycan recently implicated in several adhesion events including that of lymphocytes to endothelium. The CD44 antigen, reactive with monoclonal antibody (MAb) 44D10, has been shown previously to be expressed in normal human white matter homogenates and to be found at higher concentrations in brain homogenates of victims of multiple sclerosis (MS). The cellular localization of CD44 in human brain of normal individuals and in those afflicted with MS has now been determined. Monoclonal antibody 44D10 reacted with astrocyte-like cells in 40 microns thick paraformaldehyde-fixed sections but not in thin (6 microns) fixed sections. A double labeling experiment performed on a frozen brain section with MAb 44D10 and rabbit anti-glial fibrillary acidic protein (GFAP), a cytoplasmic marker of astrocytes, confirmed the co-localization of these two antigens. The reactivity with brain tissue sections of a rabbit antiserum produced against lymphocyte-CD44 could be absorbed by a preparation of the CD44 glycoprotein, purified 2,100-fold from a white matter homogenate. The antiserum was shown by Western blot analysis to be specific for p80 glycoprotein in brain extracts derived from a normal and MS patients. This antibody reacted with fibrous astrocytes predominantly in white matter; staining was also noted in subependymal and subpial regions. Inhibition studies using a cellular radioimmunoassay indicated that the highest concentrations of CD44 in three MS victims were found in plaques, followed by periplaques and non-involved areas of white matter which were higher than normal white matter. Reactive astrocytes, identified in active lesions, expressed high levels of CD44 on their surfaces. Thus, CD44 is associated with astrocytes in human brain and the increased expression observed in MS brain may reflect activation and/or proliferation of astrocytes implicated in the pathogenesis of this disease.

Localization of CD44 (P80) on the external surface of a human astrocytoma cell.

A brain antigen, originally identified by a MAb 44D10, has been shown to be a glycoprotein with an Mr of 80 kDa. Cellular localization studies of sections of brain showed that the antigen was associated with the membrane of astrocytes. In the present study we demonstrate its localization to the membrane of an astrocytoma cell line by fluorescence and electron microscopic immunogold methods. Heavy labelling with immunogold was found along cellular processes. Labelling of the smooth surfaces of cells and the microvilli was also observed.

Purification and characterization of the P-80 glycoprotein from human brain.

A glycoprotein antigen was purified from human brain by immunoaffinity chromatography using the 44D10-monoclonal IgG, and its chemical nature was investigated. The yield of antigen was estimated at 91% and a 4340-fold purification was obtained relative to the white-matter homogenate. The antigen preparation from brain was further purified by preparative SDS/polyacrylamide-gel electrophoresis (PAGE) to obtain a glycoprotein with an Mr of 80,000 consisting of a single polypeptide. Amino acid analyses revealed a composition which was high in acidic and neutral amino acids, and low in basic residues. The presence of both glucosamine and galactosamine suggested that the glycoprotein contained both N- and O-linked glycans. Neutral sugar analyses showed that fucose, galactose and mannose were present. An assay for sialic acid determined that there were approximately 20 mol of sialic acid per mol of glycoprotein. Chemical cleavage of oligosaccharides by trifluoromethanesulphonic acid followed by SDS/PAGE showed that carbohydrate accounted for 25,000 of the 80,000-Mr glycoprotein.

Purification and characterization of a protein antigen (p94) from human brain and its identification in other species.

A protein antigen was chromatographically purified from human brain by its immunoaffinity to 44E3 monoclonal IgG and its chemical nature was investigated. The yield of antigen was estimated at 71%, and a 3160-fold purification was achieved relative to the homogenate. The antigen preparation from brain showed a very high degree of purity when analysed by SDS/polyacrylamide-gel electrophoresis and was composed of a single polypeptide of Mr 94,000. Amino-sugar and neutral-sugar analyses indicated that the protein was not glycosylated. The amino acid composition of the purified protein from brain was compared with that of the analogous protein purified from an acute-lymphoblastic-leukaemic cell line, HOON. The compositions were very similar, suggesting that the two proteins were closely related. Both purified proteins were equivalent in their ability to inhibit the reactivity of monoclonal antibodies 44E3 and 44H4 with leukaemic cells. These two antibodies appear to recognize spatially related, if not identical, epitopes on the same molecule. The antibodies were shown to cross-react with a polypeptide of Mr 94,000 in homogenates of human, bovine and guinea-pig brain white matter. Indirect immunoperoxidase staining of human grey- and white-matter acetone-fixed tissue sections incubated with either antibody indicated that the antigen was present on neuronal and glial cells; the staining was seen as clusters in the cytoplasm, starting at the plasma membrane, but leaving the nucleus unstained. The concentration of the protein in human brain was shown to be similar throughout postnatal development and aging.