Pediatric liver transplantation for urea cycle disorders and organic acidemias: United Network for Organ Sharing data for 2002-2012.

Decision making concerning liver transplantation is unique for children with urea cycle disorders (UCDs) and organic acidemias (OAs) because of their immediate high priority on the waiting list, which is not related to the severity of their disease. There are limited national outcome data on which recommendations about liver transplantation for UCDs or OAs can be based. This study was a retrospective analysis of United Network for Organ Sharing data for liver recipients who underwent transplantation at an age < 18 years in 2002-2012. Repeat transplants were excluded. Among the pediatric liver transplants, 5.4% were liver-only for UCDs/OAs. The proportion of transplants for UCDs/OAs increased from 4.3% in 2002-2005 to 7.4% in 2010-2012 (P < 0.001). Ninety-six percent were deceased donor transplants, and 59% of these patients underwent transplantation at <2 years of age. Graft survival improved as the age at transplant increased (P = 0.04). Within 5 years after transplantation, the graft survival rate was 78% for children < 2 years old at transplant and 88% for children ≥ 2 years old at transplant (P = 0.06). Vascular thrombosis caused 44% of the graft losses, and 65% of these losses occurred in children < 2 years old. Patient survival also improved as the age at transplant increased: the 5-year patient survival rate was 88% for children with UCDs/OAs who were <2 years old at transplant and 99% for children who were ≥2 years old at transplant (P = 0.006). At the last-follow-up (54 ± 34.4 months), children who underwent transplantation for UCDs/OAs were more likely to have cognitive and motor delays than children who underwent transplantation for other indications. Cognitive and motor delays for children with UCDs/OAs were associated with metabolic disorders, but they were not predicted by age or weight at transplant, sex, ethnicity, liver graft type (split versus whole), or hospitalization at transplant in univariate and multivariate analyses. In conclusion, most liver transplants for UCDs/OAs occur in early childhood. Further research on the benefits of early transplantation for patients with UCDs/OAs is needed because a younger age may increase posttransplant morbidity.

Time to transplantation as a predictor of hepatocellular carcinoma recurrence after liver transplantation.

In the United States, there are significant geographic disparities in the time to transplantation for patients with hepatocellular carcinoma (HCC); it is possible that rapid transplantation contributes to higher rates of posttransplant HCC recurrence because there is insufficient time for the tumor biology to manifest. In this study, we compared HCC recurrence in rapid transplant patients and their slower transplant counterparts. We identified adult liver transplantation (LT) candidates in the Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) data set who were granted an initial exception for an HCC diagnosis between January 1, 2006 and September 30, 2010 and underwent transplantation in the same time window. Patients were followed until HCC recurrence, non-HCC-related death, or last follow-up. The cumulative incidence of HCC recurrence was compared for patients waiting ≤ 120 days and patients waiting >120 days from an HCC exception to LT. The association between the risk of posttransplant recurrence and the wait time was further evaluated via competing risks regression with the Fine and Gray model. For 5002 LT recipients with HCC, the median wait time from an exception to LT was 77 days, and it varied from 30 to 169 days by UNOS region. The cumulative incidence of posttransplant HCC recurrence was 3.3% [95% confidence interval (CI) = 2.8%-3.8%] and 5.6% (95% CI = 5.0%-6.3%) within 1 and 2 years, respectively. The rate of observed recurrence within 1 year of transplantation was significantly lower for patients waiting >120 days versus patients waiting ≤ 120 days (2.2% versus 3.9%, P = 0.002); however, the difference did not persist at 2 years (5.0% versus 5.9%, P = 0.09). After we accounted for clinical factors, the HCC recurrence risk was reduced by 40% for patients waiting >120 days (subhazard ratio = 0.6, P = 0.005). In conclusion, the risk of HCC recurrence within the first year after transplantation may be lessened by the institution of a mandatory waiting time after an exception is granted.

An examination of liver offers to candidates on the liver transplant wait-list.

BACKGROUND & AIMS: We aimed to characterize offers of organs to candidates awaiting liver transplantation (LT). METHODS: We analyzed data from the United Network for Organ Sharing registry on all US LT candidates with nonfulminant disease who were offered livers from February 1, 2005, to January 31, 2010, and ultimately received transplants. We excluded candidates with a final Model for End-stage Liver Disease score of less than 15. Livers were classified as high quality if they were from donors 18-50 years of age who were ≥ 170 cm tall, of non-black race, suffered brain death secondary to trauma, hepatitis C antibody-negative, not categorized as high risk by the Centers for Disease Control, and locally or regionally located. RESULTS: Of 33,389 candidates for LT, 20% died or were removed from the list and 64% received LT; the median (interquartile range) number of liver offers for all candidates was 5 (range, 2-12). Of those who died or were removed from the list, 84% received 1 or more liver offers. Overall, 55% of those who died or were removed from the list, and 57% of those who received LT, received 1 or more offers of a high-quality liver when they had Model for End-stage Liver Disease scores of 15 or greater (P = .005). However, the proportion of last liver offers of high quality to patients who underwent LT was twice that of patients who died or were removed from the list (28% vs 14%; P < .001). Most liver offers (68%) were refused for reasons related to donor quality. CONCLUSIONS: Most candidates for LT who died or were removed from the list received 1 or more offers of a liver beforehand, and 55% received 1 or more offers of a high-quality liver. These findings indicate that a substantial proportion of wait-list mortality results in part from declined livers, rather than lack of opportunity, for transplantation. Understanding the real-time factors involved in the complex decision to accept a liver offer is vital to reducing wait-list mortality for LT candidates.

Decadal analysis of deceased organ donation in Spain and the United States linking an increased donation rate and the utilization of older donors.

After the foundation of the National Transplant Organization, Spanish rates of deceased donor donation rapidly outpaced US growth over the decade from 1989 to 1999. An analysis of the following decade, 1999-2009, demonstrated a markedly flattened growth curve for Spanish deceased donor organ procurement, which increased only 2.4% from 33.6 to 34.4 donors per million population (pmp). In comparison, over the same decade in the United States, the rate of deceased donation increased from 20.9 to 26.3 donors pmp (25.8%). An age group comparison demonstrated a much higher donation rate among older donors in Spain. For example, the number of donors older than 70 years increased from 3.8 to 8.8 pmp (a 132% increase), and they now constitute 25.4% of all Spanish organ donors. In contrast, the number of US donors older than 70 years increased from 1.0 to 1.3 pmp, and they constitute only 4.4% of total deceased donors. Over the same decade, the number of younger donors (15-30 years old) decreased from 6.6 to 2.5 pmp (a 62% decrease) in Spain, and this contrasted with a slightly increased US donation rate for the same age subgroup (a 15.5% increase from 5.8 to 6.7 pmp). Although older donors were more rarely used in the United States, growth in donation over the 2 decades (1989-2009) was strongly associated with the utilization of donors aged 65 or older (P < 0.01). United Network for Organ Sharing regions demonstrated significant differences in utilization rates for older donors. In conclusion, strategies aimed toward achieving US donation rates equivalent to the Spanish benchmark should target improved utilization rates for older donors in the United States instead of emulating elements of the Spanish organ procurement system.

Center competition and outcomes following liver transplantation.

In the United States, livers for transplantation are distributed within donation service areas (DSAs). In DSAs with multiple transplant centers, competition among centers for organs and recipients may affect recipient selection and outcomes in comparison with DSAs with only 1 center. The objective of this study was to determine whether competition within a DSA is associated with posttransplant outcomes and variations in patients wait-listed within the DSA. United Network for Organ Sharing data for 38,385 adult cadaveric liver transplant recipients undergoing transplantation between January 1, 2003 and December 31, 2009 were analyzed to assess differences in liver recipients and donors and in posttransplant survival by competition among centers. The main outcome measures that were studied were patient characteristics, actual and risk-adjusted graft and patient survival rates after transplantation, organ quality as quantified by the donor risk index (DRI), wait-listed patients per million population by DSA, and competition as quantified by the Hirschman-Herfindahl index (HHI). Centers were stratified by HHI levels as no competition or as low, medium (or mid), or high competition. In comparison with DSAs without competition, the low-, mid-, and high-competition DSAs (1) performed transplantation for patients with a higher risk of graft failure [hazard ratio (HR) = 1.24, HR = 1.26, and HR = 1.34 (P < 0.001 for each)] and a higher risk of death [HR = 1.21, HR = 1.23, and HR = 1.34 (P < 0.001 for each)] and for a higher proportion of sicker patients as quantified by the Model for End-Stage Liver Disease (MELD) score [10.0% versus 14.8%, 20.1%, and 28.2% with a match MELD score of 31-40 (P < 0.001 for each comparison)], (2) were more likely to use organs in the highest risk quartile as quantified by the DRI [18.3% versus 27.6%, 20.4%, and 31.7% (P ≤ 0.001 for each)], and (3) listed more patients per million population [18 (median) versus 34 (P = not significant), 37 (P = 0.005), and 45 (P = 0.0075)]. Significant variability in patient selection for transplantation is associated with market variables characterizing competition among centers. These findings suggest both positive and negative effects of competition among health care providers.

Validating posttransplant hepatocellular carcinoma recurrence data in the United Network for Organ Sharing database.

The Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) database is the most comprehensive collection of liver transplantation data, but the quality of these data with respect to hepatocellular carcinoma (HCC) recurrence has not been well assessed. In this study, we compared observed HCC recurrence rates in the UNOS database to expected rates calculated with a hierarchical model for recurrence adjusted for recipient and tumor characteristics. We used the UNOS Standard Transplant Analysis and Research data set for adult transplant patients with an initial exception for an HCC diagnosis granted between January 1, 2006 and September 30, 2010 who underwent transplantation within the same time window. We developed a risk-adjusted Poisson model with patients as the unit of analysis, random effects for transplant centers, and years of follow-up as an offset to predict expected recurrences for each center. To further investigate the possibility of underreporting, we imputed expected recurrences for non-HCC deaths. In all, 5034 HCC liver transplant recipients were identified, and 6.8% experienced recurrence at a median of 1 year after transplantation. The covariate-adjusted shrinkage estimates of the observed/expected HCC recurrence ratios by transplant center ranged from 0.6 to 1.76 (median = 0.97). The 95% confidence intervals for the shrinkage ratios included unity for every center, and this indicated that none could be unambiguously identified as having lower or higher than expected HCC recurrence rates. Imputing outcomes for patients potentially experiencing unreported recurrence changed the center-specific shrinkage ratios to 0.72 to 1.39 (median = 0.98), with no centers having a shrinkage ratio significantly different from 1. The observed HCC recurrence rate was not significantly lower than the expected rate at any center, and this suggests that no systematic underreporting has occurred. This study validates the OPTN HCC recurrence data and supports their potential for further analysis.

Identification of liver transplant candidates with hepatocellular carcinoma and a very low dropout risk: implications for the current organ allocation policy.

It has been shown that patients with hepatocellular carcinoma (HCC) meeting the United Network for Organ Sharing T2 (Milan) criteria have an advantage in comparison with patients without HCC under the current organ allocation system for liver transplantation (LT). We hypothesized that within the T2 HCC group, there is a subgroup with a low risk of wait-list dropout that should not receive the same listing priority. This study evaluated 398 consecutive patients with T2 HCC listed for LT with a Model for End-Stage Liver Disease exception from March 2005 to January 2011 at our center. Competing risk (CR) regression was used to determine predictors of dropout. The probabilities of dropout due to tumor progression or death without LT according to the CR analysis were 9.4% at 6 months and 19.6% at 12 months. The median time from listing to LT was 8.8 months, and the median time from listing to dropout or death without LT was 7.2 months. Significant predictors of dropout or death without LT according to a multivariate CR regression included 1 tumor of 3.1 to 5 cm (versus 1 tumor of 3 cm or less), 2 or 3 tumors, a lack of a complete response to the first locoregional therapy (LRT), and a high alpha-fetoprotein (AFP) level after the first LRT. A subgroup (19.9%) that met certain criteria (1 tumor of 2 to 3 cm, a complete response after the first LRT, and an AFP level ≤ 20 ng/mL after the first LRT) had 1- and 2-year probabilities of dropout of 1.3% and 1.6%, respectively, whereas the probabilities were 21.6% and 26.5% for all other patients (P = 0.004). In conclusion, a combination of tumor characteristics and a complete response to the first LRT define a subgroup of patients with a very low risk of wait-list dropout who do not require the same listing priority. Our results may have important implications for the organ allocation policy for HCC.

Left hepatectomy versus right hepatectomy for living donor liver transplantation: shifting the risk from the donor to the recipient.

Living donor liver transplantation (LDLT), originally used in children with left lateral segment grafts, has been expanded to adults who require larger grafts to support liver function. Most adult LDLT procedures have been performed with right lobe grafts, and this means a significant risk of morbidity for the donors. To minimize the donor risk for adults, there is renewed interest in smaller left lobe grafts. The smaller graft size increases the recipient risk in the form of small-for-size syndrome (SFSS) and essentially transfers the risk from the donor to the recipient. We review the donor and recipient risks of LDLT and pay particular attention to the different types of liver grafts and the use of graft inflow modification to ameliorate the risk of SFSS. Finally, a new metric is proposed for quantifying the recipient benefit in exchange for a specific donor risk.

Impact of outcomes monitoring on innovation and risk in liver transplantation.

KEY POINTS: 1. The reporting of liver transplant center outcomes is required by the final rule of the Department of Health and Human Services. The reported patient and graft survival outcomes are risk-adjusted for specific donor and recipient factors, and the observed survival is compared to the expected survival. Both the Centers for Medicare and Medicaid Services and the Organ Procurement and Transplantation Network flag programs for corrective action when the observed survival is significantly less than the expected survival. Both agencies can take action up to the closure of a center. In the last 5 years, the Organ Procurement and Transplantation Network has not taken an adverse action that required the closure of a liver transplant center because of outcomes. 2. Center survey data suggest that centers may try to select donors and recipients to minimize poor outcomes. This strategy may not be effective if centers stop accepting donors or recipients according to factors that are included in the risk adjustment model. For example, limiting recipients to those less than 65 years old may improve the observed outcomes, but the expected outcomes will also improve because a recipient 65 years or older is included in the model's risk adjustment. 3. For factors such as cardiovascular risk that are not included in the model, it may be reasonable to exclude patients in an attempt to improve the observed outcomes without affecting the expected outcomes. Other examples of these types of factors are smoking, nutritional status, and donor liver biopsy findings. 4. Currently, there is no exemption for patients undergoing experimental protocols. Down-staging for hepatocellular carcinoma, transplantation for human immunodeficiency virus-positive recipients, and the use of left lobe grafts with inflow modification are relatively recent areas of innovation in liver transplantation. Because innovation is frequently associated with a learning curve and, therefore, poor outcomes, the inclusion of patients in innovative protocols potentially could lead to centers being subjected to an adverse action by the Organ Procurement and Transplantation Network or the Centers for Medicare and Medicaid Services. Active consideration is being given to the exclusion of patients in innovative protocols from center-specific outcomes.

Impact of the donor body mass index on the survival of pediatric liver transplant recipients and post-transplant obesity.

In adult liver transplant recipients, the donor body mass index (dBMI) is associated with posttransplant obesity but not with graft or patient survival. Because of the obesity epidemic in the United States and the already limited supply of liver donors, clarifying whether the dBMI affects pediatric outcomes is important. United Network for Organ Sharing data for pediatric liver transplants in the United States (1990-2010) were evaluated. Data on transplants performed between 2004 and 2010 (n = 3788) were used for survival analyses with Kaplan-Meier and Cox proportional hazards models and for posttransplant obesity analyses with generalized estimating equations. For children receiving adult donor livers, a dBMI of 25 to <35 kg/m(2) was not associated with graft or patient survival in univariate or multivariate analyses. A dBMI ≥ 35 kg/m(2) increased the risk of graft loss [hazard ratio (HR) = 2.54, 95% confidence interval (CI) = 1.29-5.01, P = 0.007] and death (HR = 3.56, 95% CI = 1.64-7.72, P = 0.001). For pediatric donors, the dBMI was not associated with graft loss or mortality in a univariate or multivariate analysis. An overweight or obese donor was not a risk factor for posttransplant obesity. Overweight and obesity are common among liver transplant donors. This analysis suggests that for adult donors, a body mass index (BMI) of 25 to <35 kg/m(2) should not by itself be a contraindication to liver donation. Severe obesity (BMI ≥ 35 kg/m(2)) in adult donors increased the risk of graft loss and mortality, even after adjustments for recipient, donor, and transplant risk factors. Posttransplant obesity was not associated with the dBMI in this analysis. Further research is needed to clarify the impact of donor obesity on pediatric liver transplant recipients.

Overweight and obesity in pediatric liver transplant recipients: prevalence and predictors before and after transplant, United Network for Organ Sharing Data, 1987-2010.

Obesity is extremely common in adult liver transplant recipients and healthy U.S. children. Little is known about the prevalence or risk factors for post-transplant obesity in pediatric liver transplant recipients. UNOS data on all U.S. liver transplants 1987-2010 in children 6 months-20 yr at transplant were analyzed. Subjects were categorized as underweight, normal weight, overweight, or obese by CDC guidelines. Predictors of weight status at and after transplant were identified using multivariate logistic regression. Of 3043 children 6-24 months at transplant, 14% were overweight. Of 4658 subjects 2-20 yr at transplant, 16% were overweight and 13% obese. Children overweight/obese at transplant were more likely to be overweight/obese at one, two, and five yr after transplant in all age groups after adjusting for age, ethnicity, primary diagnosis, year of transplant, and transplant type. Weight status at transplant was not associated with overweight/obesity by 10 yr after transplant. The prevalence of post-transplant obesity remained high in long-term follow-up, from 20% to 50% depending on age and weight status at transplant. Weight status at transplant is the strongest predictor of post-transplant overweight/obesity. To optimize long-term outcomes in pediatric liver transplant recipients, monitoring for obesity and its comorbidities is important.

Trans-radial versus trans-femoral access in patients with end-stage liver disease undergoing cardiac catheterization.

Cardiac catheterization has been increasingly utilized to evaluate coronary artery disease in patients with end stage liver disease (ESLD). It is known in other populations that radial access reduces access site complications;however, there is a paucity of data in ESLD patients. We investigated vascular and bleeding complications rates between trans-femoral and trans-radial cardiac catheterizations in this high risk population. In this retrospective cohort study, three hundred and thirty four ESLD patients were identified between August 2004 and December 2012 who had undergone trans-femoral (femoral group) or trans-radial (radial group) cardiac catheterizations at our institution. The radial group was not significantly different from the femoral group in age (p = 0.056), proportions of genders (p = 0.85), and weight (p = 0.19); however, compared to the femoral group, the radial group had significantly lower blood pressure (p < 0.0001), hemoglobin (10.4 ± 1.9 vs 11.1 ± 2.02 g/dL, p = 0.001), and hematocrit (30.3 ± 5.7% vs 32.6 ± 6.0%, p < 0.0006), and had a significantly higher INR (1.94 ± 1.16 vs 1.59 ± 0.62, p = 0.0001). In terms of vascular complications, the radial group had a significantly lower rate of pseudoaneurysms (0% vs 3.7%, p = 0.019) than the femoral group. While there were no bleeding complications in either group or differences in transfusion requirements, there was a significantly lower percentage drop in hematocrit in the radial group compared to the femoral group (5.4% vs 7.8%, p = 0.039). In conclusion, trans-radial catheterization is associated with lower rates of vascular access site complications compared to trans-femoral catheterization.

Fatal transplant-associated west nile virus encephalitis and public health investigation-california, 2010.

BACKGROUND: In December 2010, a case of West Nile virus (WNV) encephalitis occurring in a kidney recipient shortly after organ transplantation was identified. METHODS: A public health investigation was initiated to determine the likely route of transmission, detect potential WNV infections among recipients from the same organ donor, and remove any potentially infected blood products or tissues. Available serum, cerebrospinal fluid, and urine samples from the organ donor and recipients were tested for WNV infection by nucleic acid testing and serology. RESULTS: Two additional recipients from the same organ donor were identified, their clinical and exposure histories were reviewed, and samples were obtained. WNV RNA was retrospectively detected in the organ donor's serum. After transplantation, the left kidney recipient had serologic and molecular evidence of WNV infection and the right kidney recipient had prolonged but clinically inapparent WNV viremia. The liver recipient showed no clinical signs of infection but had flavivirus IgG antibodies; however, insufficient samples were available to determine the timing of infection. No remaining infectious products or tissues were identified. CONCLUSIONS: Clinicians should suspect WNV as a cause of encephalitis in organ transplant recipients and report cases to public health departments for prompt investigation of the source of infection. Increased use of molecular testing and retaining pretransplantation sera may improve the ability to detect and diagnose transplant-associated WNV infection in organ transplant recipients.