Canadian Forum on Combined Organ Transplantation.

The Canadian Society of Transplantation and Canadian Blood Services conducted a consensus forum on combined renal/nonrenal transplants, as they are not part of Canadian organ-specific allocation models at present. The purpose of this initiative was to make recommendations, develop eligibility criteria, and a decision-making model on listing and allocation. Forty-two participants with expertise in combined transplantation participated in the consensus forum. The United States and Canadian data were reviewed. The consensus forum made recommendations regarding the following: (1) investigation of etiology, severity, duration, and level of renal dysfunction; (2) documentation of degree of nonreversible kidney injury; (3) eligibility for combined (either simultaneous or staged) transplantation; (4) research. Key recommendations were: (1) patients with end-stage nonrenal disease with estimated glomerular filtration rate less than 30 mL/min per 1.73 m for longer than 1 month or on dialysis less than 3 months, who fulfill criteria for nonreversibility of renal dysfunction (by level and duration of renal dysfunction, imaging, and pathology findings), would be eligible for combined renal/nonrenal transplantation; (2) patients on dialysis longer than 3 months would be eligible for combined renal/nonrenal transplantation; (3) staged renal after nonrenal transplantation with subsequent prioritized allocation of renal transplant was endorsed in selected cases. The validation and impact of these recommendations on allocation will require further studies.

Risk of Bacterial Infection in Patients With Cirrhosis and Acute Variceal Hemorrhage, Based on Child-Pugh Class, and Effects of Antibiotics.

BACKGROUND & AIMS: Antibiotics frequently are overused and are associated with serious adverse events in patients with cirrhosis. However, these drugs are recommended for all patients presenting with acute variceal hemorrhage (AVH). We investigated whether patients should be stratified for antibiotic prophylaxis based on Child-Pugh scores, to estimate risks of bacterial infection, rebleeding, and mortality, and whether antibiotics have equal effects on patients of all Child-Pugh classes. We performed a sensitivity analysis using model for end-stage liver disease (MELD) scores. METHODS: In a retrospective study, we analyzed data from 381 adult patients with cirrhosis and AVH (70% men; mean age, 56 y), admitted from 2000 through 2009 to 2 tertiary care hospitals in Edmonton, Alberta, Canada. We excluded patients with bacterial infection on the day of AVH. The association between antibiotic prophylaxis and outcomes was adjusted by liver disease severity and by a propensity score. RESULTS: The patients included in the study had mean MELD scores of 16, and 54% received antibiotic prophylaxis. Overall, antibiotic therapy was associated with lower risks of infection (adjusted odds ratio, 0.37; 95% confidence interval, 0.91-0.74) and mortality (adjusted odds ratio, 0.63; 95% confidence interval, 0.31-1.29). Among patients categorized as Child-Pugh class A given antibiotics, only 2% developed infections and the mortality rate was 0.4%. Among patients categorized as Child-Pugh class B given antibiotics, 6% developed infections, compared with 14% of patients who did not receive antibiotics; antibiotics did not affect mortality. Administration of antibiotics to patients categorized as Child-Pugh class C reduced infections and mortality by approximately 50%, compared with patients who did not receive antibiotics. MELD scores were not as useful as Child-Pugh class in identifying patients at risk for infection. CONCLUSIONS: Based on a retrospective analysis of patients with cirrhosis and AVH, those categorized as Child-Pugh class A had lower rates of bacterial infection and lower mortality rates in the absence of antibiotic prophylaxis than patients categorized as classes B or C. The recommendation for routine antibiotic prophylaxis for this subgroup requires further evaluation.

VSL#3 ® probiotic therapy does not reduce portal pressures in patients with decompensated cirrhosis.

BACKGROUND & AIMS: In patients with decompensated cirrhosis, bacterial translocation can contribute to splanchnic vasodilatation, decreased effective circulating volume, and portal hypertension. The primary objective of this randomized, double blind placebo controlled trial was to evaluate the effect of the probiotic VSL#3(®) on the hepatic venous pressure gradient (HVPG). METHODS: Seventeen patients with decompensated cirrhosis and an HVPG of ≥ 10 mmHg were randomized to receive 2 months of VSL#3(®) or an identical placebo. HVPG, endotoxin, interleukin (IL)-6, IL-8, IL-10, renin, aldosterone, nitric oxide and stool microbiota were measured at baseline and study end. RESULTS: Two of the 17 patients were taken off the trial before completion (one for alcohol abuse and the second for SBP - both in placebo arm). Data were analysed on the remaining 15 patients. The median model for end-stage liver disease score was 12, and 80% of patients had Child Pugh B disease. The treatment arm had a greater decrease in HVPG from baseline to study end than the placebo arm (median change from baseline -11.6% vs +2.8%), although this reduction was not statistically significant in either group. There was a significant reduction in the plasma aldosterone level in the VSL#3(®) group, but no significant changes in the other measured parameters, including the stool microflora analysis. CONCLUSIONS: Within the limitations of our sample size, VSL#3(®) therapy does not appear to have a significant impact on portal pressure reduction in patients with decompensated cirrhosis.

Managing the post-liver transplantation anastomotic biliary stricture: multiple plastic versus metal stents: a systematic review.

BACKGROUND: Anastomotic biliary strictures (ABSs) are common after liver transplantation, especially with living donors. The strategy of balloon dilation and multiple plastic stents (MPSs) is effective in treating ABSs, but requires multiple ERCPs with the associated risks, cost, and patient burden. Covered self-expandable metal stents (SEMSs) have been increasingly used in this setting. However, it is not clear whether there are definite advantages of using SEMSs over MPSs. OBJECTIVE: To compare the efficacy and safety of MPSs and SEMSs in ABS after orthotopic liver transplantation (OLT) and living donor liver transplantation (LDLT). DESIGN: Systematic review by searching MEDLINE and EMBASE databases. PATIENTS: OLT and LDLT patients. INTERVENTIONS: MPSs versus SEMSs. MAIN OUTCOME MEASUREMENTS: Stricture resolution and adverse event rates. RESULTS: Eight studies (446 patients) using MPSs in OLT, 3 studies (120 patients) using MPSs in LDLT, and 10 studies (200 patients) using SEMSs fulfilled the inclusion and exclusion criteria. The stricture resolution rates were highest (94%-100%) when MPS duration was 12 months or longer. The stricture resolution rates with SEMSs in OLT patients were also high when stent duration was 3 months or longer (80%-95%) compared with a duration less than 3 months (53%-88%). Although the overall adverse event rates were low, the overall SEMS migration rate was significant at 16%. LIMITATIONS: No randomized, controlled trials were identified; only small case series using either MPSs or SEMSs were included. CONCLUSIONS: Although SEMSs appeared to be a promising option in the endoscopic management of ABSs after liver transplantation, current evidence does not suggest a clear advantage of SEMS use over MPSs for this indication.

The natural history of inflammatory bowel disease and primary sclerosing cholangitis after liver transplantation--a single-centre experience.

OBJECTIVE: To describe the natural history of primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) after liver transplant, the predictors of PSC and IBD recurrence, and the interaction of these disease processes. METHODS: Data regarding patients who received liver transplants for PSC at the University of Alberta Hospital (Edmonton, Alberta) from 1989 to 2006 were retrospectively reviewed. Recurrent PSC (rPSC) was defined by the Mayo Clinic criteria. Cox proportional hazards modelling and Kaplan-Meier statistics were used. RESULTS: Fifty-nine patients were studied, with a median follow-up of 68 months. A total of 71.2% of patients were diagnosed with IBD pretransplant. Clinical IBD severity post-transplant compared with severity pretransplant was unchanged in 67%, worse in 26.5% and improved in 6.1% of patients. Twenty-five per cent of patients developed rPSC posttransplant. The occurrence of at least one episode of acute cellular rejection (hazard ratio 5.7; 95% CI 1.3 to 25.8) and cytomegalovirus mismatch (hazard ratio 4.2; 95% CI 1.1 to 15.4) were found to be significant predictors of rPSC. Although not statistically significant, there was no rPSC in patients without pre- or post-transplant IBD, and in only one patient with a colectomy. Actuarial patient survival rates at one, five and 10 years posttransplant were 97%, 86% and 79%, respectively. Although a significant proportion of patients experienced worsening IBD post-transplantation, the presence or severity of IBD did not influence rPSC or patient survival. CONCLUSION: Acute cellular rejection and cytomegalovirus mismatch were both identified as independent predictors of rPSC. The impact of steroids and the ideal immunosuppressive regimen for the control of both IBD and PSC post-transplant requires further examination in prospective studies.

Effects of probiotic therapy on portal pressure in patients with cirrhosis: a pilot study.

BACKGROUND: Recent literature has supported the role of bacterial translocation as a mediator of splanchnic vasodilatation and portal hypertension. The objective of this study was to determine whether the probiotic VSL#3 would reduce portal pressure in patients with cirrhosis. METHODS: Eight patients with compensated or very early decompensated cirrhosis and hepatic venous pressure gradient (HVPG) >10 mmHg, received 2 months of VSL#3 (3600 billion bacteria daily). The HVPG, intestinal permeability, endotoxin, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, renin and aldosterone were measured at baseline and study end. RESULTS: There was no change in the HVPG or intestinal permeability from baseline to study end but there was a trend to reduction in plasma endotoxin (P=0.09), a mild but significant increase in serum TNF-alpha (P=0.02) and a significant reduction in plasma aldosterone (P=0.03). CONCLUSIONS: Within the limitations of small sample size, there does not appear to be a benefit of probiotic therapy for portal pressure reduction in patients with compensated or early decompensated cirrhosis. The reductions in endotoxin and aldosterone suggest possible beneficial effects of probiotics for this patient population. The clinical significance of the small but unexpected increase in TNF-alpha is unclear. Future studies are planned in patients with decompensated cirrhosis.

Outcomes of peginterferon alpha-2a and ribavirin hepatitis C therapy in Aboriginal Canadians.

BACKGROUND: There is little published information on baseline characteristics and therapeutic outcomes in hepatitis C virus (HCV)-infected Aboriginal Canadians. It is unclear what proportion of HCV-infected Aboriginal people receive therapy relative to other populations. METHODS: Adults with chronic HCV infection, quantifiable serum HCV-RNA levels and compensated liver disease were assigned, at the physician's discretion, to either 24 or 48 weeks of treatment with peginterferon alpha-2a 180 mug/week plus ribavirin at a dose of 800 mg/day, or 1000 mg/day or 1200 mg/day in an open-label, expanded access program. The primary outcome was sustained virological response, defined as undetectable HCV-RNA by qualitative polymerase chain reaction (less than 50 IU/mL) at the end of 24 weeks of untreated follow-up. Baseline characteristics and outcomes in Aboriginal and non-Aboriginal patients were compared. RESULTS: A total of 2614 patients were eligible for the analysis; 44 individuals (1.7%) self-identified as being of Aboriginal heritage. The baseline characteristics of these two groups were similar. An overall sustained virological response was achieved in 47.7% and 46.5% of Aboriginal and non-Aboriginal patients, respectively. The overall frequencies of adverse events and laboratory abnormalities were similar between the two groups, although cytopenias occurred less frequently in Aboriginal patients. INTERPRETATION: Aboriginal patients were greatly under-represented in the present 'community'-based treatment program, yet viral responses were similar to those of a non-Aboriginal cohort. To increase the uptake of HCV therapy in the Aboriginal population, clarification of the obstacles to treatment is warranted.

Hepatitis B virus replication in damaged endothelial tissues of patients with extrahepatic disease.

Hepatitis B virus (HBV) infection may be complicated by extrahepatic manifestations such as polyarteritis nodosa (PAN), glomerulonephritis, polymyositis, and dermatitis, but the etiology of these processes is not yet clear. HBV replication has been demonstrated in a variety of extrahepatic tissues and cell types, but the possible pathogenetic role of extrahepatic HBV replication has not been fully explored in patients with extrahepatic manifestations of HBV infection. In this case series, immunohistochemistry and in situ hybridization studies were performed on extrahepatic tissues from one HBsAg-positive patient with PAN and another HBsAg-positive patient with polymyositis, using HBsAg-seronegative control subjects with the same vasculitic disorders as controls. Tissue samples from the two study patients had detectable HBV RNA, replicative intermediates of HBV DNA, as well as HBsAg and HBcAg localized to vascular endothelium. In contrast, HBsAg-negative control patients had no tissue reactivity. Our results suggest that patients with HBV-related extrahepatic disease have evidence of viral replication in damaged extrahepatic endothelial tissues. While further studies would be required to support a hypothesis of causality, these findings suggest a role for both immune complex deposition and viral replication within diseased endothelial tissue in the pathogenesis of these poorly understood extrahepatic disorders.

Early steroid withdrawal after liver transplantation: the Canadian tacrolimus versus microemulsion cyclosporin A trial: 1-year follow-up.

Corticosteroid therapy contributes significant toxicity to liver transplantation. The safety and efficacy of early steroid withdrawal were determined in patients treated with either tacrolimus or microemulsion cyclosporin A (micro-CsA). The primary outcome was the proportion of patients who were steroid-free 1 year posttransplantation. From the seven Canadian adult liver transplant centers, 143 patients were randomly allocated oral treatment with either tacrolimus (n = 71) or micro-CsA (n = 72), together with corticosteroids and azathioprine. Eligibility criteria for steroid withdrawal included freedom from acute rejection for a minimum of 3 months, and prednisone