Diagnostic Accuracy of Transient Elastography for Detecting Liver Fibrosis After Liver Trannsplantation: A Specific Cut-Off Value Is Really Needed?

INTRODUCTION: Liver transplant recipients often perform liver biopsy (LB), specially in the context of potentially recurring diseases, such as hepatitis C infection. However, the LB has risks of complications, despite being the gold standard. Transient elastography (TE) is a noninvasive method comparable to the LB to evaluate liver fibrosis in various settings, but its accuracy among transplant recipients is not fully understood. OBJECTIVE: To determine the accuracy of TE in liver transplant recipients compared with LB to successfully predict liver fibrosis. PATIENTS AND METHODS: Patients who underwent liver transplantation at Hospital Israelita Albert Einstein from 2010 to 2012 and presented with LB indication were also subjected to TE at the time of LB. The medium value of ten successful measurements was kept as a representative of the liver stiffness. The definition of cut-off points was made to ensure specificity of ≥90 % for all fibrosis stages (F0-F4). RESULTS: LB was performed in 267 patients. TE was not analyzed in only 8 (3 %) due to an elevated body mass index. The optimal liver stiffness cut-off value and diagnostic performance were 8.1 kPa for F ≥ 1, 12.3 kPa for F ≥ 2, 15.1 for F ≥ 3, and 16.7 for F = 4 for all patients and were 8.1 kPa for F ≥ 1, 12.3 kPa for F ≥ 2, 16.5 for F ≥ 3, and 17.6 for F = 4 for patients with hepatitis C. CONCLUSIONS: TE demonstrated good performance in defining cut-off points for fibrosis on liver histology observed in transplant recipients. The TE can be considered an alternative to LB in post-liver transplantation.

Time of Dropout From the Liver Transplant List in Patients With Hepatocellular Carcinoma: Clinical Behavior According to Tumor Characteristics and Severity of Liver Disease.

BACKGROUND: Prolonged time on the waiting list affects post-transplant survival of patients with hepatocellular carcinoma (HCC). However, it is not yet known which patients will be at higher risk for early dropout from the list. We investigate specific risk factors for early waiting list dropout in patients with HCC. METHODS: This was a single-center, intention-to-treat analysis of adults with HCC, within the Milan criteria, from July 2006 through September 2013. Patients were divided into groups according to waiting list time. The main end point was dropout from the list. RESULTS: The dropout rates of the study cohort at 3, 6, and 12-months were 6.4%, 12.4%, and 17.7%, respectively. Patients who dropped out from the list tended to be older, with blood types A and O, and with higher Child-Pugh and Model for End-Stage Liver Disease (MELD) scores. They also had larger nodules, responded poorly to trans-arterial chemo-embolization (TACE), and had a higher alpha-fetoprotein. Those with blood types B and AB appeared to be protected for dropout (odds ratio [OR] = 0.21, P = .02). Patients who responded to TACE were also protected (OR = 0.22, P < .001). When we looked into time to dropout, the only baseline characteristic that stood out was a higher MELD score (13 for those dropping out up to 90 days vs 10 for those dropping out after 180 days, P = .0025). CONCLUSIONS: We conclude that patients who drop out early from the list are primarily driven by the severity of liver disease. Patients who had progressive HCC had a high tumor load and poor response to loco-regional therapies, dropping out from the list after 180 days of inclusion.

Right Accessory Hepatic Artery Arising From Celiac Trunk-Case Report of a Variation that Must Be Looked for During Multiorgan Procurement.

Knowledge of the anatomy of the hepatic artery and its variations is important to hepatobiliary and liver transplant surgeons and interventional radiologists. We report a rare anatomic variation of liver hepatic arterial supply: a right accessory hepatic artery arising directly from the celiac trunk and observed at the time of multiorgan procurement. The anatomic variation described in this case occurs in up to 2% of cases and their knowledge is essential to avoid injuries during multiorgan procurement that could require multiple anastomoses or lead to inadvertent vessel injury. This variation is very rarely reported in the medical literature. We document successful deceased-donor liver transplantation with a graft that had an accessory right accessory hepatic artery from the celiac trunk.

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.

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.

Addressing geographic disparities in liver transplantation through redistricting.

Severe geographic disparities exist in liver transplantation; for patients with comparable disease severity, 90-day transplant rates range from 18% to 86% and death rates range from 14% to 82% across donation service areas (DSAs). Broader sharing has been proposed to resolve geographic inequity; however, we hypothesized that the efficacy of broader sharing depends on the geographic partitions used. To determine the potential impact of redistricting on geographic disparity in disease severity at transplantation, we combined existing DSAs into novel regions using mathematical redistricting optimization. Optimized maps and current maps were evaluated using the Liver Simulated Allocation Model. Primary analysis was based on 6700 deceased donors, 28 063 liver transplant candidates, and 242 727 Model of End-Stage Liver Disease (MELD) changes in 2010. Fully regional sharing within the current regional map would paradoxically worsen geographic disparity (variance in MELD at transplantation increases from 11.2 to 13.5, p = 0.021), although it would decrease waitlist deaths (from 1368 to 1329, p = 0.002). In contrast, regional sharing within an optimized map would significantly reduce geographic disparity (to 7.0, p = 0.002) while achieving a larger decrease in waitlist deaths (to 1307, p = 0.002). Redistricting optimization, but not broader sharing alone, would reduce geographic disparity in allocation of livers for transplant across the United States.

Testing liver allocation in São Paulo, Brazil: the relationship of model for end-stage liver disease implementation with a reduction in waiting-list mortality.

INTRODUCTION: In 2006, the model for end-stage liver disease (MELD) was launched as a new liver allocation system in Sao Paulo, Brazil. We designed this study to assess the results of the new allocation policy on waiting list mortality. METHODS: We reviewed the state of Sao Paulo liver transplant database from July 2003 through July 2009. Patients were divided in those who were transplanted before (pre-MELD group) and those who were transplanted after (post-MELD group) the implementation of the MELD system. Included were adult liver transplant candidates. Waiting list mortality was the primary endpoint. RESULTS: The unadjusted death rate in patients on the waiting list decreased significantly after the implementation of the MELD system (from 91.2 to 33.5/1000 patients/year, P < .0001). Multivariate analysis has shown a significant drop of the risk of waiting list death for post-MELD patients (odds ration 0.34, P < .0001). CONCLUSION: There was a reduction in waiting time and list mortality after the implementation of the MELD system in Brazil. Patients listed in the post-MELD era had a significant reduction of death risk on the waiting list. Future studies should assess posttransplant outcomes.

Increasing the donor pool reduces the severity of liver disease: lessons learned from São Paulo, Brazil.

INTRODUCTION: A new liver allocation system driven by the model for end-stage liver disease (MELD) score was implemented in Brazil in 2006. In association with the new allocation policy, there was a concomitant expansion of the number of donors. We designed this study to assess whether a potential expansion of the donor pool with these educational campaigns had reduced the severity of liver disease at transplantation. METHODS: We retrospectively reviewed the state of São Paulo liver transplant database from July 2003 through July 2009. Patients were divided into groups: those who were transplanted before (pre-MELD group) and those who were transplanted after (post-MELD group) the implementation of the MELD system. The number of transplantations and the severity of liver disease were the endpoints of the study. RESULTS: There has been a significant shift towards an older donor population, mainly those who are dying of cerebrovascular accidents. The average MELD score has changed over time. Approximately one quarter of the patients have been transplanted with a MELD score of more than 30 in the post-MELD era. However, this number has decreased over the past 3 years (P = .012). Currently, it has been possible to transplant patients with a MELD score from 25 to 30. The number of transplantations due to hepatocarcinoma (HCC) has increased 8-fold. CONCLUSION: An aggressive educational campaign has successfully expanded the donor pool with a concomitant yearly reduction of the average MELD score at the time of transplantation. Patients with HCC have been benefited tremendously with the new allocation system.

Liver grafts procured by other transplant teams do not affect posttransplantation outcomes.

BACKGROUND: Transplant surgeons have one the riskiest jobs in medicine. Multiple reports have described fatalities involving transplant team members who were traveling to recover organs for transplantation. There are few initiatives to use allografts recovered by local teams. We tested the impact of local organ procurement on posttransplantation survival. METHODS: This single-center retrospective study included primary deceased-donor liver grafts transplanted under the Model for End-stage Liver Disease system. Multivariate analysis was performed to evaluate whether liver allografts procured outside of the organ procurement organization (OPO) region were related to allograft loss. We also studied posttransplantation survival according to local procurement. RESULTS: There were 271 transplantations performed with local donors, 19 from other states, and 54 from within our state but outside of our OPO. Recipient demographic data were similar among the groups. There were more male (P = .007), slim (P = .01), and younger (P = .008) donors among allografts from other states (national group). Local or regional donors had brain death more often related to cerebrovascular accidents. National donors had brain death related to trauma (P = .01). Multivariate analysis confirmed that local organ retrieval was not related to posttransplantation survival. Kaplan-Meier curves showed no difference in patient and graft survivals among the groups. CONCLUSIONS: Local procurement did not affect posttransplantation survival. Liver allografts procured by other teams showed equivalent posttransplantation outcomes. Policies that stimulate the training of local teams to procure liver allografts for distant transplant centers should be launched to increase job safety for transplant surgeons.

Clinical profile and liver explant findings in patients with and without pretransplant downstaging for hepatocellular carcinoma.

INTRODUCTION: Since August 2010, The Brazilian National Transplantation System has allowed performance of liver transplantation (OLT) for patients with hepatocellular carcinoma (HCC) beyond the Milan criteria (MC) who have been successfully treated with preoperative downstaging (DS). Herein we sought to compare the clinical profiles and liver explant findings among patients with versus without preoperative DS. METHODOLOGY: Prospective cohort of patients with HCC within and beyond the MC undergoing OLT. Patients were considered for DS if they were beyond the MC without evidence of vascular invasion or extrahepatic disease. Transcatheter arterial chemoembolization was used for DS, which was considered to be successful if the MC were achieved at any moment during the follow-up. RESULTS: Between May 2006 and May 2010, we performed 130 OLTs in HCC patients, among whom 10 received preoperative DS. Both groups were comparable for gender, age, viral etiology, serum levels of alpha fetoprotein, and Child-Pugh and Model for End-Stage Liver Disease (MELD) scores (P > .05). The liver explants were within the MC in 80% of patients with preoperative DS and 90% of those without preoperative DS. They were comparable for the number of HCC nodules, total tumor size, histologic grade, and presence of microvascular invasion. Patients with pretransplant DS showed larger HCC nodules (33.3 ± 9.65 vs 26.3 ± 9.62 mm; P .029) and more frequent macrovascular invasion (1 vs 1 patient, P = .024). CONCLUSION: Preoperative DS for unresectable HCC may provide a curative treatment for patients who would otherwise be candidates for palliative therapy only. The baseline characteristics and liver explant findings were similar in both groups. We have yet to determine whether the differences observed regarding the size of the largest nodule and the higher frequency of macrovascular invasion have an impact on outcome.

Early allograft dysfunction and liver transplant outcomes: a single center retrospective study.

BACKGROUND: Early allograft dysfunction (EAD) had been related to poor transplant outcomes during the early years of liver transplantation. We sought to determine the incidence of EAD at our unit and to evaluate its impact on posttransplant outcomes. METHODS: This single-center retrospective study included primary deceased donor liver grafts transplanted under the model for end-stage liver disease system. EAD was defined as a peak values of aminotransferase >2000 IU/mL during the first week or an international normalized ratio of ≥1.6 and/or bilirubin ≥10 mg/dL at day 7. The main endpoints were patient and graft survivals. RESULTS: Patients with versus without EAD showed similar recipient characteristics. Donors who experienced EAD who comprises 56% of recipients were heavier with larger body mass indices. EAD was an independent risk factor for allograft loss. Most retransplants were performed early due to nonfunction. The primary nonfunction rate among subjects with versus without EAD were 7% and 12% respectively (P < .05). Patient survival among those with EAD was 87.4%, while without EAD it was 90% (P = NS) with graft survivals of 81.4% and 88.7% respectively (P < .05). CONCLUSION: Patients with EAD show a significantly higher risk for allograft loss, but with a comparable survival after transplantation. Despite their worse outcomes, it seems that not all of these recipients behave equally.

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.

MELD Exceptions and Rates of Waiting List Outcomes.

Model for End-stage Liver Disease (MELD)-based allocation of deceased donor livers allows exceptions for patients whose score may not reflect their true mortality risk. We hypothesized that organ procurement organizations (OPOs) may differ in exception practices, use of exceptions may be increasing over time, and exception patients may be advantaged relative to other patients. We analyzed longitudinal MELD score, exception and outcome in 88 981 adult liver candidates as reported to the United Network for Organ Sharing from 2002 to 2010. Proportion of patients receiving an HCC exception was 0-21.4% at the OPO-level and 11.9-18.8% at the region level; proportion receiving an exception for other conditions was 0.0%-13.1% (OPO-level) and 3.7-9.5 (region-level). Hepatocellular carcinoma (HCC) exceptions rose over time (10.5% in 2002 vs. 15.5% in 2008, HR = 1.09 per year, p<0.001) as did other exceptions (7.0% in 2002 vs. 13.5% in 2008, HR = 1.11, p<0.001). In the most recent era of HCC point assignment (since April 2005), both HCC and other exceptions were associated with decreased risk of waitlist mortality compared to nonexception patients with equivalent listing priority (multinomial logistic regression odds ratio [OR] = 0.47 for HCC, OR = 0.43 for other, p<0.001) and increased odds of transplant (OR = 1.65 for HCC, OR = 1.33 for other, p<0.001). Policy advantages patients with MELD exceptions; differing rates of exceptions by OPO may create, or reflect, geographic inequity.

The economic implications of broader sharing of liver allografts.

Liver transplantation has evolved over the past four decades into the most effective method to treat end-stage liver failure and one of the most expensive medical technologies available. Accurate understanding of the financial implication of recipient severity of illness is crucial to assessing the economic impact of allocation policies. A novel database of linked clinical data from the Organ Procurement and Transplantation Network with cost accounting data from the University HealthSystem Consortium was used to analyze liver transplant costs for 15,813 liver transplants. This data was then utilized to consider the economic impact of alternative allocation systems designed to increase sharing of liver allografts using simulation results. Transplant costs were strongly associated with recipient severity of illness as assessed by the MELD score (p < 0.0001); however, this relationship was not linear. Simulation analysis of the reallocation of livers from low MELD patients to high MELD using a two-tiered regional sharing approach (MELD 15/25) resulted in 88 fewer deaths annually at estimated cost of $17,056 per quality-adjusted life-year saved. The results suggest that broader sharing of liver allografts offers a cost-effective strategy to reduce the mortality from end stage liver disease.

Transplant outcomes and economic costs associated with patient noncompliance to immunosuppression.

We describe factors associated with immunosuppression compliance after kidney transplantation and examine relationships between compliance with allograft outcomes and costs. Medicare claims for immunosuppression in 15 525 renal transplant recipients with at least 1 year of graft function were used to calculate compliance as medication possession ratio. Compliance was categorized by quartiles as poor, fair, good and excellent. We modeled adjusted associations of clinical factors with the likelihood of persistent compliance by multiple logistic regressions (aOR), and estimated associations of compliance with subsequent graft and patient survival with Cox proportional hazards (aHR). Adolescent recipients aged 19-24 years were more likely to be persistently noncompliant compared to patients aged 24-44 years (aOR 1.49 [1.06-2.10]). Poor (aHR 1.80 [1.52-2.13]) and fair (aHR 1.63[1.37-1.93]) compliant recipients were associated with increased risks of allograft loss compared to the excellent compliant recipients. Persistent low compliance was associated with a $12 840 increase in individual 3-year medical costs. Immunosuppression medication possession ratios indicative of less than the highest quartile of compliance predicted increased risk of graft loss and elevated costs. These findings suggest that interventions to improve medication compliance among kidney transplant recipients should emphasize the benefits of maximal compliance, rather than discourage low compliance.

Predictive ability of pretransplant comorbidities to predict long-term graft loss and death.

Whether to include additional comorbidities beyond diabetes in future kidney allocation schemes is controversial. We investigated the predictive ability of multiple pretransplant comorbidities for graft and patient survival. We included first-kidney transplant deceased donor recipients if Medicare was the primary payer for at least one year pretransplant. We extracted pretransplant comorbidities from Medicare claims with the Clinical Classifications Software (CCS), Charlson and Elixhauser comorbidities and used Cox regressions for graft loss, death with function (DWF) and death. Four models were compared: (1) Organ Procurement Transplant Network (OPTN) recipient and donor factors, (2) OPTN + CCS, (3) OPTN + Charlson and (4) OPTN + Elixhauser. Patients were censored at 9 years or loss to follow-up. Predictive performance was evaluated with the c-statistic. We examined 25 270 transplants between 1995 and 2002. For graft loss, the predictive value of all models was statistically and practically similar (Model 1: 0.61 [0.60 0.62], Model 2: 0.63 [0.62 0.64], Models 3 and 4: 0.62 [0.61 0.63]). For DWF and death, performance improved to 0.70 and was slightly better with the CCS. Pretransplant comorbidities derived from administrative claims did not identify factors not collected on OPTN that had a significant impact on graft outcome predictions. This has important implications for the revisions to the kidney allocation scheme.

Association of lower costs of pulsatile machine perfusion in renal transplantation from expanded criteria donors.

Pulsatile machine perfusion (PMP) has been shown to reduce delayed graft function (DGF) in expanded criteria donor (ECD) kidneys. Here, we investigate whether there is a cost benefit associated with PMP utilization in ECD kidney transplants. We analyzed United States Renal Data System (USRDS) data describing Medicare-insured ECD kidney transplant recipients in 1995-2004 (N = 5840). We examined total Medicare payments for transplant hospitalization and annually for 3 years posttransplant according to PMP utilization. After adjusting for other recipient, donor and transplant factors, PMP utilization was associated with a $2130 reduction (p = 0.007) in hospitalization costs. PMP utilization was also associated with lower DGF risk (p < 0.0001). PMP utilization did not predict differences in rejection, graft survival, patient survival, or costs at 1, 2 and 3 years posttransplant. PMP utilization is correlated with lower costs for the transplant hospitalization, which is likely due to the associated reduction in DGF among recipients of PMP kidneys. However, there is no difference in long-term Medicare costs for ECD recipients by PMP utilization. A prospective trial is necessary as it will help determine if the associations seen here are due to PMP utilization and not differences in the population studied.

Patient and graft survival implications of simultaneous pancreas kidney transplantation from old donors.

We investigated graft and patient survival implications of simultaneous pancreas kidney (SPK) transplant from old donors. Data describing patients with type 1 diabetes mellitus listed for an SPK transplant from 1994 to 2005 were drawn from Organ Procurement and Transplant Network registries. Allograft survival, patient survival and long-term survival expectations among SPK recipients from young (age <45 years) and old (age >/=45 years) donors were modeled by multivariate regression. We also examined predictors of reduced early access to young donor transplants. Of 16 496 eligible SPK candidates, 8850 patients (53.6%) received an SPK transplant and 776 (8.8%) of these transplants were from old donors. Reasonable 5-year, death-censored kidney (77.8 %) and pancreas (71.3%) survivals were achieved with old donors. SPK transplantation from both young and old donors predicted lower mortality compared to continued waiting. An additional expected wait of 1.5 years for a young donor equalized long-term survival expectations to that achieved with use of old donors. Early allocation of young donor transplants declined in the more recent era and varied by region, candidate age, blood type and sensitization. We conclude that old SPK donors should be considered for patients with decreased access to young donor transplants. Prospective evaluation of this practice is needed.