The OPTN Deceased Donor Potential Study: Implications for Policy and Practice.

The Organ Procurement and Transplantation Network (OPTN) Deceased Donor Potential Study, funded by the Health Resources and Services Administration, characterized the current pool of potential deceased donors and estimated changes through 2020. The goal was to inform policy development and suggest practice changes designed to increase the number of donors and organ transplants. Donor estimates used filtering methodologies applied to datasets from the OPTN, the National Center for Health Statistics, and the Agency for Healthcare Research and Quality and used these estimates with the number of actual donors to estimate the potential donor pool through 2020. Projected growth of the donor pool was 0.5% per year through 2020. Potential donor estimates suggested unrealized donor potential across all demographic groups, with the most significant unrealized potential (70%) in the 50-75-year-old age group and potential Donation after Circulatory Death (DCD) donors. Actual transplants that may be realized from potential donors in these categories are constrained by confounding medical comorbidities not identified in administrative databases and by limiting utilization practices for organs from DCD donors. Policy, regulatory, and practice changes encouraging organ procurement and transplantation of a broader population of potential donors may be required to increase transplant numbers in the United States.

Photodynamic therapy provides local control of cholangiocarcinoma in patients awaiting liver transplantation.

Many transplant centers use endoscopically directed brachytherapy to provide locoregional control in patients with otherwise incurable cholangiocarcinoma (CCA) who are awaiting liver transplantation (LT). The use of endoscopic retrograde cholangiopancreatography (ERCP)-directed photodynamic therapy (PDT) as an alternative to brachytherapy for providing locoregional control in this patient population has not been studied. The aim of this study was to report on our initial experience using ERCP-directed PDT to provide local control in patients with unresectable CCA who were awaiting LT. Patients with unresectable CCA who underwent protocol-driven neoadjuvant chemoradiation and ERCP-directed PDT with the intent of undergoing LT were reviewed. Four patients with confirmed or suspected CCA met the inclusion criteria for protocol LT. All four patients (100%) successfully underwent ERCP-directed PDT. All patients had chemoradiation dose delays, and two patients had recurrent cholangitis despite PDT. None of these patients had progressive locoregional disease or distant metastasis following PDT. All four patients (100%) underwent LT. Intention-to-treat disease-free survival was 75% at mean follow-up of 28.1 months. In summary, ERCP-directed PDT is a reasonably well tolerated and safe procedure that may have benefit by maintaining locoregional tumor control in patients with CCA who are awaiting LT.

Outcomes of living and deceased donor liver transplant recipients with hepatocellular carcinoma: results of the A2ALL cohort.

Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. In the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, patients with HCC and an LDLT or deceased donor liver transplant (DDLT) for which at least one potential living donor had been evaluated were compared for recurrence and posttransplant mortality rates. Mortality from date of evaluation of each recipient's first potential living donor was also analyzed. Unadjusted 5-year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p = 0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p = 0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five-year posttransplant survival was similar in LDLT and DDLT recipients from time of transplant (HR = 1.32; p = 0.27) and from date of LDLT evaluation (HR = 0.73; p = 0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pretransplant HCC management and waiting time.

Regional variability in symptom-based MELD exceptions: a response to organ shortage?

MELD (model for end-stage liver disease) exception awards affect the liver allocation process. Award rates of specific nonhepatocellular carcinoma exceptions, termed symptom-based exceptions (SBE), differ across UNOS regions. We aimed to characterize the regional variability in SBE awards and examine predictive factors for receiving a SBE in the MELD era. The OPTN liver transplant and waiting list dataset was analyzed for waiting list registrants during the MELD allocation on February 27, 2002, until November 22, 2006. Competing risks proportional hazards regression analysis was used to examine predictors for receiving a SBE in 39 169 registrants. The hazard ratios for receiving a SBE differed significantly across regions when adjusted for multiple variables including age, gender, ethnicity, physiologic MELD score, blood group, functional status, etiology of liver disease, insurer and education level. Utilization of SBE is highly significantly variable across UNOS regions, and does not correlate with organ availability as estimated by the regional mean physiologic MELD score at transplantation. Patients with Medicaid as their primary payer have a lower likelihood of receiving a SBE award, while patients with cryptogenic/NASH cirrhosis or cholestatic liver disease have a higher likelihood of receiving a SBE. Reasons for these regional and demographic disparities deserve further investigation.

Database comparison of the adult-to-adult living donor liver transplantation cohort study (A2ALL) and the SRTR U.S. Transplant Registry.

Data submitted by transplant programs to the Organ Procurement and Transplantation Network (OPTN) are used by the Scientific Registry of Transplant Recipients (SRTR) for policy development, performance evaluation and research. This study compared OPTN/SRTR data with data extracted from medical records by research coordinators from the nine-center A2ALL study. A2ALL data were collected independently of OPTN data submission (48 data elements among 785 liver transplant candidates/recipients; 12 data elements among 386 donors). At least 90% agreement occurred between OPTN/SRTR and A2ALL for 11/29 baseline recipient elements, 4/19 recipient transplant or follow-up elements and 6/12 donor elements. For the remaining recipient and donor elements, >10% of values were missing in OPTN/SRTR but present in A2ALL, confirming that missing data were largely avoidable. Other than variables required for allocation, the percentage missing varied widely by center. These findings support an expanded focus on data quality control by OPTN/SRTR for a broader variable set than those used for allocation. Center-specific monitoring of missing values could substantially improve the data.

Virologic and clinical outcomes of hepatitis B virus infection in HIV-HBV coinfected transplant recipients.

Liver transplantation (LT) is the treatment of choice for end-stage liver disease, but is controversial in patients with human immunodeficiency virus (HIV) infection. Using a prospective cohort of HIV-hepatitis B virus (HBV) coinfected patients transplanted between 2001-2007; outcomes including survival and HBV clinical recurrence were determined. Twenty-two coinfected patients underwent LT; 45% had detectable HBV DNA pre-LT and 72% were receiving anti-HBV drugs with efficacy against lamivudine-resistant HBV. Post-LT, all patients received hepatitis B immune globulin (HBIG) plus nucleos(t)ide analogues and remained HBsAg negative without clinical evidence of HBV recurrence, with a median follow-up 3.5 years. Low-level HBV viremia (median 108 IU/mL, range 9-789) was intermittently detected in 7/13 but not associated with HBsAg detection or ALT elevation. Compared with 20 HBV monoinfected patients on similar HBV prophylaxis and median follow-up of 4.0 years, patient and graft survival were similar: 100% versus 85% in HBV mono- versus coinfected patients (p = 0.08, log rank test). LT is effective for HIV-HBV coinfected patients with complications of cirrhosis, including those who are HBV DNA positive at the time of LT. Combination HBIG and antivirals is effective as prophylaxis with no clinical evidence of HBV recurrence but low-level HBV DNA is detectable in approximately 50% of recipients.

Fully covered self-expandable metallic stents in the management of complex biliary leaks: preliminary data - a case series.

Techniques for management of bile leaks include biliary sphincterotomy and stenting. Partially covered self-expandable metallic stents have been used in complex bile leaks, but they are associated with migration and hyperplasia. A fully covered self-expandable metallic stent (CSEMS) with anchoring fins might be effective in treating bile leaks without these complications. The aim of this study was to investigate the safety and efficacy of temporary placement of a CSEMS for resolving complex bile leaks. Thirteen patients with complex bile leaks underwent endoscopic retrograde cholangiopancreatography (ERCP) with temporary placement of a CSEMS following cholecystectomy (n = 8) or liver transplantation (n = 5). All patients had resolution of their bile leaks. Two patients developed a stricture below the confluence. Three patients died from unrelated causes. Two deaths occurred prior to CSEMS removal. Ten of 11 patients had evidence of biliary debris at the time of CSEMS removal. Overall, temporary placement of CSEMS is efficacious atresolving bile leaks. CSEMS are less prone to migration, but are associated with ulcerations, de novo choledocholithiasis, and strictures.

Liver and intestine transplantation in the United States 1998-2007.

Liver transplantation numbers in the United States remained constant from 2004 to 2007, while the number of waiting list candidates has trended down. In 2007, the waiting list was at its smallest since 1999, with adults > or =50 years representing the majority of candidates. Noncholestatic cirrhosis was most commonly diagnosed. Most age groups had decreased waiting list death rates; however, children <1 year had the highest death rate. Use of liver allografts from donation after cardiac death (DCD) donors increased in 2007. Model for end-stage liver disease (MELD)/pediatric model for end-stage liver disease (PELD) scores have changed very little since 2002, with MELD/PELD <15 accounting for 75% of the waiting list. Over the same period, the number of transplants for MELD/PELD <15 decreased from 16.4% to 9.8%. Hepatocellular carcinoma exceptions increased slightly. The intestine transplantation waiting list decreased from 2006, with the majority of candidates being children <5 years old. Death rates improved, but remain unacceptably high. Policy changes have been implemented to improve allocation and recovery of intestine grafts to positively impact mortality. In addition to evaluating trends in liver and intestine transplantation, we review in depth, issues related to organ acceptance rates, DCD, living donor transplantation and MELD/PELD exceptions.

Liver and intestine transplantation in the United States, 1997-2006.

Liver transplantation in 2006 generally resembled previous years, with fewer candidates waiting for deceased donor liver transplants (DDLT), continuing a trend initiated with the implementation of the model for end-stage liver disease (MELD). Candidate age distribution continued to skew toward older ages with fewer children listed in 2006 than in any prior year. Total transplants increased due to more DDLT with slightly fewer living donor liver transplants (LDLT). Waiting list deaths and time to transplant continued to improve. In 2006, there also were fewer DDLT for patients with MELD <15, fewer pediatric Status 1A/B transplants and more transplants from donation after cardiac death (DCD) donors. Adjusted patient and graft survival rates were similar for LDLT and DDLT. This article also contains in-depth analyses of transplantation for hepatocellular carcinoma (HCC). Recipients with HCC had lower adjusted 3-year posttransplant survival than recipients without HCC. HCC recipients who received pretransplant ablative treatments had superior adjusted 3-year posttransplant survival compared to HCC recipients who did not. Intestinal transplantation continued to slowly increase with the largest number of candidates on the waiting list since 1997. Survival rates have increased over time. Small children waiting for intestine grafts continue to have the highest waiting list mortality.

Donor factors predicting recipient survival after liver retransplantation: the retransplant donor risk index.

The use of extended criteria liver donors (ECD) is controversial, especially in the setting of retransplantation. The aims of this study are to investigate the effects of ECD grafts on retransplantation and to develop a predictive mortality index in liver retransplantation based on the previously established donor risk index. The United Network for Organ Sharing (UNOS) liver transplant dataset was analyzed for all adult, non-status 1, liver retransplantations occurring in the United States since February 2002. All donors were categorized for multiple characteristics of ECD, and using multivariate survival models a retransplant donor risk index (ReTxDRI) was developed. A total of 1327 retransplants were analyzed. There were 611 (46%) recipients who received livers with at least one ECD criterion. The use of ECD grafts in recipients with HCV did not incur worse survival than the non-ECD grafts. The addition of the cause of recipient graft failure to the donor risk index formed the ReTxDRI. After adjusting for multiple recipient factors, the ReTxDRI was predictive of overall recipient survival and was a strongly independent predictor of death after retransplantation (HR 2.49, 95% CI 1.89-3.27, p < 0.0001). The use of the ReTxDRI can improve recipient and donor matching and help to optimize posttransplant survival in liver retransplantation.

Hepatocellular carcinoma recurrence and death following living and deceased donor liver transplantation.

We examined mortality and recurrence of hepatocellular carcinoma (HCC) among 106 transplant candidates with cirrhosis and HCC who had a potential living donor evaluated between January 1998 and February 2003 at the nine centers participating in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). Cox regression models were fitted to compare time from donor evaluation and time from transplant to death or HCC recurrence between 58 living donor liver transplant (LDLT) and 34 deceased donor liver transplant (DDLT) recipients. Mean age and calculated Model for End-Stage Liver Disease (MELD) scores at transplant were similar between LDLT and DDLT recipients (age: 55 vs. 52 years, p = 0.21; MELD: 13 vs. 15, p = 0.08). Relative to DDLT recipients, LDLT recipients had a shorter time from listing to transplant (mean 160 vs. 469 days, p < 0.0001) and a higher rate of HCC recurrence within 3 years than DDLT recipients (29% vs. 0%, p = 0.002), but there was no difference in mortality or the combined outcome of mortality or recurrence. LDLT recipients had lower relative mortality risk than patients who did not undergo LDLT after the center had more experience (p = 0.03). Enthusiasm for LDLT as HCC treatment is dampened by higher HCC recurrence compared to DDLT.

Survival after adult liver transplantation does not correlate with transplant center case volume in the MELD era.

It has been demonstrated that low-volume orthotopic liver transplant centers have poorer outcomes compared to high-volume centers. In light of the recent significant changes in liver transplantation, we performed an analysis of transplant center procedure volume and mortality with data from the Model for End-stage Liver Disease (MELD) era. We analyzed 9909 adult liver transplants performed in the United States since the beginning of the MELD allocation system. Transplant centers were categorized by volume of transplants performed per year. Multivariate survival models were constructed with raw survival as the primary endpoint for both high- and low-volume centers. Thirty percent of centers were categorized as low volume (< or =20 liver transplants per year) and 8.2% of all transplants were performed at low-volume centers. The unadjusted raw mortality rate at 1-year post-transplant at high-volume centers (9.5%, 95% CI 9.4-9.5) was significantly lower than the rate at low-volume centers (10.9%, 95% CI 10.4-11.4), p < 0.001. However, after adjusting for disease severity and multiple donor and recipient factors, transplant center volume was no longer a significant predictor of post-transplant survival (HR 0.99, 95% CI 0.99-1.00, p = 0.22). We conclude that transplant center case volume is no longer a significant predictor of post-transplant survival in the MELD era and factors which are currently unaccounted for in present survival models should be investigated.

SRTR center-specific reporting tools: Posttransplant outcomes.

Measuring and monitoring performance--be it waiting list and posttransplant outcomes by a transplant center, or organ donation success by an organ procurement organization and its partnering hospitals--is an important component of ensuring good care for people with end-stage organ failure. Many parties have an interest in examining these outcomes, from patients and their families to payers such as insurance companies or the Centers for Medicare and Medicaid Services; from primary caregivers providing patient counseling to government agencies charged with protecting patients. The Scientific Registry of Transplant Recipients produces regular, public reports on the performance of transplant centers and organ procurement organizations. This article explains the statistical tools used to prepare these reports, with a focus on graft survival and patient survival rates of transplant centers--especially the methods used to fairly and usefully compare outcomes of centers that serve different populations. The article concludes with a practical application of these statistics--their use in screening transplant center performance to identify centers that may need remedial action by the OPTN/UNOS Membership and Professional Standards Committee.

Characterization of a human plasma membrane heme transporter in intestinal and hepatocyte cell lines.

Heme is the most bioavailable form of dietary iron and a component of many cellular proteins. Controversy exists as to whether heme uptake occurs via specific transport mechanisms or passive diffusion. The aims of this study were to quantify cellular heme uptake with a fluorescent heme analog and to determine whether heme uptake is mediated by a heme transporter in intestinal and hepatic cell lines. A zinc-substituted porphyrin, zinc mesoporphyrin (ZnMP), was validated as a heme homolog in uptake studies of intestinal (Caco-2, I-407) and hepatic (HepG2) cell lines. Uptake experiments to determine time dependence, heme inhibition, concentration dependence, temperature dependence, and response to the heme synthesis inhibitor succinylacetone were performed. Fluorescence microscope images were used to quantify uptake and determine the cellular localization of ZnMP; ZnMP uptake was seen in intestinal and hepatic cell lines, with cytoplasmic uptake and nuclear sparing. Uptake was dose- and temperature dependent, inhibited by heme competition, and saturated over time. Preincubation with succinylacetone augmented uptake, with an increased initial uptake rate. These findings establish a new method for quantifying heme uptake in individual cells and provide strong evidence that this uptake is a regulated, carrier-mediated process.

Endogenous opioids and reward.

The discovery of endogenous opioids has markedly influenced the research on the biology of addiction and reward brain processes. Evidence has been presented that these brain substances modulate brain stimulation reward, self-administration of different drugs of abuse, sexual behaviour and social behaviour. There appears to be two different domains in which endogenous opioids, present in separate and distinct brain regions, are involved. One is related to the modulation of incentive motivational processes and the other to the performance of certain behaviours. It is concluded that endogenous opioids may play a role in the vulnerability to certain diseases, such as addiction and autism, but also when the disease is present, such as alcoholism.