Federico G. Villamil

A Report of the Vancouver Forum on the Care of the Live Organ Donor: Lung, Liver, Pancreas, and Intestine Data and Medical Guidelines

An international conference of transplant physicians, surgeons, and allied health professionals was held in Vancouver, Canada, on September 15 and 16, 2005 to address the care of the live lung, liver, pancreas, and intestine organ donor. The Vancouver Forum was convened under the auspices of the Ethics Committee of The Transplantation Society. Forum participants included over 100 leaders in organ transplantation, representing many countries from around the world, including participants from the following continents: Africa, Asia, Australia, Europe, North and South America. The objective of the Vancouver Forum was to develop an international standard of care for the live lung, liver, pancreas and intestinal organ donor. This Vancouver Forum followed a conference convened in Amsterdam on the care of the live kidney donor (1, 2). There were four organ specific work groups at the Vancouver Forum: lung, liver, pancreas and intestine. Each organ work group addressed the following topics in concert and reported their findings in a plenary presentation to all participants:

Should we use living donor grafts for patients with hepatocellular carcinoma? ethical considerations†

Elizabeth A. Pomfret, J. Peter A. Lodge, Federico G. Villamil, and Mark Siegler Department of Transplantation and Hepatobiliary Diseases, Lahey Clinic Medical Center, Burlington, MA; Hepatobiliary and Transplant Unit, St. James’s University Hospital, Leeds, United Kingdom; Liver Transplantation Unit, British Hospital, Buenos Aires, Argentina; and Department of Medicine, MacLean Center for Clinical Medical Ethics, University of Chicago, Chicago, IL

Who should get a liver graft

Division of Transplantation, Box 40, Tufts Medical Center, 800 Washington Street, Boston, MA 02111, USA Department of Surgery, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK Department of Biostatistics, University of Michigan, Ann Arbor, USA Department of Hepatobiliary Surgery and Liver Transplantation, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Liver Unit, Favaloro Foundation and University, Buenos Aires, Argentina

MicroRNA Signature at the Time of Clinical HCV Recurrence Associates With Aggressive Fibrosis Progression Post-Liver Transplantation

Diagnosis and prediction of the severity of hepatitis C virus recurrence (HCVrec) after liver transplantation (LT) remain a challenge. MicroRNAs have been recently recognized as potential disease biomarkers. Archival liver biopsy samples from 43 HCV+ LT recipients were collected at clinical HCVrec time and at 3 years post‐LT. Patients were classified as progressors (P = F0/F1) or nonprogressors (NP = F3/F4) according to the severity of fibrosis on the 3‐year biopsy. Training (n = 27) and validation (n = 16) sets were defined. RNA was isolated from all biopsies at clinical HCVrec time, labeled and hybridized to miRNA‐arrays. Progressors versus nonprogressors were compared using the two‐sample t‐test. A p‐value ≤0.01 was considered significant. The ingenuity pathway analysis tool was used for microRNA and miRNA:mRNA ontology data integration. Nine microRNAs were differentially expressed between groups. A supervised cluster analysis separated samples in two well‐defined groups (progressors vs. nonprogressors). Pathway analysis associated those microRNAs with hepatitis, steatosis, fibrosis, cirrhosis and T cell‐related immune response. Data integration identified 17 genes from a previous genomic study as 9‐microRNAs signature targets. Seven microRNAs were successfully validated in the validation set using QPCR. We have identified a 9‐microRNA signature able to identify early post‐LT patients at high risk of severe HCVrec during long‐term follow‐up.

Transcriptome at the time of hepatitis C virus recurrence may predict the severity of fibrosis progression after liver transplantation

Allograft gene expression analysis may provide insights into the mechanisms involved in liver damage during hepatitis C virus recurrence (HCVrec) after orthotopic liver transplantation (OLT) and allow the identification of patients who have a higher risk of developing severe disease. Forty‐three OLT recipients with hepatitis C virus (HCV) were evaluated. Genomewide gene expression analysis was performed with formalin‐fixed, paraffin‐embedded (FFPE) liver biopsy samples obtained from 21 OLT recipients with HCV at the time of clinical HCVrec, which was defined as increased alanine aminotransferase levels and detectable HCV RNA levels in serum. Patients were classified into 3 groups according to the severity of the fibrosis in the liver biopsies at 36 months post‐OLT : group 1 (G1) for mild fibrosis (F0‐F1), group 2 for moderate fibrosis (F2), and group 3 (G3) for severe fibrosis (F3‐F4). No significant differences were observed between the groups with respect to donor age, histology during HCVrec, treated episodes of acute cellular rejection, or immunosuppression therapy. The results were validated in the remaining 22 OLT recipients with HCV using quantitative real‐time polymerase chain reaction. Fifty‐seven beadtypes showed significantly different expression (P < 0.001) between the groups during HCVrec. In G3, the gene expression of interleukin‐28RA (IL‐28RA), IL‐28, and angiotensin‐converting enzyme was up‐regulated. Samples from G1 and G3 were used to determine whether a multigenetic classifier could be derived to predict the group class. The final model included the intercept and 9 bead types. Pairwise scatter plots of these 9 bead types revealed that G1 and G3 were well separated with respect to each gene. Our analysis has demonstrated the utility of a set of molecular markers indicating HCVrec severity early after OLT. Liver Transpl 17:824‐835, 2011.

REFINE: A Randomized Trial Comparing Cyclosporine A and Tacrolimus on Fibrosis After Liver Transplantation for Hepatitis C

REFINE was a 12‐month, prospective, open‐label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL‐2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA‐treated patients (71.6%) and 52/77 tacrolimus‐treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between‐group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid‐free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus‐ and CsA‐treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy‐proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV‐induced liver fibrosis between patients treated with CsA or tacrolimus in steroid‐containing regimens, whereas CsA in steroid‐free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant.

Hepatitis C virus recurrence after liver transplantation: biomarkers of disease and fibrosis progression

End-stage liver disease due to hepatitis C virus infection (HCV) is the principal indication for liver transplantation. In the USA, over a third of available liver allografts are transplanted into recipients with chronic HCV infection. Reinfection of the graft is universal, but the impact of reinfection on short- and long-term liver function is highly variable. HCV infection in liver transplantation recipients is characterized by an accelerated fibrogenesis, with approximately a third of patients developing cirrhosis within 5 years of follow-up. HCV is associated with decreased patient and graft survival when compared with other indications of orthotopic liver transplantation. The mechanisms responsible for the accelerated liver damage in HCV-infected orthotopic liver transplantation recipients remain largely unknown.

C-reactive protein and model for end-stage liver disease score: Have we found the fifth element?

The natural history of cirrhosis varies from patient to patient, depends on a number of factors, and is largely unpredictable. The transition from the compensated phase to the decompensated phase is dictated on one hand by the loss of liver cell mass and on the other hand by the development of complications of portal hypertension. Many studies have confirmed that the Model for End-Stage Liver Disease (MELD) is highly accurate for assessing the degree of hepatic insufficiency and short-term prognosis (90 days) in patients with cirrhosis in both transplant and nontransplant settings. However, approximately 15% to 20% of candidates for liver transplantation are not well served by MELD. A few years ago, our group showed that the addition of serum sodium to the MELD formula significantly increased its efficacy. The replacement of MELD by MELD-Na will allow earlier access to liver transplantation, especially for patients with severe portal hypertension and ascites but with relatively well-preserved liver function and normal serum creatinine. Serum sodium thus became the fourth element of MELD. The transition to the decompensated stage of cirrhosis is usually a slow and gradual process evolving over months or even years. However, the natural course of cirrhosis is often complicated by acute episodes of decompensation triggered by a precipitating event. The outcome and reversibility of decompensation vary according to the nature and severity of the acute hepatic insult and according to the degree of dysfunction of extrahepatic organ systems. Recent studies have shown that in acutely ill patients with cirrhosis, systemic inflammatory response syndrome (SIRS), with or without a documented bacterial infection, is an independent predictor of survival and is also associated with the development of portal hypertension–related complications. Liver function appears not to be the main determinant of outcome in patients with cirrhosis who experience multiorgan failure. Therefore, the negative impact of systemic inflammation in this scenario may be poorly predicted by MELD. Conventional parameters for diagnosing SIRS lack sensitivity and specificity in patients with advanced cirrhosis because of hypersplenism, hyperventilation associated with encephalopathy, hyperkinetic circulation, or the use of beta-blockers. C-reactive protein (CRP) is considered a surrogate marker for acute or chronic systemic inflammation and bacterial infection, although elevated levels have been described in many other conditions, such as acute alcoholic hepatitis, malignant tumors (including hepatocellular carcinoma), tissue necrosis, and bacterial translocation. In a series of 148 consecutive patients with predominantly alcoholic cirrhosis and a Child-Pugh status B8, Cervoni et al. found that CRP was a statistically significant predictor of death [area under the receiver operating characteristic curve (AUROC), 0.63] and SIRS (AUROC, 0.73). The prognostic value of CRP was independent of SIRS, bacterial infection, and alcoholic hepatitis. Interestingly, the majority of patients with

Donor selection criteria for liver transplantation in Argentina: are current standards too rigorous?

Organ shortage is the major limitation for the growth of deceased donor liver transplant worldwide. One strategy to ameliorate this problem is to maximize the liver utilization rate. To assess predictors of liver utilization in Argentina. The national database was used to analyze transplant activity in 2010. Donor, recipient, and transplant variables were evaluated as predictors of graft utilization of number of rejected donor offers before grafting and with the occurrence of primary nonfunction (PNF) or early post‐transplant mortality (EM). Of the 582 deceased donors, 293 (50.3%) were recovered for liver transplant. Variables associated with the nonrecovery of the liver were age ≥46 years, umbilical perimeter ≥92 cm, organ procurement outside Gran Buenos Aires, AST ≥42 U/l and ALT ≥29 U/l. The median number of rejected offers before grafting was 4, and in 71 patients (25%), there were ≥13. The only independent predictor for the occurrence of PNF (3.4%) or EM (5.2%) was the recipients emergency status. During 2010 in Argentina, the liver was recovered in only half of donors. The low incidence of PNF and EM and the characteristics of the nonrecovered liver donors suggest that organ acceptance criteria should be less rigorous.

Are we still searching for the fifth element of MELD

level of CRP had the worst prognosis [7,8]. Prospective studies providing serial copeptin measurements to evaluate the potential effects on survival of variations in serum copeptin concentrations over time are still lacking. Like CRP, a persistently high level of plasma copeptin may be harmful, especially for the heart. Indeed, chronic overexpression of the V1A receptor (or persistent stimulation of these receptors) may lead to cardiac dysfunction by remodeling the myocardium via V1A receptors on cardiac myocytes [9]. Cardiac dysfunction, reflected by an altered cardiac index, predicts the development of hepatorenal syndrome, a condition associated with significantly increased mortality in cirrhotic patients [10]. Consequently, it would not be surprising that a long-standing increase in copeptin may accurately predict death. For future research, it would be interesting to investigate the effect of V1A-selective vasopressin antagonists in cirrhotic patients with high levels of copeptin (i.e., vasopressin). We wonder whether prognostic models using CRP would be as well fitted as those built with leukocyte count in the study by Solà [1]. Patients included in this latter cohort study had a complication of liver cirrhosis but did not suffer from acute on chronic liver failure (ACLF), as previously defined [3]. it would be interesting to investigate whether there is an association between copeptin levels and the risk of development of ACLF in patients admitted for acute decompensation of cirrhosis, since ACLF is the most common cause of death in patients with decompensated cirrhosis. We also suggest assessing copeptin in the ‘‘selected population” of cirrhotic patients waiting for liver transplantation, because we need to know whether copeptin may improve the efficacy of MELD for prioritizing candidates for transplantation according to the ‘‘sickest first” policy.