M.D. Almeida

Liver transplantation: history, outcomes and perspectives

In 1958 Francis Moore described the orthotopic liver transplantation technique in dogs. In 1963, Starzl et al. performed the first liver transplantation. In the first five liver transplantations no patient survived more than 23 days. In 1967, stimulated by Calne who used antilymphocytic serum, Starzl began a successful series of liver transplantation. Until 1977, 200 liver transplantations were performed in the world. In that period, technical problems were overcome. Roy Calne, in 1979, used the first time cyclosporine in two patients who had undergone liver transplantation. In 1989, Starzl et al. reported a series of 1,179 consecutives patients who underwent liver transplantation and reported a survival rate between one and five years of 73% and 64%, respectively. Finally, in 1990, Starzl et al. reported successful use of tacrolimus in patents undergoing liver transplantation and who had rejection despite receiving conventional immunosuppressive treatment. Liver Transplantation Program was initiated at Hospital Israelita Albert Einstein in 1990 and so far over 1,400 transplants have been done. In 2013, 102 deceased donors liver transplantations were performed. The main indications for transplantation were hepatocellular carcinoma (38%), hepatitis C virus (33.3%) and alcohol liver cirrhosis (19.6%). Of these, 36% of patients who underwent transplantation showed biological MELD score > 30. Patient and graft survival in the first year was, 82.4% and 74.8%, respectively. A major challenge in liver transplantation field is the insufficient number of donors compared with the growing demand of transplant candidates. Thus, we emphasize that appropriated donor/receptor selection, allocation and organ preservation topics should contribute to improve the number and outcomes in liver transplantation.

List and Liver Transplant Survival According to Waiting Time in Patients With Hepatocellular Carcinoma

The time that patients with hepatocellular carcinoma (HCC) can safely remain on the waiting list for liver transplantation (LT) is unknown. We investigated whether waiting time on the list impacts transplant survival of HCC candidates and transplant recipients. This is a single‐center retrospective study of 283 adults with HCC. Patients were divided in groups according to waiting‐list time. The main endpoint was survival. The median waiting time for LT was 4.9 months. The dropout rates at 3‐, 6‐, and 12‐months were 6.4%, 12.4%, and 17.7%, respectively. Mortality on the list was 4.8%, but varied depending of the time on the list. Patients who waited less than 3‐months had an inferior overall survival when compared to the other groups (p = 0.027). Prolonged time on the list significantly reduced mortality in this analysis (p = 0.02, HR = 0.28). Model for End Stage Liver Disease (MELD) score at transplantation did also independently impact overall survival (p = 0.03, HR = 1.06). MELD was the only factor that independently impacted posttransplant survival (p = 0.048, HR = 1.05). We conclude that waiting time had no relation with posttransplant survival. It is beneficial to prolong the waiting list time for HCC candidates without having a negative impact in posttransplant survival.

Liver transplant outcome: a comparison between high and low MELD score recipients

OBJECTIVE To compare low and high MELD scores and investigate whether existing renal dysfunction has an effect on transplant outcome. METHODS Data was prospectively collected among 237 liver transplants (216 patients) between March 2003 and March 2009. Patients with cirrhotic disease submitted to transplantation were divided into three groups: MELD > or = 30, MELD < 30, and hepatocellular carcinoma. Renal failure was defined as a +/- 25% decline in estimated glomerular filtration rate as observed 1 week after the transplant. Median MELD scores were 35, 21, and 13 for groups MELD > or = 30, MELD < 30, and hepatocellular carcinoma, respectively. RESULTS Recipients with MELD > or = 30 had more days in Intensive Care Unit, longer hospital stay, and received more blood product transfusions. Moreover, their renal function improved after liver transplant. All other groups presented with impairment of renal function. Mortality was similar in all groups, but renal function was the most important variable associated with morbidity and length of hospital stay. CONCLUSION High MELD score recipients had an improvement in the glomerular filtration rate after 1 week of liver transplantation.

Hepatocellular Carcinoma Recurrence Among Liver Transplant Recipients Within the Milan Criteria

INTRODUCTION Orthotopic liver transplantation (OLT) is an excellent option for patients with unresectable hepatocellular carcinoma (HCC) within the Milan criteria. Recurrence of HCC has a severe impact on post-OLT survival. In this study, we performed an analysis of post-OLT recurrence pattern of HCC. METHODS The prospective cohort of OLT patients included those with unresectable HCC within the Milan criteria, and those beyond the Milan criteria who were downstaged with transcatheter arterial embolization until they achieved the Milan criteria. RESULTS Between May 2006 and May 2011, we performed 130 OLT for unresectable HCC within the Milan Criteria among whom 9 patients (6.9%) experienced tumor recurrence. Two (22.2%) had undergone preoperative downstaging. At the time of OLT, mean serum alpha-fetoprotein levels were 623.8 ± 682.9 ng/mL. The liver explants showed 7 (77.8%) subjects were within the Milan criteria, with an average 2.6 ± 2.2 tumors, most of which (89%) were moderately differentiated. Microvascular and macrovascular invasion were observed in 5 (55.6%) and 2 (22.2%) cases, respectively. Liver explants were beyond the Milan criteria in both patients who had undergone preoperative downstaging. Recurrence occurred 23.1 ± 14.3 months after OLT, having been detected in the liver (n = 3; 33.3%), lung (n = 3; 33.3%), brain, peritoneum, and adrenal gland (n = 1 each; 11.1% each). Mean survival after detection of recurrence was 137.4 ± 96.4 days. CONCLUSIONS Despite strict candidate selection criteria, HCC recurrence may occur after OLT, bearing a significant impact on posttransplant outcomes to optimize results requires refinements in candidate selection, as well as well-defined cost-effective post-OLT surveillance protocols.

Liver transplant outcome

OBJECTIVE To compare low and high MELD scores and investigate whether existing renal dysfunction has an effect on transplant outcome. METHODS Data was prospectively collected among 237 liver transplants (216 patients) between March 2003 and March 2009. Patients with cirrhotic disease submitted to transplantation were divided into three groups: MELD > or = 30, MELD < 30, and hepatocellular carcinoma. Renal failure was defined as a +/- 25% decline in estimated glomerular filtration rate as observed 1 week after the transplant. Median MELD scores were 35, 21, and 13 for groups MELD > or = 30, MELD < 30, and hepatocellular carcinoma, respectively. RESULTS Recipients with MELD > or = 30 had more days in Intensive Care Unit, longer hospital stay, and received more blood product transfusions. Moreover, their renal function improved after liver transplant. All other groups presented with impairment of renal function. Mortality was similar in all groups, but renal function was the most important variable associated with morbidity and length of hospital stay. CONCLUSION High MELD score recipients had an improvement in the glomerular filtration rate after 1 week of liver transplantation.

Response to Transarterial Chemoembolization in Candidates With Hepatocellular Carcinoma Within Milan Criteria Does not Predict Post-Transplant Disease-Free Survival

INTRODUCTION Few groups have studied the impact of pretransplant transarterial chemoembolization (TACE) in the outcomes of liver transplant recipients with hepatocellular carcinoma (HCC). We verified whether response to TACE in HCC candidates impacts post-transplant disease-free survival. METHODS This a single center retrospective study of patients who underwent liver transplantation from 2006-2013. Included were those transplanted due to HCC within the Milan criteria who were treated with TACE in the pre-transplant period. Response to TACE followed the modified RECIST (mRECIST) criteria. Disease free-survival was the main endpoint of the study. RESULTS We included 187 patients in this study. The population had an average age of 57.5 years, predominantly formed by men (82.5%), with an average IMC of 26.7, MELD of 13, with viral hepatitis as main cause of liver disease. Average waiting time was 253 days and follow-up was 27.3 months. Based on response to TACE, 3-year disease-free survival was 84.1% for those with complete response to TACE, 84.1% for those with partial response to TACE, 85.7% for those with stable disease and 100% for patients with progressive disease. Multivariate analysis did not identify response to TACE as a predictor of disease-free post-transplant survival. CONCLUSIONS Response to TACE in candidates with HCC within Milan criteria does not predict post-transplant disease-free survival.

Intestinal and multivisceral transplantation

Intestinal transplantation has shown exceptional growth over the past 10 years. At the end of the 1990’s, intestinal transplantation moved out of the experimental realm to become a routine practice in treating patients with severe complications related to total parenteral nutrition and intestinal failure. In the last years, several centers reported an increasing improvement in survival outcomes (about 80%), during the first 12 months after surgery, but long-term survival is still a challenge. Several advances led to clinical application of transplants. Immunosuppression involved in intestinal and multivisceral transplantation was the biggest gain for this procedure in the past decade due to tacrolimus, and new inducing drugs, mono- and polyclonal anti-lymphocyte antibodies. Despite the advancement of rigid immunosuppression protocols, rejection is still very frequent in the first 12 months, and can result in long-term graft loss. The future of intestinal transplantation and multivisceral transplantation appears promising. The major challenge is early recognition of acute rejection in order to prevent graft loss, opportunistic infections associated to complications, post-transplant lymphoproliferative disease and graft versus host disease; and consequently, improve results in the long run.

Results of Retransplantation for Primary Nonfunction in a Single Center

INTRODUCTION Early graft dysfunction has a negative impact on allograft and patient survivals, evolving to retransplantation or death in the majority of cases. The outcome of a second liver transplant is usually worse than the first procedure. Considering the increasing number of recipients on the waiting list, and the discrepancy between the number of accessible donors and recipients, we sought to analyze the results of retransplantation at our institution and at those within the State of Sao Paulo. METHODS We reviewed the data of 419 deceased donor transplants on 367 patients from June 2005 to April 2010. Twenty-three patients underwent retransplantation due primary nonfunction (PNF) or early graft dysfunction. The following variables were studied: age, gender, disease that lead to the first transplant, Model for End-Stage Liver Disease (MELD) score on the day before the retransplantation, intensive care unit (ICU) length of stay, and duration of orotracheal intubation (OTI). We compared our patient survival at 30 days and 1 year with that of other patients undergoing retransplantation due to PNF in the Sao Paulo State during the same period. RESULTS The majority of patients were females (60.87%), with a mean age of 44.6 years. The etiology that led to our first transplantation was cirrhosis due to hepatitis C virus (HCV; n = 6), followed by acute liver failure, (n = 5). The average of ICU stay was 15.08 days (range, 5-45). The mean MELD score was 34.43 (range, 19-50). The survival was 73.92% and 60.78% at 30 days and 1 year postretransplantation, respectively, whereas for São Paulo State, it was 63.04% and 51.63%, respectively.

Predictors of renal function recovery among patients undergoing renal replacement therapy following orthotopic liver transplantation

Renal dysfunction frequently occurs during the periods preceding and following orthotopic liver transplantation (OLT), and in many cases, renal replacement therapy (RRT) is required. Information regarding the duration of RRT and the rate of kidney function recovery after OLT is crucial for transplant program management. We evaluated a sample of 155 stable patients undergoing post-intensive care hemodialysis (HD) from a patient population of 908 adults who underwent OLT. We investigated the average time to renal function recovery (duration of RRT required) and determined the risk factors for remaining on dialysis > 90 days after OLT. Log-rank tests were used for univariate analysis, and Cox proportional hazards models were used to identify factors associated with the risk of remaining on HD. The results of our analysis showed that of the 155 patients, 28% had pre-OLT diabetes mellitus, 21% had pre-OLT hypertension, and 40% had viral hepatitis. Among the patients, the median MELD (Model for End-Stage Liver Disease) score was 27 (interquartile range [IQR] 22-35). When they were listed for liver transplantation, 32% of the patients had serum creatinine (Scr) levels > 1.5 mg/dL or were on HD, and 50% had serum creatinine (Scr) levels > 1.5 mg/dL or were on HD at the time of OLT. Of the transplanted patients, 25% underwent pre-OLT intermittent HD, and 14% and 41% underwent continuous renal replacement therapy (CRRT) pre-OLT and post-OLT, respectively. At 90 days post-OLT, 118 (76%) patients had been taken off dialysis, and 16 (10%) patients had died while undergoing HD. The median recovery time of these post-OLT patients was 33 (IQR 27–39) days. In the multivariate analysis, fulminant hepatic failure as the cause of liver disease (p<0.001), the absence of pre-OLT hypertension (p = 0.016), a lower intraoperative fresh-frozen plasma (FFP) transfusion volume (p = 0.019) and not undergoing pre-OLT intermittent HD (p = 0.032) were associated with performing RRT for less than 90 days. Therefore, a high proportion of OLT patients showed improved renal function after OLT, and those who were diagnosed with fulminant hepatic failure, had no pre-OLT hypertension, received a lower transfused volume of intraoperative FFP and did not undergo pre-OLT intermittent HD had a higher probability of recovery.

Time is a crucial factor for the use of oncological treatment for post-transplantation recurrence of hepatocellular carcinoma

Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: clinical patterns and outcome variables. Eur J Surg Oncol 2010;36:275–280. [7] Shin WY, Suh KS, Lee HW, Kim J, Kim T, Yi NJ, et al. Prognostic factors affecting survival after recurrence in adult living donor liver transplantation for hepatocellular carcinoma. Liver Transpl 2010;16:678–684. Guilherme Felga⇑ Paolo Rogerio Salvalaggio Marcelo Bruno de Rezende Marcio Dias de Almeida Liver Transplantation Unit – Hospital Israelita Albert Einstein, Sao Paulo, Brazil ⇑Corresponding author. Tel.: +55 11 981225832 E-mail address: gfelga@einstein.br Letters to the Editor