Valeria Descalzi

Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone

In this study, we investigated the prognostic value of serum sodium and hyponatremia (≤130 mEq/L) in 262 cirrhotic patients consecutively listed, 19 of which died (7%), 175 survived (67%), and 68 underwent liver transplantation (26%) during 3 months of follow‐up. Hyponatremia was present in 63% of patients who died, compared to 13% of those who survived (P < .001), whereas the proportion with elevated creatinine (≥1.4 mg/dL) was low and similar in both groups (10.5 vs. 3%). Prevalence of hyponatremia was higher than that of elevated serum creatinine across all model for end‐stage liver disease (MELD) categories. Using logistic regression, hyponatremia and serum sodium were significant predictors of mortality with concordance statistics (c‐statistics) .753 for hyponatremia, .784 for sodium, .894 for MELD, .905 for MELD plus hyponatremia (P = .006 vs. MELD alone), and .908 for MELD plus serum sodium (P = .026 vs. MELD alone). Risk of death across all MELD scores was higher for patients with hyponatremia than without hyponatremia. Cox regression considering data within 6 months of follow‐up yielded qualitatively similar results, with hyponatremia being a significant predictor of greater mortality risk with an odds ratio of 2.65 (P = .015). Each increase of 1 mEq/L of serum sodium level was associated with a decreased odds ratio of .95 (P = .048). Our results indicate that hyponatremia appears to be an earlier and more sensitive marker than serum creatinine to detect renal impairment and / or circulatory dysfunction in patients with advanced cirrhosis. In conclusion, addition of serum sodium to MELD identified a subgroup of patients with poor outcome in a more efficient way than MELD alone and significantly increased the efficacy of the score to predict waitlist mortality. (Liver Transpl 2005;11:336–343.)

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.

How common is delayed cyclosporine absorption following liver transplantation

The mean time to peak absorption of cyclosporine (CsA) in liver transplant patients is approximately 2 hours, but in some patients the peak occurs later. The goal of this study was, therefore, to investigate the incidence of delayed absorption in 27 de novo liver transplant recipients receiving CsA ≥10 mg/kg/day (C2 monitoring) and in 15 maintenance patients. Patients were categorized as ‘normal’ absorbers (C2 exceeding C4 and C6) or ‘delayed’ absorbers (C4 or C6 exceeding C2), and as ‘good’ (>800 ng/mL at C0, C2, C4, or C6) or ‘poor’ absorbers (C0, C2, C4 and C6 <800 ng/mL) on the day of study. Among de novo patients, 15 (56%) had ‘normal’ CsA absorption and 12 (44%) ‘delayed’ absorption. Good CsA absorption occurred in 16 patients (59%) and poor absorption in 11 (41%). The proportion of poor absorbers was similar in patients with normal (6 / 15, 40%) or delayed (5 / 12, 42%) absorption. Among the 12 delayed absorbers, 11 had peak CsA concentration at C4. Mean C0 level was significantly higher in delayed absorbers (282 ± 96 ng/mL) than in normal absorbers (185 ± 88ng/mL; P = .01). Delayed absorbers reverted to normal absorption (C2 > C4) after a median of 6 days from the day of study, and no cases of delayed absorption were found among maintenance patients. In conclusion, almost 50% of the patients had delayed CsA absorption early posttransplant; around half of these exhibited normal CsA exposure. Measurement of C4 in addition to C2 differentiates effectively between delayed and poor absorbers of CsA such that over‐ or underimmunosuppression can be avoided. (Liver Transpl 2005;11:167–173.)

Effectiveness and safety of original and generic sofosbuvir for the treatment of chronic hepatitis C: A real world study

We report the first real‐world prospective multicenter cohort study that evaluated the effectiveness and safety of original or generic sofosbuvir‐based regimens in patients with chronic hepatitis C in Latin America. The main endpoints were assessment of sustained virological response and serious adverse events rates. A total of 321 patients with chronic hepatitis C treated with the following regimens were included: sofosbuvir plus daclatasvir for 12 (n = 34) or 24 (n = 135) weeks, sofosbuvir plus daclatasvir plus ribavirin for 12 (n = 84) or 24 (n = 56) weeks, or sofosbuvir plus ribavirin for 12 (n = 8) or 24 (n = 2) weeks. Patients received either original sofosbuvir (Sovaldi®, Gilead Sciences, n = 135) or generic sofosbuvir (Probirase®, Laboratorios RICHMOND, n = 184) which were randomly assigned by the National Ministry of Health. Overall, 292 (91%) patients had cirrhosis, 136 (42%) were treatment experienced, and 240 (75%) genotype 1. The overall sustained virological response was 90% (95% CI 86‐93%); 91% (95% CI 84‐95%) in patients who received Sovaldi®, and 89% (95% CI 84‐93%) in patients who received Probirase®. Anemia was the most common adverse event and was reported in 52 (17%) patients. Bacterial infection, gastrointestinal bleeding, worsening of ascites or encephalopathy occurred in less than 5% of the patients. During the study, seven (2%) patients died, four of whom died of cirrhosis‐related complications. In summary, we observed similar sustained virological response rates than prior studies, both in patients who received Sovaldi® or Probirase®. Serious adverse events were infrequent, in line with prior studies that included patients with cirrhosis treated with protease‐inhibitor‐free regimes.

Three liver transplants after a single cadaveric procurement: Split liver transplantation plus domino liver transplantation, an infrequent but valid alternative for maximizing transplant sharing and applicability—report of the first Latin American case

The development of liver surgery and the need to overcome the shortage of cadaveric grafts have stimulated the creativity of surgeons in describing different options for using segmental liver grafts. Reduced size liver transplantation, ex vivo and in situ split liver transplantation, and living related donor liver transplantation are options that have spread since their original descriptions. In the setting of these accepted strategies, the option of performing sequential or domino liver transplantation with livers from patients with familial amyloidotic polyneuropathy (FAP) has become possible, and these patients have started to be used worldwide as whole living donors for patients who otherwise would not benefit from the current allocation system and cannot apply for a segmental adult living donor graft. The success of some of the aforementioned techniques can be currently followed via Web-based registries such as the Familial Amyloidotic Polyneuropathy World Transplant Registry, which includes 62 centers in 21 countries performing orthotopic liver transplantation with FAP donors. The need to foster maximal sharing has led to surgical innovations for further splitting FAP livers or performing split liver transplants for a pediatric recipient and an adult recipient with FAP followed by sequential or domino liver transplantation; however, only a small number of cases of this kind have been described. Therefore, we report here our experience with the first case of split transplantation plus domino transplantation in Latin America at 2 Argentinean institutions.

Characteristics of Liver Transplantation in Argentina: A Multicenter Study

INTRODUCTION There is a lack of information regarding outcomes after liver transplant in Latin America. OBJECTIVES This study sought to describe outcomes after liver transplant in adult patients from Argentina. METHODS We performed an ambispective cohort study of adult patients transplanted between June 2010 and October 2012 in 6 centers from Argentina. Only patients who survived after the first 48 hours postransplantation were included. Pretransplantation and posttransplantation data were collected. RESULTS A total of 200 patients were included in the study. Median age at time of transplant was 50 (interquartile range [IQR] 26 to 54) years. In total, 173 (86%) patients had cirrhosis, and the most frequent etiology in these patients was hepatitis C (32%). A total of 35 (17%) patients were transplanted with hepatocellular carcinoma. In patients with cirrhosis, the median Model for End-Stage Liver Disease (MELD) score at time of liver transplant was 25 (IQR 19 to 30). Median time on the waiting list for elective patients was 101 (IQR 27 to 295) days, and 3 (IQR 2 to 4) days for urgent patients. Almost 40% of the patients were readmitted during the first 6 months after liver transplant. Acute rejection occurred in 27% of the patients. Biliary and vascular complications were reported in 39 (19%) and 19 (9%) patients, respectively. Renal failure, diabetes, and dyslipidemia were present in 40 (26%), 87 (57%), and 77 (50%) at 2 years, respectively. CONCLUSIONS We believe the information contained in this article might be of value for reviewing current practices and developing local policies.

Applicability of Liver Transplantation for Patients with Acute on Chronic Liver Failure

Liver transplantation (LT) for acute on chronic liver failure (ACLF) may become the only chance to survive when other therapeutic measures fail. However, to reach a LT in this condition is difficult given its high short term mortality. Prevalence rates were reported between 24 to 34%.This data has not been described in our population Aim: to evaluate the prevalence and outcome of ACLF patients (pts) listed in our LT unit. Patients and Methods: Adults pts with chronic liver disease that were consecutive listed for LT between Jan/15 and Jun/16 were included and divided in two groups: ACLF and Non-ACLF. Age, gender, etiology of liver disease, presence of hepatocellular carcinoma, comorbid conditions, Child-Pugh and MELD, and pre and post LT outcome were compared on both groups. The chronic liver failure (CLIF) Consortium Organ Failure Score was used in the diagnosis and grading of ACLF, and the CLIF Consortium ACLF score (CLIF-C ACLF) was used to estimate probability of dying Results Prevalence of ACLF was 15%, 13 of 86 pts fulfilled ACLF criteria, 4 at the time of inclusion in the waiting list and 9 after 52 (13-360) days Precipitating events were bacterial infection (31%), gastrointestinal bleeding (15%), active alcoholism (8%), hemoperitoneum (8%) and non identified in the remaining 38%. Resolution of ACLF, access to LT or death for ACLF grade 1 (n=6) were 33%/50%/17%, for grade 2 (n=2) 0%,50%,100% and for grade 3 (n=5) 0%, 0%,100% respectively. The real waiting list mortality and the predicted by CLIF-C ACLF on ACLF pts at 28 days were 36%/42% and at 90 days 62%/56% (p=NS). Post-LT survival for non-ACLF/ACLF pts at 28, 90 and 180 days were 96%/75%, 92%/75% and 88%/75% (p=NS) Conclusions 1)Patients with ACLF grade 1 had the higher chance of resolution and / or transplantation 2) CLIF-C ACLF had a good correlation with the mortality found in this study 3) Post-LT survival was lower in pts with ACLF compared to non- ACLF, however, this difference was not statistically significant 4)More studies are required to define criteria to prioritize or reject the inclusion in the list of patients, according to the degree of ACLF

22 Years of Experience in Hepatic Re-Transplantation: Value of Predictive Survival Scores

Liver re-transplantation (re-LT) is an infrequent indication for LT, with a reported prevalence close to 10% in different reported series. Re-LT is the unique therapeutic option when graft failure occurs. Although is a high risk population with poor prognosis, a strict selection of candidates is mandatory. Aims 1) To evaluate the prevalence and outcome of re-LT at our centre, 2) To identify predictors of survival after re-LT. Patients and Methods: From 6/95 to 11/17, 977 consecutive adult liver transplantations were performed. Clinical, biochemical, and demographic variables, and survival prediction scores (Rosen modified, Markmann and UCLA) were retrospectively applied and analyzed from donors and receptors of re-LT. Statistical Analysis: Chi-square, T-Test, and Kaplan Meier. Results 57 out of 977 were re-LT (5.8 %) and 5 received a 2nd re-LT (0.5 %). Median age of re-LT was 43±14 years, 52 % were males with median time between LT and re-LT of 4.1 years. Main causes for re-LT were vascular (22%), ductopenia (19%), biliary (19%), recurrence HCV (14%), recurrence HAI (14%), and primary non-function (7%). According to priority for re-LT, in 42 patients (73%) re-LT was elective (>60 days) and urgent in 15 (27%). From the 57 re-LT patients, 23 died, with an overall, elective and urgent survival rate at 3 months, 1, 5 and 10 years of 78.9%, 73.5%, 65.2% y 55.7% coinciding with graft survival. The patients were grouped by evolution to death. There were no significant differences in age, laboratory, etiologies, HCV prevalence, transplants as urgency and early transplants. Independent predictors of mortality were cold ischemia time (CIT) > 450 minutes (p=0.019) and preoperative mechanical ventilation (p=0.007). The only one that predicted overall survival was the modified Rosen score (p=0.001). UCLA score was statistically significantly associated with 1 year mortality (p=0.001). Conclusions 1) Re-LT represents a safety option for patients with graft failure, with survival rate over 65% at 5 year post re-LT. 2) CIT and mechanical ventilation were useful predictors in our series. 3) We have validated the modified Rosen and UCLA scores. 4) A prospective multicenter validation study is necessary.

Is faster always better? A comparative study between associating liver partition and portal vein ligation for staged hepatectomy vs classic portal vein ligation for two-stage hepatectomy in rats

Background: The associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been proposed to avoid liver failure after major liver resection. We thought to define the mechanism by which ALPPS enlarges liver remnant and if it is really more effective than classic two-stage hepatectomy. Objectives: To compare if ALPPS is superior to portal vein ligation (PVL) to increase liver volume. Methods: Sprague-Dawley rats were divided in sham, ALPPS and PVL groups. Animal weight, volumetric assessment of the liver middle lobe, mitotic index, binucleate cells index, Ki-67 index and histological evaluation were done to assess liver regeneration. Results: No differences were found in liver volume after both procedures. (48, 65 ± 15 %, 43, 97 ± 13, 4 % and 155 ± 40 %; on 3, 7, 14 POD, for ALPPS and PVL) The liver volume/ animal weight ratios were similar in both groups. Ki67, binucleate cells and mitotic index were significantly higher in PVL and ALPPS compared with sham group, only on 3 postoperative day, (p=0.01), but were not different at the end of follow up (14 days). The histological liver damage score was slightly higher in ALPPS. Conclusion: Both procedures are useful to achieve increases in future remnant liver volume. There is no difference in the final volume reached; observing that the increase achieved by ALPPS is faster.